The emerging battlefield: should the use of a nonmonotonic, non-threshold dose-response curve for alleged endocrine-disrupting chemicals survive a Daubert/Frye challenge?

• Author: Surprenant, Mark C.

IN Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses, (1) the authors contend that the toxicological significance of alleged endocrine-disrupting chemicals ("EDCs") cannot be assessed using the traditional monotonic threshold dose-response curve. In contrast, they suggest that EDCs can cause adverse human biological effects at low, regulatory-approved dose levels. Although this article only focuses on biological effects per se and not on whether the effect is adverse or not, they contend that it is improper to extrapolate that harmful effects cannot occur at environmentally relevant, regulatory-approved low-dose levels just because no effects are seen at the much higher regulatory-accepted no observable adverse effect level (NOAEL).

Plaintiffs' attorneys and their retained experts will point to the Vandenberg paper in support of the position that the EDC at issue proximately caused their plaintiff's cancer, reproductive or developmental problem, even when the plaintiff only was exposed to the alleged EDC at the regulatory-approved safe level. Through a weight-of-the-evidence methodology, plaintiffs' experts may attempt to use some sort of nonmonotonic, non-threshold dose-response curve to opine that the health condition at issue generally and specifically was caused by exposure to very low doses of the alleged EDC at regulatory approved levels. Accordingly, defendants must mount a convincing Daubert/Frye argument to defeat this theory.

This article demonstrates how-to construct a successful Daubert/Frye challenge against an expert's attempted use of a nonmonotonic, non-threshold dose-response curve to support an adverse causation opinion about an alleged EDC.

1. Dose-Response Curves

   There are three dose-response curves that come into play in any personal injury environmental toxic tort case. First, the traditional monotonic, nonlinear threshold dose-response curve provides that the dose has to reach a recognized threshold level before the chemical likely will have any adverse human health consequences. Once the chemical exerts an adverse effect, the adverse effect will continue to worsen as the dose increases. The generally recognized phrase "the dose makes the poison" is associated with a monotonic, nonlinear dose-response curve.

   Second, the monotonic, linear non-threshold dose-response curve states that a chemical can have an adverse human health effect at any dose level. Thus, there is no safe dose level and no threshold dose level. As such, exposure to even one molecule of the chemical at issue puts an individual at risk for the development of an adverse health condition. This concept is referred to as the "one hit theory" because allegedly just one dose of the chemical at any level can start the disease process.

   Third, the nonmonotonic, non-threshold dose-response curve, suggested by the Vandenberg article as being particularly applicable to EDCs, provides that a chemical can have effects at regulatory approved low dose levels; have no effects at moderately higher dose levels and have effects at the highest dose levels. A nonmonotonic, non-threshold dose-response curve is described as either Ushaped or inverted U-shaped.

   Allowing a plaintiff's expert to opine that the chemical on trial should be analyzed through the use of a nonmonotonic, non-threshold dose-response curve would present significant problems for a defendant. Specifically, the defendant's assertion of the common regulatory compliance defense that the plaintiffs dose level never exceeded the applicable regulatory-acceptable safe dose level would be seriously questioned and could be disregarded completely by the fact finder. Moreover, the plaintiff would be able to raise a significant question in the jurors' minds as to whether the defendant was negligent for only testing the alleged EDC at regulatory-accepted high levels instead of also including in its test protocol environmentally relevant low dose levels.

2. Ongoing Scientific Debate

   There is an ongoing scientific debate over whether regulatory-approved, environmentally relevant low dose levels of alleged EDCs can cause adverse human health effects. The National Toxicology Program (NTP) and the United States EPA have been studying the issue, but have reached no definitive conclusion about any alleged EDC from a human health standpoint. As observed by the EPA:

   In recent years, some scientists have proposed that chemicals might inadvertently be disrupting the endocrine system of humans and wildlife.... However, the relationship of human diseases of the endocrine system and exposure to environmental contaminants is poorly understood and scientifically controversial .... The science related to measuring and demonstrating endocrine disruption is in its infancy, so validated methods of testing that indicate specific effects of an endocrine disruptor are still being developed.... While EPA has some data on endocrine-disrupting pesticides, currently insufficient scientific data are available on most of the estimated 87,000 chemicals produced today to allow for an evaluation of endocrine associated risks. (2) Neither the EPA nor any state regulatory body has implemented any risk assessment program using anything other than the traditionally recognized monotonic, nonlinear threshold dose-response curve. Although there are some studies, discussed in the Vandenberg article, arguably supporting the use of a nonmonotonic, non-threshold dose-response curve for some specifically alleged EDCs, the scientific validity of those studies has been questioned by independent bodies such as the EPA for a variety of reasons, including lack of replication. The theory that an alleged EDC causes adverse human health effects at dose levels approved by the EPA is an unproven hypothesis at best.

   Cognizant of the ongoing scientific debate regarding EDCs and potential adverse human low dose effects, Vandenberg et al. stress the use of a weight-of-the-evidence methodology in support of their position that a nonmonotonic, non-threshold dose-response curve should be applicable to alleged EDCs. In employing such a methodology, the authors severely discount study results that do not support their EDC low dose hypothesis. If confronted by any of the authors in any litigation setting, it will be critical to demonstrate that the exclusion of their discounted studies is scientifically unfounded and largely activist-generated.

3. Daubert Analysis

   We know of no reported decision by any Daubert court examining an expert's attempted use of a nonmonotonic, non-threshold dose-response curve in the context of any chemical. Therefore, it is important to review how Daubert courts have responded when a plaintiffs expert has attempted to use a monotonic, non-threshold dose-response curve to support an opinion that the adverse health condition at issue was caused by the chemical on trial.

   Courts predominantly have encountered the monotonic, non-threshold dose response curve in cases involving exposure to benzene, radiation, chemicals consumed through food and drugs, chemical vapors, chemical mixtures and asbestos. The rationale behind the monotonic, non-threshold theory, as alleged in a typical cancer case, is that "exposure to one molecule of a cancer-causing agent has some finite possibility of causing a genetic mutation leading to cancer." (3) The majority of courts have rejected the monotonic, non-threshold dose response theory, requiring a plaintiff's expert instead to utilize the traditional threshold dose response concept to establish causation. (4)

   In Whiting v. Boston Edison Co., (5) the decedent's estate alleged that the decedent had contracted acute lymphocytic leukemia while exposed to ionizing radiation at the defendant's nuclear power station. An expert testifying on behalf of the plaintiffs relied on the non-threshold dose-response model to establish that the decedent's 5 to 10 rem dose of radiation contributed to his development of leukemia. (6) The court ruled that the non-threshold dose model was unreliable under Daubert and contrary to the report issued by the National Research Council of the National Academy of Sciences Committee on the Biological Effects of Ionizing Radiation ("BEIR V"), which found no increased risk of cancer in populations chronically exposed to elevated levels of natural background radiation. (7) In excluding the plaintiff's expert from testifying, the court criticized the non-threshold dose model as follows:

   It fails all of the Daubert reliability factors. The linear non-threshold model cannot be falsified, nor can it be validated. To the extent that it has been subjected to peer review and publication, it has been rejected by the overwhelming majority of the scientific community. It has no known or potential rate of error. It is merely a hypothesis. In sum, it has no capacity to be of assistance to a jury in resolving the ultimate issues in this case. (8) In McClain v. Metabolife International, Inc., (9) plaintiffs alleged that they suffered strokes and heart attacks from consuming Metabolife 356, an herbal appetite suppressant containing ephedrine and caffeine. Although a jury returned a verdict in plaintiffs' favor, the Eleventh Circuit reversed because the expert testimony was unreliable under Daubert. (10) Specifically, the plaintiffs failed to establish general causation because they offered no expert testimony concerning the dose-response levels for Metabolife's toxicity. (11) Although one expert opined that any dose of Metabolife would cause harm, the Eleventh Circuit rejected that expert's opinion because it violated the "essential principles of toxicology." (12) In quoting toxicologist Dr. Eaton, the court noted that "[d]ose is the single most important factor to consider in evaluating whether an alleged exposure caused a specific adverse effect," and that "low dose exposures--even for many years--will have no consequence at all, since...