Endocrine Disrupters: The Potential Cloud of Manufacturer Toxic Tort Liability

May 24, 03:41 AM

Current Headlines: By Berger, Bruce J; Junk, Michael L

THE PUBLICATION of Our Stolen Future" in 1996 created a firestorm of publicity and public anguish concerning the possibility that tiny amounts of some widely-used chemicals - characterized as "endocrine disrupters" ("EDs") - might be causing a variety of adverse human health effects. Congress took action at that time, directing EPA to commission scientific studies of such low-level effects.2 The government-funded and governmentconducted research has ground along and, if anything, seems to be accelerating. Yet today, ten years into the EPA scientific program on EDs, answers remain elusive. Although public anxiety about EDs has largely abated, numerous sources continue to report on the myriad human health and environmental effects possibly attributable to EDs.

As recently as September, 2006, for instance, the front page of The Washington Post carried an article that reported widespread ED pollution in the Potomac River. The article characterized EDs as "pollution that drives hormone systems haywire," and speculated that EDs may be causing male large- and small-mouth bass in the river to develop immature eggs inside their sex organs:

The cause of the abnormalities is unknown, but scientists suspect a class of waterborne contaminants that can confuse animals' growth and reproductive systems. These pollutants are poorly understood, however, leaving many observers with questions about what the problems in fish mean for the Potomac and the millions of people who take their tap water from it.3

The tone of the article is typical of the numerous publications about EDs: On one hand, the article readily concedes that little is understood about the human health effects associated with exposure to EDs; nonetheless, an unmistakable alarm is sounded.

Interestingly, the speculation and uncertainty surrounding EDs is not constrained to purely new chemical inventions. Many will recall that the makers of DES were plunged into litigation over claims that its use by pregnant mothers caused birth defects. Today, DES is alleged to be an ED with other possible health implications. On October 17, 2006, the Reuters Health Information service reported that "fw]omen who were exposed to diethylstilbestrol (DES) in utero tend to go through menopause at a younger age than non-exposed women," an important finding since, according to the article, young age at menopause is associated with heart disease, osteoporosis, and breast and endometrial cancer. The short article concluded with a quote from one of the study's authors, stating that "there could be some health implications for the DES exposed," even though the results of the study showed a very small difference in age of menopause in the exposed versus the unexposed groups.4

Growing concerns about the identity, location, and possible effects of EDs are manifest in today's toxic tort and products liability landscape.5 On November 17, 2006, for example, the online Insurance Journal reported on DuPont's expanding studies (and potential liabilities) concerning the largely unknown health effects associated with PFOA, a chemical - and a suspected ED - used in the manufacture of Teflon-coated, non-stick housewares. As part of its settlement with West Virginia and Ohio residents who claimed personal injuries associated with their exposure to PFOA contaminated in groundwater, DuPont agreed to sponsor nine studies to be performed by a panel of independent scientists. Those studies contemplate health screenings of approximately 70,000 residents in two states, and at this time are projected to take an estimated three to six years to complete. The panelists are now urging that a tenth study be performed and funded by DuPont. Depending upon the outcome of the studies - which "will look at possible links between [PFOA] and heart disease, stroke, diabetes and other disorders" - DuPont could be required to spend an additional $235 million to monitor the health of the residents allegedly exposed to EDs.6

It is clear that the ongoing research and speculation about an ever-growing list of potential EDs casts a cloud of potential toxic tort liability for manufacturers of EDs and the numerous, everyday products incorporating them. And while some suspected EDs are relatively new chemicals borne out of modern scientific advances, ED theories give rise to new toxic tort claims and potential liabilities with older chemicals, such as DES.

This article briefly reviews the concept of endocrine disrupters and then describes the findings and the faults of some medical and scientific arguments and studies that future product liability and environmental tort claimants are likely to utilize.

Endocrine Disrupter Theory

Essentially, endocrines are chemicals (commonly known as hormones) secreted by various bodily organs such as the ovaries, the testes, the adrenal gland, or the pituitary gland. Endocrines serve as messengers to other cells throughout the body when they attach to receptors on the surface of such cells. EDs are chemicals that interfere with, i.e., "disrupt," the normal signaling of the endogenous hormones at these receptors. For example, by occupying the receptor itself, the ED might block the body's own hormone (e.g. estrogen or androgen) and prevent the physiologically "correct" response of the target cell. Similarly, by occupying the receptor an ED might cause the cell to overreact (or underreact) and create more (or less) of an effect on bodily function than would the body's own chemical. Thus, an ED is simply any chemical that, at low levels, can act at endocrine, androgen, or steroid receptors and cause toxic effects.7

The chemicals that are now alleged to be endocrine disrupters are numerous and include: diethylstilbestrol ("DES"), bisphenol-A ("BPA") (a building block of polycarbonate plastic typically found in baby bottles, compact discs, computer parts, dental sealants, eyeglasses, and food containers), poly chlorinated biphenyls ("PCBs"), polyfluorinated octanoic acid ("PFOA") (an ingredient used in the manufacture of some non-stick coatings), brominated flame retardants (PDBEs) (commonly used in many consumer products such as Styrofoam, carpets, office equipment), dioxin, and foods containing high soy proteins and isoflavones.8

Like so many indispensable chemicals that have found wide usage in all manner of products, potential EDs are everywhere, including in our bodies. The Natural Resources Defense Council's advice on how to reduce one's risk of exposure to EDs speaks volumes about the prevalence of EDs in modern society. That advice consists of the following:

* Educate yourself about endocrine disrupters, and educate your family and friends.

* Buy organic food whenever possible.

* Avoid using pesticides in your home or yard, or on your pet - use baits or traps instead, keepin[g] your home especially clean to prevent ant or roach infestations.

* Find out if pesticides are used in your child's school or day care center and campaign for non-toxic alternatives.

* Avoid fatty foods such as cheese and meat whenever possible.

* If you eat fish from lakes, rivers, or bays, check with your state to see if they are contaminated.

* Avoid heating food in plastic containers, or storing fatty foods in plastic containers or plastic wrap.

* Do not give young children soft plastic teethers or toys, since these leach potential endocrine disrupting chemicals.

* Support efforts to get strong government regulation of and increased research on endocrine disrupting chemicals.9

But following the NRDC's advice simply may not be enough to avoid exposure to suspected EDs. Indeed, given rapid developments in analytical chemistry that allow scientists to find low levels of chemicals in blood and urine, it is now known that many potential EDs are found generally in the population at median levels of about 1 part per billion (ppb).10 In effect, everyone is exposed, and, if such low levels of EDs actually cause harm, everyone is potentially at some level of risk.

Studies of Possible Human Health & Environmental Effects Attributable to EDs

According to Our Stolen Future, "the most dramatic and troubling sign that hormone disrupters may already have taken a major toll comes from reports that human male sperm counts have plummeted over the past half century" and that "Danish researchers found that the average male sperm count has dropped forty-five (45) percent from 1940 to 1990." In the years since Our Stolen Future was first published, numerous other "signs" of the possible illeffects of EDs have been identified. In 2006, R. Hauser reported on a possible connection between exposure to widelyused industrial chemicals and "altered semen quality,"11 providing further possible support for the theory that exposure to EDs adversely affects the human reproductive system. D-H Lee published a study in 2006 reporting a statistically significant association between exposure to six "persistent organic pollutants" and type II diabetes, a common medical condition generally thought to be associated with hereditary factors and poor dietary habits.12 Another 2006 study found that adults working in rooms with ED-containing plastic walling materials are more than twice aslikely to develop asthma. The authors also found that the risk of asthma was higher for people working in settings with wall-to-wall carpeting, especially in the presence of mold.1 Zhang published a study in 2004 in the American Journal of Epidemiology on EDs and the risk of breast cancer.14 The authors reported a higher risk of breast cancer in women with a particular genetic variant having higher blood levels of PCBs. For such women, increased levels of PCBs resulted in a statistically-significant Odds Ratio of 4.2, i.e., suggesting that exposure to PCBs may have increased the risk of breast cancer by a factor of four. Yang, et al., published the abstract of a case-control study in 2005 of girls who experienced early puberty.15 They reported a statistically- significant increase in this condition among girls with higher levels of BPA in their urine than in girls with lower levels of BPA.16

Because of Congressional directives and EPA's intense interest in the area, it should not be surprising that research concerning ED toxicology remains alive and vibrant. Since January, 2004, more than 100 articles involving endocrine disruption have been published in the medical and scientific literature.17 The 46th Annual Meeting of the Society of Toxicology in March, 2007 featured one symposium ("Hormones, the Environment and Cancer") and two workshop sessions on EDs ("Environmental Influences on the Ovary and Hypothalamic Pituitary Gonadal Axis" and "Thyroid Hormone Disruption: From Kinetics to Dynamics").18 Many of the studies today are actually performed by the EPA itself, in conjunction with its Office of Research and Development ("ORD").19 Echoing results presented by Yang,20 the ORD's Suzanne Fenton21 points to "precocious puberty," defined as the onset of puberty before the age of eight years, which according to various statistics has increased four-fold in the United States from 1969 to the 1990s.22 According to Fenton, precocious puberty in girls results in a prolonged developmental stage, which in turn subjects the precocious girls to an increased risk of cancer. The EPA also now attributes "decreases in IQ tests and increases in aggression in children" with exposure to EDs, as well as "severe malformations of the genitals of boys [which] have increased steadily over the last two decades and fertility [which] has decreased in young males."23

In addition to potential problems related to human health, research currently suggests that EDs have environmental impacts as well. According to the EPA, "evidence is continuing to mount that wildlife [as well as humans] may be at risk from exposure to chemicals operating through an endocrine mediated pathway."24 In fact, the EPA believes that "[w]ildlife effects have been more thoroughly documented [than human effects]," and that "[abnormalities in birds, marine mammals, fish, amphibians, alligators, and shellfish have been documented [and] linked to specific chemical exposures."25 In short, EPA policy statements essentially take the view that the same effects attributed to DDT when Rachel Carson published Silent Spring are now due to potentially hundreds of other chemicals dispersed at minuscule levels in the environment.

EPA has failed to spell out how it has managed to attribute specific effects to "specific chemical exposures" and which effects it attributes to which exposures. Nonetheless, human health and environmental effects attributed to suspected EDs may direct future agency action to restrict or eliminate certain widelyused chemicals. Although many chemicals presently in mass production have been deemed EDs, the likelihood is that scores more will be added to the list in the coming years. Congress directed EPA to develop a screening program that could potentially reach any chemical to which a "substantial population" may be exposed.26 EPA regards its screening program to identify EDs as part of its formal agenda "necessary to protect public health and the environment."27 The screening program eventually will be a high-velocity system running hundreds of chemicals in short term tests.28 Although EPA guidance offers a caveat that a positive result in any of the screening programs will not mean that the subject chemical is in fact an ED - and that the screening will only lead to more sophisticated testing - it is likely that public opinion and the fear of liability may create intense pressure for companies using such chemicals to find alternatives quickly.

It is equally likely that manufacturers and users of suspected EDs and the products containing them will confront toxic tort and products liability litigation as the science continues to mature. Scientists will continue by using multiple linear and logistic regression to find or attempt to find correlations between levels of particular chemicals in various bodily organs or substances (placental blood, breast milk, urine, etc.) and adverse effects. At the standard level of statistical significance (p < 0.05), one out of every twenty studies would be expected to show a correlation even if no such correlation truly exists. With implications as broad as breast and prostate cancer, neurotoxicity, precocious puberty, and given the voracious appetite of plaintiffs' attorneys for new substances upon which to frame essentially the same kinds of personal injury and class action law suits that they have pursued for decades with respect to substances as diverse as asbestos, benzene, and prescription drugs, it seems only a matter of time before "endocrine disrupter" litigation joins the list.

Toxic Tort and Products Liability Litigation Implications and Strategies

Future toxic tort cases will be fought primarily on the battlefield of medical causation. In all federal courts and in most state courts, proponents of expert testimony bear the burden of establishing that the opinions they offer are scientifically reliable and based upon scientifically-relevant evidence.29 And, in other states, the general acceptance test of Frye v. United States thrives.30 These rubrics provide the bases for a multifaceted attack in an effort to exclude testimony that EDs can or did cause the alleged harm about which a plaintiff complains.

Causation: Product ID Perspective.

Product identification will be a key litigation hurdle for plaintiffs and their experts. It is now axiomatic that a toxic tort or products liability plaintiff bears the burden of proving that the named defendant or its product is responsible for the plaintiff's alleged harm. Yet, given the multiplicity of sources of EDs into the environment, plaintiffs and even their experts may have tremendous difficulty tracing the chemicals that allegedly caused them harm to a specific source, process, product or potential defendant.32

Causation: Medical and Scientific Perspective

Even where a defendant has been identified as the source of the ED that has allegedly caused the plaintiffs harm, a defendant may still successfully defend allegations against it by showing that the plaintiff's expert's general and specific causation opinions are unfounded and inadmissible. As to general causation (i.e., whether the substance at issue can cause the specific human health problem at issue), human studies can be attacked by epidemiologists, among other reasons, as not properly controlling for confounding factors, which arguably supply alternative explanations for any associations identified in the studies. The Reference Manual on Scientific Evidence succinctly explains the importance of confounding factors:

Even when an association exists, researchers must determine whether the exposure causes the disease or whether the exposure and disease are caused by some other confounding factor. A confounding factor is both a risk factor for the disease and a factor associated with the exposure of interest. For example, researchers may conduct a study that finds individuals with gray hair have a higher rate of death than those with hair of another color. Instead of hair color having an impact on death, the results might be explained by the confounding factor of age. If old age is associated differentially with the gray-haired group (those with gray hair tend to be older), old age may be responsible for the association found between hair color and death. Researchers must separate the relationship between gray hair and risk of death from that of old age and risk of death. When researchers find an association between an agent and a disease, it is critical to determine whether the association is causal or the result of confounding. Some epidemiologists classify confounding as a form of bias. However, confounding is a reality - that is, the observed association of a factor and a disease is actually the result of an association with a third, confounding factor. Failure to recognize confounding can introduce a bias - error - into the findings of the study.33

Likewise, an expert's reliance upon animal studies can be undermined by the testimony of lexicologists and others who can explain the difficulty - if not the impossibility - of extrapolating from the results of animal studies to predict health effects in humans. Indeed, much animal research concerning EDs has been published in the last few years, and there are now scores of animal studies that purport to show adverse effects from exposure to low levels of EDs. A recent review claims that there are at least ninety- four such studies showing positive effects.34 Although many cases reject reliance upon animal studies because they use doses hundreds or thousands of times higher than those to which human beings are exposed, ED advocates contend that the studies they rely upon utilize doses comparable to those observed in humans. Even so, cases are legion in which courts exclude animal studies and an expert's reliance upon them when the results of those studies have not been corroborated in human beings, because the physiological \differences between species are great and the experts relying upon such evidence cannot effectively connect the animal study to the human health event in issue.

For example, in Soldo v. Sandoz Pharmaceuticals Corporation,35 the plaintiffs alleged that the drug Parlodel had caused the plaintiff to have an intracerebral hemorrhage ("ICH"). The court excluded such testimony as not scientifically reliable, rejecting the opinions of plaintiffs' experts based, in part, on animal studies. Specifically, a study allegedly showing that bromocriptine, the active ingredient of Parlodel, caused constriction in the hind limb of a dog could not be extrapolated to an ICH in a human being.36 Similarly, in the case entitled In re Diet Drug Products Liability Litigation ,37 the court substantially granted the phentermine defendants' motions to exclude the opinions of plaintiffs' experts who opined that the drug acts synergistically with fenfluramine to increase the risk of primary pulmonary hypertension. Among other things, the court ruled that the animal studies that the experts extrapolated from had no valid scientific connection or "fit" to the case given that "[a]nimal and human systems differ."38 Yet another case, Fabrizi v. Rexall Sundown, Inc.,39 included an expert who attempted to testify that St. John's Wort caused the development of bilateral cataracts on the basis of in vitro or test tube studies, in the absence of supporting clinical (or human) studies. The court held that, because the in vitro studies were preliminary, the opinion testimony based upon such studies had "none of the earmarks of reliability" required for admission.40

An argument could be mounted as well that ED theory is not "generally accepted," notwithstanding the groundswell of research in support, because it contravenes general theories of toxicology such as the principle that "the dose makes the poison" and that for each toxic effect there is a threshold level below which the effect is not seen. This argument goes to the very "heart" of ED theory:

At the heart of today's approach to chemical regulation is an assumption about the relationship between dose and response. Higher doses are supposed to cause greater harm. This assumption - that "the dose makes the poison" - is used to plan tests of chemicals to identify which ones are dangerous and to determine the level of exposure beneath which contamination should pose no risk.

This old assumption may be true for many chemicals and for many classic health effects, but it is demonstrably misleading for endocrine disrupting chemicals. What this means is that countless experiments that have been done to test the safety of chemicals in use may have lulled us falsely into a sense of security. . . . The puzzling but observable fact is that low doses may actually cause greater impact than high doses for a specific response.41

The so-called "non-monotonie dose response"42 theory espoused by ED theorists is attractive to plaintiffs and their experts alike because, if accepted by the courts, any level of exposure - no matter how minimal - would easily support a toxic tort or product liability claim. Of course, this theory runs counter to another "old assumption" that a plaintiff must provide evidence of actual exposure to harmful levels of a toxic substance - not de minimis levels - in order to recover damages against a defendant.43

As to specific causation, i.e., whether (assuming general causation can be established) the substance at issue did in fact cause the specific effect in the plaintiff, the opinions of plaintiffs' experts will be attacked as not scientifically-reliable because, among other reasons, they cannot rule out the possibility of causation by factors wholly separate from the product or chemical at issue.44 For this reason, isolated studies like those published by Lee,45 which purports to find an association between Type II diabetes and exposure to EDs, will not in and of themselves support a plaintiffs expert's theory that common medical conditions with widely-known and generally-accepted alternative causes are actually caused by exposure to EDs.

Toxic Tort and Products Liability Litigation Strategies Applied

A closer look at some recent ED-related studies may provide greater context for application of the defense strategies discussed more generally above.

1. Limitations of Animal Studies

Because the vast majority of data concerning EDs emerges from tests in rodents, particularly rats and mice, if there is any substantial future litigation concerning EDs, plaintiffs' experts can be expected to attempt to rely primarily on these rodent studies. Accordingly, it is critical for defendants to determine the usefulness, if any, of rodent studies in establishing the potential for human harm, for many results observed in animal studies cannot be translated to human models. One study, for example, advocates the "exquisite sensitivity of the fetal urogenital system in male mice from an outbred stock (Charles River CF-I) to endogenous and exogenous estrogen."46 Similarly, these authors point out that the CD-I mouse, used by the National Toxicology Program, has a "high sensitivity . . . to estrogenic chemicals when exposure occurs during critical periods in development."47 The purported desirability of choosing such sensitive animal models, in the opinion of these authors, arises because other animal models may be completely insensitive to the effects of "potent estrogenic drugs."48 The authors, point out that the Charles River CD - Sprague- Dawley rat is such an insensitive model and argue that a negative study using this model on low doses of BPA, Tyl, et al., Three- generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats is misleading.49 They suggest that Tyl, et al.'s failure to use positive controls negates any value of the study, because the insensitive CD-SD rat model would not have responded to any estrogenic drugs and therefore could not have been expected to show a result from low level BPA.

Given the juxtaposition highlighted by the vom Saal research, one may well ask what relevance the extremely sensitive CF-1 and CD-1 mouse models have to human beings. The vom Saal approach assumes that the positive results in these assays are meaningful to human beings and demonstrate that human beings are at high risk from low dose exposures to alleged endocrine disrupters such as BPA. The fallacy inherent in the assumption should be obvious, however. The results of testing on the supremely responsive CF-1 and CD-1 mice do not predict what happens when similar exposures occur in their rodent cousins, the rat. If the mice assays cannot predict what happens in the rat - which clearly they cannot - then how can they predict what happens in human beings? The truthful scientific answer is that - although such sensitive assays can be useful as gross screening devices - they are utterly useless in giving solid information about which endocrine disrupters, if any, do in fact cause adverse health effects at such levels in human beings. When seen in this light, the lack of a positive control in the rat studies is truly insignificant. To put this another way, the idea behind vom Saal, et al.'s derogatory comments concerning the CD-SD rat studies is that the rat model is no good because the rat is not as "exquisitely sensitive" as the CF-1 and CD-1 mice. The vom Saal research has simply proven that different animal species can have vastly different responses to the same environmental exposure. This underscores all the more the critical importance, not of animal data, but human epidemiologic data if real scientific truth on the question of utmost importance is to be pursued.

The vom Saal researchers also contend that as of July, 2005 there were 109 published studies reporting "significant effects of low doses of BPA in experimental animals, with many adverse effects occurring at blood levels in animals within and below average blood levels in human beings."50 By contrast, vom Saal research claims that eleven published studies "funded by the chemical industry" conclude that BPA causes no significant effects. The lack of consistency suggested by these data raises an important question: whose data are more scientifically reliable? The vom Saal researchers take the position that the industry-funded studies are not worth anything at all, contending that these studies lacked adequate "positive controls." In short, vom Saal proposes that industry purposely designed poor studies that were destined not to show any adverse effects of endocrine disrupters. When confronted with allegations like these, a defendant must keep in mind that a toxic tort plaintiff must offer more than mere criticism of a defendant's or an industry's studies in order to carry his or her burden of proof.51

2. Limitations of Human Studies

Human studies reportedly showing ED-related effects must be carefully scrutinized. A recent study entitled "Interior Surface Materials and Asthma in Adults: A Population-based Incident case- Control Study," found a statistically-significant increased risk of asthma in adults who worked in the presence of "plastic wall material."52 At first glance, the study arguably provides compelling evidence for a cause-and-effect relationship between a relatively common adult malady and an equally common exposure in adults and children alike. Strangely, however, the study found "no statistically significant associations between the risk of asthma [in adults] and the presence of any surface materials at home."53 Given that people typically spend far more time at home than they do at work, the lack of a positive association between asthma and exposure to plastic surface materials at home suggests that the study's already-tenuous findings are not true ones, but instead are the result of one or more confounding factors. One such confounding factor could be the fact t\hat "[a] larger proportion of cases than controls were . . . current or former smokers, [or were] exposed to environmental tobacco smoke (at work or at home)."54 Although the authors attempted to adjust for these specific factors, multivariate analyses cannot adequately control for all confounding factors, and therefore one must naturally consider whether these factors and others explain the disparate results obtained by the authors. Alternatively, the findings could be result of bias introduced by the study design itself, in which the study participants' "[e]xposure[s] to emissions from interior surface materials w[ere] assessed by questionnaire information on the type of interior surface materials at home and at work."55 Questionnaires of this type are known to suffer from numerous biases. For one, study participants already diagnosed with asthma (i.e., "cases") are more likely to recall and therefore report exposures that they believe to be associated with their condition. This is especially true where the exposures of interest are suggested to the participant in the form of a questionnaire, as was the case with the questionnaire utilized in this case.

Conclusion

Manufacturers and industrial users of EDs must prepare for the not-so-distant future of toxic tort litigation as both public awareness of and scientific research into the suspected toxic effects of EDs increases. Despite the mounting "evidence" in plaintiffs' favor, novel ED theories are defensible so long as defendants hold plaintiffs to their customary evidentiary burdens. To do so, it is vitally important that defendants and their counsel keep abreast of both the legal and scientific developments in this area, and then be prepared to educate courts and juries alike about how little is truly known about the possible human health effects, if any, associated with exposure to EDs.

1 THEO COLBORN, DIANNE DUMANOSKI, AND JOHN PETER MEYERS, OUR STOLEN FUTURE: How WE ARE THREATENING OUR FERTILITY, INTELLIGENCE AND SURVIVAL - A SCIENTIFIC DETECTIVE STORY (Penguin Books 1996).

2 Congress directed EPA to "develop a screening program, using appropriate validated test systems and other scientifically relevant information, to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effect as [EPA] may designate." Federal Food, Drug, and Cosmetic Act ("FDCA"), 21 U.S.C. 346a(p)(l). Congress also mandated that "[i]n the case of any substance that is found, as a result of testing and evaluation . . . , to have an endocrine effect on humans, the [EPA] shall, as appropriate, take action under such statutory authority as is available to the [EPA] . . . as is necessary to ensure the protection of public health." FDCA, 21 U.S.C. 346a(p)(6). As a result, "[i]n 1996, EPA's Office of Research and Development identified endocrine disruption as one of its top six research priorities and developed a risk-based research approach to address some of [the many scientific] uncertainties [concerning EDs]." see Endocrine Disrupters Research Initiative at http://www.epa.gov/ endocrine/index. html.

3 David A. Fahrenthold, Male Bass Across Region Found to Be Bearing Eggs, THE WASHINGTON POST, Sept. 6, 2006 at AOl. see also Christine Dell'amore, Growing Concern Over Estrogen-Like Compounds In US Rivers, UNITED PRESS INTERNATIONAL, Oct. 18, 2006, available at www.terradaily.com/reports/Growing_Concern_Ov er_Estrogen_Like_Compounds_In_US_Rivers_999 .html ("A motley assortment of chemicals, pollutants containing hormones and estrogen- like compounds are likely the culprit for the irregularities in these 'intersex' fish. Such substances are called 'endocrine dismptors,' as they can mimic estrogen's role in the body or can affect enzymes that produce sex hormones.").

4 Michelle Rizzo, Early Menopause seen in DES Daughters, REUTERS HEALTH INFORMATION, Oct. 17, 2006, available at www.reutershealth.com/ archive/2006/10/17/professional/links/ 20061017epi d002.html (citing Am. J. Epid. (2006) 164: 68288).

5 Legislative initiatives surrounding BPA are starting to pick up. A number of bills have been introduced recently in state legislatures in the United States that would ban or curtail the use of BPA and other suspected EDs. see, e.g., 2007 California Assembly Bill No. 1108 (Feb. 23, 2007) (bill to prohibit the manufacture, sale, or distribution in commerce of certain toys and child care articles if they are intended for a child under three years of age and if they contain any amount of BPA); 2007 Maine House Paper No. 636 (Feb. 27, 2007) ("An Act to Prevent Infant Exposure to Harmful Hormone-disrupting Substance"); 2007 Maryland House Bill No. 833 (Feb. 9, 2007); 2007 Minnesota House File No. 2100 (March 14, 2007). Some of these bills have adverse legislative "findings." see, e.g., Minn. House File No. 2100 ("Bisphenol-A has been shown to have hormone disrupting effects"). The statewide legislative initiative in California stems from recent BPA- and phthalate-related legislation enacted by the City of San Francisco. Effective December 1, 2006, "[n]o person or entity shall manufacture, sell, or distribute into commerce within . . . San Francisco any toy or child care article intended for use by a child under three years of age if that product has been made with or contains [BPA]." San Francisco Ordinance No. 120-06 ("Child Product Safety Ordinance") (June 6, 2006). Likewise, "[n]o person or entity shall manufacture, sell, or distribute in commerce within . . . San Francisco any toy or child care article intended for use by a child under three years of age if that product can be placed in the child's mouth and has been made with or contains . . . [phthalates] in concentrations exceeding 0.1 percent." Id.

6 Tom Breen, Court - Appointed Scientists Say Teflon Health Studies Could Take Years, INS. J. (Nov. 17, 2006) available at www.insurancejournal.com/news/national/2006/l 1/ 17/74421.htm.

7 see EPA Endocrine Disruptor Screening Program ("Disruption of the endocrine system can occur in various ways. Some chemicals mimic a natural hormone, fooling the body into over-responding to the stimulus (e.g., a growth hormone that results in increased muscle mass), or responding at inappropriate times (e.g., producing insulin when it is not needed). Other endocrine disrupting chemicals block the effects of a hormone from certain receptors (e.g., growth hormones required for normal development). Still others directly stimulate or inhibit the endocrine system and cause overproduction or underproduction of hormones (e.g., an over or underactive thyroid). Certain drugs are used to intentionally cause some of these effects, such as birth control pills. In many situations involving environmental chemicals, however, an endocrine effect is not desirable.") see www.epa.gov/oscpmont/oscpendo/pubs/edspovervi ew/whatare.htm.

8 For examples of alleged "[widespread [pjollutants with [e]ndocrine-disrupting [e]ffects," and scientific articles that describe the effects of the EDs, see www.ourstolenfuture.org/Basics/ chemlist. htm.

9 see generally Natural Resources Defense Council website, at www.nrdc.org/health/effects/qendoc. asp#reduce.

10 Frederick S. vom Saal and Claude Hughes, An Extensive New Literature Concerning Low-dose Effects of Bisphenol A Shows the Need for a New Risk Assessment ENV. HEALTH PERSP 113:926-933 (2005).

11 R. Hauser, et al.. Altered Semen Quality in Relation to Urinary Concentrations of Phthalate Monoester and Oxidative Metabolites, EPIDEMIOLOGY (2006) 17: 682-691. Study found a statistically significant relationship between urine levels of the phthalate DBP and decreased sperm motility and sperm concentration.

12 D-H Lee, et al., A Strong Dose-Response Relation Between Serum Concentrations of Persistent Organic Pollutants and Diabetes, RESULTS FROM THE NATIONAL HEALTH AND EXAMINATION SURVEY 1999-2002. Diabetes Care (2006) 29:1638-1644. Study examined levels of six persistent organic pollutants ("POPs"): a PCB (hexachlorobiphenyl), two dioxins (heptadioxin and OCDdioxin), two pesticides (oxychlordane and trans-nonachlor) and a pesticide metabolite (DDE, a metabolite of DDT). The authors reported a strong dose response relationship between the risk of type II diabetes and body burden of the six POPs.

13 J.J.K. Jaakkola, et al., Interior Surface Materials and Asthma in Adults: A Population-based Incident case-Control Study, AM. J. EPID. (2006) 164:742749.

14 Zhang, et al., Serum Poly chlorinated Biphenyls, Cytochrome P- 450 IAl, and Risk of Breast Cancer in Connecticut Women, AM J. EPID. (2004) 160: 1177-1183.

15 Yang, et al., Bisphenol - A Exposure and Endocrine Disorders in Children, (SOT Abstract 2005).

16 In this study, the results of concern were significant at a level of p = 0.04, suggesting that the likelihood that the results are due solely to chance is only four percent. However, the fact that study results are deemed "statistically significant" does not address issues such as confounding or other biases, no does it eliminate the possibility that the results are due solely to chance.

17 A December 17, 2006, search of the PubMed website (operated by the National Center for Biotechnology Information) identified at least 102 medical and scientific articles published since January 2004 with the words "endocrine" and "disrupt" in either the abstract or the title of the article.

18 According to the Society's website (www.toxicology.org/ai/ meet/am2007/am.asp),

'The Society of Toxicology . . . Annual Meeting is the largest toxicology meeting and exhibition in the world, attracting approximately 6,000 scientists from industry, academia, and government. The program includes a plenary and other special lectures, symposia, workshops, roundtable discussions, and platform and poster presentations."

19 As stated in the EPA's website, the "ORD's research program isbased on a peer-reviewed Research Plan . .. and has three long- term goals: 1) Providing a better understanding of the science underlying the effects, exposure, assessment, and risk management of endocrine disrupters. Research in this area includes determining dose-response relationships, the effects of exposure to multiple endocrine disrupters, major sources of exposure, and approaches for managing risks; 2) Determining the extent of the impact of endocrine disrupters on humans, wildlife, and the environment. Research includes determining: what effects are occurring in human and wildlife populations, the chemical classes of greatest concern, the ambient levels of exposure, and how unreasonable risks can be mitigated; 3) Supporting EPA's screening and testing program. ORD is developing needed computational tools as well as in vitro and in vivo assays in support of the implementation of a screening and testing program for endocrine disrupters, required by the 1996 Food Quality Protection Act." see "Endocrine Disrupters Research Initiative" (www.epa.gov/endocrine/index.html).

20 Yang, supra note 15.

21 Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency.

22 Environmental Toxicants and Disrupted Mammary Gland Development, Proceedings from Fifth Annual Conference on Sex and Gene Expression see also S.E. Fenton, EndocrineDisrupting Compounds and Mammary Gland Development: Early Exposure and Later Life Consequences, ENDOCRINOLOGY (2006) 147(6 Suppl): s 18-24 ("Exposures to certain chemicals and hormone-mimicking or endocrine-disrupting compounds ... are suspected of contributing to increased breast cancer incidence as well as precocious puberty in the United States.").

23 Endocrine Disrupter Screening Program (EDSP); Chemical Selection Approach for Initial Round of Screening, 69 FED. REG. 72819-01,72825 (Dec. 13, 2004).

24 Id.

25 Id.

26 21 U.S.C. 346a(p)(3)(A) & (B); 42 U.S.C. 300j-17.

27 Endocrine Disrupter Screening Program (EDSP); Chemical Selection Approach For Initial Round Of Screening, 69 Fed. Reg. 72819-01, 72824 (Dec. 13, 2004).

28 Systems being developed include Development and Application of a Bioluminescent YeastReporter System for Screening Chemicals for Estrogenic and Androgenic Effects (University of Tennessee, due 2006), Biomarkers for the Assessment of Exposure and Toxicity in Children (EPA, due 2006), Mechanistic Approach to Screening Chemicals and Mixtures for Endocrine Activity Using an Invertebrate Model, (North Carolina State University, due 2007), and A High Throughput Zebraflsh Embryo Gene Expression System for Screening Endocrine Disrupting Chemcials, (Boston University, due 2007).

29 Daubert v. Merrell-Dow Pharms., Inc., 509 U.S. 573 (1993).

30 293 F. 1013 (D.C. Cir. 1923).

31 see, e.g., Gray v. United States, 445 F. Supp. 337, 338 (S.D. Tex. 1978) ("It is a fundamental principle of products liability law that a plaintiff must prove, as an essential element of his case, that a defendant manufacturer actually made the particular product which caused injury."); Moore ex rel Moore v. Miss. Valley Gas Co., 863 So. 2d 43, 46 (Miss. 2003) ("[I]t is incumbent upon the plaintiff in any products liability action to show that the defendant's product was the cause of the plaintiff's injuries."); Gaulding v. Celotex Corp., 772 S.W.2d 66 (Tex. 1989) (rejecting application of "alternative liability," "concert of action," "enterprise liability," and "market share liability" theories of liability that might otherwise allow recovery where plaintiff could not prove exposure to asbestos manufacturer's product).

32 Product identification difficulties like these, however, do not prevent plaintiffs' firms from suing every possible defendant even in the absence of product identification evidence. For example, cases of this nature are being filed against all manufacturers of "benzene-containing products" in the United States - alleging that such products caused various kinds of leukemia or other blood cancers - without evidence connecting the product of the defendant to the plaintiff.

33 reference manual on scientific evidence 369-370(2d ed. 2000) (references omitted).

34 vom Saal, et al., supra note 10.

35 244 F. Supp. 2d 434 (W.D. Pa. 2003).

36 Id. at 466-67.

37 No. MDL 1203, 2000 WL 962545 (E.D. Pa. June 28, 2000).

38 Id. at *11.

39 No. 01-289, WL 1202984 (W.D. Pa. June 2, 2004).

40 Id. at *8.

41 Our Stolen Future website (www.ourstolenfuture org/NewScience/ lowdose/nonmonotonic.htm).

42 Id.

43 See, e.g., McClain v. Metabolife Intern., Inc., 401 F.3d 1233, 1241-42 (11th Cir. 2005) ("When analyzing an expert's methodology in toxic tort cases, the court should pay careful attention to the expert's testimony about the dose-response relationship. The dose- response relationship is '[a] relationship in which a change in amount, intensity, or duration of exposure to an agent is associated with a change-either an increase or decrease-in risk of disease.' The expert who avoids or neglects this principle of toxic torts without justification casts suspicion on the reliability of his methodology.") (citing REFERENCE MANUAL ON SCIENTIFIC EVIDENCE 392 (2 ed. 2000); Mitchell v. Gencorp Inc., 165 F.3d 778, 781 (10th Cir. 1999) ("It is well established that a plaintiff in a toxic tort case must prove that he or she was exposed to and injured by a harmful substance manufactured by the defendant. In order to carry this burden, a plaintiff must demonstrate 'the levels of exposure that are hazardous to human beings generally as well as the plaintiffs actual level of exposure to the defendant's toxic substance before he or she may recover.'") (citations omitted).

44 The interplay between a plaintiffs general and specific causation burdens cannot be overstated. Plaintiffs' experts often explain their specific causation opinions by claiming that their "differential diagnosis" ruled out all other alternative causes of the plaintiffs alleged injuries. However, numerous courts have held that the plaintiff and his experts must provide relevant and reliable evidence that the suspect toxin is capable of causing the plaintiffs injuries (i.e., general causation) before that toxin can properly be considered on a differential diagnosis in support of the plaintiffs specific causation burden. see, e.g., McClain v. Metabolite Intern., Inc., 401 F.3d 1233, 1253 (11th Ck. 2005) ("[A]n expert does not establish the reliability of his techniques or the validity of his conclusions simply by claiming that he performed a differential diagnosis on a patient."); Hollander v. Sandoz Pharms. Corp., 289 F.3d 1193, 1211 (10th Cir. 2002) ("In order to 'rule in' Parlodel as a scientifically plausible cause of [the plaintiffs] stroke, the [plaintiffs] experts would need to present reliable evidence that the drug can cause strokes."); Glastetter v. Novartis Pharms. Corp., 252 F.3d 986, 989 (8th Cir. 2001) ("[T]he district court properly excluded the differential diagnoses performed by [the plaintiffs] expert physicians because they lacked a proper basis for 'ruling in' Parlodel as a potential cause of [stroke] in the first place.").

45 Lee, supra note 12.

46 vom Saal, et al., Large Effects From Small Exposures. II. The Importance of Positive Controls in Low-Dose Research on Bisphenol A. ENVTL. RESEARCH 100 (2006) 50-76 at 52.

47 Id.

48 Id.

49 TOXICOL. SCI. 69, 121-146 (2002).

50 Id.

51 "Plaintiffs' well - taken criticisms of the epidemiological studies does not satisfy their burden of proof." Siharath v. Sandoz Pharms. Corp., 131 F. Supp. 2d 1347, 1358 (N.D. Ga. 2001) (citing Glastetter, 107 F. Supp. 2d 1015, 1044 (E.D. Mo. 2000) ("In the absence of their own epidemiological evidence supporting the conclusions of their experts that Parlodel can cause [disease], the best plaintiffs can do is attack defendant's studies.")). see also Brumbaugh, 77 F. Supp. 2d 1153, 1156 (D. Mont. 1999) ("The plaintiff criticizes certain aspects of these studies, but she produced no epidemiological study, or other reliable scientific proof that does make the causal link between Parlodel and her condition, or any related condition. Plaintiffs lawyer's attack on defendant's studies does not meet the law's requirements. She must come forward with reliable scientific evidence of her own....").

52 Jaakkola, et al., supra note 13, at 746.

53 Jaakkola, et al., supra note 13, at 746.

54 Jaakkola, et al., supra note 13, at 746.

55 Jaakkola, et al., supra note 13, at 744.

Mr. Berger is a partner with Spriggs & Rollings-worth in Washington, DC. Mr. Berger has expertise in pharmaceutical product liability defense, environmental litigation, and toxic tort defense. He represents manufacturers and industrial clients in a range of complex solvent and benzene-related cases. He has defended gasoline manufacturers and successfully obtained summary judgment in leukemia cases relating to alleged exposure to benzene in gasoline. He also has successfully advocated the causation defense relating to alleged benzene exposures in complex workplace settings involving contract laborers and bystanders. Mr. Berger also defends against claims that prescription and over-the-counter drugs have caused serious personal injuryincluding strokes, congestive heart failure, immune system dysregulation, and dermatological disorders.

Michael L. Junk is an associate with Spriggs & Hollingsworth. Mr. Junk practices in the Firm 's Toxic Torts & Products Liability and Pharmaceutical Products groups and specializes in the defense of complex serial and mass tort litigation. Working on behalf of the Firm 's clients as part of their national trial and litigation teams, Mr. Junk has coordinated the defense of nationwide litigation with local counsel and other defense firms across the country.

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