After checking to see whether the new Reference Manual on Scientific Evidence[1] attended to some long overdue corrections, I turned my attention to the substance of the chapter on epidemiology. A cursory comparison between the third[2] and fourth[3] editions of the epidemiology chapter in the Reference Manual a lot of carry over from the third edition, some change in authorship, and at least one interesting change.

The two lawyer authors, Steve Gold and Michael Green, remain, but the authors with reasonable pretense to subject-matter expertise have changed. Gold and Green are both law professors with a long history of commenting on American tort and evidence law. Both are aligned with the lawsuit industry. Previous epidemiology authors, Daryl Michal Freedman and Leon Gordis are now gone from the chapter. Leon Gordis, who had been a chairman of the department of epidemiology, in the Bloomberg School of Public Health, Johns Hopkins University, died in September 2015, after the third edition was published. Daryl Michal Freedman, who been the other subject-matter expert on the third edition’s chapter on epidemiology, has been an epidemiologist with the Biostatistics Branch of the National Cancer Institute, for many years. It is not clear why he left the project.

Replacing Gordis and Freedman are Jonathan Chevrier and Brenda Eskenazi. Chevrier is an associate professor on the faculty of medicine, in the department of epidemiology, in McGill University. The focus of his work is on “common environmental contaminants,” and the role in the development and health of children. Brenda Eskenazi is professor emerita, in the University of California Berkeley School of Public Health, where she is the Director of the Center for Environmental Research and Children’s Health. Eskenazi is a member of a dodgy group known as the Collegium Ramazzini, which was responsible for staging an ex parte presentation of plaintiffs’ expert witnesses to judges presiding in asbestos litigation.[4] Eskenazi was not, however, a member of the Collegium at the time the group conspired with the late Irving Selikoff to pervert the course of justice in American asbestos litigation.

The second significant change is substantive; the fourth edition has added a new subsection to the epidemiology chapter. Comparing the texts of the third and fourth editions of this chapter reveals a new subheading in the new edition:[5]

Genetic and Molecular Epidemiologic Studies

Alas, there is not as much substance to the new subsection, which is less than four pages. Lawyers in the trenches might well have hoped for more substantive treatment of genetic epidemiology, and genetic causation. The chapter’s authors explain their abbreviated treatment with the comment:

“Although commentators have long forecast that the output of genetic and molecular epidemiology would revolutionize causal proof, as of this writing few judicial opinions have addressed these types of studies, and it is far from clear that a revolution is in the offing.”[6] 

The chapter authors are correct that some authors in the past proffered unrealistic predictions of how genetics would supplant correlational studies. Nonetheless, this area has not been as quiescent as the authors’ parsimonious treatment would suggest.

On the question of how prevalent are genetic causation issues, whether raised by plaintiffs or defendants, the chapter might have benefitted from the contributions of a practicing lawyer. Genetic issues come up with some frequency in the litigation of cases involving mesothelioma. The days of plaintiffs who had 30 years of amphibole asbestos exposure in the workplace are largely over. Today’s cases involve little to no exposure, and it stands to reason that the origins of the recently diagnosed cases are different from those diagnosed in the 1970s and 1980s.[7] Genetic cause of mesothelioma is a salient current issue that is passed over in this new Reference Manual.

The authors acknowledge a single birth defects case in which genetic causation was litigated,[8] which was already old news when the last edition of the Manual was published. There are now many more reported cases that cry out for discussion in this under-covered area of the Manual.[9] There are also many cases not reported that have turned on genetic issues. For instance, in some cancer and birth defect cases, the existence of a highly penetrant genetic mutation that could explain the occurrence of a disease completely raises a serious question whether the plaintiff who fails to test for the mutation can possibly have carried his burden of proof.[10] And then there are myriad cases in which the parties have engaged in motion practice, sometimes extended, over access to genetic testing materials.

Genetic issues have arisen in the litigation of high-profile general causation disputes. For instance, the failure to control for genetic effects in epidemiologic studies was a significant issue in the acetaminophen-autism litigation, with both sides presenting geneticists to explain whether the relevant studies were undermined by failure to control for genetic effects.[11]

In the Manual’s epidemiology chapter’s new section on genetics, the authors describe some basic terms and explain that genetic epidemiology may provide evidence for, or against, claims of health effects. The authors’ views come through most clearly in the following short passage:

“Alternatively, genetic epidemiology may reveal associations between genetic variations and a plaintiff’s disease, raising the issue of whether or not a genetic variation may be a competing cause of the disease. This requires assessment of whether the gene–disease association is causal in a general sense, whether it acts independently of the exposure, and whether it is a competing cause in the plaintiff’s specific instance. The extreme, though not typical, example would be a health outcome or disease entirely determined by genetics, ⁵⁵ as is the case with sickle cell anemia.⁵⁶”[12]

The authors never explain or defend their claim that cases involving diseases caused entirely by genetics are “extreme” and “not typical.” At several points, the authors emphasize that gene-environment interactions are the more prevalent determinants of diseases.[13] If we were to catalog the currently known genetic determinants of diseases, the authors may be correct on a percentage basis, but the issue in any given case is whether the disease or harm claimed by the plaintiff is one of the “extreme” cases of complete genetic causation, or an instance of genetic susceptibility. The authors’ generalization, even if it were correct, would not be very helpful or informative for any specific case.

Perhaps even more important for lawyers, there is a substantive issue on which the new chapter manages to provide confusing guidance. The epidemiology chapter appears to create a false dichotomy between rare, highly penetrant genetic mutations that are uncommon causes of certain diseases, and the more prevalent genetic mutations and polymorphisms that leave persons more susceptible to the deleterious effects of exogenous exposures to toxic chemicals.[14] There is, however, another scenario omitted in the chapter’s discussion of genetic causation. Genetic mutations and polymorphisms may leave persons susceptible to normal, endogenous chemicals, stochastic cellular events, and biological processes that result in diseases such as cancers. In other words, the knee-jerk reflex to invoke exogenous, external toxic chemical exposures promotes a false dichotomy and obscures the obvious implication that susceptibility mutations and polymorphisms may lead to cancer without environmental exposures to harmful chemicals.[15]

The number of endogenous events leading to DNA alterations is enormous, and requires us to rethink the mantra that attributes chronic diseases to gene-environment interaction. At the very least, we need to stop thinking of “environment” as chemical exposures from without ourselves. The epidemiology chapter authors, like many writers, point to external chemical exposures as the culprits in gene-environment reactions, but they ignore the normal, endogenous events that lead to DNA damage, for which genetic susceptibility may be relevant. Mutations that result in increased susceptibility to cancer may affect DNA alterations from both endogenous and metabolic factors as well as from exposures to external chemicals.

Ignorance is never a good thing, and the chapter does the bar and bench a disservice in not adequately exploring genetic susceptibility in view of both exogenous and endogenous exposures that may be responsible for chronic diseases, such as cancers.

[1] National Academies of Sciences, Engineering, and Medicine & Federal Judicial Center, REFERENCE MANUAL ON SCIENTIFIC EVIDENCE (4^th ed. 2025) (cited as RMSE 4^th ed.)

[2] Michael D. Green, D. Michal Freedman & Leon Gordis, Reference Guide on Epidemiology, 549, in RMSE 3^rd ed.

[3] Steve C. Gold, Michael D. Green, Jonathan Chevrier, & Brenda Eskenazi, Reference Guide on Epidemiology, in RMSE 4^th ed.

[4] See In re School Asbestos Litigation, 977 F.2d 764 (3d Cir. 1992). See also Cathleen M. Devlin, Disqualification of Federal Judges – Third Circuit Orders District Judge James McGirr Kelly to Disqualify Himself So As To Preserve ‘The Appearance of Justice’ Under 28 U.S.C. § 455 – In re School Asbestos Litigation (1992), 38 VILL. L. REV. 1219 (1993); Bruce A. Green, May Judges Attend Privately Funded Educational Programs? Should Judicial Education Be Privatized?:  Questions of Judicial Ethics and Policy, 29 FORDHAM URB. L. J. 941, 996-98 (2002).

[5] Steve Gold, et al., Reference Guide on Epidemiology, at 914, in RMSE 4^th ed.

[6] Id. at 916.

[7] ToxicoGenomica, The Litigator’s Guide to Using Genomics in a Toxic Tort Case (2018).

[8] Id. at 917 & n.55 (citing Bowen v. E.I. Du Pont de Nemours & Co., No. CIV.A. 97C-06-194 CH, 2005 WL 1952859 (Del. Super. Ct. June 23, 2005), aff’d, 906 A.2d 787 (Del. 2006) (discussing the importance of a test for a genetic mutation, which was the defense’s alternative causation theory to plaintiff’s claim that a toxic exposure caused the birth defect at issue). The authors fail to mention that the Bowen case was actually dismissed.

[9] See, e.g., Oliver v. Sec’y Health & Human Servs., 900 F.3d 1357 (Fed. Cir. 2018); Ortega v. United States, 2021 WL 4477896, 2021 U.S. Dist. LEXIS 188969 (N.D.Ill. Sept. 30, 2021); Vanslembrouck ex rel. Braverman v. Halperin, 2014 WL 5462596 (Mich. App. 2014).

[10] See, e.g., Halter v. Boehringer Ingelheim Pharms. Inc., no. 2023-L-001382, Cir. Ct. Cook Cty., Illinois, jury verdict (Aug. 27, 2025) (defense verdict in colorectal cancer case in which plaintiff failed to test for genetic mutation); see also Lauraann Wood, Boehringer Wins Another Zantac Cancer Trial In Illinois, LAW360, Chicago (Aug. 27, 2025).

[11] See, e.g., In re Acetaminophen – ASD-ADHD Prods. Liab. Litig., 707 F.Supp.3d 309, 320  (S.D.N.Y. 2023).

[12] Id. at 916-17 (emphasis added).

[13] Id. at 915.

[14] See, e.g., id. at 967n.190, citing McMillan v. Dep’t of Veterans Affairs, 294 F. Supp. 2d 305, 312 (E.D.N.Y. 2003) (“It is generally accepted that genetic susceptibility plays a key role in determining the adverse effects of environmental chemicals. . . . [I]f polymorphisms of the gene encoding the AhR [protein] exist in humans as they do in laboratory animals, some people would be at greater risk or at lesser risk for the toxic and carcinogenic effects of TCDD [dioxin].”).

[15] See Edward J. Calabrese, Changing the paradigm: The biggest polluter and threat to your health is your body, J. OCCUP. & ENVT’L HYG. (2025), published on-line, ahead of print.

The third edition of the Reference Manual on Scientific Evidence[1] had some problems with its discussion of so-called signature diseases.[2] There was a distinct need for the  epidemiology chapter in particular to improve in its fourth edition[3] on the issue of so-called signature diseases, diseases caused by only a single cause. The third edition carved out a limited exception to its questionable generalization that epidemiology had nothing useful to say about specific causation by stating that some diseases do not occur without exposure to a specific chemical or substance.

The new, fourth edition carries forward its assertion that “[t]here are some diseases that do not occur without exposure to an agent; these are known as signature diseases.”[4] And in a footnote, the authors of the epidemiology chapter, fourth edition, attempt to explain:

“There are, however, some diseases that do not occur without exposure to a given toxic agent. This is the same as saying that the toxic agent is a necessary cause for the disease, and the disease is sometimes referred to as a signature disease (also, the agent is pathognomonic) because the existence of the disease necessarily implies the causal role of the agent. Two examples are asbestosis, which is a signature disease for asbestos, and vaginal adenocarcinoma (in young adult women), which is a signature disease for in utero DES exposure. See Kenneth S. Abraham & Richard A. Merrill, Scientific Uncertainty in the Courts, in Issues Sci. & Tech. 93, 101 (1986).”[5]

Much of this language in the footnote is repeated from the third edition, as is the citation to the article by Abraham and Merrill. That article was written by lawyers, not scientists, and is now 40 years old, inaccurate and out of date.

With respect to asbestosis, the epidemiology chapter is correct, at least in part. By definition, only asbestos can cause asbestosis, but asbestosis presents clinically in ways that are indistinguishable in many cases from idiopathic pulmonary fibrosis and other interstitial fibrotic diseases of the lungs. Over the years, the diagnostic criteria for asbestosis have changed, but these criteria have always had a specificity and sensitivity less than 100%. Saying that a case of asbestosis must have been caused by asbestos begs the clinical question whether the case really is asbestosis. The situation might be clearer for a pathology diagnosis of asbestosis, but even then there is often the problem of coincidental findings of asbestos bodies in the presence of interstitial fibrosis from another cause.

On the other hand, the chapter’s characterization of vaginal adenocarcinoma as a signature disease of in utero DES exposure is clearly not correct.  Although this cancer in young women is rather rare, there is a baseline risk that allows the calculation of relative risks for young women exposed in utero.[6] In older women, the relative risks are lower because the baseline risks are higher, and because the effect of DES is diminished for older onset cases.[7] The disease, however, was known before the use of DES in pregnant women, which began after World War II,[8] and thus not an apt or accurate example of signature disease.

The Reference Manual should really not weigh in on controversies that may arise in courtroom litigations, unless it has a very solid basis. Here the chapter on epidemiology cited to a decades old article, by lawyers, on a technical topic. The proposition about DES was readily falsified by a wee bit of research in PubMed.

[1] National Academies of Sciences, Engineering, and Medicine & Federal Judicial Center, REFERENCE MANUAL ON SCIENTIFIC EVIDENCE (3^rd ed. 2011) (cited as RMSE 3^rd ed.)

[2] See Schachtman, Reference Manual – Desiderata for 4th Edition – Part I – Signature Diseases, TORTINI (Jan. 30, 2023); see also Reference Manual on Scientific Evidence v4.0 (Feb. 28, 2021); Reference Manual on Scientific Evidence – 3rd Edition is Past Its Expiry (Oct. 17, 2021).

[3] National Academies of Sciences, Engineering, and Medicine & Federal Judicial Center, REFERENCE MANUAL ON SCIENTIFIC EVIDENCE (4^th ed. 2025) (cited as RMSE 4^th ed.).

[4] RMSE 4^th ed. at 927-28 n.90.

[5] RMSE 4th at 990 n.274, citing Kenneth S. Abraham & Richard A. Merrill, Scientific Uncertainty in the Courts, 2 ISSUES SCI. & TECH. 93, 101 (Winter 1986). Thankfully, the new epidemiology chapter did not put its finger on the scale about the now discredited view that mesothelioma is a signature disease of asbestos exposure. See Michele Carbone, Harvey Pass, et al., “Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations,” 17 J. THORACIC ONCOL. 873 (2022). See also Mitchell Cheung, et al., Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors, 30 HUMAN MOL. GENETICS 1750 (2021); Thomas Wiesner, et al., “Toward an Improved Definition of the Tumor Spectrum Associated With BAP1 Germline Mutations,” 30 J. CLIN. ONCOL. e337 (2012); Alexandra M. Haugh, et al., Genotypic and Phenotypic Features of BAP1 Cancer Syndrome: A Report of 8 New Families and Review of Cases in the Literature, 153 J.AM. MED. ASS’N DERMATOL. 999 (2017).

[6] See, e.g., Kadir Güzin, et al., “Primary clear cell carcinoma of the vagina that is not related to in utero diethylstilbestrol use,” 3 GYNECOL. SURG. 281 (2006).

[7] Janneke Verloop, et al., Cancer risk in DES daughters, 21 CANCER CAUSES & CONTROL 999 (2010).

[8] See Risk Factors for Vaginal Cancer, American Cancer Soc’y website (last visited Jan. 16, 2026).