The fourth edition of the Reference Manual on Scientific Evidence is by all accounts under way. Each of the first three editions represented an improvement over previous editions, but the last edition continued to have substantive problems. The bar, the judiciary, and the scientific community hopefully await an improved fourth edition. Although I have posted previously about issues in the third edition, I am updating and adding to what I have written.[1] There were only a few reviews and acknowledgments of the third edition.[2] The editorial staff provided little to no opportunity for comments in advance of the third edition, and to date, there has been no call for public comment about the pending fourth edition. I hope there will be more opportunity for the legal and scientific community to comment in the production of the fourth edition.
There are several issues raised by the third edition’s treatment of specific causation, which I hope will be improved in the fourth edition. One such issue is the epidemiology chapter’s brief discussion of so-called signature diseases. The chapter takes the curious position that epidemiology has nothing to say about individual or specific causation, a position I will discuss in later posts. The chapter, however, carves out a limited exception to its (questionable) edict that epidemiology does not concern itself with specific causation. The chapter tells us, uncontroversially, that some diseases do not occur without exposure to a specific chemical or substance. In my view, the authors of this chapter then go astray in telling us that “[a]bestosis is a signature disease for asbestos, and vaginal adenocarcinoma (in young adult women) is a signature disease for in utero DES exposure.”
Now, by definition, only asbestos can cause asbestosis, but asbestosis presents clinically in a way that is 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 chapter’s characterization of vaginal adenocarcinoma as a signature disease of in utero DES exposure is also not correct. Although this cancer in young women is extremely rare, there is a baseline risk that allows the calculation of relative risks for young women exposed in utero. 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.[3] The disease was known before the use of DES in pregnant women began after World War II.[4]
For support of their discussion of “signal diseases,” the authors of the epidemiology chapter chose, remarkably, to cite an article that was over 25 years old (now over 35 years old) at the time the third edition was published.[5] The referenced passage asks us to:
“Consider tort claims for what have come to be called signature disease. These are diseases characteristically caused by only a few substances – such as the vaginal adenocarcinoma usually associated with exposure to DES in utero – and mesothelioma, a cancer of the pleura caused almost exclusively by exposure to asbestos fibers in the air.”[6]
Well, “usually associated” does equal signature disease.[7] The relative risks for smoking and some kinds of lung cancer are higher than for DES in utero and clear cell vaginal adenocarcinoma, but no one calls lung cancer a signature disease of smoking. (Admittedly, smoking is the major cause and perhaps the most preventable cause of lung cancer in Western countries.)
The third edition’s reference to a source that describes mesothelioma as “caused almost exclusively by exposure to asbestos fibers” is also out of date.[8] Recognizing that casual comments and citations can influence credulous judges, the authors of the fourth edition should strive for greater accuracy in their discussions of such scientific issues. It may be time to find new examples of signature disease.
[1] “Reference Manual on Scientific Evidence v4.0” (Feb. 28, 2021); “Reference Manual on Scientific Evidence – 3rd Edition is Past Its Expiry” (Oct. 17, 2021).
[2] See, e.g., Adam Dutkiewicz, “Book Review: Reference Manual on Scientific Evidence, Third Edition,” 28 Thomas M. Cooley L. Rev. 343 (2011); John A. Budny, “Book Review: Reference Manual on Scientific Evidence, Third Edition,” 31 Internat’l J. Toxicol. 95 (2012); James F. Rogers, Jim Shelson, and Jessalyn H. Zeigler, “Changes in the Reference Manual on Scientific Evidence (Third Edition),” Internat’l Ass’n Def. Csl. Drug, Device & Biotech. Comm. Newsltr. (June 2012). See Schachtman “New Reference Manual’s Uneven Treatment of Conflicts of Interest” (Oct. 12, 2011).
[3] Janneke Verloop, Flora E. van Leeuwen, Theo J. M. Helmerhorst, Hester H. van Boven, and Matti A. Rookus, “Cancer risk in DES daughters,” 21 Cancer Causes & Control 999 (2010).
[4] See “Risk Factors for Vaginal Cancer,” American Cancer Soc’y website (last visited Jan. 29, 2023).
[5] Kenneth S. Abraham & Richard A. Merrill, Scientific Uncertainty in the Courts, 2 Issues Sci. & Tech. 93, 101 (Winter 1986).
[6] Id.
[7] See, e.g., Kadir Güzin, Semra Kayataş Eserm, Ayşe Yiğit, and Ebru Zemheri, “Primary clear cell carcinoma of the vagina that is not related to in utero diethylstilbestrol use,” 3 Gynecol. Surg. 281 (2006).
[8] Michele Carbone, Harvey I. Pass, Guntulu Ak, H. Richard Alexander Jr., Paul Baas, Francine Baumann, Andrew M. Blakely, Raphael Bueno, Aleksandra Bzura, Giuseppe Cardillo, Jane E. Churpek, Irma Dianzani, Assunta De Rienzo, Mitsuru Emi, Salih Emri, Emanuela Felley-Bosco, Dean A. Fennell, Raja M. Flores, Federica Grosso, Nicholas K. Hayward, Mary Hesdorffer, Chuong D. Hoang, Peter A. Johansson, Hedy L. Kindler, Muaiad Kittaneh, Thomas Krausz, Aaron Mansfield, Muzaffer Metintas, Michael Minaai, Luciano Mutti, Maartje Nielsen, Kenneth O’Byrne, Isabelle Opitz, Sandra Pastorino, Francesca Pentimalli, Marc de Perrot, Antonia Pritchard, Robert Taylor Ripley, Bruce Robinson, and Valerie Rusch, “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, Yuwaraj Kadariya, Eleonora Sementino, Michael J. Hall, Ilaria Cozzi, Valeria Ascoli, Jill A. Ohar, and Joseph R. Testa, “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 Molecular Genetics 1750 (2021); Thomas Wiesner, Isabella Fried, Peter Ulz, Elvira Stacher, Helmut Popper, Rajmohan Murali, Heinz Kutzner, Sigurd Lax, Freya Smolle-Jüttner, Jochen B. Geigl, and Michael R. Speicher, “Toward an Improved Definition of the Tumor Spectrum Associated With BAP1 Germline Mutations,” 30 J. Clin. Oncol. e337 (2012); Alexandra M. Haugh, BA1; Ching-Ni Njauw, MS2,3; Jeffrey A. Bubley, 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).
