Examples are certainly helpful to explain and to show judges how real scientists reach causal conclusions. The Reference Manual should certainly give such examples of how scientists determine whether a claim has been adequately tested, and whether the claim has eliminated the myriad kinds of error that threaten such claims and require us to withhold our assent. The third edition of the Manual, however, advances some dodgy examples, without any data or citations. I have already pointed out that the third edition’s reference to clear cell adenocarcinoma of the vagina in young women as a “signal” disease caused only by DES is incorrect.[1] There are, alas, other troubling examples in the third edition, which are due for pruning.
Claimed Interaction Between Asbestos and Tobacco Risks for Lung Cancer
The third edition’s chapter on epidemiology discusses the complexities raised by potential interaction between multiple exposures. The discussion is appropriately suggesting that a relative risk cannot be used to determine the probability of individual causation “if the agent interacts with another cause in a way that results in an increase in disease beyond merely the sum of the increased incidence due to each agent separately.” The suggestion is warranted, although the chapter then is mum on whether there are other approaches that can be invoked to derive probabilities of causation when multiple exposures interact in a known way. Then the authors provided an example:
“For example, the relative risk of lung cancer due to smoking is around 10, while the relative risk for asbestos exposure is approximately 5. The relative risk for someone exposed to both is not the arithmetic sum of the two relative risks, that is, 15, but closer to the product (50- to 60-fold), reflecting an interaction between the two.200 Neither of the individual agent’s relative risks can be employed to estimate the probability of causation in someone exposed to both asbestos and cigarette smoke.”[2]
Putting aside for the moment the general issue of interaction, the chapter’s use of the Mt. Sinai catechism, of 5-10-50, for asbestos and tobacco smoking and lung cancer, is a poor choice. The evidence for multiplicative interaction was advanced by the late Irving Selikoff, and frankly the evidence was never very good. The supposed “non-smokers” were really “never smoked regularly,” and the smoking histories were taken by postcard surveys. The cohort of asbestos insulators was well aware of the study hypothesis, in that many of its members had compensations claims, and they had an interest in downplaying their smoking. Indeed, the asbestos workers’ union helped fund Selikoff’s work, and Selikoff had served as a testifying expert witness for claimants.
Given that “never smoked regularly” is not the same as never having smoked, and given that the ten-fold risk from smoking-alone was already an underestimate of lung cancer risk from smoking alone, the multiplicative model never was on a firm basis. The smoking-alone risk ratio was doubled in the American Cancer Society’s Cancer Prevention Survey Numbers One and Two, but the Mt. Sinai physicians, who frequently testified in lawsuits for claimants steadfastly held to their outdated statistical control group.[3] It is thus disturbing that the third edition’s authors trotted out a summary of asbestos / smoking lung cancer risks based upon Selikoff’s dodgy studies of asbestos insulation workers. The 5-10-50 dogma was already incorrect when the first edition went to press.
Not only were Selikoff’s study probably incorrect when originally published, updates to the insulation worker cohort published after his death, specifically undermine the multiplicative claim. In a 2013 publication by Selikoff’s successors, asbestos and smoking failed to show multiplicative interaction. Indeed, occupational asbestos exposure that had not manifested in clinically apparent asbestosis did not show any interaction with smoking. Only in a subgroup of insulators with clinically detectable asbestosis did the asbestosis and smoking show “supra-additive” (but not multiplicative) interaction.[4]
Manganese and Parkinson’s Disease
Table 1, of the toxicology chapter in the third edition, presented a “Sample of Selected Toxicological End Points and Examples of Agents of Concern in Humans.” The authors cautioned that the table was “not an exhaustive or inclusive list of organs, end points, or agents. Absence from this list does not indicate a relative lack of evidence for a causal relation as to any agent of concern.”[5] Among the examples presented in this Table 1 was neurotoxicity in the form of “Parkinson’s disease and manganese”[6]
The presence of this example of this example in Table 1 is curious on a number of fronts. First, one of the members of the Development Committee for the third edition was Judge Kathleen O’Malley, who presided over a multi-district litigation involving claims for parkinsonism and Parkinson’s disease against manufacturers of welding rods. It seemed unlikely that Judge O’Malley would have overlooked this section. See, e.g., In re Welding Fume Prods. Liab. Litig., 245 F.R.D. 279 (N.D. Ohio 2007) (exposure to manganese fumes allegedly increased the risk of later developing brain damage). More important, however, the authors’ inclusion of Parkinson’s disease as an outcome from manganese exposure is remarkable because that putative relationship has been extensively studied and rejected by leading researchers in the field of movement disorders.[7] In 2010, neuro-epidemiologists published a comprehensive meta-analysis that confirmed the absence of a relationship between manganese exposure and Parkinson’s disease.[8] The inclusion in Table 1 of a highly controversial relationship, manganese-Parkinson’s disease, suggests either undisclosed partisanship or ignorance of the relevant scientific evidence.
Mesothelioma
The toxicology chapter of the third edition also weighed in on mesothelioma as a supposed signature disease of asbestos exposure. The chapter’s authors described mesothelioma as “almost always caused by asbestos,”[9] which was no doubt true when mesothelioma was first identified as caused by fibrous amphibole minerals.[10] The last two decades, however, has seen a shift in the incidence of mesothelioma among industrially exposed workers, which reveals more cases without asbestos exposure and with other potential causes. Leading scientists in the field have acknowledged non-asbestos causes,[11] and recently researchers have identified genetic mutations that completely account for the causation of individual cases of mesothelioma.[12] It is time for the fourth edition to acknowledge other causes of mesothelioma, and to offer judges and lawyers guidance on genetic causes of sporadic diseases.
[1] See “Reference Manual – Desiderata for the Fourth Edition – Signature Disease” (Jan. 30, 2023).
[2] RMSE3d at 615 & n. 200. The chapter fails to cite support for the 5-10-50 dogma, but it is readily recognizable as the Mt. Sinai Catechism that was endlessly repeated by Irving Selikoff and his protégés.
[3] Michael J. Thun, Cathy A. Day-Lally, Eugenia E. Calle, W. Dana Flanders, and Clark W Heath, “Excess mortality among cigarette smokers: Changes in a 20-year interval,” 85 Am. J. Public Health 1223 (1995).
[4] Steve Markowitz, Stephen Levin, Albert Miller, and Alfredo Morabia, “Asbestos, Asbestosis, Smoking and Lung Cancer: New Findings from the North American Insulator Cohort,” 188 Am. J. Respir. & Critical Care Med. 90 (2013); see “The Mt. Sinai Catechism” (June 7, 2013).
[5] RMSE3d at 653-54.
[6] Reference Manual at 653.
[7] See e.g., Karin Wirdefeldt, Hans-Olaf Adami, Philip Cole, Dimitrios Trichopoulos, and Jack Mandel, “Epidemiology and etiology of Parkinson’s disease: a review of the evidence. 26 European J. Epidemiol. S1, S20-21 (2011); Tomas R. Guilarte, “Manganese and Parkinson’s Disease: A Critical Review and New Findings,” 118 Environ Health Perspect. 1071, 1078 (2010) (“The available evidence from human and nonhuman primate studies using behavioral, neuroimaging, neurochemical, and neuropathological end points provides strong support to the hypothesis that, although excess levels of [manganese] accumulation in the brain results in an atypical form of parkinsonism, this clinical outcome is not associated with the degeneration of nigrostriatal dopaminergic neurons as is the case in PD [Parkinson’s disease].”)
[8] James Mortimer, Amy Borenstein, and Lorene Nelson, “Associations of welding and manganese exposure with Parkinson disease: Review and meta-analysis,” 79 Neurology 1174 (2012).
[9] Bernard D. Goldstein & Mary Sue Henifin, “Reference Guide on Toxicology,” RMSE3d 633, 635 (2011).
[10] See J. Christopher Wagner, C.A. Sleggs, and Paul Marchand, “Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province,” 17 Br. J. Indus. Med. 260 (1960); J. Christopher Wagner, “The discovery of the association between blue asbestos and mesotheliomas and the aftermath,” 48 Br. J. Indus. Med. 399 (1991); see also Harriet Hardy, M.D., Challenging Man-Made Disease: The Memoirs of Harriet L. Hardy, M.D. 95 (1983); “Harriet Hardy’s Views on Asbestos Issues” (Mar. 13, 2013).
[11] Richard L. Attanoos, Andrew Churg, Allen R. Gibbs, and Victor L. Roggli, “Malignant Mesothelioma and Its Non-Asbestos Causes,” 142 Arch. Pathol. & Lab. Med. 753 (2018).
[12] Angela Bononia, Qian Wangb, Alicia A. Zolondick, Fang Baib, Mika Steele-Tanjia, Joelle S. Suareza , Sandra Pastorinoa, Abigail Sipesa, Valentina Signoratoa, Angelica Ferroa, Flavia Novellia , Jin-Hee Kima, Michael Minaaia,d, Yasutaka Takinishia, Laura Pellegrinia, Andrea Napolitanoa, Ronghui Xua , Christine Farrara , Chandra Goparajua, Cristian Bassig, Massimo Negrinig, Ian Paganoa , Greg Sakamotoa, Giovanni Gaudinoa, Harvey I. Pass, José N. Onuchic , Haining Yang, and Michele Carbone, “BAP1 is a novel regulator of HIF-1α,” 120 Proc. Nat’l Acad. Sci. e2217840120 (2023).
