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The Proper Study of Mankind

December 24th, 2023

“Know then thyself, presume not God to scan;

The proper study of Mankind is Man.”[1]

 

Kristen Ranges recently earned her law degree from the University of Miami School of Law, and her doctorate in Environmental Science and Policy, from the University of Miami Rosenstiel School of Marine, Atmospheric, and Earth Science. Ranges’ dissertation was titled Animals Aiding Justice: The Deepwater Horizon Oil Spill and Ensuing Neurobehavioral Impacts as a Case Study for Using Animal Models in Toxic Tort Litigation – A Dissertation.[2] At first blush, Ranges would seem to be a credible interlocutor in the never-ending dispute over the role of whole animal toxicology (and in vitro toxicology) in determining human causation in tort litigation. Her dissertation title is, however, as Martin Short would say, a bit of a tell. Zebrafish become sad when exposed to oil spills, as do we all.

Ranges recently published a spin-off of her dissertation as a law review article with one of her professors. “Vermin of Proof: Arguments for the Admissibility of Animal Model Studies as Proof of Causation in Toxic Tort Litigation.”[3] Arguments for; no arguments against. We can thus understand this is an advocacy piece, which is fair enough. The paper was not designed or titled to mislead anyone into thinking it would be a consideration of arguments for and against extrapolation from (non-human) animal studies to human beings. Perhaps you will think it churlish of me to point out that animal studies will rarely be admissible as evidence. They come into consideration in legal cases only through expert witnesses’ reliance upon them. So the issue is not whether animal studies are admissible, but rather whether expert witness opinion testimony that relies solely or excessively on animal studies for purposes of inferring causation is admissible under the relevant evidentiary rules. Talking about the admissibility of animal model studies signals, if nothing else, a serious lack of familiarity with the relevant evidentiary rules.

Ranges’ law review is clearly, and without subtlety, an advocacy piece. She argues:

“However, judges, scholars, and other legal professionals are skeptical of the use of animal studies because of scientific and legal concerns, which range from interspecies disparities to prejudice of juries. These concerns are either unfounded or exaggerated. Animal model studies can be both reliable and relevant in toxic tort cases. Given the Federal Rules of Evidence, case law relevant to scientific evidence, and one of the goals of tort law-justice-judges should more readily admit these types of studies as evidence to help plaintiffs meet the burden of proof in toxic tort litigation.”[4]

For those of you who labor in this vineyard, I would suggest you read Ranges’ article and judge for yourself. What I see is a serious lack of scientific evidence for her claims, and a serious misunderstanding of the relevant law. One might, for starters, putting aside the Agency’s epistemic dilution, ask whether there are any I.A.R.C. category I (“known”) carcinogens based solely upon animal evidence. Or has the U.S. Food & Drug Administration ever approved a medication as reasonably safe and effective based upon only animal studies?

Every dog owner and lover has likely been told by a veterinarian, or the Humane Society, that we should resist their lupine entreaties and withhold chocolate, raisins, walnuts, avocados, and certain other human foods. Despite their obvious intelligence, capacity for affection, when it comes to toxicology, dogs are not people, although some people act like the less reputable varieties of dogs.

Back in 1985, in connection with Agent Orange litigation, the late Judge Jack Weinstein wrote what was correct then, and even more so today, that “laboratory animal studies are generally viewed with more suspicion than epidemiological studies, because they require making the assumption that chemicals behave similarly in different species.”[5] Judge Weinstein was no push-over for strident defense counsel or expert witnesses, but the legal consequences were nonetheless obvious to him, when he looked carefully at the animal studies plaintiffs’ expert witnesses were claiming to support their opinions. “[A]nimal studies are of so little probative value as to be inadmissible.  They cannot be a predicate for an opinion under Rule 703.”[6] One of the several disconnects between the plaintiffs’ expert witnesses’ animal studies and the human diseases claimed was the disparity of dose and duration between the relied upon studies and the service men claimants. Judge Weinstein observed that when the hand waving stopped, “[t]here is no evidence that plaintiffs were exposed to the far higher concentrations involved in both animal and industrial exposure studies.”[7]

Ranges and Oakley unfairly deprecate the Supreme Court’s treatment of animal evidence in the 1997 Joiner opinion.[8] Mr. Joiner had been an electrician by a small city in Georgia, where he experienced dermal exposure, over several years, to polychlorinated biphenyls (PCB’s), a chemical found in electrical transformer coolant. He alleged that he had developed small-cell lung cancer from his occasional occupational exposure. In the district court, a careful judge excluded the plaintiffs’ expert witnesses, who relied heavily upon animal studies and who cherry picked and distorted the available epidemiology.[9] The Court of Appeals reversed, in an unsigned, non-substantive opinion that interjected an asymmetric standard of review.[10]

After granting review, the Supreme Court engaged with the substantive validity issues passed over by the intermediate appellate court. In addressing the plaintiff’s expert witnesses’s reliance upon animal studies, the Court was struck by an extrapolation from a different species, different route of administration, different dose, different duration of exposure, and different disease.[11] Joiner was an adult human whose alleged exposure to PCBs was far less than the exposure in the baby mice that received injections of PCBs in a high concentration. The mice developed alveologenic adenomas, a rare tumor that is usually benign, not malignant.[12] The Joiner Court recognized that these multiple extrapolations were a bridge to nowhere, and reversed the Court of Appeals, and reinstated the judgment of the district court. What is particular salient about the Joiner decision, and about which you will find no discussion in the law review paper by Ranges and Oakley, is how well the Joiner opinion has held up over quarter of a century that passed. Today, in the waning moments of 2023, there is still no valid, scientifically sound support for the claim that the sort of exposure Mr. Joiner had can cause small-cell lung cancer.[13]

Perhaps the most egregious lapses in scholarship occur when Ranges, a newly minted scientist, and her co-author, a full professor of law, write:

“For example, Bendectin, an antinausea medication prescribed to pregnant women, caused a slew of birth defects (hence its nickname ‘The Second Thalidomide’).49”[14]

I had to re-read this sentence many times to make sure I was not hallucinating. Ranges’ and Oakley’s statement is, of course, demonstrably false. A double whooper, at least, and a jarring deviation from the standard of scholarly care.

But their statement is footnoted you say. Here is what the cited article, footnote 40 in “Vermin of Proof,” says:

“RESULTS: The temporal trends in prevalence rates for specific birth defects examined from 1970 through 1992 did not show changes that reflected the cessation of Bendectin use over the 1980–84 period. Further, the NVP hospitalization rate doubled when Bendectin use ceased.

CONCLUSIONS: The population results of the ecological analyses complement the person-specific results of the epidemiological analyses in finding no evidence of a teratogenic effect from the use of Bendectin.”[15]

So the cited source actually says the exact opposite of what the authors assert. Apparently, students on law review at Georgetown University Law Center do not check citations for accuracy. Not only was the statement wrong in 1993, when the Supreme Court decided the famous Daubert case, it was wrong 20 years later, in 2013, when the United States Food and Drug Administration (FDA) approved  Diclegis, a combination of doxylamine succinate and pyridoxine hydrochloride, the essential ingredients in Bendectin, for sale in the United States, for pregnant women experiencing nausea and vomiting.[16] The return of Bendectin to the market, although under a different name, was nothing less than a triumph of science over the will of the lawsuit industry.[17] 

Channeling the likes of plaintiffs’ expert witness Carl Cranor (whom they cite liberally and credulously), Ranges and Oakley argue for a vague “weight of the evidence” (WOE) methodology, in which several inconclusive and lighter-than-air pieces of evidence somehow magically combine in cold fusion to warrant a conclusion of causation. Others have gone down this dubious path before, but these authors’ embrace of the plaintiffs’ expert witnesses’ opinion in Bendectin litigation reveals the insubstantiality and the invalidity of their method.[18] As Professor Ronald Allen put the matter:

“Given the weight of evidence in favor of Bendectin’s safety, it seems peculiar to argue for mosaic evidence [WOE] from a case in which it would have plainly been misleading.”[19]

It surely seems like a reduction ad absurdum of the proposed methodology.

One thing these authors get right is that most courts disparage and exclude expert witness opinion that relies exclusively or excessively upon animal toxicology.[20] They wrongly chastise these courts, however, for ignoring scientific opinion. In 2005, the Teratology Society issued a position paper on causation in teratology-related litigation,[21] in which the Society specifically addressed the authors’ claims:

“6. Human data are required for conclusions that there is a causal relationship between an exposure and an outcome in humans. Experimental animal data are commonly and appropriately used in establishing regulatory exposure limits and are useful in addressing biologic plausibility and mechanism questions, but are not by themselves sufficient to establish causation in a lawsuit. In vitro data may be helpful in exploring mechanisms of toxicity but are not by themselves evidence of causation.”[22]

Ranges and Oakley are flummoxed that courts exclude expert witnesses who have relied upon animal studies when regulatory agencies use such studies with abandon. The case law on the distinction between precautionary standards in regulation and causation standards in tort law is clear, and explains the difference in approach, but these authors are determined to ignore the obvious difference.[23] The Teratology Society emphasized what should be hornbook law; namely, regulatory standards for testing and warnings are not particularly germane to tort law standards for causation:

“2. The determination of causation in a lawsuit is not the same as a regulatory determination of a protective level of exposure. If a government agency has determined a regulatory exposure level for a chemical, the existence of that level is not evidence that the chemical produces toxicity in humans at that level or any other level. Regulatory levels use default assumptions that are improper in lawsuits. One such assumption is that humans will be as sensitive to the toxicity of a chemical as is the most sensitive experimental animal species. This assumption may be very useful in regulation but is not evidence that exposure to that chemical caused an adverse outcome in an individual plaintiff. Regulatory levels often incorporate uncertainty factors or margins of exposure. These factors may result in a regulatory level much lower than an exposure level shown to be harmful in any organism and are an additional reason for the lack of utility of regulatory levels in causation considerations.”[24]

The suggestion from Ranges and Oakley that the judicial treatment of reliance upon animal studies is based upon ossified, ancient precedent, prejudice, and uncritical acceptance of defense counsel’s unsupported argument is simply wrong. There are numerous discussions of the difficulty of extrapolating teratogenicity from animal data to humans,[25] and ample basis for criticism of the glib extension of rodent carcinogenicity to humans.[26]

Ranges and Oakley ignore the extensive scientific literature questioning extrapolation from high exposure rodent models to much lower exposures in humans.[27] The invalidity of extrapolation can result in both false positives and false negatives. Indeed the thalidomide case is a compelling example of the failure of animal testing. Thalidomide was tested on pregnant rats and rabbits without detecting teratogenicity; indeed most animal species do not metabolize thalidomide or exhibit teratogenicity as seen in humans. Animal models simply do not have a sufficient positive predictive value to justify a conclusion of causation in humans, even if we accept a precautionary principle recognition of such animal testing for regulatory purposes.[28]

As improvident as Ranges’ pronouncements may be, finding her message amplified by Professor Ed Cheng on his podcast series, Excited Utterances, was even more disturbing. In November 2023, Cheng interviewed Kristen Ranges in an episode of his podcast, Vermin of Proof, in which he gave Ranges a chance to reprise her complaints about the judiciary’s handling of animal evidence, without much in the way of specificity, and with some credulous cheerleading to aid and abet. In his epilogue, Cheng wondered why toxicologic evidence is disfavored when such evidence is routinely used by scientists and regulators. What Cheng misses is that regulators use toxicologic evidence for regulation, not for assessments of human causation, and that the two enterprises are quite different.  The regulatory exercise goes something like asking about the stall speed of a pig. It does not matter that pigs cannot fly; we skip that fact and press on to ask what the pig’s take off and stall speeds are.

Seventy years ago, no less than Sir Austin Bradford Hill, observed that:

“We may subject mice, or other laboratory animals, to such an atmosphere of tobacco smoke that they can — like the old man in the fairy story — neither sleep nor slumber; they can neither breed nor eat. And lung cancers may or may not develop to a significant degree. What then? We may have thus strengthened the evidence, we may even have narrowed the search, but we must, I believe, invariably return to man for the final proof or proofs.”[29]

[1] Alexander Pope, “An Essay on Man” (1733), in Robin Sowerby, ed., Alexander Pope: Selected Poetry and Prose at 153 (1988).

[2] Kristen Ranges, Animals Aiding Justice: The Deepwater Horizon Oil Spill and Ensuing Neurobehavioral Impacts as a Case Study for Using Animal Models in Toxic Tort Litigation – A Dissertation (2023).

[3] Kristen Ranges & Jessica Owley, “Vermin of Proof: Arguments for the Admissibility of Animal Model Studies as Proof of Causation in Toxic Tort Litigation,” 34 Georgetown Envt’l L. Rev. 303 (2022) [Vermin]

[4] Vermin at 303.

[5] In re Agent Orange Prod. Liab. Litig., 611 F. Supp. 1223, 1241 (E.D.N.Y. 1985), aff’d, 818 F.2d 187 (2d Cir. 1987), cert. denied, 487 U.S. 1234 (1988).

[6] Id.

[7] Id.

[8] General Elec. Co. v. Joiner, 522 U.S. 136, 144 (1997) [Joiner]

[9] Joiner v. General Electric Co., 864 F. Supp. 1310 (N.D. Ga. 1994).

[10] Joiner v. General Electric Co., 134 F.3d 1457 (11th Cir. 1998) (per curiam). 

[11] Joiner, 522 U.S. at 144-45.

[12] See Leonid Roshkovan, Jeffrey C. Thompson, Sharyn I. Katz, Charuhas Deshpande, Taylor Jenkins, Anna K. Nowak, Rosyln Francis, Carole Dennie, Dominique Fabre, Sunil Singhal, and Maya Galperin-Aizenberg, “Alveolar adenoma of the lung: multidisciplinary case discussion and review of the literature,” 12 J. Thoracic Dis. 6847 (2020).

[13] See “How Have Important Rule 702 Holdings Held Up With Time?” (Mar. 20, 2015); “The Joiner Finale” (Mar. 23, 2015).

[14] Vermain at 312.

[15] Jeffrey S Kutcher, Arnold Engle, Jacqueline Firth & Steven H. Lamm, “Bendectin and Birth Defects II: Ecological Analyses, 67 Birth Defects Research Part A: Clinical and Molecular Teratology 88, 88 (2003).

[16] See FDA News Release, “FDA approves Diclegis for pregnant women experiencing nausea and vomiting,” (April 8, 2013).

[17] See Gideon Koren, “The Return to the USA of the Doxylamine-Pyridoxine Delayed Release Combination (Diclegis®) for Morning Sickness — A New Morning for American Women,” 20 J. Popul. Ther. Clin. Pharmacol. e161 (2013).

[18] Michael D. Green, “Pessimism About Milward,” 3 Wake Forest J. Law & Policy41, 62-63 (2013); Susan Haack, “Irreconcilable Differences? The Troubled Marriage of Science and Law,” 72 Law & Contemporary Problems 1, 17 (2009); Susan Haack, “Proving Causation: The Holism of Warrant and the Atomism of Daubertm” 4 J. Health & Biomedical Law 273, 274-78 (2008).

[19] Ronald J. Allen & Esfand Nafisi, “Daubert and its Discontents,” 76 Brooklyn L. Rev. 132, 148 (2010). 

[20] See In re Zoloft (Sertraline Hydrochloride) Prods. Liab. Litig., 26 F. Supp. 3d 466, 475 (E.D. Pa. 2014) (noting that “causation opinions based primarily upon in vitro and live animal studies are unreliable and do not meet the Daubert standard.”), aff’d, 858 F.3d 787 (3rd Cir. 2017); Chapman v. Procter & Gamble Distrib., LLC, 766 F.3d 1296, 1308 (11th Cir. 2014) (affirming exclusion of testimony based on “secondary methodologies,” including animal studies, which offer “insufficient proof of general causation.”); The Sugar Ass’n v. McNeil-PPC, Inc., 2008 WL 11338092, *3 (C.D. Calif. July 21, 2008) (finding that plaintiffs’ expert witnesses, including Dr. Abou-Donia, failed to provide the requisite analytical  support for the extrapolation of their Five Opinions from rats to humans”); In re Silicone Gel Breast Implants Prods. Liab. Litig., 318 F. Supp. 2d 879, 891 (C.D. Cal. 2004) (observing that failure to compare similarities and differences across animals and humans could lead to the exclusion of opinion evidence); Cagle v. The Cooper Companies, 318 F. Supp. 2d 879, 891 (C.D. Calif. 2004) (citing Joiner, for observation that animal studies are not generally admissible when contrary epidemiologic studies are available; and detailing significant disadvantages in relying upon animal studies, such as (1) differences in absorption, distribution, and metabolism; (2) the unrealistic, non-physiological exposures used in animal studies; and (3) the use of unverified assumptions about dose-response); Wills v. Amerada Hess Corp., No. 98 CIV. 7126(RPP), 2002 WL 140542, at *12 (S.D.N.Y. Jan. 31, 2002) (faulting expert’s reliance on animal studies because there was no evidence plaintiff had injected suspected carcinogen in same manner as studied animals, or at same dosage levels), aff’d, 379 F.3d 32 (2nd Cir. 2004) (Sotomayor, J.); Bourne v. E.I. du Pont de Nemours & Co., 189 F. Supp. 2d 482, 501 (S.D. W.Va. 2002) (benlate and birth defects), aff’d, 85 F. App’x 964 (4th Cir.), cert. denied, 543 U.S. 917 (2004); Magistrini v. One Hour Martinizing Dry Cleaning noted that “[a]nimal bioassays are of limited use in determining whether a particular chemical causes a particular disease, or type of cancer, in humans.”190 180 F. Supp. 2d 584, 593 (D.N.J. 2002); Soutiere v. BetzDearborn, Inc., No. 2:99-CV-299, 2002 WL  34381147, at *4 (D. Vt. July 24, 2002) (holding expert’s evidence inadmissible when “[a]t best there are animal studies that suggest a link between massive doses of [the substance in question] and the development of certain kinds of cancers, such that [the substance in question] is listed as a ‘suspected’ or ‘probable’ human carcinogen”); Glastetter v. Novartis Pharms. Corp., 252 F.3d 986, 991 (8th Cir. 2001); Hollander v. Sandoz Pharm. Corp., 95 F. Supp. 2d 1230, 1238 (W.D. Okla. 2000), aff’d, 289 F.3d 1193, 1209 (10th Cir. 2002) (rejecting the relevance of animal studies to causation arguments in the circumstances of the case); Allison v. McGhan Medical Corp., 184 F.3d 1300, 1313–14 (11th Cir.1999); Raynor v. Merrell Pharrns. Inc., 104 F.3d 1371, 1375-1377 (D.C. Cir.1997) (observing that animal studies are unreliable, especially when “sound epidemiological studies produce opposite results from non-epidemiological ones, the rate of error of the latter is likely to be quite high”); Lust v. Merrell Dow Pharms., Inc., 89 F.3d 594, 598 (9th Cir.1996); Barrett v. Atlantic Richfield Co., 95 F.3d 375 (5th Cir. 1996) (extrapolation from a rat study was speculation); Nat’l Bank of Comm. v. Dow Chem. Co., 965 F. Supp. 1490, 1527 (E.D. Ark. 1996) (“because of the difference in animal species, the methods and routes of administration of the suspect chemical agent, maternal metabolisms and other factors, animal studies, taken alone, are unreliable predictors of causation in humans”), aff’d, 133 F.3d 1132 (8th Cir. 1998); Hall v. Baxter Healthcare Corp., 947 F. Supp. 1387, 1410-11 (D. Or. 1996) (with the help of court-appointed technical advisors, observing that animal studies taken alone fail to predict human disease reliably); Daubert v. Merrell Dow Pharrns., Inc., 43 F.3d 1311, 1322 (9th Cir. 1995) (on remand from Supreme Court with directions to apply an epistemic standard derived from Rule 702 itself); Sorensen v. Shaklee Corp., 31 F.3d 638, 650 (8th Cir.1994) (affirming exclusion of expert witness opinions based upon animal mutagenicity data not germane to the claimed harm); Elkins v. Richardson-Merrell, Inc., 8 F.3d 1068, 1073 (6th Cir. 1993);Wade-Greaux v. Whitehall Labs., Inc., 874 F. Supp. 1441, 1482 (D.V.1. 1994), aff’d, 46 F.3d 1120 (3d Cir. 1994) (per curiam); Renaud v. Martin Marietta Corp., Inc., 972 F.2d 304, 307 (10th Cir.1992) (“The etiological evidence proffered by the plaintiff was not sufficiently reliable, being drawn from tests on non-human subjects without confirmatory epidemiological data.”) (“Dr. Jackson performed no calculations to determine whether the dose or route of administration of antidepressants to rats and monkeys in the papers that she cited in her report was equivalent to or substantially similar to human beings taking prescribed doses of Prozac.”); Bell v. Swift Adhesives, Inc., 804 F. Supp. 1577, 1579–81 (S.D. Ga. 1992) (excluding expert opinion of Dr. Janette Sherman, who opined that methylene chloride caused liver cancer, based largely upon on animal studies); Conde v. Velsicol Chem. Corp., 804 F. Supp. 972, 1025-26 (S.D. Ohio 1992) (noting that epidemiology is “the primary generally accepted methodology for demonstrating a causal relation between a chemical compound and a set of symptoms or a disease”), aff’d, 24 F.3d 809 (6th Cir. 1994); Turpin v. Merrell Dow Pharm., Inc., 959 F.2d 1349, 1360-61 (6th Cir. 1992) (“The analytical gap between the [animal study] evidence presented and the inferences to be drawn on the ultimate issue of human birth defects is too wide. Under such circumstances, a jury should not be asked to speculate on the issue of causation.”); Brock v. Merrell Dow Pharm., 874F.2d 307, 313 (5th Cir. 1989) (noting the “very limited usefulness of animal studies when confronted with questions of toxicity”); Richardson v. Richardson-Merrell, Inc., 857 F. 2d 823, 830 (D.C. Cir. 1988) (“Positive results from in vitro studies may provide a clue signaling the need for further research, but alone do not provide a satisfactory basis for opining about causation in the human context.”);  Lynch v. Merrell-Nat‘l Labs., 830 F.2d 1190, 1194 (1st Cir. 1987) (“Studies of this sort [animal studies], singly or in combination, do not have the capability of proving causation in human beings in the absence of any confirmatory epidemiological data.”). See also Merrell Dow Pharrns., Inc. v. Havner, 953 S.W.2d 706, 730 (Tex. 1997); DePyper v. Navarro, No. 83-303467-NM, 1995 WL 788828, at *34 (Mich. Cir. Ct. Nov. 27, 1995), aff’d, No. 191949, 1998 WL 1988927 (Mich. Ct. App. Nov. 6, 1998); Nelson v. American Sterilizer Co., 566 N.W.2d 671 (Mich. Ct. App. 1997)(high-dose animal studies not reliable). But see Ambrosini v. Labarraque,  101 F.3d 129, 137-140 (D.C. Cir.1996); Dyson v. Winfield, 113 F. Supp. 2d 44, 50-51 (D.D.C. 2000).

[21] Teratology Society Public Affairs Committee, “Position Paper Causation in Teratology-Related Litigation,” 73 Birth Defects Research (Part A) 421 (2005) [Teratology Position Paper]

[22] Id. at 423.

[23]  See “Improper Reliance Upon Regulatory Risk Assessments in Civil Litigation” (Mar. 19, 2023) (collecting cases).

[24] Teratology Position Paper at 422-423.

[25] See, e.g., Gideon Koren, Anne Pastuszak & Shinya Ito, “Drugs in Pregnancy,” 338 New England J. Med. 1128, 1131 (1998); Louis Lasagna, “Predicting Human Drug Safety from Animal Studies: Current Issues,” 12 J. Toxicological Sci. 439, 442-43 (1987).

[26] Bruce N. Ames & Lois S. Gold, Too Many Rodent Carcinogens: Mitogenesis Increases Mutagenesis, 249 Science 970, 970 (1990) (noting that chronic irritation induced by many chemicals at high exposures is itself a cause of cancer in rodent models); Bruce N. Ames & Lois Swirsky Gold, “Environmental Pollution and Cancer: Some Misconceptions,” in Jay H. Lehr, ed., Rational Readings on Environmental Concerns 151, 153 (1992); Mary Eubanks, “The Danger of Extrapolation: Humans and Rodents Differ in Response to PCBs,” 112 Envt’l Health Persps. A113 (2004)

[27] Andrea Gawrylewski, “The Trouble with Animal Models: Why did human trials fail?” 21 The Scientist 44 (2007); Michael B. Bracken, “Why animal studies are often poor predictors of human reactions to exposure,” 101 J. Roy. Soc. Med. 120 (2008); Fiona Godlee, “How predictive and productive is animal research?” 3348 Brit. Med. J. g3719 (2014); John P. A. Ioannidis, “Extrapolating from Animals to Humans,” 4 Science Translational Med. 15 (2012); Pandora Pound & Michael Bracken, “Is animal research sufficiently evidence based to be a cornerstone of biomedical research?” 348 Brit. Med. J. g3387 (2014); Pandora Pound, Shah Ebrahim, Peter Sandercock, Michael B Bracken, and Ian Roberts, “Where is the evidence that animal research benefits humans?” 328 Brit. Med. J. 514 (2004) (writing on behalf of the Reviewing Animal Trials Systematically (RATS) Group).

[28] See Ray Greek, Niall Shanks, and Mark J. Rice, “The History and Implications of Testing Thalidomide on Animals,” 11 J. Philosophy, Sci. & Law 1, 19 (2011).

[29] Austin Bradford Hill, “Observation and Experiment,” 248 New Engl. J. Med. 995, 999 (1953).

Posted in Causation, Expert Witnesses, Rule 702, Rule 703, Toxicological Evidence | 56 Comments »

Improper Reliance upon Regulatory Risk Assessments in Civil Litigation

March 19th, 2022

Risk assessments would seemingly be about assessing risks, but they are not. The Reference Manual on Scientific Evidence defines “risk” as “[a] probability that an event will occur (e.g., that an individual will become ill or die within a stated period of time or by a certain age).”[1] The risk in risk assessment, however, may be zero, or uncertain, or even a probability of benefit. Agencies that must assess risks and set “action levels,” or “permissible exposure limits,” or “acceptable intakes,” often work under great uncertainty, with inspired guesswork, using unproven assumptions.

The lawsuit industry has thus often embraced the false equivalence between agency pronouncements on harmful medicinal, environmental, or occupational exposures and civil litigation adjudication of tortious harms. In the United States, federal agencies such as the Occupational Safety and Health Administration (OSHA), or the Environmental Protection Agency (EPA), and their state analogues, regularly set exposure standards that could not and should not hold up in a common-law tort case. 

Remarkably, there are state and federal court judges who continue to misunderstand and misinterpret regulatory risk assessments, notwithstanding efforts to educate the judiciary. The second edition of the Reference Manual on Scientific Evidence contained a chapter by the late Professor Margaret Berger, who took pains to point out the difference between agency assessments and the adjudication of causal claims in court:

[p]roof of risk and proof of causation entail somewhat different questions because risk assessment frequently calls for a cost-benefit analysis. The agency assessing risk may decide to bar a substance or product if the potential benefits are outweighed by the possibility of risks that are largely unquantifiable because of presently unknown contingencies. Consequently, risk assessors may pay heed to any evidence that points to a need for caution, rather than assess the likelihood that a causal relationship in a specific case is more likely than not.[2]

In March 2003, Professor Berger organized a symposium,[3] the first Science for Judges program (and the last), where the toxicologist Dr. David L. Eaton presented on the differences in the use of toxicology in regulatory pronouncements as opposed to causal assessments in civil actions. As Dr. Eaton noted:

“regulatory levels are of substantial value to public health agencies charged with ensuring the protection of the public health, but are of limited value in judging whether a particular exposure was a substantial contributing factor to a particular individual’s disease or illness.”[4]

The United States Environmental Protection Agency (EPA) acknowledges that estimating “risk” from low level exposures based upon laboratory animal data is fraught because of inter-specie differences in longevity, body habitus and size, genetics, metabolism, excretion patterns, genetic homogeneity of laboratory animals, dosing levels and regimens. The EPA’s assumptions in conducting and promulgating regulatory risk assessments are intended to predict the upper bound of theoretical risk, while fully acknowledging that there may be no actual risk in humans:

“It should be emphasized that the linearized multistage [risk assessment] procedure leads to a plausible upper limit to the risk that is consistent with some proposed mechanisms of carcinogenesis. Such an estimate, however, does not necessarily give a realistic prediction of the risk. The true value of the risk is unknown, and may be as low as zero.”[5]

The approach of the U.S. Food and Drug Administration (FDA) with respect to mutagenic impurities in medications provides an illustrative example of how theoretical and hypothetical risk assessment can be.[6] The FDA’s risk assessment approach is set out in a “Guidance” document, which like all such FDA guidances, describes itself as containing non-binding recommendations, which do not preempt alternative approaches.[7] The agency’s goal is devise a control strategy for any mutagenic impurity to keep it at or below an “acceptable cancer risk level,” even if the risk or the risk level is completely hypothetical.

The FDA guidance advances the concept of a “Threshold of Toxicological Concern (TTC),” to set an “acceptable intake,” for chemical impurities that pose negligible risks of toxicity or carcinogenicity.[8] The agency describes its risk assessment methodology as “very conservative,” given the frequently unproven assumptions made to reach a quantification of an “acceptable intake”:

“The methods upon which the TTC is based are generally considered to be very conservative since they involve a simple linear extrapolation from the dose giving a 50% tumor incidence (TD50) to a 1 in 10-6 incidence, using TD50 data for the most sensitive species and most sensitive site of tumor induction. For application of a TTC in the assessment of acceptable limits of mutagenic impurities in drug substances and drug products, a value of 1.5 micrograms (µg)/day corresponding to a theoretical 10-5 excess lifetime risk of cancer can be justified.”

For more potent mutagenic carcinogens, such as aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds, the acceptable intake or permissible daily exposure (PDE) is set lower, based upon available animal toxicologic data.

The important divide between regulatory practice and the litigation of causal claims in civil actions arises from the theoretical nature of the risk assessment enterprise. The FDA acknowledges, for instance, that the acceptable intake is set to mark “a small theoretical increase in risk,” and a “highly hypothetical concept that should not be regarded as a realistic indication of the actual risk,” and thus not an actual risk.[9] The corresponding hypothetical or theoretical risk to the acceptable intake level is clearly small when compared with the human’s lifetime probability of developing cancer (which the FDA states is greater than 1/3, but probably now approaches 40%).

Although the TTC concept allows a calculation of an estimated “safe exposure,” the FDA points out that:

“exceeding the TTC is not necessarily associated with an increased cancer risk given the conservative assumptions employed in the derivation of the TTC value. The most likely increase in cancer incidence is actually much less than 1 in 100,000. *** Based on all the above considerations, any exposure to an impurity that is later identified as a mutagen is not necessarily associated with an increased cancer risk for patients already exposed to the impurity. A risk assessment would determine whether any further actions would be taken.”

In other words the FDA’s risk assessment exists to guide agency action, not to determine a person’s risk or medical status.[10]

As small and theoretical as the risks are, they are frequently based upon demonstrably incorrect assumptions, such as:

  1. humans are as sensitive as the most sensitive species;
  2. all organs are as sensitive as the most sensitive organ of the most sensitive species;
  3. the dose-response in the most sensitive species is a simple linear relationship;
  4. the linear relationship runs from zero exposure and zero risk to the exposure that yields the so-called TD50, the exposure that yields tumors in 50% of the experimental animal model;
  5. the TD-50 is calculated based upon the point estimate in the animal model study, regardless of any confidence interval around the point estimate;
  6. the inclusion, in many instances, of non-malignant tumors as part of the assessment of the TD50 exposure;
  7. there is some increased risk for any exposure, no matter how small; that is, there is no threshold below which there is no increased risk; and
  8. the medication with the mutagenic impurity was used daily for 70 years, by a person who weights 50 kg.

Although the FDA acknowledges that there may be some instances in which a “less than lifetime level” (LTL) may be appropriate, it places the burden on manufacturers to show the appropriateness of higher LTLs. The FDA’s M7 Guidance observes that

“[s]tandard risk assessments of known carcinogens assume that cancer risk increases as a function of cumulative dose. Thus, cancer risk of a continuous low dose over a lifetime would be equivalent to the cancer risk associated with an identical cumulative exposure averaged over a shorter duration.”[11]

Similarly, the agency acknowledges that there may be a “practical threshold,” as result of bodily defense mechanisms, such as DNA repair, which counter any ill effects from lower level exposures.[12]

“The existence of mechanisms leading to a dose response that is non-linear or has a practical threshold is increasingly recognized, not only for compounds that interact with non-DNA targets but also for DNA-reactive compounds, whose effects may be modulated by, for example, rapid detoxification before coming into contact with DNA, or by effective repair of induced damage. The regulatory approach to such compounds can be based on the identification of a No-Observed Effect Level (NOEL) and use of uncertainty factors (see ICH Q3C(R5), Ref. 7) to calculate a permissible daily exposure (PDE) when data are available.”

Expert witnesses often attempt to bootstrap their causation opinions by reference to determinations of regulatory agencies that are couched in similar language, but which use different quality and quantity of evidence than is required in the scientific community or in civil courts.

Supreme Court

Industrial Union Dep’t v. American Petroleum Inst., 448 U.S. 607, 656 (1980) (“OSHA is not required to support its finding that a significant risk exists with anything approaching scientific certainty” and “is free to use conservative assumptions in interpreting the data with respect to carcinogens, risking error on the side of overprotection, rather than underprotection.”).

Matrixx Initiatives, Inc. v. Siracusano, 563 U.S. 27, 131 S.Ct. 1309, 1320 (2011) (regulatory agency often makes regulatory decisions based upon evidence that gives rise only to a suspicion of causation) 

First Circuit

Sutera v. Perrier Group of America, Inc., 986 F. Supp. 655, 664-65, 667 (D. Mass. 1997) (a regulatory agency’s “threshold of proof is reasonably lower than that in tort law”; “substances are regulated because of what they might do at given levels, not because of what they will do. . . . The fact of regulation does not imply scientific certainty. It may suggest a decision to err on the side of safety as a matter of regulatory policy rather than the existence of scientific fact or knowledge. . . . The mere fact that substances to which [plaintiff] was exposed may be listed as carcinogenic does not provide reliable evidence that they are capable of causing brain cancer, generally or specifically, in [plaintiff’s] case.”); id. at 660 (warning against the danger that a jury will “blindly accept an expert’s opinion that conforms with their underlying fears of toxic substances without carefully understanding or examining the basis for that opinion.”). Sutera is an important precedent, which involved a claim that exposure to an IARC category I carcinogen, benzene, caused plaintiffs’ leukemia. The plaintiff’s expert witness, Robert Jacobson, espousing a “linear, no threshold” theory, and relying upon an EPA regulation, which he claimed supported his opinion that even trace amounts of benzene can cause leukemia.

In re Neurontin Mktg., Sales Practices, and Prod. Liab. Litig., 612 F. Supp. 2d 116, 136 (D. Mass. 2009) (‘‘It is widely recognized that, when evaluating pharmaceutical drugs, the FDA often uses a different standard than a court does to evaluate evidence of causation in a products liability action. Entrusted with the responsibility of protecting the public from dangerous drugs, the FDA regularly relies on a risk-utility analysis, balancing the possible harm against the beneficial uses of a drug. Understandably, the agency may choose to ‘err on the side of caution,’ … and take regulatory action such as revising a product label or removing a drug from the marketplace ‘upon a lesser showing of harm to the public than the preponderance-of-the-evidence or more-like-than-not standard used to assess tort liability’.’’) (internal citations omitted) 

Whiting v. Boston Edison Co., 891 F. Supp. 12, 23-24 (D. Mass. 1995) (criticizing the linear no-threshold hypothesis, common to regulatory risk assessments, because it lacks any known or potential error rate, and it cannot be falsified as would any scientific theory)

Second Circuit

Wills v. Amerada Hess Corp., No. 98 CIV. 7126(RPP), 2002 WL 140542 (S.D.N.Y. Jan. 31, 2002), aff’d, 379 F.3d 32 (2d Cir. 2004) (Sotomayor, J.). In this Jones Act case, the plaintiff claimed that her husband’s exposure to benzene and polycyclic aromatic hydrocarbons on board ship caused his squamous cell lung cancer. Plaintiff’s expert witness relied heavily upon the IARC categorization of benzene as a “known” carcinogen, and an “oncogene” theory of causation that claimed there was no safe level of exposure because a single molecule could induce cancer. According to the plaintiff’s expert witness, the oncogene theory dispensed with the need to quantify exposure. Then Judge Sotomayor, citing Sutera, rejected plaintiff’s no-threshold theory, and the argument that exposure that exceeded OHSA permissible exposure level supported the causal claim.

Mancuso v. Consolidated Edison Co., 967 F. Supp. 1437, 1448 (S.D.N.Y. 1997) (“recommended or prescribed precautionary standards cannot provide legal causation”; “[f]ailure to meet regulatory standards is simply not sufficient” to establish liability)

In re Agent Orange Product Liab. Litig., 597 F. Supp. 740, 781 (E.D.N.Y. 1984) (Weinstein, J.) (“The distinction between avoidance of risk through regulation and compensation for injuries after the fact is a fundamental one.”), aff’d in relevant part, 818 F.2d 145 (2d Cir.1987), cert. denied sub nom. Pinkney v. Dow Chemical Co., 484 U.S. 1004 (1988). Judge Weinstein explained that regulatory action would not by itself support imposing liability for an individual plaintiff.  Id. at 782. “A government administrative agency may regulate or prohibit the use of toxic substances through rulemaking, despite a very low probability of any causal relationship.  A court, in contrast, must observe the tort law requirement that a plaintiff establish a probability of more than 50% that the defendant’s action injured him.” Id. at 785.

In re Ephedra Prods. Liab. Litig., 393 F. Supp. 2d 181, 189 (S.D.N.Y. 2005) (improvidently relying in part upon FDA ban despite “the absence of definitive scientific studies establishing causation”)

Third Circuit

Gates v. Rohm & Haas Co., 655 F.3d 255, 268 (3d Cir. 2011) (affirming the denial of class certification for medical monitoring) (‘‘plaintiffs could not carry their burden of proof for a class of specific persons simply by citing regulatory standards for the population as a whole’’).

In re Schering-Plough Corp. Intron/Temodar Consumer Class Action, 2009 WL 2043604, at *13 (D.N.J. July 10, 2009)(“[T]here is a clear and decisive difference between allegations that actually contest the safety or effectiveness of the Subject Drugs and claims that merely recite violations of the FDCA, for which there is no private right of action.”)

Rowe v. E.I. DuPont de Nemours & Co., Civ. No. 06-1810 (RMB), 2008 U.S. Dist. LEXIS 103528, *46-47 (D.N.J. Dec. 23, 2008) (rejecting reliance upon regulatory findings and risk assessments in which “the basic goal underlying risk assessments . . . is to determine a level that will protect the most sensitive members of the population.”)  (quoting David E. Eaton, “Scientific Judgment and Toxic Torts – A Primer in Toxicology for Judges and Lawyers,” 12 J.L. & Pol’y 5, 34 (2003) (“a number of protective, often ‘worst case’ assumptions . . . the resulting regulatory levels . . . generally overestimate potential toxicity levels for nearly all individuals.”)

Soldo v. Sandoz Pharms. Corp., 244 F. Supp. 2d 434, 543 (W.D. Pa. 2003) (finding FDA regulatory proceedings and adverse event reports not adequate or helpful in determining causation; the FDA “ordinarily does not attempt to prove that the drug in fact causes a particular adverse effect.”)Wade-Greaux v. Whitehall Laboratories, Inc., 874 F. Supp. 1441, 1464 (D.V.I.) (“assumption[s that] may be useful in a regulatory risk-benefit context … ha[ve] no applicability to issues of causation-in-fact”), aff’d, 46 F.3d 1120 (3d  Cir. 1994)

O’Neal v. Dep’t of the Army, 852 F. Supp. 327, 333 (M.D. Pa. 1994) (administrative risk figures are “appropriate for regulatory purposes in which the goal is to be particularly cautious [but] overstate the actual risk and, so, are inappropriate for use in determining” civil liability)

Fourth Circuit

Dunn v. Sandoz Pharmaceuticals Corp., 275 F. Supp. 2d 672, 684 (M.D.N.C. 2003) (FDA “risk benefit analysis” “does not demonstrate” causation in any particular plaintiff)

Yates v. Ford Motor Co., 113 F. Supp. 3d 841, 857 (E.D.N.C. 2015) (“statements from regulatory and official agencies … are not bound by standards for causation found in toxic tort law”)

Meade v. Parsley, No. 2:09-cv-00388, 2010 U.S. Dist. LEXIS 125217, * 25 (S.D.W. Va. Nov. 24, 2010) (‘‘Inasmuch as the cost-benefit balancing employed by the FDA differs from the threshold standard for establishing causation in tort actions, this court likewise concludes that the FDA-mandated [black box] warnings cannot establish general causation in this case.’’)

Rhodes v. E.I. du Pont de Nemours & Co., 253 F.R.D. 365, 377 (S.D. W.Va. 2008) (rejecting the relevance of regulatory assessments, which are precautionary and provide no information about actual risk).

Fifth Circuit

Moore v. Ashland Chemical Co., 126 F.3d 679, 708 (5th Cir. 1997) (holding that expert witness could rely upon a material safety data sheet (MSDS) because mandated by the Hazard Communication Act, 29 C.F.R. § 1910.1200), vacated 151 F.3d 269 (5th Cir. 1998) (affirming trial court’s exclusion of expert witness who had relied upon MSDS).

Johnson v. Arkema Inc., 685 F.3d 452, 464 (5th Cir. 2012) (per curiam) (affirming exclusion of expert witness who upon regulatory pronouncements; noting the precautionary nature of such statements, and the absence of specificity for the result claimed at the exposures experienced by plaintiff)

Allen v. Pennsylvania Eng’g Corp., 102 F.3d 194, 198-99 (5th Cir. 1996) (“Scientific knowledge of the harmful level of exposure to a chemical, plus knowledge that the plaintiff was exposed to such quantities, are minimal facts necessary to sustain the plaintiffs’ burden in a toxic tort case”; regulatory agencies, charged with protecting public health, employ a lower standard of proof in promulgating regulations than that used in tort cases). The Allen court explained that it was “also unpersuaded that the “weight of the evidence” methodology these experts use is scientifically acceptable for demonstrating a medical link. . . .  Regulatory and advisory bodies. . .utilize a “weight of the evidence” method to assess the carcinogenicity of various substances in human beings and suggest or make prophylactic rules governing human exposure.  This methodology results from the preventive perspective that the agencies adopt in order to reduce public exposure to harmful substances.  The agencies’ threshold of proof is reasonably lower than that appropriate in tort law, which traditionally makes more particularized inquiries into cause and effect and requires a plaintiff to prove that it is more likely than not that another individual has caused him or her harm.” Id.

Burst v. Shell Oil Co., C. A. No. 14–109, 2015 WL 3755953, *8 (E.D. La. June 16, 2015) (explaining Fifth Circuit’s rejection of regulatory “weight of the evidence” approaches to evaluating causation)

Sprankle v. Bower Ammonia & Chem. Co., 824 F.2d 409, 416 (5th Cir. 1987) (affirmed Rule 403 exclusion evidence of OSHA violations in claim of respiratory impairment in a non-employee who experienced respiratory impairment after exposure to anhydrous ammonia; court found that the jury likely be confused by regulatory pronouncements)

Cano v. Everest Minerals Corp., 362 F. Supp. 2d 814, 825 (W.D. Tex. 2005) (noting that a product that “has been classified as a carcinogen by agencies responsible for public health regulations is not probative of” common-law specific causation) (finding that the linear no-threshold opinion of the plaintiffs’ expert witness, Malin Dollinger, lacked a satisfactory scientific basis)

Burleson v. Glass, 268 F. Supp. 2d 699, 717 (W.D. Tex. 2003) (“the mere fact that [the product] has been classified by certain regulatory organizations as a carcinogen is not probative on the issue of whether [plaintiff’s] exposure. . .caused his. . .cancers”), aff’d, 393 F.3d 577 (5th Cir. 2004)

Newton v. Roche Labs., Inc., 243 F. Supp. 2d 672, 677, 683 (W.D. Tex. 2002) (FDA’s precautionary decisions on labeling are not a determination of causation of specified adverse events) (“Although evidence of an association may … be important in the scientific and regulatory contexts…, tort law requires a higher standard of causation.”)

Molden v. Georgia Gulf Corp., 465 F. Supp. 2d 606, 611 (M.D. La. 2006) (“regulatory and advisory bodies make prophylactic rules governing human exposure based on proof that is reasonably lower than that appropriate in tort law”)

Sixth Circuit

Nelson v. Tennessee Gas Pipeline Co., 243 F.3d 244, 252-53 (6th Cir. 2001) (exposure above regulatory levels is insufficient to establish causation)

Stites v Sundstrand Heat Transfer, Inc., 660 F. Supp. 1516, 1525 (W.D. Mich. 1987) (rejecting use of regulatory standards to support claim of increased risk, noting the differences in goals and policies between regulation and litigation)

Mann v. CSX Transportation, Inc., case no. 1:07-Cv-3512, 2009 U.S. Dist. Lexis 106433 (N.D. Ohio Nov. 10, 2009) (rejecting expert testimony that relied upon EPA action levels, and V.A. compensation for dioxin exposure, as basis for medical monitoring opinions)

Baker v. Chevron USA, Inc., 680 F. Supp. 2d 865, 880 (S.D. Ohio 2010) (“[R]egulatory agencies are charged with protecting public health and thus reasonably employ a lower threshold of proof in promulgating their regulations than is used in tort cases.”) (“[t]he mere fact that Plaintiffs were exposed to [the product] in excess of mandated limits is insufficient to establish causation”; rejecting Dr. Dahlgren’s opinion and its reliance upon a “one-hit” or “no threshold” theory of causation in which exposure to one molecule of a cancer-causing agent has some finite possibility of causing a genetic mutation leading to cancer, a theory that may be accepted for purposes of setting regulatory standards, but not as reliable scientific knowledge)

Adams v. Cooper Indus., 2007 WL 2219212 at *7 (E.D. KY 2007).

Seventh Circuit

Wood v. Textron, Inc., No. 3:10 CV 87, 2014 U.S. Dist. LEXIS 34938 (N.D. Ind. Mar. 17, 2014); 2014 U.S. Dist. LEXIS 141593, at *11 (N.D. Ind. Oct. 3, 2014), aff’d, 807 F.3d 827 (7th Cir. 2015). Dahlgren based his opinions upon the children’s water supply containing vinyl chloride in excess of regulatory levels set by state and federal agencies, including the EPA. Similarly, Ryer-Powder relied upon exposure levels’ exceeding regulatory permissible limits for her causation opinions. The district court, with the approval now of the Seventh Circuit would have none of this nonsense. Exceeding governmental regulatory exposure limits does not prove causation. The con-compliance does not help the fact finder without knowing “the specific dangers” that led the agency to set the permissible level, and thus the regulations are not relevant at all without this information. Even with respect to specific causation, the regulatory infraction may be weak or null evidence for causation. (citing Cunningham v. Masterwear Corp., 569 F.3d 673, 674–75 (7th Cir. 2009)

Eighth Circuit

Glastetter v. Novartis Pharms. Corp., 107 F. Supp. 2d 1015, 1036 (E.D. Mo. 2000) (“[T]he [FDA’s] statement fails to affirmatively state that a connection exists between [the drug] and the type of injury in this case.  Instead, it states that the evidence received by the FDA calls into question [drug’s] safety, that [the drug] may be an additional risk factor. . .and that the FDA had new evidence suggesting that therapeutic use of [the drug] may lead to serious adverse experiences.  Such language does not establish that the FDA had concluded that [the drug] can cause [the injury]; instead, it indicates that in light of the limited social utility of [the drug for the use at issue] and the reports of possible adverse effects, the drug should no longer be used for that purpose.”) (emphasis in original), aff’d, 252 F.3d 986, 991 (8th Cir. 2001) (FDA’s precautionary decisions on labeling are not a determination of causation of specified adverse events; “methodology employed by a government agency results from the preventive perspective that the agencies adopt”)( “The FDA will remove drugs from the marketplace upon a lesser showing of harm to the public than the preponderance-of-the-evidence or the more-like-than-not standard used to assess tort liability . . . . [Its] decision that [the drug] can cause [the injury] is unreliable proof of medical causation.”), aff’d, 252 F.3d 986 (8th Cir. 2001)

Wright v. Willamette Indus., Inc., 91 F.3d 1105, 1107 (8th Cir. 1996) (rejecting claim that plaintiffs were not required to show individual exposure levels to formaldehyde from wood particles). The Wright court elaborated upon the difference between adjudication and regulation of harm:

“Whatever may be the considerations that ought to guide a legislature in its determination of what the general good requires, courts and juries, in deciding cases, traditionally make more particularized inquiries into matters of cause and effect.  Actions in tort for damages focus on the question of whether to transfer money from one individual to another, and under common-law principles (like the ones that Arkansas law recognizes) that transfer can take place only if one individual proves, among other things, that it is more likely than not that another individual has caused him or her harm.  It is therefore not enough for a plaintiff to show that a certain chemical agent sometimes causes the kind of harm that he or she is complaining of.  At a minimum, we think that there must be evidence from which the factfinder can conclude that the plaintiff was exposed to levels of that agent that are known to cause the kind of harm that the plaintiff claims to have suffered. See Abuan v. General Elec. Co., 3 F.3d at 333.  We do not require a mathematically precise table equating levels of exposure with levels of harm, but there must be evidence from which a reasonable person could conclude that a defendant’s emission has probablycaused a particular plaintiff the kind of harm of which he or she complains before there can be a recovery.”

Gehl v. Soo Line RR, 967 F.2d 1204, 1208 (8th Cir. 1992).

Nelson v. Am. Home Prods. Corp., 92 F. Supp. 2d 954, 958 (W.D. Mo. 2000) (FDA’s precautionary decisions on labeling are not a determination of causation of specified adverse events)

National Bank of Commerce v. Associated Milk Producers, Inc., 22 F. Supp. 2d 942, 961 (E.D.Ark. 1998), aff’d, 191 F.3d 858 (8th Cir. 1999) 

Junk v. Terminix Internat’l Co., 594 F. Supp. 2d 1062, 1071 (S.D. Iowa 2008) (“government agency regulatory standards are irrelevant to [plaintiff’s] burden of proof in a toxic tort cause of action because of the agency’s preventative perspective”)

Ninth Circuit

Henrickson v. ConocoPhillips Co., 605 F. Supp. 2d 1142, 1156 (E.D. Wash. 2009) (excluding expert witness causation opinions in case involving claims that benzene exposure caused leukemia) 

Lopez v. Wyeth-Ayerst Labs., Inc., 1998 WL 81296, at *2 (9th Cir. Feb. 25, 1998) (FDA’s precautionary decisions on labeling are not a determination of causation of specified adverse events)

In re Epogen & Aranesp Off-Label Marketing & Sales Practices Litig., 2009 WL 1703285, at *5 (C.D. Cal. June 17, 2009) (“have not been proven” allegations are an improper “FDA approval” standard; the FDA’s determination to require warning changes without establishing causation is established does not permit a court or jury, bound by common-law standards, to impose such a duty to warn when common-law causation requirements are not met).

In re Hanford Nuclear Reservation Litig., 1998 U.S. Dist. Lexis 15028 (E.D. Wash. 1998) (radiation and chromium VI), rev’d on other grounds, 292 F.3d 1124 (9th Cir. 2002).

Tenth Circuit

Hollander v. Shandoz Pharm. Corp., 95 F. Supp. 2d 1230, 1239 (W.D. Okla. 2000) (distinguishing FDA’s threshold of proof as lower than appropriate in tort law), aff’d in relevant part, 289 F.3d 1193, 1215 (10th Cir. 2002)

Mitchell v. Gencorp Inc., 165 F.3d 778, 783 n.3 (10th Cir. 1999) (benzene and CML) (quoting Allen, 102 F.3d at 198) (state administrative finding that product was a carcinogen was based upon lower administrative standard than tort standard) (“The methodology employed by a government agency “results from the preventive perspective that the agencies adopt in order to reduce public exposure to harmful substances.  The agencies’ threshold of proof is reasonably lower than that appropriate in tort law, which traditionally makes more particularized inquiries into cause and effect and requires a plaintiff to prove it is more likely than not that another individual has caused him or her harm.”)

In re Breast Implant Litig., 11 F. Supp. 2d 1217, 1229 (D.Colo. 1998)

Johnston v. United States, 597 F. Supp. 374, 393-394 (D. Kan.1984) (noting that the linear no-threshold hypothesis is based upon a prudent assumption designed to overestimate risk; speculative hypotheses are not appropriate in determining whether one person has harmed another)

Eleventh Circuit

Rider v. Sandoz Pharmaceuticals Corp., 295 F.3d 1194, 1201 (11th Cir. 2002) (FDA may take regulatory action, such as revising warning labels or withdrawing drug from the market ‘‘upon a lesser showing of harm to the public than the preponderance-of-the-evidence or more-likely-than-not standard used to assess tort liability’’) (“A regulatory agency such as the FDA may choose to err on the side of caution. Courts, however, are required by the Daubert trilogy to engage in objective review of the evidence to determine whether it has sufficient scientific basis to be considered reliable.”)

McClain v. Metabolife Internat’l, Inc., 401 F.3d 1233, 1248-1250 (11th Cir. 2005) (ephedra) (allowing that regulators “may pay heed to any evidence that points to a need for caution,” and apply “a much lower standard than that which is demanded by a court of law”) (“[U]se of FDA data and recommendations raises a more subtle methodological issue in a toxic tort case. The issue involves identifying and contrasting the type of risk assessment that a government agency follows for establishing public health guidelines versus an expert analysis of toxicity and causation in a toxic tort case.”)

In re Seroquel Products Liab. Litig., 601 F. Supp. 2d 1313, 1315 (M.D. Fla. 2009) (noting that administrative agencies “impose[] different requirements and employ[] different labeling and evidentiary standards” because a “regulatory system reflects a more prophylactic approach” than the common law)

Siharath v. Sandoz Pharmaceuticals Corp., 131 F. Supp. 2d 1347, 1370 (N.D. Ga. 2001) (“The standard by which the FDA deems a drug harmful is much lower than is required in a court of law.  The FDA’s lesser standard is necessitated by its prophylactic role in reducing the public’s exposure to potentially harmful substances.”), aff’d, 295 F.3d 1194 330 (11th Cir. 2002)

In re Accutane Products Liability, 511 F.Supp.2d 1288, 1291-92 (M.D. Fla. 2007)(acknowledging that regulatory risk assessments are not necessarily realistic in human populations because they are often based upon animal studies, and that the important differences between experimental animals and humans are substantial in various health outcomes).

Kilpatrick v. Breg, Inc., 2009 WL 2058384 at * 6-7 (S.D. Fla. 2009) (excluding plaintiff’s expert witness), aff’d, 613 F.3d 1329 (11th Cir. 2010)

District of Columbia Circuit

Ethyl Corp. v. E.P.A., 541 F.2d 1, 28 & n. 58 (D.C. Cir. 1976) (detailing the precautionary nature of agency regulations that may be based upon suspicions)

STATE COURTS

Arizona

Lofgren v. Motorola, 1998 WL 299925 (Ariz. Super. Ct. 1998) (finding plaintiffs’ expert witnesses’ testimony that TCE caused cancer to be not generally accepted; “it is appropriate public policy for health organizations such as IARC and the EPA to make judgments concerning the health and safety of the population based on evidence which would be less than satisfactory to support a specific plaintiff’s tort claim for damages in a court of law”)

Colorado

Salazar v. American Sterilizer Co., 5 P.3d 357 (Colo. Ct. App. 2000) (allowing testimony about harmful ethylene oxide exposure based upon OSHA regulations)

Georgia

Butler v. Union Carbide Corp., 712 S.E.2d 537, 552 & n.37 (Ga. App. 2011) (distinguishing risk assessment from causation assessment; citing the New York Court of Appeals decision in Parker for correctly rejecting reliance on regulatory pronouncements for causation determinations)

Illinois

La Salle Nat’l Bank v. Malik, 705 N.E.2d 938 (Ill. App. 3d) (reversing trial court’s exclusion of OSHA PEL for ethylene oxide), writ pet’n den’d, 714 N.E.2d 527 (Ill. 2d 1999)

New York

Parker v. Mobil Oil Corp., 7 N.Y.3d 434, 450, 857 N.E.2d 1114, 1122, 824 N.Y.S.2d 584 (N.Y. 2006) (noting that regulatory agency standards usually represent precautionary principle efforts deliberately to err on side of prevention; “standards promulgated by regulatory agencies as protective measures are inadequate to demonstrate legal causation.” 

In re Bextra & Celebrex, 2008 N.Y. Misc. LEXIS 720, *20, 239 N.Y.L.J. 27 (2008) (characterizing FDA Advisory Panel recommendations as regulatory standard and protective measure).

Juni v. A.O. Smith Water Products Co., 48 Misc. 3d 460, 11 N.Y.S.3d 416, 432, 433 (N.Y. Cty. 2015) (“the reports and findings of governmental agencies [declaring there to be no safe dose of asbestos] are irrelevant as they constitute insufficient proof of causation”), aff’d, 32 N.Y.3d 1116, 116 N.E.3d 75, 91 N.Y.S.3d 784 (2018)

Ohio

Valentine v. PPG Industries, Inc., 821 N.E.2d 580, 597-98 (Ohio App. 2004), aff’d, 850 N.E.2d 683 (Ohio 2006). 

Pennsylvania

Betz v. Pneumo Abex LLC, 44 A. 3d 27 (Pa. 2012).

Texas

Borg-Warner Corp., 232 S.W.3d 765, 770 (Tex. 2007)

Exxon Corp. v. Makofski, 116 S.W.3d 176, 187-88 (Tex. App. 2003) (describing “standards used by OSHA [and] the EPA” as inadequate for causal determinations)

[1] Michael D. Green, D. Michal Freedman, and Leon Gordis, “Reference Guide on Epidemiology,” in Reference Manual on Scientific Evidence 549, 627 (3d ed. 2011).

[2] Margaret A. Berger, “The Supreme Court’s Trilogy on the Admissibility of Expert Testimony,” in Reference Manual On Scientific Evidence at 33 (Fed. Jud. Center 2d. ed. 2000).

[3] Margaret A. Berger, “Introduction to the Symposium,” 12 J. L. & Pol’y 1 (2003). Professor Berger described the symposium as a “felicitous outgrowth of a grant from the Common Benefit Trust established in the Silicone Breast Implant Products Liability Litigation to hold a series of conferences at Brooklyn Law School.” Id. at 1. Ironically, that “Trust” was nothing more than the walking-around money of plaintiffs’ lawyers from the Silicone-Gel Breast Implant MDL 926. Although Professor Berger was often hostile the causation requirement in tort law, her symposium included some well-qualified scientists who amplified her point from the Reference Manual about the divide between regulatory risk assessment and scientific causal assessments.

[4] David L. Eaton, Scientific Judgment and Toxic Torts- A Primer in Toxicology for Judges and Lawyers, 12 J.L. & Pol’y 5, 36 (2003). See also Joseph V. Rodricks and Susan H. Rieth, “Toxicological risk assessment in the courtroom: are available methodologies suitable for evaluating toxic tort and product liability claims?” 27 Regul. Toxicol. & Pharmacol. 21, 27 (1998) (“The public health-oriented resolution of scientific uncertainty [used by regulators] is not especially helpful to the problem faced by a court.”)

[5] EPA “Guidelines for Carcinogen Risk Assessment” at 13 (1986).

[6] The approach is set out in FDA, M7 (R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk: Guidance for Industry (2018) [FDA M7]. This FDA guidance is essentially an adoption of the M7 document of the Expert Working Group (Multidisciplinary) of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

[7] FDA M7 at 3.

[8] FDA M7 at 5.

[9] FDA M7 at 5 (emphasis added).

[10] See Labeling of Diphenhydramine Containing Drug Products for Over-the-Counter Human Use, 67 Fed. Reg. 72,555, at 72,556 (Dec. 6, 2002) (“FDA’s decision to act in an instance such as this one need not meet the standard of proof required to prevail in a private tort action. . .. To mandate a warning or take similar regulatory action, FDA need not show, nor do we allege, actual causation.”) (citing Glastetter).

[11] FDA M7 at “Acceptable Intakes in Relation to Less-Than-Lifetime (LTL) Exposure (7.3).”

[12] FDA M7 at 12 (“Mutagenic Impurities With Evidence for a Practical Threshold (7.2.2)”).

Posted in Causation, Expert Witnesses, Reference Manual on Scientific Evidence, Rule 702, Toxicological Evidence | 9 Comments »

California Roasts Fear-Mongering Industry

June 16th, 2019

A year ago, California set out to create an exemption for coffee from its Proposition 65 regulations. The lawsuit industry, represented by the Council for Education and Research on Toxics (CERT) had been successfully deploying Prop 65’s private right of action provisions to pick the pockets of coffee vendors. Something had to give.

In 2010, Mr. Metzger, on behalf of CERT, sued Starbucks and 90 other coffee manufacturers and distributors, claiming they had failed to warn consumers about the cancer risks of acrylamide. CERT’s mission was to shake down the roasters and the vendors because coffee has minor amounts of acrylamide in it. Acrylamide in very high doses causes tumors in rats[1]; coffee consumption by humans is generally regarded as beneficial.

Earlier last year a Los Angeles Superior Court ordered the coffee companies to put cancer warnings on their beverages. In the upcoming damages phase of the case, Metzger sought as much as $2,500 in civil penalties for each cup of coffee the defendants sold over at least a decade. Suing companies for violating California’s Proposition 65 is like shooting fish in a barrel, but the State’s regulatory initiative to save California from the embarrassment of branding coffee a carcinogen was a major setback for CERT.

And so the Office of Environmental Health Hazard Assessment (OEHHA) began a rulemaking largely designed to protect the agency from the public relations nightmare created by the application of the governing statute and regulations to squeeze the coffee roasters and makers.[2] The California’s agency’s proposed regulation on acrylamide in coffee resulted in a stay of CERT’s enforcement action against Starbucks.[3] CERT’s lawyers were not pleased; they had already won a trial court’s judgment that they were owed damages, and only the amount needed to be set. In September 2018, CERT filed a lawsuit in Los Angeles Superior Court against the state of California challenging OEHHA’s proposed rule, saying it was being rammed through the agency on the order of the Office of the Governor in an effort to kill CERT’s suit against the coffee companies. Or maybe it was simply designed to allow people to drink their coffee without the Big Prop 65 warning.

Earlier this month, after reviewing voluminous submissions and holding a hearing, the OEHHA announced its ruling that Californians do not need to be warned that coffee causes cancer. Epistemically, coffee is not known to the State of California to be hazardous to human health.[4] According to Sam Delson, a spokesperson for the OEHHA, “Coffee is a complex mixture of hundreds of chemicals that includes both carcinogens and anti-carcinogens. … The overall effect of coffee consumption is not associated with any significant cancer risk.” The regulation saving coffee goes into effect in October 2019. CERT, no doubt, will press on in its litigation campaign against the State.

CERT is the ethically dodgy organization founded by C. Sterling Wolfe, a former environmental lawyer; Brad Lunn; Carl Cranor, a philosophy professor at University of California Riverside; and Martyn T. Smith, a toxicology professor at University of California Berkeley.[5] Metzger has been its lawyer for many years; indeed, Metzger and CERT share the same office. Smith has been the recipient of CERT’s largesse in funding toxicologic studies. Cranor and Smith have both testified for the lawsuit industry.

In the well-known Milward case,[6] both Cranor and Smith served as paid expert witnesses for plaintiff. When the trial court excluded their proffered testimonies as unhelpful and unreliable, their own organization, CERT, came to the rescue by filing an amicus brief in the First Circuit. Supporting by a large cast of fellow travelers, CERT perverted the course of justice by failing to disclose the intimate relationship between the “amicus” CERT and the expert witnesses Cranor and Smith, whose opinions had been successfully challenged.[7]

The OEHHA coffee regulation shows that not all regulation is bad.

[1]  National Cancer Institute, “Acrylamide and Cancer Risk.”

[2]  See Sam Delson, “Press Release: Proposed OEHHA regulation clarifies that cancer warnings are not required for coffee under Proposition 65” (June 15, 2018).

[3]  Council for Education and Research on Toxics v. Starbucks Corp., case no. B292762, Court of Appeal of the State of California, Second Appellate District.

[4]  Associated Press, “Perk Up: California Says Coffee Cancer Risk Insignificant,” N.Y. Times (June 3, 2019); Sara Randazzo, “Coffee Doesn’t Warrant a Cancer Warning in California, Agency Says; Industry scores win following finding on chemical found in beverage,” W.S.J. (June 3, 2019); Editorial Board, “Coffee Doesn’t Kill After All: California has a moment of sanity, and a lawyer is furious,” Wall.St.J. (June 5, 2019).

[5]  Michael Waters, “The Secretive Non-Profit Gaming California’s Health Laws,” The Outline (June 18, 2018); Beth Mole, “The secretive nonprofit that made millions suing companies over cancer warnings,” Ars Technica (June 6, 2019); NAS, “Coffee with Cream, Sugar & a Dash of Acrylamide” (June 9, 2018); NAS, “The Council for Education & Research on Toxics” (July 9, 2013); NAS, “Sand in My Shoe – CERTainly” (June 17, 2014) (CERT briefs supported by fellow-travelers, testifying expert witnesses Jerrold Abraham, Richard W. Clapp, Ronald Crystal, David A. Eastmond, Arthur L. Frank, Robert J. Harrison, Ronald Melnick, Lee Newman, Stephen M. Rappaport, David Joseph Ross, and Janet Weiss, all without disclosing conflicts of interest).

[6]  Milward v. Acuity Specialty Products Group, Inc., 664 F. Supp. 2d 137, 148 (D.Mass. 2009), rev’d, 639 F.3d 11 (1st Cir. 2011), cert. den. sub nom. U.S. Steel Corp. v. Milward, 565 U.S. 1111 (2012), on remand, Milward v. Acuity Specialty Products Group, Inc., 969 F.Supp. 2d 101 (D.Mass. 2013) (excluding specific causation opinions as invalid; granting summary judgment), aff’d, 820 F.3d 469 (1st Cir. 2016).

[7]  NAS, “The Council for Education & Research on Toxics” (July 9, 2013) (CERT amicus brief filed without any disclosure of conflict of interest). The fellow travelers who knowingly or unknowingly aided CERT’s scheme to pervert the course of justice, included some well-known testifiers for the lawsuit industry: Nicholas A. Ashford, Nachman Brautbar, David C. Christiani, Richard W. Clapp, James Dahlgren, Devra Lee Davis, Malin Roy Dollinger, Brian G. Durie, David A. Eastmond, Arthur L. Frank, Frank H. Gardner, Peter L. Greenberg, Robert J. Harrison, Peter F. Infante, Philip J. Landrigan, Barry S. Levy, Melissa A. McDiarmid, Myron Mehlman, Ronald L. Melnick, Mark Nicas, David Ozonoff, Stephen M. Rappaport, David Rosner, Allan H. Smith, Daniel Thau Teitelbaum, Janet Weiss, and Luoping Zhang. See also NAS, “Carl Cranor’s Conflicted Jeremiad Against Daubert” (Sept. 23, 2018); Carl Cranor, “Milward v. Acuity Specialty Products: How the First Circuit Opened Courthouse Doors for Wronged Parties to Present Wider Range of Scientific Evidence” (July 25, 2011).

 

 

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Toxicology for Judges – The New Reference Manual on Scientific Evidence (2011)

October 5th, 2011

I have begun to dip into the massive third edition of the Reference Manual on Scientific Evidence.  To date, there have been only a couple of acknowledgments of this new work, which was released to the public on September 28, 2011.  See “A New Day – A New Edition of the Reference Manual of Scientific Evidence”; and David Kaye, “Prometheus Unbound: Releasing the New Edition of the FJC Reference Manual on Scientific Evidence.”

Like previous editions, the substantive scientific areas are covered in discrete chapters, written by subject matter specialists, often along with a lawyer who addresses the legal implications and judicial treatment of that subject matter.  From my perspective, the chapters on statistics, epidemiology, and toxicology are the most important in my practice and in teaching, and I decided to start with the toxicology.  The toxicology chapter, “Reference Guide on Toxicology,” in the third edition is written by Professor Bernard D. Goldstein, of the University of Pittsburgh Graduate School of Public Health, and Mary Sue Henifin, a partner in the law firm of Buchanan Ingersoll, P.C.

CONFLICTS OF INTEREST

At the question and answer session of the public release ceremony, one gentleman rose to note that some of the authors were lawyers with big firm affiliations, which he supposed must mean that they represent mostly defendants.  Based upon his premise, he asked what the review committee had done to ensure that conflicts of interest did not skew or distort the discussions in the affected chapters.  Dr. Kassirer and Judge Kessler responded by pointing out that the chapters were peer reviewed by outside reviewers, and reviewed by members of the supervising review committee.  The questioner seemed reassured, but now that I have looked at the toxicology chapter, I am not so sure.

The questioner’s premise that a member of a large firm will represent mostly defendants and thus have a pro-defense  bias is probably a common perception among unsophisticated lay observers.  What is missing from their analysis is the realization that although gatekeeping helps the defense lawyers’ clients, it takes away legal work from firms that represent defendants in the litigations that are pretermitted by effective judicial gatekeeping.  Erosion of gatekeeping concepts, however, inures to the benefit of plaintiffs, their counsel, as well as the expert witnesses engaged on behalf of plaintiffs in litigation.

The questioner’s supposition in the case of the toxicology chapter, however, is doubly flawed.  If he had known more about the authors, he would probably not have asked his question.  First, the lawyer author, Ms. Henifin, is known for having taken virulently anti-manufacturer positions.  See Richard M. Lynch and Mary S. Henifin, “Causation in Occupational Disease: Balancing Epidemiology, Law and Manufacturer Conduct,” 9 Risk: Health, Safety & Environment 259, 269 (1998) (conflating distinct causal and liability concepts, and arguing that legal and scientific causal criteria should be abrogated when manufacturing defendant has breached a duty of care).

As for the scientist author of the toxicology chapter, Professor Goldstein, the casual reader of the chapter may want to know that he has testified in any number of toxic tort cases, almost invariably on the plaintiffs’ side.  Unlike the defense lawyer, who loses business revenue, when courts shut down unreliable claims, plaintiffs’ testifying or consulting expert witnesses stand to gain by minimalist expert witness opinion gatekeeping.  Given the economic asymmetries, the reader must thus want to know that Prof. Goldstein was excluded as an expert witness in some high-profile toxic tort cases.  See, e.g., Parker v. Mobil Oil Corp., 7 N.Y.3d 434, 857 N.E.2d 1114, 824 N.Y.S.2d 584 (2006) (dismissing leukemia (AML) claim based upon claimed low-level benzene exposure from gasoline) , aff’g 16 A.D.3d 648 (App. Div. 2d Dep’t 2005).  No; you will not find the Parker case cited in the Manual‘s chapter on toxicology. (Parker is, however, cited in the chapter on exposure science.)

I have searched but I could not find any disclosure of Professor Goldstein’s conflicts of interests in this new edition of the Reference Manual.  I would welcome a correction if I am wrong.  Having pointed out this conflict, I would note that financial conflicts of interest are nothing really compared to ideological conflicts of interest, which often propel scientists into service as expert witnesses.

HORMESIS

One way that ideological conflicts might be revealed is to look for imbalances in the presentation of toxicologic concepts.  Most lawyers who litigate cases that involve exposure-response issues are familiar with the “linear no threshold” (LNT) concept that is used frequently in regulatory risk assessments, and which has metastasized to toxic tort litigation, where LNT often has no proper place.

LNT is a dubious assumption because it claims to “known” the dose response at very low exposure levels in the absence of data.  There is a thin plausibility for genotoxic chemicals claimed to be carcinogens, but even that plausibility evaporates when one realizes that there are defense and repair mechanisms to genotoxicity, which must first be saturated before there can be a carcinogenic response.  Hormesis is today an accepted concept that describes a dose-response relationship that shows a benefit at low doses, but harm at high doses.

The toxicology chapter in the Reference Manual has several references to LNT but none to hormesis.  That font of all knowledge, Wikipedia reports that hormesis is controversial, but so is LNT.  This is the sort of imbalance that may well reflect an ideological bias.

One of the leading textbooks on toxicology describes hormesis:

“There is considerable evidence to suggest that some non-nutritional toxic substances may also impart beneficial or stimulatory effects at low doses but that, at higher doses, they produce adverse effects. This concept of “hormesis” was first described for radiation effects but may also pertain to most chemical responses.”

Curtis D. Klaassen, Casarett & Doull’s Toxicology: The Basic Science of Poisons 23 (7th ed. 2008) (internal citations omitted).

Similarly, the Encyclopedia of Toxicology describes hormesis as an important phenomenon in toxicologic science:

“This type of dose–response relationship is observed in a phenomenon known as hormesis, with one explanation being that exposure to small amounts of a material can actually confer resistance to the agent before frank toxicity begins to appear following exposures to larger amounts.  However, analysis of the available mechanistic studies indicates that there is no single hormetic mechanism. In fact, there are numerous ways for biological systems to show hormetic-like biphasic dose–response relationship. Hormetic dose–response has emerged in recent years as a dose–response phenomenon of great interest in toxicology and risk assessment.”

Philip Wexler, Bethesda, et al., eds., 2 Encyclopedia of Toxicology 96 (2005).  One might think that hormesis would also be of great interest to federal judges, but they will not learn about it from reading the Reference Manual.

Hormesis research has come into its own.  The International Dose-Response Society, which “focus[es] on the dose-response in the low-dose zone,” publishes a journal, Dose-Response, and a newsletter, BELLE:  Biological Effects of Low Level Exposure.  In 2009, two leading researchers in the area of hormesis published a collection of important papers:  Mark P. Mattson and Edward J. Calabrese, eds., Hormesis: A Revolution in Biology, Toxicology and Medicine (N.Y. 2009).

A check in PubMed shows that LNT has more “hits” than “hormesis” or “hermetic,” but still the latter phrases exceed 1,267 references, hardly insubstantial.  In actuality, there are many more hermetic relationships identified in the scientific literature, which often fails to identify the relationship by the term hormesis or hermetic.  See Edward J. Calabrese and Robyn B. Blain, “The hormesis database: The occurrence of hormetic dose responses in the toxicological literature,” 61 Regulatory Toxicology and Pharmacology 73 (2011) (reviewing about 9,000 dose-response relationships for hormesis, to create a database of various aspects of hormesis).  See also Edward J. Calabrese and Robyn B. Blain, “The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: An overview,” 202 Toxicol. & Applied Pharmacol. 289 (2005) (earlier effort to establish hormesis database).

The Reference Manual’s omission of hormesis is regrettable.  Its inclusion of references to LNT but not to hormesis appears to result from an ideological bias.

QUESTIONABLE SUBSTANTIVE OPINIONS

One would hope that the toxicology chapter would not put forward partisan substantive positions on issues that are currently the subject of active litigation.  Fondly we would hope that any substantive position advanced would at least be well documented.

For at least one issue, the toxicology chapter dashes our fondest hopes.  Table 1 in the chapter presents a “Sample of Selected Toxicological End Points and Examples of Agents of Concern in Humans.” No documentation or citations are provided for this table.  Most of the exposure agent/disease outcome relationships in the table are well accepted, but curiously at least one agent-disease pair is the subject of current litigation is wildly off the mark:

Parkinson’s disease and manganese

Reference Manual at 653.  If the chapter’s authors had looked, they would have found that Parkinson’s disease is almost universally accepted to have no known cause, except among a few plaintiffs’ litigation expert witnesses.  They would also have found that the issue has been addressed carefully and the claimed relationship or “concern” has been rejected by the leading researchers in the field (who have no litigation ties).  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.”)

WHEN ALL YOU HAVE IS A HAMMER, EVERYTHING LOOKS LIKE A NAIL

The substantive specialist author, Professor Goldstein, is not a physician; nor is he an epidemiologist.  His professional focus on animal and cell research shows, and biases the opinions offered in this chapter.

“In qualitative extrapolation, one can usually rely on the fact that a compound causing an effect in one mammalian species will cause it in another species. This is a basic principle of toxicology and pharmacology.  If a heavy metal, such as mercury, causes kidney toxicity in laboratory animals, it is highly likely to do so at some dose in humans.”

Reference Manual at 646.

Such extrapolations may make sense in regulatory contexts, where precauationary judgments are of interest, but they hardly can be said to be generally accepted in controversies in civil actions over actual causation.  Crystalline silica, for instance, causes something resembling lung cancer in rats, but not in mice, guinea pigs, or hamsters.  It hardly makes sense to ask juries to decide whether the plaintiff is more like a rat than a mouse.

For a sober second opinion to the toxicology chapter, one may consider the views of some well-known authors:

“Whereas the concordance was high between cancer-causing agents initially discovered in humans and positive results in animal studies (Tomatis et al., 1989; Wilbourn et al., 1984), the same could not be said for the reverse relationship: carcinogenic effects in animals frequently lacked concordance with overall patterns in human cancer incidence (Pastoor and Stevens, 2005).”

Hans-Olov Adami, Sir Colin L. Berry, Charles B. Breckenridge, Lewis L. Smith, James A. Swenberg, Dimitrios Trichopoulos, Noel S. Weiss, and Timothy P. Pastoor, “Toxicology and Epidemiology: Improving the Science with a Framework for Combining Toxicological and Epidemiological Evidence to Establish Causal Inference,” 122 Toxciological Sciences 223, 224 (2011).

Once again, there is a sense that the scholarship of the toxicology chapter is not as complete or thorough as we would hope.

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