Delayed Glyphosate Population Study Further Undermines IARC & Judicial Conclusions
The delayed publication of the North American Pooled Project (NAPP) study of glyphosate produced findings with significant implications for the glyphosate debate. Despite the importance of NAPP study conclusions and findings, its evolution to final publication reflected apparent conflicts of interests and a seeming intent for delaying and minimizing awareness of relevant findings. Even today, knowledge of the NAPP study is such that many followers of the glyphosate debate only became aware of the 2019 NAPP final publication through a recent journal article, On recent meta-analyses of exposure to glyphosate and risk of non-Hodgkin’s lymphoma in humans (Kabat, Price and Tarone; 2021).
The NAPP study “pooled” exploratory case-control studies conducted in four Midwestern U.S. states and six Canadian provinces during the 1980–90s. The study, Glyphosate use and associations with non-Hodgkin lymphoma major histological sub-types: findings from the North American Pooled Project (Pahwa, 2019) did not find any significant association between glyphosate based herbicides (GBHs) and Non-Hodgkin’s Lymphoma (NHL) or its sub-types, when datasets are adjusted for confounding pesticide usage, proxy respondents and the most reliable usage data. Concurrent with the NAPP study, an update for the Agricultural Health Study (AHS) was also drafted during the 2013–2014 timeframe and incurred similar types of delays and aberrations. The AHS update was published during November, 2017 with a highly confident conclusion of “no evidence of an association between glyphosate use and risk of any solid tumors or lymphoid malignancies, including NHL and its sub-types”.
The article Viewpoint: North American scientists, IARC officials conspired to misrepresent glyphosate health risks (Heitz, 2018) provides a detailed review of irregularities occurring with NAPP and AHS activities as well as the International Agency for Research on Cancer (IARC). Heitz also describes the circumstances causing an atypical leap in priority leading to earlier dates for a GBH Working Group review and resultant IARC Monograph on Glyphosate (2015). The Monograph’s hazard-based assessment concluded glyphosate causation of NHL was dependent on finding “limited evidence of cancer in humans from real-world exposures that actually occurred…”, namely epidemiological studies such as NAPP and AHS. However, neither study was considered within the Monograph, nor was there a recommendation for delay, though authors from each study were included within the IARC Working Group. The IARC Monograph led to glyphosate lawsuits in the United States and extensive other consequences.
The AHS update was published with unambiguous conclusions and supportive sensitivity analyses. In contrast, the various NAPP publications (draft, professional presentations and final publication) were less than forthright in the identification of relevant findings and associated significance. NAPP documents consistently reflected an apparent aversion for clearly stating the proven validity of odds ratios and confidence intervals adjusted for confounding variables of other pesticide usage. Similarly, there is also a reluctance to confirm that measurements using only self-respondents are more reliable than those combined with proxy respondents, particularly when there is a large percentage of proxy respondents as shown in Figure 1 of NAPP study.
The most reliable measurements are presumably those which fully adjust for confounding pesticide usage, exclude proxy respondents and utilize duration of usage. Extracted charts reflecting these characteristics are drawn from Supplementary Materials appendix of the NAPP study:
Similar studies examining the relationship of GBHs and NHL overall as well as NHL sub-types are limited. McDuffie (2001) and Ericsson (2008) are exploratory case studies with a small number of glyphosate exposures and no adjustments of NHL sub-types for confounding pesticide usage, among other limitations. The AGRICOH study (Leon, 2019) imputes pesticide usage for French and Norwegian cohorts as well as not using recent years’ data from American AHS cohort. The AHS study, Glyphosate Use and Cancer Incidence in the Agricultural Health Study (Andreotti, 2018), provides comparatively much larger numbers for respondents, NHL cases, sub-type cases and especially for respondents with glyphosate exposures; only self-respondents by study design; extensive range of exposure intensities; and NHL overall as well as sub-type measurements:
Note: The AHS update did not include never used/ever used measurements, but the U.S. EPA calculated a risk ratio of 0.85 and 95% confidence interval of (0.73–0.99). Predecessor AHS study (DeRoos, 2005) has never/ever risk ratio of 1.1 and 95% confidence interval of (0.7–1.9).
The most important finding derived from the NAPP study is the implicit refutation of elevated overall NHL odds ratios for previously published component studies of DeRoos (2003) and McDuffie (2001). The NAPP study and updated AHS study with a lower risk ratio than the predecessor study (DeRoos, 2005) present a collective weight most certainly sufficient for invalidating the original epidemiological analyses fundamental to IARC’s glyphosate causation of NHL with “limited evidence of cancer in humans from real-world exposures that actually occurred…”. Confirmation is provided by epidemiological evaluations of key worldwide regulatory agencies performed subsequent to the IARC Monograph.
An obvious solution for the flawed IARC decision would be a reevaluation by IARC, including the NAPP and AHS studies as well as other relevant studies conducted since the 2015 Monograph. Stakeholders should however be mindful the IARC is an autonomous entity of the World Health Organization with minimal transparency. Regardless, IARC guidelines for convocation of working groups should consider current, but unpublished research with significant implications before establishing firm review dates.
The U.S. legal systems (federal and state) do not consider the IARC hazard-based conclusion to be a valid basis for civil litigation. District Court Judge Chhabria, presiding judge for the consolidated federal glyphosate (Roundup) cases, noted in regard to the IARC classification:
“As IARC takes pains to point out, its decision that a substance is “probably carcinogenic to humans” is a hazard assessment –merely the first step in determining whether the substance currently presents a meaningful risk to human health. IARC leaves the second step –risk assessment –to other public health entities. Moreover, even with its hazard assessment, IARC makes clear that although it uses the word “probably,” it does not intend for that word to have any quantitative significance. Therefore, the public health inquiry does not map nicely onto the inquiry required by civil litigation. And the hazard assessment IARC undertakes is too limited and too abstract to fully serve the plaintiffs’ purposes here”.
The same rationale requiring risk assessments also requires courts provide substantially more weight to epidemiological studies demonstrating effects directly on humans than animal or mechanistic studies requiring speculation as to human effects. It is therefore not surprising pre-trial activity for the glyphosate litigation recognized the recently published AHS and draft NAPP studies as qualified for expert witness testimony of epidemiological evidence. However, the impact of these newer studies was greatly diminished when plaintiffs’ expert witnesses, including an author of the NAPP study, overwhelmed juries with misleading and irrelevant epidemiological technical data. For example, plaintiffs’ expert witnesses regularly informed juries the McDuffie study found a very elevated odds ratio for glyphosate if used two days or more per year. However, these same witnesses did not explain the results were not adjusted for confounding pesticide usage or sulfur, a relatively innocuous organic fungicide, had an odds ratio larger than glyphosate for one or more days of usage per year. Compounding the harm, another plaintiff’s expert witness testified the same non-adjusted odds ratio from the McDuffie study as well as another similarly non-adjusted odds ratio from a separate study were factors for determining glyphosate was the cause for plaintiff’s NHL.
Strictly applied, Federal Rule 702 or a state’s equivalent allows judges little flexibility to use highly technical expert testimony as an issue of weight or credibility for jury consideration rather than a question of admissibility by the court. However, certain states and federal circuit court jurisdictions maintain they are not abdicating the court’s “gatekeeper” role by allowing additional technical information, instead they are allowing juries to be a trier of facts. The example of non-adjusted odds ratios and confidence intervals illustrates why this type of invalid or irrelevant testimony manipulates juries.
Similarly, courts can allow expert witnesses to present opinion through a “differential diagnosis” in which expert witnesses identify possible causes of a person’s disease or condition and one-by-one eliminate improbable causes until only one cause remains. This process can be valid, but only when courts ensure expert witness testimony for risks, causes and eliminations is supported by reliable epidemiological studies. A differential diagnosis or etiology can also be inappropriately used if the cause for a disease is largely unknown (idiopathic). In glyphosate litigation the relevant disease is NHL with more than 30 sub-types and each sub-type may have known risk factors; e.g., current or previous medical conditions. However, “the etiologies of most lymphomas remain unknown” (Morton,2008), including the sub-types of NHL involved with the three glyphosate court cases. Apparently, the largely idiopathic nature of these sub-types did not inhibit plaintiffs’ experts in their differential diagnoses from confidently testifying the cause for each NHL case was GBH usage.
There are also concerns with Federal Rule 702 or state equivalent rulings associated with the pre-trial expert witness qualification process (also known as Daubert or Frye proceedings). For example, Judge Chhabria noted in his pre-trial ruling the flexibility afforded by the Ninth Circuit for qualifying experts offering “shaky” opinions to be resolved by the jury.
“However, the question at this phase is not whether the plaintiffs’ experts are right, the question is whether they have offered opinions that would be admissible at a jury trial. And the case law –particularly Ninth Circuit case law –emphasizes that a trial judge should not exclude an expert opinion merely because he thinks it’s shaky, or because he thinks the jury will have cause to question the expert’s credibility. So long as an opinion is premised on reliable scientific principles, it should not be excluded by the trial judge; instead, the weaknesses in an unpersuasive expert opinion can be exposed at trial, through cross-examination or testimony by opposing experts.”
There is no readily apparent and timely solution for requiring originally intended strict standards for Federal Rule 702 or state equivalent. There could be another “Daubert” type case where the Supreme Court establishes a precedent for stimulating more stringent application of guidelines. Absent that eventuality, the Advisory Committee on Evidence Rules of U.S. Courts administration has been working for years with the U.S. Judicial Conference to apply improvements to Rule 702:
A series of anomalous activities exacerbated by misinformation campaigns of tort lawyers, NGOs and other activist organizations created a scientific deception of far-reaching consequences. The only positive elements of this glyphosate assessment failure are the key worldwide regulatory agencies, all of whom conducted risk assessments post IARC and determined glyphosate not likely to be carcinogenic in humans. (Key agencies included U.S. Environmental Protection Agency, European Food Safety Authority, European Chemicals Agency, Australian Pesticides and Veterinary Medicine Authority, New Zealand Environmental Protection Authority and Health Canada.) During the most recent risk assessment, Health Canada conducted a comprehensive reevaluation of glyphosate with additional studies/data developed or published after 2015. Health Canada’s reevaluation team of 20 scientists paid special attention to raw data for claims allegedly contained within discovery documents known by the name of “Monsanto Papers”; recent epidemiological studies, including NAPP and AHS; an additional seven rodent studies; and more recent mechanistic studies.
A fundamental predicate for objective and defensible outcomes of science-based disputes is consistency across scientific, regulatory and judicial organizations. The glyphosate case represents an obvious “out of synch” situation caused by a series of deficient actions and omissions largely attributable to the IARC and the U.S. judiciary. Moreover, the same deficiencies causing the glyphosate failure also implicate a broader range of similar problematic situations and heighten the urgency for implementing corrective actions.
