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[2024] FCA 807
Federal Court of Australia
2024-07-25
Lee J
Original judgment source is linked above.
Introduction 309 It is not an overstatement to describe the AHS as a highly significant study. Much time was devoted to it in oral and written submissions and, as will become evident, the AHS constituted a study that Monsanto pointed to as being the single most important aspect of the evidence contrary to Mr McNickle's case. Despite this, at least initially, its reception into evidence was far from certain and the road to its adduction was a long and windy one. 310 As I noted in McNickle v Huntsman Chemical Company Australia Pty Ltd (Additional Expert Conclave) (at [1]), in December 2022, an interlocutory application was filed by Mr McNickle whereby permission was sought to communicate with Mr Cowpe, the independent barrister, who convened the expert conclaves (see above (at [24])) for the purpose of requesting that he facilitate the provision of a data transfer agreement, and the data underlying two epidemiology studies based on the AHS papers. As I noted (at [7]-[11]): [7] What emerged following Conclave D was that the main disagreement between the experts in analysing both De Roos and Andreotti relates to what is described as the "the correct allocation of person years and consequent calculation of rate ratios." It is Professor Gordon's opinion that the allocation of person years to levels of cumulative exposure to glyphosate was incorrectly carried out, and led to incorrect calculations of rate ratios. Dr Harris' opinion, however, was that the allocation of person years was correctly carried out, and led to accurate calculations of rate ratios. [8] Hence, the parties are at issue as to what Professor Gordon describes as a "serious analytic error". The consequence of this error is said to be that it could result in a "downward bias in the risk of NHL in the highest category of glyphosate exposure". It is said by Dr Harris that Professor Gordon has provided "no direct evidence of this error", and that this belief could only be substantiated "if the underlying AHS data were obtained and reanalysed". [9] No doubt I am missing something, but it seems to me it is a tad curious that the applicant, Mr McNickle, is the party seeking to obtain the AHS data. It is the respondents who seek to deploy opinions contained in articles from both Dr Roos and Andreotti in their case. If there is some prima facie, rational basis for suggesting that this material might have a serious analytical error, which can only be ascertained upon the checking of the underlying data, the failure to produce the data by the party seeking to adduce and rely upon the evidence, might have been relied upon to ground an application by the other party for rejection, or discretionary exclusion, or limitation of the material or, alternatively, support submissions going to the weight of the representations contained in the articles. But as it happens, both parties have reached a consensus that it is appropriate that the AHS data be obtained and reanalysed … [10] So far, so good. One would have thought this would be a relatively straightforward process of obtaining the data, providing it to the experts and obtaining their further opinions on it. But like so many matters in this case, it is not quite as simple as that. The AHS data is maintained by the National Cancer Institute (NCI), a United States government body that is part of the Department of Health and Human Services, being part of the executive government of the United States of America. For well over a year, efforts have been made by the solicitors for the applicant to obtain a copy of this data. [11] Remarkably, since August 2021, around 60 communications have been exchanged concerning the appropriate facilitation of the data to experts. I had indicated at a case management hearing in September 2022 that I was content for the parties to continue to make efforts to obtain material to be provided to the facilitator in the same way as other documents in order for the experts, if they thought the material relevant, to express their opinions as to the questions posed to them. What has become apparent, however, following communications by the solicitors for both parties and representatives of the NCI, is that the position of the NCI is as follows (as explained in the Affidavit of Mr Lee Taylor sworn 7 November 2022 (at [18])): (a) The NCI explained that the raw data are not contained in simple spreadsheets that are legible or reviewable by non-specialists. Rather, the data - which comprise the records of over 50,000 participants in the AHS - are raw text which can only be analysed within statistical software platforms. The NCI maintains the data in a software suite known as SAS (Statistical Analysis System) which, I understand, was developed in part by the National Institute of Health, of which the NCI is a part. Dr Beane-Freeman explained that they are able to export the data in a form that can be used in comparable analytic platforms (such as MATLAB). (b) Because the data are in the form described above, there would be no utility to providing the AHS Data in its raw form to the parties' lawyers or indeed to the Court. The data cannot be interpreted or "interrogated" by non-specialists without appropriate statistical qualifications, training, and experience, as well as the necessary statistical analysis software. To the extent, therefore, that the parties' lawyers need to challenge any expert's analysis of the AHS Data, they will likely need to rely on their own expert(s) (who will have the data). (c) The NCI's policy and practice of providing AHS Data to expert researchers is critical to their overarching mission as a public health body. The AHS Data comprise personal medical information of rural farmers enrolled in the AHS, and if the NCI is unable to guarantee that its subjects' privacy is fully protected, the integrity of the AHS (and similar projects) would be fundamentally at risk. That imperative is served by providing data only to experts in relevant fields who are properly trained in managing and using health data, and who are experienced in deploying that data in a manner consistent with the privacy requirements (such as in publications using the data), and whose institutions typically use such data and therefore have appropriate systems in place to manage and protect the data. (d) The NCI is aware that the AHS Data are sought in connection with this proceeding and that they would be used by expert witnesses. (e) The Proposed DTA does not restrict the experts or the parties from using the experts' analyses of the data (as distinct from the raw data themselves) in open court, nor would it preclude those analyses being incorporated into the Court's analysis. (f) Under the Proposed DTA, the lawyers and/or the Court can request the experts to generate data outputs from the raw AHS Data. There is no restriction on how many or what type of outputs can be generated by the experts, other than that those outputs cannot be based on fewer than five individual study participants (of over 50,000). This is to ensure that study participants' privacy is protected. A data output is generated by aggregating the raw data of individual AHS participants to allow this data to be analysed and studied under different circumstances. Data outputs would reflect the results of particular analytic queries or calculations performed on the raw data; for example, the number of AHS participants were exposed to glyphosate in a particular year, might be extracted and then rendered in a form that would be intelligible to laypersons, such as a graph or chart, a table, or a textual description. Similarly, more complex outputs might be generated such as a re-calculation of participants' intensity-weighted cumulative lifetime days exposure (which is a focus of Professor Gordon's analysis), which would also be rendered in a form intelligible to the parties' legal representatives and the Court. (g) These outputs will enable the data to be digested and analysed so that the parties' lawyers and the Court can properly understand what the data show. These outputs from the raw data can be used by the parties' lawyers or the Court to test the experts' opinions, methodology and analyses. The outputs from the raw AHS Data can be referred to in open court. (h) The lawyers and the Court would then be able to ask the experts questions regarding their analyses, opinions and methodology, including based upon any outputs generated by the experts from the raw AHS Data. 311 As I then explained (at [19]-[25]), I facilitated an arrangement agreed between the parties for material to be provided by the NCI to the two experts in Conclave D. 312 Without access being obtained to the underlying data so that the conclusions of the AHS could be tested, it would have at least been open to Mr McNickle to move for the discretionary exclusion of opinions based on the AHS, as the refusal of the NCI to produce those materials would have occasioned prejudice to Mr McNickle in seeking to challenge the conclusions drawn from the AHS. But this was not the forensic course adopted by Mr McNickle and a pragmatic solution was reached in order to allow this important material to be placed before the Court. 313 Returning to the AHS itself, the study is a prospective cohort study conducted in Iowa and North Carolina. It includes 57,311 private and commercial licensed pesticide applicators, who were recruited between 1993 and 1997. Among private and commercial applicators, 75.5% (or approximately 43,000 people) reported ever using glyphosate. Exposures to glyphosate and other pesticides were assessed from responses to self-administered questionnaires completed by study participants. 314 Two studies (that is, the AHS papers) are follow-up reports on the AHS, namely: (1) De Roos A J, Blair A, Rusiecki JA, et al. (2005) "Cancer incidence among glyphosate-exposed pesticide applicators in the Agricultural Health Study" 113 Environ Health Perspect 49 (De Roos (2005)); and (2) Andreotti G, Koutros S, Hofmann J N, et al. (2018) "Glyphosate use and cancer incidence in the Agricultural Health Study" 110 J Natl Cancer Inst 509 (Andreotti (2018)). 315 For this reason, and partly because of the way in which Mr McNickle developed his arguments with respect to its findings, I will deal with it in a slightly modified sequence. 316 First, I will outline, at a high level, the conclusions of the AHS papers. Secondly, I will deal with Mr McNickle's contentions made in the context of Conclave D with respect to the reliability of the AHS papers. Thirdly, I will set out what I consider to be the key strengths of the AHS and make findings as to the weight to be attributed to it in the light of the above.
The AHS papers 317 Findings from the AHS reported by De Roos (2005) and Andreotti (2018) do not indicate an association between glyphosate exposure and the risk of development of NHL in humans. 318 De Roos (2005) represents the first follow-up study of the AHS. Among 54,315 subjects included in age-adjusted analyses, 41,035 (75.5%) reported having ever personally mixed or applied products containing glyphosate and 13,280 (24.5%) did not. As the authors note (at 51), the cohort, both exposed and never exposed, was composed primarily of male, middle-aged, private applicators with a relatively low smoking prevalence. In both the exposed and never-exposed groups, more than half of the subjects reported that they had never smoked. 319 The authors of De Roos (2005) found that glyphosate exposure (grouped as ever/never) was not significantly associated with cancer overall (age-adjusted RR: 1.0, 95% CI: 0.9-1.1; fully-adjusted RR: 1.0, 95% CI: 0.9-1.2) or with most of the cancer subtypes identified (at JRC [202]). Table 2 below extracted from De Roos (2005) (at 51) sets out these results: 320 As can be seen, the age-adjusted and fully-adjusted RRs for NHL were 1.2 (95% CI: 0.7-1.9) and 1.1 (95% CI: 0.7-1.9) based on 92 NHL cases and a prevalence of exposure of 77.2% indicating no risk of NHL associated with glyphosate use (at JRC [202]; De Roos (2005) (at 51)). Further, the evaluation of additional glyphosate exposure metrics using the lowest tertile as a reference group found no positive associations between glyphosate use and NHL. For cumulative exposure days (divided into tertiles), RR estimates for the second and third exposure tertiles were RR: 0.7 (95% CI: 0.4-1.4) and RR: 0.9 (95% CI: 0.5-1.6) respectively as compared to the reference group. For the third exposure metric, intensity-weighted exposure days, the RR estimates decreased to RR: 0.6 (95% CI: 0.3-1.1) and RR: 0.8 (95% CI: 0.5-1.4) indicating a non-significant protective effect (at JRC [203]; De Roos (2005) (at 52)). 321 Andreotti (2018) represents the second follow-up of the AHS cohort. It included 57,310 participants who enrolled between 1993 and 1997, with telephone interviews being conducted approximately five years after enrolment (1999-2005). Andreotti (2018) extended the cancer incidence follow-up to 2012 in North Carolina and 2013 in Iowa and, in relation to the latter, extended the median time follow-up of 6.7 years in De Roos (2005) by 11 to 12 years (at JRC [207]-[208]; Andreotti (2018) (at 509)). 322 Of the initial 57,310 private and commercial applicators, those who reported a history of cancer at enrolment, those who lived out of state, and those who did not report any glyphosate information (that is, missing data) at enrolment, were excluded from the analysis. This resulted in an analytic sample of 54,251 individuals. Based on this sample, 44,932 subjects (82.8%) used glyphosate, including 5,779 incident cancer cases (79.3%) (at JRC [213]; Andreotti (2018) (at 509)). 323 Andreotti (2018) concluded that glyphosate was not statistically significantly associated with total cancer (RR: 0.99, 95% CI: 0.91-1.08) or cancer at any site in the unlagged analysis. Glyphosate use was not associated with lymphohematopoietic malignancies (RR: 1.0, 95% CI: 0.74-1.34) and it was not associated with NHL or any NHL subtypes (see Table 3 of Andreotti (2018) (at 514-515); at JRC [214]). In the top exposure quartile, the RR was 0.87 for NHL (95% CI: 0.64-1.20) and the RR for multiple myeloma (MM) was 0.87 (95% CI: 0.45-1.69). The authors reported that the association for NHL was unchanged when MM was excluded from the NHL category (RR: 0.85, 95% CI: 0.62-1.18) (at JRC [214]; Andreotti (2018) (at 514-515)). Based on these results, subject to some observations in relation to positive findings in previous case-control studies, the authors concluded (at 515): In our study, we observed no associations between glyphosate use and NHL overall or any of its subtypes. This lack of association was consistent for both exposure metrics, unlagged and lagged analyses, after further adjustment for pesticides linked to NHL in previous AHS analyses, and when we excluded multiple myeloma from the NHL grouping. The lack of association between glyphosate and NHL is also consistent with the previous AHS analysis. (Footnotes omitted) 324 As noted earlier, the AHS was the subject of detailed discussion over the course of the Conclave C and D joint sessions. Professor Checkoway opined that the AHS is an "excellent study" and "[i]n terms of study design and methodology, I think it is perhaps the best study we have" (T959.14-15; T959.44-45). AP Harris also concluded that "the AHS analysis conducted and presented by [Andreotti (2018)] represents the most comprehensive analysis of the relationship between glyphosate and NHL" (at JRC [220]). 325 Before coming to the reasons for those conclusions and my findings as to the AHS, it is necessary first to address Mr McNickle's contentions.
Mr McNickle's contentions 326 One could not help but reach the conclusion that having recognised the threat posed by the AHS to Mr McNickle's epidemiological case, every possible attempt was made to undermine its veracity, which started with the sort of arguments referred to in McNickle v Huntsman Chemical Company Australia Pty Ltd (Additional Expert Conclave) (at [7]-[8]), being Professor Gordon's opinion that the study contained a "serious analytical error" in that the allocation of person years to levels of cumulative exposure to glyphosate was incorrectly carried out, and led to incorrect calculations of rate ratios. This attack, for reasons I will explain, ultimately ran into the sand on detailed analysis. 327 The apogee of Mr McNickle's attack upon the AHS later emerged in the context of Conclave D, relying largely upon Professor Gordon's identification of three alleged methodological flaws with the AHS papers, which I address below. 328 Having failed to make out its "serious analytical error", Mr McNickle's revised position is that the AHS papers should be considered by the Court in weighing all the epidemiological evidence. With that said, he contends that the Court should not accept Monsanto's submissions that: first, the AHS papers are more reliable than the case-control studies; secondly, the fact that the AHS papers did not show a positive association between glyphosate and NHL means that there is no such association; or thirdly, the AHS papers suggest that the many case-control studies indicating a positive association can or should be discounted or dismissed. Mr McNickle's submissions may be summarised as follows: (1) the AHS papers are affected by exposure misclassification, the effect of which is bias that results towards the null hypothesis (exposure misclassification proposition); (2) there is a fundamental problem with the multiple imputation procedure used in Andreotti (2018) such that the results of the paper are not reliable; (multiple imputation proposition); and (3) the absence of a positive association in the AHS does not disprove the fact of positive associations evident in the case-control studies (no positive association proposition). 329 I will deal with each in turn.
Consideration 362 Having dealt with Mr McNickle's contentions with respect to the AHS, I set out below my findings and what I consider to be the key strengths of the AHS and why it is appropriate that significant weight should be placed upon it. 363 First, in this context, size matters. The AHS involved more than 57,000 participants; over three-quarters of whom were ever exposed to glyphosate. As a result, the AHS offers a level of statistical power which vastly exceeds that of the individual case-control studies addressed above, which, on average, ranged between a few hundred to a few thousand participants. Professor Checkoway agreed that the large number of participants in the AHS "dwarfed any of the case [control] studies" (T951.7-10) and that as a result, offered greater statistical precision (T949.5-8; T952.9-10). AP Harris also identified the number of participants in the AHS as a key strength of the study (at JRC [204]). It was no doubt for this reason that numerous attempts were made by Mr McNickle, starting with Professor Gordon's conjecture that it contained a "serious analytic error" (see McNickle v Huntsman Chemical Company Australia Pty Ltd (Additional Expert Conclave) (at [8])) to undermine the cogency of the study. 364 Secondly, the sample used in the AHS is highly relevant in assessing an etiologic relationship between exposure to glyphosate and/or GBFs and cancer, including NHL and its subtypes. It consisted of private (mostly farmers) and commercial applicators of pesticides who are regularly exposed to GBFs and other exposures thought to be linked to cancer. As AP Harris noted (at JRC [204]): The AHS is a large prospective cohort study with many applicators occupationally exposed to levels much higher and with greater variation than those that occur in population-based/community studies. The collection of exposure information occurred prior to the cancer outcomes (i.e. no issues with recall bias) and included additional details on pesticide use and possible exposures that are often not collected in retrospective studies. (Emphasis added) 365 AP Harris reiterated this point during the joint session when highlighting the prevalence of exposure among participants, noting that "whether it's a case control or a cohort study and - but here we've got a much higher prevalence of exposure. So we're going to have more power to detect those associations in the AHS given its sufficient follow-up" (T951.42-952.1). Professor Checkoway agreed with this proposition (T952.1). 366 Thirdly, the participants in the AHS have been followed for a significant period of time. Enrolment in the study occurred between 1993 and 1997. As noted earlier, De Roos (2005) was the first follow-up study which considered cancers up and until December 2001, which was a median follow-up period of 6.7 years. The second follow-up, Andreotti (2018), obtained further exposure information from follow-up questionnaires completed between 1999 and 2005 and considered cancers identified until 2012 (for North Carolina) and 2013 (for Iowa). As AP Harris noted in relation to the findings of Andreotti (2018), the additional years of follow-up increased the statistical power of the study and allowed for a study of NHL overall including several of its subtypes, adding that the five-, 10-, 15- and 20-year lagged analyses did not significantly affect results for NHL (at JRC [217]). 367 Fourthly, coupled with the large number of participants involved in the AHS, the questionnaires were designed in a way to procure detailed and granular responses from subjects concerning, among other things, the types of pesticides used, the duration and frequency of exposure, the way the pesticide was applied, and personal health information. The AHS questionnaire was the only questionnaire available for inspection by the expert witnesses in this proceeding and, when asked about its level of detail, despite initial criticisms with respect to the utilisation of self-reporting, Professor Checkoway agreed that the enrolment questionnaire for the AHS "dug down to an appropriately granular level of exposure to particular pesticides" (T955.44-956.1). 368 Fifthly, and relatedly, the reliability of exposure histories given by licensed pesticide applications (as in the AHS) has been verified in other specific studies. The authors of Andreotti (2018) note this as a strength of the study, stating (at 7) that "this AHS analysis includes only licensed pesticide applicators who have been shown to reliably report their pesticide use (28, 29)". The two studies referenced by the authors are: (1) Blair A, Tarone R, Sandler D, et al. (2002) "Reliability of Reporting on Lifestyle and Agricultural Factors by a Sample of Participants in the Agricultural Health Study from Iowa" 13 Epidemiology 94; and (2) Hoppin J A, Yucel F, Dosemeci M, et al. (2002) "Accuracy of Self-reported Pesticide Use Duration Information from Licensed Pesticide Applicators in the Agricultural Health Study" 12(5) J Expo Anal Environ Epidemiol. 313. 369 Professor Checkoway agreed that the authors of the AHS papers had regard to studies which specifically addressed the reliability of the type of study participants who comprised its participants (T962.21; T963.33), noting that there had not been "any studies equivalent to those set out in [Blair (2002)] and other validating the accuracy of the recall of the cohorts of people used in any of those case controlled studies" (T963.40).
Conclusion 370 For these reasons, it is difficult to come to any conclusion other than that the AHS represents the largest, most comprehensive and reliable analysis to date concerning whether there exists an etiologic relationship between exposure to glyphosate and/or GBFs and NHL.
Introduction 371 Conclave E addressed the discrete question of whether the methodologies used, and conclusions drawn in Crump, K "The Potential Effects of Recall Bias and Selection Bias on the Epidemiological Evidence for the Carcinogenicity of Glyphosate" (2020) 40(4) Risk Analysis 696 (Crump (2020)) are reliable. 372 That study concludes that four case-control studies relied upon by Mr McNickle, namely McDuffie (2001); Hardell (2002); Eriksson (2008); and Orsi (2009) (collectively, Crump (2020) case-control studies) are "contaminated by statistical bias, likely stemming in the main from recall bias" (Conclave E Joint Report (JRE) (at [125])). In addition to recall bias being potentially responsible for increased ORs in the case-control studies cited, Crump (2020) suggests that Hardell (2002) and Eriksson (2008) used a non-standard method of computing ORs liable to cause a form of selection bias, which exacerbates the effect of any recall bias. 373 Dr Crump's extra-curial reasoning in his article (which was admitted without objection by Mr McNickle, notwithstanding the difficulty in testing his evidence given in Court) is that systemic bias is present in these studies because of the high proportion of ORs elevated above 1.0 (Table II, Crump (2020) (at 700)). It is contended that the proportion of ORs he calculated as being above one is consistent with two possible hypotheses: first, all the pesticide groups considered are capable of causing NHL; and secondly, all of the OR calculations are biased. Given that it is very unlikely that every category of pesticide examined is capable of causing NHL, Dr Crump concludes that results from at least four of the five case-control studies (that is, the Crump (2020) case-control studies, excluding De Roos (2003)) are biased due to a form of recall bias, which is possibly exacerbated in Hardell (2002) and Eriksson (2008) by selection bias (at JRE [106]-[109]). 374 Before turning to my findings, it is necessary to address Mr McNickle's contentions with respect to Crump (2020) (that is, out-of-court representations made by Dr Crump).
Mr McNickle's contentions 375 Mr McNickle contends that there are several flaws in the analysis conducted in Crump (2020). 376 First, it is said that Dr Crump's description of the two possible hypotheses (at JRE [107]) overstates the results which his hypotheses purport to explain. It is convenient here to set out Table II of Crump (2020) (at 700) (footnotes omitted): 377 Dr Crump refers to "all" of the pesticide groups causing NHL and "all" of the OR calculations being biased in his articulation of the "two possible hypotheses" (at JRE [107]). However, as can be seen above, on Dr Crump's calculations, it is not the case that all ORs are above 1.0. For example, the proportion of ORs above 1.0 are as low as 33.3% in De Roos (2003), 66.7% in Orsi (2009) and 83.3% in McDuffie (2001). It is contended that by virtue of those numbers alone, it cannot be said that the ORs are consistent only with two possible hypotheses, being that all the pesticide groups considered are causing NHL or that all the ORs are biased. 378 Secondly, it is contended that Dr Crump's methodology for calculating the proportion of ORs above 1.0 in Table II involved, in effect, double-counting (at JRE [131]-[134]; First Gordon Report (at [336]-[344]); T1168.10-16, T1169.46-47, T1242.4-18, T1246.5-1247.4). This is said to be for two reasons. 379 The first reason is that the same exposed cases and controls were included in the calculation of more than one OR used by Dr Crump (T1238.44-1239.3). As a result, the ORs used by Dr Crump were not statistically independent, which has the effect of inflating the proportion of ORs above 1.0 (T1240.26-34). 380 The second reason is that the same individuals were likely exposed to more than one pesticide. Dr Crump conceded that that would mean the number of ORs above 1.0 could be the result of several pesticides showing an association across the population: (T1241.40-45). For example, an OR for Pesticide A might be above 1.0 even if Pesticide A is not associated with NHL, because some of those exposed to Pesticide A were also exposed to Pesticides B and C, where Pesticides B and C do cause NHL. This is another form of double counting, because Pesticides B and C may cause the ORs to appear elevated for Pesticide A as well as for Pesticides B and C, even though Pesticide A itself is not causing the OR to be elevated. 381 It is said that this lack of statistical independence or double counting means that the proportion of ORs above one is consistent with more than the two hypotheses Dr Crump identified (at JRE [107]). Two other hypotheses that the pattern of ORs are consistent with are: (1) the same exposed cases and controls are included in multiple of the ORs, and thus if there is an association for that exposure, one would expect that the ORs based upon those same exposed cases and controls would all be elevated; and (2) exposure to multiple pesticides by the same cases and controls could also explain the pattern of elevated ORs in the studies. 382 Thirdly, Professor Gordon and Dr Crump agreed that although Dr Crump's simulation of the effect of recall bias looks at the effect on the OR assuming there is an absence of an association (that is, where the true OR equals 1.0), where the true OR has some different value (that is, greater than 1.0), then recall bias can cause a decrease in the OR, depending on the accuracy of exposure recall (sensitivity) and the accuracy of non-exposure recall (specificity) (at JRE [170]-[171]; T1233.18-1234.1). This downward effect on the OR is demonstrated by the sensitivity analysis undertaken by Professor Gordon for De Roos (2003) (see First Gordon Report (at [268])). Professor Gordon notes that in many of the combinations that would reflect recall bias (that is, where there is differential recall between cases and controls), the OR is underestimated and not overestimated and, as a result, contradicts Dr Crump's simulated results (First Gordon Report (at [290]-[301]) and Figures 6, 7). 383 Fourthly, the literature cited by Dr Crump in support of his opinion that recall bias is a well-known problem does not support the conclusion that recall bias will necessarily be present or will necessarily result in ORs being inflated (at JRE [147], [149], [150]; T1194.44-1201.4). 384 Fifthly, it is said that the conclusions drawn by Dr Crump are contradicted by what the data in the papers show about the presence (or absence) of recall bias, as reported by the authors of the papers themselves or of other papers that analysed the same data. This is apparent from a review of McDuffie (2001) (at 1161); De Roos (2003) (at 8); Pahwa (2019) (at 607), Cantor (1992) (at 2543-2545), Lee (2004) (at 301); Hardell (2002) (at 1046) and Eriksson (2008) (at 1658, 1660) and other papers. 385 In relation to each of McDuffie (2001) and De Roos (2003), based upon what was said in those papers about whether recall bias was present (and other papers), Dr Crump said that "[t]here was not evidence for case recall bias" in those studies (T1218.40-1219.1; see also T1207.23-34; T1209.1-34; T1213.5-38; T1215.12-16). In relation to Hardell (2002), Dr Crump conceded that if recall bias was present, then it would be expected that farmers as an occupation would show an elevated trend (T1220.1-10). As a result, the absence of an association being observed for farmers points against recall bias being the cause for the elevated ORs (as was identified by the authors of the paper). Dr Crump did not disagree that that conclusion followed from the concession he made, instead stating that he "would have to think about it more seriously" and "[s]pend more time thinking about it" (T1220.16-17). 386 In relation to Eriksson (2008), Dr Crump conceded that there was some information available from the paper itself that there was no recall bias (T1226.1-4). In relation to Eriksson (2008), the paper showed elevated ORs for some, but not all, lymphoma types. Dr Crump accepted earlier in his evidence that where different diseases are studied within the one study and an association is identified for one but not another disease, that would suggest that recall bias was unlikely (T1200.38-46). It is said the Court should not conclude that this constitutes evidence that recall bias is "likely" and that Dr Crump's concessions in cross-examination undermine the reliability of Crump (2020).
Consideration 387 Before going further, it is important to keep two things separate. The first are the out-of-court representations contained in Crump (2020) and the second are the in-court representations of Dr Crump in his opinions adduced in chief, including through the JRE. As noted above, the out-of-court opinions were admitted without objection by Mr McNickle and following the difficulties encountered during his cross-examination, no suggestion was made that those out-of-court representations be rejected or the subject of some limitation - indeed, the submissions about the diminished weight being given to his evidence were focussed on his in-court representations. In particular, there was no attempt by Mr McNickle to develop an argument that I ought to approach the out-of-court representations made by Dr Crump any differently to any other scientific article that was placed in evidence without objection. 388 Despite all this, in assessing the evidence, it is necessary to keep in mind that the Conclave E concurrent evidence session was hampered by Dr Crump's difficulty hearing and comprehending questions, to which I have already made reference above (at [162]-[168]). In any event, it is difficult to come to any other conclusion that Crump (2020) is of limited assistance. 389 The chief reason for this is that broadly speaking, I have already found the Crump (2020) case-control studies suffer from a series of limitations to which I have already referred above in Sections I, II and III. Nothing about Crump (2020) changes this conclusion, notwithstanding that recall and selection bias was a factor in my assessment as to the case-control studies. Although I consider this issue to be somewhat of a distraction, for completeness, however, I will make the following observations. 390 First, with respect to the preponderance of ORs being above 1.0 in Table II, that table must be read in conjunction with Figure 1 in the study, which illustrates that the mean and median OR of the Crump (2020) case-control studies (that is, with the exception of De Roos (2003)) are well-over 1.0. As Dr Crump notes (at 699): Fig. 1 shows plots of the tabulated ORs or RRs by study, with the pesticide groupings upon which the ORs are based (including ORs derived for both individual pesticides and groups of pesticides), classified as to fungicides, herbicides not containing glyphosate, impregnating agents, insecticides, and pesticide groupings that include glyphosate. The individual pesticides and groupings for each study are listed in the footnote to Table II. The tabulated RRs from the two cohort studies are similarly classified into cancer groupings not containing NHL and groupings containing NHL. Since the logarithms of ORs are plotted, we are interested in the proportion of log-transformed ORs that are greater than 0.0 (equal to the proportion of untransformed ORs greater than 1.0). … These figures show that ORs in McDuffie et al. (2001), Hardell et al. (2002), and Eriksson et al. (2008) are all practically greater than 1.0. Also, there is an excess of ORs greater than 1.0 in Orsi et al. (2009). These excesses of ORs greater than 1.0 occur in all categories of pesticides considered in these studies. (Emphasis added) 391 Professor Gordon accepted in cross-examination that the preponderance of ORs for NHL greater than 1.0 for practically all categories of pesticides suggested that recall bias may be responsible for the observed associations in the Crump (2020) case-control studies, the effect of which will tend to make glyphosate appear carcinogenic even if it is not (T1160.7-12); at JRE [158]). As Dr Crump explains, "[t]his bias would be expected to be present in exposure of all pesticides because cases and controls would respond differently when questioned about their past exposure" (at JRE [130]). 392 Secondly, with respect to double-counting, it was suggested to Dr Crump that he counted ORs for pesticide groups (for example, phenoxy herbicide) and also ORs from the individual chemicals within that group (for example, 2,4-D and mecoprop) such that double-counting would artificially generate a higher proportion of elevated ORs. It is clear from the Crump (2020) supplementary files that in relation to McDuffie (2001), the calculation of the generic pesticide ORs (phenoxy herbicide) was based on a different number of exposed participants than the ORs for individual chemicals within the relevant pesticide group. That is, they are different exposures with different ORs. The table below extracted by Monsanto helpfully illustrates that the participants exposed to phenoxy herbicide (generic) were different to those exposed to the specific phenoxy herbicides, necessitating separate OR calculations: 393 The following exchange occurred between the Assessor and Professor Gordon (T1243.22-32): ASSESSOR: So I'm still intrigued why they reported phenoxy herbicide generic as well as the individual phenoxy herbicide. Aren't they all different exposures with different odds ratios? PROFESSOR GORDON: Well, potentially, yes, that's right, Sir John, they are. But sometimes people might consider, you know, a grouping of exposures, I guess, if they think they can be meaningfully grouped in some way. ASSESSOR: But they're different exposures. PROFESSOR GORDON: Yes, they are. 394 With respect to the second form of double-counting alleged, being that the same individuals were likely exposed to more than one pesticide, Professor Gordon accepted that even if the premise were true that a confounding agent (that is, Pesticides B and C, see above (at [380])) is capable of causing NHL, there is no evidence that the relevant agent is glyphosate (T1168.22-1169.10). As Dr Crump noted in the JRE (at [129]): If there is only one such carcinogenic pesticide, the presence of that pesticide would need to be consistently highly correlated with all the other pesticide categories to see the consistent pattern of ORs > 1 in all categories of pesticides examined. Although I acknowledge that exposure to different pesticides may be correlated, I know of no evidence for such high correlations, and Professor Gordon has not presented such evidence. 395 This is not to say that some form of double counting in Crump (2020) did not, in fact, occur. As Professor Gordon recognised, there is duplication present, for example, in rows 14 and 15 in relation to dinitroanilines and trifluralin (T1246.43-1247.4) which pertain to the same study participants. Mr McNickle, however, did not present any modelling of the effect of removing such duplications which, as Dr Crump notes, would not alter the excess of ORs above 1.0 (and would be, in any event, not possible in this study) (T1247.9-1247.26). 396 Thirdly, although Professor Gordon and Dr Crump agreed that it is theoretically possible that in circumstances where the OR is greater than 1.0, then recall bias can decrease the OR (rather than increase it) (at JRE [170]-[171]; T1233.18-1234.1), this proposition was not tested with respect to Dr Crump's simulated results in the JRE. Accordingly, it is difficult to come to any conclusion as to whether Dr Crump's simulation can be contradicted on this basis. 397 Fourthly, as to the literature and data cited in Crump (2020) and the contention that the case-control studies referred to by Dr Crump tended against the presence of recall bias in those studies, three points should be made: (1) the apparent differences between the degree of elevation in ORs for one disease (but not others) in any given study is not compelling evidence against the presence of recall bias. In Eriksson (2008), for example, the other disease with a non-elevated OR was an outlying subset of NHL (that is, unspecified B-cell lymphoma, which exhibits unusually low ORs); (2) recall bias in any given study is not excluded by claims from authors that pilot studies or samples indicated a correlation between reported exposures and objective measures of exposure (such as the purchase of pesticides); and (3) recall bias does not arise solely from publicity about glyphosate, therefore it is not excluded by pre-publicity dates of undertaking questionnaires. 398 Fifthly, without making any firm conclusion as to Crump (2020) and recall and selection bias for reasons I have explained, Professor Gordon accepted (at JRE [183]) that the exclusion of the unexposed cases and controls in the two studies was "strange and non-standard" and that he was "not convinced" that Eriksson (2008) and Hardell (2002) excluded other exposures among the unexposed to glyphosate group. In cross-examination, however, Professor Gordon accepted that this method had been used to derive the ORs in Eriksson (2008) (T1184.16) and Hardell (2002) (T1184.5), and accepted that to the extent there are ORs that are infected by selection bias "[they are] the odds ratios that Dr Crump included in table 2 [of Crump [2020])" (T1185.18-21).
Conclusion 399 For these reasons, I have derived only limited assistance from Crump (2020).
VI Conclusion 400 Overall, having regard to the weight I have attributed to the epidemiological evidence adduced, I am not satisfied that the epidemiological evidence supports an etiological association between glyphosate and/or GBFs and NHL. 401 Broadly summarised, that conclusion follows for three reasons. 402 First, I have derived limited assistance from the case-control studies addressed in Sections I, II and III above. As I have explained, the case-control studies share common limitations which, when viewed collectively, significantly diminish the reliability of those publications in demonstrating an etiologic connexion between glyphosate and/or GBF exposure and NHL. It is worth highlighting two, namely: (1) the failure to correct for exposure to other pesticides (that is, confounding); and (2) the small number of study participants who reported exposure to glyphosate. 403 As to the first limitation, confounding is a frequently recurring issue in the case-control studies. To take four examples, in Eriksson (2008), Professor Checkoway conceded that none of the results for glyphosate in Table II were adjusted for exposure to other pesticides, with the authors noting (at 1660) that exposure to multiple pesticides was "common among the study participants" (see above (at [208])). In Hardell (2023), the authors indicated (at 999) that in calculating the risk estimate for different pesticides, "exposure to other types were not included for cases and controls", thereby including subjects with no exposure to any type of pesticides (see above (at [284])). In Orsi (2009), the authors allocated an agent to study participants based upon crop type, thereby introducing potential exposure misclassification (see above (at [298])). In Lee (2004), one non-asthmatic case of NHL was on average exposed to about four pesticides. The corollary is that in a large proportion of the case-control studies, there was a failure or inability to address confounding factors or to isolate appropriately the purported carcinogenic effect of glyphosate as an agent. 404 As to the second limitation, most of the case-control papers involved a relatively small number of cases and controls who were exposed to glyphosate. In Meloni (2021), for example, Professor Checkoway and AP Harris agreed that a limitation of the study was the small number of participants ever exposed to glyphosate (21 cases and 15 controls). The authors acknowledged this as a "major interpretive limitation" of the study (see above (at [222])), and further noted that it was not clear in any event whether the 21 cases had in fact ever been exposed to glyphosate. In Hardell (2023), a similar number of cases (37) and controls (26) had ever been exposed to glyphosate, which was noted by Professor Checkoway as a weakness of the study (see above (at [283])). In Hardell and Eriksson (1999), Professor Checkoway accepted that the sample size for glyphosate (four cases and three controls) was too small to derive any reliable conclusion from the study as to an etiological association between glyphosate and/or GBFs and NHL. As noted earlier, he agreed with AP Harris' observation that the number of cases and controls in that study could have been even smaller than four and three respectively due to missing data in other variables (see above (at [182])). As a result, due to the relatively small sample sizes involved, the case-control studies generally suffer from low statistical precision and an inability to extrapolate the results for the population at risk. 405 Secondly, putting to one side the issue of confounding and small sample sizes, to the extent that the case-control studies can be relied upon for the purposes of examining whether there is a causal connexion between glyphosate and/or GBF exposure and NHL, it is clear that the OR results in many of the studies include the null hypothesis (that is, do not exclude the possibility of no causal relationship between exposure to glyphosate and/or GBFs and NHL). To list five examples (emphasis added): (1) Hardell and Eriksson (1999) (OR 2.3, 95% CI: 0.4-13); (2) McDuffie (2001) (OR 1.26, 95% CI: 0.87-1.80) (unadjusted); (3) Eriksson (2008) (OR 1.51, 95% CI: 0.77-2.94); (4) De Roos (2003) (OR 1.6, 95% CI: 0.9-2.8) (adjusted for hierarchical regression); and (5) Meloni (2021) (OR 1.4, 95% CI: 0.62-2.94). 406 It is worth reiterating in respect of these results that a wide confidence interval is indicative of a small number of observations, and hence a less reliable point estimate (see particularly Hardell and Eriksson (1999) and Meloni (2021)). 407 Thirdly, for reasons I have explained and in contrast to the bulk of the case-control studies, the AHS represents the most comprehensive and reliable analysis to date of whether there is a causal relationship between exposure to glyphosate and/or GBFs and NHL. 408 At the risk of repetition, it is well to emphasise two points: (1) in the light of the sheer number of study participants involved, the AHS offers a level of statistical precision which vastly exceeds any comparable study on the etiologic relationship between glyphosate and NHL. Professor Checkoway and AP Harris agreed that this represented a "key strength" of the AHS in contrast to the case-control studies, which frequently ranged from a few hundred to a few thousand participants; and (2) in contrast to population-based and community studies, the sample in the AHS consists of applicators who were occupationally exposed to GBFs and other agents thought to be carcinogenic. As noted earlier, Professor Checkoway and AP Harris agreed that as a result of the high prevalence of exposure, the AHS offers a far greater facility to detect potential associations between GBFs and various cancers. 409 Having dealt with epidemiology, it is now necessary to turn to the rats and mice.
F THE SECOND STREAM: ANIMAL STUDIES (CONCLAVES H, I AND J)
I Introduction 410 The animal studies stream concerns long-term studies conducted on experimental animals. It is comprised of studies which address whether a substance or chemical is capable of inducing cancer development in laboratory animals, and if so, whether this information provides insight into carcinogenic potential or risk for humans (Conclave H Joint Report (JRH) (at [16])). 411 Animal studies can provide two insights into the carcinogenic potential or risk for humans of a substance: first, whether there is a potential carcinogenic hazard; and secondly, whether there is a dose-response relationship. As stated by the US Environmental Protection Agency (USEPA) "Guidelines for Carcinogen Risk Assessment" (March 2005) (USEPA Guidelines) (at JRH [17]): The objective of long-term carcinogenesis bioassays is to determine the potential carcinogenic hazard and dose-response relationships of the test agent. Carcinogenicity rodent studies are designed to examine the production of tumours as well as preneoplastic lesions and other indications of chronic toxicity that may provide evidence of treatment-related effects and insights into the way the test agent produces tumours. 412 Mr McNickle contends that the evidence adduced in the animal studies stream establishes that more likely than not, glyphosate causes cancer in rats and mice, and that the results of the animal bioassays provide important evidence as to glyphosate's carcinogenicity in humans. 413 Before turning to that evidence, it is necessary to make some further introductory observations with respect to the methodology used in animal studies the subject of this stream.
II Methodology 414 Animal studies involve experiments on mammals. They are typically performed on rats and mice over a period of 18 to 24 months under a set of hygienic, procedural, and humane conditions known as "good laboratory practices" (GLP). Consistently with the first law of toxicology that "the dose makes the poison", GLP is achieved by procuring, randomising, dosing and caring for the animals to ensure that the only difference between the animal groups is the amount of chemical they receive (First Bayard Report (at [1])). 415 A typical experiment will involve an animal bioassay set (a term to which I will return shortly) of at least 50 animals per sex, per dose group in three treatment groups, and in a concurrent control group (at JRH [20]). One of the groups receives none of the chemical (that is, the concurrent control group), while the treatment groups receive different amounts of the chemical up to a maximum dose, known as the maximum tolerated dose (MTD). Testing at the MTD is not done because humans are expected to be exposed at such high doses, rather it is done to determine if the tested chemical has carcinogenic potential, and to limit the numbers of animals in the study. If a chemical is found to cause cancer at high doses, it is almost always considered to cause less (but not zero) cancer at lower doses (at JRI [44]). 416 When the animals die or are slain, they are autopsied for findings of chronic toxicity and cancer in most organs or systems. Reports are prepared and the results are analysed by toxicologists, and by statisticians who perform a series of statistical tests to determine whether or not the cancers in the treatment groups differ from those in the control group (First Bayard Report (at [1])). 417 Cancer biologists gain insights into cancer biology by using animal model systems. The term "animal model" usually refers to studying an animal and its susceptibility to the agent administered to develop a disease which is the same as or like a disease in humans. Some animal models are specifically developed by modifying the animal host to increase susceptibility. In other models, the animal is administered the disease for the purpose of further experimentation, such as slowing the progress of the disease by using a drug (at JRI [18]). 418 Animal models are evaluated according to whether experimental findings can be translatable to humans (at JRI [16]). With respect to murine models (that is, models involving rats and mice) used in cancer research, the vast majority are developed for the purposes of (at JRI [19]): (1) studying an animal and its susceptibility to the agent administered to develop a disease which is the same as or like a disease in humans; (2) studying the biological processes that occur during cancer development. In such cases, the mice may start the experiment without cancer or already have the cancer at the start of the experiment; and (3) establishing a cancer in a small animal and assessing the response to a given therapy (that is, a new drug). Such animal model systems can be considered "contrived or artificial", in that the mouse biology is somehow manipulated to "host" a cancer. 419 Such studies frequently involve use of "bioassays". Bioassays are a quantitative assessment of the potency of a chemical or biological substance by observing and measuring its effects on cells, tissues, living organisms, or humans (at JRI [21]), and include experiments conducted on living animals (in vivo) and on living cells or organ tissue (in vitro). 420 Animal bioassays are an important tool in evaluating the carcinogenic potential of most chemicals. Bioassays on murine subjects are typically conducted for registration purposes for commercial products, including pesticides, if and as required by regulatory agencies or bodies and by law. If a registration requirement under law requires the conduct of long-term carcinogenic studies, then it is incumbent upon the registrants of a chemical that is being developed with the intention of it becoming commercially available to conduct such studies and submit them to the relevant regulatory authorities (at JRH [14]). For pesticide registrations globally, there exist standardised test guidelines for various and multiple toxicological effects and outcomes, but specific to evaluation of carcinogenic potential, there are existing test guidelines (TG) for both the Organisation for Economic Co-operation and Development (OECD) and USEPA regulatory authorities. The TGs specify the framework and specific scientific details and parameters by which long-term cancer studies are conducted on laboratory animals and also provide guidance on test result interpretation relative to carcinogenic potential of a chemical or substance. 421 The following represent some of the key study design or data interpretation guidance from the OECD when conducting chronic or carcinogenicity studies in laboratory animals (at JRH [19]; see further Guidance Notes for Analysis and Evaluation of Chronic Toxicity and Carcinogenicity Studies (2002) OECD (OECD Guidance Notes)): (a) OECD Test Guideline 451 (i.e., for carcinogenicity evaluation) requires at least three dose levels, as well as controls for determination of the dose-response relationship. (b) The largest administered dose should not compromise the biological interpretability of the observed responses. (c) In a carcinogenicity study, this dose should not significantly affect the survival rate except through tumour production or cause a body weight decrement greater than 10-12% of concurrent control values. (d) Overt toxicity or inappropriate toxicokinetics as a result of excessive dosing may result in tumorigenesis that is secondary to toxicity rather than directly attributable to the agent. (e) The clearest indication of a positive carcinogenic response is obtained when the incidence of tumours rises above concurrent and historical control levels in both sexes and is higher at higher doses. Further significant observations in treated animals include an increase in rare types of tumour, metastases, reduced latency, and the presence of tumours at multiple sites. (f) Although statistical comparisons are of treated animals and concurrent controls, additional insights into the significance of tumours can be obtained from examination of historical control data. 422 The USEPA's key study design requirements and data interpretation guidance for animal studies are as follows (at JRH [20]): (a) Current standardised carcinogenicity studies in rodents test at least 50 animals per sex per dose group in each of three treatment groups and in a concurrent control group, usually for 18 to 24 months. (b) The high dose (i.e., maximum tolerated dose or MTD) in long-term studies is generally selected to provide the maximum ability to detect treatment-related carcinogenic effects while not compromising the outcome of the study through excessive toxicity or inducing inappropriate toxicokinetics (e.g., overwhelming absorption or detoxification mechanisms). (c) The purpose of two or more lower doses is to provide some information on the shape of the dose-response curve. (d) Trend tests and pairwise comparison tests are the recommended tests for determining whether chance, rather than a treatment-related effect, is a plausible explanation for an apparent increase in tumour incidence. A statistically significant response may or may not be biologically significant and vice versa. (e) A trend test such as the Cochran-Armitage test (Snedecor and Cochran, 1967) asks whether the results in all dose groups together increase as dose increases. A pairwise comparison test such as the Fisher exact test (Fisher, 1950) asks whether an incidence in one dose group is increased over that of the control group. By convention, for both tests a statistically significant comparison is one for which p is less than 0.05 that the increased incidence is due to chance. Significance in either kind of test is sufficient to reject the hypothesis that chance accounts for the result. A statistically significant response may or may not be biologically significant and vice versa. (f) The standard for determining statistical significance of tumour incidence comes from a comparison of tumours in dosed animals with those in concurrent control animals. Additional insights about both statistical and biological significance can come from an examination of historical control data. Historical control data can add to the analysis, particularly by enabling identification of uncommon tumour types or high spontaneous incidence of a tumour in a given animal strain. 423 The USEPA also provides guidelines on the issue of multiple comparisons, to which I will return below (at [481]) and which assumes some importance in the context of Dr Bayard's evidence. 424 While the OECD and USEPA guidance above contain similar recommendations relative to study design or data interpretation, this reflects the desire by regulatory authorities for global harmonisation of toxicology study design and data interpretation. Relative to evaluation of results from long-term cancer bioassays in laboratory animals include the following (USEPA Guidelines (at 2-20) (at JRH [21])): Assessment of evidence of carcinogenicity from long-term animal studies. In general, observation of tumors under different circumstances lends support to the significance of the findings for animal carcinogenicity. Significance is generally increased by the observation of more of the factors listed below. For a factor such as malignancy, the severity of the observed pathology can also affect the significance. The following observations add significance to the tumor findings: • uncommon tumor types; • tumors at multiple sites; • tumors by more than one route of administration; • tumors in multiple species, strains, or both sexes; • progression of lesions from preneoplastic to benign to malignant; • reduced latency of neoplastic lesions; • metastases; • unusual magnitude of tumor response; • proportion of malignant tumors; and • dose-related increases. In these cancer guidelines, tumors observed in animals are generally assumed to indicate that an agent may produce tumors in humans. Mode of action may help inform this assumption on a chemical-specific basis. Moreover, the absence of tumors in well-conducted, long-term animal studies in at least two species provides reasonable assurance that an agent may not be a carcinogenic concern for humans. 425 Tumours at multiple sites, for instance, show that the chemical can be absorbed, distributed widely throughout the body, and have adverse effects on multiple systems. Tumours occurring in multiple species, strains and both sexes add to the confidence that the chemical's effects are not constrained to just one site or laboratory strain. These studies include a broad spectrum of cancers, including NHL. Furthermore, in the case of NHL in humans, malignant lymphomas in mice have been used as laboratory models for NHL based on similarities of lymphocyte development. 426 Further to the USEPA and OECD guidelines, the International Agency for Research on Cancer (IARC) has adopted a system for classifying chemicals for their carcinogenic potential to humans, namely (at JRI [24]-[25]): (1) Group 1 (Carcinogenic to humans); (2) Group 2A (Probably carcinogenic to humans); (3) Group 2B (Possibly carcinogenic to humans); and (4) Group 3 (Not classifiable as to its carcinogenicity to humans). 427 Classification of a chemical depends upon an evaluation of the three streams of evidence the subject of this proceeding, not only animal studies. With that said, the IARC notes that for some agents, carcinogenicity in experimental animals was demonstrated before epidemiological studies identified carcinogenicity in human beings. While this observation does not mean that all agents which can cause cancer in experimental animals can cause cancer in humans, it is biologically plausible that agents for which there is sufficient evidence of carcinogenicity in experimental animals present a carcinogenic hazard to humans. Importantly, although such agents are considered to pose a potential carcinogenic hazard, that inference does not imply tumour concordance across species (at JRI [27]). 428 In terms of the evaluation of human carcinogenic potential, bodies (such as the USEPA) utilise carcinogen classification like that used by the IARC. In arriving at a rating, the Bradford Hill criteria (see above (at [105]-[106])) are often used. The USEPA Guidelines, for example, uses the Bradford Hill criteria for evaluation of human carcinogenic potential, with "evidence from experimental animals" relating to "consistency", "strength", "temporal, "biological gradient", "biological plausibility" and "coherence" criteria.
I Overview 429 The animal studies stream spanned Conclaves H, I and J and involved the following expert witnesses: (1) Conclave H - Animal studies A (toxicological analysis of results of animal studies) Dr Bayard and Dr Juberg (2) Conclave I - Animal studies B (relevance of animal studies and bioassays to humans) Dr Bayard and Professor Prince (3) Conclave J - Animal studies C (statistical analysis of results of animal studies) Dr Bayard and Dr Crump 430 I should pause to note that Monsanto, for reasons I will explain, made a forensic decision not to call Dr Crump to give evidence in Conclave J. Accordingly, I have not had regard to Dr Crump's contribution to the JRJ or his individual report in informing my conclusions below (except to the extent that it is appropriate to make something of Monsanto's failure to call him in this part of its case). 431 As with the other streams, individual reports were prepared by each of the experts, as set out in the table below: Report Date Report Topic Expert Report of Dr Bayard (First Bayard Report) 4 April 2022 The carcinogenicity of glyphosate in laboratory rodent lifetime studies. Supplementary Report of Professor Prince (Second Prince Report) 16 July 2022 Response to the First Bayard Report and basis for presumption that "growth control mechanisms at the cellular level are homologous between species (US EPA, 2005)". Supplementary Expert Report of Dr Juberg (Second Juberg Report) 14 July 2022 Response to the First Bayard Report (at [141]-[151]) which addresses, among other things, whether it is more likely than not that glyphosate causes cancer in animals and should be considered a human carcinogen.
432 In the following section, I will introduce each of the experts who participated in the animal studies stream before turning to making some general observations as to credit.
Dr Bayard 433 Dr Steven Bayard is a retired statistician and risk assessor with over 40 years of experience in health and quantitative risk assessment of toxic chemical hazards. Mr McNickle had initially engaged Dr Christopher Portier to give evidence in the animal studies stream, however, Dr Bayard was engaged by the applicant following Dr Portier's decision to no longer take part in this proceeding (a matter to which I will return below). 434 Dr Bayard holds a bachelor's degree in mathematics from Tufts University (1965) and a PhD in biostatistics from Johns Hopkins University (1971). He also holds graduate credits in toxicology from the Massachusetts Institute of Technology (1979) (a non-degree programme). Dr Bayard's experience includes working with the CPSC, USEPA and OSHA where, among other things, he authored cancer risk assessments for various chemicals. Dr Bayard also has experience teaching graduate courses in statistics, biostatistics, epidemiology and demography, and in various project management and consulting roles. 435 Dr Bayard's conclusion in the animal studies stream is that based upon his analysis and evaluation of 13 lifetime glyphosate cancer bioassays, glyphosate is carcinogenic in mammals (at JRH [24]; JRI [54]). Monsanto contends that the Court should reject this proposition principally because Dr Bayard was not an impartial witness. 436 This is said to be for three interrelated reasons, namely that Dr Bayard: (1) recited the work of Dr Portier with little or no independence; (2) approached the task of giving evidence as an advocate, rather than an impartial expert; and (3) came to this proceeding with a fixed view from his involvement in glyphosate litigation in the United States. 437 As to the first reason, Monsanto contends that critical aspects of Dr Bayard's evidence involved a replication of Dr Portier's analysis. It will suffice to set out a few examples given by Monsanto. When Dr Bayard was asked about the unavailability of data underlying one of the studies on which he relied (Takahashi (1999)), Dr Bayard said that he had "relied on the JMPR and Dr Portier" (T1644.25-30), before clarifying that he had "relied mostly - more on the JMPR than I did on Dr Portier" (T1645.1-2). Further, when Dr Bayard was asked whether he looked at Dr Portier's data when he made corrections to his report in the week leading up to the concurrent evidence session, Dr Bayard said that he did look at the data beforehand and must have drawn some of his data from the analyses conducted by Dr Portier (T1666.39-43). Monsanto also submits that Dr Bayard had replicated the method Dr Portier had used for adjusting for multiple comparisons, which apparently had not been featured in the scientific literature and had never been used other than by Dr Portier (T1772.12-13; T1774.46; T1773.8; T1774.17-28). 438 As to the second reason, Monsanto submits that aspects of Dr Bayard's oral evidence indicated that he approached his task as an advocate for Mr McNickle, rather than as an independent expert witness. It is said that Dr Bayard, among other things: (1) resisted the proposition that he is not a qualified toxicologist and that he was not an expert on the mode of action of glyphosate on the basis that he had read Wang (2019) (T1613.41-1614.3; T1629.23-1630.9; T1629.32, 44; T1630.8); (2) failed to disclose to the Court that the original study pathologist in Takahashi (1999) revised the incidence of tumours upon re-examination (T1647.15-20; T1649.26-33); (3) conceded that he did not give any reasons as to why the pathologist's re-examination results should not be preferred over the old slides (T1650.6-10), noting that "I probably should have said that there was a re-examination" (T1647.26-27); and (4) approached his evidence with a view to "defend[ing] the report [he] wrote in court" (T1778.22). 439 Monsanto further submits that Dr Bayard's approach was obfuscatory advocacy, highlighting that he was repeatedly entreated by the Court and by counsel to attend to the question asked (see, for example, T1614.11-21; T1615.25; T1623.24-25; T1627.43; T1644.45; T1646.11; T1677.18; T1681.27-31; T1691.38; T1697.13; T1699.17; T1713.6-11; T1727.38-39; T1733.30; T1747.15; T1763.17; T1767.43; T1664.10-16; T1728.30; T1755.31-32; T1756.5-6; T1774.15). 440 As to the third reason, Monsanto highlights that Dr Bayard had been engaged as a consultant to a US law firm, Lundy Lundy Soileau & South, in glyphosate litigation prior to replacing Dr Portier in this proceeding (T1619.28-36). When asked as to whether he had seen Dr Portier's evidence when giving evidence previously in glyphosate litigation in the United States (namely, Kane v Monsanto (No. 1622-CC10172) in the Circuit Court of the City of St Louis, State of Missouri (Kane v Monsanto)), Dr Bayard recalled reviewing deposition material of Dr Portier in forming his opinion (T1622.25-46) and that he had reviewed analyses that Dr Portier had prepared in another case that Dr Portier had participated in prior to Dr Bayard preparing his report in Kane v Monsanto (T1625.45-1626.6). Further, when it was put to Dr Bayard that when he gave evidence in those proceedings in 2018 that he had a "fixed view" that glyphosate was an animal carcinogen, he responded that "I probably forgot about it soon after that but yes" and that "in 2018 I thought that way" (T1617.35-45). 441 Although I think these submissions are, in part, put too highly, Dr Bayard was not a responsive witness and did at times stray into advocacy, rather than presenting as a disinterested expert in the Anglo-Australian tradition. Having said that, by his own lights, I suspect that Dr Bayard was attempting to assist the Court and it is worthwhile making the following points. 442 First, as I have noted earlier (at [32]-[33]), the fact that an expert witness has expressed an opinion previously in analogous litigation as to whether, for example, glyphosate is carcinogenic is not a satisfactory reason simpliciter to reduce the weight to be afforded to the expert's present opinion. There is no dispute that Dr Bayard had formed an opinion that glyphosate was an animal carcinogen in April 2018 (T1618.1-2). Although this does not necessarily mean Dr Bayard approached his evidence in this proceeding as an advocate or with a fixed view, sometimes he did fall into this trap. But having said that, I do not think, for example, that Dr Bayard deliberately attempted to obfuscate the findings of Takahashi (1999) by failing to explain that the original study pathologist in that study had conducted a re-examination. Nor do I consider that Dr Bayard intentionally gave a less than complete picture of the evidence by concluding that Lankas (1981) provided a reliable foundation for the proposition that glyphosate causes Thyroid C-cell adenomas and carcinomas in Sprague-Dawley (SD) rats (T1739.15-1740.34; at JRH [70]-[76]). 443 Secondly, it is neither necessary nor helpful to wade into the question of the extent to which Dr Bayard saw or relied upon materials prepared by Dr Portier in advance of the initial trial. For the reasons I have explained above, this is an exercise liable to distract from the task of assessing the underlying scientific merit of the relevant expert's opinion. To some extent, Dr Bayard relied upon Dr Portier's work, but I do not think that it amounted to a "faithful replication". Dr Bayard's evidence, which I accept, is that Portier (2020) used similar method to his own but that Dr Portier "did not look at tumours where [Dr Bayard] analysed them by type" (T1773.8-1774.17). In any event, insofar as Dr Bayard did rely upon Portier (2020), he was entitled to do so for the reasons I have explained above (at [62]) with reference to Karpik v Carnival. 444 Overall, although I accept Monsanto's submission that Dr Bayard was, at times, less than responsive and frequently engaged in speeches, in my view this was reflective of a natural tendency, common among the expert witnesses, to come to the defence of one's own work, rather than any conscious attempt to obscure the evidence. 445 Before moving on, it is important to distinguish this finding as to credit from Monsanto's submission that Dr Bayard's evidence should be afforded less weight because of: (1) his alleged flawed statistical approach with respect to the animal bioassays; and (2) his alleged limited expertise to conduct a critique of multi-disciplinary animal bioassay studies. It is convenient to deal with these submissions when I come to the animal studies evidence in Section F.3 below.
Dr Juberg 446 Dr Daland Juberg is an independent consultant with Juberg Toxicology Consulting LLC. Dr Juberg earned a PhD in toxicology and MS in Environmental Health Sciences (water quality), from the University of Michigan, along with a bachelor's degree in biology from Wittenberg University. Dr Juberg was engaged by Monsanto. 447 Dr Juberg was formerly the Global Leader of Human Health Science Policy at Corteva agriscience, and previous roles included Global Leader, North American Leader, and Senior Toxicologist of the Human Health Assessment group within Dow AgroSciences (Dow). Dr Juberg was also a Principal with the International Centre for Toxicology and Medicine (Washington, DC), Senior Toxicologist for Eastman Kodak Company (NY), and Environmental Scientist with Environmental Control Technology Corporation (MI). 448 Dr Juberg's conclusion in the animal studies stream is that the long-term cancer bioassays in rats and mice do not demonstrate that glyphosate is carcinogenic in mammals (at JRH [103]). Mr McNickle submits that Dr Juberg did not bring an independent mind to giving evidence in the initial trial, primarily because Dr Juberg deferred to the decisions of several regulatory bodies in support of his opinions without actively engaging with that material. 449 This submission was developed as follows. 450 First, it is said that Dr Juberg relied upon decisions reached by the OECD regarding the carcinogenicity of glyphosate, despite the OECD never having conducted an evaluation of glyphosate. When Dr Juberg purported to set out the conclusions of the OECD, what he most often did, Mr McNickle submits, was set out the submission made by the "Glyphosate Taskforce" (GTF) in support of its application for renewal of glyphosate's registration, represented by Monsanto (T1892.5-1894.12). The corollary is that Dr Juberg's evidence, at least in part, consisted of repeating what was submitted by the GTF, as represented by Monsanto, instead of any independent analysis or conclusions reached by a regulator. Relatedly, Mr McNickle submitted that notwithstanding Dr Juberg's opinion regarding the USEPA's compliance with their guidelines (at JRH [150]), he was nonchalant about the vacation of the 2020 Interim Decision by the 9th Circuit Court on the bases that the USEPA had failed to comply with its own guidelines (T1867.40-1868.36). 451 Secondly, it is said that Dr Juberg took a slapdash approach to his evidence by failing to respond to Dr Bayard's opinions in the JRH. In short, when purporting to respond to Dr Bayard's opinions about whether glyphosate is carcinogenic to mammals (Question 3(a)), he in fact addressed the wrong question (Question 4) which related to the specific issue of timing. It is said that Dr Juberg missed the substantial body of Dr Bayard's analysis of the bioassays concerning carcinogenicity to mammals (in response to Question 3(a)). Further, it is contended that Dr Juberg repeated aspects of his evidence from the Second Juberg Report in the JRH in response to Dr Bayard's answers to Questions 3(b) and (c) (at JRH [128]-[135]). 452 Thirdly, and relatedly, to the extent that Dr Juberg provided opinions based upon his review of the animal bioassays, in contrast to Dr Bayard's analysis, Dr Juberg did not undertake any statistical analysis himself (T1781.3-14). He relied on the statistical analysis and conclusions reached in the study reports, and therefore relied on the decisions and judgments made by the study authors in undertaking their analysis and in reaching those conclusions (T1781.7-9; T1793.32-1795.8). Those decisions and judgments include information about what statistical test was used, what threshold was used for statistical significance, and what data was used in the statistical analysis (such as whether males and females were analysed separately or were combined) (T1793.35-1794.25). Mr McNickle contends that as a result, Dr Juberg's opinions on the animal bioassays must be seen through the prism of an expert whose opinions are premised on the recitation of another expert's analysis. 453 Before turning to my findings, it is worth pausing to say something about Dr Juberg's evidence in the animal studies stream. 454 Naturally enough, Mr McNickle's submissions as to the animal bioassays are replete with criticisms of Dr Juberg's evidence which, broadly speaking, reiterate the points made above, and can otherwise be grouped into two categories: (1) that Dr Juberg made criticisms of Dr Bayard's findings in circumstances where he did not perform the statistical analyses himself (at AS [398], [404], [428], [431], [436], [442], [444], [449], [452]); and (2) that Dr Juberg did not review or have regard to particular reports or matters relied upon by Dr Bayard (at AS [412], [421], [423]). 455 I have had regard to all these submissions in evaluating the animal bioassays evidence and in informing my conclusion as to Dr Juberg's credit. But it is important at this juncture to reinforce a point I made earlier in these reasons (at [32]-[33]). 456 Putting to one side Dr Juberg's credit, even if I was satisfied that there was some force in Mr McNickle's criticisms, it would not perforce follow that Dr Bayard's evidence would, as a consequence, necessarily become more persuasive. As will become clear when turning to the animal studies evidence, I have formed the view that there are not insignificant limitations associated with Dr Bayard's findings. For that reason, this makes it strictly unnecessary to address Mr McNickle's criticisms above. 457 To the extent that it matters, however, and for the purpose of informing my conclusion as to Dr Juberg's credit, I do not find Mr McNickle's submissions persuasive, for the following reasons. 458 First, as to Dr Juberg's references to findings purportedly made by the OECD, those initial references in the JRH were corrected in a letter to Mr McNickle's solicitors (Maurice Blackburn) dated 30 September 2023, which was tendered in the proceeding. As was acknowledged in cross-examination (T1894.39-1895.6): MS SZYDZIK: And so I think this is now probably clear from the corrections table that has been provided to us. But in a number of instances - actually almost entirely, but there are some exceptions, where you rely upon the 2015 RAR, what you are including in your table is a statement that was made by the GTF Glyphosate Taskforce? DR JUBERG: Yes. We tried - again, we tried to amend and provide more clarity as to what my summary was, certainly what the notifier's conclusions are, and then if there was an RMS comment. I would agree with you. MS SZYDZIK: Yes. But to the extent that you are - you are identifying matters that have been included in that unitalicised text, that is almost verbatim what, according to this document, the RAR, what the Glyphosate Taskforce itself put into its submission? DR JUBERG: Yes. I think that's reflected in this revised table there. 459 Further, with respect to the US 9th Circuit Court decision, it is not unusual that Dr Juberg, as a toxicologist, was not particularly focussed on those findings. The USEPA has made it clear that although its Interim Registration Review Decision for Glyphosate has been withdrawn, this does not mean that the decision (or its underlying findings) are incorrect as a matter of science. As noted in the USEPA Memorandum "Withdrawal of the Glyphosate Interim Registration Review Decision" (September 2022) (at 5): Although the glyphosate ID is now vacated in part and the remainder withdrawn, that does not automatically mean that EPA's underlying scientific findings regarding glyphosate, including its finding that glyphosate is not likely to be carcinogenic to humans, are either incorrect or cannot be used as support for a future decision following reconsideration in accordance with the court's decision. 460 Secondly, I do not consider that Dr Juberg failed in any fundamental respect to respond to Dr Bayard's opinions in the JRH. I accept Monsanto's submission that Dr Juberg's evidence on the animal studies placed Dr Bayard's evidence in its biological context, rather than engaging with Dr Bayard's statistical analysis at large. As Dr Juberg explained in the Second Juberg Report (at 19): In his expert report, Dr. Bayard focuses on statistical analyses, at the exclusion of multiple other biological factors which must be considered in an evaluation of carcinogenic potential for a compound, and then relies on the Wang et al (2019) study as the basis for his conclusions on the carcinogenicity of glyphosate, both in animals and in humans. 461 Thirdly, in my view Dr Juberg did not jeopardise his independence by relying upon the statistical analysis of other experts in the study reports. As he explained during cross-examination "[I went] to the pathology in all eight bioassays and look for what I referred to this morning as a star or an asterisk indicating that that would be statistically significant" (T1781.7-9). In any event, insofar as Dr Juberg did rely upon such analyses, like Dr Bayard, provided his reasoning was transparent, he was entitled to do so for the reasons I have explained earlier with reference to Karpik v Carnival (see above (at [62])) 462 Overall, my impression is that Dr Juberg did his best to bring an independent mind to the initial trial. It will, however, be necessary to say something further with regards to Dr Juberg's evidence in the third stream.
Professor Prince 463 Professor Miles Prince AM is a professional haematologist and holds a bachelor's degree in medicine and a bachelor's degree in surgery from Monash University. Professor Prince is a full Professor of Medicine at both the University of Melbourne and Monash University. He was engaged by Monsanto. 464 Previously, Professor Prince was head of haematology at the Peter MacCallum Cancer Centre in Melbourne. In 2016, he was appointed the Professor/Director of Molecular Oncology and Cancer Immunology at Epworth Healthcare; a joint appointment between Epworth Healthcare and the University of Melbourne overseeing the clinical practice, research and teaching conducted at the Molecular Oncology and Cancer Immunology Department at Epworth Healthcare. In the same year, Professor Prince founded Precision Haematology. There, he is the lead clinician with two other clinical haematologists, a specialist haematology nurse, a haematology and oncology dietitian and an oncology psychologist. 465 As noted above, Professor Prince participated in the JRI and concurrent evidence session, in which he concluded, in summary, that the field of animal studies are not robust enough to determine if the use of or exposure to glyphosate and/or GBFs can cause NHL. 466 Mr McNickle made extensive submissions as to why the Court should have significant concerns about Professor Prince's independence. These submissions, however, are largely made in the context of Professor Prince's evidence in the JRA and JRB concurrent sessions and, for that reason, I do not intend to address them here. Subject to some matters to which I will return, it suffices to note for the purposes of my approach to Professor Prince's evidence in the animal studies stream and the JRI that I consider these concerns to be somewhat overstated and, broadly speaking, I have formed the view that Professor Prince was an impressive witness. 467 I will return to the topic of Professor Prince's credit in Section G.2 below.
Dr Crump 468 I have already introduced Dr Crump as a witness above in the context of the epidemiology stream (at [162]) and explained then why little can be gained by way of an assessment Dr Crump's credibility. Less can be gained from the concurrent evidence session in Conclave J because, as I have explained, that session did not proceed as a result of Monsanto's decision not to call Dr Crump or rely upon evidence in respect of the questions asked in Conclave J, nor the parts of Dr Crump's report relevant to the conclave. 469 As a result of Monsanto's decision not to call Dr Crump in Conclave J, Mr McNickle submits that the Court should draw a Jones v Dunkel inference. Mr McNickle contends that two consequences flow from that decision: first, that the Court should draw an inference that Dr Crump's evidence on multiple comparisons would not have assisted Monsanto; and secondly, that the Court should more readily accept Dr Bayard's evidence. I will address this submission below in the context of Mr McNickle's submissions as to the issue of multiple comparisons.
F.3 The Animal Studies Evidence 470 Mr McNickle contends that the evidence establishes that glyphosate more likely than not causes cancer in mice and in rats, and that the results of the animal bioassays provide important evidence as to glyphosate's carcinogenicity to humans. This contention is founded upon Dr Bayard's evidence and conclusion (at JRH [24]) that: … based on my analysis and evaluation of 13 lifetime glyphosate cancer bioassays in both sexes of rats and mice, I conclude that glyphosate is carcinogenic in mammals. Since glyphosate is the active and predominant ingredient in GBF's, I conclude that GBF's are also carcinogenic in mammals. This reasoning follows the guidance of the USEPA (EPA, 1986, 2000) on chemical mixtures. 471 In evaluating the animal studies evidence, it is necessary to address the 13 bioassays (animal bioassays) relied upon by Dr Bayard, which consist of seven studies of glyphosate oral administration in rats, and six in mice. The animal bioassays are set out in the table below: No. Study Species 1 Lankas G P "A Lifetime Study of Glyphosate in Rats (1981) Report No. 77-2062 (Bio/Dynamics, Inc.) (Lankas (1981)) Rat 2 Knezevich A L and Hogan G K (1983) "A Chronic Feeding Study of Glyphosate in Mice" Report No. 77-2061 (Bio/Dynamics, Inc.) (Knezevich and Hogan (1983)) Mouse 3 Stout L D and Ruecker P A (1990) "Chronic Study of Glyphosate Administered in Feed to Albino Rats" MRID No. 41643801 (Stout and Ruecker (1990)) Rat 4 Atkinson C, Strutt A, Henderson W et al. (1993a) "104-week Chronic Feeding/Oncogenicity Study in Rats with 52-week Interim Kill" MRID No. 49631701 (Atkinson (1993a)) Rat 5 Atkinson C, Martin T, Hudson P, and Robb D (1993b) "Glyphosate: 104-week Dietary Carcinogenicity Study in Mice" Inversek Research International (Tranent, EH33 2NE, Scotland) (Atkinson (1993b)) Mouse 6 Suresh T P, "Combined Chronic Toxicity and Carcinogenicity Study with Glyphosate Technical in Wistar Rats" (1996) Toxicological Department Rallis Research Centre (Rallis India Limited, Syngenta) (Suresh (1996)) Rat 7 Sugimoto K, "18-month Oral Oncogenicity Study in Mice, Vol. 1 and 2" (1997) Institute of Environmental Toxicology 2-772 (Suzuki-cho, Kodaria-shi, Tokyo, 187, Japan) (Sugimoto (1997)) Mouse 8 Enemoto K "24-month Oral Chronic Toxicity and Oncogenicity Study in Rats, Vol. 1" Institute of Environmental Toxicology (Kodaria-shi, Tokyo, Japan) (Enemoto (1997)) Rat 9 Takahashi M "Oral Feeding Carcinogenicity Study in Mice with AK-01" (1999) Nippon Experimental Medical Research Institute Co. Ltd (Agatsuma, Gunma, Japan) (Takahashi (1999)) Mouse 10 Kumar D P S "Carcinogenicity Study with Glyphosate Technical in Swiss Albino Mice" (2001) Toxicology Department Rallis Research Centre (Rallis India Limited) (Kumar (2001)) Mouse 11 Brammer A "Glyphosate Acid: Two Year Dietary Toxicity and Oncogenicity Study in Rats" (2001) Central Toxicology Laboratory (Alderley Park, Macclesfield, Cheshire, UK, Syngenta) (Brammer (2001)) Rat 12 Wood E, Dunster J, Watson P and Brooks P (2009) "Glyphosate Technical: Dietary Combined Chronic Toxicity/Carcinogenicity Study in the Rat" Harlan Laboratories Limited (Shardlow, Derbyshire DE72 2GD, UK) (Wood (2009a)) Rat 13 Wood E, Dunster J, Watson P and Brooks P "Glyphosate Technical: Dietary Carcinogenicity Study in the Mouse" (2009) Harlan Laboratories Limited (Shardlow, Derbyshire DE72 2GD, UK) (Wood (2009b)) Mouse
472 In addition to the animal bioassays, Dr Bayard also relied upon a mechanistic study of MM in mice, namely Wang (2019). 473 As noted earlier, the thrust of Monsanto's submissions in the animal studies stream consisted of an attack upon Dr Bayard's alleged flawed statistical approach and limited expertise to conduct a multi-disciplinary critique of the animal bioassays. It is convenient to address those submissions first, before turning to the animal bioassays; Dr Bayard's reliance on Wang (2019); and the relevance of the animal studies evidence to humans in Conclave I. 474 Accordingly, this section will adopt the following structure: Section I will address Dr Bayard's alleged flawed statistical approach; Section II will address Dr Bayard's alleged limited expertise in conducting multi-disciplinary animal bioassay studies; Section III will set out my findings as to the animal bioassays; Section IV will address Dr Bayard's reliance on Wang (2019); Section V will address the relevance of animal studies to humans in Conclave I; Section VI will set out my conclusion as to the animal studies stream.
I Dr Bayard's alleged flawed statistical approach 475 Monsanto contends that Dr Bayard's approach to the animal bioassays was flawed in two fundamental respects: first, that he failed to account for multiple comparisons; and secondly, that he engaged in a pooling exercise which undermined the integrity of the bioassay process. 476 I will deal with each in turn.
Multiple comparisons 477 The multiple comparisons problem arises when a set of statistical inferences are considered simultaneously. The more inferences that are made, the more likely it is that erroneous inferences are drawn. 478 A good illustration of the multiple comparisons problem comes from calculating the family-wise error rate (FWER). The FWER is the probability of drawing at least one false-positive in a family of hypotheses tests. It can be calculated using the following formula: 1 - (1 - p-value) number of tests 479 As I have explained above (at [124]), the p-value represents the probability that a finding was due to chance and is conventionally set at p=0.05 (that is, an assumption that there is a 5% chance of rejecting the null hypothesis when it is in fact true). If a single outcome is tested at a p-value of 0.05, then the assumption that there is a 5% chance of drawing a false-positive inference is true. However, where multiple outcomes are tested, the more likely it is that a false-positive result is drawn. This can be illustrated by increasing the number of tests in the FWER formula: Test Formula FWER 1 1 - (1 - 0.05)1 5% 2 1 - (1 - 0.05)2 10% 3 1 - (1 - 0.05)3 14% 4 1 - (1 - 0.05)4 19% 5 1 - (1 - 0.05)5 23%
480 As seen above, when conducting five tests at a p-value of 0.05, there is a 23% chance of drawing a false-positive result. For 100 tests conducted at p=0.05, the probability of drawing at least one false-positive is approximately 99.4%. In order to correct for the inflation of false-positives, methods such as the Bonferroni or the Benjamini-Hochberg method are often used to adjust the p-value to account for the false-positive error rate (T1766.24-27; T1768.1-12). 481 As would already be obvious, the issue of multiple comparisons is well-known in the field of animal studies given the necessity to evaluate large animal bioassay datasets. As the USEPA Guidelines state (at 2-20): Considerations of multiple comparisons should also be taken into account. Haseman (1983) analyzed typical animal bioassays that tested both sexes of two species and concluded that, because of multiple comparisons, a single tumor increase for a species-sex-site combination that is statistically significant at the 1% level for common tumors or 5% for rare tumors corresponds to a 7-8% significance level for the study as a whole. Therefore, animal bioassays presenting only one significant result that falls short of the 1% level for a common tumor should be treated with caution. 482 Mr McNickle submits that Dr Bayard, consistently with the USEPA Guidelines, took into account the problem of multiple comparisons in concluding that glyphosate more likely than not causes cancer in rats and mice, and that the results of the animal bioassays provide important evidence as to glyphosate's carcinogenicity to humans (T1633.32). 483 These submissions may be summarised as follows. 484 First, as Dr Bayard explained, multiple comparisons should be considered by evaluating consistency, reproducibility and other weight of evidence factors. Dr Bayard did so by treating a statistically significant result as a "signal" to look for consistencies and inconsistencies for that tumour response in other studies (at JRJ [125]; JRH [32]; First Bayard Report (at [46]-[47]); T1643.33-38). For any one tumour site in a study, Dr Bayard conducted his statistical tests and, depending on the outcome, the response was either statistically significant or not. Dr Bayard explained his method in the First Bayard Report (at [47]) as follows: For each study the probability is 1 in 20 that a P<0.05 could happen by chance. Repeating the same process 5 times, once for each study, would result in one P-value <0.05 about 20% of the time, even if there is no true response. Thus, concluding a positive carcinogenic response for a chemical solely on one positive cancer response study out of five would result in declaring too many false positives. However, the probability of 2 chance positive (false positive) responses in the same tumor site from those 5 studies is only slightly more than 2%. So, if I see 2 positive response studies, and three negative studies, in my professional judgement I would initially call that a positive tumor response for that species/strain/sex. I also need to consider the magnitude of the P-value. A highly statistically significant P-value, say P<0.01, has more weight than one that is just statistically significant at P<0.05. 485 Dr Bayard's evidence was that this was method was a statistical method (T1772.37). 486 Secondly, it is said that there is nothing in the USEPA Guidelines which mandates how multiple comparisons are to be accounted for, nor do the guidelines require any statistical adjustment to the p-value. Indeed, the method for accounting for multiple comparisons described in the guidelines (that "animal bioassays presenting only one significant result that falls short of the 1% level for a common [tumour] should be treated with caution") does not involve any adjustment to p-value results. 487 Thirdly, and relatedly, Mr McNickle submits that the aide-memoire (and the documents summarised therein) relied upon by Monsanto (MFI-46A, which excludes reference to documents not tendered which had been previously included in MFI-46 (T2248.37-2249.24)) in support of the proposition that statistical adjustment for multiple comparisons is a well-known issue in the conduct and evaluation of animal cancer bioassay reports should be disregarded by the Court. In short, it is said that first, the documents referred to in MFI-46A do not support that proposition; and secondly, that those documents provide no evidentiary foundation which contradicts Dr Bayard's methodology or its appropriateness. 488 Fourthly, it is said that Monsanto mischaracterised Dr Bayard's evidence about the ways in which multiple comparisons can be taken into account. Contrary to Monsanto's submissions, Dr Bayard did not identify two statistical methods for considering multiple comparisons (the Bonferroni method and the Benjamini-Hochberg correction method) but noted that there are various ways to address the problem of multiple comparisons (T1720.27-41; 1772.31-33). 489 Fifthly, as I noted earlier (at [469]), in the absence of calling Dr Crump to give evidence in Conclave J, Mr McNickle submits that the Court should draw a Jones v Dunkel inference that Dr Crump's evidence concerning multiple comparisons would not have assisted Monsanto's case, and that the Court should more readily accept Dr Bayard's evidence that he did account for the problem of multiple comparisons. 490 When the matter returned for hearing in late January 2024, it became evident that the real point of departure between the parties as to this issue was whether it was necessary for Dr Bayard to have made a statistical adjustment for multiple comparisons, rather than having to account for the issue (in the words of the USEPA Guidelines) (see above (at [481]); T2147.41-2149.43). As Ms Szydzik explained (T2149.32-40): MS SZYDZIK: So, in our submission, the caution that the US EPA guidelines that you need to approach certain results with in order to account for multiple comparisons when analysing the animal bioassays is exactly what Dr Bayard did, and he did that by looking for consistency, reproducibility and other weight of evidence factors, and that was his evidence. His evidence also was that his approach was the common approach in risk assessment. Now, as I've already said, the guidelines don't say that a statistical adjustment is required, Dr Bayard did not say that a statistical adjustment was required, and the respondents have led no evidence to say that statistical adjustment was required. … 491 While I recognise there is some force in the proposition that the necessity to account for the problem of multiple comparisons is a broader concept than the necessity to make a statistical adjustment or correction, when one has regard to the USEPA Guidelines and the evidence as a whole, a laser-like focus on use of the word "account" distracts from the underlying rationale for the existence of recognised methods which address the issue of multiple comparisons. 492 As I explained above (at [478]-[480]), the FWER can be used to illustrate the inflation of false-positives when conducting multiple hypotheses tests. Plainly enough, the inflation of the false-positive error rate is a statistical problem, and properly accounting for that problem necessitates a corrective method which admits of a statistical answer. As the authors of Haseman (1983) (the report referred to in the USEPA Guidelines when discussing the necessity to account for multiple comparisons) note (at 336): It should be emphasized that no rigid statistical decision rule is currently being employed by the NTP in the evaluation of tumor incidence data. Moreover, it is not the purpose of this paper to derive and advocate the use of such a procedure. Nevertheless, to obtain meaningful estimates of false-positive rates, one should base calculations on a statistical procedure whose "statistical positives" correlate highly with tumor increases that are regarded as "biological positives." (Emphasis added) 493 There are several recognised statistical procedures in the literature for correcting the false-positive rate; two of which Dr Bayard recognised (T1768.1; T1772.23-33) (and to which I have already referred (at [480], [488])), being the Bonferroni method and the Benjamini-Hochberg method. The latter was used in the USEPA's "Revised Glyphosate Issue Paper: Evaluation of Carcinogenic Potential" (December, 2017) (USEPA Issue Paper), where it was noted (at 71): … the 2005 EPA Guidelines for Carcinogen Risk Assessment state that "considerations of multiple comparisons should also be taken into account". Multiple comparison methods control the familywise error rate, such that the probability of Type I error (incorrect rejection of the null hypothesis or "false positive") for the pairwise comparisons in the family does not exceed the alpha [p-value] level. In the current evaluation, the Benjamini-Hochberg correction method was used to adjust for multiple comparisons (Benjamini and Hochberg, 1995). (Emphasis added) 494 It follows, having regard to the USEPA Guidelines and its broader context, that in order to account properly for multiple comparisons, it is necessary to undertake a statistical procedure which is capable of correcting outcomes for false positives. Dr Bayard, in my view, did not undertake such a procedure and, accordingly, I am not persuaded that Dr Bayard appropriately accounted for the issue of multiple comparisons. Two observations should be made in this regard. 495 First, Dr Bayard's method, in summary, involved excluding tumours from his analysis that did not have at least one statistically significant value (T1772.31-1773.2). Despite his claim that a similar method was employed in Portier (2020) (T1773.4-26), it did not involve the application of an established or recognised procedure for correcting outcomes for multiple comparisons (such as the Bonferroni or Benjamini-Hochberg method). During cross-examination, I asked whether this approach was reflected anywhere else in the scientific literature (T1773.4-26): HIS HONOUR: Other than Portier, which you've mentioned now on a number of occasions, I'm asking for anyone else other than that - other than that gentleman? DR BAYARD: I probably do. But it's just kind of common type of analyses that you're doing. That people who do risk assessment the way I do, they look by tumour types and they figure out - - - HIS HONOUR: I'm not asking you to explain it. I'm not asking you to explain the method. DR BAYARD: Sorry. HIS HONOUR: You've been asked now several times and I would be very grateful if you would assist me with a direct responsive answer: is it referred to anywhere in the literature? DR BAYARD: I haven't seen this type exactly done in any way. 496 Secondly, whether the method undertaken by Dr Bayard can be classified as a "statistical method", for the reasons above, I do not think much assistance can be derived from it. The process of excluding tumours from the analysis which do not have at least one statistically significant result does not admit of a statistical outcome which can provide information as to: (1) whether that outcome is a false positive; and (2) the probability of obtaining a false positive result. Put another way, Dr Bayard's method does not meaningfully assist in estimating false positive rates because it does not involve any adjustment to the p-value which accounts for the problem of multiple comparisons. 497 This conclusion has caused me to view Dr Bayard's calculations in the animal studies stream with real caution. With that said, in the light of my overall conclusion as to this stream (and for reasons I will come to when assessing the animal studies evidence itself), my overall conclusion would not change even if I was wrong to have found that Dr Bayard did not account properly for the problem of multiple comparisons. 498 Before leaving this topic, however, it is necessary to say something about Jones v Dunkel. 499 During the initial trial, there was some back and forth about the precise reason Monsanto elected not to call Dr Crump to give evidence in Conclave J. From my vantage point, I assumed the reason was obvious and related to the evident personal difficulties he had in giving evidence, but Monsanto was at pains to disabuse me of what they contended was my misapprehension. Indeed, on the final day of the trial, senior counsel for Monsanto, Mr Craig KC, having disavowed any other reason, identified the reason for not calling Dr Crump as follows (T2218.24; referring to T1947.12-21): MR CRAIG: … Having regard to the evidence adduced in conclave H, regarding the tumours and studies relied upon by Dr Bayard, and Dr Bayard's evidence on pooling and multiple comparisons, I don't need to and I'm not going to call Professor Crump in conclave J. 500 I found Monsanto's approach passing strange. Foundational to the consideration as to whether an adverse inference should be drawn is whether there is a reasonable excuse for the failure to call a witness whose evidence would be expected to be adduced by a party. Given the difficulties I had seen unfold before me, a reasonable excuse was obvious. However, in the light of the fact that Dr Crump's earlier difficulties in giving evidence at the trial were expressly disavowed as the reason why he was not called, it seems to me that I must put what I assumed was the reasonable reason to one side. 501 It was open for Monsanto to take a robust view that they did not call Dr Crump in Conclave J because they considered that Dr Bayard concessions adverse to Mr McNickle's case. But this seems to me simplistic: we are dealing with a complex scientific inquiry where there is a degree of prima facie cogency in arguments being put by competing experts. To decide not to call an expert who has been subject of a joint conclave, and has put before the Court apparently reasoned opinions, is no small thing. I think, in all the circumstances, it would be appropriate to conclude the forensic decision by Monsanto was made because a considered view was taken it was in the interests of Monsanto that he not enter the witness box again on the basis that his evidence would not assist its case. An adverse inference should be drawn. 502 I hasten to add, however, that the drawing of a Jones v Dunkel inference cannot be used to fill gaps in the evidence. In all the circumstances, it is of limited utility to Mr McNickle's case in circumstances where Dr Crump's evidence on multiple comparisons could not have made up for deficiencies in Dr Bayard's approach to the animal bioassays.
Pooling 503 Dr Bayard's analysis in the JRH included results which pooled data from the animal bioassays (see, for example, JRH [52]-[53]; Table 4; First Bayard Report (at [102])). As I noted in the first stream (at [122]-[123]), pooled studies can increase statistical precision, provided the studies included in the pool have the same or similar study design. As explained in Gart J, Chu K, Tarone R "Statistical Issues in Interpretation of Chronic Bioassay Tests for Carcinogenicity" (1979) 62(4) National Cancer Institute 957 (at 963): Usually, the control incidences are limited to the laboratory where the compound is tested. If a formal significance test is to be made involving such a "pooled laboratory" control group, it is usually required that the pathologic examination for the control groups and the treated groups be done by, or at least be reviewed in all instances by, the same pathologist. Other aspects of the protocol should be the same or similar for all the control groups to be pooled. These aspects include the length of time on study, the supplier, and the mean birth dates for the animals. Statistical tests of homogeneity among the individual control groups that are candidates for pooling should be done for both the survival curves and the [tumour] incidences. 504 I have not derived significant assistance from Dr Bayard's pooled analyses, for the following reasons. 505 Dr Bayard accepted that there were a variety of differences between the animal bioassays including that they: (1) operated for different durations; (2) operated across different laboratories; (3) involved different generations of CD-1 mice; (4) had different reviewing pathologists; and (4) involved such different doses that a mouse in the high-dose group in one study could in fact be a mouse in the mid-dose or low-dose group in another study (T1722.45-1723.41). For these reasons, Dr Bayard conceded that he did not place weight on his pooled analyses in arriving at his conclusion that glyphosate more likely than not causes cancer in rats and mice. As Dr Bayard said in cross-examination (T1700.10-45): DR BAYARD: Yes. But I don't put - I talked about it in my - in my report that I don't put much weight into pooling because not much has been written on it and because of what it does to the control groups. MR CRAIG: All right. Let's talk about pooling then. When you were preparing your report, you didn't make any evaluation in your report for whether or not the mice in the various studies were fed the same or a similar diet? DR BAYARD: No, I did not factor diet in. MR CRAIG: And you did not do that for the rat studies either? DR BAYARD: No. I basically assumed that the controls were fed the same diet and so the comparison should be against treated versus controlled. MR CRAIG: But when you're pooling you're comparing animals from two different studies, aren't you? DR BAYARD: You're absolutely right. That's why I put no weight on it. MR CRAIG: His Honour should put no weight on pooled studies, should he? DR BAYARD: You can try and see what happens. But I agree that - the problem is that you're really messing up your control groups because they - they just don't have much to compare against. You're pooling controls groups and that's - that - that really contaminates the study. 506 The following was later put to Dr Bayard in cross-examination (T1724.1-10): MR CRAIG: Yes. Thank you. Now - and you accept that pooling studies across laboratories, generations, different pathologists and different operating time periods is a highly unusual procedure, don't you? DR BAYARD: You mean for statistical purposes, the way I did it? MR CRAIG: Yes. DR BAYARD: Yes. I - again I didn't put much weight on it, I just did the analysis so I put it in. 507 For these reasons, I do not consider much can be gained from Dr Bayard's pooled analyses in informing my ultimate conclusion in the animal stream.
II Dr Bayard's alleged limited expertise 508 Monsanto submits that Dr Bayard lacked expertise to conduct a critique of the multi-disciplinary animal bioassays in two respects. The first is that Dr Bayard, who is not a pathologist, was not qualified to challenge the conclusions of the pathologists who conducted the animal bioassays. The second is that Dr Bayard could not give reliable evidence as to how a particular dose exposure to glyphosate in animals translates to human exposures because he is not a toxicologist. 509 As it emerged when the matter returned in late January, the high watermark of this submission (and where Dr Bayard's alleged lack of expertise in pathology and toxicology converged) concerned the distinction between whether Dr Bayard, in forming his opinion as to the animal bioassays, was engaged in an exercise of merely interpreting the results of the animal bioassays, or whether (as Monsanto contends) that exercise involved an assessment of the biological significance (that is, whether the outcome has an effect on the health or survival of a living organism) of a statistically significant result (T2200.13-30). This is important because as Dr Bayard accepted, a "major role" of the pathologist and toxicologist in undertaking an animal cancer bioassay is to assess the biological significance of the findings in the study (a proposition with which Dr Juberg agreed) (T1765.31-46). 510 To the extent that it matters, my impression of Dr Bayard's evidence is that he did occasionally stray outside of his area of expertise and gave firm scientific opinions on topics in which he lacked the requisite qualifications, including the biological significance of statistically significant results in the animal bioassays. This is not to be unduly critical of Dr Bayard: as I said earlier (at [444]), I do not consider that he made any deliberate attempt to obscure the evidence. Most scientists, after all, are not lawyers, and do not approach the task of giving evidence (particularly oral evidence) conscious at all times that their words will be poured over by teams of solicitors and barristers. 511 With that said, it will suffice here to set out one example of where I consider Dr Bayard gave evidence beyond his field of expertise. I will return to other instances when I come to the animal bioassays and Dr Bayard's evidence given in relation to Wang (2019) in Section IV below. 512 Dr Bayard in the JRH (at [57]; Table 5) relied upon figures from Knezevich and Hogan (1983) which had been calculated following a re-examination by a pathology working group (PWG) (T1714.41-1716.4). The PWG reached the opposite conclusion that Dr Bayard had as to causation and whether the tumours the subject of the study were caused by glyphosate, noting (at 24-25): This PWG firmly believes and unanimously concurs with the original pathologist and reviewing pathologist that the incidences of renal tubular-cell neoplasms in this study are not compound related. The following points were taken into consideration in reaching this decision: a) Renal tubular-cell tumors are spontaneous lesions for which there is a paucity of historical control data for this mouse stock. However, clustering can occur and the incidence in this study is comparable to the available historical control range from several laboratories (Appendix B). Since there were 3 treated groups and only 1 control group, there is a greater possibility of more variation from mean control incidences in the treated mice. b) None of the treatment groups differed from the controls by the Fisher exact test at the 0.05 level of significance. Over all groups there was not evidence of a significant linear trend at the 0.05 level by a one-tailed CochranArmitage Test. c) Multiple renal tumors were not found in any animal. d) Compound related nephrotoxic lesions, including preneoplastic changes, were not present in this study. In addition, renal toxicity was not noted in the 3-month subchronic toxicity study reported in December 1979. (Underlining in original) 513 During cross-examination, however, Dr Bayard first sought to challenge the PWG's conclusion that renal tubular cell tumours are spontaneous lesions (T1717.26-39): HIS HONOUR: No. So you disagree with the statement of fact that renal tubular cell tumours are spontaneous lesions? DR BAYARD: From what I've seen of data I do disagree with that. They can also be compound related. HIS HONOUR: I just wanted to understand your evidence. Thank you. DR BAYARD: Thank you. MR CRAIG: You're not an expert of whether renal cell tumours are spontaneous lesions, are you, Dr Bayard. DR BAYARD: I am not an expert on that, that's correct. 514 Dr Bayard then went on to give the following evidence (T1718.1-9): MR CRAIG: And so these views of the reviewing pathologists are important qualifications to any conclusion that these tumours were caused by glyphosate, aren't they? DR BAYARD: There's certainly opinions. MR CRAIG: Yes. Held by those who have expertise that you do not have? DR BAYARD: That's correct 515 Dr Juberg also gave evidence that focus should be placed on the conclusions of the PWG (T1800.1-7). 516 In the light of this evidence, I do not think that Dr Bayard was in a position to substitute his opinion with the findings of the PWG and the reviewing pathologist in relying upon the figures in Knezevich and Hogan (1983) and, accordingly, I do not think much assistance can be derived from it. As Mr Craig submitted, an assessment of the biological significance of the tumours the subject of the animal bioassays cannot be divorced from the expertise that is brought to bear by those pathologists who have actually inspected and evaluated the tumours. Consistently with my approach to the expert evidence as a whole, a proper assessment of the totality of the evidence necessitates engaging with the statistical and pathological conclusions, and the overall coherence of the animal bioassays, to which I will now turn.
III Animal bioassays 517 It is well to note from the outset that in the light of my findings above, I have approached the task of evaluating aspects of Dr Bayard's evidence in relation to the animal bioassays through a somewhat different prism. I use the term aspects advisedly because those specific findings do not constitute a broader finding that the Court, when having regard to the whole of the evidence, should approach the relevant task cautious of placing any weight upon Dr Bayard's conclusions in the animal studies stream as if his credit has been seriously impugned (notwithstanding that in certain respects, it is necessary to be cautious about aspects of his evidence). 518 Where relevant, and in order to aid comprehension, I have explained in the following section how those specific findings bear upon my conclusions with respect to each of the specific tumours Dr Bayard contends were caused by exposure to glyphosate. Further, I should note that several of Dr Bayard's calculations in Conclave H were the subject of corrections, which were set out in a schedule provided to the Court and tendered (which document I will refer to as the Bayard Corrections).
Mice 519 Dr Bayard gave evidence that glyphosate induces four types of tumours in mice, namely: (1) malignant lymphomas; (2) hemangiomas and hemangiocarcinomas; (3) kidney tumours; and (4) lung adenocarcinomas. 520 I will address each in turn.
Rats 573 Dr Bayard gave evidence that it is more likely than not glyphosate causes cancer in rats (at JRH [87]). This conclusion, however, was qualified by his opinion (at JRH [69]) that the evidence of carcinogenicity in rats is "not as strong, or, at least, not as consistent, as it is in mice". 574 With that said, Dr Bayard contended that glyphosate induces three categories of tumours in rats, namely: (1) thyroid C-cell carcinomas and adenomas; (2) liver hepatocellular adenomas and carcinomas (in male rats); and (3) kidney adenomas. 575 I will address each in turn.
IV Wang (2019) 615 This is a study which assumes some importance in the mechanistic evidence stream, and, for that reason, I do not propose to deal with it at any length here. In any event, for present purposes, I can be brief with respect to Dr Bayard's reliance upon it in this stream. 616 Wang (2019) was a 72-week mechanistic study of a VkMYC mouse model for the purposes of assessing the development of MM in humans. Dr Bayard gave evidence that it claimed to provide direct evidence of in vivo mode of action (or mechanism of action) that glyphosate causes increased MM, a cancer that affects B-cells (and a subtype of NHL) (at JRH [45]; JRI [61]), and concluded that the VkMYC mouse is a reasonable model for determining potential carcinogenic effects for glyphosate in humans (at JRI [66]). Mr McNickle submits that Dr Bayard's evidence on Wang (2019) supports the evidence given by Professor Smith and Dr Flecknoe-Brown in the third stream and their contention that glyphosate can cause NHL by causing an upregulation of activation-induced cytidine deaminase (AID). 617 It is not an overstatement to say that the evidence adduced in the third stream revealed some not insignificant methodological problems with Wang (2019). It is unnecessary for present purposes to wade into those problems, to which I will return, because we are here focussed on Dr Bayard's reliance on the study and the extent to which it provides supportive evidence of his thesis as to carcinogenicity. I do not think that it does, for the following reasons. 618 First, as I noted earlier in Section II, Dr Bayard is not a toxicologist. In cross-examination, Dr Bayard accepted that in assessing the reliability or otherwise of the results of Wang (2019), it is a matter for toxicologists as to whether the evidence indicates that glyphosate provides a mechanism of action by which it can cause cancer (T1776.20-1778.1). As the following exchange records (T1630.5-22): MR CRAIG: … are you an expert on the mode of action of glyphosate and I suggest to you that you're not. DR BAYARD: I know what I learned from the Wang study but I - that is the extent of my knowledge on the mechanism of glyphosate. MR CRAIG: I'm going to put it to you one more time. HIS HONOUR: As I understand your evidence - and please correct me if I'm wrong - you accept that, prior to reading the Wang study, that you weren't an expert? DR BAYARD: I did not know anything about that mechanism. HIS HONOUR: And any expertise that you gained you gained from your analysis of the Wang material? DR BAYARD: On the mechanism. That's correct. 619 Dr Bayard later gave evidence that he had no expertise in NHL (T1761.38-41): MR CRAIG: Okay. Dr Bayard, you don't claim any expertise in non-Hodgkin lymphoma, do you? DR BAYARD: I do not. 620 Secondly, Wang (2019) was not a compliant animal carcinogenicity study. Dr Bayard accepted that the study did not comply with the USEPA or OECD guidelines for the conduct of a carcinogenicity study (T1604.1-4). To take four examples highlighted by Dr Juberg: (1) the number of animals per dose group was 10, which is well below the 50 animals per sex per dose group required by the regulatory authorities (see above (at [416])) (at JRH [133(f)]); (2) a singular dose was used instead of the required three, which precludes any ability to assess dose-response relationships for any of the reported effects (particularly for the noted increase in MM) (at JRH [133(b)]); (3) no historical control data on any tumour type or finding was reported by the authors of the study (at JRH [133(g)]); and (4) the use of 1000 mg/L from is approximately 50,000,000 times greater than the Median US surface water concentration of 0.02 ug/L as reported in the study, which "raises serious doubt as to the relevance of this administered dose for humans" (at JRH [133(b)]). 621 I accept Mr McNickle's submission, so far as it goes, that Wang (2019) was not required to comply with the regulatory guidelines because it did not purport to be a long-term animal carcinogenicity or toxicity study (with which Dr Juberg agreed (T1565.37-44)). It does not follow axiomatically, however, that the deficiencies associated with Wang (2019) borne out by the evidence merely "fall away" as a result. The examples I have set out above, among others (to which I will return in the third stream), disclose some significant issues in relying upon it as evidence that there exists a mode or mechanism of action by which glyphosate can cause MM in Vk*MYC mice, which evidence can be extrapolated to the development of NHL in humans. 622 For these reasons, Dr Bayard's evidence with respect to Wang (2019) is of limited assistance.
V Conclave I and the relevance of animal studies to humans 623 As noted above, Conclave I (Animal Studies B) involved Dr Bayard and Professor Prince and concerns the relevance of the animal studies and bioassays to humans. It should be noted from the outset, however, that there is an unavoidable degree of overlap between this conclave and the other streams. This is because, as I have explained earlier (at [420]), although the animal bioassays provide important evidence when assessing the potential carcinogenicity of a chemical in humans, classification of a chemical into one of IARC's categories depends upon an evaluation of evidence from all of the streams in order to assess carcinogenicity overall (at JRI [24], [28], [35], [37]). 624 In the final version of the JRI in evidence (which was the subject of agreed rulings), Dr Bayard gave evidence that if an agent is shown to cause cancer in non-human mammals, it is capable of causing cancer in humans (at JRI [51]). A related question is whether site concordance of carcinogenic potential between animals and humans is pertinent, and to what degree (at JRI [51]). Using the example of malignant lymphoma, Dr Bayard points to site concordance between animals and humans to strengthen the confidence that glyphosate caused lymphomas in animals will also occur in humans (at JRI [86]). As Mr McNickle submits, however, this is not a matter considered in isolation, and there are a range of matters relied on by Dr Bayard in reaching his opinion including Wang (2019) (at JRI [55], [61]). 625 I consider Dr Bayard's evidence to be of limited assistance in demonstrating the translatability of animal bioassays and evidence to humans, for the following reasons. 626 First, it is uncontroversial that the conduct of long-term animal carcinogenicity studies is a feature of the process of seeking registration for the relevant chemical. The utility of such studies differs once a chemical becomes registered and is available for commercial use. That is because prior to that time, the absence of human exposure precludes the ability to conduct relevant epidemiological studies, which attempt to ascertain whether there is in fact a relationship between exposure and cancer in humans. After that time however, it becomes possible to conduct such studies, and the need to rely on long-term animal carcinogenicity studies to predict cancer in humans decreases. 627 As the Agreed Facts record (see Section C above), glyphosate was first registered for use in the mid-1970s and has been available for commercial use for decades. In the time since its initial registration, there have been a multitude of epidemiological studies conducted. Accordingly, there is far less need to rely on the results of long-term animal carcinogenicity studies to predict what effect exposure to glyphosate and/or GBFs will have in humans than prior to its initial registration. 628 Secondly, while I do not consider that Dr Bayard deliberately obfuscated the evidence, in my view Dr Bayard overstated the scientific basis for the presumption that chemicals which can cause cancer in animals can do so in humans. As Dr Bayard noted (at JRI [31]): Agencies that regulate use of these chemicals presume that if they cause cancer in animals, they can also cause cancer in humans. The scientific basis for this presumption is that growth control mechanisms at the cellular level are homologous between species (U.S. EPA, 2005). See comment below by Professor Prince in paragraph 46. Site concordance between species is not a requirement. (Emphasis in original) 629 In contrast to the above passage cited by Dr Bayard: (1) the USEPA Guidelines (at [2.2.2.1.5]) is not concerned with the presumption that "growth control mechanisms at the [level of the cell] are homologous [among mammals]" simpliciter, but in the context of a much narrower issue, namely site concordance; and (2) relatedly, that sentence is prefaced by the USEPA with the words "there is evidence", as opposed to amounting to a scientific presumption. 630 Thirdly, Professor Prince gave evidence (at JRI [46]) as to why Dr Bayard's statement that "growth control mechanisms at the cellular level are homologous between species" (at JRI [31]) is "incorrect and outdated" in the light of various differences between species, which can be summarised as follows: (1) it does not consider the differences in the immune system structure and responses across species; (2) it ignores that genes and gene expression differ across species; (3) it does not consider tumour-predisposing or tumour-protective gene mutations, which vary within and across species; and (4) it disregards variations of epigenetic changes that occur across species. 631 Professor Prince's evidence was not to the effect that animal studies cannot provide any meaningful evidence that could be extrapolated to humans, and I accept Mr McNickle's submission that he gave evidence to the effect that: (1) mice share a great deal of genetic similarities with humans (T305.42-47); (2) the laboratory mouse is a highly effective model for lymphoid malignancies due to its small size and significant physiological and molecular similarities between humans and mice (T308.7-13); (3) animal modelling helps add to the weight of evidence (T308.36); (4) animal models are useful (T309.9-10); and (5) animal models, including the mouse model, has greatly impacted the study of lymphoid cancer, biology and its treatment (T309.12-17). As Dr Juberg noted (T1465.29): DR JUBERG: We - ethically, we can't do cancer studies in humans, but we do the next best thing. We do them in two species - mice, rats - and so that's why we follow them up with required 18-month studies in mice, which is the lifetime of a mouse, two years in rats to mimic the lifetime of a human, which is 70 years. So that's - that's - you know, it's a - you've got different biological layers of organisation. You've got mutagenic gene tox, we talked about chronic toxicity, but then we ultimately go to oncogenicity studies. 632 Notwithstanding the utility of such models generally, it is important to recognise, however, there exist a number of criteria by which an animal model would need to be evaluated in order to extrapolate any findings validly from such a model to humans. As Professor Prince notes (at JRI [56]-[57]): [56] I believe that animal studies do have the theoretical potential to provide reliable data to predict behaviour of GBFs in humans. In other words, if the study methodology is appropriate, it may theoretically be able to demonstrate positive associations. Thus, to reliably predict the effect of GBFs on humans, the animal model must demonstrate high translatability to the human. [57] In my opinion, currently there is no animal model that has demonstrated any meaningful translatability. (Italics in original) 633 Fourthly, as I have noted above in Section IV, Dr Bayard gave evidence that Wang (2019) claimed to provide direct evidence of in vivo mode of action (or mechanism of action) that glyphosate causes MM (at JRH [45]; JRI [61]), concluding that the VkMYC mouse is a reasonable model for determining potential carcinogenic effects for glyphosate in humans (at JRI [66]). I do not propose to rehearse the limitations I have already found with respect to that study in demonstrating the translatability of the findings in relation to the VkMYC model to humans (to which I will return in the third stream), save to reiterate that in the light of those limitations, I do not consider Dr Bayard's evidence to be at all compelling in demonstrating the translatability of the animal studies evidence to humans.
VI Conclusion 634 Having regard to the whole of the evidence before me in the animal studies stream, I am not persuaded that the weight of the evidence in this stream supports the conclusion that glyphosate more likely than not causes cancer in mice and in rats, nor that the results of the animal bioassays provide important evidence as to glyphosate's carcinogenicity to humans. 635 In broad terms, that conclusion follows for three reasons. 636 The first is that Dr Bayard's evidence from the outset was marred by an approach to the animal bioassays which: (1) did not meaningfully assist in estimating false-positive rates because it did not involve any adjustment to the p-value which accounted for the problem of multiple comparisons; (2) included pooled analyses in circumstances where there existed a variety of substantive differences between the animal bioassays (such as different durations and dose-levels); and (3) involved Dr Bayard giving scientific opinions on fields outside of his expertise. 637 As I noted above, these matters caused me to view Dr Bayard's evidence as to the animal bioassays in a different light and noting, where necessary, how those findings affected the relative assistance I derived from Dr Bayard's findings in relation to a particular study. To take two examples: (1) Dr Bayard reached a diametrically opposite conclusion on causation in contrast to the PWG and reviewing pathologist in relation to the findings in Knezevich and Hogan (1983); and (2) considered that Wang (2019) provided direct evidence of in vivo mode of action (or mechanism of action) that glyphosate causes increased MM - both in circumstances where he is not a qualified toxicologist. 638 Secondly, as would already be evident, I have derived limited assistance from each of the animal bioassays (and Wang (2019)) relied upon by Dr Bayard in the light of several limitations which, when viewed collectively, can be grouped into several common categories. It is well to say something about four of them: (1) In relation to each tumour type in rats and mice, most of the studies did not indicate a statistically significant result according to Dr Bayard's predetermined criteria for significance. To take two examples: (a) for malignant lymphomas, it will be recalled that there were no statistically significant findings for male CD-1 mice in the majority of studies (Knezevich and Hogan (1983); Atkinson (1993); and Takahashi (1999)), and for female CD-1 mice, four out of five studies did not satisfy Dr Bayard's predetermined test for statistical significance (the exception being Takahashi (1999)); and (b) for liver hepatocellular adenomas and carcinomas, the only statistically significant result for adenomas in male SD rats was in Stout and Ruecker (1990). Mr McNickle submits that this lack of consistency ought not diminish the overall weight to be placed on the animal bioassays on the basis that the absence of a statistically significant result in one study does not entail that a highly significant result in a second study should be discounted (echoing the submission made in the first stream in relation to Koutros (2019) and Alavanja (2014)) (see above (at [358]-[361])). To repeat, for the purposes of emphasis, my conclusion as to the animal studies (which in due course will affect my ultimate conclusion) rests upon an analysis of the whole of the evidence in this stream. This does not involve weighing the relative strength of the animal studies in isolation but mandates, among other things, an assessment of the consistency of the evidence viewed as a whole. As Dr Bayard explained (at JRH [32]): If a tumour increase is seen in one study of, for example, male CD-1 mice, then, theoretically it should be seen in every study. These animal studies are designed such that the only difference among the four groups in each study is the amount of glyphosate they receive. By comparing individual tumour types within the same species/strain and sex, the multiple studies should allow a good estimate of consistency. However, there are several differences among the studies that limit these direct comparisons. Chief among these are (1) different sources for stocks of animals, (2) genetic drift of the animals' DNA over time, (3) differences in diets among labs, (4) different study dosing levels among labs, (5) different laboratories, and (6) different pathologists' diagnoses. All these contribute to different results. Nevertheless, consistency is the backbone of science and the evaluation of it is primary in my analysis. (Emphasis added) (2) Relatedly, a number of the animal bioassays reported inconsistent results when assessing relative dose levels. This was seen most clearly in Lankas (1981) and Stout and Ruecker (1990) where no correlation between glyphosate and thyroid C-cell carcinomas in female rats was found in relation to the latter study in circumstances where it was conducted at higher doses; and in relation to Sugimoto (1997) in circumstances where other studies conducted at higher dose levels (namely, Knezevich and Hogan (1983)) and lower (Wood (2009b)) revealed no statistically significant occurrences of hemangiosarcoma in mice. (3) A number of the tumours identified by Dr Bayard are not rare in rats and mice. The evidence established, for example, that malignant lymphoma is the "most common spontaneously occurring tumour category in the mouse" and, as Dr Bayard accepted, the most common category of tumour in CD-1 mice (T1655.23-26). Further, with respect to testis interstitial cell tumours, Dr Bayard gave evidence that such tumours are not uncommon in the SD rat (averaging approximately 6.5%). (4) Several of the animal bioassays lacked cross-gender significance. For kidney tumours in mice, for example, there were no incidences in female mice across all of the mouse studies. Further, for kidney adenomas in rats, the result in Enemoto (1997) was not replicated in females, nor any other study for female SD rats. Mr McNickle submits that this is not a reason to reduce the weight of such studies because the absence of a statistically significant result in one sex does not justify discounting statistically significant results in the other sex, given that the USEPA Guidelines specify that tumours in both sexes "adds to the significance of tumour findings" (see JRH [21]). When read in context, however, I do not consider that is a fair reading of the USEPA Guidelines. Although it was not expressly referred to by Monsanto, the USEPA noted in the Issues Paper (at 73) when referring to the relevant passage of the guidelines: Other observations can strengthen or lessen the significance of tumor findings in carcinogenicity studies. Such factors include: uncommon tumor types; tumors at multiple sites; tumors in multiple species, strains, or both sexes; progression of lesions from preneoplastic to benign to malignant; reduced latency of neoplastic lesions (i.e., time to tumor); presence of metastases; unusual magnitude of tumor response; and proportion of malignant tumors (EPA, 2005). (Emphasis and underlining added) 639 Thirdly, in relation to Dr Bayard's reliance on Wang (2019) and his evidence given in Conclave I, I do not consider Dr Bayard's evidence to be of assistance in demonstrating the translatability of the animal studies evidence to humans, primarily for two reasons: (1) notwithstanding the limitations associated with Wang (2019) that were borne out by the evidence, Dr Bayard lacked the requisite qualifications to conclude that that study provided evidence that glyphosate provides a mode or mechanism of action by which it can cause MM and NHL; and (2) despite the utility of animal models generally and the theoretical potential of animal studies to provide reliable data to predict the behaviour of diseases in humans (such as GBFs), as Professor Prince noted, the extrapolation of findings the subject of such models to humans is a different question which necessitates "high translatability" and the application of a number of criteria, including, inter alia, the animal species, dose exposure, and similarities in biological response (at JRI [132]). 640 For the foregoing reasons, on the material before me, I am not satisfied the animal studies evidence supports a conclusion that glyphosate more likely than not causes cancer in mice and in rats, nor that the results of the animal bioassays provide important evidence as to glyphosate's carcinogenicity to humans.
G THE THIRD STREAM: MECHANISTIC EVIDENCE (CONCLAVES A, B AND G)
I Introduction 641 The third stream concerns mechanistic evidence. Broadly speaking, it involves two questions: first, whether the mechanistic studies support a finding that glyphosate and/or GBFs have any of the ten key characteristics of carcinogenicity; and secondly, whether the mechanistic studies support a finding that there is a biologically plausible mechanism by which glyphosate and/or GBFs cause NHL in humans. 642 Before turning to the mechanistic evidence, it is necessary to say something about the methodologies adopted in this stream.
Cancer biology and NHL 643 Conclave A concerned with NHL causation and the field of cancer biology, which may be defined as follows (at JRA [17]): Cancer occurs when cells develop changes that allow them to grow uncontrollably. Our cancer biology researchers are working to understand what causes these changes, how this leads to cancer, and what factors determine the success of cancer treatments. This is leading to better ways to diagnose and treat cancer. Our cancer researchers are discovering: • The changes that make a normal cell become cancerous. • The genes and proteins required for the growth and progression of cancer. • New ways to treat cancer that target molecules essential for the cancer cell's growth and survival. • How to select the best treatment for a person with cancer. 644 Cancer is defined by the National Institute of Health (NIH) as "[a] term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems" and is divided into several subtypes (some of which we have already encountered above), including (at JRA [27]-[28]): (1) carcinomas (which begin in the skin or in tissues that line or cover internal organs); (2) sarcomas (which begin in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue); (3) leukaemia (which forms in blood-forming tissue, such as the bone marrow, and causes too many abnormal blood cells to be made); (4) lymphoma (Hodgkin type and NHL) and MM (which are cancers that begin in the cells of the immune system); and (5) central nervous system cancers (which are begin in the tissues of the brain and spinal cord). 645 Lymphoma is a general term given to blood cancers that develop in the lymphatic system, which is a critical part of the immune system that includes the spleen, thymus, tonsils, adenoids and bone marrow. Lymphatic tissue is also found in the skin, gut and stomach, and brain. The lymphatic system generates specialist white blood cells (lymphocytes) to fight disease and infection (at JRA [55]). The NIH defines lymphoma and its subtypes as follows (at JRA [60]): Cancer that begins in cells of the immune system. There are two basic categories of lymphomas. One kind is Hodgkin lymphoma [(also known as Hodgkin's disease)], which is marked by the presence of a type of cell called the Reed-Sternberg cell. The other category is non-Hodgkin lymphomas, which includes a large, diverse group of cancers of immune system cells. Non-Hodgkin lymphomas can be further divided into cancers that have an indolent (slow-growing) course and those that have an aggressive (fast-growing) course. These subtypes behave and respond to treatment differently. Both Hodgkin and non-Hodgkin lymphomas can occur in children and adults, and prognosis and treatment depend on the stage and the type of cancer. 646 Around 85% of lymphomas are diagnosed as NHL. The remainder are Hodgkin lymphoma (at JRA [61]). 647 In lymphoma, the lymphocyte is altered so that it grows and multiplies uncontrollably and can form a tumour, usually in the lymph nodes (at JRA [42]). Lymphocytes include a number of different cell subtypes, including (at JRA [51]): (1) B-cells (also known as B lymphocytes) which are critical to the making of antibodies that, among other things, target micro-organisms such as bacteria and viruses; and (2) T-cells (also known as T lymphocytes) and NK cells that kill viruses, parasites and cancer cells, and produce cytokines (chemicals involved in messaging in growth of white blood cells and the immune response) which can recruit other cells to make antibodies that target micro-organisms. 648 B-cells and T-cells have receptors which are formulated within the cell to recognise foreign proteins (antigens). These are called B-cell receptors (BCR) and T-cell receptors (TCR), respectively. To make these receptors unique to the thousands of different antigens that a human can be exposed to, these cells undergo a very specific engineering process in the lymph nodes which involves multiple complex gene mutations aimed at giving these lymphocytes antigen-specificity. This is called somatic hypermutation (SHM). These mutational processes go wrong in NHL development: a phenomenon not observed in other cancers (at JRA [56]). 649 B-cells (or B lymphocytes) are also critical in the process of antibody production. Antibodies are a part of the immune system's response to "foreign" invaders like viruses. Antibodies recognise, target and bind to specific proteins (referred to as antigens) expressed on the surface of bacteria, viruses and some cancer cells, and cause the cell's destruction (at JRA [57]). 650 Lymph nodes are found at various points around the lymphatic system and are filled with lymphocytes, being B-cells and T-cells, which act as filtering stations for the lymph fluid. Lymphocytes help protect the body against infection by seeking out and destroying bacteria, viruses, parasites, and fungus. An example is when the body experiences a sore throat: the lymph nodes under the jawbone become swollen and tender because the B-cells and T-cells in the lymph node become activated and multiply in response to the identified virus or bacteria causing the infection (at JRA [58]). 651 NHL arises when developing B-cells or T-cells undergo a malignant change and multiply in an uncontrolled way and without order. These cells also become long-lived. The increasing numbers of abnormal lymphocytes (called lymphoma cells) accumulate and form the collections of cancer cells. These cancer cells initially become a single tumour in a lymph node and usually, over time, spread to other parts of the body (at JRA [59]). 652 NHL, however, is not a single entity: its different subtypes are broadly divided into the following two main groups: (1) B-cell NHL (arising from developing B-cells); and (2) T-cell NHL (arising from developing T-cells or NK cells) (at JRA [62]). There are more than 80 different sub-types of lymphoma currently recognised by a classification system developed by the World Health Organisation (WHO). Five of these subtypes belong to a group of diseases called Hodgkin lymphoma. All other subtypes are commonly grouped together and are called NHL (at JRA [66]). 653 In evaluating the evidence on GBFs and NHL causation, the experts employ three principles (at JRA [32]): (1) over-arching biological plausibility based on what is known of the pathogenesis (that is, the development of a disease and the chain of events leading to it); (2) the current biological experimental evidence (in vivo and in vitro experimental data) that has been proposed that GBFs can cause NHL in humans; and (3) one's interpretation of the clinical relevance of the epidemiological evidence that exposure to GBFs is associated with the development of NHL. 654 As would already be evident, this approach mirrors the weight of evidence approach taken by IARC and most authoritative bodies that perform carcinogenicity evaluation (at JRA [32]). In the context of Conclave A, however, Dr Flecknoe-Brown and Professor Prince are particularly concerned with using the field of cancer biology to: (1) examine the scientific evidence of the biological plausibility based on what is known of the pathogenesis of NHL; and (2) evaluate the current biological experimental evidence (in vivo and in vitro experimental data) that contends that exposure to GBFs can cause NHL in humans (at JRA [33]). 655 Notwithstanding that both Dr Flecknoe-Brown and Professor Prince have some understanding and familiarity with the interpretation of epidemiological studies, they are not experts in the field and defer to the interpretation of such studies the subject of the epidemiological stream (as discussed in Section E.3 above).
Key characteristics 656 Replete throughout the transcript are references to the "key characteristics" (KCs). This was not a reference to those members of the inner bar who appeared in the initial trial and who are His Majesty's counsel, but rather a reference to the ten key characteristics of carcinogenicity. The KCs, to which I will return shortly, aid in our understanding of carcinogenesis (that is, how cancers grow). Carcinogenesis is a multi-step process by which normal cells are transformed into cancer cells by acquiring various properties that allow them to form tumours (at JRB [40]). 657 The "Hallmarks of Cancer" is a concept developed by Hanahan and Weinberg (2000) and is central to understanding carcinogenesis, which comprises eight biological capabilities acquired during the multistep development of human tumours (hallmarks). The hallmarks constitute an organising principle for rationalising the complexities of cancer and include (as of 2011) (at JRB [41]-[42]): (1) sustaining proliferative signalling, (2) evading growth suppressors, (3) resisting cell death, (4) enabling replicative immortality, (5) inducing angiogenesis, (6) activating invasion and metastasis; (7) reprogramming of energy metabolism; and (8) evading immune destruction. 658 Underlying the hallmarks are the following enabling characteristics: (1) genome instability, which generates the genetic diversity that expedites their acquisition; (2) inflammation, which fosters multiple hallmark functions; and (3) creation of a "tumour microenvironment" (at JRB [44]). Although the hallmarks provide a framework as to what is required for a cancer to develop, it is not comprehensive in that the importance of each of the hallmarks will vary across different cancer types (at JRA [46]). 659 The KCs, on the other hand, were developed by IARC in 2015 to support cancer hazard identification and reflect the known properties of established carcinogens (at JRB [47]), as follows: (1) Is electrophilic or can be metabolically activated to an electrophile (KC1); (2) Is genotoxic (KC2); (3) Alters DNA repair or causes genomic instability (KC3); (4) Induces epigenetic alterations (KC4); (5) Induces oxidative stress (KC5); (6) Induces chronic inflammation (KC6); (7) Is immunosuppressive (KC7); (8) Modulates receptor-mediated effects (KC8); (9) Causes immortalization (KC9); (10) Alters cell proliferation, cell death, or nutrient supply (KC10). 660 Whereas the hallmarks are the properties of cancer cells, the KCs are the properties of human carcinogens that induce cancer. Thus, while the hallmarks describe what biology exists in a cancer, the KCs describe the actions of carcinogens that can cause those hallmarks to become acquired. The hallmarks and the KCS are, however, interrelated in that the hallmarks set boundaries for the KCs in biological terms. Indeed, some of the KCs produce effects analogous to the hallmarks (for example, carcinogens that induce genome instability (KC3) can produce this hallmark in both normal and cancer cells, and those that induce immunosuppression produce an effect analogous to cancer cells evading immune destruction by suppressing immune surveillance mechanisms). However, there often is not a one-to-one relationship and it is generally not possible to identify individual relationships between specific KCs of carcinogens and a single hallmark of cancer (at JRB [54]-[55]). 661 In relation to KC1, many chemicals that induce cancer and are carcinogenic to humans are either electrophilic or are converted in the body to electrophiles. Electrophilic substances can bind to DNA directly and cause DNA damage or can bind to the active sites of proteins thereby blocking key biochemical reactions, such as DNA repair. This typically means they are genotoxic (DNA damaging) and/or able to inhibit proteins which maintain the structure and integrity of DNA. Hence, many known human carcinogens possess KC1 and KC2 (and less frequently, KC3). Possession of these KCs indicates that the chemical is very likely to produce mutations in DNA (an inherited change in the sequence of DNA) that may lead to cancer. These mutations may take the form of a single change in the DNA sequence or a change at the chromosome level causing a large change. If these changes occur at the locations of genes controlling cell growth and division then cancer may be initiated or promoted (at JRB [48]). 662 In contrast to these irreversible mutations, epigenetic alterations (KC4) are reversible mechanisms that cause altered gene expression. Epigenetic modifications include methylation of the DNA, modifications of histone proteins which coat the DNA, and differential expression of non-coding RNAs (such as microRNAs) which control how genes are expressed. Many carcinogens induce these epigenetic alterations and therefore possess KC4 (at JRB [49]). 663 For reasons that will assume some importance later, many human carcinogens, including radiation and asbestos, induce a phenomenon known as "oxidative stress". This can lead to damage to DNA and other cell components and the ability to induce it is KC5 (at JRB [50]). 664 The remaining five KCs do not involve DNA. Rather they are properties which increase the likelihood that cells containing mutations, however generated, be it by spontaneous mutation, oxidative stress, viruses, or other chemicals, will divide, proliferate and escape the immune system. Chemicals which possess KC6 will induce chronic inflammation that promotes the growth of small, undetected tumours into larger, more aggressive ones and those which possess KC7 will suppress the immune system and allow tumour cells to escape surveillance and spread. Chemicals which possess KC8 will alter hormone levels and promote the growth of hormone sensitive cancers (at JRB [51]). 665 In relation to KC9, normal cells have a finite lifespan controlled by sections of DNA at the end of chromosomes called telomeres. However, cancer cells can become immortal and do not die unless killed by an outside agent, such as a chemotherapy drug. Chemicals and other agents, such as viruses, may promote this immortalisation process and therefore possess KC9 (at JRB [52]). 666 Finally, with respect to KC10, cancer cells usually divide faster than normal cells; do not undergo programmed cell death; and often have an altered metabolic state that allows them to survive. Chemicals which enhance these processes possess KC10 and will promote the proliferation of cancers cells and tumours in general. 667 The KCs are not a mandatory component in determining the carcinogenicity of a substance but a set of guiding principles which, together with sufficient evidence of cancer induction in humans (usually because of epidemiological studies) can assist in determining whether the substance is capable of causing cancer (at JRB [58]). If, however, the evidence in humans is limited (that is, less than sufficient to determine carcinogenicity) or non-existent (for example, because of a lack of epidemiological studies), then an evaluation of the mechanistic evidence for carcinogenicity becomes important (at JRB [59]). 668 One way to assess this mechanistic evidence is to use the KCs. Since this approach allows the reviewer to identify and assess all the available information in a systematic manner, it has become the method of choice for IARC and other institutions (such as the USEPA's IRIS program[me] and California EPA Proposition 65 committee and is endorsed by the US National Academies of Sciences, Engineering and Medicine) (at JRB [60]). 669 When the epidemiological evidence for carcinogenicity in humans is limited or insufficient, then the evaluation of the mechanistic evidence using the 10 KCs becomes critical, as does the evaluation of evidence from long-term studies in experimental animals. If, for example, there is sufficient evidence of cancer induction in two species of experimental animals, or in multiple studies in one species, combined with strong mechanistic evidence - based on the KCs in exposed humans - then IARC would conclude based on its preamble (a document which describes how it reaches its conclusions and guides all working groups) that the substance was "carcinogenic to humans") (at JRB [60]). Specifically, the relevant sections for IARC evaluation are (at JRB [61]): (1) exposure data; (2) studies of cancer in humans which summarises all of the pertinent epidemiological studies and identifies tumour sites for which there is sufficient, limited, or inadequate evidence of carcinogenicity in humans; (3) studies of cancer in experimental animals; (4) mechanistic and other relevant data; (5) summary; and (6) evaluation and rationale. 670 As Professors Smith and Prince explain, in another scenario, if the evidence for cancer in humans was limited from the available epidemiological studies (that is, there is a positive association, but bias, chance and confounding cannot be ruled out) and the evidence in experimental animals was either insufficient or inconclusive, then the mechanistic evidence based on the 10 KCs can play an important role. If such evidence based on the KCs is considered strong, then the substance would be considered "probably carcinogenic to humans". In other words, the available scientific evidence indicates that such a substance is reasonably anticipated to be a human carcinogen (at JRB [62]). Conversely, the mechanistic evidence can also play a role in downgrading the evaluation of a substance. This would occur if there were little or no evidence for one or more KCs, or if the mechanism of cancer induction in animals is not thought to operate in humans (at JRB [63]). 671 Viewed in isolation, the 10 KCs are not definitive and/or accurate for demonstrating that a substance is carcinogenic. If there is inadequate evidence of cancer in humans and less than sufficient evidence in experimental animals, then even if there is strong evidence for multiple KCs in humans, human cells, or other experimental systems, it can only be concluded that the substance in question is "possibly carcinogenic to humans". This indicates that further study is required before a definitive and/or accurate determination can be made. However, in evaluating the evidence of mechanisms alone, the use of the KCs is a valuable tool (at JRB [64]). 672 Lastly, Professors Smith and Prince emphasise that the interpretation or evaluation of the quality of the scientific data examining the KCs is based on expert judgment. Indeed, as all such evaluations are, different individual or groups of scientists may reach different conclusions regarding the strength of the evidence for each of the 10 KCs. Further, the KCs are not intended to be static, but are likely to evolve over time as knowledge of the biological understanding of cancer and the mechanisms of carcinogenesis improve, and new methodologies of testing the KCs appear (at JRB [65]-[66]).
Mechanistic toxicology 673 In determining whether there is a biologically plausible mechanism by which glyphosate and/or GBFs can cause NHL in humans, mechanistic toxicology plays an important role. 674 As Professor Smith and Dr Juberg note (at JRG [26]), the field mechanistic toxicology aims to understand how a chemical works to exert its effects or cause toxicity at the molecular level. It is essentially the identification and understanding of how a substance works in a living system related to the subsequent expression of effects or toxicity. A toxicological mechanism of action relates to a sufficient understanding of the molecular basis to assist in establishing causality between exposure to a substance or chemical and a specified outcome or effect. 675 Toxicological mechanisms can be identified for numerous toxicological outcomes including carcinogenicity, neurotoxicity, and developmental toxicity. Scientists often design and conduct mechanistic studies which aim to provide insight into possible toxicological mechanisms and these studies can be used in conjunction with other sources of information (for example, laboratory animal studies, human or epidemiological data) to make decisions about the probability of a chemical causing harm to humans (at JRG [27]). Other mechanistic toxicology studies can be designed and conducted to determine if one or more components of a toxicological mechanism can be demonstrated and may increase our insight and confidence in the proposed toxicological mechanism for a chemical or substance (at JRG [29]). 676 While one goal of conducting mechanistic toxicology studies is to probe and further understand toxicological mechanism between exposure and effect (for example, in the present case related to carcinogenicity), this is not always possible and hence a less refined, but nevertheless important priority is to propose a mode of action for tumour induction by a chemical or substance. Mode of action outlines the thought processes involved in making use of mechanistic data in risk assessment in a structured way. In this context, a supported mode of action would have evidence provided by robust mechanistic data to establish a biologically plausible explanation for a particular toxicological outcome (at JRG [30]). 677 The USEPA Guidelines places importance on mode of action for carcinogens, as follows (at JRG [31]): The use of mode of action in the assessment of potential carcinogens is a main focus of these cancer guidelines. Elucidation of a mode of action for a particular cancer response in animals or humans is a data-rich determination. Significant information should be developed to ensure that a scientifically justifiable mode of action underlies the process leading to cancer at a given site. (Emphasis added) 678 Importantly, mechanistic studies can provide evidence for each of KCs. In turn, this evidence can be categorised to determine if it is sufficiently strong to conclude that the chemical or substance possesses that KC (at JRG [32]). As noted above, it is recognised in the field of mechanistic toxicology that the KCs in isolation are not an appropriate and sufficient framework for evaluating and/or determining whether a substance, such as glyphosate and/or GBFs, causes cancers, including NHL. However, in combination with epidemiological studies of exposed humans and long-term cancer studies in experimental animals, they form an important component of the weight of evidence approach (at JRG [48]). 679 Further, all relevant mechanistic toxicology studies, data, and other scientific information which inform carcinogenic potential may need to be considered along with other evidence before rendering a conclusion on the potential for glyphosate and/or GBFs to be capable of causing cancer in humans. Ordinarily, the process involves using the data from the mechanistic studies in combination with data from epidemiological studies of exposed humans and long-term cancer studies in experimental animals. Together they form the components of the weight of evidence evaluation to determine if exposure to glyphosate and/or GBFs is carcinogenic, including as a cause of NHL (that is, an evaluation of the three streams) (at JRG [33]-[35]). 680 Mechanistic studies may include laboratory studies in experimental animals, micro-organisms like bacteria and yeast, cell cultures including cultures of human cells, sub-cellular fractions and purified enzymes and studies using biological markers (biomarkers) of injury in humans. For example, blood can be drawn from persons occupationally exposed to a chemical or substance of interest and the number and types of cells in the blood measured and compared with those levels in a matched control set of unexposed people to see if there are differences. Similar experiments can be performed in experimental animals by exposing them to different doses of the same chemical and measuring the cell make-up of their blood (at JRG [41]). 681 To determine if the chemical damages DNA, multiple different types of tests can be performed, including measures of DNA damage in the white blood cells of exposed humans. Alternatively, simple test systems can be used, such as Salmonella bacteria in a petri dish. One such test is called the Ames test, which allows one to screen for mutations in the DNA of bacteria exposed to a chemical of interest (at JRG [42]). 682 Mechanistic toxicology studies have been consistently used to provide evidence regarding the ability of a chemical or substance to cause cancer, especially regarding the relevance to humans of findings in experimental animals and to screen for the ability of the chemical to cause genotoxicity and mutagenicity. The goal is to gain insight into how a chemical may produce toxic effects. In addition to established types of mechanistic studies, another approach towards understanding toxicological mechanism is to conduct hypothesis-based testing, whereby one is able to develop an a priori hypothesis related to how a chemical may cause a certain effect; properly design an approach to test that hypothesis; and then conduct the study to ascertain whether the hypothesised outcome was realised (at JRG [43]-[44]). 683 The results of these mechanistic studies are then used in conjunction with other sources of information to make decisions about the probability of a chemical's propensity for causing harm to humans, including causing cancer or another toxicological outcome. The weight of evidence approach discussed above is the methodology that it is typically used by both authoritative and regulatory bodies when assessing the relationship between exposure to a chemical or substance and subsequent toxicological outcomes (at JRG [45]).
I Overview 684 The mechanistic evidence stream spanned Conclaves A, B and G and involved the following expert witnesses: (1) Conclave A - Cancer biology (causation of NHL) Dr Flecknoe-Brown and Professor Prince (2) Conclave B - Cancer biology (hallmarks of cancer and key characteristics of human carcinogens) Professor Smith and Professor Prince (3) Conclave G - Mechanistic toxicology Professor Smith and Dr Juberg 685 Several individual reports were prepared by each of the experts for the purposes of this stream, as set out in the table below. For the purposes of Conclave A, Dr Flecknoe-Brown did not prepare an individual report: Report Date Report Topic Expert Report of Professor Smith (First Smith Report) 11 August 2021 Whether mechanistic studies of glyphosate provide the necessary biological plausibility and mechanistic basis for the conclusion that use or exposure to glyphosate and/or GBFs such as Roundup Biactive and Roundup Herbicide can cause NHL. Expert Report of Professor Prince (First Prince Report) 1 February 2022 The relationship, if any, between glyphosate and/or GBFs and NHL and Mr McNickle's prognosis. Expert Report of Dr Juberg (First Juberg Report) 2 February 2022 Evaluation of the mutagenic and genotoxic profile for glyphosate, GBFs, surfactants, and aminomethyl phosphonic acid and to form a scientifically-based opinion on whether these materials possess mutagenic or genotoxic potential and whether they represent potential genotoxic carcinogens. Supplementary Expert Report of Dr Juberg (Second Juberg Report) 16 July 2022 Response to the First Bayard Report (at [141]-[151]) which addresses, among other things, whether it is more likely than not that glyphosate causes cancer in animals and should be considered a human carcinogen. Supplementary Report of Professor Smith (Second Smith Report) 7 September 2023 The significance of the Chang (2023), Alvarez-Moya (2023) and Rana (2023) studies and whether those studies support the conclusion that use or exposure to glyphosate and/or GBFs such as Roundup Biactive and Roundup Herbicide can cause NHL. Further Supplementary Report of Dr Juberg (Third Juberg Report) 10 September 2023 Review and commentary on the Second Smith Reports noting any specific agreement or disagreement with statements in that report.
686 In the following section, to the extent I have not already done so in the preceding streams, I will introduce each of the experts who participated in this stream and make some general observations as to their credit.
Dr Flecknoe-Brown 687 Dr Stephen Flecknoe-Brown is a medical practitioner in the field of haematology and an Associate Professor of Medicine at the University of New South Wales. Dr Flecknoe-Brown was engaged by Mr McNickle. 688 Dr Flecknoe-Brown commenced practice as a haematologist in 1982. Dr Flecknoe-Brown studied at Haileybury College and Luther College and the Melbourne Monash University Faculty of Medicine before commencing residency at the Royal Prince Alfred Hospital. Between 1980-1982, Dr Flecknoe-Brown was admitted as a fellow in the Royal Australasian College of Physicians (RACP); the Royal College of Pathologists of Australasia; the University of California (as a hematology-oncology fellow); and as a research fellow at the Ludwig Institute for Cancer Research Sydney. He holds a number of honours and appointments, including, among other things: a life fellowship in the Royal Society of Medicine and the RACP and a fellowship in the Royal College of Physicians in Edinburgh; and an appointment on the Governance Committee of the RACP and as Secretary of the Regional Medical Specialists' Association. He is also the editor of Common Sense Pathology. Dr Flecknoe-Brown ceased practising as a haematologist in 2020 and currently practises in general medical work. 689 In summary, Dr Flecknoe-Brown's conclusion in the JRA is that it is more likely than not that glyphosate and/or GBFs cause NHL in humans (at JRA [176]). Monsanto contends that the Court should place little to no weight on Dr Flecknoe-Brown's conclusion and opinions, for four reasons: (1) he lacks independence from Mr McNickle (or his solicitors); (2) he lacks the requisite expertise in areas in which he purported to give expert opinion evidence; (3) he failed to disclose limitations in various studies he relied upon; and (4) his treatment of the epidemiological evidence was contrary to the approach of the expert epidemiologists who gave evidence for both parties and were therefore better qualified to give that evidence. 690 Monsanto developed these submissions as follows. 691 First, in relation to his alleged lack of independence, Dr Flecknoe-Brown was initially engaged by Maurice Blackburn as a consulting expert (T118.6-7). It is said that he understood that: (1) the firm was acting for plaintiffs in a class action against Monsanto concerning an allegation that exposure to Roundup caused NHL; (2) understood that Maurice Blackburn was seeking compensation for people in that category (T116.37-38); (3) had already provided advice to another law firm in a class action on this question (T117.3-16); (4) had carried out research to support that advice (T117.18); (5) stated that he "admire[d] Maurice Blackburn and … its mission" (T117.38-42); and (6) understood that at least part of that "mission" was "to achieve the compensation which was going to be sought in the action" (T117.44-45). 692 It is also said that over a number of years, Dr Flecknoe-Brown carried out a variety of tasks which are ordinarily carried out by a consulting expert, as opposed to an independent expert, including, for example, drafting and reviewing pleadings (T121.8-11; T118.13-17; T137.5; T121.24-33) and discussing the forensic debate that would ensue arising out the concept of carcinogenicity (T120.23-24), including the implications of the narrowness or width of what "carcinogenicity" meant (T120.37-39). Further, it is contended that Dr Flecknoe-Brown understood that his role included, among other things, providing advice to Maurice Blackburn concerning evidence that might emerge from Monsanto's experts (T123.30-32) and attended to multiple research tasks given by Maurice Blackburn (T125.4-9; T127.8-15), which are matters that are the kind of tasks ordinarily carried by consulting experts. 693 Secondly, it is contended that Dr Flecknoe-Brown repeatedly omitted from his opinions in the JRA limitations and qualifications that were expressly identified by the authors of the studies on which he relied. For example, Dr Flecknoe-Brown relied upon Donato (2020) in support of the proposition that the epidemiology evidence indicates an association between glyphosate and/or GBFs and NHL in humans in circumstances where the authors of Donato (2020) stated that "we found no consistent indication of an association between exposure to glyphosate and risk of NHL or MM" (at 9) (T162.36-44). In cross-examination, it is said Dr Flecknoe-Brown conceded that this observation applied to the highest exposure categories to glyphosate (T163.12-15) and amounted to the Donato (2020) study indicating that its findings were of no significance (T163.36-38). However, neither Dr Weisenburger (a prior expert who ultimately did not participate in the proceeding) nor Dr Flecknoe-Brown disclosed that limitation (T164.1-5). To take another example, Dr Flecknoe-Brown relied on Paz-y-Mino (2007) in support of his opinion, which he considered was a "fair summary" and "wouldn't modify the wording terribly much" (T206.31-35), but then went on, it is said, to make a series of concessions in relation to it, including, among other things, that: (1) the study does not disclose whether any of the participants developed any sort of cancer at all (T210.19-23); (2) blood sampling from exposed individuals varied from two weeks to two months after exposure, thereby allowing time for confounders to affect the study (T210.25-211.29); and (3) it is unknown whether participants were exposed to other pesticides in the two months after the first group was tested (T211.33-45). I will return to other examples below when addressing the mechanistic evidence. 694 Relatedly, it is submitted that Dr Flecknoe-Brown recited the work of Dr Weisenburger with little to no independence. Dr Flecknoe-Brown generally accepted that the stated basis for his contribution to the JRA as to his belief concerning the carcinogenicity of glyphosate and/or GBFs was the IARC Monograph 2017 (IARC Monograph 2017) and Weisenburger (2021) (T158.44-159.7; T15922-26; T159.34-38; T160.16-34; T169.1-30; T170.18-26; T191.24-40; T203.31-46; T204.5-11; T205.34-37). Dr Flecknoe-Brown gave evidence that the paper "seemed a good guide so that I didn't miss anything" (T195.27-28) and accepted that he assumed Dr Weisenburger's paper was an exercise of objective and impartial analysis (T195.30-38). It is said the significance of this is that, given Dr Weisenburger's history and involvement in glyphosate litigation in the United States (which he acknowledged in his disclosure statement for the article (at 8), Dr Flecknoe-Brown cannot be expected to bring an objective mind to this proceeding. 695 Thirdly, it is contended that Dr Flecknoe-Brown lacked expertise in a number specialised fields relevant to his opinion, namely that: (1) after admission to the College of Physicians, Dr Flecknoe-Brown has undertaken no higher research study (T112.32-33); (2) none of the research he has undertaken has concerned the causes of NHL (T113.10; T114.40-43; T115.3-5); (3) none of his research activities have involved examining the relationship between glyphosate, GBFs and NHL (T114.42-43); (4) he has never published a paper on the causes of NHL, or the relationship between glyphosate and cancer (T114.29-33); (5) research has not comprised a large proportion of his professional work (T114.45-47); (6) his publication record only contains four publications that relate to NHL; (7) he does not consider himself to be an expert in epidemiology (T115.21-23); (8) he has not trained in toxicology and would not describe himself as a toxicologist, but says he has a working knowledge of toxicology concepts (T115.25-30); and (9) he has never conducted a micronucleus assay (T218.23-26). 696 As to the approach Dr Flecknoe-Brown took in making his contribution to the JRA, it is said he conceded first in giving the overview of epidemiology (at JRA [178]-[179]), he had only reviewed the individual epidemiology studies "in the generalist perspective" because he said, "I don't think I'm qualified to interrogate them in detail" (T191.15-16); and secondly, when expressing his opinion concerning the USEPA's treatment of the animal bioassays (at JRA [184]): (a) he was not qualified to express a view about the efficacy or methodological security of any animal studies as an expert (T200.25-28); and (b) he had not reviewed the same data that the USEPA had reviewed (T200.30-32). 697 Fourthly, it is contended that Dr Flecknoe-Brown's approach to the epidemiology evidence was misguided. It is said that his treatment of the epidemiology evidence concerning glyphosate and/or GBFs (at JRA [178]-[179]) was contrary to the approach taken by AP Harris and Professor Checkoway in that it was solely reliant on meta-analyses and conceded that he would accept their views about the utility of meta-analyses (T193.4). 698 Although I did not find all aspects of Dr Flecknoe-Brown's evidence persuasive, in my view, I think he did his best to provide assistance to the Court. 699 As Monsanto notes, prior to Dr Flecknoe-Brown's engagement, I had expressed some preliminary concerns that in the light of his previous consulting work, Dr Flecknoe-Brown may not bring an independent mind to the task of giving expert evidence in this proceeding (see, for example, T40.18-19; T40.31-33; T40.42-46; T41.15-20 (Case Management Hearing, 3 August 2022)). Notwithstanding those preliminary views, as I noted earlier (at [32]-[33]), the mere fact that an expert has expressed an opinion in this case which aligns with a previously held opinion on the same issue is not a complete nor satisfactory basis for the Court to reduce the weight to be afforded to the expert's opinion evidence, let alone reject its admission. It would be an error to allow a rigorous attempt to uncover alleged motivations of an expert as directing attention away from an assessment of the overall substantive merits of the witness' evidence. 700 Although the circumstances of his retention and the fact that Dr Flecknoe-Brown had been involved in making minor amendments to the pleadings are less than ideal, in the end I think that Dr Flecknoe-Brown tried to live up to his obligations under the Expert Witness Code of Conduct as best he could. Moreover, I do not accept Monsanto's submission that his failure to highlight various limitations identified by the authors of studies he relied upon (such as Donato (2020) or Paz-y-Mino (2007)) as conduct deliberately aimed at obfuscating the scientific evidence. The principal reason for this, having had the benefit of seeing this evidence unfold, is that notwithstanding that he occasionally demonstrated a degree of reluctance, Dr Flecknoe-Brown made appropriate concessions, particularly when certain matters were outside of his area of expertise. It will suffice to note two examples. 701 The first is that in relation to Bolognesi (2009), a study relied upon by Dr Flecknoe-Brown, the authors noted that "[t]he smaller number of subjects recruited in this study and small amount of information about the exposure precluded any conclusions. Many pesticides are used in conventional agriculture in Colombia and many pesticides are used in the production of coca … however, there is not sufficient information to correlate the frequency of MN to the pesticide exposure" (at 544). Although Dr Flecknoe-Brown omitted that qualification in the JRA, he conceded, inter alia, that: (1) he would not place his expertise above that of the authors themselves (T220.29-35); (2) he went further than the authors themselves were prepared to go (T232.35-38); and (3) he was not familiar with the other agricultural chemicals used in South America (T233.27-28). Dr Flecknoe-Brown later gave evidence that he should have referred to these qualifications in the JRA (T241.1-14): MR FINCH: Well, it wasn't really the best you could do, was it? You left out important qualifications. PROFESSOR FLECKNOE-BROWN: That's correct. MR FINCH: And you substituted your opinion for those of the authors. PROFESSOR FLECKNOE-BROWN: My independent assessment, yes. MR FINCH: But that's not the best you can do to give a fair assessment of the data, is it? PROFESSOR FLECKNOE-BROWN: If - yes, I agree that strengths and weaknesses are best included in reports and qualifications should be acknowledged. 702 The second is that in relation to the overview given of the epidemiology studies (at JRA [178]-[179]), Dr Flecknoe-Brown conceded that he only gave an overview in a "generalist perspective" and "[was not] qualified to interrogate them in detail" (T191.15-22). Later, when the opinion of AP Harris and Professor Checkoway was put to Dr Flecknoe-Brown concerning the utility of meta-analyses and the consistency of the epidemiology studies, Dr Flecknoe-Brown deferred to their assessment, noting (T193.1-4): MR FINCH: … Now, putting it bluntly, you would accept the views of the expert epidemiologists, wouldn't you, about that? PROFESSOR FLECKNOE-BROWN: They're the experts, yes. 703 For these reasons, I do not consider that Dr Flecknoe-Brown came to this trial with a fixed view, intent on avoiding concessions adverse to Mr McNickle's case theory. Overall, my impression is that he is a knowledgeable and highly experienced clinician who conscientiously sought to assist the Court. That is not to diminish the reality, however, that a combination of his lack of expertise in certain areas and omission of various limitations in the studies he relied upon in the JRA has rendered aspects of his evidence unsatisfactory. 704 I will return to these issues when addressing the mechanistic evidence below.
Professor Prince 705 I have already introduced Professor Prince in Section II above and noted that Mr McNickle made extensive submissions as to why the Court should have significant concerns about his evidence. In summary, Professor Prince gave evidence in support of his conclusion that he was not satisfied that exposure to GBFs increases the risk of NHL in humans or can cause an individual to develop NHL (at JRA [267]). Professor Prince also expressed the opinion that he does not believe that there is a biologically plausible mechanism by which GBFs could cause NHL (at JRA [207]; JRB [118]). 706 Mr McNickle's submissions may be summarised as follows. 707 First, Professor Prince gave untrue evidence in relation to the joint reports he had reviewed for the purposes of the initial trial. On 6 September 2023, Professor Prince gave evidence that the only joint report that he had been given, other than those of which he was a joint author, was the JRG, whereas the true position, it is said, was that two weeks earlier, on or around 23 August 2023, he had been given a folder which included two other joint reports of which he was not a co-author, being the JRC and JRH, both of which he had read to differing extents (T309.26-45). Mr McNickle contends that that evidence casts a pall of unreliability over Professor Prince's evidence and raises doubts as to his independence. 708 Secondly, approximately three weeks before the initial, Monsanto's solicitors (Freehills) provided Professor Prince with a table which set out experimental concerns that Dr Juberg had expressed in the First Juberg Report and in the JRG in relation to Paz-y-Mino (2007) and Bolognesi (2009) (Juberg Table). Professor Prince also attended a meeting with Freehills in August 2023 at which time there was a discussion about those studies (T528.35-43). Mr McNickle contends that the provision of the Juberg Table to Professor Prince, less than one month before the start of the trial, at the very least, created a significant risk that his opinions about Paz-y-Mino (2007) and Bolognesi (2009) would be inappropriately influenced by having been informed of what another one of the Monsanto's experts had said about those studies in another conclave. 709 It is said that this risk materialised when Professor Prince gave evidence and made the same (or very similar) criticisms of those studies, despite Professor Prince not expressing such criticisms in his written reports. To take two examples: (1) Professor Prince made the same criticism of Paz-y-Mino (2007) that Dr Juberg had made relating to sample collection and processing having occurred at different times, as acknowledged by Professor Prince (T210.38-211.16; T533.31-37); and (2) Professor Prince made the same criticism of Paz-y-Mino (2007) that Dr Juberg had made relating to individuals who were the subject of the study possibly having been exposed to pesticides other than glyphosate, as acknowledged by Professor Prince (T540.34-39). 710 Thirdly, when asked whether he had been given any other tables drawing his attention to various aspects of evidence given in other conclaves, Professor Prince stated: "the only other table that I've ever been given was the one … about the discrepancies of the quotations, et cetera, between what I had written and what needed to be … clarified" (T541.33-36). It is said that evidence was incorrect. Professor Prince was shown another document prepared by Freehills entitled "Studies to Show Prof Prince from Applicant's Opening Submissions", followed by the exchange (T571.17-23): MR CLEMENTS: Thank you, your Honour. Professor, having now seen that document, does that refresh your memory that, in fact, you had received more than two tables? PROFESSOR PRINCE: Yes, it is. It's formally a table. Yes. I misrepresented because I didn't think of this as a table. 711 Fourthly, it is said Professor Prince gave inconsistent evidence about whether he had looked for EZH2 in Table S3 of Lohr (2012). In cross-examination, Professor Prince gave evidence that he was not able to find EZH2 in that table (T409.35-38), which was consistent with a note he had provided to Freehills during the initial trial (T187.29-47). However, Professor Prince later gave evidence that he was able to find EZH2 (T413.42-47). Professor Prince gave evidence (T415.13-36): HIS HONOUR: Sorry, can I just ask a question. I just want to understand Professor Prince's evidence because it may be - I will have a look at the transcript. But I had thought you earlier said that, when you looked at the table, you couldn't find any reference to EZH2 and that led to your chain of reasoning. Now, that was part of your chain of reasoning. But I think in response to a question - the last question you were asked you said you did look at the table and did find EZH2 or I'm just wondering - did I misunderstand your evidence? PROFESSOR PRINCE: So I wasn't able to fully explain but it's about the numbers of genes. So - - - HIS HONOUR: No. No. No. I'm just asking you, when you looked at the table - - - PROFESSOR PRINCE: Yes. HIS HONOUR: - - - for the purposes of preparing, did you find EZH2 or did you not find it? PROFESSOR PRINCE: In that table, yes, I did. 712 Fifthly, it is contended that Professor Prince made a substantial change to the JRI on the eve of the initial trial when prompted by Monsanto's solicitors. In a series of email exchanges between him and Freehills on 1 September 2023, Professor Prince agreed to amend the statement (at JRI [78]) that "… it is recognised that increased expression of AID always leads to more mutations" to "it is recognised that increased expression of AID does not always lead to more mutations" (emphasis added). In cross-examination, Professor Prince gave evidence (T373.3-34): MR CLEMENTS: … but there has been no relevant change in the science between the time you signed off on the joint report in December 2022 and the time of this email exchange last Friday, has there? PROFESSOR PRINCE: No. MR CLEMENTS: The only thing that has changed is that - and this isn't your fault - the only thing that has changed is that the respondent's solicitors have done an exercise in trying to establish if there's any inconsistencies between your first report and your second to try to assist their defence in this case; that's true, isn't it? PROFESSOR PRINCE: Yes. Because both statements are true. It will be - it can always and it can not always, depending on the situation - and depending on the situation it's working in under, whether it's working in under an abnormal scenario, so for the layman as terms, an increased in AID is considered as just an increase in AID but when we're thinking about its capacity to - to be translated and then produce functioning AID, they're two different scenarios and that's all that I was trying - that we discussed in the two different situations. In the Conclave we were talking about the normal situation of AID. MR CLEMENTS: Well, you didn't qualify it like that in paragraph 78 of the Conclave, did you? PROFESSOR PRINCE: No, I didn't. No. 713 Mr McNickle submits that Professor Prince's evidence "both statements are true …" and his readiness to accept the amendment to the JRI should diminish his reliability as an expert witness. 714 Sixthly, it is contended that Professor Prince gave argumentative and inconsistent evidence concerning whether smoking increases the risk of follicular lymphoma (FL) (a type of NHL). Professor Prince was cross-examined in relation to a paper he co-authored with Odutola et al in 2022, which paper concluded "the totality of these epidemiological findings implicates tobacco smoke as carcinogenic for FL" (at 18) (T318-321). It is said that Professor Prince refused to admit in cross-examination that persons with a history of smoking tobacco had an increased risk of FL, noting that "I just don't know if smoking causes - is associated with follicular lymphoma" (T318.27-31; T319.33-43), but later conceded that when he signed off on Odutola (2022) as co-author, he was satisfied that the risk of FL increases with both smoking and pesticide exposure (T327.5-9). Mr McNickle submits that Professor Prince's refusal, a short time earlier in cross-examination, to accept smoking increases the risk of FL reflected poorly on his reliability and credibility as a witness. 715 It is fair to describe Professor Prince as someone uninhibited by any discernible self-doubt. His overweening confidence in the correctness of his opinions was manifest in his presentation in the witness box. He was adamant that he was right in asserting that glyphosate does not cause NHL. 716 Although this assertive approach was somewhat disconcerting, it is perhaps unsurprising for two reasons. 717 The first is that in his role as Professor/Director of Molecular Oncology and Cancer Immunology, Professor Prince is often responsible for difficult life and death decisions in the treatment of cancer patients. It is not to stretch unduly the bounds of s 144 EA to observe that is a role and clinical culture which necessitates eschewing indecisiveness and equivocation. The second is that as Monsanto's "star" expert witness in the proceeding, having participated in three of the ten expert conclaves, and in the light of his qualifications and extensive clinical experience and research on NHL, Professor Prince considered himself one of the most authoritative voices on NHL causation in Australia. I mention these matters not because I have placed more or less weight on Professor Prince's opinions as a consequence, but because it goes some way in explaining some of his answers given in cross-examination and general demeanour in the witness box. 718 With that aside, subject to a matter to which I will return shortly, I have some difficulty accepting Mr McNickle's submissions as to Professor Prince's credit. 719 The bulk of Mr McNickle's submissions above can be broadly categorised as allegations seeking to impugn Professor Prince's credit on the basis he knowingly misrepresented that he had (or had not) been provided with certain material, or that he had (or had not) read certain material in advance of giving evidence (see above (at [707]-[713])). 720 I do not regard these submissions as helpful. Apart from distracting from the substantive merits of the evidence, there may be several explanations for Professor Prince: (1) giving evidence as to the joint reports that he had (or had not) read prior to the trial; (2) reviewing material prepared by another expert witness prior to the trial; (3) giving evidence as to whether what he had read constituted a "table" or not; (4) giving evidence as to whether EZH2 was found in Table S3 of Lohr (2012); and (5) giving evidence as to opinions previously expressed in journal articles he co-authored - chief among them being mere inadvertence. This is not to exclude the possibility that Professor Prince did give incorrect evidence as to one or more of these matters, but I am not satisfied on the evidence that they are explicable for a reason other than a lapse of memory or inadvertence. In any event, insofar as Professor Prince had regard to the analyses of other experts in the proceeding, he was entitled to do so for the reasons I have explained earlier with reference to Karpik v Carnival (see above (at [62])). 721 The only remaining matter which gave me some pause was Professor Prince's amendment to the JRI (at [78]) at the eleventh hour. Although not directly relevant to this stream, I consider it was more than a mere oversight for Professor Prince to have approved the initial wording of the JRI and not to have qualified his subsequent amendment to the JRI with the explanation adduced from him in cross-examination (see above (at [712])). 722 With that said, and notwithstanding my observations as to Professor Prince's general demeanour in the witness box, my overall impression is that Professor Prince approached the task of giving evidence with integrity and attempted to assist the Court. As will be seen, when pressed on his evidence, Professor Prince made some (albeit grudging) concessions, and his tendency to engage in long-winded answers was largely a product, in my view, of a genuine attempt to explain his strongly held opinions in the JRA, JRB and JRG and the scientific evidence, rather than stray into the role of an advocate for Monsanto.
Professor Smith 723 Professor Martyn Smith is a Professor of Toxicology and holds the Kenneth and Marjorie Kaiser Chair of Cancer Epidemiology in the School of Public Health, University of California at Berkeley. Professor Smith was engaged by Mr McNickle. 724 Professor Smith holds a Bachelor of Science in Biology from Queen Elizabeth College, University of London (1977) and a PhD in Biochemistry from the Medical College of St. Bartholomew's Hospital, London, England (1980). His PhD research involved studies of oxidative drug metabolism using quantitative cytochemical and biochemical methods. Professor Smith performed post-doctoral research on mechanisms of toxicity in the Department of Toxicology at the Karolinska Institute, Stockholm, Sweden (1980-1981) under the supervision of Professor Sten Orrenius, before returning to the University of London in 1981 to teach the first combined Bachelor of Science degree course in toxicology and pharmacology offered in the United Kingdom. As of the date of his first report, Professor Smith teaches toxicology classes in "Health Risk Assessment and Regulation" and "Riskscapes and Environmental Justice" to approximately 20-30 graduate students each year and supervises the research of undergraduate and graduate students and post-doctoral fellows and participates on thesis committees. 725 Professor Smith has been a full professor since 1992 and has been employed at Berkeley since 1982. Previously, Professor Smith held the titles of Assistant Professor (1982-1987) and Associate Professor (1987-1992). Between 1993-2003 and 2007-2010, Professor Smith served in the rotating positions of head and deputy-head of the Division of Environmental Health Sciences. From 2003-2005, he served as Chair of the Faculty in the School of Public Health and, from 2012-2014, served as Director of the Berkeley Institute of the Environment. Professor Smith is also Director of the Superfund Research Centre at Berkeley (a position held continuously since 1987). Professor Smith holds several awards, including as a Fellow of the American Association for the Advancement of Science and as a member of the Collegium Ramazzini, an independent international academy comprised of 180 internationally renowned experts in the fields of occupational and environmental health. Professor Smith is also a member of the editorial boards of the journals Cancer Epidemiology, Biomarkers and Prevention, Exposome and Cell Biochemistry and Function and has previously served on the board of several other peer-reviewed journals. 726 Professor Smith's conclusion in the JRB and JRG, in summary, is that there exist biologically plausible mechanisms by which use of or exposure to glyphosate and/or GBFs can lead to the development of NHL (at JRB [169]), and that glyphosate and/or GBFs are genotoxic, mutagenic, and genotoxic carcinogens (at JRG [93]). 727 Monsanto devoted some time developing submissions as to why the Court should find that Professor Smith was not an independent witness. In short, it contends that in the light of his professional background, Professor Smith is a "hired gun" for plaintiff law firms pursuing litigation concerning the alleged carcinogenic effects of glyphosate. 728 Regrettably, it is necessary to descend into some detail concerning this allegation. 729 First, Monsanto submits that Professor Smith has extensive experience working in plaintiff-litigation. It is said Professor Smith has been involved in litigation as an expert for 40 years (T1276.26-28); has given depositions in hundreds of items of litigation in the United States (T1276.33-34); testified in court between 15-20 times (T1276.30-31); and has been retained by over 100 law firms in the United States (T1276.40-41). All those items of litigation have involved a substance of some kind or medical product (T1276.36-38). Since 1998, he has only given evidence for plaintiffs (T1276.43-45). Professor Smith first received money for glyphosate litigation in February or March 2016 from the US law firm, Andrus Wagstaff (T1277.1-3). He first acted as a consultant to Andrus Wagstaff before his role was changed into a "testifying" witness (T1284.12-16). Professor Smith has given evidence by deposition or at trial in four different glyphosate proceedings in the United States over a total of eight days between September 2018 and May 2023 (T1277.5-10) and has spent at least 300 hours liaising with lawyers based in the United States on glyphosate litigation (T1278.10-18; T1317.15-17). 730 Secondly, it is contended that Professor Smith is motivated by a desire to defend IARC and his colleagues, being a member of IARC's Scientific Advisory Board between 2010-2014 (T1278.26-27). He was also an editor of the IARC publication known as Molecular Epidemiology Principles and Practice in April 2012 (T1278.29-31); was a speaker and presenter on KCs at an IARC conference in June 2016 (T1278.33-37); was a speaker and presenter at IARC in September 2018 (T1282.14-24); was a co-author of several articles, papers or presentations that appear in IARC publications (T1282.26-27); and has served on IARC Working Groups (T1282.29). Against this background, it is said Professor Smith conceded that a reason underpinning his decision to become a testifying witness in glyphosate litigation was that he was "annoyed" by what he regarded to be an attack on IARC and its scientists so that he felt he should step up and act as a testifying witness (T1284.18-25). 731 Thirdly, Monsanto contends that consistently with that motivation, Professor Smith has propagated a number of allegations about Monsanto. It is said that during the time that Professor Smith was engaged as a testifying expert for plaintiffs in glyphosate litigation in the United States, he used his Twitter account to re-tweet serious allegations against Monsanto. For example, on 18 January 2019, he re-tweeted an allegation that Monsanto had engaged in improper practices in briefing journalists (T1284.37-1285.31) and, on 17 January 2019, he re-tweeted a further message disparaging Monsanto because he "wanted to support IARC and the IARC Working Group" (T1286.23-25). On 27 January 2019, Professor Smith re-tweeted a message by Dr Chris Wild disparaging of Monsanto (T1286.30-1287.12), and by doing so sought to demonstrate his support for Dr Wild and IARC (T1287.14-15). On 3 June 2019, he re-tweeted another aspersion about Monsanto (T1287.20-1288.29), allegedly because "I just wanted to make people aware of the article" (T1288.41-42). 732 Fourthly, it is said that Professor Smith prioritises defending IARC over scientific candour. Professor Smith accepted that, in the pursuit of scientific accuracy, publishers should have processes in place to address conflicts of interest (T1279.7-8). When asked whether an agency dedicated towards scientific candour should disclose studies that the agency is aware of that do not support a particular conclusion, Professor Smith at first gave a non-responsive answer (T1279.22-24), then said "it depends on the agency" (T1279.26-28), then conceded "generally, I agree with you agencies should do that" (T1279.28), and then, it is said, conceded more definitively "[y]es. Generally yes" (T1279.34-36). When asked whether it was desirable in the pursuit of scientific knowledge that draft reports and revisions of draft reports by agencies be made available for public comment to obtain the benefit of comments from experts outside an organisation, Professor Smith said, "[m]aybe in some circumstances, yes" (T1280.36-39). Monsanto submits that contrary to these concessions, Professor Smith was a signatory to a letter submitting that IARC funding should not be made contingent on adopting a review process in which drafts and revisions were publicly available online (T1281.19-22), a proposal to introduce a process to address conflicts of interest at IARC (T1281.34-40), and providing summaries of studies that did not support the agency's conclusions (T1282.4-12). 733 Fifthly, Monsanto contends that Professor Smith is a supporter (and benefits from) toxic tort suits in the United States. Professor Smith was a co-founding member of an organisation in the known as the Council for Education and Research on Toxics (CERT), together with others including Mr Raphael Metzger, who brings toxic tort lawsuits (T1292.32-43). The activities of that organisation included the filing of toxic tort lawsuits (T1292.45-47). Professor Smith has been allegedly hired as an expert in proceedings commenced by CERT (T1293.7-9), including proceedings regarding chemicals created when making potato fries (T1293.7-9) and proceedings against Starbucks (T1293.11-12). CERT has given more than $150,000 to advance research topics of Professor Smith's interest (T1293.14-21). 734 Sixthly, it is submitted that Professor Smith withheld from the Court important limitations on studies upon which he relied. Professor Smith accepted under cross-examination that "in the event and to the extent that [a] study was demonstrated [to have] limitations, then the conclusions must also be modified to that extent" (T459.3-7; T500.11-16); that "it was important to draw to the Court's attention not only the findings that might establish whether or not glyphosate and [GBFs] were carcinogenic but what the limitations were on that hypothesis" (T1314.10-13); that "studies done with unreliable methods or design deficiencies must be given less weight" (T1327.17-21); that an important consideration when assessing the quality of studies is whether the study accounts for important confounding and modifying variables (T1328.23-36); and that a good quality mechanistic toxicology study is one that is designed to account for confounding variables (T1329.8-11). However, it is said the evidence demonstrates that Professor Smith omitted from his evidence fundamental limitations and qualifications that were often expressed in the direct terms by the authors of the studies on which he relied. Monsanto refers to a number of examples in its submissions to which I will return in the context of addressing the mechanistic evidence below. 735 Seventhly, it is said Professor Smith has approached this proceeding with a fixed view from his involvement in glyphosate litigation in the United States. Professor Smith accepted that, in the process of giving evidence by way of deposition in 2018 in glyphosate proceedings, he had reached the view that glyphosate and/or GBFs were carcinogenic (T1316.10-11). He expressed that view in 2018 (T1316.17-18) and maintained that view at the time he was retained by Maurice Blackburn to give evidence in this proceeding (T1316.20-21). He confirmed that he had a firm view about the carcinogenic nature of glyphosate at the time he was retained as an expert in this proceeding by Maurice Blackburn (T1316.27-31). Monsanto submits that although he asserted that he always held an open mind, Professor Smith's approach to giving evidence suggests otherwise, and questions put to him in re-examination did not elicit any explanation that would allow the Court to understand what, if anything, would have changed his mind as to the carcinogenicity of glyphosate. 736 Based on the conduct described above, Monsanto submits that the Court should find that Professor Smith was determined to act as an advocate for Mr McNickle. In the alternative, Monsanto contends that Dr Juberg's opinion should be preferred to Professor Smith's in the third stream. Those submissions may be summarised as follows. 737 First, it is said Professor Smith failed to carry out any thorough review of the mechanistic studies despite propounding the KCs typology on the basis that it enables a systematic review of the studies to be undertaken (First Smith Report (at [74])). Professor Smith accepted in cross-examination "that the question of whether or not glyphosate and glyphosate-based formulations cause cancer needs to be assessed by reference to the full set of reliable and relevant studies" (T1321.14-18). He also accepted that "mechanistic toxicology studies on a single substance may be numerous and diverse" (T1325.4-7) and "often report on a multitude of end points and toxicity pathways" (T1325.9-12). 738 On several occasions, however, Professor Smith conceded that he had identified peer-reviewed studies that purported to show a positive association between glyphosate and five of the KCs without attempting to examine basic features of those studies that are well-accepted to define the reliability of the study. To take one example, Professor Smith placed significant weight on the three human biomonitoring studies concerning genotoxicity even though each of those studies was carried out on populations who lived among illicit cocaine crops (T1294.38-39), and even though Professor Smith had not looked at the issue of whether cocaine is genotoxic (T1336.46-1337.1). Professor Smith also admitted that Paz-y-Mino (2011) did not control for drug use (T1339.9-25). 739 Secondly, and relatedly, it is said that Professor Smith included in his analysis studies which he ought to have rejected as bad science. Professor Smith, for example, identified Geier (2023) for the first time in this proceeding when giving oral evidence in Conclave B (T512.5-14, T1298.46-1299.8). Professor Smith described the paper in terms (T512.9-14): PROFESSOR SMITH: … there is a recent paper correlating the levels of glyphosate in the urine as measured in the American and Hayne study, which is an American study of large numbers of people throughout the US, and they've correlated lower oestrogen levels being present in people with high levels of glyphosate in their urine. 740 Professor Smith accepted in oral evidence that he relied on that study despite knowing that Dr Geier had been suspended as a licensed medical practitioner (T1299.32-33); that Dr Geier falsely claimed to be a board-certified geneticist and a board-certified epidemiologist (T1299.41-42); that he "generally was aware of the controversies surrounding Dr Geier" (T1299.44-45), and that "Dr Geier was a controversial physician" (T1302.25). Monsanto submits that Professor Smith did not seek to bring any of those matters to the attention of the Court when identifying Geier (2023) as scientific evidence on which the Court should make findings in respect of KC8 (T1300.1-5; T1302.35). 741 Thirdly, Monsanto submits that Professor Smith drew conclusions beyond what was available from the evidence and in such a way consistently to support Mr McNickle's case. In his first report (at [138]), Professor Smith cited a number of studies for the proposition that "multiple laboratories [had found] that glyphosate and/or GBFs, including Roundup, alter the make-up of the gut microbiome in several species and cause extensive inflammation". However, it is contended that those studies provided no basis for a conclusion that there is any evidence (let alone evidence from "multiple laboratories") that glyphosate and/or GBFs cause "systemic chronic inflammation". 742 Fourthly, Monsanto repeats its submission above (at [734]) that Professor Smith failed to disclose a range of limitations associated with Paz-y-Mino (2007); Bolognesi (2009); and Paz-y-Mino (2011). It is said that his failure to identify in his written reports the limitations of the studies on which he relied particularly detracts from his credibility and is especially strong evidence of his willingness to act as an advocate for Mr McNickle, given that Professor Smith had reason to know that his responsibilities to the Court as an expert required him to identify those limitations. Professor Smith stated in cross-examination that he "guess[ed]" (T1313.31-32) that he was aware of the criticism that had been made by the US District Court of his evidence in Perry v Novartis 564 F Supp 2d 452 (2008) (at 466 per Dalzell DCJ) when the Court found: It therefore appears that Dr. Smith's analysis of the i3 report focused not on the findings that were most relevant to the hypothesis he sought to test but on the findings that were most helpful to his paying client. While this approach is, sadly, not uncommon, it is incompatible with the reliable application of the scientific method. 743 Fifthly, it is said that Professor Smith refused to make reasonable concessions in cross-examination. For example, after Professor Smith had given evidence that chronic inflammation "needs to be prolonged" (T1307.44) and, is in that respect, different from "sub-chronic inflammation" (that is, inflammation of a shorter duration) (T1307.46-1308.1), Professor Smith refused to concede that Hamdaoui and Naifar (2008) (being a study that Professor Smith cited as evidence that GBFs cause chronic inflammation) was not a chronic inflammation study. Monsanto submits that Professor Smith avoided making that concession on four occasions (T1308.17-31). To take another example, when asked whether the nutritional deficiencies of children in Paz-y-Mino (2011) was a potential confounder that needed to be considered, Professor Smith gave evidence that was "hypothetically" a confounding factor (T1336.12-44). It is said that Professor Smith sought to deflect attention from discussion about the extent of the malnutrition in the children of the families by contending that the nutritional status related only to children and the studies concerned adults, and ultimately gave evidence that the nutritional problems were "potentially" a confounding factor (T1337.35-45). 744 For essentially the reasons that Monsanto identifies, I have reservations about the way in which Professor Smith approached the task of giving evidence in this proceeding. Without any intended disrespect, he seemed to me to be representative of a certain type of expert who has committed himself to one side of a controversy. Although this criticism was directed at a number of experts on both sides in this case, it was most effectively made in relation to Professor Smith (and another expert to whom I will return below). In saying this, I have reminded myself that the focal point of the relevant task is not the preconceived opinions of the relevant expert, but the overall substantive merits of their evidence given in the witness box and in their expert reports. 745 In this regard, it is worth making the following observations. 746 First, as noted above (at [735]), Professor Smith gave evidence that by the time he was retained by Maurice Blackburn in this proceeding, it would be fair to say that he held a "firm view" about the alleged carcinogenic nature of glyphosate (T1316.27-31). He also gave evidence that since 2018, he has remained open to be persuaded otherwise as to whether glyphosate and/or GBFs are carcinogenic or can cause NHL (T1437.1-3). I have some misgivings about the cogency of that evidence after observing him in the witness box, even though he has kept abreast of recent studies concerning the potential carcinogenic effects of exposure to glyphosate and/or GBFs. 747 Secondly, albeit reluctantly, Professor Smith made concessions, including: (1) in relation to Paz-y-Mino (2007), Bolognesi (2009), and Paz-y-Mino (2011), noting the studies had "some limitations" (at [83]); (2) in relation to Bolognesi (2009) specifically, that its findings were "somewhat conflicting" (First Smith Report (at [90])); (3) that there were a number of limitations in Lucia (2022) (T493.44-496.11); and (4) significantly, for reasons that will become clear, that the KCs are not conclusive of carcinogenicity. As Professor Smith said in cross-examination (T445.29-35): MR FINCH: Now, I will use the expression ticking the boxes. Ticking the box of five of the 10 KCs may suggest a possibility that a substance is carcinogenic but is not conclusive, of course? PROFESSOR SMITH: Yes. If you only had that information, and you had no epidemiological information and no toxicological data in experimental animals, you could only say that the chemical was possibly carcinogenic in humans. 748 A further example of Professor Smith making a concession in an area where there are conflicting findings (only some of which support his view as to the carcinogenicity of glyphosate) is provided by an exchange he had with the Assessor (T603.45-604.20). ASSESSOR: This is a question first for Professor Smith and it's about that figure 2 in Wozniak et al 2020. You said, perfectly correctly, I think, that reduction in p53 expression might ultimately lead to tumour formulation. The question I have for you is whether you think that reduction that's seen at 100 [micromolar] is significant? It's statistically significant but is halving the level of gene expression likely to have a big consequence for the functions of p53? And I ask that because, of course, the knockout mouse doesn't have a phenotype if it's a heterozygote, it only has a phenotype if it's a homozygotes. So the level of p53 would have to be pretty low to lead to a tumour was my thinking. What do you think about that level shown in that bottom right hand panel? PROFESSOR SMITH: I think it's - I think your scepticism is reasonable because - but I think it's not the only mechanism by which you can get changes in p53. So, for example, through the mutagenic actions of glyphosate on things like 8-hydroxyguanosine and other things, you could get mutations in one copy of p53, and that mutated copy, you could then get - in the regular copy you could then get ..... of 50 per cent change and you could significantly change the amount of p53 present. So, on its own, with such a high concentration, I'm not going to put my hat on. That's really tremendously important. For the purposes of key characteristics though if you want to say does glyphosate induce epigenetic alterations? Then these papers significantly contribute to that statement. But I - I understand your scepticism that that alone wouldn't be enough. ASSESSOR: Right. PROFESSOR SMITH: You would need other things. 749 Thirdly, Professor Smith's involvement in CERT of which he was a board member (T1294.22-24); his previous involvement in toxic tort lawsuits in the US commenced by CERT; or (to the extent they were tendered) his views published on Twitter or other media reinforced my impression above (at [744]) that Professor Smith had placed himself on one side of this scientific controversy. Although I do not think Professor Smith acted as an advocate or surrogate for the views of CERT, IARC or any other organisation in such a way as to jeopardise his independence in this proceeding, these matters did cause me to give increased scrutiny to his evidence.
Dr Juberg 750 I have already made findings about Dr Juberg's credit above (at [446]-[462]). It is necessary, however, to say something further about his evidence in the context of this stream. 751 Mr McNickle submits there is an important difference between the expertise of Dr Juberg and Professor Smith which is particularly relevant to the mechanistic evidence. Dr Juberg accepted that he has no specialised knowledge on the topic of NHL in humans (T1443.15-16), whereas Professor Smith has authored or co-authored several articles that specifically relate to NHL (First Smith Report (at [12])). It is said that Dr Juberg adhered to the view that glyphosate and/or GBFs performed for regulatory purposes are more reliable and should carry more weight than studies on glyphosate and/or GBFs published in peer-reviewed, publicly available journals, which Dr Juberg allegedly discounted (at JRG [61], [113]; T1502.29-45). 752 It is said further that Dr Juberg's preference for the regulatory studies is of limited utility in this proceeding because the central issue is whether the use of or exposure to Roundup Products (which contain glyphosate) can increase the risk of NHL in humans, whereas most regulatory studies are on bacteria, mice, rats and other animals. Few of them, it is said, are in human lymphocytes and none are in vivo studies on humans. Regulatory studies on bacteria will show whether glyphosate is mutagenic to bacteria but, as Dr Juberg accepted, the results of those bacterial studies do not reveal whether glyphosate is genotoxic or mutagenic to humans (T1480.26-34). 753 Mr McNickle also submits that Dr Juberg's approach runs counter to IARC's recommendation that studies in exposed humans or in human cells should be emphasised in the assessment of whether a substance is carcinogenic to humans (IARC Monographs on the Identification of Carcinogenic Hazards to Humans Preamble (2019) (at 27)). Professor Smith gave evidence in (at JRG [92]) that he considers the regulatory animal studies and bacterial mutagenicity tests on glyphosate and/or GBFs to be "of little value, compared to studies in actual humans and human cells" (see also T1508.21-26). Professor Prince and Dr Flecknoe-Brown expressed a similar opinion (T246.1-17). 754 It is perhaps unsurprising that in the light of his professional background, Dr Juberg displayed a preference for the regulatory studies. There may be advantages to such an approach. Regulatory studies are conducted according to internationally recognised standardised guidelines (such as the OECD Test Guidelines for Mutagenicity, Genotoxicity, and Carcinogenicity (at JRG [56]); and the USEPA Test Guidelines for Mutagenicity, Genotoxicity, and Carcinogenicity (at JRG [57])). As Dr Juberg explained (at JRG [111]), he placed higher confidence on such studies because the development of standardised and harmonised test guidelines, coupled with GLP when conducting toxicological testing, "results in an objective and high-quality testing regime aimed at critically evaluating the toxicological profile of pesticides". The use of guidelines ensures that there is "general harmonisation across the globe when data are generated for various toxicological effects" and that there is "a standard for how, and by which, to conduct toxicity testing regardless of who is generating the data for regulatory purposes" (at JRG [53]). 755 In contrast, according to Dr Juberg, peer-reviewed studies are not limited in their design and conduct by any a priori set of standardised guidelines. Dr Juberg explained that "[a]cademic studies or other publicly available literature studies typically do not adhere to either test guideline study design or GLP, but often use other approaches to serve their research needs and goals" (at JRG [53]; see also T1330.7-44; T1331.3-7). The authors of the peer-reviewed studies are free to design their studies in a way that best serves whatever "research needs and goals" they have (at JRG [53]). Notwithstanding this freedom may facilitate exploratory science, it is said that a potential drawback is that it leaves open the possibility that publication bias may infect the reliability of the studies' design, conduct, and results. As Professor Smith explained in cross-examination (T1332.1-15): MR CRAIG: And publication bias effects peer reviewed studies because peer reviewed studies are reviewed for the purposes of publication, aren't they? PROFESSOR SMITH: They are. MR CRAIG: But it doesn't affect regulated studies because those studies are generally not submitted for publication, are they? PROFESSOR SMITH: No. It's unfortunate but they are not. MR CRAIG: So an example of publication bias might include a study author providing an unpublished manuscript which includes an important caveat but the publishing editor removing that important caveat? PROFESSOR SMITH: Perhaps. Yes. 756 With that said, the danger with this approach, it seems to me, is to assume that those dealing with the regulators will play with a straight bat. For obvious reasons, this may be an unsafe assumption in the circumstances of this case, and, in this regard, it is necessary to say something about the evidence adduced concerning Professor James Parry. 757 Professor Parry was the Professor of Genetics and Chairman of the Centre for Molecular Genetics and Toxicology at the University of Wales. In or around early 1999, Monsanto engaged Professor Parry to conduct a review of four published genotoxicity studies which identified that glyphosate and/or GBFs may be genotoxic, being: Rank (1993); Bolognesi (1997); Lioi (1998); and Peluso (1998). Professor Parry prepared a report on those four studies (Parry (1999)) which he provided to Monsanto. Professor Parry concluded (at 7): The overall data provided by the four publications provide evidence to support a model that Glyphosate is capable of producing genotoxicity both in vivo and in vitro by a mechanism based upon the production of oxidative damage. 758 Professor Parry also recommended that further work be undertaken to clarify the potential genotoxic activity of glyphosate. Parry (2019), however, was not provided to regulatory authorities, including the APVMA, by Monsanto. In cross-examination, I raised this issue with Dr Juberg (T1472.36-1473.4): HIS HONOUR: … Dr Juberg, if you go to page 7 of the document in front of you, the second paragraph, "The overall data," down to the word "damage" and then you've already pointed out the second sentence there, "If confirmed." That is, there's a representation made and then - on the basis of the work that has been done by Professor Parry. Thinking back to your time at Dow and your responsibility for dealing with regulators, if you at Dow in respect of a matter in which you were engaging with regulators had from a respected scientist that the overall data provided by publications, irrespective of whether you had reason to think the publications were in the hands of the EPA, provide evidence to support a model the product is capable of producing genotoxicity in both in vivo and in vitro by a mechanism based on the production of oxidative damage, would you regard it as - would you think, given your knowledge of dealing with regulators, it would be important to convey that information to the regulator? DR JUBERG: Yes. 759 Although it was not the subject of detailed evidence, this is a matter of some concern and is redolent of the kind of danger I have referred to above in assuming that agrochemical companies will provide all relevant studies to agrochemical regulators. Having said that, it must be balanced against the fact that: (1) Parry (1999) did not involve a weight of evidence approach; (2) each of the studies the subject of Parry (1999) appear to have been considered by the relevant regulators; and (3) Professor Smith and Dr Juberg gave evidence concerning three of the four studies the subject of Parry (1999) (Rank (1993); Bolognesi (1997); Lioi (1998)) (Professor Smith did not rely upon Peluso (1998) (T1586.39-1587.5)). Although it caused me some disquiet and would certainly give me concerns about accepting anything from Monsanto at face value, in the light of these matters, and in the absence of any cross-examination of Professor Parry, I consider the evidence concerning Parry (1999) is of limited assistance in resolving the central issue.
G.3 The Mechanistic Evidence 760 Mr McNickle contends that the mechanistic evidence strongly supports the conclusion that glyphosate and/or GBFs (and thus Roundup Products) are human carcinogens; increase the risk of NHL in humans; and can cause NHL in humans. This is for two reasons. 761 First, it is said glyphosate exhibits five KCs of carcinogenicity, namely: KC2 (genotoxicity); KC4 (induces epigenetic alterations); KC5 (induces oxidative stress); KC6 (induces chronic inflammation); and KC8 (modulates receptor-mediated effects). 762 Secondly, and relatedly, Mr McNickle submits that there are five identifiable biologically plausible mechanisms by which use of or exposure to glyphosate and/or GBFs (and thus Roundup Products) can cause NHL in humans, as follows: (1) glyphosate and/or GBFs are genotoxic to human lymphocytes and capable of causing double-strand breaks of DNA in human lymphocytes, and thus could cause the kind of genetic mutations which can lead to the development of NHL in humans (first hypothesised mechanism); (2) glyphosate and/or GBFs cause an upregulation of the AID enzyme in humans that increases the amount of SHM, class switch recombination (CSR) and V(D)J recombination taking place in B-cells and therefore increases the number of mutations occurring within the B-cells including the kind of mutations that cause NHL (second hypothesised mechanism); (3) glyphosate and/or GBFs cause oxidative stress in humans which leads to damage to DNA, including double-strand breaks of DNA, and cause haematological cancers such as NHL (third hypothesised mechanism); (4) glyphosate and/or GBFs induce epigenetic alterations in human lymphocytes, including alterations of DNA methylation and hence the expression of key cancer genes, including NHL (fourth hypothesised mechanism); and (5) glyphosate and/or GBFs are preferentially distributed to the bone marrow, where it remains longer than in other tissues. Given that lymphocytes develop from lymphoid stem cells, which develop in the bone marrow, it is said that they may there be exposed to the alleged genotoxic and mutagenic effects of glyphosate and/or GBFs (fifth hypothesised mechanism). 763 It should be reiterated here that although a substance "ticks the box" of one or more of the KCs, it does not necessarily follow that there is a corresponding biologically plausible mechanism by which exposure to that substance can cause cancer. As Professor Smith explained in cross-examination (T1324.17-21): MR CRAIG: … in terms of your KC framework, the 10 KCs do not themselves determine whether a substance has a mechanism of action for causing cancer? PROFESSOR SMITH: No. You have to use the information from that to form one. 764 It is convenient therefore to deal with the former question separately from what might be described as the latter "significance" question when I address whether there is any biological plausible mechanism by which use of or exposure to glyphosate and/or GBFs can cause NHL. 765 Accordingly, I will adopt the following structure: Section I will detail my findings as to KC2 (genotoxicity); Section II will set out my findings in relation to KC4 (induces epigenetic alterations); Section III will address some other studies referred to KC5 (induces oxidative stress); Section IV will set out my findings as to KC6 (induces chronic inflammation); Section V will detail my findings as to KC8 (modulates receptor-mediated effects); Section VI will set out my findings as to the hypothesised biologically plausible mechanisms of action; and Section VII will set out my conclusion as to the mechanistic evidence stream.
I KC2 (genotoxicity) 766 As noted earlier (at [661]), KC2 (genotoxicity) is the ability of a chemical substance to cause DNA damage. This damage may or may not produce a mutation, which is a permanent and heritable change in the structure of the genome. If it does, it may lead to cancer (at JRG [13]). 767 Genotoxicity can include a wide range of effects on the genome, including, among other things, DNA adducts, strand breaks, sister chromatid exchanges, and chromosome aberrations. These types of genotoxic effects may lead to mutations where only a single base is changed in the DNA or to much larger ones where a whole chromosome is lost, or parts of chromosomes are deleted entirely (at JRG [14]). A mutagen is a genotoxic agent that produces mutations. All mutagens are genotoxic, but not all genotoxicants are mutagenic (that is, leading to a permanent and heritable change in the DNA or genetic material) (at JRG [15]). 768 Professor Smith concluded that based upon the studies pertaining to glyphosate and/or GBFs genotoxicity, there is "strong evidence" that they are genotoxic, mutagenic and can cause NHL (at JRB [160]; JRG [84]). Dr Flecknoe-Brown similarly concluded that glyphosate and/or GBFs are genotoxic and mutagenic to humans (at JRA [185]-[189], [205], [283], [326]). 769 For reasons that will become clear, KC2 is near the top of the shopping list for Mr McNickle's case in the third stream. Indeed, the question of whether glyphosate and/or GBFs exhibit KC2 was the subject of prolix submissions and extensive evidence adduced in the initial trial. It is necessary to delve into some detail in the following sections of these reasons which, for convenience, will adopt the following structure: (1) the in vitro studies, which will address: (a) the regulatory studies on the genotoxicity of glyphosate and/or GBFs sponsored by Monsanto or other corporations (see First Smith Report (at [104]-[120])); (b) the in vitro studies, namely: Santovito (2018); Wozniak (2018); Kwiatkowska (2017); Nagy (2021); Mladinic (2009); Alvarez-Moya (2023); and Roma (2023) (in vitro studies); and (c) Dr Flecknoe Brown's evidence given in Conclave A; (2) the in vivo studies, which will include consideration of four studies (Paz-y-Mino (2007); Bolognesi (2009); Paz-y-Mino (2011); and Chang and Andreotti (2023)) (in vivo studies); and (3) the in vivo significance of in vitro studies, which will address the question of the "real world" significance of concentrations at which glyphosate and/or GBFs may, in artificial in vitro conditions, cause damage to DNA.
The in vitro studies 770 It will be recalled that in vitro studies are studies conducted on living cells or organ tissue outside of their normal biological context (often referred to colloquially as "test-tube experiments"). It is convenient first to address the regulatory studies, before turning to the in vitro studies and Dr Flecknoe-Brown's evidence given in Conclave A.
Santovito (2018) 779 This study conducted an analysis of the clastogenic and/or aneugenic effects of glyphosate by chromosomal aberrations and micronuclei assays. Peripheral venous blood was collected from six healthy subjects (two males and four females), non-smoking, not alcoholics, not under drug therapy, and with no recent history of exposure to mutagens. Human lymphocytes were exposed to five glyphosate concentrations (0.500, 0.100, 0.050, 0.025, and 0.0125 μg/mL, where 0.500 μg/mL represents the established acceptable daily intake value) and the other concentrations were tested in order to establish the genotoxicity threshold for the compound (at 34693-4). The authors concluded (at 34693): We observed that chromosomal aberration (CA) and micronuclei (MNi) frequencies significantly increased at all tested concentrations, with exception of 0.0125 μg/mL. Vice versa, no effect has been observed on the frequencies of nuclear buds and nucleoplasmic bridges, with the only exception of 0.500 μg/mL of glyphosate that was found to increase in a significant manner the frequency of nucleoplasmic bridges. 780 As Professor Smith explained (First Smith Report (at [91])), the authors found that the cytokinesis-block proliferation index and the mitotic index were not significantly reduced, indicating that glyphosate did not produce significant cytotoxicity (that is, damage or death to the cell, rather than genotoxicity which involves disruption to the DNA) or effects on the proliferation of the cells at the tested concentrations. Glyphosate therefore produced significant chromosome damage (a form of genotoxicity) in the human lymphocytes in the absence of cytotoxic effects. 781 It is worth noting from the outset that Santovito (2018) is one (if not the only) study that Monsanto concedes provides some evidence that glyphosate and/or GBFs are genotoxic. Notwithstanding some minor limitations, I accept that the evidence established that the study does provide reliable evidence that glyphosate is genotoxic, for the following reasons. 782 First, the study demonstrated that glyphosate was genotoxic by two pathways, namely: (1) where exposure to a substance causes increased chromosomal aberrations in lymphocytes; or (2) where exposure to a substance causes increased frequency of micronuclei (MN) in lymphocytes, either or both circumstances is an indication that the substance is genotoxic to lymphocytes (T554.32-43). As noted above, the authors observed that chromosomal aberrations and micronuclei frequencies significantly increased at all tested concentrations except for the lowest concentration. Professor Prince in cross-examination accepted that this result demonstrated genotoxicity (T555.18-27): MR CLEMENTS: Professor Smith opines in his report that those results showed, in that study, glyphosate produced significant chromosome damage which is a form of genotoxicity in human lymphocytes; he's right about that, isn't he? PROFESSOR PRINCE: Yes. MR CLEMENTS: So the Santovito study showed that glyphosate was genotoxic to human lymphocytes in two different ways, didn't it? PROFESSOR PRINCE: Yes. 783 Professor Prince was then taken to the kind of chromosomal aberrations that the authors observed were caused by glyphosate (at 34695), where it was noted: Glyphosate was found to induce the following structural CAs: gaps, chromatid and chromosome breaks, dicentric chromosomes, rings, tri-tetraradials, and acentric fragments. This last, together to chromatid breaks, represent the most frequent observed aberrations (Table 1). Because of the conflicting opinions about the possibility to consider gaps as indicators of genomic damage, we decided to exclude gaps from statistical analysis. 784 Professor Prince agreed that this presented evidence of double-strand breaks in the DNA (T557.8-20): MR CLEMENTS: I suggest it would be wrong to say that the Santovito study was unable to demonstrate any double strand DNA breaks, wouldn't it? PROFESSOR PRINCE: The Santovito study, correct. Yes. MR CLEMENTS: It showed double strand breaks, didn't it? PROFESSOR PRINCE: Yes. 785 Secondly, despite concerns that: (1) the "purity of the test material and presence of possible impurities were not noted which creates doubt as to the reliability of the study results"; and (2) that Santovito (2018) was not conducted according to OECD Guideline 487 (T1519.6-14), Dr Juberg accepted in cross-examination that Santovito (2018) presented evidence that glyphosate is genotoxic (T1542.28-35). 786 Thirdly, Professor Smith gave evidence (at JRG [87]) that it was notable the study used six healthy donors (two males and four females) and scored 200 cells per donor such that 1200 cells were scored for each dose rather than only 100 or 200 in the studies sponsored by Monsanto "making the study much more powerful than those performed under OECD guidelines". As Professor Smith noted in response to a question from the Assessor (T1501.43-5): PROFESSOR SMITH: … And in this particular study [Santovito (2018)], they didn't just use one donor; they used six. And this is a combination of the pooled data from six people, and they've scored 200 cells in each person. So they've scored 1200 cells, which is much more than normal. And so this is why this study, I believe, is a very important one because it has a very large number of cells scored, it has a large number of individuals studied and this means that - and it also is using a chromosome aberration test, which is more sensitive than the - than the comet assay and less variable because it's scored under a microscope blind. And you see a stronger dose response with this. So I would - I would rely more on this than I would on the comet assay. Variability with the comet does not surprise me too much. 787 Fourthly, subject to matter to which I will return later in this section, as Professor Smith explained (at JRG [88]), the study used much lower doses of glyphosate than the studies sponsored by Monsanto (ranging from 0.0125 to 0.5 ug/ml) and, subject to matter to which I will return, were likely to be more relevant to levels of human exposure. A total of five doses was used rather than three and glyphosate was added to the cultures at 24 hours (the same as the industry studies) but was not washed off and remained in the cultures exposing the cells until they were harvested 28 hours later. 788 Overall, for these reasons, and notwithstanding the authors noted that: (1) there are limitations associated with an in vitro study due to the reduced sample size (at 34698); and (2) the increased cytogenetic damage at glyphosate concentrations equal and lower than the established acceptable daily intake (ADI) value "requires further investigations" in order to establish the effective genotoxicity threshold of glyphosate (at 34699) (a matter to which I will return), I am satisfied that Santovito (2018) presents reliable evidence that glyphosate is genotoxic.
Wozniak (2018) 789 This study assessed the effect of glyphosate, its formulation (Roundup 360 PLUS) and its main metabolite (aminomethylphosphonic acid, AMPA) in the concentration range from 1-1000 μM on DNA damage in human peripheral blood mononuclear cells (PBMC). 790 As Professor Smith explained (First Smith Report (at [92])), the compounds studied and formulation induced DNA single and double strand-breaks and caused purine and pyrimidine oxidation. Roundup 360 PLUS caused damage to DNA at 5 μM, while glyphosate and AMPA induced DNA lesions only at higher concentrations of 250 μM and 500 μM, respectively. The authors concluded that the observed changes were not likely associated with the direct interaction of herbicide components studied with DNA, but most probably occurred through effects related to the induction of oxidative stress (to which I will return below). 791 In my view, Wozniak (2018) presents some evidence that glyphosate is genotoxic, for two reasons. 792 First, in cross-examination, Professor Prince agreed that the effect of glyphosate and Roundup 360 Plus on PBMCs (the predominant cell type in which are lymphocytes) showed that those substances induced DNA damage in the PBMCs, including single and double strand-breaks (T558.16-25): MR CLEMENTS: And the results of the test by Wozniak was that both glyphosate and the Roundup formulation and AMPA induced DNA damage in the PBM cells including single strand breaks and double strand breaks; correct? PROFESSOR PRINCE: Yes. MR CLEMENTS: And Wozniak et al also observed that the Roundup formulation caused greater DNA damage than glyphosate on its own; is that correct? PROFESSOR PRINCE: Yes. 793 Professor Prince went on to give evidence (T559.1-10): MR CLEMENTS: Yes. All right. Thank you. So one thing was crystal clear from the study [Wozniak (2018)], the effect of exposing human PBM cells to glyphosate or the Roundup formulation was damage to DNA including single and double strand breaks? PROFESSOR PRINCE: Yes. MR CLEMENTS: And so this adds to the body of evidence, I suggest to you, that glyphosate and GBFs are genotoxic to human lymphocytes; do you agree with that. PROFESSOR PRINCE: Yes. 794 Secondly, notwithstanding his concern (at JRG, Annexure E), that there were "no effects reported at lower exposure concentrations … which indicates that these findings have a practical threshold and have little relevance for humans if one extrapolates the experimental concentrations to expected human exposures. The laboratory proficiency for study conduct and availability of historical control data were not noted, which represent potential experimental variables that influence the interpretation and reliability of the study results", Dr Juberg accepted in cross-examination that Wozniak (2018) provided some evidence that glyphosate and Roundup are genotoxic (albeit in concentrations higher than real world applications) (T1550.15-19): MR CLEMENTS: Do you accept that the Wozniak study shows that glyphosate and Roundup are genotoxic in concentrations higher than you would expect humans to encounter in real-world use of GBFs? DR JUBERG: Yes. 795 Accordingly, I consider that Wozniak (2018) provides some evidence that glyphosate is genotoxic. I will return to this study in the context of addressing KC5 (induces oxidative stress).
Kwiatkowska (2017) 796 This study assessed DNA damage (determination of single and double strand-breaks by the comet assay) and DNA methylation (global DNA methylation and methylation of p16 (CDKN2A) and p53 (TP53) promoter regions) in human PBMCs exposed to glyphosate. PBMCs were incubated with the compound studied at concentrations ranging from 0.1-10 millimolar (mM) for 24 hours. 797 The authors concluded that glyphosate induced DNA lesions, which were effectively repaired. However, PBMCs were unable to repair completely DNA damage induced by glyphosate. The study, in summary, indicated that glyphosate (at high concentrations from 0.5-10 mM) may induce DNA damage in leucocytes such as PBMCs and cause DNA methylation in human cells (at 93). 798 I accept that Kwiatkowska (2017) provides some evidence that glyphosate is genotoxic. 799 Notwithstanding that there was some disagreement as to whether the study indicated evidence of double-strand breaks, Professor Prince ultimately agreed with Professor Smith's conclusion and gave evidence that the study showed that glyphosate was genotoxic to human lymphocytes (T578.4-37): MR CLEMENTS: Perhaps I will break it up: do you agree that the 2017 Kwiatkowska study shows that glyphosate causes DNA damage to human lymphocytes in the form of single strand breaks? PROFESSOR PRINCE: Yes. MR CLEMENTS: But you disagree that it shows double strand breaks, do you? PROFESSOR PRINCE: Yes. MR CLEMENTS: And on what basis do you say that? PROFESSOR PRINCE: Because I don't think the assay that they've done, that they've performed and described in the methods section, has the capacity to differentiate between single and double strand breaks. There may be double strand breaks in there but they can't demonstrate them clearly. MR CLEMENTS: So you say it's an issue with the sensitivity of the particular assay used? PROFESSOR PRINCE: Correct. MR CLEMENTS: And what do you say about that, Professor Smith? PROFESSOR SMITH: I say that they used the classical comet assay which measures both single and double strand breaks. I agree with Professor Prince that the assay can't separate them but there's no reason to suggest that there's only single and no double strand breaks present. MR CLEMENTS: Thank you. Just back to you for a minute, Professor Prince, do you agree with this: the study - this is another study that shows that glyphosate is genotoxic to human lymphocytes? PROFESSOR PRINCE: Correct. 800 For this reason, I consider that Kwiatkowska (2017) provides some evidence that glyphosate is genotoxic.
Nagy (2021) 801 This study compared the cytogenetic effect of the active ingredient glyphosate and three marketed GBHs (Roundup Mega, Fozat 480, and Glyfos) by investigating cytotoxicity with fluorescent co-labelling and WST-1 cell viability assay as well as genotoxicity with cytokinesis block micronucleus assay in isolated human mononuclear white blood cells. 802 The authors concluded that glyphosate had no notable cytotoxic activity over the tested concentration range (0-10,000 micromolar (µM)), whereas all the selected GBHs induced significant cell death from 1,000 µM regardless of metabolic activation. MN formation induced by glyphosate and its formulations at sub-cytotoxic concentrations (0-100 µM) exhibited a diverse pattern. Glyphosate caused statistically significant increase of MN frequency at the highest concentration (100 µM) after 20 hours of exposure. 803 Further, Roundup Mega exerted "a significant genotoxic effect" at 100 µM both after four- and 20-hour exposures showing a stronger and more rapid effect than glyphosate alone (at 1). Moreover, Glyfos and Fozat 480 also resulted in a statistically significant increase of MN frequency from the lower concentration of 10 µM after 4-h and 20-h treatment, respectively. The authors also concluded that the differences observed between the active principle (glyphosate) and formulations (at 1): … confirm the previous concept that the presence of co-formulants in the formulations or the interaction of them with the active ingredient is responsible for the increased toxicity of herbicide products, and draw attention to the fact that GBFs are still currently in use, the toxicity of which rivals that of POEA-containing formulations (e.g., Glyfos) already banned in Europe. Hence, it is advisable to subject them to further comprehensive toxicological screening to assess the true health risks of exposed individuals, and to reconsider their free availability to any users. 804 I consider that limited assistance can be derived from Nagy (2021) in support of a conclusion that glyphosate is genotoxic. 805 In cross-examination, Professor Prince agreed with Professor Smith's conclusion that the results of the study indicated that glyphosate and/or GBFs are genotoxic to human cells (T580.9-12; T584.8-14). Professor Smith, however: (1) could not opine what chemicals were used in Glyfos and Fozat 480 and did not research their composition (T1381.46-1382.1); and (2) had not seen data that suggested that the 10 µM dose for four hours or 20 hours mimics a does realistically possible in human applicators (T1382.3-7). Further, Nagy (2018) only observed damage above 100 µM glyphosate and observed no effects at 0.1, 1 or 10 µM (which result is inconsistent with Santovito (2018)). 806 Dr Juberg also gave evidence on Nagy (2021) and noted, among other things, the presence of unknown contaminants in the use of Glyfos and Fozat 480 (at JRG, Annexure E): The formulations used in [Nagy (2021)] were reportedly obtained from applicators which does not follow good laboratory practice and is not a typical experimental practice. The presence of possible contaminants is unknown and thus attribution of effects to glyphosate or GBHs is not certain. This study used a different positive control than recommended by the standard test guideline and laboratory proficiency and historical control data were not noted, all of which create doubt as to the reliability of the study results. 807 For these reasons, I do not think much assistance can be derived from Nagy (2021).
Mladinic (2009) 808 Mladinic (2009) studied the genotoxic and oxidative potential of glyphosate on human lymphocytes. Testing was conducted with and without metabolic activation. Genotoxicity was evaluated by the alkaline comet assay and analysis of MN and other nuclear instabilities applying centromere probes (at 800). 809 Following glyphosate exposure, the comet assay showed significantly increased tail length (20.39 μm) and intensity (2.19%) for 580 μg/ml, and increased tail intensity (1.88%) at 92.8 μg/ml, compared to control values of 18.15 μm for tail length and 1.14% for tail intensity. With S9, tail length was significantly increased for all concentrations tested: 3.5, 92.8, and 580 μg/ml (at 800). 810 I do not think much assistance can be derived from Mladinic (2009). 811 The authors conclusion in Mladinic (2009) was that "no clear dose-dependent effect was observed, [indicating] that glyphosate in concentrations relevant to human exposure do not pose significant health risk". Professor Smith disagreed with this conclusion (First Smith Report (at [96])), noting that the data "clearly show a genotoxic effect for all concentrations of glyphosate tested using the comet assay, including the very low dose of 3.5 microgr/ml", but did not include that qualification in his reports. As Dr Juberg noted (at JRG, Annexure E): It is questionable whether the in vitro concentrations used [in Mladinic (2009)], coupled with lack of a clear dose-response, as noted by the authors, are relevant to expected human exposures. 812 With respect to this latter point, I should pause here to note that during the concurrent evidence session, Mladinic (2009) was the subject of an important exchange between Professor Smith and the Assessor concerning the apparent variation between the assays in that study and how the threshold concentration for detecting the genotoxicity (or otherwise) of glyphosate can vary significantly by dint of the use of different assays. This is an important issue and one to which I will return below when addressing the real world significance of the in vitro studies.
Alvarez-Moya (2023) 813 This was a study of the effect of various concentrations of glyphosate and three commercial GBFs on human lymphocytes. Human PMBCs obtained from 40 donors were exposed to glyphosate at 0.1, 1, 10 and 50 mM as well as to equivalent concentrations of glyphosate as commercial formulations. 814 Genetic damage was assessed in this study using the comet assay and was significantly increased at all concentrations of glyphosate and with two formulations. These formulations showed genotoxicity that was concentration-dependent but in a higher proportion compared to pure glyphosate. Professor Smith relied on this study in the Second Smith Report (at [10]) to conclude that glyphosate and/or GBFs are genotoxic. 815 I accept that Alvarez-Moya (2023) provides some evidence that glyphosate and/or GBFs are genotoxic, for the following reasons. 816 First, Professor Smith highlighted in his second report (at [10]) the fact that 40 separate human donors were used for this study as a typical study of human blood cells, whereas under the OECD guidelines, one to two donors are recommended. Professor Smith gave evidence that the use of a much larger number of donors will "clearly provide a better understanding of how a human population will respond to a chemical exposure and the use of 40 donors by Alvarez-Moya and Reynoso-Silva makes it the largest study to date of glyphosate's effects on human lymphocytes from differing donors" (Second Smith Report (at [10])). 817 Secondly, Dr Juberg accepted that the data obtained in the study showed the genotoxicity of glyphosate and the GBFs tested in the study. In cross-examination, Dr Juberg was taken to the conclusion of the authors (at 4) that "our data clearly showed the genotoxicity of [glyphosate] and GBH …". Dr Juberg noted the qualification by the authors in the previous paragraph that "although there is evidence of the genotoxic activity of [glyphosate], this is controversial, and it is necessary to increase the degree of certainty of its genotoxicity" but gave evidence (T1559.22-43): MR CLEMENTS: Our data clearly showed the genotoxicity of G - glyphosate - and GBH - glyphosate-based herbicide. MR CLEMENTS: I suggest to you that conclusion is correct, the data generated by this study did clearly show the genotoxicity of glyphosate and GBH. Do you agree with that? DR JUBERG: Well, I would just counter that with maybe the first sentence of the discussion: Although there is evidence of the genotoxic activity of [glyphosate], this is controversial and it is necessary to increase the certainty of its genotoxicity. So within this study, I would agree with you. But I would refer to that upper paragraph as well in - in all fairness, bring that into play. 818 Accordingly, I consider that Alvarez-Moya (2023) provides some evidence that glyphosate and/or GBFs are genotoxic.
Roma (2023) 819 In this study, HEK293 cells were exposed to various concentrations of Roundup Control Max. The authors found that in the three highest glyphosate concentrations (70, 700, and 3,500 μg/L) increased levels of DNA damage compared to the control at the three exposure times tested and that cells initially exposed to 3,500 μg/L of glyphosate for 24 hours were unable to repair the breaks in DNA strands after four hours of incubation in culture medium (at 1). The authors concluded (at 1): The present study demonstrated for the first time that Roundup® Control Max may induce genetic damage and cause alterations in the DNA repair system in human embryonic kidney cells even at concentrations found in blood and breast milk of people exposed through residues of the herbicide in food, which values have been poorly assessed or not studied yet according to the existent literature. 820 I consider that Roma (2023) is of limited assistance in demonstrating that glyphosate and/or GBFs are genotoxic, for the following reasons. 821 First, as noted above, Roma (2023) was conducted on immortalised kidney cells (HEK293), as opposed to human lymphocytes; the corollary being that it is of little relevance to the development of NHL in humans. Dr Juberg gave evidence that to his knowledge, the cell line used in Roma (2023) was not referred to in either the OECD or USEPA Guidelines (T1944). 822 Secondly, as Dr Juberg explained (T1942.14-1943.19): (1) the study incorrectly referred to the US OSHA permissible exposure limit (where there is no such exposure limit for glyphosate); and (2) the highest concentration of glyphosate used in the study is 175,000 times the median water concentration for glyphosate. Relatedly, the authors' claim that Roundup Control Max was deployed at "environmentally relevant concentrations" is questionable. The relevant source cited by the authors (Aris and Leblanc (2011)) reported that none of the 30 pregnant women and only two of the 39 non-pregnant women had detectable glyphosate in their blood (with the mean of the two outliers being 73.6 micrograms per litre (0.43 µM)), whereas the authors of Roma (2023) suggest that this is an "environmentally relevant concentration" routinely found in "people exposed mainly through the consumption of food containing pesticide residues" (at 6). 823 Thirdly, Dr Juberg identified that there were findings in Roma (2023) which indicated there was a threshold below which DNA damage was not seen because effects were seen in the top three dose levels and not the bottom two (T1943.14-16), and that DNA repair was reported with reversibility at both 70 and 700 micrograms per litre after 24 hour exposure within four hours (T1943.16-19). 824 Fourthly, the precise formulation of Roundup Control Max ("79.2% w/w of glyphosate monoammonium salt, plus adjuvants") is not provided in the study; the corollary being that even in the event Roma (2023) provided reliable evidence as to the presence of genotoxicity, those results could not be isolated to glyphosate. 825 For these reasons, I do not consider that Roma (2023) is of significant assistance in demonstrating that glyphosate and/or GBFs are genotoxic.
Dr Flecknoe-Brown (Conclave A) 826 It is convenient here to address Dr Flecknoe-Brown's evidence in relation to in vitro studies conducted on humans as to whether glyphosate and/or GBFs exhibit KC2. The basis for his conclusion is summarised (at JRA [185], [188]-[189]) as follows: 185 The IARC 2017 monograph concluded that there was sufficient evidence that glyphosate and GBFs were genotoxic in various systems to support its conclusion that glyphosate is probably carcinogenic to humans. … 188 The IARC 2017 monograph analysed 16 genotoxicity studies using standard methods on cultured human cells. All but two showed significant or highly significant evidence of genotoxicity in cells exposed to glyphosate or GBFs. Genotoxicity was shown in four of five studies of cultured non-human mammalian cells exposed to glyphosate or GBFs. 189 Weisenburger [(2021)] presents results of another nine in vitro studies using human and non-human cells published since the IARC 2017 monograph. These show evidence of DNA strand breaks, DNA aberrations, micronuclei formation and epigenetic effects in cells exposed to glyphosate or its metabolite, aminomethylphosphonic acid. 827 As mentioned earlier (at [694]), the IARC Monograph 2017 analysed a number of genotoxicity studies which broadly overlap with the studies referred to in Professor Smith's evidence (see, for example, Table 4.1 "Genetic and related effects of glyphosate in exposed humans" (at 367)). Dr Flecknoe-Brown gave evidence that he believed he did review the 16 genotoxicity studies the subject of the IARC Monograph 2017 individually (T241.33-34), but then gave evidence (T241.36-242.4): MR FINCH: But you say nothing in your report about the limitations and qualifications expressed in any of those reports, do you? PROFESSOR FLECKNOE-BROWN: That's probably, right. Yes. I haven't got it in front of me. MR FINCH: And we can't conclude from reading your report what the qualifications or limitations were in those studies, can we? PROFESSOR FLECKNOE-BROWN: I, again, looked at them carefully and drew my conclusions from them. MR FINCH: Well, you said you did that in the Colombian and Ecuadorian studies too but you left out the qualifications of those, didn't you? PROFESSOR FLECKNOE-BROWN: Yes. 828 Although I have recorded above (at [698]-[704]) the reasons Dr Flecknoe-Brown did his best to assist the Court, aspects of his evidence were unsatisfactory. As was seen in relation to Bolognesi (2009) (to which I will return), Dr Flecknoe-Brown conceded that he had omitted several limitations which rendered the findings of that study in demonstrating that glyphosate and/or GBFs are genotoxic of little assistance (see above (at [701])). Similarly, in relation to Weisenburger (2021), which study he relied upon (at JRA [189]) in support of his conclusion that glyphosate and/or GBFs are genotoxic, Dr Flecknoe-Brown gave evidence as follows (T242.28-46): MR FINCH: Thank you. Now, at paragraph 189 of your joint report paragraphs, you summarise the article from Dr Weisenburger of 2021. You see there he presents results of another nine in vitro studies, do you see that? PROFESSOR FLECKNOE-BROWN: Yes. Yes. MR FINCH: And did you look at each of those nine studies? PROFESSOR FLECKNOE-BROWN: I believe so. I - - - MR FINCH: You don't extract from them anything - - - PROFESSOR FLECKNOE-BROWN: I haven't - if I haven't commented on them I can't say that I've looked at them beyond a read. MR FINCH: You haven't extracted from any of those studies any of the limitations or qualifications in those studies either, have you? PROFESSOR FLECKNOE-BROWN: No. 829 Dr Flecknoe-Brown was then taken to extracts of Weisenburger (2021) and gave evidence as follows (T246.39-7; T247.32-43): MR FINCH: So that Dr Weisenburger, whose report you summarised, places, as he says, greater weight on those two studies, but you would agree with me, Dr Flecknoe-Brown, wouldn't you, that Dr Weisenburger nowhere qualifies his article by mentioning the reservations that we've already gone through in those two studies; that's true, isn't it? PROFESSOR FLECKNOE-BROWN: Without a detailed re-examination for that flaw I couldn't - - - MR FINCH: For the moment, you will accept me subject to me getting it wrong? PROFESSOR FLECKNOE-BROWN: Yes. MR FINCH: Is that right? PROFESSOR FLECKNOE-BROWN: Yes. … MR FINCH: So out of all the studies he refers to, including the 16 referred to in paragraph 188 and the nine referred to in paragraph 189, the only two that we can positively identify are the two that we've already dealt with, the Ecuadorian and the Colombian studies? PROFESSOR FLECKNOE-BROWN: Yes. MR FINCH: And he leaves out any qualification, subject to your reservation about not having read it, about those? PROFESSOR FLECKNOE-BROWN: Yes. Although later in the paper I'm sure he does come to those other stuff. 830 In short, with respect to his conclusion as to genotoxicity, I accept Monsanto's submission that Dr Flecknoe-Brown largely recited and, as a result, did not adequately interrogate the studies underlying the findings of the IARC Monograph 2017 and Weisenburger (2021) which resulted in the omission of a number of salient limitations in the JRA. 831 Accordingly, I consider that Dr Flecknoe-Brown's evidence is of limited assistance in assessing whether glyphosate and/or GBFs exhibit KC2.
Conclusion 832 In contrast to the regulatory studies (which Dr Juberg and Professor Smith agreed were largely or uniformly negative) (see above (at [773]-[774])), the in vitro studies provided satisfactory evidence that glyphosate and/or GBFs are capable of generating a genotoxic signal in laboratory conditions. Save for Roma (2023) and Dr Flecknoe-Brown's evidence given in Conclave A, the experts broadly agreed that the in vitro studies demonstrate genotoxicity by, among other things, increased frequency of chromosomal aberrations, including single and double-strand DNA breaks, and increased frequency of MN in lymphocytes (see particularly Santovito (2018) and Wozniak (2018)). 833 I will return to this evidence below when giving my conclusion as to KC2.
The in vivo studies 834 The in vivo studies analyse the effects of accidental or incidental exposure to glyphosate and/or GBFs in humans. It is necessary to address four studies which, for reasons I will explain below, provide limited assistance as to whether glyphosate and/or GBFs exhibit KC2.
Conclusion 871 Overall, the in vivo studies did demonstrate some evidence of glyphosate and/or GBFs exhibiting genotoxicity. Professors Smith and Prince agreed that Paz-y-Mino (2007) demonstrated genotoxicity by (among other things) a statistically significant lengthening of the DNA tail in comet assays, and Professor Prince and Dr Flecknoe-Brown agreed that Bolognesi (2009) demonstrated that glyphosate presents a genotoxic risk to humans. 872 With that said, the evidence established some not insignificant limitations with the in vivo studies as a whole which rendered their findings of limited assistance, including, inter alia: (1) the failure to match controls and account for pre-existing levels of exposure; (2) the high levels of concentration used; (3) the small number of subjects and controls utilised in the studies; and (4) the presence of nutritional problems as a potential confounding factor. It is worth noting here that although Monsanto contended that the use of Cosmoflux in the Paz-y-Mino studies and Bolognesi (2009) presented as a potential confounder, which was the subject of some evidence given by Professor Smith and Dr Flecknoe-Brown, I think this was largely a distraction in the light of Dr Juberg's evidence (which I accept) that in his experience in dealing with various herbicides and pesticides, he was unaware of any adjuvants that could be described as genotoxic (T1585.34-38). 873 Accordingly, in contrast to the in vitro studies, I do not consider that the in vivo studies present reliable evidence that glyphosate and/or GBFs exhibit KC2.
The real world significance of the in vitro studies
879 Before going further, it is convenient to address two studies together which received some attention from the parties in relation to this topic.
Conclusion 903 Before setting out my conclusion as to whether glyphosate exhibits KC2, it is useful to give an overview of my findings above as to the evidence given in relation to the regulatory studies; in vitro studies; in vivo studies; and other studies. 904 First, with respect to the regulatory studies relied on by Mr McNickle, Dr Juberg and Professor Smith agreed that the regulatory studies were either largely or uniformly negative in terms of demonstrating that glyphosate and/or GBFs are genotoxic. In contrast, however, notwithstanding the presence of some minor limitations, and despite Roma (2023) and Dr Flecknoe-Brown's evidence being of limited assistance, the experts were largely in agreement that the in vitro studies provided reliable evidence that glyphosate and/or GBFs are genotoxic. 905 In short: (1) Professors Prince and Smith gave evidence that the results of Santovito (2018) demonstrated genotoxicity by: (a) a number of increased chromosomal aberrations, including double-strand DNA breaks; and (b) increased frequency of MN in lymphocytes; (2) Professor Smith, Dr Juberg and Professor Prince agreed that Wozniak (2018) indicated that glyphosate induced DNA damage in PMBCs, including single and double-strand breaks; (3) Professors Smith and Prince accepted that Kwiatkowska (2017) demonstrated DNA damage to lymphocyte in the form of single-strand DNA breaks; (4) Professors Smith and Prince agreed that the results of Nagy (2021) showed that glyphosate and/or GBFs are genotoxic; and (5) Dr Juberg (subject to the authors' qualification) and Professor Smith agreed that Alvarez-Moya (2023) provided evidence of genotoxicity. 906 Secondly, however, the in vivo studies presented a different picture. Although the experts were largely ad idem in relation to two of the in vivo studies demonstrating that glyphosate and/or GBFs pose a genotoxic risk (Paz-y-Mino (2007) and Bolognesi (2009)), the evidence established that the in vivo studies suffered from several limitations which rendered their findings of limited assistance, which may be broadly categorised as follows: (1) failure to match controls and account for pre-existing levels of exposure (Paz-y-Mino (2007); Bolognesi (2009)); (2) aerial spraying exceeding the maximum application rate for the formulated product (Paz-y-Mino (2007); Paz-y-Mino (2011)); (3) the small number of subjects and controls used (Paz-y-Mino (2007)); and (4) the presence of nutritional problems as a confounding factor (Paz-y-Mino (2007) (Paz-y-Mino (2011)). It was also seen in relation to Chang and Andreotti (2023) that contrary to Professor Smith's evidence, the authors only went so far as to conclude that the study demonstrated the presence of oxidative stress, rather than evidence of genotoxicity, and that the authors' reliance on Aris and Leblanc (2011) rendered its findings less reliable in relation to any conclusion as to KC2. 907 Subject to a matter to which I will return momentarily, I am satisfied, having regard to the whole of the mechanistic evidence before me, that glyphosate and/or GBFs are genotoxic and therefore exhibit KC2. Notwithstanding the limitations to which I have referred, it is difficult to come to any other conclusion, particularly given the weight placed upon the in vitro studies by the experts and Professors Smith and Prince agreeing they demonstrate that glyphosate and/or GBFs satisfy the requirements of KC2. 908 The rub, however, is one I have introduced earlier in relation to the in vivo significance of the in vitro studies: that is, the weight of the evidence may demonstrate that glyphosate and/or GBFs may exhibit genotoxic effects on human blood cells, but whether this constitutes evidence that those substances are capable of inducing genotoxicity, let alone cancer or NHL, in the real world is a different question. I will return to this issue in the context of the first hypothesised mechanism in Section VI below. 909 Before leaving this section, however, it is necessary to say something briefly in relation to mutagenicity. 910 Professor Smith concluded in his reports that there is strong evidence that glyphosate and/or GBFs are genotoxic and mutagenic (at JRB [160]; JRG [84]). Dr Flecknoe-Brown similarly concluded (at JRA [198]-[205], [270]) that GBFs have a "mutagenic effect" or contain "mutagenic substances". It will be recalled that a mutagen is a genotoxic agent that produces mutations and while all mutagens are genotoxic, not all genotoxicants are mutagenic (that is, leading to a permanent and heritable change in the DNA or genetic material) (see above (at [766]-[767])). 911 Notwithstanding my conclusion above as to genotoxicity, I am not persuaded that the evidence establishes that glyphosate and/or GBFs exhibit mutagenicity, for the following reasons. 912 First, Professors Smith and Prince agreed that mutagenicity involves the induction of permanent mutations in the DNA (T316.34-36; T462.41) and that genotoxic damage must cause permanent cell mutation in order to lead to cancer (T462.32-36). As Professor Prince explained in cross-examination (T584.27-585.15): MR CLEMENTS: I suggest to you it is right because double strand breaks in lymphocytes results in the kind of chromosomal rearrangement commonly seen in human NHL. PROFESSOR PRINCE: There's no evidence for that. There's no evidence that the chromosomal breaks that we see - that glyphosate is, one, that they persist; and, secondly, if they do persist, are they the chromosomal breaks that we see in lymphoma. If I had that evidence, I would be able to answer you a different way. … MR CLEMENTS: So you disagree with me? PROFESSOR PRINCE: Totally. Are you looking for proof of the actual mutation caused by double strand breaks, caused by glyphosate? PROFESSOR PRINCE: Yes. We're all looking for that, yes. MR CLEMENTS: But you say this, do you - you say, "I accept that exposure to glyphosate will resulted in double strand breaks in lymphocytes, but I can't [prove] that those double strand breaks actually happen in chromosomes which can then trigger NHL"; is that - - - PROFESSOR PRINCE: Absolutely correct. 913 Secondly, notwithstanding evidence of genotoxicity in the studies relied upon by Professor Smith, none of the studies demonstrated that glyphosate and/or GBFs caused DNA damage that was permanent or lead to mutations which cause NHL in humans. 914 Thirdly, I do not regard Dr Flecknoe-Brown's evidence in the JRA (at [198]-[205], [270]) concerning the mutagenicity of glyphosate and/or GBFs as persuasive, for the reasons identified by Professor Prince above (at [905]). Further, Dr Flecknoe-Brown does not state the basis for his assumption in those paragraphs that glyphosate and/or GBFs are mutagenic substances. 915 Accordingly, although I am satisfied, subject to the qualification above, that glyphosate and/or GBFs exhibit KC2, I do not consider that the evidence establishes that glyphosate and/or GBFs are mutagenic substances.
II KC4 (induces epigenetic alterations) 916 It will be recalled that epigenetic alterations (KC4) are reversible mechanisms that cause altered gene expression. Epigenetic modifications include methylation of the DNA, modifications of histone proteins which coat the DNA, and differential expression of non-coding RNAs (such as microRNAs) which control how genes are expressed. Many carcinogens induce these epigenetic alterations and therefore possess KC4 (see above (at [662])). 917 Professor Smith concluded that there is strong evidence that glyphosate and/or GBFs induce epigenetic alterations, including in human lymphocytes, and therefore possess KC4 (at JRB [112], [157]; First Smith Report (at [129])). Professor Smith maintained this opinion in oral evidence, adding that "epigenetic changes are a common event in the development of non-Hodgkin lymphoma" (T487.33-34). In support of his opinion, Professor Smith primarily relied on Rossetti (2021) and, to a lesser extent, Lucia (2022).
Consideration 924 Before going further, it is worthwhile to say something about the "significance" question as it relates to KC4. 925 As noted above (at [916]), epigenetic alterations can include methylation of the DNA, modifications of histone proteins which coat the DNA, and differential expression of non-coding RNAs (such as microRNAs). That is, to satisfy KC4 simpliciter, it is sufficient that the evidence demonstrates that the substance in question causes (for instance) methylation of the DNA. The next step involves asking whether the evidence demonstrates that the epigenetic alteration points to a change in gene expression which leads to cancer - in other words, does the epigenetic alteration matter? 926 As Professors Smith and Prince noted during the concurrent evidence session (T494.2-19): PROFESSOR SMITH: … so for the purposes of saying key characteristic 4, independent of whether there's functional changes, gene expression or whatever, it shows you that in humans you see epigenetic alterations which is really what KC4 is all about. MR FINCH: Yes. So do you accept that, Professor Prince, that you see KC4? PROFESSOR PRINCE: Yes. … KC4 - and I didn't write the KC - is the recognition of epigenetic changes - - - MR FINCH: Yes. PROFESSOR PRINCE: - - - I would say two things: one would have to be, well, what is a significant epigenetic change and an insignificant epigenetic change? MR FINCH: Sure. PROFESSOR PRINCE: So I think that's what we're arguing over. 927 Professors Smith and Prince went on to give evidence (T495.10-25): PROFESSOR SMITH … I mean, the idea for KC4 is: does it induce epigenetic alterations? And this study adds to - adds to the findings from the intact human blood cells in culture where we see methylation changes also that glyphosate, both in human beings and in human cells, induces epigenetic alteration which is what KC4 is. MR FINCH: Yes. PROFESSOR SMITH: What the consequences of those are and whether they're truly significant alterations is an open question. But for the purposes of checking the box KC4, [methylation of the DNA] would do it. MR FINCH: Now, without going back over things you've already said, Professor Prince, do you agree with that? PROFESSOR PRINCE: Yes, I agree with that. 928 This is important because although the studies suggest that glyphosate and/or GBFs cause epigenetic changes (such as methylation of the DNA), there is less evidence as to whether those changes are "significant" or linked to the development of cancer. As noted earlier, we are here concerned with the first question, namely whether glyphosate and/or GBFs "tick the box" of inducing epigenetic alterations: the significance question will be addressed when dealing with the fourth hypothesised mechanism of action below in Section VI. 929 With that aside, the evidence established that Rossetti (2021) and Lucia (2022) suffered from several limitations which largely went to the significance question. I will address those limitations later, but, for the following reasons, I am satisfied that glyphosate can induce epigenetic alterations and therefore exhibits KC4. 930 Professor Prince agreed with Professor Smith's conclusion that exposure to GBFs causes epigenetic changes in B-cells (T403.37-41; at JRA [208]). In cross-examination, Professor Prince was taken to Rossetti (2021) and its summary of the findings of Kwiatkowska (2017) (which we have seen earlier in relation to KC2). He gave the following evidence: MR CLEMENTS: So in terms of the Rossetti paper … this is at page 3 and it's the last paragraph on the right-hand column … so you will see there it says: The effect of glyphosate on DNA methylation was first reported by Kwiatkowska et al in vitro. These authors showed that high concentrations of glyphosate induced DNA lesions in peripheral blood mononuclear cells, decreased global 5mC percentage and increased methylation of p53 promoter. I suggest to you that's a fair summary of the findings of Kwiatkowska in relation to the epigenetic changes induced by glyphosate. Bearing in mind it's - the summary is silent, I'm just wondering about that expression? PROFESSOR PRINCE: Yes. MR CLEMENTS: So you agree with that? PROFESSOR PRINCE: I agree. 931 Professor Prince then gave the following evidence in relation to two studies authored by Wozniak et al cited in Rossetti (2021) (at (34) and (60)) (T597.47-598.5): MR CLEMENTS: … Do you agree that - and you tell me if you need to look at the abstract or read the whole paper but do you agree that the two Wozniak 2020 studies reported similar results to Kwiatkowska in relation to the effect of glyphosate on DNA methylation? PROFESSOR PRINCE: Correct. … 932 In relation to Wozniak (2021), Professor Prince gave evidence in the JRI (at [129]) (see also T601.7-45): Woźniak et al. found that glyphosate changes the expression of DNMT1, DMNT3A, and histone deacetylase (HDAC) 3 in PBMCs. These enzymes are involved in the regulation of chromatin architecture and, thus, could affect methylation patterns and histone modification, leading to changes in gene expression but they did not actually study this. (Citations omitted) 933 Professor Prince then gave the following evidence in relation to the studies referred to above in Rossetti (2021): MR CLEMENTS: Just trying to wrap this up, Professor Prince, I suggest the study I've asked you about; namely, Kwiatkowska 2021, and the three Wozniak ones in 2020 and 2021, are consistent in that they've all showed that when human cells are exposed to glyphosate in vitro that causes global hypomethylation of DNA in the cells; that is, a reduction of methylation of the DNA in the cells; do you agree with that? PROFESSOR PRINCE: Correct. MR CLEMENTS: And, similarly, they have consistently showed that there was hypermethylation; that is, increased methylation, in the TP53 tumour suppressor gene? PROFESSOR PRINCE: Correct. MR CLEMENTS: And, similarly, they've consistently showed that there was hypomethylation; that is, reduced methylation, in the p21 promoter gene? PROFESSOR PRINCE: Correct. MR CLEMENTS: And so I suggest to you it's fair to say that the studies that have examined the effect of glyphosate on methylation of human cells in vitro are consistent; do you agree with that? PROFESSOR PRINCE: Yes. MR CLEMENTS: And it's fair to say, I suggest, that those studies have consistently showed that exposure to glyphosate results in aberrant DNA methylation; correct? PROFESSOR PRINCE: I agree. 934 In short, Professors Smith and Prince agreed that the Wozniak (2020) studies, Wozniak (2021), and Kwiatkowska (2017) the subject of Rossetti (2021) demonstrated evidence of epigenetic alterations resulting from glyphosate and/or GBFs in the form of: (1) global hypomethylation; (2) hypermethylation in the TP53 tumour suppressor gene; (3) hypomethylation in the p21 promoter gene; and (4) aberrant DNA methylation.
Conclusion 935 For these reasons, I am satisfied that glyphosate and/or GBFs induce epigenetic alterations. I will return to this topic in relation to the "significance" question when addressing the fourth hypothesised mechanism of action in Section VI below.
III KC5 (induces oxidative stress) 936 KC5 (oxidative stress) occurs when cells produce an excess of reactive oxygen species (ROS). As noted earlier (at [663]), many human carcinogens can induce oxidative stress which can lead to damage to DNA and other cell components. 937 Professor Smith's opinion is that there is "strong evidence" that glyphosate and/or GBFs induce oxidative stress (First Smith Report (at [130]-[134]); at JRB [112]). 938 Professor Smith notes that there are more than ten in vitro studies that have reported oxidative stress from glyphosate and/or GBFs resulting in increased ROS formation; decreased antioxidant activity; decreased oxidative detoxification; increased oxidative DNA damage; and increased lipid peroxidation. It is said that when cells are exposed to glyphosate and/or GBFs, increased ROS formation causes oxidative stress and the re-regulation of cell signalling associated with apoptosis or necrosis. Reduced antioxidant activity also reduces the defensive ability for inflammation response in cells (First Smith Report (at [132])). Professor Smith notes further that numerous animal studies have shown that glyphosate induces oxidative stress. Biomarkers of oxidative stress have been reported in various tissues in rats and mice, including liver, skin, kidney, brain, and plasma (First Smith Report (at [133])). 939 Notwithstanding that I harbour some concerns as to whether Professor Prince has sufficient expertise in toxicology and inflammation to give a comprehensive opinion as to whether glyphosate exhibits KC5, I am satisfied on the evidence before me that glyphosate and/or GBFs can induce oxidative stress, for the following reasons. 940 First, in cross-examination, Professor Prince agreed that exposure to glyphosate and/or GBFs "tick the box" of KC5 but that oxidative stress induced by glyphosate falls short of acting as a biologically plausible mechanism to induce lymphoma (T500.38-43): MR FINCH: … is it too broad a summary to say that your view is you may see oxidative stress being induced by glyphosate exposure but you don't see it moving all the way to an expression in the human body or is that too rough a summary? PROFESSOR PRINCE: No. That's a perfect summary. … 941 Professor Prince went on to note (T501.19-25): PROFESSOR PRINCE: … I think that it's a question of what we were talking about before in terms of - I agree that there's enough data to put [glyphosate] into tick[ing] the box of oxidative stress as a KC but it's a question of whether it is relevant or not relevant to lymphoma. The second issue is that there's just a huge amount in the data as to what causes these measurements of oxidative stress and the non-specific nature of we're getting oxidative stress all the time through a variety of things and how they relate to is what complicates the area. 942 Secondly, Professor Smith relied on Chang and Andreotti (2023) (which I have addressed above in the context of KC2 (at [863]-[870])). That study indicated that: (1) there was a significant positive association between urinary glyphosate concentrations and oxidative stress markers (including levels of 8-OHdG; and (2) there was an association between use of glyphosate the previous day and significantly increased 8-OHdG in the urine, notwithstanding that Professor Smith conceded that in theory, the 8-OHdG detected could have arisen by oxidation of cell-free DNA living outside of living cells (T619.35-41). Despite a close scrutiny of the supplementary data establishing that it was unsafe for the authors to conclude that glyphosate induced oxidation of DNA in vivo (a topic dealt with earlier in relation to KC2 (at [867]-[870])), the authors of concluded that: Our findings contribute to the weight of evidence supporting an association between glyphosate exposure and oxidative stress in humans and may inform evaluations of the carcinogenic potential of this herbicide. 943 Thirdly, notwithstanding Dr Juberg expressed some ambivalence as to what conclusions could be drawn from Chang and Andreotti (2023) (T1583.4-9; T1584.5-9; Third Juberg Report (at [6])) and some limitations highlighted by Monsanto (which, broadly speaking, go to the question of whether oxidative stress induced by glyphosate is a biologically plausible mechanism for cancer, to which will return in Section VI), Professors Smith and Prince both agreed that the study provided reliable evidence that exposure to glyphosate induces oxidative stress in humans. 944 As noted earlier (at [865]), Professor Smith concluded in the Second Smith Report (at [7]-[9]) that the findings by the authors of Chang and Andreotti (2023) indicate that glyphosate induces oxidative stress in humans which results in damage to the DNA, and that constitutes "the strongest evidence to date that glyphosate induces oxidative stress [KC5] and is genotoxic [KC2] in humans". Professor Prince agreed with that conclusion, save for Professor Smith's statement with regards to KC2 (see above (at [865])). In cross-examination, Professor Prince gave evidence as follows (T615.8-616.1): MR CLEMENTS: … The results of the Chang Andreotti study showed that there was a positive association between urinary glyphosate concentrations and levels of 8-OHdG; that's correct? PROFESSOR PRINCE: Yes. I understand, in certain - there was certain correlations, yes. … MR CLEMENTS: … there was also an association between use of glyphosate the previous day and significantly increased 8-OHdG in the urine; is that correct? PROFESSOR PRINCE: Correct. MR CLEMENTS: And in their conclusion on page 1 the authors state: Our findings contribute to the weight of evidence supporting an association between glyphosate exposure and oxidative stress in humans. I suggest to you that's a fair conclusion from the results of the study; do you agree? PROFESSOR PRINCE: I agree. 945 Fourthly, Professors Prince and Smith agreed that Sidthilaw (2022), a study introduced by Mr McNickle during the concurrent evidence session concerning maize farmers in Thailand who were exposed to glyphosate, demonstrated that the spraying of glyphosate induced oxidative stress. The authors' conclusion (at 5) was put to Professors Smith and Prince, who gave the following evidence (T623.21-624.16): MR CLEMENTS: And the results are set out on page 5 of the study… : The comparison of urinary glyphosate levels, oxidative stress, inflammation and lung function before and after applying glyphosate, showed that there was a statistically significant increase in urinary glyphosate levels, oxidative stress and serum MDA, while serum GHS levels showed a statistically significant decrease. There was a statistically significant increase in inflammation and CRP. However, lung function decreased statistically significantly. CRP stands for C-reactive protein; is that correct? PROFESSOR PRINCE: Correct. MR CLEMENTS: And that's a biomarker of inflammation; is that correct? PROFESSOR PRINCE: Once it exceeds a threshold, it's not a continuous variable. MR CLEMENTS: Right. Okay. Is CPR secreted by the body as a result of inflammatory processes? PROFESSOR PRINCE: Yes. CRP - it's secreted by certain sorts of cells. MR CLEMENTS: Yes. Thank you. MDA, which is referred to in that Results paragraph, stands for malondialdehyde? PROFESSOR PRINCE: Yes. MR CLEMENTS: Is that a biomarker of oxidative stress. PROFESSOR PRINCE: Yes, it is. MR CLEMENTS: The higher the MDA level the more oxidative stress the cell has been subjected to; is that right? PROFESSOR PRINCE: I can't answer that. I'm not actually sure. MR CLEMENTS: Professor Smith, do you have anything to say about that? Is it correct to say the higher the MDA level the more oxidative stress a cell has been subjected to? PROFESSOR SMITH: Yes. 946 Professor Prince was then asked about the biomarker "glutathione" (GHS) and its relationship to oxidative stress (T624.18-38): MR CLEMENTS: GHS stands for glutathione, which, I suggest, is another biomarker of oxidative stress. Professor Prince, do you agree with that? PROFESSOR PRINCE: It's an uncommon one but I believe it has been used, yes. MR CLEMENTS: GHS plays a role in protecting cells from damage from oxidative stress; is that correct? PROFESSOR PRINCE: My understanding, yes. MR CLEMENTS: And when a cell is subjected to oxidative stress GHS gets used up in a process of breaking down - sorry, I will go back a step: when a cell is subjected to oxidative stress by glyphosate, GHS gets used up in a process of breaking down glyphosate; is that correct? PROFESSOR PRINCE: Correct. MR CLEMENTS: And, therefore, a reduction in the levels of GHS in cells is an indication that the cells have been subjected to oxidative stress? PROFESSOR PRINCE: Yes, that's correct. 947 Professor Prince then gave evidence, based on those results (T624.40-625.4): MR CLEMENTS: At the bottom of the left-hand column of page 5, the authors state as follows - there's a paragraph that starts with the words, "In the case of." So: In the case of serum oxidative stress and inflammation, our results indicate that serum MDA and CRP levels increased statistically significantly after the application of the glyphosate but that GHS decreased. So I suggest to you what that study showed is that spraying glyphosate induced oxidative stress in the bodies of the farmers who had sprayed the glyphosate. PROFESSOR PRINCE: Yes. 948 Fifthly, it will be recalled that Professor Prince agreed in cross-examination that Wozniak (2018) demonstrated that glyphosate induced single and double-strand DNA breaks (thus exhibiting KC2) (see above (at [793])). He also gave evidence as follows (T558.30-44): MR CLEMENTS: The Wozniak study also observed that glyphosate and the Roundup formulation generated reactive oxygen species in the PBM cells; correct? PROFESSOR PRINCE: Yes. MR CLEMENTS: And they concluded that the observed DNA damage was not associated with direct interaction between glyphosate and Roundup with the DNA molecule. PROFESSOR PRINCE: Yes. MR CLEMENTS: But likely occurred as a result of the effects of the reactive oxygen species generated as a result of exposure to glyphosate and Roundup. PROFESSOR PRINCE: That was their interpretation of "likely" and I think it's reasonable. 949 In the light of this evidence, I am satisfied that glyphosate and/or GBFs induce oxidative stress. It will be necessary to return to this topic in the context of addressing the third hypothesised mechanism of action below in Section VI: that is, whether oxidative stress of the type observed in the studies is implicated in causing NHL in humans.
IV KC6 (induces chronic inflammation) 950 KC6 (chronic inflammation) concerns inflammation caused by the body's response to potentially harmful irritants or pathogens. The function of inflammation is to eliminate the cause of cell injury and initiate tissue repair. It has been shown that chronic inflammation can increase the risk of some cancers, including, for example, colorectal cancer and mesothelioma (T622.12-27; T1307.44). 951 Professor Smith's opinion is that there is "strong evidence" that glyphosate and/or GBFs cause chronic inflammation (First Smith Report (at [135]-[143])). In reaching that conclusion, Professor Smith relied upon the following studies: (1) Pandey (2019); (2) Hamdaoui (2018); (3) Kumar (2014); (4) Yamamoto (2013), Kruger (2013), Shehata (2013), Aitbali (2018), Davoren (2018), Kittle (2018), Lozano, Defarge (2018), Mao (2018), Motta (2018), Nielsen (2018), Blot (2019) and Tang (2020) (gut microbiome studies); and (5) Mesnage (2021) (collectively, chronic inflammation studies). 952 It is convenient first to summarise Professor Smith's findings with respect to the chronic inflammation studies and other studies relied upon by Mr McNickle in relation to KC6.
Relevant studies 953 First, in relation to Pandey (2019) and Kumar (2014), the former study exposed rats to various doses of Roundup (0, 5, 10, 25, 50, 100 and 250 mg/kg bodyweight glyphosate) orally, every day for 14 days. On day 15, liver and adipose tissues from dosed rats were analysed for inflammation markers. CRP in liver, cytokines IL-1β, TNF-α, IL-6, and inflammatory response markers, and prostaglandin-endoperoxide synthase were upregulated in liver and adipose of rats exposed to higher (100 and 250 mg/kg bw/d) doses of Roundup. Professor Smith notes that these data show that short-term GBF exposure induces inflammation in the liver and adipose tissue. In relation to the latter, Kumar (2014) indicated that inhalation of glyphosate-rich air samples and glyphosate induced airway inflammation in mice (First Smith Report (at [136])). 954 Secondly, Professor Smith notes that chronic inflammatory outcomes from longer term exposures have also been reported. It is said that Hamdaoui (2018) indicated that histological examination of liver tissue from rats sub-chronically exposed to GBFs revealed the presence of Kupffer cells (a form of macrophage associated with inflammation), hepatocyte vacuolisation, inflammatory reaction, and necrosis (though the latter occurred in the absence of fibrosis or tissue remodelling) (First Smith Report (at [137])). 955 Thirdly, it is said that another way in which glyphosate and/or GBFs may induce systemic chronic inflammation has been discovered that may be especially important for the induction of lymphoma (Yamamoto (2013)). According to Professor Smith, with reference to the gut microbiome studies, this mechanism relates to the finding from multiple laboratories that glyphosate and/or GBFs, including Roundup, alter the make-up of the gut microbiome in several species and cause extensive inflammation (First Smith Report (at [138])). An altered microbiome can cause both local and systemic chronic inflammation and, as a result, produce systemic oxidative stress and genotoxicity (Yamamoto (2013)). This, in turn, can promote lymphoma-genesis (the growth and development of lymphoma) (First Smith Report (at [140])). As Professor Smith notes (First Smith Report (at [141])): As stated above multiple studies show that GBFs and glyphosate can alter the gut microbiome. In 2013, it was reported that glyphosate altered the gut microbiomes of cattle and poultry (Kruger, Shehata et al. 2013, Shehata, Schrodl et al. 2013), leading Samsel and Seneff to speculate that glyphosate's effects on the gut microbiome may be responsible for a plethora of diseases, including nonceliac gluten sensitivity and autism spectrum disorders (Samsel and Seneff 2013). These proposed associations remain controversial, but it is clear that glyphosate and GBFs can alter the gut microbiome. 956 During the concurrent evidence session, Professor Smith also relied upon Lehman (2023), which, it is said, demonstrated changes in gut microbiota and upregulation of pro-inflammatory cytokine IL-17A in mice exposed to low doses of glyphosate (T506.39-46; T634.35-635.29). 957 Fourthly, and relatedly, Mesnage (2021) used a combination of "shotgun-metagenomics" and metabolomics to investigate the gut microbiome of rats exposed to increasing doses of glyphosate and the GBF, MON 52276. The authors demonstrated that glyphosate treatment resulted in "higher levels of intermediates of the shikimate pathway in the ceca, suggesting inhibition of EPSPS in the cecum microbiome". Professor Smith notes that this mechanism also leads to increases in shikimic acid in soil micro-organisms following application of GBFs. Serum metabolomics suggested that MON 52276 had a greater impact than glyphosate on the serum metabolome, indicating additional systemic toxic effects. Hence, the purported safety of glyphosate and/or GBFs, based on the fact that mammals including humans lack the shikimate pathway, therefore ignores the presence of this pathway in micro-organisms which play a central role in the well-being of many species from honey-bees to humans. The toxic effect of glyphosate on these beneficial micro-organisms in our gut and elsewhere could have "profound consequences including producing chronic inflammation and contributing to lymphomagenesis" (First Smith Report (at [142])). 958 Mr McNickle also relies upon Sidthilaw (2022) as evidence for the proposition that exposure to glyphosate and/or GBFs induce chronic inflammation. In that study, the authors concluded (at 5): The comparison of urinary glyphosate levels, oxidative stress, inflammation, and lung function before and after applying glyphosate showed that there was a statistically significant increase in urinary glyphosate levels, oxidative stress and serum MDA (p < 0.001), while serum GHS levels showed a statistically significant (p < 0.001) decrease. There was a statistically significant increase in inflammation and CRP (p < 0.001), however lung function decreased statistically significantly (p < 0.001) (Fig. 1). (Emphasis added) 959 In cross-examination, Professor Prince gave evidence (see above (at [945]-[946])) that CRP is a biomarker of inflammation as it is secreted by certain cells of the body due to inflammatory processes (T623.32-43). Professor Smith also gave evidence that Sidthilaw (2022) adds to the evidence that exposure to GBFs induces chronic inflammation (T625.26-30).
Consideration 960 I do not consider the evidence supports the conclusion that glyphosate and/or GBFs exhibit KC6, for the following reasons. 961 First, Professor Smith gave evidence that "chronic inflammation associated with the development of cancer is a prolonged response to persistent infections or irritants that inflict cell death and tissue injury" (T1307.44) and is therefore different from: (1) "sub-chronic inflammation" (that is, inflammation of a shorter duration) (T1307.46-1308.1); and (2) acute or temporary inflammation in that "you would require repeated exposure to the irritant or the infectious agent in order to generate that chronic inflammation" (T1307.40-43). This is significant because Professor Smith accepted that Pandey (2019), Hamadoui (2008) and Kumar (2014) upon which he relied in his first report are not studies in chronic inflammation but studied sub-chronic inflammation (T1308.3-1309.10): MR CRAIG: Now, when one comes to your evidence on chronic inflammation you deal with chronic inflammation at paragraph 136 of the primary report that you filed in this proceeding - if I can ask that that be brought up, please - and at paragraph 136 you rely on Pandey and Kumar as two of the studies relied upon for the purposes of demonstrating chronic inflammation. That's correct, isn't it?---Well, no, I mean, if you look at the next paragraph we're talking on Pandey that it's really about more acute or sub-chronic inflammation. MR CRAIG: Okay. So it's not a study in respect of chronic inflammation, is it?---It's a study showing that there is acute or sub-chronic inflammation from exposure but not - - - MR CRAIG: Answer my question: it's not a study demonstrating chronic inflammation, is it?---It's not long enough. It's only 14 days. It couldn't do. MR CRAIG: Thank you. Now, at paragraph 137 you refer to a study entitled Hamdaoui, Naifar et al?---Yes. MR CRAIG: And, again, that's not a chronic inflammation study, is it?---Again, it's a sub-chronic longer-term exposure. MR CRAIG: Thank you. So, again, it's not a study that demonstrates chronic inflammation, is it?---It demonstrates inflammation that's for sure. MR CRAIG: Answer my question, Professor Smith. It's not a study that demonstrates chronic inflammation, is it?---Well, they're sub-chronically exposed. So it's a sub-chronic inflammation. MR CRAIG: Thank you. So it's not a prolonged exposure. It's a exposure of a shorter duration?---It's not a lifetime or lengthy exposure but it is a longer-term exposure. … MR CRAIG: Thank you. Now, if we go back to paragraph 136, you will see reference to a study Kumar and Khodoun?---Yes. MR CRAIG: That's not a study demonstrating chronic inflammation, is it?---I don't recall the study exactly how long it was - there were exposed to. … MR CRAIG: [Kumar (2014)] ran for a shorter period of time than the Pandey study which you referred to earlier as not being a study demonstrating chronic inflammation?---True. MR CRAIG: And so it is not a study demonstrating or evidencing chronic inflammation, is it?---No, it's sub-chronic. 962 Professor Smith then gave evidence (T1309.12-18): MR CRAIG: Thank you. Now, I want to suggest to you that nowhere in your primary report do you draw his Honour's attention to the fact that each of Pandey, Hamdaoui and Kumar are sub-chronic rather - are not studies of chronic inflammation, are they?---They're studies of inflammation. That's all. MR CRAIG: Thank you. But you rely on them to ask his Honour to conclude, or as demonstrative of the existence of KC6, being chronic inflammation, don't you?---I do. 963 Secondly, in relation to the gut microbiome studies, Professor Smith conceded in cross-examination that those studies do not measure inflammation; nor demonstrate the existence of extensive inflammation, and mainly concern "glyphosate-induced dysbiosis of the microbiome". Indeed, Kruger (2013), Aitbali (2018), Mao (2018) and Blot (2019) do not mention the word "inflammation" (T510.32-35). As Professor Smith said in cross-examination (T1310.17-37): MR CRAIG: And I want to also suggest to you that those studies, upon proper consideration, do not demonstrate the existence of extensive inflammation?---I would agree with you that that was an overinterpretation in the report. I agree. MR CRAIG: Thank you. And is sitting here today the first time it has occurred to you that it was a overinterpretation in your primary report?---Yes. That's the first time I've done a direct comparison. MR CRAIG: And so before coming to court today to give evidence, and after publishing a supplementary report on Rana itself, it has not occurred to you that you have overinterpreted those studies in opining that they cause excessive inflammation - sorry, extensive inflammation?---I think the more accurate statement is the one in Rana. MR CRAIG: Now, is it your evidence to his Honour that those studies demonstrate the existence of actual inflammation?---They're mainly about the glyphosate-induced dysbiosis of the microbiome. MR CRAIG: Yes. And I want to suggest to you that those studies do not demonstrate the existence of actual inflammation, do they?---I don't think they measure inflammation in those studies, no. HIS HONOUR: Does that mean the answer is no the question? I will just have counsel repeat the question. MR CRAIG: Yes. MR CRAIG: I want to put to you, Professor Smith - and we can do this the short way or do this the long way - the studies that are referred to in paragraph 138 of your report do not identify the existence of actual inflammation, do they?---No, they look for dysbiosis of the microbiome. 964 Thirdly, in relation to Sidthilaw (2022), it is doubtful whether that study can assist with respect to chronic inflammation. Although the study demonstrates some correlation between glyphosate exposure and a particular biomarker CRP (which is described in that study as a "marker for inflammation"), the study only took samples from farmers for the 24 hours prior and 24 hours after exposure to glyphosate. Accordingly, it did not show any result in a period over which a "chronic" response could be measured and there is no "prolonged" or "repeated" exposure which is required for chronic inflammation according to Professor Smith's evidence (see above (at [961]-[962])). Indeed, the authors concluded that "further studies to assess the long-term effects of glyphosate are warranted" (at 9).
Conclusion 965 For these reasons, I am not satisfied that the evidence supports the conclusion that glyphosate and/or GBFs induce chronic inflammation.
V KC8 (modulates receptor-mediated effects) 966 KC8 refers to effects that may be caused by chemical carcinogens which act directly on specific cell receptors or modulate synthesis, transport, distribution, biotransformation, and clearance of the natural ligand, such as a hormone. As Professor Smith explained (T510.43-7): MR FINCH: … We move lastly in the terms of KCs I think to KC8, that is modulates receptor mediated effects; what does that mean? PROFESSOR SMITH: Well, the hormones in your body which control much of your life, things like testosterone, oestrogen and other things, they act through receptors and so a chemical may modulate receptor effects by changing levels of hormones but it may also change it by changing the receptor itself, here is the expression, or the amount of protein on the cell surface or the type of receptor that is expressed. And so modulates, receptor, mediated effects, was meant to be a catch-all phrase for hormone changes and changes in the receptors that interact with hormones. 967 In his characteristically assertive way, Professor Smith opined that there exists "strong evidence" that glyphosate and/or GBFs impact the synthesis of estrogen in human cells and experimental animals and, in this manner, modulate receptor-mediated effects (First Smith Report (at [146]-[148])). In summary, Professor Smith cites several studies in his first report in support of the following propositions: (1) that glyphosate and/or GBFs interfere with the synthesis of estrogen, lowering circulating levels and potentially promoting the development of NHL (at [146]); (2) glyphosate and/or GBFs may act by disrupting the hypothalamic-pituitary axis by reducing adrenocorticotrophic hormone levels, protein kinase A activity, and steroidogenic acute regulatory protein mRNA, including phosphorylated StAR, a protein that carries out a key regulatory step in steroidogenesis (at [147]). 968 During the concurrent evidence session, however, it became clear that the evidence was lacking in several key respects. 969 First, Professor Smith conceded that in his written reports, none of the studies cited in support of his opinion that glyphosate and/or GBFs module receptor-mediated effects were conducted on humans (T1419.31-39): MR CRAIG: Thank you. In your written expert reports in this proceeding, you did not cite any studies done in humans to conclude that there is strong evidence that glyphosate modulates receptor mediated effects; is that correct? PROFESSOR SMITH: In my report? MR CRAIG: In your written reports. PROFESSOR SMITH: Correct. 970 Secondly, the evidence established that the IARC Working Group 112 (2015) did not share Professor Smith's opinion that the evidence for glyphosate for KC8 was strong and instead said it was weak (T511.47). Professor Smith gave evidence that the study which changed his view as to KC8 since that time was Geier (2023) (T512.5-14) (recalling the controversies surrounding Dr Geier set out above (at [739]-[740])), but that he did not "particularly" rely upon that study in advancing his opinions before the Court (T1413.19-21). 971 Thirdly, the USEPA Memorandum "Weight of Evidence Conclusions on the Tier 1 Screening Assays for the List 1 Chemicals" (2015) (USEPA 2015 Memorandum) subjected 52 chemicals to a weight of evidence evaluation. The USEPA concluded that the evidence for glyphosate exhibiting KC8 was weak and that it was not necessary to undertake a mammalian or wildlife EDSP Tier 2 testing. It concluded (at 34): Based on weight of evidence considerations, mammalian or wildlife EDSP Tier 2 testing is not recommended for glyphosate since there was no convincing evidence of potential interaction with the estrogen, androgen or thyroid pathways. 972 In his third report, Dr Juberg explained (at [14]-[16]) the reasons why the USEPA's EDSP programme did not provide evidence that glyphosate modulates receptor-mediated effects: 14. I strongly disagree with the Rana et al (2023) [which study cited Geier (2023)] conclusion "a growing body of evidence indicates that glyphosate and its formulations are endocrine-disrupting chemicals…" Rana et al (2023) looked at but a fraction of the available information for glyphosate related to endocrine disruption, focusing primarily on estrogen synthesis, estrogen receptor activity, and endocrine ligand synthesis. Glyphosate has been thoroughly tested in the USEPA's EDSP Testing Program[me] (USEPA, 2015) (EPA-HQ-OPP-2009-0361-0047) not only for estrogen-mediated interactions/effects (including aromatase activity and steroidogenesis), but also for androgenmediated effects, and thyroid activity. In reviewing Rana et al (2023), their evaluation of KC8 only included discussion on estrogen and aromatase and did not consider or discuss other important facets of the endocrine system including androgen, thyroid-, or steroidogenesis-related effects. The USEPA's EDSP Program[me] took more than 10 years to develop and validate and their review for glyphosate (USEPA, 2015) was extensive and exhaustive as noted by their inclusion of the following: • For evaluation of estrogen-related effects, the analysis incorporated 7 different endocrine assays and 20 different studies (other scientifically relevant information or OSRI) • For evaluation of androgen-related effects, the analysis incorporated 5 different endocrine assays and 18 OSRI studies. • For evaluation of thyroid-related effects, the analysis incorporated 3 different endocrine assays and 11 OSRI studies. • The assays used in the evaluation of glyphosate's endocrine activity potential included in vitro (i.e., cellular-based), in vivo (i.e., whole animal), and considered both mammalian and ecological species. • In the USEPA's evaluation of estrogen, androgen, and thyroid (EAT) effects from glyphosate exposure, there were multiple measurements and parameters including receptor binding, receptor activation, relevant organ weights, histopathology, systemic toxicity, among others. 15. In total, there were multiple lines of evidence that the EPA evaluated for EAT activity including some 15 parameters for EAT which cross multiple layers of biological organization and which in my opinion are superior to the limited review by Rana et al (2023), which only looked at estrogen and aromatase endpoints and which did not include review of any of the EDSP findings for glyphosate which are publicly available. 16. The USEPA review of numerous empirical studies that were conducted on glyphosate according to established and validated test methods for endocrine activity concluded that "Based on weight of evidence considerations, mammalian or wildlife EDSP Tier 2 testing is not recommended for glyphosate since there was no convincing evidence of potential interaction with the estrogen, androgen or thyroid pathways." 973 Professor Smith gave evidence that he did not place weight on the results of the USEPA 2015 Memorandum (T1417.29-34). The reason given was that (T512.40-44): PROFESSOR SMITH: … the EPA only look at influence directly onto the oestrogen receptor. So they have a very strict interpretation. And although it appears as though glyphosate in some studies can alter the expression of the oestrogen receptor, I don't think that's really a major component, and I think that they have missed the association with oestrogen itself in the body. 974 Professor Smith conceded, however, in forming those opinions, that he did not recall having regard to Table 2 of the USEPA 2015 Memorandum, which was subject of the following evidence (T1419.11-19): MR CRAIG: Thank you. Let's go to table 2, then, on the following page. The first row of the table states: Lines of evidence indicating potential interaction with oestrogenic/anti-oestrogenic pathways for glyphosate. Do you see that? PROFESSOR SMITH: Yes. MR CRAIG: And this table demonstrates that the EPA tested more than just the influence of glyphosate directly onto the oestrogen receptor, doesn't it? PROFESSOR SMITH: Well, they're testing on the oestrogen receptor and its subsequent effects in the pathway. MR CRAIG: Yes. So the answer to my question is "yes", isn't it? PROFESSOR SMITH: Yes. 975 For these reasons, I am not satisfied that the evidence supports the conclusion that glyphosate and/or GBFs exhibit KC8.
VI Hypothesised biologically plausible mechanisms 976 It will be recalled that Mr McNickle contends that there are five identifiable biologically plausible mechanisms by which use of or exposure to glyphosate and/or GBFs (and thus Roundup Products) can cause NHL in humans (see above (at [762])). It is important here to distinguish evidence which supports the existence of a biologically plausible hypothesis or theory, and evidence which establishes a biologically plausible mechanism. As Professor Prince explained in relation to KC4 (T405.14-18) (to which I will return): PROFESSOR PRINCE: It's a biologically plausible theory or hypothesis. It's not a biologically plausible mechanism because we haven't proven the mechanism. MR CLEMENTS: In other words, it's plausible but you say not yet established by experiments; is that a fair - - - PROFESSOR PRINCE: Yes. 977 Related to this notion is that the process of identifying whether a chemical substance possesses a biologically plausible mechanism of action does not axiomatically follow from a conclusion that the substance exhibits one or more of the KCs simpliciter. Indeed, it is a "data-rich determination" (see above (at [677])) and, as Sonich-Mullin (2001) noted (at 2): … a supported mode of action would have evidence provided by robust mechanistic data to establish a biologically plausible explanation. Mechanism of action, in contrast, relates to sufficient understanding of the molecular basis to establish causality; it is at the other end of the continuum from little or no evidence of mode of action to scientific proof of mechanism of action. (Emphasis added) 978 Bearing these matters in mind, I turn now to addressing each of the five hypothesised mechanisms of action advocated for by Mr McNickle.
First hypothesised mechanism 979 The first hypothesised mechanism is that glyphosate and/or GBFs are genotoxic to human lymphocytes and capable of causing double-strand breaks of DNA in human lymphocytes, and accordingly, are capable of causing the kind of genetic mutations which can lead to the development of NHL in humans. Although I have found that the weight of evidence supports the conclusion that glyphosate and/or GBFs satisfy KC2, the next step of whether there exists reliable evidence that those substances are capable of inducing genotoxicity, let alone cancer or NHL, in the real world is a different question (see above (at [875]-[877])). 980 For the reasons set out below, I am not persuaded that Mr McNickle has established the first hypothesised mechanism. 981 First, shortly after the exchange between Professor Smith and the Assessor concerning the variability between the concentrations which produced positive results for genotoxicity in Mladinic (2009) referred to above (at [893]-[894]), Professor Smith gave the following evidence in response to a question from the Assessor (T1503.1-14): ASSESSOR: … And then final question, which we touched on yesterday, was I explained how I'm obsessed by risk rather than hazard and why that's the case. So does this huge variation in the concentration of glyphosate that has a positive result in these studies in vitro - does that tell us anything about risk in the real world? PROFESSOR SMITH: … I don't think so, no. I mean, I think the way that we do - the way that this works typically in the - in the environmental and occupational arena is that you first of all decide, is the chemical a carcinogen or probable carcinogen on the basis of epidemiological studies, studies in animals and all of these sort of cell studies and mechanistic studies, and a weight of the evidence evaluation as we explained. But after that - after you've decided it's a carcinogen - of course, you could buy a bottle of a carcinogen and put it in your garage and never open it. And as long as it's not volatile, unless somebody goes and drinks it or something, there's no risk, really, right? 982 Put another way, as I explained earlier (at [875]-[877]), although it is possible to demonstrate that glyphosate and/or GBFs have a genotoxic effect on human blood cells under artificial in vitro cell culture conditions, this evidence says very little about the risk of genotoxicity to humans resulting from exposure to glyphosate and/or GBFs in the real world. 983 This is for two reasons: first, the majority of the in vitro studies (Wozniak (2018); Kwiatkowska (2017); Nagy (2021) and Alvarez-Moya (2023)) (Mladinic (2009) may also be included in this list (see Table 2; T1499.3-15)) used concentrations of glyphosate which exceeded the lowest intoxication threshold identified in evidence by Professor Smith (5 µM) by several orders of magnitude (in other words, at doses that no human would have any prospect of being exposed to in the real world) (see above (at [901])); and secondly, even with respect to the results in studies which did not exceed that threshold (Santovito (2018) and Mladinic (2009)), it was demonstrated that it is possible to detect a genotoxic signal at ever-lower concentrations of glyphosate by changing in vitro conditions and using different assays (see above (at [901])). 984 Secondly, and in any event, none of the studies the subject of the mechanistic evidence suggested that the genotoxic effect observed from glyphosate and/or GBFs is implicated in causing NHL in humans. A fortiori, it will be recalled at least three studies suggested that the effect of glyphosate is "transient" and capable of repair: (1) in relation to Paz-y-Mino (2011), Professor Smith accepted that the effects of exposure are "[t]ransient only in the sense that lymphocytes in your body turn over. So the damaged ones are removed and the regular ones, the new ones, appeared and basically that took away the damage that as observed in the first study" (T472.13); (2) in relation to Bolognesi (2009), the authors concluded that the data suggested that genotoxic damage associated with glyphosate spraying for control of illicit crops is "small and appears to be transient" (at 994-995); and (3), in relation to Roma (2023), Dr Juberg gave evidence that DNA repair was reported with reversibility at both 70 and 700 micrograms per litre after 24 hour exposure within four hours (T1943.16-19). 985 Thirdly, as noted earlier (at [912]), Professors Smith and Prince agreed that mutagenicity involves permanent mutations in the DNA and that genotoxic damage must cause permanent cell mutation to lead to cancer or NHL. None of the mechanistic studies, however, demonstrated that glyphosate and/or GBFs induced DNA damage that was permanent or could lead to mutations which would induce NHL in humans. 986 In short, although I am satisfied on balance that glyphosate and/or GBFs exhibit KC2, this conclusion must be tempered by the reality that genotoxicity has been demonstrated in what might be described as extreme in vitro conditions which, on the evidence before me, is not translatable to a form of carcinogenic risk in humans. Accordingly, for the reasons set out above, I do not consider there is robust mechanistic data to support a conclusion that there exists a biologically plausible mechanism by which glyphosate and/or GBFs are capable of causing the kind of genetic mutations which can lead to the development of NHL in humans.
Third hypothesised mechanism 1025 The third hypothesised mechanism is that glyphosate and/or GBFs cause oxidative stress in humans which leads to damage to DNA, including double-strand breaks of DNA, and cause haematological cancers such as NHL. 1026 I have already found above (at [949]) that glyphosate and/or GBFs can induce oxidative stress, but I am not satisfied that it is a biologically plausible mechanism which leads to the development of NHL, for the following reasons. 1027 First, Professor Smith gave evidence as follows (T500.1-3): MR FINCH: Yes. Now, is it fair to say that, up until you saw the Chang 2023 study, you had expressed the view, had you not, that oxidative stress was probably the weakest of the 10 KCs? PROFESSOR SMITH: Well, I didn't mean that for glyphosate. That was expressed as in general because as we've already talked about, there are several things that will produce oxidative stress that are not necessarily carcinogenic. 1028 Secondly, as noted earlier, although Professor Prince agreed that glyphosate and/or GBFs "tick the box" of KC5, he gave evidence that it falls short of acting as a biologically plausible mechanism because there is little to indicate that the data supports the conclusion that the non-specific nature of oxidative stress can cause NHL (T500.38-43; T501.19-25). As Professor Smith explained shortly after the exchange above (T500.22-36): PROFESSOR PRINCE: At a high level I think it's important to recognise that it's not one of the hallmarks for cancer per se. Oxidative stress. So somehow it has got to get to one of the hallmarks of cancer. And so that's part of the dilemma that I have particularly in the context of lymphoma. So it's the question: how does it get there? And of the - because it can affect a variety of pathways, lipids, protein, inflammatory pathway and direct DNA binding, the formation of hydroxy radicals on the surface. And the issue has been is that that removal becomes the measurement, the so-called eight hydroxy deoxyguanosine, and that then becomes a suggestion that that's demonstrating DNA damage, which it is, but that DNA damage can then go the next step and has implications and an automatic assumption that that's a genotoxic effect leading to lymphoma. And there's a number of reviews that have been reported in that - in the report - in the documents. And really none of them demonstrate a clear association with reactive oxygen species causing lymphoma in humans. So I think the - it really steps from how does it fit from the hallmarks of cancer all the way through to lymphoma.
Fourth hypothesised mechanism 1029 The fourth hypothesised mechanism is that glyphosate and/or GBFs induce epigenetic alterations in human lymphocytes, including alterations of DNA methylation and hence the expression of key cancer genes, including NHL. 1030 As noted earlier, I have found that glyphosate and/or GBFs exhibit KC4, but that there is less evidence as to whether those changes are "significant" or linked to the development of cancer. Accordingly, I am not satisfied that there is persuasive evidence in favour of the fourth hypothesised mechanism, for the following reasons. 1031 First, as noted earlier (at [929]), the authors of the relevant studies highlighted several limitations which lessen their weight in favour of a conclusion that glyphosate and/or GBFs induce epigenetic alterations which could be functionally implicated in the development of NHL. In relation to Rossetti (2021), for example, the authors concluded (at 1) that "[o]verall, more studies are needed to identify epigenetic targets, to define how they are dysregulated in human disease and their functional role, and to determine the critical windows of vulnerability by herbicide exposures" (emphasis added). In relation to Lucia (2022), Professor Smith accepted from the outset that the authors highlighted several limitations (T491.10-11), as follows: (1) the study consisted of post-menopausal women aged between 45 and 66, therefore the results "may not be generalisable to other populations or those residing outside California" (T492.10-24); (2) that a further limitation of the study was "the lack of gene expression data" (T493.5-19) (that is, as Professor Prince explained, it is not clear whether the changes in methylation affect the gene expression or are otherwise inert (T493.26-32); (3) that no inference can be drawn regarding the "temporal relationship between DNA methylation differences and glyphosate exposure" (T494.21-495.2); (4) that although the authors did not observe a relationship between recent herbicide use and glyphosate and AMPA concentrations, "those data were missing for 37 per cent of participants which should be considered another limitation of the study" (T496.1-31); (5) importantly, that the authors' conclusion was tentative ("that informs the hypothesis that glyphosate and/or AMPA exposure might elevate the risk for disease" (emphasis added)); and (6) that "[f]urther studies are warranted to replicate our results, determine the functional impact of glyphosate- and AMPA-associated differential DNA methylation, and further explore whether DNA methylation could serve as a biomarker of glyphosate exposure" (emphasis added) (T496.43-497.15). 1032 Secondly, Professor Prince gave evidence that any conclusion that glyphosate and/or GBFs are capable of causing epigenetic alterations does not axiomatically lead to the conclusion that glyphosate and/or GBFs cause NHL in humans. As he explained, quoting Professor Smith's 2020 article (at JRB [144]-[145]): [144] KC 4- Epigenetic alterations: The inability of the KCs to evaluate epigenetics is clearly stated in [Smith (2020)]: The difficulty with interpreting the KC 'induces epigenetic modifications' is that the relevance of a particular epigenetic change for carcinogenesis by a specific agent may not be clear and causality is hard to establish. More validation is clearly needed to fully understand which epigenetic endpoints are most indicative of carcinogenic risk. [145] Indeed, this issue is definitely true for NHL - while epigenetic changes are extremely common in NHL, it is generally accepted by cancer biologists that epigenetic changes are not the earliest events in NHL development. Put another way, epigenetic changes (particularly non-mutational epigenetic changes) do not cause the NHL initiation but are rather part of the proliferation and pro-survival process that develops later during the growth of the NHL. (Emphasis added) 1033 In relation to this latter point, as Professor Prince explained in his first report (at [197]), "[i]n summary, although epigenetic changes are commonly observed in B-cell NHLs, they are generally considered to be late events that contribute to, but are not proven drivers of, the initiation of [NHL-genesis]" (emphasis added). He also noted (at [200]) with respect to studies involving glyphosate and/or GBFs that "epigenetic changes have been observed in some in vitro lymphocyte studies (where lymphocytes have been exposed to glyphosate-based herbicides)" but that "these in vitro changes are inconsistent and non-specific and there is no evidence that they induce lymphoma-genesis. These epigenetic changes are not dissimilar to changes that we observe in aging cells" (emphasis added). 1034 In cross-examination, Professor Prince gave further evidence as follows (T488.5-25): MR FINCH: And I will come back to that article in a moment. So we will spend a little time on that, not much. Professor Prince, what's your view about the significance, if any, of epigenetic alteration? PROFESSOR PRINCE: So my opinion is, having looked at the data pretty carefully, the issue is about the level of evidence of the epigenetic - true epigenetic influence. In other words, what can - what we see - and I agree with the studies - is that we see hypermethylation in some of the promoters and we see hypomethylation across the genome and we know that that is associated with lymphoma. The key, though, is that there's no studies that have shown a clear association between those and the expression of genes. So one of the things that we clearly show - have to show in the laboratory is that those genes that are being methylated or hypomethylated actually somehow changes expression. Now, there is one paper, which is a later Wozniak paper, that comments that there is expression changes but, in fact, when you look at that paper it's not correlated with the methylation status. So something is changing expression but the methylation isn't. And so for me to be convinced that the glyphosate is having an impact on the pathogenesis of lymphoma, I need to see the hyper or hypomethylation on the specific gene and then I need to see a change in the gene expression and then preferably the protein production. All of those things are possible. In fact, there's a lovely paper showing exactly that with the use of antibiotics. So just because you can see these changes it doesn't, last of all, necessarily mean that it leads to lymphoma. 1035 Professor Prince conceded that the "disruption of the proper functioning of epigenetic processes can cause NHL" (T403.37-46), but qualified that statement by explaining (T405.4-20): MR CLEMENTS: … I suggest to you that what follows from that is if exposure to glyphosate disrupts the proper functioning of epigenetic processes in B-cells, that is a biologically plausible mechanism by which exposure to glyphosate can cause NHL, isn't it? PROFESSOR PRINCE: It's a biologically plausible theory or hypothesis. It's not a biologically plausible mechanism because we haven't proven the mechanism. MR CLEMENTS: In other words, it's plausible but you say not yet established by experiments; is that a fair - - - PROFESSOR PRINCE: Yes. 1036 Professor Smith agreed with Professor Prince's assessment insofar as the mechanism has not yet been established by the evidence (T608.4-16): PROFESSOR SMITH: … I agree with Professor Prince we don't have absolute proof that certain genes are changed at specific time in a specific level but overall the evidence where you see multiple epigenetic changes in genes, that we know are important in the development of NHL, and this predictive hypomethylation that you see, I think, is very strong evidence that aberrant gene methylation and DNA methylation play a role in development of NHL from glyphosate exposure. 1037 As Professor Prince explained earlier in cross-examination (T607.33-45): MR CLEMENTS: Yes. Hence, I suggest to you, the conclusion that ought be drawn is that the because several studies show that glyphosate induces epigenetic changes in human cells and epigenetic changes in human cells can cause NHL, that supports the proposition that glyphosate is a human carcinogen and can cause NHL, doesn't it? PROFESSOR PRINCE: No. As Sir John just pointed out, you can change - you need to see a significant change of gene expression for that hypothesis. And so the significant change can both be firstly demonstrated change and there's lacking data in the literature about a clear demonstration of that change, both methylation and histone modification, and then that change in expression needs to be clinically significant and translatable to the development of lymphoma. So those steps are missing and that's why I have to disagree with you.
Fifth hypothesised mechanism 1038 I can be even briefer in relation to this hypothesised mechanism. 1039 The fifth hypothesised mechanism is that glyphosate and/or GBFs are preferentially distributed to the bone marrow, where it remains longer than in other tissues. Given that lymphocytes develop from lymphoid stem cells, which develop in the bone marrow, it is said that they may there be exposed to the genotoxic and mutagenic effects of glyphosate and/or GBFs. 1040 In support of the fifth hypothesised mechanism, Mr McNickle relies on Dr Sawyer's opinion that exposure to glyphosate and/or GBFs can cause NHL in humans and that it is preferentially distributed to the bone marrow (Conclave F Joint Report (JRF) (at [36]-[40])). It is said that Dr Sawyer's opinion is cumulative evidence which adds to the opinion evidence to the same effect given by Dr Flecknoe-Brown, Professors Smith and Checkoway. 1041 For reasons that will become apparent, Dr Sawyer withdrew his evidence on the hypothesised mechanisms, deferring to the "oncologist" (T2036.24-25). Further, Professor Prince and Dr Flecknoe-Brown did not give evidence in support of the fifth hypothesised mechanism and, accordingly, I do not consider the evidence supports the existence of the fifth hypothesised mechanism.
VII Conclusion 1042 The third stream might be regarded as the strongest aspect of the evidence in favour of Mr McNickle's case theory (although I use this adjective in a relative sense). 1043 The evidence established that: (1) genotoxic effects on human blood cells can be observed from exposure to glyphosate and/or GBFs, and therefore exhibit KC2 (genotoxicity) (see above (at [903]-[907])); (2) glyphosate and/or GBFs induce epigenetic changes, including, among other things, methylation of the DNA (see above (at [935])); and (3) glyphosate and/or GBFs induce oxidative stress which can damage the DNA (see above (at [949])). With that said, having regard to the mechanistic evidence, the KCs, and the hypothesised mechanisms of action, I am not satisfied that the whole of the mechanistic evidence supports the conclusion that there exists a biologically plausible mechanism by which glyphosate and/or GBFs can cause NHL. 1044 Notwithstanding my findings as to the KCs, as I have explained, the mechanistic evidence stream turned on the "significance" question: that is, a chemical may "tick the box" of one or more of the KCs, but the next step of establishing a biologically plausible mechanism is the relevant question for the purposes of concluding that the mechanistic evidence supports Mr McNickle's case. This is particularly evident in relation to KC2 where although the weight of the evidence demonstrated that glyphosate and/or GBFs may exhibit genotoxic effects in artificial in vitro environments, the mechanistic evidence did not support the conclusion that that finding is translatable to a genotoxic risk to humans in the real world due to either the use of excessive doses or the potential to detect a genotoxic signal at ever-lower concentrations of glyphosate by modifying in vitro conditions and using different assays (see above (at [901])). Similarly, in relation to KC4, it is evident that there does not exist a data-rich or robust association between epigenetic changes induced by exposure to glyphosate and/or GBFs (such as hypomethylation) and the development of NHL in humans. As Professor Smith noted in his 2020 article "[t]he difficulty with [KC4] is that the relevance of a particular epigenetic change for carcinogenesis by a specific agent may not be clear and causality is hard to establish" (see above (at [1032])). 1045 For those hypothesised mechanisms which did not relate directly to one or more of the KCs, Mr McNickle devoted some time to the second hypothesised mechanism and Wang (2019). 1046 The evidence established, however, that Wang (2019) suffered from several significant methodological problems, which may be summarised as follows: (1) NHL and MM are different diseases with different cells of origin which limits the extent to which any findings can be applied to the pathogenesis of NHL in humans (see above (at [1001]-[1004])); (2) the use of Vk*MYC mice, which are bred to produce large amounts of MYC protein (which, in turn, can influence the production of AID) resulted in inconsistent findings as to the upregulation of AID (see Figure 5 and above (at [999]-[1002])); (3) Dr Flecknoe-Brown conceded that the study suffered from a number of significant methodological flaws, including, to highlight three: (a) that only one "representative" mouse was demonstrated for each experimental condition; (b) the authors did not record the actual glyphosate levels in any of the surviving mice; and (c) Dr Flecknoe-Brown and Professor Prince were not confident that the data presented in the study demonstrated reliable evidence that glyphosate and/or GBFs cause an upregulation of AID; (3) Professor Smith and Dr Juberg agreed that the dose used in the study was "excessive" compared to any dose a human would be exposed to in the real world; and (4) even in the event that Wang (2019) is evidence that glyphosate and/or GBFs cause an upregulation of AID, there is no compelling evidence that there exists a biologically plausible mechanism whereby the mutagenic substances in glyphosate and/or GBFs can lead to the development of NHL by mutation of the EZH2 gene. 1047 For these reasons, having regard to the whole of the mechanistic evidence, I am not satisfied that there exists a biologically plausible mechanism by which the use of or exposure to glyphosate and/or GBFs can cause NHL in humans.
I Introduction 1048 Conclave F concerned the absorption and exposure of glyphosate and/or GBFs. The two expert participants in this conclave were Dr Sawyer and Dr Jeffrey Driver. Dr Sawyer was engaged by Mr McNickle and Dr Driver was engaged by Monsanto. 1049 The concurrent evidence session involving both experts was due to commence in the sixth week of the initial trial. However, on the evening of the prior Friday, the solicitors for Monsanto sent the following email to my Associate: Dear Associate The Respondents wish to provide an update in relation to Conclave F which is scheduled to commence on Monday, 9 October. In light of the common questions and the written and oral evidence provided to date, the Respondents do not consider it necessary and do not intend to call Dr Jeffrey Driver to give evidence at this initial trial. We have copied the Applicant's solicitors to this email. … 1050 As foreshadowed in this email, Dr Driver was not called as a witness and hence Monsanto did not rely on Dr Driver's report dated 18 March 2022 (Driver Report); and, by consent of the parties, JRF was redacted to remove the portions setting out Dr Driver's opinions before being adduced into evidence. As a result, the evidence comprising reports prepared by the experts in relation to Conclave F that were ultimately tendered (subject to limitations pursuant to s 136 EA) is the JRF and the Expert Report of Dr Sawyer dated 8 September 2021 (Sawyer Report). 1051 Several consequences are said to flow from Monsanto's forensic decision not to call Dr Driver, primarily that a Jones v Dunkel inference should be drawn, to which I will return later in this section. More importantly, however, as I foreshadowed earlier, Dr Sawyer's evidence revealed some not insignificant issues. 1052 Before turning to those issues, it is convenient first to give an overview of the JRF and some key concepts relating to absorption and exposure.
Absorption 1053 For a compound or chemical to reach a tissue, it usually must be taken into the bloodstream from a route of exposure, which is generally via the oral, dermal and/or inhalation route. For example, following oral exposure, chemicals often enter the body via mucous surfaces like the digestive tract (intestinal absorption), before being taken up by the target cells. Factors such as poor compound solubility, gastric emptying time, intestinal transit time, chemical instability in the stomach, and inability to permeate the intestinal wall can all reduce the extent to which a chemical is absorbed after oral administration (at JRF [21]). 1054 Dermal absorption is influenced by factors such dose density, duration of exposure, molecular size, lipophilicity, water solubility, and skin thickness. Absorption critically determines the compound's bioavailability (that is, the percentage of the chemical that makes it into the body). Routes of administration are an important consideration for pharmacokinetics and dynamics (an area of science which measures movement of chemicals into and throughout the body and their interaction with target or affected tissues, cells, and biochemical processes) (at JRF [15], [21]). Some factors can increase dermal bioavailability such as chemicals, for example, dimethyl sulfoxide that affect barrier function, irritations of the skin, sweating, dermal inflammation and epidermal damage from scratches, cuts, and other injuries (at JRF [22]). 1055 It is said that absorption of Roundup ingredients, glyphosate and polyoxyethylene amine occurs principally through the skin, which is called dermal absorption or "percutaneous absorption". The skin is the predominant route of exposure for most occupational uses of pesticides, including GBFs. As a result, knowledge of skin penetration or dermal absorption is critical to evaluate absorbed dose of a pesticide in an operator. Airborne absorption via inhalation of glyphosate is more efficient but contributes much less to systemic dose than dermal absorption. (at JRF [23]-[25]).
Distribution 1056 Compounds are most often carried to its target site via the bloodstream. From there, the compound may distribute into muscle and organs, usually to differing extents. After entry into the systemic circulation, either by intravascular injection or by dermal absorption from any of the various extracellular sites, the chemical is subjected to various distribution processes that tend to lower its concentration in plasma while the concentration at other sites may differ (at JRF [26]). 1057 Distribution is defined as the reversible transfer of a chemical between one compartment (for example, fat, blood, muscle, and bone) to another. Some factors affecting chemical distribution include regional blood flow rates, molecular size, water and lipid solubility and binding to serum proteins or bone minerals, forming a complex (at JRF [27]).
Metabolism 1058 Compounds begin to break down as soon as they enter the body. The majority of small-molecule chemical metabolism is carried out in the liver. As metabolism occurs, the initial (parent) compound is converted to new compounds called metabolites. When metabolites are pharmacologically inert, metabolism deactivates the chemical and usually reduces the toxicity effects on the body (at JRF [28]).
Excretion 1059 Compounds and their metabolites are removed from the body via excretion, usually through the kidneys or the liver. Unless excretion is complete, accumulation of foreign substances can adversely affect normal metabolism (at JRF [29]). 1060 There are three main sites where systemically circulating chemical excretion occurs. The kidney is an important site, and it is where products are excreted through urine. Hepatic faecal excretion is the process that initiates in the liver and passes through to the gut until the products are finally excreted along with waste products or faeces. Excretion through pulmonary exhalation can occur with certain volatiles (at JRF [30]). 1061 Excretion or elimination of a chemical can be characterized by its half-life (that is, the time it takes for the concentration of that substance to fall to half of its initial value). For human exposure and dose assessment, human data are the most relevant and reliable for estimating half-life. However, given ethical considerations when dealing with humans, such studies have unavoidable limitations resulting in some uncertainties in interpreting the data. Human biomonitoring studies (studies which measure chemical concentration in biological samples such as blood or urine) with multiple collection intervals allow estimates of excretion rate of absorbed dose (at JRF [31]-[32]).
H.2 The Absorption and Exposure Evidence 1062 Mr McNickle contends that Dr Sawyer's evidence supports the conclusion that glyphosate and/or GBFs are capable of being absorbed through human skin and into circulation in the body, and that exposure to glyphosate and/or GBFs increases the risk of NHL and can cause NHL in humans (at JRF [36], [40]). 1063 These submissions were developed as follows. 1064 First, Mr McNickle relies on Dr Sawyer's opinions in the JRF that absorption of Roundup products occurs principally through the skin via dermal absorption (and to a lesser extent inhalation), which occurs at an approximately permeability factor of between 2-3% (at JRF [23], [36], [90]). Once it is absorbed, glyphosate is distributed via the vascular and lymphatic system to all tissues in the body (at JRF [92]). Roundup Products can be absorbed by exposed skin and/or by penetrating through clothing which comes into prolonged contact with the skin (at JRF [147]). Further, although aerosol inhalation represents a minor route of exposure (20% or less), it is nonetheless relevant particularly when spraying in a horizontal position and should be afforded weight (at JRF [153]). It is also necessary to consider exposure through irritated or damaged skin in the light of studies that have demonstrated that glyphosate deposition in damaged skin is approximately five times that of healthy skin, and penetration through damaged skin is increased 20-fold (at JRF [154]). 1065 Secondly, it is said that: (1) Professor Prince and Dr Flecknoe-Brown accepted that glyphosate can be absorbed through human skin exposed to Roundup Products (at JRA [182]); (2) that glyphosate absorption through the skin is supported by a number of studies (including Chang and Andreotti (2023) and Sidthilaw (2022), which studies found that glyphosate was present in the urine of individuals exposed to GBFs (see also T623.1-625.5)); (3) insofar as Dr Sawyer's opinion that dermal absorption of glyphosate occurs at an approximate permeability factor of between 2-3% (at JRF [36]), that opinion is consistent with the "Dermal Penetration Figure" of 3% referred to in Monsanto's Operator Exposure Assessment for MON2139 (at 2) (at JRF [80]). 1066 Thirdly, as noted earlier (at [1040]), Dr Sawyer contends that exposure to glyphosate and/or GBFs increases the risk of NHL and can cause NHL because glyphosate is cleared more slowly from the bone marrow than other parts of the body (which opinion is relied on by Mr McNickle as cumulative evidence to that given by Dr Flecknoe-Brown, Professors Smith and Checkoway). It is said that Brewster (1991) demonstrates that following initial absorption, the concentration of glyphosate is shown to decrease in the tissues examined over the time frame with the rate of elimination from the plasma far exceeding the elimination rate from the bone marrow (at JRF [38]). Other than the carcass, the last organ or tissue to clear the glyphosate was the bone and bone marrow. Dr Sawyer notes that Brewster (1991) "clearly demonstrated that there was significant retention of glyphosate in bone marrow versus plasma. This is a highly significant finding as bone marrow can play a fundamentally important role in the early development of NHL" (at JRF [38]).
I Introduction 1067 It will be recalled that in the context of the first stream, I recorded (at [130]) that with the notable exception of one witness in this proceeding, issues going to credit are not the centrepiece of this case. That witness is Dr Sawyer and, regrettably, for reasons that will shortly become apparent, issues going to his credit assumed some significance. 1068 Before going further, however, it is well to emphasise two related matters. 1069 The first is that I have reiterated more than once (at [32]-[33]) that the mere fact that an expert witness has a pre-existing opinion on a key issue is an infirm basis for rejecting the expert's opinion evidence or placing less weight on it. The focus of the Court is not the preconceived opinions of the relevant expert; but the overall substantive merits of their evidence given in the witness box and in their expert reports. 1070 The second matter is that both parties made extensive oral and written submissions as to Dr Sawyer's credit which, broadly speaking, relate to the allegation that he is a professional "glyphosate-plaintiff" expert. But without wishing to add to an unduly long judgment, I do not propose to set them out in full and to focus on those aspects of issues going to Dr Sawyer's credit which, in my view, merit particular attention. 1071 In the following subsections, I will set out briefly Dr Sawyer's background before turning to highlighting several matters informing my conclusion as to his creditworthiness.
II Background 1072 Dr Sawyer is a professional toxicologist with a doctorate in toxicology from the Indiana University School of Medicine. Dr Sawyer has an associate degree from the State University of New York Agricultural and Technical College at Morrisville in 1976; a Bachelor of Science degree in biology from the State University of New York in 1978; and a master's degree in cellular and molecular biology, also from the State University of New York, in 1982. He subsequently earned a doctorate in toxicology from the Indiana University School of Medicine in 1988 (Sawyer Report (at [13])). 1073 During his training at the Indiana University School of Medicine's Department of Toxicology and Pharmacology, Dr Sawyer studied under the late Dr Robert Forney. Dr Forney was the department chairman, the director of the State Department of Toxicology. Dr Sawyer studied the mechanisms and toxicity of organophosphates and organophosphorus chemicals as specialised research with respect to sarin and carbamates were ongoing within the department. He also received forensic training and worked in the State Department of Toxicology laboratory facility at the medical centre in Indianapolis, Indiana, performing forensic analyses for poisons, pharmaceuticals, drugs of abuse and alcohol (Sawyer Report (at [14])). 1074 Subsequent to his training, Dr Sawyer served full-time in public health as the toxicologist for the Onondaga County Department of Health, Syracuse, New York. His work experience included municipal and civil risk assessment, evaluation of environmental toxic exposures including petroleum products, design and execution of environmental monitoring, health assessment studies, methods to identify and effectively reduce community toxic exposures and assessment of public health matters. Further, during his employment as toxicologist for the health department, he assisted the medical examiner's office with investigations of accidental and intentional poisonings (Sawyer Report (at [15])). 1075 Dr Sawyer has previously been certified by the State of New York's Department of Health in forensic toxicology and received certificates of qualification as a clinical laboratory director and as a licensed environmental laboratory director by the States of New York, New Jersey, California and South Carolina. He has also previously been trained and certified under OSHA 29 CFR1910.120 for Hazardous Waste Operations and Emergency Response (Sawyer Report (at [16])). 1076 Dr Sawyer is presently the toxicologist for Toxicology Consultants and Assessment Specialists, LLC, in Sanibel, Florida. He has previously served as a peer-reviewer for the journal The Forensic Examiner and as a member of its editorial board and was previously an adjunct assistant professor at the Upstate Medical Centre in the Department of Medicine at SUNY Health Science Centre. Dr Sawyer is a member of various professional societies including the Sigma Xi, the Scientific Research Society, the American Academy of Forensic Sciences and the International Association of Forensic Toxicologists (Sawyer Report (at [17])).
III Credit Findings 1077 Dr Sawyer was an unsatisfactory witness. His evidence gave me some pause and it is well to highlight those aspects which caused me concern. 1078 First, Dr Sawyer's first piece of glyphosate-litigation in which he gave sworn evidence was Johnson v Monsanto (Cal. Superior Ct., San Francisco) (T1961.29-32), where he commenced as a consulting expert on the case in late 2016 or early 2017 (T1961.34-35). Dr Sawyer confirmed that by the time he gave evidence in that litigation in July 2018, he had determined that glyphosate was a human carcinogen (T1962.37-39). Dr Sawyer gave evidence that he has not resiled from that view since then (T1970.1-3, T1970.33-35, T2006.26-34). He accepted that when he was retained by Maurice Blackburn in this proceeding, he held a fixed view that glyphosate was carcinogenic (T2007.42-43) and that he proposed to give evidence in this case consistent with evidence he gave in glyphosate litigation in the United States (T2006.32-34): MR CRAIG: … And as you've said earlier today, you had formed by that stage the opinion that glyphosate was carcinogenic?---Yes. MR CRAIG: And you had determined your methodology with respect to exposure days based on the epidemiological studies?---Yes. MR CRAIG: And what you were proposing to do in this case is give evidence consistent with that you had already provided in the Pilliod litigation?---Yes. With respect to general causation, absolutely. 1079 Secondly, Dr Sawyer presented as anything but a disinterested and dispassionate witness. He described Monsanto as a "criminal" and "unethical" organisation (T1998.36-38; T2000.33-39). Dr Sawyer initially asserted that it was only after his expert conclave in this proceeding that he formed the view that Monsanto engaged in "criminal" conduct (T2000.7-8), but later gave evidence that it was since "approximately December 2022" that he held the view that Monsanto has interfered with the publication of various articles, including articles authored by him (T2021.31-32). Dr Sawyer gave evidence (T1998.36-41): DR SAWYER: … And I also have proof in 13 different emails from Monsanto how they intentionally interfered and stopped two publications, which was criminal in my opinion, and I didn't want to be in a - I didn't check with any lawyers. This was a scientific article that I submitted to a peer review journal. It had nothing to do with a law firm. I don't even know if the law firms knew I was writing the article. 1080 It later emerged that no later than November 2022 that Dr Sawyer had formed the view that: (1) Monsanto may sabotage or interfere with his publication (T2021.26-27; T2026.41-46); (2) he was concerned about that occurring (T2021.23-24); (3) he refused to answer questions on deposition about his proposed publication with Dr Benbrook and Dr Mesnage (T2021.1-24); (4) he held the belief that Monsanto has been guilty of ghost-writing (T2022.1-15); and (5) he had expressed the view that Monsanto had engaged in unethical behaviour "in any way you looked at it" (T2022.17-33). 1081 Dr Sawyer later gave evidence that he had a suspicion about Monsanto's conduct dating back to the Johnston trial in the United States, which occurred in July 2018. He then gave the following evidence (T2023.3-30): MR CRAIG: And you allege that just prior to that trial somebody from Monsanto or related to Monsanto stole the trash from outside your house?---I don't know that I - you know, I made it clear that I have no evidence that Monsanto did that. But mysteriously my trash was stolen the night before it was to be picked up. It was very unusual and well documented by other family members. Cans were ..... but the trash was gone. As a consequence of that you formed the view, as you expressed on oath at lines 8 and 9, that you believe that the trash had been stolen by somebody related to Monsanto, didn't you?---I believe it was possible that it was related to Monsanto because it coincided with the full week of my deposition. I think I was deposed four or five days that week and then on Saturday or Sunday the trash was stolen. Two large cans. The containers were left behind. In your sworn evidence - sorry, in your sworn deposition in the Cody proceeding, you didn't say you thought it was possible, you thought that somebody from - related to Monsanto had stolen your trash, didn't you?---Not exactly. If you read the full transcript - - - HIS HONOUR: I don't think that's an accurate reflection of what he said. He believed - he agreed with the proposition he believed that it was somebody related to Monsanto. DR SAWYER: Right. But I was not certain of that and I made that clear too that I couldn't say with any certainty. I couldn't prove it. MR CRAIG: Thank you. But your belief, as expressed at the deposition by sworn evidence, Dr Sawyer, was that it was somebody related to Monsanto that had stolen your trash?---Yes. 1082 Thirdly, Dr Sawyer gave evidence that he had deliberately destroyed documents that he knew were required to be produced in glyphosate litigation in the United States. Dr Sawyer understood that when he attends a deposition in the United States, he could be compelled to produce documents (T1959.1-2); that he needed to follow that compulsory process (T1959.4); and that such a notice to produce documents is compulsory (T1997.9-10). He gave evidence, however, that he was prepared to not comply with any compulsory process that, in his view, was an "unethical, illegal request" (T1997.37-39). 1083 After receiving such a compulsory notice in glyphosate litigation in the United States in January 2023 (Berns, et al. v. Monsanto (Circuit Ct., St. Louis, MO)) ordering the production of documents relating to a publication that he co-authored with Dr Benbrook and Dr Mesnage, Dr Sawyer destroyed documents that, to his knowledge, came within the scope of the notice (T1997.45-1998.24): MR CRAIG: Now, after publication of your article with Dr Benbrook, you intentionally destroyed all of the documents relating to the publication of that document, did you not?---Yes, because Monsanto was demanding documents that - I checked with the journal and also the international rules, and to disclose information in a paper that was undergoing peer review, including information that could lead Monsanto to contact the peer reviewer, it is unethical and illegal. MR CRAIG: And you unilaterally destroyed those documents without checking as to whether that was a legally available course to you, didn't you?---I did check with the journal and the - there's an actual international agency that lays out the rules for peer-reviewed literature, and I - I read those guidelines. And - - - MR CRAIG: You took no step to have that request set aside, did you?---I don't know what that means. MR CRAIG: Well, you didn't communicate with your lawyers, with the lawyers acting for Berns or with Monsanto to say, "I'm prevented from providing you with this information by journal requirements, and I refuse to do so," did you?---I read the guidelines and contacted the journal personnel and learned that - and I already knew this, but just double-checking that any documents - the rough draft manuscript, etcetera, that's under peer review is completely confidential. And I also have documents showing that Monsanto intentionally interfered with two different publications in the past. And - - - MR CRAIG: You destroyed those documents because you didn't want Monsanto to get them, didn't you?---That's correct. And interfere with it getting published, as they did in two other cases, which I have the documents to prove. 1084 Dr Sawyer later gave evidence (T2000.41-43): MR CRAIG: And so you took it into your own hands to destroy documents rather than allowing Monsanto to examine on them in the course of a deposition process?---You bet. I did. I did the right ethical thing, and I stand behind my actions. 1085 Fourthly, it is apparent that the majority of Dr Sawyer's work and income is derived from giving expert evidence for plaintiffs in glyphosate-litigation. He gave evidence that: (1) most of his income has come from litigation consulting over the past 20 years (T1970.44-45); (2) he has given evidence in approximately 34 American States (T1970.41-42); (3) has testified as a hired expert in approximately 300 or more depositions (T1971.7-8); (4) has been deposed as an expert witness in over 200 trials; (5) has prepared over 100 reports, spanning 49 proceedings in which there has been a deposition or trial, in Roundup litigation (T1968.36-1969.2); (6) conducts a litigation consulting business through a website "experttoxicologist.com" (T1971.28); (7) his largest clients have "very much" been plaintiffs' attorneys in Roundup cases (T1972.27-29); (8) he had received approximately US$2.5 million in fees in connexion with Roundup litigation in the United States over a period of six years (T1972.31-33); (9) his rate for Roundup matters is US$785 per hour and full-day rate for giving evidence at a deposition or trial is US$8,200 per day (T1972.38-1973.16); and (10) at the time he was engaged by Mr McNickle in this proceeding, more than half of his income was derived from Roundup cases (T2008.17-18; T2008.24-28). 1086 Fifthly, Dr Sawyer gave evidence that he approached the task of giving expert evidence in this proceeding in the same manner as he would in the United States. When asked about the litigation process in the United States, his understanding included that he could be first retained either as a consulting expert or a testifying expert (T1957.19-20), and that one can change from being a consulting in a case to a testifying witness (T1958.6-7). This caused me to ask Dr Sawyer, having familiarised himself with the Expert Witness Code of Conduct, whether there is anything he did in relation to approaching his role as an expert in this proceeding differently from the way in which he would have approached giving evidence, and has approached giving evidence, in United States proceedings (T1989.29-37), to which he responded (T1989.47-1990.16): DR SAWYER: … The only difference I see is actual written questions in black and white that are very succinct and clear. I never in my experience have been greeted with a very specific list of questions. And in the US, I know attorneys are very fearful of writing such because, in the US, I'm always asked to turn over my file. And I turn it over. I turn over everything, and sometimes the - so - so what happens in the US, the questions are usually asked verbally by phone. So I see that as a - as a - an outstanding difference. In terms of item 3.2(b), that your opinions are based wholly or substantially on specialised knowledge arising from your training and/or experience, that's exactly what I do. However, in the US, I - I don't recall ever being asked that question in black and white, and I think it's a very good question. HIS HONOUR: All right. Well, thank you for that. So I take it from that answer that essentially you proceeded - apart from the fact that you were asked specific questions in writing in this engagement, your approach to it was essentially the same as that you would take in relation to providing expert evidence in an American case. Would that be fair?---Yes. 1087 Sixthly, Dr Sawyer accepted that because of his extensive experience in glyphosate-litigation, he can "cut and paste" sections of his reports and include them in new reports (T1975.1-10; T1986.27-43). He accepted that, subject to any such additions and subtractions, the opinions in the reports remain essentially the same (T1975.9-10) and conceded that, in his report in the present proceeding, he had cut and pasted sections from reports he prepared in other Roundup cases, including work that he had prepared in 2021 and 2020 (T1987.1-26, T1988.24-26), without disclosing that he had replicated or recited those opinions (T1987.28-30). The copied sections came from reports that he had prepared before he received the questions or letter of instruction from Maurice Blackburn in this proceeding (T1987.32-36; T1988.1-18).
IV Consideration 1088 Following Dr Sawyer's cross-examination, senior counsel for Monsanto submitted that in the light of his evidence, the Court cannot proceed on the basis that the JRF is the product of two independent expert witnesses doing their best to assist the Court in arriving at the truth of the scientific evidence consistently with the Expert Witness Code of Conduct (T2044.35-38). Accordingly, Monsanto made an application to exclude Dr Sawyer's evidence on the basis that it might give rise to a danger of unfair prejudice or be misleading or confusing, and that as a result, the Court should exercise its discretion to exclude it pursuant to s 135 EA. 1089 In McNickle v Huntsman Chemical Company Australia Pty Ltd (Evidentiary Ruling) [2023] FCA 1268, I dealt with Monsanto's application and noted then (at [14]-[21]): [14] None of this is a bolt from the blue. [15] As long as two and a half years ago in McNickle v Huntsman (Expert Evidence), I anticipated that an objection will be made by Monsanto to the evidence of, inter alios, Dr Sawyer, who I described then (at [17]) as a witness: [w]ho has allegedly given evidence in 28 proceedings apparently dealing with the Expert Issues. [16] I went on to note (at [18]) that: Cognisant of potential issues of adversarial bias, particularly in a case such as the present involving allegations of scientific manipulation, on 22 December 2020 (and having abandoned the proposed reference), I indicated to the parties that the Court would be best assisted if the experts chosen by the parties in each area of speciality were non-partisan and were "truly independent about the issues and about their view": see T9.43-7. [17] As I indicated to the parties then (at [21]), if there was to be some attack on the independence of, among others, Dr Sawyer, then, consistently with the overarching purpose in Pt VB of the Federal Court of Australia Act 1976 (Cth), it would be utile to ensure that any such objection was resolved sooner rather than later. During that discussion, I had referred to the possibility that it may be appropriate to make an order facilitating an advance ruling pursuant to s 192A of the Evidence Act. [18] As it happened, Mr McNickle opposed this course. As I explained then (at [32]): Both in written submissions in advance of the case management hearing and orally, Mr Rush QC, counsel for Mr McNickle, submitted that it would be beyond power for the Court and the parties to embark on a process of presently determining whether any expert evidence which may be given by any expert witness would be excluded pursuant to s 135 of the Evidence Act or on admissibility grounds. Five points were made: (1) First, the "threshold jurisdictional" question for exercising the discretion in s 192A has not been satisfied. Section 192A may be enlivened where a "question arises" in relation to any of the three matters set out in subparagraphs (a)-(c) of that section. No such question presently arises. This is said to be because: (a) there is presently no "evidence" proposed to be adduced and thus, subparagraphs (a) and (b) of s 192A cannot apply; and (b) no question arises about the giving of leave, permission or direction under s 192: see s 192A(1)(c). (2) Secondly, further to the threshold issue, it would be inappropriate for the Court to exercise the discretion under s 192A at this time. Here, no expert reports have been filed, and as such, the Court would be making its discretionary decision in the absence of information which is critical to that decision. It was said that the Court is in no position to, and ought not to, make an advance ruling where all matters relevant to the issues have not been, and cannot be, ascertained. (3) Thirdly, difficulties arise in relation to any contemplated rulings since it is not clear what precise rulings would in fact be sought by Monsanto. (4) Fourthly, while it seems the process presently contemplated is intended to avoid disruption to the trial date, it will have the opposite effect. It was said that Monsanto appears to make a global complaint in respect of all of Mr McNickle's experts, and as such, five experts would need to give evidence and be cross examined at a voir dire. The processes around production of documents and materials relevant to such a voir dire will take further time, and will inevitably lead to delay in the balance of the timetable to an initial trial. (5) Fifthly, Order 1 made on 5 March 2021 focuses the inquiry concerning the independence of the experts and whether those experts have expressed certain opinions previously. It was submitted that the questions posed indicated a misunderstanding of what is required by the notions of "independence" and "impartiality" in the expert evidence context. It was further submitted that even if an expert has expressed an opinion previously (even on many occasions), this does not mean that the expert is not independent or impartial within the court processes. It was said that it simply does not follow from the fact that an expert has extensive experience and expertise, and based on that experience and expertise has formed opinions about certain questions of science (which may have been expressed previously, including in previous litigation), that the expert lacks independence or impartiality. Accordingly, it was said that as a consequence, the rulings proposed are based on an incorrect premise. [19] The fifth point was repeated during oral submissions today: that is, any issues concerning a perceived lack of independence and impartiality cannot go to issues of admissibility but rather only to weight. In this respect, I was referred to the judgment of Wigney J in Rush v Nationwide News (No 5) [2018] FCA 1622 (at [35]-[36]), where his Honour noted: [35] The relevant principle established by those and other authorities was neatly summarised by Dodds-Streeton J in Ananda Marga in the following terms (at [35]): In my opinion, relevant authority establishes that while (as reflected by the Federal Court Practice Note and like curial protocols) objectivity and independence are sought of expert witnesses, such qualities are not preconditions of competence, even in the case of expert witnesses. The sanction for failure to fulfil the obligations imposed by relevant authority and curial protocols is not the exclusion of the expert's evidence, but rather, the significant risk that it will fail to persuade. [36] In other words, an actual or perceived lack of independence, impartiality or objectivity of an expert witness goes to weight, not admissibility. [20] In response to that argument, I expressed the following views in McNickle v Huntsman (Expert Evidence) (at [34]-[35]), to which I adhere: [34] In Rush, Wigney J (at [11]-[43]) dealt with what was described as "the independence ground", which, unsurprisingly, was an argument advanced by the publisher in that case that the alleged lack of independence of two experts proposed to be called by the applicant in a defamation proceeding ought not be admitted or alternatively excluded. His Honour dealt with an argument that the applicant had not complied with Pt 23 of the FCR because, in the circumstances of the case, the expert was an advocate for the cause of the party who proposed to call him. In doing so, his Honour dealt with a decision of Mortimer J in Guy v Crown Melbourne Limited [2017] FCA 1104, expressing (at [36]) the view that: … an actual or perceived lack of independence, impartiality or objectivity of an expert witness goes to weight, not admissibility. [35] I think Mr McNickle puts the point too highly. A broad point was being made by his Honour in Rush, which is no doubt correct in the general run of cases. But I do not think this means there cannot ever be circumstances in which a lack of impartiality or objectivity would go to more than weight and would form a basis by which the proposed expert evidence would not be admitted. One would conceive of some circumstances where proposed expert evidence could fail to survive the balancing exercise required when applying s 135 of the Evidence Act, in that receiving such evidence would be of such limited assistance (by reason of its lack of independence, impartiality or objectivity) that it would be unfairly prejudicial to the other party or would result in an undue waste of time. [21] As is evident from the above, the position that Mr McNickle took in the early interlocutory stages of this proceeding was clear: the Court can only, and must only, deal with any objections to the expert evidence in the context of the initial trial. I noted then (at [39]) that I had formed no view as to whether or not the objections foreshadowed had any merit, but that I was nonetheless conscious they had been advanced by responsible counsel and solicitors who had formed the view that there is a reasonable basis for saying there was a want of independence on behalf of the relevant experts such that their evidence should be the subject of (at least) discretionary exclusion. I went on to note (at [41]-[42]) that: [41] I did think initially that it was possible for an advance ruling hearing to be held some time prior to the initial trial if it was with the active cooperation of both parties and there was no objection to this course. However, given the opposition to this course by Mr McNickle, I am not convinced that this is appropriate. Indeed, there is some prospect that adopting this course would lead to a potential interlocutory appeal. If there had have been cooperation by both parties, I would have grasped the nettle and proceeded to have had an advance ruling hearing in advance of the initial trial, even if, at the end of that hearing, I was persuaded that it was inappropriate for a ruling to be provided. Given that course is opposed, then not without some misgivings, it appears that I will have to leave the ruling on admissibility of the expert material (on presently identifiable grounds) to the initial trial (as is said to be necessary by Mr McNickle). [42] As I stressed above, I have reached no view one way or the other as to whether or not any allegations of a lack of impartiality have any substance. No doubt Mr McNickle will maintain his contention that the evidence given by the nominated experts will be of importance in resolving the issues and carries great weight. All that is yet to be seen. Of course, if at the initial trial the objection which has now been clearly flagged is upheld, I will be required to determine the appropriate remedial response. In determining any remedial measure proposed by Mr McNickle, no doubt Monsanto will submit that its attempt to resolve this issue now pragmatically (which has been objected to) will be a relevant consideration in the event that the objection is ultimately upheld on the basis of material now known to exist or able to be obtained. 1090 I explained then that the consistent position of Mr McNickle (see above (at [32]-[33])) was that the proper approach to assessing the evidence of an expert witness in respect of whom it is alleged that they have not brought an independent mind is to consider the scientific material adduced from any expert and judge it on its merits, irrespective of whether the expert has adhered to a fixed view prior to being engaged to assist the Court or, indeed, irrespective as to whether the expert harbours some justified or unjustified animus towards a party. 1091 Ultimately, I formed the view that it was unnecessary to deal with that submission because the appropriate course was to admit Dr Sawyer's evidence. As I noted then (at [24]-[27]): [24] There can be little doubt that an assessment of the weight of Dr Sawyer's opinion evidence will be the subject of detailed closing submissions. One aspect of that assessment may involve consideration of the forensic decision not to call Dr Driver, another will be the evidence given by Dr Sawyer in cross-examination, including the evidence summarised at Section B above. [25] All these aspects, and others, will require close consideration. The points made by Monsanto today attacking the cogency of the Dr Sawyer's evidence in the context of discretionary exclusion apply equally to the weight that should be afforded to that evidence. I do not propose to express any views here about the ultimate reliance that ought to be placed on the opinions expressed by Dr Sawyer or canvass any of the alleged deficiencies in the evidence relied upon by Monsanto. For the purposes of this ruling, it is necessary I form an impressionistic assessment of its probative value, but to descend into further detail without the benefit of final submissions in a matter such as this, involving complex scientific evidence, would be premature and inappropriate. [26] In exercising the discretion, I have had regard to s 192 of the Evidence Act. Without seeking to list all relevant considerations exhaustively, to exclude the evidence at this late stage of the initial trial would not shorten the length of any hearing. Relatedly, it is relevant that the forensic course taken by Monsanto was not to attack the evidence on the voir dire and then seek to object to the adduction of evidence in chief in the trial (being the more orthodox course), but to allow the evidence in at trial without objection and then seek to discredit and apply to exclude it. Further, weighing significantly in the exercise of discretion is that the topic of the opinion evidence is of some importance given the determinative issues in the proceeding. [27] In the end it must be demonstrated that the danger of unfair prejudice or relevant confusion substantially outweighs the probative value of the evidence. In the light of the potential probative value of the evidence and the reality that the matters now raised by Monsanto can be dealt with through the prism of an assessment of the weight of the evidence, I do not consider that unfair prejudice or confusion is established to a degree necessary to enliven the discretion to exclude the opinion evidence pursuant to s 135 of the Evidence Act.
V Conclusion 1092 I am conscious I am not conducting what amounts to a Royal Commission into various conduct that has occurred between Dr Sawyer and Monsanto and, unaided as I was by any relevant re-examination, I have not been invited to make findings on the cogency of various allegations that Dr Sawyer made during his colourful cross-examination. Irrespective of whether there is any basis for his evident animus, the fact is that it was manifest that Dr Sawyer did hold a real and abiding animus against Monsanto. In circumstances where I repeatedly requested the parties to pay close attention to the law and practice relating to experts as it has developed in Anglo-Australian law, and the desirability of avoiding any actual or apprehended partisanship, it was surprising that someone with the deep-rooted hostility of Dr Sawyer to one of the parties was called by Mr McNickle. Although it is necessary, as I have repeatedly stressed, to reach conclusions on the substantive merits of his opinions, it is unrealistic to consider that assessment can be wholly insulated from the distinct impression I gained from Dr Sawyer's evidence, and his manner of his giving it, that he presented as a "hired gun" and not as an independent expert in the sense contemplated by the Expert Witness Code of Conduct. 1093 It is plain that: (1) at the time he executed the JRF in December 2022, Dr Sawyer, among other things: (a) maintained a belief that glyphosate is a human carcinogen; (b) believed that Monsanto is a criminal enterprise; (c) had deliberately destroyed documents the subject of a compulsory process in glyphosate-litigation in the United States; (d) believed that Monsanto had engaged in illegal and unethical conduct, including by engaging in ghost-writing and inferring with the publication of various articles; and (e) believed that Monsanto (or its agents) had rifled through his rubbish; and (2) by the time he was engaged by Mr McNickle, intended to give evidence in this proceeding consistent with his view as to general causation. 1094 When he entered into Conclave F, Dr Sawyer was charged with the responsibility of forming a view in accordance with the dictates of the Expert Witness Code of Conduct, which provides, inter alia, that "[a]n expert witness is not an advocate for a party and has a paramount duty, overriding any duty to the party to the proceedings or other person retaining the expert witness, to assist the Court impartially on matters relevant to the area of expertise of the witness" (Expert Witness Practice Note, Annexure A (at [2])) (emphasis added). Regrettably, and perhaps inevitably given his fixed views and his hostility towards one the parties, I consider that Dr Sawyer fell short of these standards and acted as an advocate for those that retained him. Having noted this, I will now turn to the underlying substance of his evidence which, leaving aside questions of partiality, has inherent difficulties.
I Introduction 1095 It is important to recognise from the outset that this part of my reasons has, as its point of departure, the notion that the whole of the evidence has established that glyphosate and/or GBFs are genotoxic and/or mutagenic carcinogens. It concerns the question of dose: principally whether the evidence establishes that there is no safe level of exposure to a genotoxic and/or mutagenic carcinogen. It is a discrete question which is not strictly confined to issues arising out of Conclave F and, given some back-and-forth concerning Mr McNickle's case on dose (and its accompanying nomenclature), it necessitates some explanation. 1096 Mr McNickle contends that: (1) there is no safe level of exposure to a genotoxic and/or mutagenic carcinogen; and (2) the extent of the increased risk of developing NHL relates to the intensity and duration of exposure to glyphosate and/or GBFs (T2096.16-2097.14; T2220.41-2223.15; AS [5], [15], [523B]). It is worth noting that implicit in (2) (which I will call the alternative dose proposition) is the notion that glyphosate and/or GBFs are carcinogenic at some threshold dose (hence the terms "threshold carcinogen" or "non-threshold carcinogen"). 1097 Early in the initial trial, I was mindful to dispel any misapprehensions about the way in which Mr McNickle had framed his contentions as to dose (T86.35-87.47): HIS HONOUR: … Mr McNickle contends that any use of or exposure to Roundup herbicide and Roundup Biactive increases an individual risk to developing NHL and could cause an individual to develop NHL. … I might find that I accept that proposition, in which case, I will simply answer yes to question 1. I might find that, well, look, I'm not satisfied that any use or exposure to Roundup Herbicide or Roundup Biactive increases an individual's risk, there might 40 be a risk at a very, very low level but it's only really - I'm only satisfied on the evidence and reasonably satisfied the evidence is capable of causing cancer at a greater level - a greater duration or intensity of exposure, in which case, I would answer yes but qualify that answer. That's the point I made at the last case management hearing where there was certain attempts to reframe the questions. MR CRAIG: Your Honour, our point is a simple one: if your Honour is going to answer question 1 yes, your Honour must determine the dose at which that is said to occur because, implicitly in our learned friend's framing of the question, they contend that an answer of yes is possible, even without identifying for your Honour the dose - - - HIS HONOUR: That's their primary case and their alternative case. Their alternative case is that there's a point where the duration of intensity of exposure means that it's more likely than not that those Roundup products are carcinogenic and will cause an individual to develop NHL. MR CRAIG: And what's really important about that, your Honour, is what they are contending or what is implicit in that contention is that there is a systemic dose at which the product is capable of causing cancer. And they don't adduce any evidence as to that systemic dose. HIS HONOUR: The evidence hasn't started yet. MR CRAIG: Well, your Honour - - - HIS HONOUR: That might emerge during the process of cross-examination for all I know. But they're the two - I don't want there to be any pleading point in this case and I understand that the way they put it is in paragraph 8 [of the applicant's opening submissions] and I think that's within the pleadings and we will see where the evidence takes us in relation to what I described as their primary position and the more nuanced position. MR CRAIG: Yes, your Honour. And I just - at the risk of repeating myself, we accept that it's not a pleading point. In terms, paragraph 26 - - - HIS HONOUR: You say it's a no evidence point. MR CRAIG: It's a no evidence point and it's really important, your Honour, to hone in on the relevance of dose both at the thresholds carcinogen - as any use or exposure and at what your Honour's calling the alternative case which we really would submit to your Honour isn't being pressed in any meaningful way because you didn't hear our learned friend's open on conclave F at all and they haven't adduced any evidence as to systemic exposure in a way that would allow your Honour to determine that so-called alternative case. We say there really is in truth one case and one case only, that is it's an unsafe at any speed case. HIS HONOUR: No, there isn't. And I don't want that just left unanswered on the transcript. That is not the way they're running their case. The way they're running their case is paragraph 8 - now, you might say that the evidence doesn't support that contention but that's a different point. 1098 The issue was revisited when the matter was last before the Court, when senior counsel for Monsanto made the following submissions (T2221.26-42): MS O'GORMAN: If I can note firstly, your Honour, that this second proposition from paragraph 8 of the opening submissions [that is, the alternative dose proposition] is scientifically an entirely different proposition on dose from the one that the applicant addresses in closing submissions, namely, that genotoxic substances necessarily cause cancer at any dose. The second proposition - - - HIS HONOUR: Sorry, you say that's what? MS O'GORMAN: It's an entirely different proposition, and it doesn't flow from the first proposition. The first proposition is genotoxic substances are carcinogenic at any dose, and I will come to address the Calabrese paper specifically on that. HIS HONOUR: Yes. MS O'GORMAN: But the second proposition is that even having established it's carcinogenic at any dose, the risk then increases proportionately as the exposure increases. So there's a linear dose response relationship. 1099 Shortly after that exchange, I made an order that the parties each provide the Court with a note as to whether the evidence establishes that for a genotoxic carcinogen and/or mutagenic substance, there is no safe level of exposure, and as to why the approach adopted by any regulatory agency as to linear extrapolation as a default establishes, as a matter of fact, that there is no safe level of exposure. This was done and Mr McNickle identified the following evidence in support of his primary case as to dose: (1) Professor Smith's evidence that "if the compound is genotoxic, then the US EPA and most of the regulatory agencies throughout the world draw a linear no threshold line to this, and then they - society sets a limit because there is no safe dose, and that's generally accepted" (T1555.29-44); (2) Dr Juberg's evidence: (a) in relation to Professor Smith's evidence at (1), "that that's how cancer risk is done" (T1556.5); (b) that he was not aware of the USEPA having ever set a threshold or safety factor in respect of a genotoxic carcinogen (T1556.12-16); and (c) that there is "great variability between individuals as to how susceptible they are to chromosomal aberrations and or mutations" (T1510.29-43); and (3) Dr Flecknoe-Brown's opinion that there is no safe level of exposure to mutagenic substances (at JRA [201]-[202]). 1100 It is convenient to summarise Mr McNickle's contentions as to his primary case on dose before turning, to the extent necessary, the alternative dose proposition.
II Mr McNickle's submissions 1101 Mr McNickle contends that the evidence adduced from Professor Smith, Dr Juberg and Dr Flecknoe-Brown establishes that there is no safe level of exposure to a genotoxic and/or mutagenic carcinogen. 1102 First, Professor Smith gave evidence that in the human population, there is no safe level of exposure to, and no safe dose of, genotoxic carcinogens (T1551.20-1552.6). A short time later (T1555.29-35) Professor Smith stated again, in reference to genotoxic carcinogens, that "there is no safe dose, and that's generally accepted". Dr Juberg disagreed and stated that he was "of a belief that thresholds do exist within the human population" (T1552.21). Mr McNickle submits that the Court should prefer Professor Smith's opinion over Dr Juberg's opinion on this issue because: (1) Dr Juberg's opinion on this issue is difficult to reconcile with his evidence in relation to the variability between individuals within the human population as to how susceptible they are to chromosomal aberrations and or mutations; (2) Dr Juberg's opinion is based on the views of Professor Calabrese which, Mr McNickle submits, for reasons referred to below, should be given no weight; and (3) Dr Juberg's opinion on this issue is also inconsistent with the evidence of Dr Flecknoe-Brown. 1103 Secondly, Mr McNickle contends that the variability between individuals within the human population as to how susceptible they are to chromosomal aberrations and or mutations weighs in favour of a conclusion that there is no safe level of exposure to genotoxic carcinogens (T1551.20-1552.6 (Professor Smith); T1510.29-43 (Dr Juberg)). As a consequence of the variability between individuals within the human population as to how susceptible they are to mutations, some people might suffer from a mutation more easily than their neighbour, which can be due to genetic variability (T1510.38-43). Therefore, as Dr Juberg accepted, some people might cope with a large exposure to a genotoxic substance, whereas other people might end up with cancer if they just have a very small exposure to a carcinogenic substance (T1511.12-16). 1104 Thirdly, despite Mr McNickle not objecting to the representations made by Professor Calabrese in the articles tendered into evidence (or seeking a s 136 EA limitation in relation to representations contained in them), Dr Juberg relied on the views of Professor Calabrese in support of his opinion that "there are practical thresholds for carcinogens" (T1556.1-5). Mr McNickle submits that the Court should place no weight on the views expressed by Professor Calabrese. He was not called as a witness in the initial trial, and hence the views he expressed in Calabrese (2022) could not be explored or challenged. This is said to be particularly problematical because Professor Calabrese, in effect, acknowledges that he is an outlier in his criticisms of the linear non-threshold model, which he describes as the "sacrosanct dose response model used in cancer risk assessment for over half a century" and of "overwhelming pre-eminence" and which he states has, at its core, "the belief that a single carcinogenic molecule or a single ionization [sic] can initiate the complex process of carcinogenesis". 1105 Fourthly, Dr Flecknoe-Brown's evidence strengthens the evidence that there is no safe level of exposure to a mutagenic substance like glyphosate because, as he explained, "a mutation is a one off event" (at JRA [202]). Dr Flecknoe-Brown said (at JRA [201]) that "a mutation occurring due to exposure to a mutagen [such as GBFs] could directly cause the malignant change in the cell", continuing (at JRA [202]): Although a mutation is a one-off event, the more times that a person's DNA is exposed to a mutagen, the more opportunities there are for such a one-off event to occur. In the case of glyphosate and GBFs, the amount of exposure to the mutagenic substance is determined by not only the number of occasions on which the person is exposed (intensity and duration of use), but also if any barriers to exposure to the GBF are used. 1106 It is said that Professor Prince did not contradict Dr Flecknoe-Brown's opinions that "a mutation is a one off event", "a mutation occurring due to exposure to a mutagen could directly cause the malignant change in the cell" or "[a]lthough a mutation is a one-off event, the more times that a person's DNA is exposed to a mutagen, the more opportunities there are for such a one-off event to occur". Mr McNickle submits that as a result, the Court should accept Dr Flecknoe-Brown's evidence and his analysis, set out above, that there is no safe level of exposure to a mutagenic substance. 1107 Fifthly, Mr McNickle submits that evidence of the approach taken by the USEPA, or any other regulatory agency, as to linear extrapolation, or the application of safety factors or thresholds, in respect of genotoxic carcinogens, does not prove, one way or the other, whether there is, in fact, no safe level of exposure to genotoxic and or mutagenic carcinogens. Instead, such evidence can only prove, if accepted, that a regulator takes a certain approach in respect of a certain issue. The only evidence adduced in relation to the USEPA's approach in this regard is said to be that given by Professor Smith and Dr Juberg. Professor Smith gave evidence (T1555.29-44): PROFESSOR SMITH: So for genotoxic carcinogens you do not apply safety factors… So if the compound is genotoxic, then the US EPA and most of the regulatory agencies throughout the world draw a linear no threshold line to this, and then they - society sets a limit because there is no safe dose, and that's generally accepted. So if you have no safe dose, how do you actually set a public health limit? …. You do not use safety factors. You do not say there's a threshold. The US EPA has never, in my understanding, for a genotoxic carcinogen ever set a threshold or safety factors setting a standard for the human population. 1108 Dr Juberg agreed with Professor Smith's conclusion stating that "I would agree with him [Professor Smith] that that's how cancer risk is done" (T1556.5). Dr Juberg also gave evidence that he was not aware of the USEPA having ever set a threshold or safety factor for the human population in respect of a genotoxic carcinogen (T1556.12-16). 1109 Sixthly, contrary to Monsanto's submission, Mr McNickle submits that it is not possible for the USEPA Guidelines to "disprove" that the USEPA has never set a threshold or safety factor for a genotoxic carcinogen. It is said that is not possible because the USEPA Guidelines can prove no more than their content. The USEPA Guidelines themselves cannot prove what the USEPA actually does in practice (as distinct from what the guidelines say). Mr McNickle acknowledges that the guidelines (at 3.3.1) refers to the possibility of using a non-linear approach in particular situations, rather than the default approach of linear extrapolation, but points out that it is clear from the evidence of Professor Smith and Dr Juberg that, in fact, in practice, the USEPA has never set a threshold, or used safety factors, in respect of a genotoxic carcinogen.
III Consideration 1110 To the extent it is necessary to form a concluded view, I am not satisfied that the evidence supports the proposition that genotoxic and/or mutagenic carcinogens are carcinogenic at any dose, for the following reasons. 1111 First, notwithstanding the evidence summarised above (at [1101]), the USEPA does not "draw a linear no threshold line" (T1555.29-44) in respect of all genotoxic and mutagenic substances. The USEPA defaults to the assumption that some substances are carcinogenic at any dose only in circumstances where the "observed data" relevant to the issue is insufficient, only to make precautionary public health decisions (and not to make any reliable scientific finding) and only because the assumption of carcinogenicity at any dose is "a health-protective approach". Professor Smith accepted that the OECD and USEPA Guidelines are "the internationally accepted guidelines for the conduct of mechanistic toxicological carcinogenicity studies" (T1330.7-15). Dr Juberg also accepted under cross-examination that many regulatory bodies follow the OECD and USEPA Guidelines (T1461.18-24), and Professor Smith and Dr Juberg (at JRG [53]) jointly described the OECD and USEPA Guidelines as "two of the more recognised and cited sets of test guidelines" that "[m]any global regulatory bodies follow". The USEPA Guidelines (at 3.3) provide: 3.3. EXTRAPOLATION TO LOWER DOSES The purpose of low-dose extrapolation is to provide as much information as possible about risk in the range of doses below the observed data. The most versatile forms of low-dose extrapolation are dose-response models that characterize risk as a probability over a range of environmental exposure levels. These risk probabilities allow estimates of the risk reduction under different decision options and estimates of the risk remaining after an action is taken and provide the risk information needed for benefit-cost analyses of different decision options. … When the weight of evidence evaluation of all available data are insufficient to establish the mode of action for a tumor site and when scientifically plausible based on the available data, linear extrapolation is used as a default approach, because linear extrapolation generally is considered to be a health-protective approach. 1112 However, the USEPA considers it safe to infer that (as a matter of scientific fact, as compared with a matter of public health assumption) a carcinogen is carcinogenic at any dose only if: (1) "the MOA data" from the dose-response assessment for the carcinogenicity mode of action of a substance suggests that "the likely shape of the dose-response curve at lower doses" is linear; and (2) the observed "extent of inter-individual variation" supports that conclusion. As the USEPA Guidelines state (at 3.3.1): 3.3.1. Choosing an Extrapolation Approach The approach for extrapolation below the observed data considers the understanding of the agent's mode of action at each tumor site (see Section 2.4). Mode of action information can suggest the likely shape of the dose-response curve at lower doses. The extent of inter-individual variation is also considered, with greater variation spreading the response over a wider range of doses. Linear extrapolation should be used when there are MOA data to indicate that the dose-response curve is expected to have a linear component below the POD. Agents that are generally considered to be linear in this region include: • agents that are DNA-reactive and have direct mutagenic activity, or • agents for which human exposures or body burdens are high and near doses associated with key precursor events in the carcinogenic process, so that background exposures to this and other agents operating through a common mode of action are in the increasing, approximately linear, portion of the dose-response curve 1113 Although that passage indicates that substances that are carcinogenic by a mutagenic mode of action are "generally considered" (emphasis added) to be carcinogenic on a linear dose, the USEPA Guidelines provide that the issue of whether a mutagenic substance is carcinogenic at any dose is not to be assumed. Indeed, the issue depends on an analysis of the evidence derived from a dose-response assessment (at 3.3.1): When the weight of evidence evaluation of all available data are insufficient to establish the mode of action for a tumor site and when scientifically plausible based on the available data, linear extrapolation is used as a default approach, because linear extrapolation generally is considered to be a health-protective approach. Nonlinear approaches generally should not be used in cases where the mode of action has not been ascertained. Where alternative approaches with significant biological support are available for the same tumor response and no scientific consensus favors a single approach, an assessment may present results based on more than one approach. A nonlinear approach should be selected when there are sufficient data to ascertain the mode of action and conclude that it is not linear at low doses and the agent does not demonstrate mutagenic or other activity consistent with linearity at low doses. Special attention is important when the data support a nonlinear mode of action but there is also a suggestion of mutagenicity. Depending on the strength of the suggestion of mutagenicity, the assessment may justify a conclusion that mutagenicity is not operative at low doses and focus on a nonlinear approach, or alternatively, the assessment may use both linear and nonlinear approaches. (Emphasis added) 1114 In the absence of a proper dose-response assessment on the evidence, it follows that the question of whether a genotoxic or mutagenic carcinogen is carcinogenic at any dose or at a threshold dose cannot be answered reliably (T2229.27-40). 1115 Secondly, I do not consider that inter-individual variability assists Mr McNickle's primary case as to dose. The fact that that there is variability between individuals as to how susceptible they are to chromosomal aberrations and or mutations (T1510.29-43) is - of itself and absent any quantification of the range of variation - irrelevant to the issue of dose. As noted above (at [1114]), the fact of inter-individual variation does not ground the inference that a substance is carcinogenic at any dose. Instead, the data as to the "extent of inter-individual variation" is data that needs to be considered, when conducting a dose-response assessment, in order to determine whether a carcinogen is, as a matter of fact, carcinogenic at any dose or carcinogenic only at a threshold dose. No evidence is before me as to the extent of inter-individual variation by which glyphosate causes cancer in individuals, and that variation cannot, in my view, provide support for Mr McNickle's contention that glyphosate is carcinogenic at any dose. 1116 Thirdly, largely for the reasons I identified earlier (at [695]-[696]), I do not consider that Dr Flecknoe-Brown's evidence supports Mr McNickle's contentions above. Dr Flecknoe-Brown does not cite any scientific inquiry upon which he based his assertions (at JRA [201]-[202]) and, accordingly, it is of limited assistance in determining Mr McNickle's primary case as to dose. 1117 Fourthly, notwithstanding that Professor Smith characterised Professor Calabrese as "on the fringe of the community and widely considered to be a little bit crazy", I do not resile from the view that there is no evidence before me corroborating that opinion and that I must assess Calabrese (2022) like any other article in evidence (T2232.22-26). If Mr McNickle wished to maintain a submission that the representations in Calabrese (2022) ought not to be before the Court, it was open for him to take a different course. The fact that Dr Juberg relied upon Calabrese (2022) in support of his evidence and Professor Smith's criticisms of it were all matters apparent as early as 28 September 2023 - that is, well before the parties reached the joint position on the adduction of scientific articles (among other things) referred to above (at [63]-[65]). Mr McNickle could have contended that Calabrese (2022) should be treated somewhat differently, but submissions as to a lack of weight were not developed by reference to any cogent and detailed criticism of the article. As it happens, Calabrese (2022) suggests why it is not safe to assume that all mutagenic substances are carcinogenic at any dose: 5. Pharmacokinetic and pharmacodynamic factors and carcinogen dose response Mutagen genetic damage is strongly dependent on and affected by the pharmacokinetic processes of absorption, distribution, metabolism, storage and excretion. These processes involve the interaction of component parts of the biological system with unique physico-chemical properties of the mutagenic molecules, which may include both the parent mutagen and/or possible mutagenic metabolites. The occurrence of a mutagenic event having relevance to a carcinogenic outcome will be affected by the following factors: (1) the number of mutagenic molecules that survive the pharmacokinetics and can reach the DNA of targeted cells, (2) the thermodynamic parameters that affect the activation and covalent binding of the mutagenic molecules to DNA, and (3) the biological capacity and rate of DNA repair in the target cells. While each of these factors alone tends to reduce the likelihood for any single mutagen molecule (the smallest dose possible) producing a mutational event, the combination of all three factors would only further greatly reduce the likelihood, virtually eliminating the possibility. To increase the probability of a mutational outcome, it would require continually increasing the number of mutagens (i.e., dose or level of exposure) until some threshold value is exceeded and the likelihood of evading these barrierlike factors is sufficient to register a mutational event. Essentially, this describes and lends rational support to a threshold dose-response model where some low-dose value must first be exceeded before a mutagenic effect can be observed. (Emphasis added) 1118 Dr Juberg relied on Calabrese (2022) in support of his contentions as to dose (T1555.1-13; 1578.31-32) and given this line of reasoning was not the subject of challenge by Mr McNickle (and the views therein are not inherently improbable), I accept Monsanto's submission that it is evidence weighing against Mr McNickle's primary case on dose. 1119 For these reasons, to the extent it is necessary to form a view, I do not consider that the evidence establishes that genotoxic and/or mutagenic carcinogens are carcinogenic at any dose.
IV Alternative dose proposition 1120 Mr McNickle's alternative dose proposition relies upon Dr Sawyer's evidence as to cumulative exposure and exposure days. Dr Sawyer's methodology as to cumulative exposure and exposure days is summarised in the executive summary to his primary report as follows (at 5): Cumulative exposure duration is the only valid toxicological dose metric methodology for glyphosate exposures. The measurement method is based on 8- hour time-weighted "exposure-days" for comparison to threshold values in human epidemiological studies of applicators revealing statistically significant elevated NHL [ORs]. This is the only methodology that has been used to determine a measurement of exposure dose in the published in the peer-reviewed human studies. This methodology facilitates direct comparison of Mr. McNickle's exposure history to that of the epidemiological studies. It is generally accepted that childhood exposures to mutagenic carcinogens results in a 2.8-fold increased risk of malignancies compared to that expected from adult-only exposures. 1121 Dr Sawyer recognised that a causation-based enquiry, whether general or specific, requires an assessment of systemic dose (at JRF [40]-[42]; T1977.16-35). 1122 I am far from satisfied Dr Sawyer's evidence supports the alternative dose proposition, for the following reasons. 1123 First, Dr Sawyer conceded in cross-examination that: (1) his exposure threshold metric cut-off is not in any way based on results from the animal studies. He sought to justify this on the basis that, under the relevant rules of evidence in the United States, animal extrapolation is disallowed for causation purposes but then conceded that this is only in respect of specific causation (T2029.10-17); (2) his exposure threshold metric cut-off is similarly not based on any results from the mechanistic toxicology studies (T2029.19-21); (3) his exposure threshold metric cut-off is based solely on a selection of the epidemiology studies which demonstrate a positive association between glyphosate and NHL, the majority of which we have encountered in the first stream and in respect of which a number of errors and limitations were found (T2029.23-35); (4) he relies on exposure days as a metric to attempt to estimate the dose of glyphosate to which people were exposed, but that this does not measure systemic dose (T2029.37-42); (5) with the exception of Eriksson (2008), the exposure days in the epidemiology studies that he relied on did not measure the duration of exposure to glyphosate either and accepted that those studies in fact use a minimal exposure and include that in the exposure day calculation (T2032.17-24); (6) there exists a body of evidence which demonstrates that cancer risk at a cumulative dose varies substantially with the duration of exposure (T2031.14-16); (7) despite each individual being counted as having one exposure day, the dose that is relevant for each individual could be very different (T2033.10-12); and (8) that the epidemiological studies which assess the association between GBFs and NHL "do not measure dose" and that the studies use a dose metric frequency of exposure, expressed as "exposure days" (at JRF [134]). 1124 Secondly, Dr Sawyer justified the use of exposure days on the basis that the cumulative metric of "pack years" has some validity as a predictor of lung cancer risk (at JRF [160]): It should be noted that epidemiological studies have used cumulative exposure dose metrics for many decades in other studies. The best example is that of cigarette smoking and lung cancer measured in units of "pack-years"; that is the (number of packs per day) x (years). For example, a person smoking 1 pack per day for 40 years has a 40 pack-year dose metric. The scientific literature reveals numerous cigarette smoking studies assessed with in units of pack-years. More recently, biomonitoring has employed nicotine and cotinine in units of mg/kg/day in urine or blood; however, biomonitoring is incapable of assessing previous years of smoking. 1125 In cross-examination, however, Dr Sawyer was taken to an article (Peto (2012)) and gave the following evidence (T2030.32-2031.6): MR CRAIG: … Now, you will see the title of this journal article is That the Effects of Smoking Should Be Measured in Pack Years Misconceptions; do you see that?---Yes. MR CRAIG: Above the title there is an editorial. Can you read that editorial to yourself starting with the word, "Misconceptions"?---It needs to be blown up a little. Well - no, it is blown up. Okay. Yes, I read that. MR CRAIG: Thank you. I suggest to you that the use of pack years in the epidemiological literature is one of the misconceptions and ill-founded theories to which the editors refer in this editorial?---According to this editorial. However, pack years is what was originally used to determine cigarette smoking as a cause of cancer and there is a reason that sometimes we have to use a weaker methodology as opposed to a stronger methodology. For example, measuring benzoapyrene in the blood would not provide any information on how many years or at what doses smoking occurred. And the same goes true with glyphosate: measuring somebody that presents for NHL, there are no blood tests that are going to go back and historically document what the blood levels were 10, 20, 30 years earlier while working on the farm. I mean, it's just - the same holds true for cigarette smoking. Measuring - if a smoker came into the office and I, as a toxicologist, was asked to perform analyses, there are no analyses I could perform that would give me a full history of this person's smoking. 1126 In short, Dr Sawyer acknowledged that the use of "pack years" was a weaker methodology and accordingly, it is doubtful whether it can be used to enable the epidemiological studies relied upon by Dr Sawyer to provide a reliable exposure assessment.
V Conclusion 1127 For these reasons, to the extent it is necessary to form a view, I am not satisfied that the evidence establishes that genotoxic and/or mutagenic carcinogens are carcinogenic at any dose, nor that the evidence establishes a threshold dose at which glyphosate and/or GBFs (assuming they are carcinogenic) cause cancer or NHL.
H.5 Jones v Dunkel 1128 In the light of my conclusion as to Dr Sawyer's evidence in Section H.3 above, Mr McNickle no longer has much to gain from a Jones v Dunkel inference flowing in his favour because of Monsanto's decision not to call Dr Driver to give evidence. 1129 It is necessary, however, to say something about it. 1130 Mr McNickle submits that because of Monsanto's decision not to call Dr Driver: (1) the Court should draw an inference that Dr Driver's evidence would not have assisted the Monsanto's case; and (2) the Court should more readily accept the opinion evidence of Dr Sawyer on topics on which Dr Driver could have opined. Mr McNickle submits that those consequences should flow from the non-calling of Dr Driver because: (1) Dr Driver is a witness which Monsanto could reasonably have been expected to call, given he provided the Driver Report to Freehills, and then, in December 2022, participated in Conclave F with Dr Sawyer and contributed to the JRF, in which Dr Driver and Dr Sawyer set out their opinions in relation to the questions agreed by the parties; and (2) if Monsanto contends that some of the opinions expressed by Dr Sawyer are incorrect and should be rejected, Dr Driver should have been called to contradict Dr Sawyer and/or to explain any assertion to be made by Monsanto that Dr Sawyer's opinions are incorrect. 1131 I accept there is some force in Mr McNickle's submission that a Jones v Dunkel inference would ordinarily flow in circumstances where Dr Driver was in a position to contradict Dr Sawyer's evidence, in particular, those matters set out above (at [1064]-[1066]). But I am not persuaded that the matters identified by Dr Sawyer and summarised in those paragraphs are strictly relevant to the contest as to general causation in this initial trial (that is, Question 4). 1132 As senior counsel for Monsanto pointed out, the only portions of Dr Sawyer's evidence that remained unchallenged were those in respect of which it was unnecessary for Monsanto to adduce evidence. As I noted earlier (at [502]), Jones v Dunkel cannot be used to fill gaps in the evidence or to convert conjecture into inference. Even if I proceed on the basis that Dr Driver's evidence would not have assisted Monsanto's case and the Court could more readily accept Dr Sawyer, his evidence was so inherently problematical that I have not reached the requisite level of persuasion as to the cogency of his opinions given in Conclave F and as to dose.
I DRAWING THE THREADS TOGETHER 1133 We now come to the step required to be undertaken by a Court and which reflects the imperative that a judge (unlike a scientist) must decide, one way or another, whether the burden of proof is satisfied by the party positing a general causation hypothesis based upon scientific evidence. 1134 As Mr McNickle correctly submits, it would be an error of reasoning to reach the conclusion that just because each of the three streams of scientific evidence do not establish general causation that this axiomatically provides an answer to the general causation issue. 1135 As I have explained, I am required to direct myself by having regard to all the streams of scientific evidence and any other material admitted in ascertaining whether Mr McNickle's onus has been discharged. 1136 I recently noted in Lehrmann v Network Ten Pty Limited [2024] FCA 369 (at [98]), assessing whether this burden has been discharged does not involve a simple estimate of probabilities; it requires ascertaining a subjective belief in a state of facts on the part of the tribunal of fact. Mr McNickle, being the party bearing the onus, will not succeed unless the whole of the evidence establishes a reasonable satisfaction on the preponderance of probabilities such as to sustain the relevant general causation issue; put another way, I am required to assess whether I have formed a subjective belief or actual persuasion of the existence of the necessary causal connexion. As Justice Hodgson put it, I am dealing with two questions: "not just what are the probabilities on the limited material which the court has, but also whether that limited material is an appropriate basis on which to reach a reasonable decision": see Hodgson, D H "The Scales of Justice: Probability and Proof in Legal Fact-finding" (1995) 69 Australian Law Journal 731; Ho v Powell [2001] NSWCA 168; (2001) 51 NSWLR 572 (at 576 [14]-[16] per Hodgson JA). 1137 Bearing these matters in mind, the whole of the evidence in the three streams revealed some not insignificant issues with the evidence presented by Mr McNickle in favour of his contention that use of and/or exposure to glyphosate and/or GBFs can increase an individual's risk of developing NHL or cause an individual to develop NHL. Indeed, as has been seen, much of that evidence was directed towards establishing plausible or theoretical possibilities and, as Monsanto was wont to emphasise throughout the initial trial, it is not enough to persuade the Court that glyphosate and/or GBFs might cause or increase the risk of NHL - actual persuasion necessitates more: namely, that the Court be reasonably satisfied that glyphosate and/or GBFs are capable of causing NHL in humans. 1138 It is partly for this reason that I earlier described the evidence adduced in the epidemiological stream as causing difficulty in accepting Mr McNickle's case. Without placing disproportionate focus upon it, it is, after all, the stream of evidence before the Court that examines the actual occurrence of cancer in humans exposed to glyphosate and/or GBFs in the real world. This was recognised as long ago as February 2022 when Mr Clements accepted that one of the "critical areas" of expertise in which expert opinion evidence will be adduced in this case is in the field of epidemiology: McNickle v Huntsman Chemical Company Australia Pty Ltd (Hearing Vacation) (at [13]). In saying this, however, I am conscious that epidemiology may not establish a positive link between glyphosate and/or GBFs and NHL, but this does not entail that such a link does not exist, although it would have to be established by other evidence. In other words, epidemiology which establishes a positive link between agent and effect is neither a necessary nor sufficient condition for establishing causation: see Justice Jonathan Beach "Causation: The Interface Between the Scientific and Legal Methods" (at 142). 1139 But in the end, the evidence adduced in the first stream established (in order of importance) that: (1) the AHS represents the most comprehensive and reliable analysis to date of whether there is a causal relationship between glyphosate and/or GBFs and NHL because, inter alia: (a) in the light of the sheer number of study participants involved, the AHS is of a different character to any comparable study on the etiologic relationship between glyphosate and NHL; and (b) in contrast to population-based and community studies, the sample in the AHS consists of applicators who were occupationally exposed to GBFs and other agents thought to be carcinogenic; (2) the vast majority of the case-control papers: (a) involved a relatively small number of cases and controls who were exposed to glyphosate; and (b) suffered from the failure to correct for exposure to other pesticides (that is, confounding). It is for these reasons that the epidemiological literature does not support the conclusion that exposure to glyphosate and/or GBFs is capable of causing NHL in humans. It is well to emphasise again here that the AHS was not only described by Professor Checkoway as "excellent" (T952.14-15) and "perhaps the best study we have" (T959.44-45), but it is plain that in the light of its size and nature of exposure the study participants experienced, if glyphosate and/or GBFs were causative of NHL, one is faced with the reality that the relevant association was not observed. 1140 As for the animal studies stream, the evidence was insufficient to establish that: (1) glyphosate causes cancer in murine subjects; or (2) even if it does, that causation of cancer in rats and mice entails that it also causes cancer (and NHL) in humans with real world exposures. It will be recalled that: (1) Dr Bayard's evidence was marred by an approach to the animal bioassays which: (a) did not meaningfully assist in estimating false-positive rates because it did not involve any adjustment to the p-value which accounted for the problem of multiple comparisons; (b) included pooled analyses in circumstances where there were a variety of substantive differences between the animal bioassays (such as different durations and dose-levels); and (c) involved Dr Bayard giving scientific opinions on fields outside of his expertise; (2) the animal bioassays (and Wang (2019)) suffered from several limitations including, among other things: (a) in relation to each tumour type in rats and mice, and perhaps most importantly, the majority of the studies did not indicate a statistically significant result according to Dr Bayard's predetermined criteria for significance; (b) a number of the animal bioassays reported inconsistent results when assessing relative dose levels; (c) a number of the tumours identified by Dr Bayard are not rare in rats and mice; and (d) several of the animal bioassays lacked cross-gender significance; and (3) Dr Bayard's reliance on Wang (2019) in the context of the JRI was not of assistance in demonstrating the translatability of the animal studies evidence to humans because: (a) Dr Bayard lacked the requisite qualifications to conclude that that study provided evidence that glyphosate provides a mode or mechanism of action by which it can cause cancer; and (b) the extrapolation of findings the subject of such models to humans is a question which necessitates "high translatability" and the application of a number of criteria, including, inter alia, the animal species, dose exposure, and similarities in biological response. 1141 Lastly, in relation to the mechanistic evidence stream, although the evidence established that glyphosate and/or GBFs exhibit KC2 (genotoxicity); KC4 (induces epigenetic changes); and KC5 (induces oxidative stress), the evidence did not support the "next step" that there exists a corresponding biologically plausible mechanism by which glyphosate and/or GBFs can cause NHL. This was particularly evident in relation to KC2 where genotoxicity was demonstrated in artificial in vitro environments, but it was not evident that that risk was translatable to the risk of humans developing NHL from exposure to glyphosate and/or GBFs in the real world. Further, it was apparent that Mr McNickle's reliance upon the second hypothesised mechanism and Wang (2019) was misplaced in the light of a slew of limitations which rendered it of limited assistance in demonstrating whether an upregulation of AID contributes to the development of NHL in humans. Even in the event that the mechanistic evidence allowed a more definitive conclusion to be drawn as to any association between glyphosate and/or GBFs and the development of cancer, it is well to emphasise again that if there is inadequate evidence of cancer in humans and insufficient evidence in experimental animals, the mechanistic evidence and KCs can only suggest that the substance in question is "possibly carcinogenic to humans" (see above (at [671])). 1142 I am acutely conscious that during his opening, Mr Clements submitted (T34.24-31): MR CLEMENTS: I mean, it's clear from the approach [Monsanto has] taken to the three streams. So, as I said earlier, in the epidemiology conclaves, Professor Checkoway refers to four case controlled epidemiological studies that support the conclusion that exposure to GBFs increases NHL risk. What do the respondents say? All of the four studies have flaws. Two of them are not statistically significant. So it's the same old approach: ignore the smoke, there's no fire here. They do the same thing with animal studies. There are numerous studies in experimental animals which support the conclusion that glyphosate is carcinogenic in mammals. 1143 Monsanto's drumbeat as to the results of the AHS in its submissions was potentially deafening. But consistently with Mr McNickle's submissions, I have guarded against being distracted from the full sweep of the evidence by mistakenly elevating the epidemiology evidence (and, in particular, the AHS) as some form of necessary condition for establishing causation. More generally, I have sought to ensure I have not been diverted from weighing the whole of the evidence by focussing too intently on complaints about individual studies, which have ranged from the highly significant to the pettifogging. Mr Clements correctly urged me to view the evidence in the round and I have attempted to do so. 1144 In an 1898 article on British frontier policy in India, Churchill wrote: I shall take refuge in Kinglake's celebrated remark, that "a scrutiny so minute as to bring a subject under a false angle of vision is a poorer guide to a man's judgment than the most rapid glance that sees things in their true proportions". 1145 The difference here is that my consideration of the whole has been no mere rapid glance and I do not think Monsanto's minute scrutiny of individual studies has meant I have obtained any false angle of vision. 1146 Stepping back and viewing the evidence as a whole, and faithfully giving weight to those aspects I consider most cogent, but without giving disproportionate emphasis to any particular stream, the state of the evidence is not such as to sustain the necessary causal connexion. This is not to say that the evidence suggestive of a causal link did not give me some pause, and I will say something shortly about the appropriate answer to the questions posed in this initial trial and the ongoing scientific controversy more generally. But the weight of the evidence adduced in the three streams made it difficult to come to any conclusion other than the applicant has not established his general factual causation case to the requisite legal standard.
J.1 The Merck Order Questions 1147 The questions posed for determination prior to the initial trial were in the following terms: 1. Throughout the period July 1976 until 4 July 2022 (the Relevant Period), were: a. Glyphosate; and/or b. Glyphosate based formulations (GBFs)- carcinogenic to humans? 2. Throughout the Relevant Period, were: a. Roundup Herbicide; and/or b. Roundup Biactive- carcinogenic to humans? 3. Throughout the Relevant Period, if Roundup Herbicide and/or Roundup Biactive contacted the skin, did any surfactants present increase absorption in the bloodstream by reason of the factors identified in [the fourth further amended statement of claim at [29]]? 4. Throughout the Relevant Period, did or could use of and/or exposure to: a. Roundup Herbicide; b. Roundup Biactive; c. Glyphosate; and/or d. GBFs- i. increase an individual's risk of developing NHL; and/or ii. cause an individual to develop NHL? 5. If use of or exposure to Roundup Herbicide or Roundup Biactive can cause NHL in humans, would use in accordance with the Labels, Safety Data Sheets and Safety Directions detailed in paragraphs 52 to 60 of the Statement of Agreed Background Facts … amount to a use or exposure that is capable of causing NHL by reason of that use? 1148 I find myself at the conclusion of this initial trial in a similar position to that which I found myself in Lloyd v Belconnen Lakeview Pty Ltd [2019] FCA 2177; (2019) 377 ALR 234. I noted in that case (at 328-332 [374]-[385]) that in Gill v Ethicon Sàrl (No 3) [2019] FCA 587, I had earlier described s 33ZB of the FCA Act as being the most important provision within Pt IVA and noted (at [4]-[5]): [4] … This provision provides that a judgment given in a representative proceeding must describe or otherwise identify the group members affected by it and binds all such persons other than any person who has opted-out of the proceeding under s 33J. This provision was described by the Full Court in Femcare Ltd v Bright [2000] FCA 512; (2000) 100 FCR 331 at 338 [25] (Black CJ, Sackville and Emmett JJ) as, in one sense, the "pivotal provision" in Pt IVA. [5] In Timbercorp Finance Pty Ltd (in liquidation) v Collins [2016] HCA 44; (2016) 259 CLR 212…. French CJ, Kiefel, Keane and Nettle JJ explained at 235-236 [52]-[53] as follows: Part 4A creates its own kind of statutory estoppel. Section 33ZB requires that a judgment in a group proceeding identify the group members affected by it and, subject to a provision not presently relevant, provides that that judgment "binds all persons who are such group members at the time the judgment is given". In order to understand that to which the group members are bound, it is necessary to read s 33ZB in the context of Pt 4A as a whole and ss 33C(1) and 33H in particular. By that process it will be seen that group members are bound by the determination of the claims giving rise to the common questions. … 1149 The orders I made defining the issues for trial are commonly known as "Merck orders". 1150 As I explained in Belconnen Lakeview, that description comes from the decision of the Full Court in Merck Sharp & Dohme (Australia) Pty Ltd v Peterson [2009] FCAFC 26; (2009) 355 ALR 20. Merck was an application for leave to appeal and appeal from the decision of the primary judge, Jessup J, who, consistently with the then prevailing orthodoxy, had proposed that following the conclusion of the initial trial, the Court would hear further argument and make common findings which (following reflection in s 33ZB orders) would be relevant to determining the individual cases of group members. The Full Court (Moore, Sundberg and Tracey JJ), however, adopted a different approach noting (at 22 [5]) that the difficulty was that the pleading raised questions of the liability of the respondent to all group members and not just to the applicant. Their Honours went on to observe (at 22-23 [6]-[7]): [6] In our opinion it is desirable, if not necessary, to identify precisely what issues will be determined in the "trial" (and those that will not be determined) on the assumption, which the parties did not gainsay, that at the end of the "trial", orders will be made which reflect the determination made by the trial judge on both questions of fact and law or mixed questions of fact and law. That the "trial" will result in a determination of Mr Peterson's claim (personal to him), is a given. As Sackville J did in Courtney v Medtel Pty Ltd (2003) 126 FCR 219 (by making orders on 16 August 2002 posing a number of questions which were partly answered on 3 March 2003 [2003] FCA 129), an order can be made identifying Mr Peterson's claim as a matter (in the sense of subject matter entailing questions of fact and law) to which the trial will be directed. [7] Also, common issues can be determined. There is plainly a controversy about which issues are common. Merck disputes that the issues pleaded in Mr Peterson's statement of claim are, in truth, common questions. However, it is tolerably clear that the scheme of Part IVA of the Federal Court Act is that whilst a proceeding continues as a representative proceeding, the Court should, in the ordinary course (at least in relation to proceedings involving a sizable group where liability may depend on each member's individual circumstances), initially deal with issues that are common to all members of the representative group or a sub-group of that group. So much is apparent from ss 33Q and 33R. Indeed an important procedural step is contemplated by that latter section whereby an individual group member might, by direction, be permitted to appear in the proceeding for the purposes of determining an issue that relates only to the claims of that member. At the very least the Court would need to consider whether such a direction is made before determining an issue which was not a common issue and might be characterised as an issue that relates only to the claims of a particular member. 1151 I further remarked that Merck orders are useful in identifying what issues should, and are to be, determined, but like in so many instances with Pt IVA proceedings, care must be taken to avoid elevating specific decisions as to practice and procedure which may arise in one case as if they were determinative precepts and principles of universal application: see Regent Holdings Pty Ltd v State of Victoria [2012] VSCA 221; (2012) 36 VR 424 (at 429 [19] per Nettle, Redlich and Osborn JJA). In Belconnen Lakeview, I made clear (at 330 [377]) that a Merck order is not set in stone: it is an interlocutory order which may be adapted and changed as circumstances require and that it is not uncommon for deficiencies in the approach taken at an interlocutory stage to be recognised only during or at the conclusion of the initial trial. 1152 There are two issues that arise in relation to the questions identified in the Merck order: first, whether it is necessary or appropriate to answer them as initially framed; and secondly, the form of any answer to any appropriate question given my findings explained above.
J.2 The Form of Questions 1153 The central issue (which, in the end, has turned out determinative) can be seen reflected in the terms of Question 4. This is not an unexpected development and, as I explain below, informed my desire to have an initial trial on the question of general factual causation. 1154 At the close of evidence, I invited submissions as to whether I should necessarily answer any question other than a refined version of Question 4. I accept there may have been utility in answering all questions in the event that Mr McNickle had generally succeeded, but as Monsanto correctly submits, this initial trial is about the central issue and, as Mr McNickle accepts: "if the Court answers 'no' to all parts of [Question 4], it would follow that this proceeding would be dismissed" (AS [561]). 1155 The problem with Question 4 is that it is unnecessarily complicated and does not reflect the pleading. This is a case concerning Mr McNickle and other persons who have used or have been exposed, during an identified period, to Roundup Products within Australia. "Roundup Products" are defined in the pleading as the herbicide product or products, which contained glyphosate and were branded as "Roundup", or which contained glyphosate and were otherwise branded with the name "Monsanto". 1156 No-one during the trial has sought to draw any relevant distinction whatsoever between the two Roundup Products used by Mr McNickle (Roundup Herbicide or Roundup Biactive) and any other Roundup Product or, more generally (and subject to one qualification irrelevant for present purposes) any material distinction between any Roundup Product and any other GBF. 1157 The use of Roundup Products is a common thread linking all group members. Although the case was run without distinction between the carcinogenic properties of Roundup Products and other GBFs, the question posed and answered by the Court should be grounded in the common facts between group members and not stray into some hypothetical statement about any other GBFs (even if the answer would be the same on the evidence in this case). 1158 Despite written submissions contemplating some possible mixed response to Question 4 by Mr McNickle, this position was subsequently modified, and each party accepts Question 4 can be more simply expressed, and reflect the central issue, by being expressed as follows: Throughout the period between July 1976 and 19 October 2020 (relevant period) [a period I will explain below], did or could use of and/or exposure to the herbicide product or products, which contained glyphosate and were branded as "Roundup", or which contained glyphosate and were otherwise branded with the name "Monsanto" (Roundup Products) increase an individual's risk of developing non-Hodgkin lymphoma (NHL); and/or cause an individual to develop NHL? 1159 Obviously enough, an answer, which amounts to a declaration, should be clear on its terms, and hence the question and answer should be self-contained and not adopt defined terms taken from another document. I will call this question the central common question. 1160 This is not the place to discuss the logical difficulties of a criterion of group membership which includes a causal element, which I have discussed before (see, for example, Perera v GetSwift Limited [2018] FCA 732; (2018) 263 FCR 1 (at 27-28 [79]-[81])). But adopting a realistic approach, when one has regard to the group definition (discussed below), by reason of the causal element introduced by the pleader (the group member must have been diagnosed with NHL by reason of the use of and/or exposure to Roundup Products), an adverse answer to the central common question is determinative of the claims of group members unless general causation is established. 1161 On 26 April 2023, an order was made pursuant to ss 33ZF and 37P(2) of the FCA Act that this proceeding be listed for an initial trial of the common questions specified in an annexure to that order (being those identified above (at [1147])). There is no need to modify that interlocutory order given its terms, but for reasons I have explained, the best approach in the light of the conduct of the trial and the conclusions I have reached, is to just answer the central common question. 1162 Having identified the central common question, it is now appropriate to identify the answer, and then the persons the answer should bind.
J.3 The Appropriate Answer 1163 The difficulty is that my resolution of the central issue is not captured by a simplistic binary response to the central common question. The answer to a separate question, such as the central common question, operates as a form of declaration of legal rights. As I have already explained, and as reflects the legal approach to proof of a fact, and that just because a moving party fails to persuade a Court to make a declaration in the terms it seeks, does not mean the opposing party is entitled to a declaration in opposite terms. 1164 If, as Monsanto asserts, I simply answer "no", this would amount to a distortion of my resolution of the central issue according to law. This is because to say Mr McNickle has not proved to my reasonable satisfaction on the balance of probabilities on the state of the evidence adduced at this trial that the use of and/or exposure to Roundup Products increases an individual's risk of developing NHL or causes an individual to develop NHL, is not the same thing as saying affirmatively that it does not. As I have explained, whatever else is unclear, one thing is plain: the science is all not one way. Even leaving aside evidence adduced on behalf of Mr McNickle: (1) Professor Prince accepted there is some evidence that exposure to GBFs cause or contribute to the development of NHL (T631.36-40); further, he accepted "there's aspects of what GBF can do which are known to be causative of lymphoma" (although asserting "there's no compelling link to me to demonstrate that it causes lymphoma" (T631.46-632.2)); (2) AP Harris accepted it is "quite possible" that glyphosate use may be associated with increased risk of NHL (T1078.41-44); and (3) Dr Juberg gave evidence (at JRH [154]) that "[b]ased on my review of available and accessible cancer bioassays for glyphosate in rats and mice … I conclude that none of these studies support a clear and compelling basis for carcinogenicity of glyphosate in mammals" (emphasis added). 1165 As Justice Beach remarked in his recent article (see above (at [69])), "at the forensic level in litigation, truth is static", but the scientific method involves the positing of testable hypotheses based upon empirical observation and any theory formed, by its nature, is generally contestable (at 116, 120). It suggests hubris and defies commonsense to assume future scientific research and analysis could not mean more definitive conclusions may be able to be drawn using the scientific method, including buttressing the notion that Roundup Products are possible carcinogens. One cannot foreclose the possibility that further research may reveal a "compelling link" (a fortiori, a sufficiently persuasive link on the balance of probabilities) demonstrating that the use of and/or exposure to glyphosate and/or GBFs causes NHL. As I have been at pains to emphasise, I am deciding as to my reasonable satisfaction on the balance of probabilities based upon the evidence selected by the parties and which can only represent a snapshot of the state of scientific knowledge as at the time the evidence closed. 1166 Although any s 33ZB order would not operate in rem and would only relevantly bind Mr McNickle and group members specified in the order to the answer to the central common question, it is important the orders of the Court not distort the result of the forensic contest in this trial.
J.4 Group Membership 1167 Mr McNickle has brought this case as the representative for a finite group of persons. The parties now say that they are those persons who: (a) have been diagnosed with NHL by reason of the use of and/or exposure to, at any time between July 1976 and 4 July 2022, Roundup Products, within Australia; or (b) are the executors or administrators of, or beneficiaries of or persons with an interest in, the estates of deceased persons who would have been group members had they not died prior to 4 July 2022; or (c) the dependents of persons who would otherwise have been group members where a cause of action had vested in or may be brought by that person. 1168 The italicised terminal date of the now pleaded "Relevant Period" is alleged to be the date of the fourth further amended statement of claim. At the time leave was granted to amend, the parties (and, in particular, Mr McNickle who sought the amendment), did not seek leave to amend the group definition pursuant to s 33K of the FCA Act. For the reasons explained by the Full Court in Ethicon Sàrl v Gill [2018] FCAFC 137; (2018) 264 FCR 394 (Allsop CJ, Murphy and Lee JJ) this course should not have occurred. As was explained by the Full Court (at 401 [29]), Pt IVA puts in place an opt out regime. Irrespective of any positive step taken by a claimant, if at the time of an order which changes the group definition in a proceeding, they fall within the group definition as amended, they would become group members. 1169 The purported inclusion of claimants here (who may have had no knowledge about being purportedly joined to the class) is problematical. Opt out occurred pursuant to orders made on 28 May 2021 and, pursuant to s 33J(1) of the FCA Act, 20 July 2021 was fixed as the date by which group members could opt out of this class action. 1170 I raised this issue when it belatedly became apparent to me. My research suggests no s 33K order was sought by either party; nor was one made when the third further amended statement of claim was filed on 10 February 2022. Hence, the composition of group members at the time of opt out was that as defined in the second further amended statement of claim filed on 19 October 2020. 1171 My initial response, adopted by the parties, was to propose that I make a regularising s 33K order to operate nunc pro tunc from the date of the fourth amended statement of claim. But, upon reflection, I am not satisfied this is an appropriate course. 1172 As was explained in Ethicon Sàrl (at 406-407 [50]-[52]): [50] By the amendment of a group definition, a new group member affected is not becoming a party, still less is the group member an existing party seeking to bring a new cause of action arising out of similar circumstances. The legal consequence is that the claim of a new group member, which claim gives rise to at least one substantial issue of law or fact with others, has become subject to the operation of the Part, subject to opt out or declassing. When one recognises that the regime expressly contemplates and provides for the individuality of claims within a group proceeding, what is brought into focus is that an order for amendment, which has the consequence of expanding the group definition, is sui generis and that analogies drawn from other contexts are apt to mislead. [51] It is consistent with the scheme introduced by Part IVA and, in particular, the need for there to be certainty as to the persons who comprise the class at all times, that the Group Definition Amendment should have been ordered to take effect from the date of amendment…. To adopt that course is consistent with the expansion of the class effected by the earlier Amendment Orders which, unfortunately, were not drawn to the attention of the primary judge in the present context. Apart from anything else, this prevents the topsy turvy notion that someone retrospectively becomes a group member on commencement, when the Court has thus far proceeded on the basis that they are not group members. As a matter of principle, such an approach would avoid the vice of potentially resuscitating causes of action by persons who have never sought to agitate them. It would be odd that by becoming a group member through the augmentation of a class, substantive rights were conferred on a claimant that had been either extinguished or barred by operation of statute and could not otherwise be advanced by that claimant. [52] Before leaving this topic it is worth making a further point. Given the suspension of limitations caused by the operation of s 33ZE, the question of inclusion (or, as occurred here, unusually, exclusion) of group members has potentially important consequences on substantive rights. As does the date when any such order is to take effect. Whatever might be the nature of other amendments to a statement of claim, or to relief claimed in an application, attention must be given by parties to the legal consequences of class composition changes. Irrespective as to when other amendments might take effect, the consequences of amendments to group definition can affect the rights of third parties, being the absent group members or proposed group members. Although it would be inappropriate to lay down inflexible rules, the default position is that a s 33K order (or an equivalent order under s 33ZF) has effect from the time the definition is changed, consistent with the requirements of class certainty. It is a sound practice for applicants, in seeking such orders, to deal separately with amendments concerning class composition to assist in avoiding any confusion. 1173 The failure to heed this warning has led to the current problem. No doubt I should have been more vigilant, but there is a limit as to how much time one can spend double-guessing and checking consent orders provided by experienced class action lawyers. 1174 Whatever the reason or reasons for this problem, the result is there are a group of persons who, subject to leave being granted to augment the class, could have become group members because they first fell within its literal terms after 19 October 2020 but prior to 4 July 2022. I will call these people potential group members. 1175 A belated s 33K order being now made which operates from 4 July 2022 in order to bind potential group members to a s 33ZB order would, of course, operate adversely to the interests of these third parties without them having had any opportunity to be heard. Moreover, I would be substantively affecting their legal rights, notwithstanding they have been deprived of the fundamental right in an opt out regime, being the making of an informed choice as to whether they wish to be part of this class action. There may have been a range of steps I could have taken at an earlier time to direct notices to potential group members if I had known of this problem in a timely way. 1176 I raised this issue with the parties when the matter was last before the Court in January 2024, but I remain unconvinced a retrospective order should be made which operates adversely to non-parties. If a statutory estoppel is to bind strangers, the strangers have to be group members and be dealt with fairly and in accordance with Pt IVA. Any s 33ZB order should be made binding the current group members as defined in the second further amended statement of claim filed on 19 October 2020 other than those that used the opportunity thereafter given to them to opt out.
I The Nature of the Discretion 1177 It continues to be said that the Court's discretion as to awarding costs is "unfettered" but that is, at best, overly simplistic and, at worst, inaccurate. 1178 As the Full Court (Besanko, Jagot and Lee JJ) explained in LFDB v SM No 2 [2017] FCAFC 207 (at [7]): … in exercising the discretion to award costs, s 37N(4) of the Act requires the Court to take account of any failure by a party to comply with the overarching purpose of the civil procedure provisions, namely to facilitate the just resolution of disputes according to law … 1179 Moreover, and more generally, any power to award costs must be exercised in a way "that promotes the overarching purpose" (s 37M(3)): Bellamy's Australia Limited v Basil [2019] FCAFC 147; (2019) 372 ALR 638 (at 643 [24] per Murphy, Gleeson and Lee JJ). 1180 These mandatory statutory considerations inform the discretion, but so do a miscellany of principles emerging from the cases, for example: a costs order should reflect the degree of success attained; a successful party may be ordered to pay some costs in respect of unsuccessful aspects of the case; and that costs are compensatory in nature and not punitive: see, for example, Hockey v Fairfax Media Publications Pty Ltd (No 2) [2015] FCA 750 (at [37] per White J). Further, and importantly, although there is "no absolute rule", one of the "general propositions" regarding an award of costs is that "the award is discretionary but generally that discretion is exercised in favour of the successful party": Foots v Southern Cross Mine Management Pty Ltd [2007] HCA 56; (2007) 234 CLR 52 (at 62-63 [25] per Gleeson CJ, Gummow, Hayne and Crennan JJ). 1181 Apart from the obvious and weighty consideration that Monsanto has prevailed at the initial trial, there are three factors which bear upon the discretion as to making an award of costs, which have not been the subject of submissions.
II The Parties' Conduct and the Overarching Purpose 1182 The first is the relevance of the conduct of this litigation by the parties. To adopt what I said in a defamation case (Kumova v Davison (No 2) [2023] FCA 1 (at [86])), Pt VB of the FCA Act does not contain empty rhetoric. There is a statutory duty requiring practitioners to assist their clients in facilitating the just resolution of disputes according to law and as quickly, inexpensively and efficiently as possible (s 37N(2)). This means that in conducting litigation and identifying issues, including separate issues which may be determinative, the parties, including a respondent, must be engaged in trying to ascertain ways to simplify and expedite the resolution of matters. This obligation is reflected in the Central Practice Note: National Court Framework and Case Management (CPN-1) (at [7.2]). 1183 This obligation at the initial stages of a proceeding to give real thought as to how a case might be most efficiently resolved is particularly important in large class actions, which demand and consume so many public resources. Any notion practitioners can just roll the arm over and conduct litigation and incur costs like they are in a time warp that has transported them back to a time when provisions such as Pt VB did not exist cannot persist. 1184 My preliminary view, subject to hearing further on this issue from the parties, is that despite the efficient and skilled way the initial trial was eventually conducted, it is open to conclude that both parties share responsibility for this case not proceeding to trial much earlier and with vastly less cost. 1185 The first time this matter came before me, as long ago as 1 May 2020, I raised with senior counsel for Monsanto my view that "it seems to me that whether or not the allegation [in] paragraphs 23, 24, 25 and 26 are made out or not made out [the paragraphs of the pleading alleging the carcinogenic properties of Roundup Products] is likely to be of central importance to the claim" (T55), and that it is a scientific matter, that is, the scientific evidence would inform the factual issue, that is, jury question raised on the pleading. 1186 I then requested the parties to think about a way these scientific (and potentially determinative) issues could be resolved by a special jury as efficiently as possible and foreshadowed listing argument on that question later that day. This was opposed, and I then said (T60): HIS HONOUR: … there are two ways of doing it, … we could debate this at greater length, but I might as well indicate to the parties the various options now so they can go away and think about them and consider it. I'm anxious to try to hear this case and deliver a judgment in it by the latter part of next year, if at all possible. I think it's important for the court that these sort of cases do not languish in the list for years, as they've been allowed to in various other matters, and it's in the interests - if we're doing more than paying lip service to the overarching purpose and trying to resolve these cases quickly, we've got to approach and manage these cases in a way which allows us to do that. I appreciate the force in what is said, that it would be appropriate to give some detailed consideration as to (1) whether or not a referee ought be appointed and, secondly, if a referee is to be appointed, should there be a series of what's been described elsewhere as a subject matter referees or, alternatively, a referee who's hearing from a series of subject matter experts? And the two courses since - I mean, when referees first came about, they originated in the second Judicature Bill in 1873. There were really two types of referees. There were official referees, and one of the reasons why in some court rules you had this legacy of special referees was the distinction between an official referee, who was actually an officer of the High Court, and you had special referees. … HIS HONOUR: And so there's two types of referees, and you could either have a retired judge referee, like a Mr Lindgren or somebody else, who is dealing with the parties adducing - in a less formal and less costly way - expert material that they deploy and inquiring and reporting and preparing a report for the court. Now, that's one mode of special jury, one mode of reference. The other is to have a series - if it's a complex matter, to have a series of subject matter referees. Now, ordinarily it would be for that referee, and the usual orders that I make for reference, which I can provide to the parties, would be laws of evidence don't apply, the legal representatives will have no involvement in relation to that. And the referee will be the one that makes such inquiries of experts and any other person as they see fit, and then provide a report to the client. So it's a very flexible arrangement which has a series of different ways that one can do it. And I don't have any particular view save for the fact that in my experience at least - and I have been involved in both - subject matter referees generally are far cheaper, far more efficient, and actually do serve to engender the sort of cost savings and time savings than a judge hearing all these issues at a trial. The beauty of it also is the fact that it can happen well in advance of the trial. So there would be proceedings on the reference, I would hope, in the early part of next year after the reference process has been completed. Parties then have certainty of, if the report is adopted, fine, if the report is rejected, then there may need to be consideration given as to whether the case can proceed on the fixed date because it may be the parties would need to then seek to adduce some expert evidence. Or alternatively, as you can see in the rules, there's the ability for supplementary reports and the like to be prepared if that was thought appropriate. So I just thought I would indicate to you that there are a variety of different ways of doing this. You know, if this is a particular type of issue that simply is too complex and too difficult and inapt for the appointment of a referee, then we will proceed in the orthodox way. But I've said enough to make it clear that my view that these are the sort of scientific type issues which may very well be apt for the appointment of a referee. 1187 When the matter next came before me on 12 August 2020, when the spectre of scientific manipulation had been raised and the parties were united in their opposition to any reference process, I observed (T39): HIS HONOUR: … common ground ha[s] broken out about the folly of the course that I had proposed… I thought it might - there might be - this is relevant for the exercise of discretion either by me or by a full court [as to a reference], you've suggested some alternatives, but there may be others. I mean, one of the complications about this case which is similar to the complications about the PFAS case is that - and this presented some challenges in PFAS but was able to be overcome - is that there are aspects of the questions which reflected a significant divide in the scientific community, and that is people were of particular camps. And … we don't want this like - a District Court personal injuries case in the 1980's where there's plaintiff's doctors and defendant's doctors, and one knows exactly what they're going to say, and with all the unsatisfactory aspects of that. So even if we didn't go down the reference course, it may be that at least one alternative is the idea of one or two court appointed experts together with perhaps an assessor. Anyway, I raise this because it - I accept the force of the submissions that have been made by the parties, and it's something which does cause on pause, and you have to think through these things about what's best for not only the parties and the Court, and the just determination of the issues. But, I'm just not going to let this case proceed down the path where there is entrenched experts on one side, entrenched experts on the other, and I'm sit here with this tsunami of expert material having to make a determination of which I think, in some respects, courts are ill-equipped to do. Anyway, I say that apropos of nothing other than just to entreat you to start thinking about these issues even if the reference process isn't to proceed, because I think those sorts of issues need to be thought through very carefully before we were to make decisions about processes for conclaves and the like. 1188 On 22 March 2021, when issues had been raised about the extent of discovery, upon which it became evident an enormous amount of money was being spent, a roundtable conference was held and attended by counsel, solicitors and the eDiscovery and technology mangers for the solicitors for the parties, during which I observed (T101): HIS HONOUR: … I must say, when I see the limited relevance of these documents in the overall case, I can't help getting the feeling that a vast amount of money is being spent in relation to this discovery process - like in a large number of other class actions, which is not consistent with the overarching purpose. This case is likely to be determined on - and which has been conceded before in response to my proposal we have a referee - the assessment of the expert evidence about the properties of… these products. It's not going to be determined - I can see some issues in the case to which the relevance of Monsanto Australia - of the carcinogenic - of the alleged carcinogenic property - that character of these products to be relevant, but - arguably irrelevant, but it's the tail - I just get the feeling it's just the tail wagging the dog - that a vast amount of money is being spent…which is not directed to the primary issue about what these - what - whether or not these two products were toxic and carcinogenic. 1189 These entreaties again fell on deaf ears. After coming back to the need to conduct this litigation in accordance with the overarching purpose on several occasions in 2021 and 2022, by 9 December 2022 (and after having vacated an earlier hearing of the initial trial in February 2022) and perhaps revealing my exasperation that the resolution of the case had been made unnecessarily costly and complicated, the following exchange occurred (T20): HIS HONOUR: The whole case comes down to whether or not this thing is carcinogenic. And I just want to entreat you again to think about ways that we could make this trial simpler. MS SZYDZIK: We will do so. HIS HONOUR: Yes. I know I was talked out of having a separate question about whether or not it's carcinogenic. I can't quite understand how I was talked out of that, but I was. MR FINCH: ... HIS HONOUR: … I decided it was a good idea after hearing submissions, but not I've seen the expert reports and I still can't understand why that's not a preferable course. MS SZYDZIK: We maintain that it isn't, but perhaps we don't really want to re-enliven that. HIS HONOUR: Well, either it's me or somebody else that's going to have to sit down at a trial in separate next year and decide whether or not this is - you win or you lose. And that's going to turn on the question of carcinogenicity, it seems to me. 1190 After delivering an ex tempore judgment on an unrelated matter, later that day the following exchange occurred (T30): HIS HONOUR: … Now, just remind me why - just remind me again - humour me by reminding me again as to why it's still not sensible to deal with just the issues of carcinogenicity first? MS SZYDZIK: Because it's not as straightforward as that. Because it is an issue that is bound up with questions relating to the respondent's knowledge and, as your Honour has also said, questions relating to the tainting conduct that has been set out in the reply. HIS HONOUR: So peripheral this tainting business for reasons I've explained, I just - even more that I've seen when I've read the joint expert reports. It just does not seem to me - we have really real misgivings about this. I was talked out of a reference process. Having seen the joint reports, I don't know why. This spectre of scientific fraud has been - which doesn't seem to have anything to do with the way in which the experts have expressed their views. It only goes to the question of what the knowledge was of Monsanto at relevant times for the negligence case if you're going to win on carcinogenicity anyway. And it can't be determined. It's fairyland to think that's going to be determined if it seems to me it's a safety defect point. So anyway, all I'm saying I will ask you to think about it again. And I will entertain - if anyone wanted to make an application again now that I've had the benefit of the expert reports and after I've seen the rejoinders, as to some other more efficient way of dealing with this which would not involve a judge of the court having to spend a vast, vast amount of its time on the balance of issues in the case if the view was formed that it's not carcinogenic. And if a view is formed that it is carcinogenic, then order the parties to a mediation after that finding has been made. Then I will entertain it on 2 February. But again, look, you may be able to convince me again that it's inappropriate. It's just that I'm finding it really hard to reconcile the amount of time that's allocated to this when there seems to me a fairly confined question which is going to leave the parties, irrespective of which ways it goes, in a much better position. And if we then have to have a subsequent hearing, we have a subsequent hearing. But I know I have expressed these views before and it must be an element of frustration, but I don't think we should just necessarily continue to going down the same path if the path becomes increasingly rocky and the alternative path seems to lead to the broad sunlit uplands of making life easier for the person deciding the case. 1191 Indeed, as it turned out, it was "as straightforward as that". Finally, on 2 February 2023, senior counsel for Monsanto said (T3-4): MR FINCH: On two occasions on 9 December, your Honour entreated the parties to give some thought about ways in which the hearing can be made more simple - - - HIS HONOUR: I did. MR FINCH: - - - and shorter, not to put too fine a point on it, with particular reference to the issue of the causation of NHL/cancer/carcinogenicity issue more generally. Can I be disarmingly frank about this. There's a great deal of attraction in the debate that your Honour has instigated on a number of occasions about focusing on that. There are some difficulties, so far as we can tell for the moment, in having a traditional separate question concerning that, and this is an issue your Honour has heard about before, because our learned friends wish to, amongst other things, put to our expert witnesses that their conclusions might be different had they been aware of certain scientific misconduct as it affects some of the basal data. Scientific misconduct, of course, doesn't affect the witnesses; it affects some of the data, some of the articles, if it be established. I have some problems, if I can be forgiven for speaking in the first person, with forcing the applicants not to be able to do that, because they say, "This is something which we want to say which vitiates the respondent's scientific case about causation." And, with respect, it seems to us to be dangerous to ask your Honour to force them not to do that either. But there is another way forward which we want to float now… 1192 What was then suggested was an embryonic version of the trial plan eventually put in place. Unfortunately, those acting for Mr McNickle were not able to respond that day and said they required an adjournment, but this trial plan was eventually put in place. Why the parties resisted simplification of the initial trial and why a version of the final trial plan could not have been put in place years before is, on my present understanding of the material, difficult to fathom. 1193 To repeat, my instinctive view, raised at the beginning of the case, is that it was possible to separate out potentially determinative issues. Subject to hearing submissions, it might be thought the reasons given from time to time as to why a simplification or staging of issues did not occur at a much earlier stage did not have any substance. Although it might be said those acting for Mr McNickle steadfastly refused any simplification of the case whenever it was raised (except at the heel of the hunt), Monsanto was also responsible for facilitating and giving effect to the overarching purpose. Notwithstanding my unfeigned respect for all those involved and my gratitude to the solicitors and all counsel for conducting the final hearing with such skill and courtesy, I do not consider this case has been conducted optimally or even efficiently. 1194 As noted above, these large class actions involve the consumption not only of the private resources of the parties, but also public resources. Everyone is entitled to their day in court, but they are not entitled to another litigant's day in court. The resisting parties also have a separate obligation to identify and then promote the optimal way of resolving the dispute consistent with their separate obligations under Pt VB of the FCA Act. 1195 Over and over in these large class actions, judges of the Court see huge process costs being expended which are ultimately wasted. As I have previously remarked, a respondent is entitled to spend as much money as it wants to defend litigation and, subject to ethical constraints, a solicitor is entitled to work as instructed, which may include doing work which could be later characterised as objectively unnecessary. But this does not mean that unnecessary costs should be recoverable against an unsuccessful litigant. A singular aspect of this case is that despite active case management and judicial intervention aimed towards constraining costs from the very outset, much more money has been spent on this litigation than in truth was necessary for a fair disposition of the issues - particularly relating to issues as to Monsanto's knowledge. 1196 I wish to receive submissions on how these issues inform any order for costs.
III Public Interest Litigation 1197 The second factor is that in Turner v MyBudget Pty Limited (No 2) [2018] FCA 1509, I dealt with a costs application made in a class action by a successful respondent. After noting the submission that the "usual rule that costs follow the event" is somewhat of an oversimplification, I observed (at [8]-[14]): [8] Although the fact that [the respondent] has been successful in resisting the claim by [the applicant] is a very powerful discretionary factor militating in favour of an award of costs, it is not necessarily determinative. While the discretion as to costs is a very broad one, it is restrained in the case of representative proceedings by the prohibition on making an award for costs against group members except in defined circumstances: see s 43(1A) of the [FCA Act]. Although this provision is not directly relevant in the case of costs sought against a representative party, it recognises the reality that the questions determined in representative proceedings have a public dimension which transcends ordinary inter partes litigation and the rights of the parties to the litigation inter se. [9] The case brought by [the applicant] is an exemplar of the type of proceeding that the Australian Law Reform Commission had in mind when, in 1988, it first recommended the introduction of a class action regime in ALRC Report 46. Here, a very large number of persons were affected by a common issue of law (in this case being the proper construction of the Interest Provision). It would have made no sense whatsoever for any individual litigant to have commenced a proceeding seeking clarification of this issue given the very small amount of money at stake for any individual litigant. The benefit of a grouping of claims by a Part IVA proceeding could only be achieved in the event that one person was prepared to come forward and act as the representative applicant. Unless [the applicant] had been prepared to bring the claim… uncertainty would have continued to exist relating to the true effect of the Interest Provision. Although I have reached a view that the proper construction is as [the respondent] contended, the arguments advanced by [the applicant] were far from being unarguable and, if I may say so, were advanced in an efficient and comprehensive manner by Counsel for the applicant, and in a way which was consistent with the overarching purpose. [10] This is a world away from a commercial class action, where the applicant is part of some form of common enterprise which seeks to use the Court's processes not only for the vindication of the applicant's personal claim but also as a means by which a managed investment scheme is seeking to derive a significant financial advantage for the participants in the scheme including a litigation funder. [11] [The respondent] recognises the fact that a proceeding brought in the "public interest" may be a basis, at least in some circumstances, for not awarding against an unsuccessful applicant: see Ruddock v Vadarlis (No 2) [2001] FCA 1865; (2001) 115 FCR 229. It asserts, however, that there is no general principle that the usual "costs rule" should not apply if the subject matter of litigation is a matter of public importance. It also points to QANTAS Airways Limited v Cameron (No 3) (1996) 68 FCR 387, a case which involved the question as to whether an unsuccessful applicant in a class action should be ordered to pay costs. QANTAS Airways was a case brought to vindicate mixed public and private interests: see at 390. Lindgren and Lehane JJ considered that the litigation served the "public interest" to the extent that it elucidated the duty of care owed by international airlines to passengers in relation to environmental tobacco smoke and that this should be given some weight, but damages were claimed and it was "impossible to view the proceedings as having been brought and pursued purely in the public interest": see 389-390. In those circumstances, the applicant was ordered to pay some costs. [12] Similarly, it is submitted, [the applicant] sought monetary relief and hence "his case cannot be viewed as having been pursued purely in the public interest". [13] It may be accepted that this was not a "pure" public interest claim, but a striking feature of this case was that any claim of [the applicant] (or any group member) was very modest, yet the collective benefit was potentially large. Although the class action did seek to vindicate [the applicant's] claim, it had a very significant benefit transcending the parties relative to the stake of the personal financial claim of the applicant. 24,222 others have obtained certainty as to their position. This number includes, it is safe to infer, many persons likely to have some financial vulnerability. [14] Although I do take into account the important consideration that [the applicant's] individual case has failed, he (together with his lawyers) has performed a valuable service for the benefit of others. In all the circumstances, while taking fully into account that the costs discretion is generally to be exercised in favour of the successful party, my view is that no order for costs should be made. Although on one level this might be thought to operate unfairly on [the respondent] which has incurred not insignificant costs, it must be recalled that it has now received the benefit of quelling the controversy relating to the operation of the Interest Provision not only in relation to [the applicant], but with regard to all group members. Costs applications are not determined solely by identifying who was responsible for the litigation, but by a broad assessment as to whether the order does occasion an injustice... 1198 Given the significant public interest in this litigation, the resolution of the central issue (at least for present purposes) transcends the interests of the parties. How this informs the discretion as to costs is also something in respect of which I seek assistance.
IV The Position of Mr McNickle 1199 Thirdly, and related to the last point, as I noted in the introduction, Mr McNickle is a man of modest means; is presently unwell; and has a wife to support. However strongly I empathise with the position Mr McNickle finds himself in, I am aware, in ordinary, inter partes litigation, that any discretion exercised in such a way so as to deprive a successful party of their costs must be exercised judicially and "according to rules of reason and justice, not according to private opinion … or even benevolence … or sympathy": Williams v Lewer [1974] 2 NSWLR 91 (at 95 per Rath J); Oshlack v Richmond River Council (1998) 193 CLR 72 (at 81 per Gaudron and Gummow JJ). 1200 But this is not ordinary litigation, and he has relied on others to bring the claim and, despite being unwell, he has performed a signal service in acting as a representative applicant. Mr McNickle will no doubt be disappointed in the result, but his labours have not been in vain. His individual case has provided a means by which the evidence currently marshalled has been evaluated and assessed thus resolving the legal rights of a great many people. At the end of the day, any ordinary costs rules are subject to the ability of the Court to make further or other orders as required to achieve an overall just result: Lombard Insurance Co (Australia) Ltd v Pastro (1994) 175 LSJS 448; GEC Marconi Systems Pty Ltd v BHP Information Technology Pty Ltd [2003] FCA 688; Furber v Stacey [2005] NSWCA 242. 1201 In this last respect, I am conscious that Monsanto has made submissions as to why the Court "should not be concerned as to the ramifications" of making a costs order against Mr McNickle but, so far as I can see, those submissions go beyond any evidence that was adduced at the hearing and, subject to any "without prejudice" material relevant to costs that may be admissible because of s 131(2)(h) EA, the parties agreed that the entire "universe of material" to which I am to have regard in making any final orders has already been adduced and is in evidence (T2087.40-2088.11).
V Future Submissions 1202 If a costs order against Mr McNickle is pursued, subject to any application, I will allow for further evidence as to costs (restricted to material admissible because of the exception contained in s 131(2)(h) EA) and submissions to be made to address relevant considerations.
J.6 Orders 1203 For these reasons, I make the following orders and make the notation set out below: 1. Pursuant to s 33ZF of the Federal Court of Australia Act 1976 (Cth) (FCA Act) (and notwithstanding that no application has been made by the representative party in accordance with s 33K(1) of the FCA Act) leave be granted for the group membership to be amended nunc pro tunc so that it is defined as it is in the last version of the statement of claim filed prior to the fixing of the date for opt out (being the second further amended statement of claim filed on 19 October 2020). 2. Pursuant to ss 33ZF and 37P(2) of the FCA Act, the following question, common to the claim of the applicant and all group members (Central Common Question) be answered separately and before any other question or issue in the proceeding: Throughout the period between July 1976 and 19 October 2020 (relevant period), did or could use of and/or exposure to the herbicide product or products, which contained glyphosate and were branded as "Roundup", or which contained glyphosate and were otherwise branded with the name "Monsanto" (Roundup Products) increase an individual's risk of developing non-Hodgkin lymphoma (NHL); and/or cause an individual to develop NHL? 3. The Central Common Question be answered as follows: It is not proven in this proceeding on the balance of probabilities (in accordance with s 140(1) of the Evidence Act 1995 (Cth)), that throughout the relevant period, use of and/or exposure to Roundup Products increased an individual's risk of developing NHL; and/or caused an individual to develop NHL. 4. The proceeding be dismissed upon finalisation of any issues relating to costs. 5. Any further evidence as to costs (as contemplated in the reasons (at [1202])) and any submissions as to costs be filed by 12 noon on 30 July 2024. 6. For the purposes of s 33ZB of the FCA Act, Orders 1 to 3 above affect (and hence bind) all current group members in the class action (being those named in the second further amended statement of claim who did not opt out). 7. The proceeding be adjourned for the parties to be heard on the appropriate costs orders in conformity with these reasons at 10:15am on 31 July 2024. AND THE COURT NOTES THAT: 8. The leave granted after the date of opt out had passed to amend the statement of claim so as to file the third and fourth statement of claim did not include leave being granted on application made by the representative party to alter the description of the group pursuant to s 33K(1) of the FCA Act. I certify that the preceding one thousand two-hundred and three (1203) numbered paragraphs are a true copy of the Reasons for Judgment of the Honourable Justice Lee.
McNickle
Huntsman Chemical Company Australia Pty Ltd
t v Merrell Dow Pharmaceuticals Inc 43 F 3d 1311 (9th Cir, 1995) Ethicon Sàrl v Gill [2018] FCAFC 137; (2018) 264 FCR 394 Foots v Southern Cross Mine Management Pty Ltd [2007] HCA 56; (2007) 234 CLR 52 Fox v Percy [2003] HCA 22; (2003) 214 CLR 118 Furber v Stacey [2005] NSWCA 242 GEC Marconi Systems Pty Ltd v BHP Information Technology Pty Ltd [2003] FCA 688 Gill v Ethicon Sàrl (No 3) [2019] FCA 587 GLJ v The Trustees of the Roman Catholic Church for the Diocese of Lismore [2023] HCA 32; (2023) 97 ALJR 857 Hockey v Fairfax Media Publications Pty Ltd (No 2) [2015] FCA 750 Jones v Dunkel (1959) 101 CLR 298 Karpik v Carnival plc (The Ruby Princess) (Evidential Ruling) [2022] FCA 1318 Kuligowski v Metrobus [2004] HCA 34; (2004) 220 CLR 363 Kumova v Davison (No 2) [2023] FCA 1 Lehrmann v Network Ten Pty Limited [2024] FCA 369 LFDB v SM No 2 [2017] FCAFC 207 Lloyd v Belconnen Lakeview Pty Ltd [2019] FCA 2177; (2019) 377 ALR 234 Lombard Insurance Co (Australia) Ltd v Pastro (1994) 175 LSJS 448 Matthews v SPI Electricity Pty Ltd (No 32) [2013] VSC 630 McNickle v Huntsman Chemical Company Australia Pty Ltd (Additional Expert Conclave) [2022] FCA 1596 McNickle v Huntsman Chemical Company Australia Pty Ltd (Assessors) [2021] FCA 780; (2021) 285 FCR 244 McNickle v Huntsman Chemical Company Australia Pty Ltd (Common Questions) [2023] FCA 662 McNickle v Huntsman Chemical Company Australia Pty Ltd (Evidentiary Ruling) [2023] FCA 1268 McNickle v Huntsman Chemical Company Australia Pty Ltd (Expert Evidence) [2021] FCA 370 McNickle v Huntsman Chemical Company Australia Pty Ltd (Hearing Vacation) [2022] FCA 133 Merck Sharp & Dohme (Australia) Pty Ltd v Peterson [2009] FCAFC 26; (2009) 355 ALR 20 Oshlack v Richmond River Council (1998) 193 CLR 72 Perera v GetSwift Limited [2018] FCA 732; (2018) 263 FCR 1 Perry v Novartis 564 F Supp 2d 452 (2008) Qantas Airways Limited v Gama [2008] FCAFC 69; (2008) 167 FCR 537 Ramsay v Watson (1961) 108 CLR 642 Re Australian Federation of Consumer Organisations Inc v Tobacco Institute of Australia Ltd (1991) 27 FCR 149 Re Joint Eastern and Southern District Asbestos Litigation 758 F Supp 199 (1991) Regent Holdings Pty Ltd v State of Victoria [2012] VSCA 221; (2012) 36 VR 424 Rhesa Shipping Co SA v Edmunds (The Popi M) [1985] 1 WLR 948 Roberts-Smith v Fairfax Media Publications Pty Limited (No 41) [2023] FCA 555 Russell v Australian Broadcasting Corporation (No 3) [2023] FCA 1223 Seltsam Pty Ltd v McGuiness [2000] NSWCA 29; (2000) 49 NSWLR 262 Transport Workers' Union of Australia v Qantas Airways Limited [2021] FCA 873; (2021) 308 IR 244 Turner v MyBudget Pty Limited (No 2) [2018] FCA 1509 Williams v Lewer [1974] 2 NSWLR 91
A INTRODUCTION 1 Mr Kelvin McNickle lived what might be thought by a young lad to be an Australian idyll. Born in September 1982, he grew up on a rural property on the beautiful Mid North Coast of New South Wales. His father operated a vegetation management business, and, during school holidays, Mr McNickle assisted his dad clearing vegetation. 2 But this was no passing stage. After completing school, Mr McNickle began working full-time for his father. No doubt it was hard work. Almost every working day, Mr McNickle and his father sprayed a weedkiller called "Roundup" on weeds and other unwanted growth using a knapsack sprayer or a drenching unit. As might be expected, drips or leaks of the Roundup soaked through his clothes and onto his skin. Mist or spray would go all over the place and get into his eyes and onto his face and fumes were inhaled. 3 Some years later, after marrying, Mr and Mrs McNickle left Coffs Harbour for Darwin. Mr McNickle is an apparently devout man. The Apostle Paul said: "let him do hard work, doing with his hands what is good work" (Ephesians 4:28). Apparently motivated by the perceived moral value of good and hard manual work, Mr McNickle volunteered to maintain the lawns and gardens of the Kingdom Hall of Jehovah's Witnesses. His evidence is that in doing so he used Roundup. 4 In May 2018, Mr McNickle was diagnosed with a type of cancer known as non-Hodgkin lymphoma (NHL). Just over a year later, he was informed by a haematologist that he was in ongoing remission. Unfortunately, about six weeks prior to the commencement of the initial trial, his NHL recurred. As a result, Mr McNickle was unable to attend the hearing. 5 I have introduced Mr McNickle, who is the lead applicant in this class action. But this judgment is not, at least directly, about him. This is not the occasion to deal with questions of individual causation. 6 Rather, when this initial trial was fixed, it was contemplated I would determine a set of common questions relating to Mr McNickle's contention that during a period from July 1976 until an end date defined at the time I made the orders (Relevant Period), glyphosate, glyphosate-based formulations (GBFs), and Roundup Herbicide and Roundup Biactive (Roundup Products) (which have glyphosate as a component), were carcinogenic to humans. The respondents (collectively, Monsanto) reject this contention completely. 7 The common questions were identified in orders made by consent following a case management hearing in April 2023. I set out the terms of those questions in Section J below and why I do not propose to answer them in the form initially proposed. 8 As it happened, issues were refined during the initial trial. In the end, for reasons that will be explained, the determinative question is whether Mr McNickle has discharged his legal onus of proving on the evidence adduced that the use of and/or exposure to Roundup Products can increase an individual's risk of developing NHL or cause an individual to develop NHL. I will call this, unimaginatively, the central issue. 9 There is no need for me to explain the issues in this proceeding any further. This is a case which has been mired in interlocutory skirmishes and, save for matters which I will mention shortly, I do not propose to rehearse that background here. There have been several judgments of the Court which identify the central issue, the utility of determining it initially, and set out what might be described as the superstructure of the proceeding: see McNickle v Huntsman Chemical Company Australia Pty Ltd (Common Questions) [2023] FCA 662; McNickle v Huntsman Chemical Company Australia Pty Ltd (Additional Expert Conclave) [2022] FCA 1596; McNickle v Huntsman Chemical Company Australia Pty Ltd (Hearing Vacation) [2022] FCA 133; McNickle v Huntsman Chemical Company Australia Pty Ltd (Assessors) [2021] FCA 780; (2021) 285 FCR 244; McNickle v Huntsman Chemical Company Australia Pty Ltd (Expert Evidence) [2021] FCA 370. 10 I will return to the common questions and the utility of answering them below, but at the outset, it is worth saying something about the proper approach to fact finding and the legal method.
B.1 Relevant Procedural Background and the Role of the Assessor 11 Enough has been said to indicate that this case presented significant challenges in fact finding. In the light of the central issue, it is an exercise in considerable understatement to describe the expert opinion evidence and underlying scientific material as dense, complex, and voluminous. 12 As I recorded in McNickle v Huntsman Chemical Company Australia Pty Ltd (Expert Evidence) (at [4]), when this matter first came before me for case management, I indicated my preliminary view was that the Court should adopt the process of appointing referees in a number of scientific disciplines to inquire into, and to report upon, questions concerning the characteristics of the Roundup Products and their alleged carcinogenic effects. 13 The parties vigorously opposed this proposed course. 14 An array of arguments were marshalled and then deployed to oppose referees, including that to proceed along these lines would be constitutionally invalid (an argument wholly devoid of merit and decisively rejected in CPB Contractors Pty Limited v Celsus Pty Limited (formerly known as SA Health Partnership Nominees Pty Ltd) (No 2) [2018] FCA 2112; (2018) 268 FCR 590). 15 With that said, there was one contention made by Mr McNickle that persuaded me (reluctantly) to adopt the course of allowing expert evidence to be deployed in a more traditional way. Mr McNickle's argument was that prevailing scientific opinion concerning the alleged carcinogenic effects of Roundup had been skewed or somehow manipulated by Monsanto. I concluded that the risk of referees assessing material said to be infected by this allegation of scientific manipulation created a prospect of complicating the inquiry process. Further, the allegation was one of some seriousness and is of a character that meant it should be resolved in open court. 16 Shortly after rejecting the process of references, and faced with what I knew was going to be a raft of highly complex opinion evidence, I noted in McNickle v Huntsman Chemical Company Australia Pty Ltd (Assessors) (at 246 [7]) that almost 100 years ago, Dean Roscoe Pound in his famous work The Spirit of the Common Law (Marshall Jones Company, 1921) (at 214-215) suggested that steps be taken to equip courts with research staffs comparable to those employed by administrative agencies in order to provide judges with specialised investigations, information, and advice. Yet, despite what some have described as centuries of legal history dotted with proof to the contrary, the traditional common law confidence that courts can handle any dispute without assistance has long persisted: see Beuscher, J H "The Use of Experts by the Courts" (1941) 54(7) Harvard Law Review 1105. 17 I also observed that in saying this, there have been attempts by courts to provide, in different ways, expert aid to determination. There are three obvious examples: (1) special juries; (2) referees (properly seen as a version of a special jury); and (3) assessors. 18 Having determined that there was to be no form of special jury, I went on to explain (at 247-253 [11]-[38]) the long history of appointment of assessors tracing back to the sixteenth century; the basis of the Court's power to order an assessor; and the scope of the role of an assessor. In this last regard, I referred to the judgment of J Forrest J in Matthews v SPI Electricity Pty Ltd (No 32) [2013] VSC 630 and relevantly noted (at 252 [37]) that the role of any assessor would be to assist the judge, but any decision would be that of the tribunal of fact, being the judge alone. Conscious of the need to avoid any procedural unfairness and define the role of the assessor precisely, I explained, with the consent of the parties, that if an assessor was appointed: (1) the assessor would sit with me during the concurrent evidence sessions, and could question the experts (or counsel) but such questioning would be limited to clarification of the evidence: that is, where the evidence given is perceived by the assessor or me to be ambiguous, unclear or incomplete; (2) I would consult with the assessor if I found a point of evidence unclear; (3) I would consult with the assessor in chambers on matters raised by the experts in their oral evidence and in their individual and joint reports, including advice as to any questions the assessor thinks should be asked; (4) I would seek the guidance of the assessor on scientific and technical matters upon which I lack the requisite knowledge to understand without qualified assistance; (5) if the assessor raised a theory or opinion that had not previously been identified by the parties, I would disclose this fact and discuss it with counsel; and (6) the assessor would, from time to time, provide me with advice on matters over which there is dispute between the experts but that such advice is not binding and the determination of a particular issue rests with me. 19 After receiving suggestions from the parties, on 16 August 2021, I made an order pursuant to s 23 and/or s 33ZF of the Federal Court of Australia Act 1976 (Cth) (FCA Act) that Professor Sir John Stewart Savill BA, MBChB, PhD, FRCP, FRCPE, FRCSEd(Hon), FRCPCH(Hon), FASN, FRSE, FMedSci, FAHMS, FRS be appointed as Assessor. In dealing with the Assessor, care has been taken not to depart from the six points identified above and, more generally, to ensure the findings I will make are mine and mine alone, notwithstanding the assistance received from the Assessor in understanding the complex evidence adduced in this case. For completeness, in my dealings with the Assessor, I record he did not raise a theory or opinion privately that had not previously been identified by the parties through their retained experts (see [18(5)] above). 20 Further, and again with the express consent of the parties, when I had completed an initial draft of these reasons without the assistance of the Assessor, I provided a copy of the draft reasons to the Assessor in order to ensure, as it was explained to the parties, that I had not committed any scientific "solecisms" caused by any fundamental misapprehension of the scientific evidence. I only adopted this course after obtaining confirmation by both parties that they regarded any communication between my chambers and the Assessor as being equivalent to an "in chambers" communication and hence wholly confidential, and that they disavowed seeking a copy of any communication of any type between my chambers and the Assessor, including on any appeal. 21 I should record that these reasons would have been significantly impoverished, and the delivery of judgment delayed, without the assistance of Sir John. It would have been much more difficult to identify and then understand the nuances of the opinion evidence without an Assessor, particularly one like Sir John with his happy facility for explaining complex scientific concepts in a way that can be comprehended by an interested layman. On behalf of myself and the Court, I express my appreciation to Sir John for his great assistance. 22 But this was not all the assistance I received. 23 As is well-known, Australia's version of concurrent evidence typically involves two interrelated processes. First, there is a pre-trial joint expert conferral or conclave phase during which the parties' experts meet to clarify the areas of agreement and/or disagreement to produce a joint report. The second part of the process is the giving of concurrent evidence. 24 In the present case, the first of these processes became particularly important and I appointed an experienced facilitator and independent barrister, Mr Edward Cowpe, who maintained the integrity of the conclave process and generally ensured the conclave process proceeded effectively and the various joint reports emerging from any conclave were expressed clearly, admissibly, and in a form that would best assist the Court. I am also grateful for his assistance.
B.2 Expert Assistance Generally 25 One of the reasons I was reluctant to abandon a reference and proceed in the time-honoured way in this case is because of my concerns in navigating potentially polarised expert views. In McNickle v Huntsman Chemical Company Australia Pty Ltd (Expert Evidence), I observed (at [1]) that controversy as to how opinion evidence is often deployed by litigants is not new, and some best placed to judge have expressed their criticism with some force. As Lord Woolf MR observed in the report, Access to Justice, Interim Report to the Lord Chancellor on the Civil Justice System in England and Wales (HMSO, London, 1995) (at 183): Expert witnesses used to be genuinely independent experts. Men of outstanding eminence in their field. Today they are, in practice, hired guns. There is a new breed of litigation hangers-on, whose main expertise is to craft reports which will conceal anything that might be to the disadvantage of their clients. 26 This might be thought as putting the point too highly in this country, but reflecting similar concerns, in Australia there has been extensive law reform discussion concerning the role, deficiencies and remedial responses to perceived difficulties with expert evidence. Most relevantly for present purposes, in the Victorian Law Reform Commission Civil Justice Review (2008) (at 484), reference was made by the Victorian Law Reform Commission (VLRC) to the notion of "adversarial bias". That conception falls into three varieties: (1) deliberate partisanship - an expert who deliberately tailors evidence to support the retaining client; (2) unconscious partisanship - the expert does not intentionally mislead the Court, but is influenced by the situation to give evidence in a way that supports the retaining client; and (3) selection bias - litigants choose as their expert witnesses persons whose views are known to support their case. 27 Given the evident polarisation of scientific views and the possibility of unconscious partisanship and selection bias, from the moment it became apparent there was to be no special jury, I explained I considered it was likely I would be best assisted if the parties could seek out and retain experts in various disciplines who might be described as "cleanskins": that is, experts who were not wedded to any particular concluded view and who could approach the questions posed informed by the Expert Evidence Practice Note (GPN-EXPT) (Expert Evidence Practice Note) (see also Harmonised Expert Witness Practice Note (Expert Witness Code of Conduct)) and without feeling the need to justify earlier expressed concluded views. 28 My suggestion was met with a mixed response. Indeed, the implicit (and sometimes explicit) suggestion made in Mr McNickle's submissions was that my suggestions or concerns in this regard were wrongheaded. I will deal with each of the experts below in detail, but it is worthwhile making four related and general points concerning the criticism that entreating the parties to engage experts who did not hold fixed views was somehow heterodox. 29 First, I accept we are dealing with abstruse areas of specialised knowledge. The relatively limited pool of qualified persons to give opinion evidence and the polarisation of scientific view as to the central issue (and matters adjectival to the central issue) would have perhaps caused some difficulty in identifying appropriate experts; a fortiori experts who had not already formed views. 30 Secondly, notwithstanding the first point, I did not come down in the last shower: like any judge who has been an experienced barrister, I understand the forensic attractions that lead to what the VLRC described as selection bias. I hope I am not being unfair in remarking that my distinct impression throughout the whole of the interlocutory stages of this case was that Mr McNickle's legal team, on one level understandably, resisted any independent referee process and eschewed engaging "cleanskins" in some areas of specialised knowledge because they felt more comfortable in the traditional approach of fixing upon experts they considered would likely reflect their case theory. 31 Thirdly, in the end, the role of the advocates acting for Mr McNickle was to persuade. As a general proposition, it stands to reason that the more objective, dispassionate, and disinterested an expert is, the more the opinions of the expert are likely to be perceived by the tribunal of fact as being: (a) unaffected by unconscious bias; and (b) persuasive. Of course, I stress this does not mean one assesses the admissibility and then reliability of an expert opinion by reference to some a priori view that it would be better to get a "cleanskin". Disputed questions of fact must be decided according to the evidence that the parties adduce, not according to some speculation about what other evidence might possibly have been led: Australian Securities and Investments Commission v Hellicar [2012] HCA 17; (2012) 247 CLR 345 (at 412-413 [165]-[167] per French CJ, Gummow, Hayne, Crennan, Kiefel and Bell JJ). 32 Fourthly, Mr McNickle in his submissions repeatedly made the point that the mere fact that an expert witness has a pre-existing opinion on a key issue is an infirm basis for rejecting the expert's opinion evidence "or placing less weight on it". He cited Born Brands Pty Ltd v Nine Network Australia Pty Ltd [2013] NSWSC 1646 (and on appeal Born Brands Pty Ltd v Nine Network Australia Pty Ltd [2014] NSWCA 369; (2014) 88 NSWLR 421), to assert a pre-existing opinion does not mean an expert is not open-minded or biased but can rather indicate an expert has come to a considered opinion after years of relevant experience. In other words, preconceived principles can inform opinion evidence, if the principles are scientifically based. 33 Of course, Born Brands was dealing with admissibility and not weight: two different concepts. But I accept the underlying point made by Mr McNickle has real merit. The mere fact that the opinion an expert has expressed in this case as to whether, for example, glyphosate is carcinogenic, is the same as the opinion previously expressed on the same issue in other cases against Monsanto in the United States, is neither a complete nor satisfactory basis for the Court to reduce the weight to be afforded to the expert's opinion evidence; let alone reject its admission. But depending upon the witness and the characteristics of the evidence, it can be part of the constellation of matters that may be relevant to assessing the persuasiveness of the evidence (depending upon how the evidence of the witness is challenged and whether procedural fairness has been provided to the witness to respond to whether the witness is approaching matters with an open mind or is fixed upon defending a pre-existing opinion). 34 In the end, each witness and the opinions expressed by the witness must be judged on their overall substantive merits, not by reference to the preconceived notion that it might have been thought more compelling to adduce evidence from an expert who first formed opinions through the prism of adherence to the Expert Witness Code of Conduct and approached the task without having formed pre-existing views. Recognising the merit of Mr McNickle's submissions, I have been careful to approach consideration of the expert evidence in this way. 35 As it happened, there was extensive cross-examination by each party alleging partisanship by some experts. Having foreshadowed this as a potential issue early on, I facilitated the experts engaging usefully with each other under the supervision of an independent barrister and settled the questions to be asked of them following extensive argument. I will deal below with the competing contentions of unconscious bias and partisanship; but I will do so as is appropriate: not by reference to sweeping generalisations; but rather informed by my impressions of the relevant expert's overall demeanour and credit and, most importantly, the perceived underlying scientific merit of the evidence given by the expert.
B.3 Fact Finding Generally in this Case 36 No lay witnesses were called. As noted above, the spectre of an attack on Monsanto for manipulating the science (decisive in my reasoning to not appoint referees) proved a damp squib, and although it was raised by one expert witness called by Mr McNickle directly, minimal evidence was adduced at this hearing directed to this allegation. 37 Leaving aside agreed facts, all the evidence was either expert or documentary. In respect of the latter, what might be described as a tsunami of scientific articles, studies and other materials was placed before me. I deal below with how, by the consent of the parties, I have approached the admissibility and weight to be given to the representations contained in that material. 38 But it must be emphasised at the outset that the Court's task in determining the central issue is not an exercise of choice between the evidence of the respective parties' expert witnesses. 39 It is trite to observe that in accordance with s 140(1) of the Evidence Act 1995 (Cth) (EA), the relevant standard of proof for the Court to apply is on the balance of probabilities, and that the applicant bears the onus of establishing that the evidence satisfies that test. 40 I will return to differences between the approach of both science and the law to causation enquiry below, but as I explained in some detail in Transport Workers' Union of Australia v Qantas Airways Limited [2021] FCA 873; (2021) 308 IR 244 (at 324-325 [284]-[288]), when the law requires proof of any fact, the tribunal of fact must feel actual persuasion as to its occurrence or existence before it can be found. A party bearing the onus will not succeed unless the whole of the evidence establishes a reasonable satisfaction on the preponderance of probabilities such as to sustain the relevant issue: Axon v Axon (1937) 59 CLR 395 (at 403 per Dixon J). In this way, the facts proved must form a reasonable basis for a definite conclusion affirmatively drawn of the truth of which the tribunal of fact may reasonably be satisfied: Jones v Dunkel (1959) 101 CLR 298 (at 305). 41 As I have also noted, despite the criticisms referred to in Transport Workers' Union of Australia v Qantas (at 325 [286]), this approach is well entrenched and unquestionably represents the current state of the law. This was reinforced by Kiefel CJ, Gageler and Jagot JJ in GLJ v The Trustees of the Roman Catholic Church for the Diocese of Lismore [2023] HCA 32; (2023) 97 ALJR 857, where their Honours observed (at 875 [60]): [60] … "[t]o satisfy an onus of proof on the balance of probabilities is not simply a matter of asking whether the evidence supporting that conclusion has greater weight than any opposing evidence ... It is perfectly possible for there to be a scrap of evidence that favours one contention, and no countervailing evidence, but for the judge to not regard the scrap of evidence as enough to persuade him or her that the contention is correct." The evidence must "give rise to a reasonable and definite inference" to enable a factual finding to be made; mere conjecture based on "conflicting inferences of equal degrees of probability" is insufficient. As Dixon CJ said in Jones v Dunkel, the law: does not authorise a court to choose between guesses, where the possibilities are not unlimited, on the ground that one guess seems more likely than another or the others. The facts proved must form a reasonable basis for a definite conclusion affirmatively drawn of the truth of which the tribunal of fact may reasonably be satisfied. (Footnotes omitted) 42 Before passing from these self-directions, it is useful to make two further points. 43 First, in final submissions, Monsanto asserted that the seriousness of Mr McNickle's allegation, being an allegation that Roundup Products cause NHL, must be considered in deciding whether Mr McNickle has discharged the onus of proof (referring to s 140(2) EA and Briginshaw v Briginshaw (1938) 60 CLR 336 (at 361-362 per Dixon J)). 44 With respect, at best, this is a distraction. Section 140(2) needs to be faithfully applied, but in considering "the gravity of the matters alleged" in s 140(2)(c), the primary focus is upon the nature of the factual allegations in the case (although the consequences of any finding is also a relevant matter). This makes sense when one considers the focus on the gravity of the finding is linked to the notion that the Court takes into account the inherent unlikelihood of alleged conduct, and common law principles concerning weighing evidence: see Qantas Airways Limited v Gama [2008] FCAFC 69; (2008) 167 FCR 537 (at 576 [137]-[138] per Branson J). There is no suggestion of knowing wrongdoing or of other intuitively unlikely conduct; here I am dealing with a question of general legal causation based upon the scientific evidence adduced and Monsanto's submission is less than helpful when the rationale of Briginshaw is understood. 45 Secondly, on the one hand, Mr McNickle asserts the evidence of general factual causation is pellucid; and on the other hand, Monsanto denies its existence completely. Often these submissions elided the concepts of legal and scientific causation, but it suffices to note for present purposes that the principal case theories adopted are polar opposites. But, as Besanko J observed in Roberts-Smith v Fairfax Media Publications Pty Limited (No 41) [2023] FCA 555 (at [117]-[118]), there is no doubt that a court is not bound to accept the case of one or other of the parties. 46 In this regard, his Honour referred to the "great clarity" of the speech of Lord Brandon of Oakbrook in Rhesa Shipping Co SA v Edmunds (The Popi M) [1985] 1 WLR 948, where his Lordship said the following (at 955): My Lords, the late Sir Arthur Conan Doyle in his book The Sign of Four, describes his hero, Mr Sherlock Holmes, as saying to the latter's friend, Dr. Watson: "How often have I said to you that, when you have eliminated the impossible, whatever remains, however improbable, must be the truth?" … In my view there are three reasons why it is inappropriate to apply the dictum of Mr Sherlock Holmes, to which I have just referred, to the process of fact-finding which a judge of first instance has to perform at the conclusion of a case of the kind here concerned. The first reason is one which I have already sought to emphasise as being of great importance, namely, that the judge is not bound always to make a finding one way or the other with regard to the facts averred by the parties. He has open to him the third alternative of saying that the party on whom the burden of proof lies in relation to any averment made by him has failed to discharge that burden. No judge likes to decide cases on burden of proof if he can legitimately avoid having to do so. There are cases, however, in which, owing to the unsatisfactory state of the evidence or otherwise, deciding on the burden of proof is the only just course for him to take…. 47 This reflects the legal reality of how the onus of proof works and the logical reality that a failure to prove a state of affairs does not necessarily mean the state of affairs does not exist. Hence, an acquittal by a jury of a person accused of a criminal charge does not amount to a declaration by the jury of the accused's innocence (although this state of affairs is taken at law to be the case by reason of the operation of a different presumption of the criminal law). 48 I come back to this important notion in Section J when I deal with the appropriateness of answering the common questions as initially framed.
B.4 The "Weight of Evidence" and the Scientific Studies 49 With metronomic regularity, Mr McNickle asserted that in determining whether glyphosate and/or GBFs can cause or increase the risk of NHL, "it is appropriate to take a weight of evidence approach" to the following three streams of scientific evidence, examined in detail below, being: (1) epidemiological studies of the effects of glyphosate and/or GBFs on humans; (2) long-term studies on experimental animals relating to whether glyphosate and/or GBFs can cause cancer in animals; and (3) mechanistic evidence, that is, evidence relating to whether there is a biologically plausible mechanism by which glyphosate and/or GBFs can induce cancer in humans. 50 The concept of the "weight of evidence" is a common term in published scientific literature, most often seen in the context of risk assessment. The concept is referred to in various conclave reports: Conclave A Joint Report (JRA) (at [19], [125]); Conclave B Joint Report (JRB) (at [72]-[78]); Conclave G Joint Report (JRG) (at [35], [39], [49]-[50], [102]); and Conclave I Joint Report (JRI) (at [13]). But this does not mean the concept is entirely clear; nor does its mere recitation explain how it is called in aid by Mr McNickle. 51 Dr Douglas Weed, an epidemiologist (who was the former Chief, Office of Preventive Oncology, and the Director of the Cancer Prevention Fellowship Program[me] at the National Cancer Institute (NCI), being an agency of the Executive Government of the United States) has published a systematic review of the scientific literature to characterise the "weight of evidence" concept. As I noted during final oral submissions, it is used apparently in three senses: (1) metaphorical, where weight of evidence refers to a collection of studies or to an unspecified methodological approach; (2) methodological, where weight of evidence points to established interpretative methodologies or where weight of evidence means that "all" rather than some subset of the evidence is examined, or rarely, where it points to methods using quantitative weights for evidence; and (3) theoretical, where weight of evidence serves as a label for a conceptual framework. Dr Weed identifies several problems associated with the frequent lack of definition of the term and a lack of consensus about its meaning: see Weed, D L "Weight of Evidence: A Review of Concept and Methods" (2005) 25(6) Risk Analysis 1545 (at 1545-57). 52 Following clarification made during the course of oral submissions, it became apparent that the parties employed the term in the second, methodological sense in that the principled approach requires attention to be given to "all", rather than some subset, of the scientific evidence. 53 Further, it became apparent during oral submissions that the assessment is suggested to take place on two different levels. 54 First, as is evident from the various conclave reports within each scientific stream, it is common ground that an expert cannot cherry-pick from the peer-reviewed studies those that support the expert's opinion, but rather carry out a comprehensive assessment of the weight of evidence of regulatory and peer-reviewed studies within that stream of scientific evidence. 55 Secondly, Mr McNickle submits, and Monsanto expressly accepts, that the Court needs to carry out a weight of evidence analysis to "weigh up the three streams of evidence". 56 I understand the way the concept is used within each scientific stream and its utility, but to the extent the concept is used in this second way, it needs to be approached with some caution and its discrete analytical utility is elusive. As I will explain, scientific causation and the legal question of general causation are different notions and it is trite that my job as a fact finder is to determine the central issue, being a factual issue, according to law, that is, by having regard to all the evidence admitted (and only the evidence admitted). 57 Subject to one matter to which I will come, evidence was admitted because the parties, through their non-objection to its adduction, accepted it was relevant because, if it was accepted, it could rationally affect (directly or indirectly) the assessment of the probability of the existence of a fact in issue at the initial trial: see ss 55 and 56 EA. As explained above, in assessing whether I have reached the level of reasonable satisfaction on the preponderance of probabilities such as to sustain Mr McNickle's case on the central issue, statute and authority demand I have regard, and only have regard, to the whole of the evidence admitted. My reasoning, inferential and otherwise, can only be based on the evidence admitted and must take account of the entirety of the evidence in reaching conclusions. 58 There is one qualification to what I have said about admissibility. I referred earlier to the scientific articles and studies placed before the Court. There is a lot of law about how a court is to deal with representations of opinion made in such material. As Heydon J explained in Dasreef Pty Limited v Hawchar [2011] HCA 21; (2011) 243 CLR 588 (at 615 [69], 631-632 [110]), there has long existed a qualification to the proof of assumption rule (under a common law exception to the hearsay rule), that experts may give evidence of hearsay matters which go to demonstrate their expertise - what is said in the writings of others in the relevant area of expertise they have read as a basis for their opinion, or what has been said to them in discussions they have had with colleagues and taken into account. 59 In short, experts are generally entitled to rely upon publications and material produced by others in the area in which they have expertise as a basis for their opinions and may give evidence of fact which is based on them. As is explained in Wigmore on Evidence (Little, Brown and Company, 3rd ed) Vol 2 (at 784-785): The data of every science are enormous in scope and variety. No one professional man can know from personal observation more than a minute fraction of the data which he must every day treat as working truths. Hence a reliance on the reported data of fellow-scientists, learned by perusing their reports in books and journals. The law must and does accept this kind of knowledge from scientific men. On the one hand, a mere layman, who comes to court and alleges a fact which he has learned only by reading a medical or a mathematical book, cannot be heard. But, on the other hand, to reject a professional physician or mathematician because the fact or some facts to which he testifies are known to him only upon the authority of others would be to ignore the accepted methods of professional work and to insist on finical and impossible standards. Yet it is not easy to express in usable form that element of professional competency which distinguishes the latter case from the former. In general, the considerations which define the latter are (a) a professional experience, giving the witness a knowledge of the trustworthy authorities and the proper source of information, (b) an extent of personal observation on the general subject, enabling him to estimate the general plausibility, or probability of soundness, of the views expressed, and (c) the impossibility of obtaining information on the particular technical detail except through reported data in part or entirely. 60 In Karpik v Carnival plc (The Ruby Princess) (Evidential Ruling) [2022] FCA 1318, Stewart J addressed this topic and, after referring to the above extract, noted (at [5]) that "[i]t can thus be seen that expert reliance on such learned publications is not excluded by the rule against hearsay (s 59) or the opinion rule (s 76)". His Honour was dealing with a case, like here, where the expert reports were replete with references to scientific articles. Having noted the need for caution in making an order under s 136 EA limiting the use of such materials, such a limitation order was not made generally but was made in relation to an article which was: (1) not referred to in any of the expert reports; (2) only referred to in cross-examination; and (3) "deal[t] with an area of expertise not possessed by any of the many expert witnesses in the case" and therefore "there is no other evidence against which to compare, or weigh, the opinions and conclusions expressed in the article", leaving the Court "in an invidious position with regard to trying to assess the weight to give to those opinions and conclusions" (at [24]). 61 His Honour explained that "[f]or that reason, taken together with the absence of any opportunity for the respondents the test or challenge those opinions and conclusions, I am satisfied that to not limit the use to which the article can be put under s 136 would be unfairly prejudicial to the respondents" (at [24]). 62 To their great credit, the parties to this case (well advised by experienced solicitors and junior counsel), took a sensible and constructive approach to all issues as to admissibility. One aspect of their agreement related to the reception and use of the scientific articles. Taking a slightly different approach to Ruby Princess, I had proposed to the parties a limitation that would restrict reception of material to those articles and studies in the experts' relevant area of expertise that were read and were said to form a basis for otherwise admissible opinion evidence or were used in cross-examination, accompanied by a general limitation under s 136 EA that the evidence was to be used for the purposes of providing a basis for, or understanding, the expert opinions adduced by the witnesses called. 63 The parties did not embrace this approach. On 19 October 2023, I was informed by the parties that a "joint position" had been reached to the following effect: All reports or decisions of regulatory authorities and authoritative scientific bodies, as well as scientific articles and reviews and other learned scientific publications, which have been referred to or relied upon by the expert witnesses who participated in the joint conclave should be admitted into evidence, with the parties being at liberty to make submissions in the course of closing submissions as to the weight that the court should place on any such document admitted into evidence. 64 As I noted when informed of this agreement, to the extent it operates to expand the admissibility and use of these scientific materials beyond the principled application of the Pt 3.3 EA exception to the Pt 3.2 hearsay rule, it was open to the parties to dispense, by consent, with the application of Pts 3.2 and 3.3 in relation to particular evidence (see s 190(1)(c) EA). 65 Accordingly, I made orders in accordance with this agreement and will proceed to deal with this aspect of the evidence in accordance with the express agreement of the parties.
B.5 The Scientific and Legal Method and Causation 66 Before passing from fact finding and causation, it is important to make a further point that was somewhat obscured during submissions. 67 In ACQ Pty Ltd v Cook [2009] HCA 28; (2009) 237 CLR 656 (at 661 [14]), French CJ, Gummow, Heydon, Crennan and Bell JJ observed, albeit in a different context, that causation is one of the most difficult fields of debate in the law and one about which "abstract discussion is seldom valuable". Perhaps recognising this, abstract discussion about causation was largely absent from the parties' submissions. But one must not gloss over important differences between the scientific and legal method in relation to causal connexions between facts. 68 These differences have been explored in many articles including, by way of example, Korn, H L "Law, Fact, and Science in the Courts" (1966) 66 Columbia Law Review 1080; Brennan, T A "Causal Chains and Statistical Links: The Role of Scientific Uncertainty in Hazardous-Substance Litigation" (1988) 73 Cornell L. Rev. 469; and Geistfeld, M "Scientific Uncertainty and Causation in Tort Law" (2001) 54 Vanderbilt Law Review 1011. It is beyond the scope of this judgment to canvass such a large topic in anything other than the most superficial way, and this judgment should not be unnecessarily diverted into epistemological or philosophical questions, but the nature of differences must be understood, at least in broad terms, so the scientific evidence is properly understood and its relationship to the legal issue of general causation is not distorted. 69 Justice Jonathan Beach has written extra-curially on this topic in a way that repays close attention. Drawing upon his earlier work ("Scientific Evidence: A Need for Caution in Decision-Making" (2010) 42(1) Australian Journal of Forensic Sciences 49 and "Indeterminacy: The Uncertainty Principle of Negligence" (2005) 13 Torts Law Journal 129), in a recent article "Causation: The Interface Between the Scientific and Legal Methods" (2022) 49(1) University of Western Australia Law Review 113, Justice Beach explained (at 113) how the objectives of legal and scientific inquiry differ as science "searches for increased knowledge, with truth as its ideal; its coverage [being] more comprehensive and not time sensitive. But the law's "objective is to resolve conflicts; its coverage is limited and time sensitive". In this way, science describes explains and predicts while the law "is concerned with regulating human affairs in accordance with values and objectives". 70 It is simplistic to say there is one "scientific method" because it depends upon the nature of the scientific task, but speaking generally, these different objectives mean there are critical contextual differences between science and the law concerning methodologies and in the expression of conclusions of their differently focused enquires. Moreover, when it comes to causation, the role of the law might be said to involve an optimistic search for truth but, as my self-directions make clear, the aim is not to discover objective truth, but rather whether the relevant factual issue (in this case of general factual causation) has been proved to the requisite standard. 71 As Justice Beach, with respect, cogently explains in his recent article (at 117-8), while recognising the differences between the legal method and the scientific method: … when lawyers analyse scientific evidence, the epistemic values that need to be applied correlate with values underpinning the scientific method. A lens must be used which provides a sophisticated picture of the content and reliability of the scientific evidence. And not to analyse scientific evidence through the appropriate lens can lead to outcomes 'determined by intuitive perceptions of the weight of authority rather than by reasoning from evidence'. Of course, the language, premises and analytical styles between the scientific method and the legal method have their differences. But when the latter is required to evaluate the former, significant correspondence of epistemic values arises. Lawyers must 'retrace and evaluate the technical analysts' logic, from empirical data to subjective judgment'. And complex issues of science require reasoning among purely technical facts analysed through complex models, statistical inference and mathematical instruments that have no comparator in legal reasoning. Now there are different modes for judicial analysis of scientific evidence. The judge might hear expert evidence in the usual way or through the mechanism of concurrent evidence sessions, which is my preferred option in patent litigation. The judge might appoint his own expert. The judge might obtain assistance from sitting with an assessor who may assist with any explanation of the scientific evidence. The judge might receive a report on the scientific question from a special referee, although this last option is remote from any direct judicial analysis of the scientific question. But whatever the procedural mode, this does not change the epistemic values and methods needed to assess scientific evidence. Moreover, judges are not obliged to accept the ipse dixit of the expert. They are obliged to test propositions, to assess one expert's opinion against another, and to synthesise a position taking into account all expert, lay and documentary evidence. 72 This is what I have attempted to do. To rely acontextually upon general statements made by scientists as to causation, or to assume that scientific expressions as to possibility or probability necessarily translate to the legal task of considering probability through the lens of general factual causation at law is simplistic. Put in more simple terms, the factual issue before me is, at bottom, a common law jury question and, as was explained by Dixon CJ, McTiernan, Kitto, Taylor and Windeyer JJ in Ramsay v Watson (1961) 108 CLR 642 (at 645): That some medical witnesses should go into the witness box and say only that in his opinion something is more probable than not does not conclude the case. A qualified medical practitioner may, as an expert, express his opinion as to the nature and cause, or probable cause, of an ailment. But it is for the jury to weigh and determine the probability. In so doing they may be assisted by the medical evidence. But they are not simply to transfer their task to the witnesses. They must ask themselves 'are we on the whole of the evidence satisfied on the balance of probabilities of the fact?'
I Introduction 93 In 1854, Dr John Snow witnessed an outbreak of cholera in London. Determined to discover its source, he plotted the location of cholera deaths on a dot-map. The dots congregated a short distance from Broad Street (now Broadwick Street) in Soho. There, the local council had installed a water pump. Suspecting that the pump was the source of the outbreak, Dr Snow persuaded the council to remove the handle. The outbreak subsided. 94 But that was not the end of the story: had the handle been contaminated? Was it the water itself? Or was the outbreak due to something else? Dr Snow thought it was the water. He continued to collect data on cholera deaths in the city and identified three water companies that supplied water to districts with the highest mortality rates. It was not clear within each district, however, which company supplied water to households where a cholera death occurred. By collecting data from individual households, Dr Snow inferred that two of the water companies were responsible for transmitting cholera poison and, by 1857, legislation had been enacted to mandate the filtering of all water in London (see Harris, S A "Epidemiology: Theory, Study Design and Planning for Education" (2000) 20 Journal of Continuing Education in the Health Profession 133). 95 Albeit in nascent form, Dr Snow was engaged in epidemiology. For his efforts, he enjoys the not inconsiderable distinction of having a pub named after him. 96 Expressed in broad terms, epidemiology is the study of distribution and determinants of disease in humans. As Spigelman CJ explained in Seltsam Pty Ltd v McGuiness [2000] NSWCA 29; (2000) 49 NSWLR 262 (at 271-272 [59]-[62]), epidemiology is based on the assumption that a disease is not distributed among populations at random: subgroups may be identified which are at increased risk of contracting particular diseases. Epidemiological evidence identifies associations between specific forms of exposure and the risk of disease in groups of individuals. 97 Epidemiologists make judgments about whether a statistical association represents a cause-effect relationship. However, those judgments focus on what is called in the epidemiological literature (as well as the law) general causation, that is, whether the factor is capable of causing the disease. Epidemiologists are not concerned with specific causation, that is, whether the factor caused the disease in an individual case. 98 For the purposes of determining whether exposure to a particular substance is the legal cause of a particular disease, epidemiology only provides evidence of possibility, which (for reasons I have explained), when expressed in opinion form and in epidemiological research, is admissible and part of the whole of the evidence to which the court must have regard: Seltsam v McGuiness (at 274-275 [78]-[79] per Spigelman CJ). 99 At bottom, this is a trial directed to the issue of general factual causation. Obviously enough, given its nature, epidemiological evidence is of real importance. Indeed, as it turns out, successfully demonstrating that the epidemiological evidence adduced in this proceeding supports the conclusion that glyphosate and/or GBFs can increase the risk of and/or cause NHL in humans is a hurdle in accepting Mr McNickle's case. 100 But it remains one hurdle. As senior counsel for Mr McNickle, Mr Clements KC, submitted in his opening (T10.32-37): Despite there being very broad agreement between the experts retained by each side, as to the appropriateness of the weight of evidence approach, the respondents, in their written opening, have submitted that the epidemiological evidence should be given primacy by the court. We contend that approach should be rejected. We contend that it's important for the court to closely consider and weigh up the evidence in each of the three separate streams of scientific evidence. 101 Put another way, the importance of the epidemiological stream does not mean that my conclusion as to whether I have reached a level of reasonable satisfaction on the preponderance of probabilities to sustain Mr McNickle's case on the central issue is the product of giving primacy to one aspect of the evidence and reducing others to some form of secondary role or, more specifically, placing unwavering and disproportionate focus upon the epidemiological evidence in a vacuum. It is not. Indeed, focussing too intently on one part of the evidence at the expense of proper consideration of another part and then assessing the accumulated whole, would not only be a legal but a logical error. 102 Of course, some parts of the evidence may emerge as being more persuasive or important than other aspects, but any conclusion on the central issue must be made with regard to the overall weight of all of the evidence.
II Methodology 103 It is largely uncontroversial among epidemiologists as to the principles or postulates which should be applied to assess evidence of a statistical correlation or association between the exposure in question and health outcome of interest: see Seltsam v McGuiness (at 285 [139] per Spigelman CJ). 104 The first step in assessing the epidemiological evidence and whether it indicates an etiologic relationship (that is, a causal relationship) between exposure to glyphosate and/or GBFs and development of NHL in humans is to identify the relevant peer-reviewed literature. The second step is to identify strengths and limitations of each publication, which, in turn, allows an identification of publications that are most relevant to the specific topic of concern, and an evaluation of the weight that should be placed on such publications (Conclave C Joint Report (JRC) (at [63])). 105 In evaluating the relevant literature, epidemiologists may attempt to distinguish between causal and non-causal explanations (at JRC [64]-[65]). While there is no agreed set of criteria to assess causation that exists in the field, lists of criteria have become popular. The most well-known of these among epidemiologists is one devised by Sir Austin Bradford Hill, then Professor Emeritus of Medical Statistics at the University of London, in his Presidential address to the Section of Occupational Medicine: "The Environment and Disease: Association or Causation" (1965) 58 Proc R Soc Medicine 295. 106 The following summary of the "Bradford Hill criteria" is extracted from French CJ's judgment in Amaca v Booth Pty Ltd [2011] HCA 53; (2011) 246 CLR 36 (at 54-55 [44]): [44] … The [Bradford Hill] criteria were expressed as the aspects of an association between two variables that should be considered before inferring that the most likely interpretation of the association is causation. In summary, they are: strength of association - eg, reflected in the ratio of the death rates between groups exposed to a suspected agent and those not so exposed; consistency in the observed association - eg, has it been repeatedly observed by different persons in different places, circumstances and times; the specificity of the association - if the association is limited to specific workers and particular sites and types of disease and there is no association between the work and other modes of dying, that is a strong argument in favour of causation; temporality - the temporal relationship of the variables; biological gradient - whether the association reveals a biological gradient or dose-response curve; plausibility - whether the expected causation is biologically plausible - a consideration which depends upon the biological knowledge of the day; coherence - the cause and effect interpretation of the data should not seriously conflict with the generally known facts of the natural history and biology of the disease; experiment - whether experimental or semi-experimental evidence supports a causation hypothesis; analogy - eg, given the effects of thalidomide and rubella it is easier to accept slighter but similar evidence with another drug or another viral disease in pregnancy. 107 These factors are not intended as a necessary condition for a cause-and-effect relationship, nor a checklist or set of hard and fast rules to be applied in evaluating causation among epidemiologists. Rather, the Bradford Hill criteria constitutes a guide or set of commonsense propositions which may be taken into account in determining whether or not the Court should infer, on the balance of probabilities, that a particular exposure caused injury (see Amaca v Booth Pty Ltd (at 54-55 [44]-[45] per French CJ); Seltsam v McGuiness (at 285 [139]-[141] per Spigelman CJ); (at JRC [66]-[71])). As was noted in a discussion of the application of the Bradford Hill criteria in the Restatement Third, Torts: Liability for Physical and Emotional Harm s28, Comment c(3) (at 406-407): Whether an inference of causation based on an association is appropriate is a matter of informed judgment, not scientific methodology, as is a judgment whether a study that finds no association is exonerative or inconclusive. No algorithm exists for applying the Hill guidelines to determine whether an association truly reflects a causal relationship or is spurious. Because the inferential process involves assessing multiple unranked factors, some of which may be more or less appropriate with regard to a specific causal assessment, judgment is required. 108 Before going further, and in an attempt to make what follows less unreadable, it is worth identifying some key terminology and demystifying some jargon frequently deployed in the epidemiological literature, which is also relevant to the two other streams of evidence.
128 In the following section, I will introduce each of the experts who participated in the epidemiology stream, before turning to making some general observations as to credit. In doing so, I am conscious that the parties have made submissions as to credit which loom large in respect of some witnesses and not others. I have had regard to all these submissions, but it would add further to an already lengthy and oppressive judgment to set them out in full, except where I consider them to be of especial importance. As will be seen, in this section I make repeated references to various aspects of the evidence and various studies. This evidence and the studies referred to are dealt with comprehensively later in my judgment. 129 With that said, for reasons that will already be obvious, a significant amount of time was expended by both sides in mounting attacks upon witnesses (not limited to the epidemiology stream) whose evidence, it is said, was marred by partisanship. As I explained in Russell v Australian Broadcasting Corporation (No 3) [2023] FCA 1223 (at [438]), many experienced judges have expressed the caution that any criticisms of a witness, which go beyond the legitimate necessities of the occasion, should be avoided. Indeed, unnecessary credit findings should be avoided partly because of a body of research casting doubt on the ability of judges to make accurate credibility findings based on demeanour: see Fox v Percy [2003] HCA 22; (2003) 214 CLR 118 (at 129 [31] per Gleeson CJ, Gummow and Kirby JJ). 130 Despite an adverse credit finding with respect to one witness, issues going to credit are not the centrepiece of this case. As the High Court explained in Fox v Percy (at 129 [31]), the Court's task is to reason its conclusions, as far as possible, on the basis of contemporary materials, objectively established facts and the apparent logic of events (in this initial trial, the scientific materials). This is not to say that my assessment of the scientific evidence in the three streams is not partly informed by impressions I have gained as to the relevant expert's overall demeanour and credit. It is. But there is an extent to which such impressions can distract the Court from the principal task of assessing the underlying scientific merit of the evidence adduced in this proceeding.
[2004] HCA 34
[2013] VSC 630
[2012] VSCA 221
(2009) 237 CLR 656
(2011) 246 CLR 36
(2012) 247 CLR 345
(1937) 59 CLR 395
(2019) 372 ALR 638
(2014) 88 NSWLR 421
(1938) 60 CLR 336
(2018) 268 FCR 590
(2011) 243 CLR 588
(2018) 264 FCR 394
(2007) 234 CLR 52
(2003) 214 CLR 118
(2023) 97 ALJR 857
(1959) 101 CLR 298
(2004) 220 CLR 363
(2019) 377 ALR 234
(2021) 285 FCR 244
(2009) 355 ALR 20
(1998) 193 CLR 72
(2018) 263 FCR 1
(2008) 167 FCR 537
(1961) 108 CLR 642
(1991) 27 FCR 149
(2012) 36 VR 424
(2000) 49 NSWLR 262
(2021) 308 IR 244
(2001) 51 NSWLR 572
(2000) 100 FCR 331
(2016) 259 CLR 212
(2003) 126 FCR 219
(2001) 115 FCR 229
(1996) 68 FCR 387
[2003] HCA 22