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 That article was written by lawyers, not scientists, and is now 40 years old, inaccurate and out of date.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 (3rd ed. 2011) (cited as RMSE 3rd 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 (4th ed. 2025) (cited as RMSE 4th ed.).
[4] RMSE 4th 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).
