Philippus Aureolus Theophrastus Bombastus von Hohenheim thankfully went by the simple moniker Paracelsus, sort of the Cher of the 1500s. Paracelsus’ astrological research is graciously overlooked today, but his 16th century dictum, in the German vernacular has created a lasting impression on linguistic conventions and toxicology:
“Alle Ding’ sind Gift, und nichts ohn’ Gift; allein die Dosis macht, dass ein Ding kein Gift ist.”
(All things are poison and nothing is without poison, only the dose permits something not to be poisonous.)
or more simply
“Die Dosis macht das Gift.”
Paracelsus, “Die dritte Defension wegen des Schreibens der neuen Rezepte,” Septem Defensiones (1538), in 2 Werke 510 (Darmstadt 1965). Today, his notion that the “dose is the poison” is a basic principle of modern toxicology, which can be found in virtually every textbook on the subject.
Paracelsus’ dictum has also permeated the juridical world, and become a commonplace in legal commentary and judicial decisions. The Reference Manual on Scientific Evidence is replete with supportive statements on the general acceptance of Paracelsus’ dictum. The chapter on epidemiology notes:
“The idea that the ‘dose makes the poison’ is a central tenet of toxicology and attributed to Paracelsus, in the sixteenth century… [T]his dictum reflects only the idea that there is a safe dose below which an agent does not cause any toxic effect.”
Michael D. Green, D. Michal Freedman, and Leon Gordis, “Reference Guide on Epidemiology,” 549, 603 & n.160, in Reference Manual on Scientific Evidence (3d ed. 2011). Citing an unpublished, non-scientific advocacy piece written for a regulatory agency, the chapter does, however, claim that “[t]he question whether there is a no-effect threshold dose is a controversial one in a variety of toxic substances areas.” The epidemiology chapter thus appears to confuse two logically distinct propositions: that there is no threshold dose and that there is no demonstrated threshold dose.
The Reference Manual’s chapter on toxicology also weighs in on Paracelsus:
“There are three central tenets of toxicology. First, “the dose makes the poison”; this implies that all chemical agents are intrinsically hazardous—whether they cause harm is only a question of dose. Even water, if consumed in large quantities, can be toxic.”
Bernard D. Goldstein & Mary Sue Henifin, “Reference Guide on Toxicology,” 633, 636, in Reference Manual on Scientific Evidence (3d ed. 2011) (internal citations omitted).
Recently, Judge Richard Mark Gergel had the opportunity to explore the relevance of dose-response to plaintiffs’ claims that atorvastatin causes diabetes. In re Lipitor (Atorvastatin Calcium) Marketing, Sales Practices & Prod. Liab. Litig., MDL No. 2:14–mn–02502–RMG, Case Mgmt. Order 49, 2015 WL 6941132 (D.S.C. Oct. 22, 2015) [Lipitor]. Plaintiffs’ expert witnesses insisted that they could disregard dose once they had concluded that there was a causal association between atorvastatin at some dose and diabetes. On Rule 702 challenges to plaintiffs’ expert witnesses, the court held that, when there is a dose-response relationship and there is an absence of association at low doses, then plaintiffs must show, through expert witness testimony, that the medication is capable of causing the alleged harm at particular doses. The court permitted the plaintiffs’ expert witnesses to submit supplemental reports to address the dose issue, and the defendants to relodge their Rule 702 challenge after discovery on the new reports. Lipitor at *6.
The Lipitor court’s holding built on the ruling by Judge Breyer’s treatment of dose in In re Bextra & Celebrex Mktg. Sales Practices & Prod. Liab. Litig., 524 F. Supp. 2d 1166, 1174-75 (N.D. Cal.2007). Judge Breyer, Justice Breyer’s kid brother, denied defendants’ Rule 702 challenges to plaintiffs’ expert witnesses who opined that Bextra and Celebrex can cause heart attacks and strokes, at 400 mg./day. For plaintiffs who ingested 200 mg/day, however, Judge Breyer held that the lower dose had to be analyzed separately, and he granted the motions to exclude plaintiffs’ expert witnesses’ opinions about the alleged harms caused by the lower dose. Lipitor at *1-2. The plaintiffs’ expert witnesses reached their causation opinions about 200 mg by cherry picking from the observational studies, and disregarding the randomized trials and meta-analyses of observational studies that failed to find an association between 200 mg/day and cardiovascular risk. Id. at *2. Given the lack of support for an association at 200mg/day, the court rejected the plaintiffs’ speculative downward extrapolation asserted.
Because of dose-response gradients, and the potential for a threshold, a risk estimate based upon greater doses or exposure does not apply to a person exposed at lower doses or exposure levels. See Michael D. Green, D. Michal Freedman, and Leon Gordis, “Reference Guide on Epidemiology,” 549, 613, in Reference Manual on Scientific Evidence (3d ed. 2011) (“[A] risk estimate from a study that involved a greater exposure is not applicable to an individual exposed to a lower dose.”).
In the Lipitor case, as in the Celebrex case, multiple studies reported no statistically significant associations between the lower doses and the claimed adverse outcome. This absence, combined with a putative dose-response relationship, made plaintiffs’ downward extrapolation impermissibly speculative. See, e.g., McClain v. Metabolife Int’l, Inc., 401 F.3d 1233, 1241 (11th Cir. 2005) (reversing admission of expert witness’s testimony when the witness conceded a dose-response, but failed to address the dose of the medication needed to cause the claimed harm).
Courts sometimes confuse thresholds with dose-response relationships. The concepts are logically independent. There can be a dose-response relationship with or without a threshold. And there can be an absence of a dose-response relationship with a threshold, as in cases in which the effect is binary: positive at or above some threshold level, and negative below. A causal claim can run go awry because it ignores the possible existence of a threshold, or the existence of a dose-response relationship. The latter error is commonplace in litigation and regulatory contexts, when science or legal advocates attempt to evaluate risk using data that are based upon higher exposures or doses. The late Irving Selikoff, no stranger to exaggerated claims, warned against this basic error, when he wrote that his asbestos insulator cancer data were inapposite for describing risks of other tradesmen:
“These particular figures apply to the particular groups of asbestos workers in this study. The net synergistic effect would not have been the same if their smoking habits had been different; and it probably would have been different if their lapsed time from first exposure to asbestos dust had been different or if the amount of asbestos dust they had inhaled had been different.”
E.. Cuyler Hammond, Irving J. Selikoff, and Herbert Seidman, “Asbestos Exposure, Cigarette Smoking and Death Rates,” 330 Ann. N.Y. Acad. Sci. 473, 487 (1979). Given that the dose-response between asbestos exposure and disease outcomes was an important tenant of the Selikoff’s work, it is demonstrable incorrect for expert witnesses to invoke relative risks for heavily exposed asbestos insulators and apply them to less exposed workers, as though the risks were the same and there are no thresholds.
The legal insufficiency of equating high and low dose risk assessments has been noted by many courts. In Texas Independent Ginners Ass’n v. Marshall, 630 F.2d 398 (5th Cir. 1980), the Circuit reviewed an OSHA regulation promulgated to protect cotton gin operators from the dangers of byssinosis. OSHA based its risk assessments on cotton dust exposures experienced by workers in the fabric manufacturing industry, but the group of workers to be regulated had intermittent exposures, at different levels, from that of the workers in the relied upon studies. Because of the exposure level disconnect, the Court of Appeals struck the OSHA regulation. Id. at 409. OSHA’s extrapolation from high to low doses was based upon an assumption, not evidence, and the regulation could not survive the deferential standard required for judicial review of federal agency action. Id.
The fallacy of “extrapolation down” often turns on the glib assumption that an individual claimant must have experienced a “causative exposure” because he has the disease that can result at some, higher level of exposure. In reasoning backwards from untoward outcome to sufficient dose, when dose is at issue, is a petitio principii, as recognized by several astute judges:
“The fallacy of the ‘extrapolation down’ argument is plainly illustrated by common sense and common experience. Large amounts of alcohol can intoxicate, larger amounts can kill; a very small amount, however, can do neither. Large amounts of nitroglycerine or arsenic can injure, larger amounts can kill; small amounts, however, are medicinal. Great volumes of water may be harmful, greater volumes or an extended absence of water can be lethal; moderate amounts of water, however, are healthful. In short, the poison is in the dose.”
In re Toxic Substances Cases, No. A.D. 03-319.No. GD 02-018135, 05-010028, 05-004662, 04-010451, 2006 WL 2404008, at *6-7 (Alleghany Cty. Ct. C.P. Aug. 17, 2006) (Colville, J.) (“Drs. Maddox and Laman attempt to “extrapolate down,” reasoning that if high dose exposure is bad for you, then surely low dose exposure (indeed, no matter how low) must still be bad for you.”)(“simple logical error”), rev’d sub nom. Betz v. Pneumo Abex LLC, 998 A.2d 962 (Pa. Super. 2010), rev’d 615 Pa. 504, 44 A.3d 27 (2012).
An obvious corollary of the fallacy of downward extrapolation is that claimants must have a reasonable estimate of their dose or exposure in order to place themselves on the dose-response curve, to estimate in turn what their level of risk was before they developed the claimed harm. For example, in Mateer v. U.S. Aluminum Co., 1989 U.S. Dist. LEXIS 6323 (E.D. Pa. 1989), the court, applying Pennsylvania law, dismissed plaintiffs’ claim for personal injuries in a ground-water contamination case. Although the plaintiffs had proffered sufficient evidence of contamination, their expert witnesses failed to quantify the plaintiffs’ actual exposures. Without an estimate of the claimants’ actual exposure, the challenged expert witnesses could not give reliable, reasonably based opinions and conclusions whether plaintiffs were injured from the alleged exposures. Id. at *9-11.
Science and law are sympatico; dose or exposure matters, in pharmaceutical, occupational, and environmental cases.
 Joseph F. Borzelleca, “Paracelsus: Herald of Modern Toxicology,” 53 Toxicol. Sci. 2 (2000); David L. Eaton, “Scientific Judgment and Toxic Torts – A Primer in Toxicology for Judges and Lawyers,” 12 J.L. & Pol’y 5, 15 (2003); Ellen K. Silbergeld, “The Role of Toxicology in Causation: A Scientific Perspective,” 1 Cts. Health Sci. & L. 374, 378 (1991). Of course, the claims of endocrine disruption have challenged the generally accepted principle. See, e.g., Dan Fagin, “Toxicology: The learning curve,” Nature (24 October 2012) (misrepresenting Paracelsus’ dictum as meaning that dose responses will be predictably linear).
 See, e.g., Curtis D. Klaassen, “Principles of Toxicology and Treatment of Poisoning,” in Goodman and Gilman’s The Pharmacological Basis of Therapeutics 1739 (11th ed. 2008); Michael A Gallo, “History and Scope of Toxicology,” in Curtis D. Klaassen, ed., Casarett and Doull’s Toxicology: The Basic Science of Poisons 1, 4–5 (7th ed. 2008).
 Michael D. Green, D. Michal Freedman, and Leon Gordis, “Reference Guide on Epidemiology,” 549, 603 & n.160, in Reference Manual on Scientific Evidence (3d ed. 2011) (Irving J. Selikoff, Disability Compensation for Asbestos-Associated Disease in the United States: Report to the U.S. Department of Labor 181–220 (1981). The chapter also cites two judicial decisions that clearly were influenced by advocacy science and regulatory assumptions. Ferebee v. Chevron Chemical Co., 736 F.2d 1529, 1536 (D.C. Cir. 1984) (commenting that low exposure effects are “one of the most sharply contested questions currently being debated in the medical community”); In re TMI Litig. Consol. Proc., 927 F. Supp. 834, 844–45 (M.D. Pa. 1996) (considering extrapolations from high radiation exposure to low exposure for inferences of causality).
 See also United States v. Reserve Mining Co., 380 F. Supp. 11, 52-53 (D. Minn. 1974) (questioning the appropriateness of comparing community asbestos exposures to occupational and industrial exposures). Risk assessment modesty was uncharacteristic of Irving Selikoff, who used insulator risk figures, which were biased high, to issue risk projections for total predicted asbestos-related mortality.
 See also In re “Agent Orange” Prod. Liab. Litig., 611 F. Supp. 1223, 1250 (E.D.N.Y. 1985), aff’d, 818 F.2d 187 (2d Cir. 1987), cert. denied, Pinkney v. Dow Chemical Co., 487 U.S. 1234 (1988) (noting that the plaintiffs’ expert witnesses relied upon studies that involved heavier exposures than those experienced by plaintiffs; the failure to address the claimants’ actual exposures rendered the witnesses’ proposed testimony legally irrelevant); Gulf South Insulation v. United States Consumer Products Safety Comm’n, 701 F.2d 1137, 1148 (5th Cir. 1983) (invalidating CPSC’s regulatory ban on urea formaldehyde foam insulation, as not supported by substantial evidence, when the agency based its ban upon high-exposure level studies and failed to quantify putative risks at actual exposure levels; criticizing extrapolations from high to low doses); Graham v. Wyeth Laboratories, 906 F.2d 1399, 1415 (10th Cir.) (holding that trial court abused its discretion in failing to grant new trial upon a later-discovered finding that plaintiff’s expert misstated the level of toxicity of defendant’s DTP vaccine by an order of magnitude), cert. denied, 111 S.Ct. 511 (1990).
Two dubious decisions that fail to acknowledge the fallacy of extrapolating down from high-exposure risk data have come out of the Fourth Circuit. See City of Greenville v. W.R. Grace & Co., 827 F.2d 975 (4th Cir. 1987) (affirming judgment based upon expert testimony that identified risk at low levels of asbestos exposure based upon studies at high levels of exposure); Smith v. Wyeth-Ayerst Labs Co., 278 F. Supp. 2d 684, 695 (W.D.N.C. 2003)(suggesting that expert witnesses may extrapolate down to lower doses, and even to extrapolate to different time window of latency).
 See also Christophersen v. Allied-Signal Corp., 939 F.2d 1106, 1111, 1113-14 (5th Cir. 1991) (en banc) (per curiam) (trial court may exclude opinion of expert witness whose opinion is based upon incomplete or inaccurate exposure data), cert. denied, 112 S. Ct. 1280 (1992); Wills v. Amareda Hess Co., 2002 WL 140542, *10 (S.D.N.Y. Jan. 31, 2002) (noting that the plaintiff’s expert witness failed to quantify the decedent’s exposure, but was nevertheless “ready to form a conclusion first, without any basis, and then try to justify it” by claiming that the decedent’s development of cancer was itself sufficient evidence that he had had intensive exposure to the alleged carcinogen).