For your delectation and delight, desultory dicta on the law of delicts.

David Egilman and Friends Circle the Wagons at the International Journal of Occupational & Environmental Health

May 4th, 2017

Andrew Maier is an associate professor in the Department of Environmental Health, in the University of Cincinnati. Maier received his Ph.D. degree in toxicology, with a master’s degree in industrial health. He is a Certified Industrial Hygienest and has published widely on occupational health issues. Earlier this year, Maier was named the editor-in-chief of the International Journal of Occupational and Environmental Health (IJOEH). See Casey Allen, “Andy Maier Named Editor of Environmental Health Journal(Jan. 18, 2017).

Before Maier’s appointment, the IJOEH was, for the last several years, the vanity press for former editor-in-chief David Egilman and “The Lobby,” the expert witness brigade of the lawsuit industry. Egilman’s replacement with Andrew Maier apparently took place after the IJOEH was acquired by the scientific publishing company Taylor & Francis, from the former publisher, Maney.

The new owner, however, left the former IJOEH editorial board, largely a gaggle of Egilman friends and fellow travelers in place. Last week, the editorial board revoltingly wrote [contact information redacted] to Roger Horton, Chief Executive Officer of Taylor & Francis, to request that Egilman be restored to power, or that the current Editorial Board be empowered to choose Egilman’s successor. With Trump-like disdain for evidence, the Board characterized the new Editor as a “corporate consultant.” If Maier has consulted with corporations, his work appears to have rarely if ever landed him in a courtroom at the request of a corporate defendant. And with knickers tightly knotted, the Board also made several other demands for control over Board membership and journal content.

Andrew Watterson wrote to Horton on behalf of all current and former IJOEH Editorial Board members, a group heavily populated by plaintiffs’ litigation expert witnesses and “political” scientists, including among others:

Arthur Frank

Morris Greenberg

Barry S. Levy

David Madigan

Jock McCulloch

David Wegman

Barry Castleman

Peter Infante

Ron Melnick

Daniel Teitelbaum

None of the signatories apparently disclosed their affiliations as corporate consultants for the lawsuit industry.

Removing Egilman from control was bad enough, but the coup de grâce for the Lobby came earlier in April 2016, when Taylor & Francis notified Egilman that a paper that he had published in IJOEH was being withdrawn. According to the petitioners, the paper, “The production of corporate research to manufacture doubt about the health hazards of products: an overview of the Exponent Bakelite simulation study,” was removed without explanation. See Public health journal’s editorial board tells publisher they have ‘grave concerns’ over new editor,” Retraction Watch (April 27, 2017).

According to Taylor & Francis, the Egilman article was “published inadvertently, before the review process had been completed. On completing that review, it was decided the article was unsuitable for publication in the journal.” Id. Well, of course, Egilman’s article was unlikely to receive much analytical scrutiny at a journal where he was Editor-in-Chief, and where the Board was populated by his buddies. The same could be said for many articles published under Egilman’s tenure at the IJOEH. Taylor & Francis owes Egilman and the scientific and legal community a detailed statement of what was in the article, which was “unsuitable,” and why. Certainly, the law department at Taylor & Francis should make sure that it does not give Egilman and his former Board of Editors grounds for litigation. They are, after all, tight with the lawsuit industry. More important, Taylor & Francis owes Dr. Egilman, as well as the scientific and legal community, a full explanation of why the article in question was unsuitable for publication in the IJOEH.

Don’t Double Dip Data

March 9th, 2015

Meta-analyses have become commonplace in epidemiology and in other sciences. When well conducted and transparently reported, meta-analyses can be extremely helpful. In several litigations, meta-analyses determined the outcome of the medical causation issues. In the silicone gel breast implant litigation, after defense expert witnesses proffered meta-analyses[1], court-appointed expert witnesses adopted the approach and featured meta-analyses in their reports to the MDL court[2].

In the welding fume litigation, plaintiffs’ expert witness offered a crude, non-quantified, “vote counting” exercise to argue that welding causes Parkinson’s disease[3]. In rebuttal, one of the defense expert witnesses offered a quantitative meta-analysis, which provided strong evidence against plaintiffs’ claim.[4] Although the welding fume MDL court excluded the defense expert’s meta-analysis from the pre-trial Rule 702 hearing as untimely, plaintiffs’ counsel soon thereafter initiated settlement discussions of the entire set of MDL cases. Subsequently, the defense expert witness, with his professional colleagues, published an expanded version of the meta-analysis.[5]

And last month, a meta-analysis proffered by a defense expert witness helped dispatch a long-festering litigation in New Jersey’s multi-county isotretinoin (Accutane) litigation. In re Accutane Litig., No. 271(MCL), 2015 WL 753674 (N.J. Super., Law Div., Atlantic Cty., Feb. 20, 2015) (excluding plaintiffs’ expert witness David Madigan).

Of course, when a meta-analysis is done improperly, the resulting analysis may be worse than none at all. Some methodological flaws involve arcane statistical concepts and procedures, and may be easily missed. Other flaws are flagrant and call for a gatekeeping bucket brigade.

When a merchant puts his hand the scale at the check-out counter, we call that fraud. When George Costanza double dipped his chip twice in the chip dip, he was properly called out for his boorish and unsanitary practice. When a statistician or epidemiologist produces a meta-analysis that double counts crucial data to inflate a summary estimate of association, or to create spurious precision in the estimate, we don’t need to crack open Modern Epidemiology or the Reference Manual on Scientific Evidence to know that something fishy has taken place.

In litigation involving claims that selective serotonin reuptake inhibitors cause birth defects, plaintiffs’ expert witness, a perinatal epidemiologist, relied upon two published meta-analyses[6]. In an examination before trial, this epidemiologist was confronted with the double counting (and other data entry errors) in the relied-upon meta-analyses, and she readily agreed that the meta-analyses were improperly done and that she had to abandon her reliance upon them.[7] The result of the expert witness’s deposition epiphany, however, was that she no longer had the illusory benefit of an aggregation of data, with an outcome supporting her opinion. The further consequence was that her opinion succumbed to a Rule 702 challenge. See In re Zoloft (Sertraline Hydrochloride) Prods. Liab. Litig., MDL No. 2342; 12-md-2342, 2014 U.S. Dist. LEXIS 87592; 2014 WL 2921648 (E.D. Pa. June 27, 2014) (Rufe, J.).

Double counting of studies, or subgroups within studies, is a flaw that most careful readers can identify in a meta-analysis, without advance training. According to statistician Stephen Senn, double counting of evidence is a serious problem in published meta-analytical studies. Stephen J. Senn, “Overstating the evidence – double counting in meta-analysis and related problems,” 9, at *1 BMC Medical Research Methodology 10 (2009). Senn observes that he had little difficulty in finding examples of meta-analyses gone wrong, including meta-analyses with double counting of studies or data, in some of the leading clinical medical journals. Id. Senn urges analysts to “[b]e vigilant about double counting,” id. at *4, and recommends that journals should withdraw meta-analyses promptly when mistakes are found,” id. at *1.

Similar advice abounds in books and journals[8]. Professor Sander Greenland addresses the issue in his chapter on meta-analysis in Modern Epidemiology:

Conducting a Sound and Credible Meta-Analysis

Like any scientific study, an ideal meta-analysis would follow an explicit protocol that is fully replicable by others. This ideal can be hard to attain, but meeting certain conditions can enhance soundness (validity) and credibility (believability). Among these conditions we include the following:

  • A clearly defined set of research questions to address.

  • An explicit and detailed working protocol.

  • A replicable literature-search strategy.

  • Explicit study inclusion and exclusion criteria, with a rationale for each.

  • Nonoverlap of included studies (use of separate subjects in different included studies), or use of statistical methods that account for overlap. * * * * *”

Sander Greenland & Keith O’Rourke, “Meta-Analysis – Chapter 33,” in Kenneth J. Rothman, Sander Greenland, Timothy L. Lash, Modern Epidemiology 652, 655 (3d ed. 2008) (emphasis added).

Just remember George Costanza; don’t double dip that chip, and don’t double dip in the data.

[1] See, e.g., Otto Wong, “A Critical Assessment of the Relationship between Silicone Breast Implants and Connective Tissue Diseases,” 23 Regulatory Toxicol. & Pharmacol. 74 (1996).

[2] See Barbara Hulka, Betty Diamond, Nancy Kerkvliet & Peter Tugwell, “Silicone Breast Implants in Relation to Connective Tissue Diseases and Immunologic Dysfunction:  A Report by a National Science Panel to the Hon. Sam Pointer Jr., MDL 926 (Nov. 30, 1998)”; Barbara Hulka, Nancy Kerkvliet & Peter Tugwell, “Experience of a Scientific Panel Formed to Advise the Federal Judiciary on Silicone Breast Implants,” 342 New Engl. J. Med. 812 (2000).

[3] Deposition of Dr. Juan Sanchez-Ramos, Street v. Lincoln Elec. Co., Case No. 1:06-cv-17026, 2011 WL 6008514 (N.D. Ohio May 17, 2011).

[4] Deposition of Dr. James Mortimer, Street v. Lincoln Elec. Co., Case No. 1:06-cv-17026, 2011 WL 6008054 (N.D. Ohio June 29, 2011).

[5] James Mortimer, Amy Borenstein & Laurene Nelson, Associations of Welding and Manganese Exposure with Parkinson’s Disease: Review and Meta-Analysis, 79 Neurology 1174 (2012).

[6] Shekoufeh Nikfar, Roja Rahimi, Narjes Hendoiee, and Mohammad Abdollahi, “Increasing the risk of spontaneous abortion and major malformations in newborns following use of serotonin reuptake inhibitors during pregnancy: A systematic review and updated meta-analysis,” 20 DARU J. Pharm. Sci. 75 (2012); Roja Rahimi, Shekoufeh Nikfara, Mohammad Abdollahic, “Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials,” 22 Reproductive Toxicol. 571 (2006).

[7] “Q So the question was: Have you read it carefully and do you understand everything that was done in the Nikfar meta-analysis?

A Yes, I think so.

* * *

Q And Nikfar stated that she included studies, correct, in the cardiac malformation meta-analysis?

A That’s what she says.

* * *

Q So if you look at the STATA output, the demonstrative, the — the forest plot, the second study is Kornum 2010. Do you see that?

A Am I —

Q You’re looking at figure four, the cardiac malformations.

A Okay.

Q And Kornum 2010, —

A Yes.

Q — that’s a study you relied upon.

A Mm-hmm.

Q Is that right?

A Yes.

Q And it’s on this forest plot, along with its odds ratio and confidence interval, correct?

A Yeah.

Q And if you look at the last study on the forest plot, it’s the same study, Kornum 2010, same odds ratio and same confidence interval, true?

A You’re right.

Q And to paraphrase My Cousin Vinny, no self-respecting epidemiologist would do a meta-analysis by including the same study twice, correct?

A Well, that was an error. Yeah, you’re right.


Q Instead of putting 2 out of 98, they extracted the data and put 9 out of 28.

A Yeah. You’re right.

Q So there’s a numerical transposition that generated a 25-fold increased risk; is that right?

A You’re correct.

Q And, again, to quote My Cousin Vinny, this is no way to do a meta-analysis, is it?

A You’re right.”

Testimony of Anick Bérard, Kuykendall v. Forest Labs, at 223:14-17; 238:17-20; 239:11-240:10; 245:5-12 (Cole County, Missouri; Nov. 15, 2013). According to a Google Scholar search, the Rahimi 2005 meta-analysis had been cited 90 times; the Nikfar 2012 meta-analysis, 11 times, as recently as this month. See, e.g., Etienne Weisskopf, Celine J. Fischer, Myriam Bickle Graz, Mathilde Morisod Harari, Jean-Francois Tolsa, Olivier Claris, Yvan Vial, Chin B. Eap, Chantal Csajka & Alice Panchaud, “Risk-benefit balance assessment of SSRI antidepressant use during pregnancy and lactation based on best available evidence,” 14 Expert Op. Drug Safety 413 (2015); Kimberly A. Yonkers, Katherine A. Blackwell & Ariadna Forray, “Antidepressant Use in Pregnant and Postpartum Women,” 10 Ann. Rev. Clin. Psychol. 369 (2014); Abbie D. Leino & Vicki L. Ellingrod, “SSRIs in pregnancy: What should you tell your depressed patient?” 12 Current Psychiatry 41 (2013).

[8] Julian Higgins & Sally Green, eds., Cochrane Handbook for Systematic Reviews of Interventions 152 (2008) (“7.2.2 Identifying multiple reports from the same study. Duplicate publication can introduce substantial biases if studies are inadvertently included more than once in a meta-analysis (Tramèr 1997). Duplicate publication can take various forms, ranging from identical manuscripts to reports describing different numbers of participants and different outcomes (von Elm 2004). It can be difficult to detect duplicate publication, and some ‘detectivework’ by the reviewauthors may be required.”); see also id. at 298 (Table 10.1.a “Definitions of some types of reporting biases”); id. at 304-05 ( Duplicate (multiple) publication bias … “The inclusion of duplicated data may therefore lead to overestimation of intervention effects.”); Julian P.T. Higgins, Peter W. Lane, Betsy Anagnostelis, Judith Anzures-Cabrera, Nigel F. Baker, Joseph C. Cappelleri, Scott Haughie, Sally Hollis, Steff C. Lewis, Patrick Moneuse & Anne Whitehead, “A tool to assess the quality of a meta-analysis,” 4 Research Synthesis Methods 351, 363 (2013) (“A common error is to double-count individuals in a meta-analysis.”); Alessandro Liberati, Douglas G. Altman, Jennifer Tetzlaff, Cynthia Mulrow, Peter C. Gøtzsche, John P.A. Ioannidis, Mike Clarke, Devereaux, Jos Kleijnen, and David Moher, “The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration,” 151 Ann. Intern. Med. W-65, W-75 (2009) (“Some studies are published more than once. Duplicate publications may be difficult to ascertain, and their inclusion may introduce bias. We advise authors to describe any steps they used to avoid double counting and piece together data from multiple reports of the same study (e.g., juxtaposing author names, treatment comparisons, sample sizes, or outcomes).”) (internal citations omitted); Erik von Elm, Greta Poglia; Bernhard Walder, and Martin R. Tramèr, “Different patterns of duplicate publication: an analysis of articles used in systematic reviews,” 291 J. Am. Med. Ass’n 974 (2004); John Andy Wood, “Methodology for Dealing With Duplicate Study Effects in a Meta-Analysis,” 11 Organizational Research Methods 79, 79 (2008) (“Dependent studies, duplicate study effects, nonindependent studies, and even covert duplicate publications are all terms that have been used to describe a threat to the validity of the meta-analytic process.”) (internal citations omitted); Martin R. Tramèr, D. John M. Reynolds, R. Andrew Moore, Henry J. McQuay, “Impact of covert duplicate publication on meta­analysis: a case study,” 315 Brit. Med. J. 635 (1997); Beverley J Shea, Jeremy M Grimshaw, George A. Wells, Maarten Boers, Neil Andersson, Candyce Hamel, Ashley C. Porter, Peter Tugwell, David Moher, and Lex M. Bouter, “Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews,” 7(10) BMC Medical Research Methodology 2007 (systematic reviews must inquire whether there was “duplicate study selection and data extraction”).

Beware the Academic-Publishing Complex!

January 11th, 2012

Today’s New York Times contains an important editorial on an attempt by some congressmen to undermine access to federally funded research.  See Michael B. Eisen, “Research Bought, Then Paid ForNew York Times (January 11, 2012).  Eisen’s editorial alerts us to this attempt to undo a federal legal requirement that requires federally funded medical research be made available, for free, on the National Library of Medicine’s Web site (NLM).

As a founder of the Public Library of Science (PLoS), which is committed to promoting and implementing the free distribution of scientific research, Eisen may be regarded as an “interested” ora  biased commentator.  Such a simple-minded ascription of bias would be wrong. The PLoS has become an important distribution source of research results in the world of science, and competes with the publishing oligarchies:  Elsevier, Springer, and others.  The articles of the sort that PLoS makes available for free are sold by publishers for $40 or more.  Subscriptions from these oligarchical sources are often priced in the thousands of dollars per year. Eisen’s simple and unassailable point is that the public, whether the medical profession, patients and citizens, students and teachers, should be able to read about the results of research funded with their tax monies.

“[I]f the taxpayers paid for it, they own.”

The United States government and its employees do not enjoy copyright protections for their creative work (and they do not), neither should their contractors.

Public access is all the more important given that the mainstream media seems so reluctant or unable to cover scientific research in a thoughtful and incisive way.

The Bill goes beyond merely unraveling a requirement of making published papers available free of charge at the NLM.    The language of the Bill, H.R.3699, the Research Works Act, creates a false dichotomy between public and private sector research:


No Federal agency may adopt, implement, maintain, continue, or otherwise engage in any policy, program, or other activity that—

(1) causes, permits, or authorizes network dissemination of any private-sector research work without the prior consent of the publisher of such work … .”

Work that is conducted in private or in state universities, but funded by the federal taxpayers, cannot be said to be “private” in any meaningful sense.  The public’s access to this research, as well as its underlying data, is especially important when the subject matter of the research involves issues that are material to public policy and litigation disputes.

Who is behind this bailout for the private-sector publishing industry?  Congressman Darrell Issa (California) introduced the Bill, on December 16, 2011.  The Bill was cosponsored by Congresswoman Carolyn B. Maloney, the Democratic representative of New York’s 14th district.  Oh Lord, Congresswoman Maloney represents me!  NOT.  How humiliating to be associated with this regressive measure.

This heavy-handed piece of legislation was referred to the House Committee on Oversight and Government Reform.  Let us hope it dies a quick death in committee.  See Michael Eisen, “Elsevier-funded NY Congresswoman Carolyn Maloney Wants to Deny Americans Access to Taxpayer Funded Research” (Jan. 5, 2012).

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.  SeeA 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.


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.


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.


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.”)


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.