33 ELR 10641 | Environmental Law Reporter | copyright © 2003 | All rights reserved

Genomics and Toxic Substances: Part II—Genetic Susceptibility to Environmental Agents

The author is Professor and Executive Director, Center for the Study of Law, Science, and Technology, Arizona State University College of Law. J.D. (1990); M.P.P. (1990); Ph.D. (Genetics) (1986). The research and preparation of this Article was supported in part by grant number 1 R01 ES12577-01 from the National Institute of Environmental Health Sciences (NIEHS) and the National Human Genome Research Institute of the National Institutes of Health (NIH). The contents of this Article are solely the responsibility of the author and do not necessarily represent the official views of either the NIEHS or the NIH. The author appreciates helpful comments from Marc Poirier and David Rajeski. Genomics and Toxic Substances: Part I—Toxicogenomics appeared in the January 2003 issue of ELR NEWS & ANALYSIS, 33 ELR 10071 (Jan. 2003).

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The sequencing of the human genome revealed that the variation in the genetic material between any two individuals averages approximately one variation for every 1,000 base pairs of deoxyribonucleic acid (DNA).¹ Even though we are remarkably 99.9% genetically identical, there are still on average three million genetic differences between any two people, given that the human genome contains approximately 3.1 billion base pairs of DNA. While many of these genetic variations appear to have no functional significance, others have important consequences, including contributing to the significant differences between individuals in their appearance, personality, abilities, and health. Of particular interest here, there are also genetic variations that affect our individual susceptibility² to disease from exposure to exogenous substances that enter our bodies, such as drugs, foods, infectious agents, and toxic substances (collectively referred to as xenobiotics).³

Genetic differences in susceptibility provide an important part of the answer to the age-old question of why do some people get sick from certain exposures while others do not.⁴ For example, it has been known for centuries that some individuals, especially people of Mediterranean and Asian origin, can develop a potentially fatal illness (called favism) from eating fava beans, while most people experience no problems from eating this food product.⁵ This differential response is now known to be caused by a genetic variation in the glucose-6-phosphate dehydrogenase gene.⁶ Every person who has to date succumbed to "mad cow disease," known technically as new variant Creutzfeldt-Jacob disease (vCJD), carried a particular genetic variation that is present in approximately 40% of the population.⁷ Genetic susceptibility [33 ELR 10642] factors now explain many examples of pharmaceuticals that are not effective in some people, or which cause toxicity in others.⁸ Indeed, it now appears to be the general case that for exposure to any xenobiotic, some members of the public will be more susceptible than others due to their genetic profile (or genotype).⁹

This Article examines the implications of recent findings of relatively common genetic variants, known as "polymorphisms,"¹⁰ within the population affecting susceptibility to environmental exposures. In particular, the Article examines the potential applications of such information in toxic tort litigation and environmental regulation.¹¹ The study of differences in genetic susceptibility to environmental toxicants is sometimes referred to as "toxicogenetics."¹² Toxicogenetics, which studies the variations in single genes, is distinct from toxicogenomics, the subject of a previous accompanying Article,¹³ which studies the expression of the entire human genome in response to toxic exposures.

Genetic Susceptibility to Environmental Agents

While it has been known for many years that individuals differ significantly in their susceptibility to xenobiotics, it is now possible to identify and characterize the genetic sources of much of that inter-individual variability.¹⁴ A number of relatively common genetic polymorphisms are present in the population that affect our individual susceptibility to environmental toxicants.¹⁵ The high variability both within and between ethnic groups for the genes responsible for the metabolism of xenobiotics is likely due to evolutionary adaption to geographical differences in diet and other environmental factors.¹⁶

One of the most important set of genetic polymorphisms affecting environmental susceptibility are those coding for the cytochrome p450 enzymes,¹⁷ which catalyze the initial step of metabolism for many foreign substances that enter the body. The cytochrome p450 enzymes are a "super-family" of related metabolic enzymes that exhibit broad, overlapping specificity for a wide range of xenobiotics, including many pharmaceuticals and industrial chemicals. These enzymes catalyze "Phase I" reactions, also sometimes referred to as the oxidation or activation stage of metabolism, in which foreign substances are oxidized to form high-energy, reactive intermediates. The reactive metabolite is then conjugated, in a reaction catalyzed by Phase II enzymes such as the glutathione S-tranferases (GSTs) or N-acetyltransferases, to a molecule such as glutathione, glucuronic acid, or cysteine, to form a non-reactive, water-soluble molecule that can be more easily transported and excreted from the body.¹⁸ A consequence of this two-step process of oxidation followed by conjugation is that the temporary reactive intermediate formed in the first step catalyzed by the cytochrome p450 enzymes has a propensity to cause cell damage by binding to DNA and other important cellular molecules before it is deactivated by the second conjugation reaction. Genetic polymorphisms that cause the reactive intermediate to be formed at a higher rate or deactivated at a slower rate thus have the potential to increase toxicity risks.

Many of the most important Phase I and Phase II metabolic enzymes are produced by genes with very common polymorphisms. It will often be the combination of the particular Phase I and Phase II enzyme polymorphisms found together in an individual that determine his or her risk to a given chemical. In the most typical case where a relatively benign parent compound is converted to a reactive intermediate by the Phase I enzymes, genetic polymorphisms that make the relevant cytochrome p450 enzyme(s) more efficient (rapid metabolizers) will increase risk, because the rate and amount of the reactive intermediate produced will be increased.¹⁹ Conversely, variants [33 ELR 10643] that make the Phase I enzyme less effective (slow metabolizers) will decrease risks, since less of the reactive intermediate will be formed.²⁰

The opposite pattern applies to the Phase II enzymes. When the intermediate metabolite is the toxic agent, individuals with "rapid metabolizer" variants for their relevant Phase II enzymes will be at reduced risk, because they will detoxify the reactive intermediate faster. Conversely, individuals with "slow metabolizer" Phase II variants will be at increased risk, because the reactive intermediates will persist longer and do more damage.²¹ Individuals at the greatest risk from exposure to a chemical that produces a toxic intermediate will therefore have both a "rapid" variant for the relevant Phase I gene and a "slow" variant for the applicable Phase II gene. Individuals with a "slow" Phase I variant and a "rapid" Phase II variant will be at the least risk.

Over 40 different human cytochrome p450 enzymes involved in Phase I metabolism have been identified, of which 6 to 8 are primarily responsible for the oxidation of most drugs and industrial chemicals.²² The genes that code for these p450 enzymes are highly polymorphic. For example, about 10% of the Caucasian population carries a "rapid metabolizer" variant of one important p450 gene (CYP1A1).²³ By increasing the rate of production of toxic metabolites, this genetic variant has been associated with increased lung cancer risk in smokers in some (but not all) studies.²⁴

The genes coding for the principal Phase II enzymes are also highly polymorphic. In approximately 50% of the Caucasian population, for example, both copies of a gene (GSTM1) coding for one enzyme in a major family of Phase II enzymes is completely deleted, which is associated with an increased risk of bladder and lung cancer from exposure to several toxic substances normally detoxified by the GSTM1 enzyme.²⁵ Another GST enzyme (GSTT1) is also highly polymorphic, with between 10% to 60% of different ethnic and racial populations having both copies of the gene deleted.²⁶ GSTT1 converts the commercially important chemical methylene chloride into a toxic intermediate, and thus individuals with both copies of the gene deleted are at significantly lower risk of cancer from methylene chloride exposure than people with at least one functional copy of the gene.²⁷ The same deletion of the GSTT1 gene appears to increase the risks from other chemicals, however, such as butadiene and ethylene oxide.²⁸

These and many other genetic polymorphisms affecting susceptibility to environmental agents have several important characteristics in common. First, most genes conferring genetic susceptibility to environmental agents require both the altered gene and the environmental exposure to increase risk.²⁹ Thus, in the absence of environmental exposure, these genes confer little or no increased risk.³⁰ Environmental susceptibility genes have been compared to a loaded gun: "A loaded gun by itself causes no harm; it is only when the trigger is pulled that the potential for harm is [33 ELR 10644] released. Genetic susceptibility creates an analogous situation, where the loaded gun is one or a combination of susceptibility genes (alleles) and the trigger is an environmental exposure."³¹

A second common feature of many polymorphisms affecting environmental susceptibility is they appear to confer increased susceptibility to some toxicants but decreased susceptibility to others.³² For example, individuals with a variant of the Phase II N-acetyltransferase gene that results in reduced activity (slow acetylators) have an increased risk of bladder cancer from substances such as aniline and tobacco smoke, but a decreased risk of colon cancer from exposure to aromatic amines³³ This tendency for many of these susceptibility genes to increase risks from some exposures but to decrease risks from others probably explains why variants of these genes persist in the population at such high frequencies.

Third, given the relatively high frequency (generally from 1% to 50%)³⁴ of many of these susceptibility genes in the population, any individual person likely carries several different variant genes.³⁵ Thus, in the context of environmental susceptibilities, it may not be accurate to speak of "high-risk" and "low-risk" groups generally, because any individual carries multiple environmental susceptibility polymorphisms that increase risk for some exposures and lower risks for others.³⁶ Nevertheless, there will be some individuals who are at a particularly high risk to a specific environmental exposure as a result of carrying a particularly strong combination of susceptibility-enhancing genes for that particular exposure.³⁷

In 1997, the National Institute of Environmental Health Sciences (NIEHS) established the Environmental Genome Project (EGP) to identify genetic polymorphisms that affect susceptibility to environmental agents.³⁸ A total of 554 genes potentially affecting susceptibility to environmental agents were initially targeted for analysis by the EGP, and the identification of functional variants of approximately 200 of these genes was announced in April 2003.³⁹ The genes affecting individual susceptibility to environmental agents include those affecting metabolism and detoxification, DNA repair, cell cycle control, receptors, hormone metabolism, and immune function.⁴⁰ Yet another category of relevant genes are those affecting risky behaviors such as smoking, alcohol consumption, and excess calorie intake, which in turn increase the risks of cancer and other adverse health conditions.⁴¹ Gene variations affecting susceptibility to many of the most important regulated toxic chemicals have been identified, including genes affecting susceptibility to ozone,⁴² particulate matter,⁴³ benzene,⁴⁴ butadiene,⁴⁵ [33 ELR 10645] methylene chloride,⁴⁶ arsenic,⁴⁷ asbestos,⁴⁸ vinyl chloride,⁴⁹ lead,⁵⁰ aromatic amines,⁵¹ ethylene oxide,⁵² acrylonitrile,⁵³ trichloroethylene,⁵⁴ beryllium,⁵⁵ and environmental tobacco smoke.⁵⁶

Despite the tremendous progress that has been made in understanding genetic susceptibility to environmental exposures in the past decade, attempts to profile the genetic susceptibility of an individual are nevertheless complicated by several factors. To begin with, most of the genes affecting susceptibility are probabilistic rather than deterministic in that they only increase the risk of disease and are neither necessary nor sufficient to cause disease.⁵⁷ The susceptibility genes are generally quite frequent in the population, but the increased (or decreased) risk in any one individual carrier is relatively modest, generally on the order of a 20% to a twofold to threefold increase or decrease in risk.⁵⁸ Nonetheless, even though the increased risk to any susceptible individual is moderate, the public health consequences of environmental susceptibility genes may be large given their high prevalence in the population.⁵⁹

Moreover, research on genetic susceptibility markers often produces inconsistent results, with some studies finding a significant increased (or decreased) risk of disease from a particular gene-environment interaction, while other studies find no such effect.⁶⁰ Because most of the genetic polymorphisms affecting environmental susceptibility have only a modest impact on risk, many studies may lack adequate sample sizes to detect such risks with sufficient confidence.⁶¹ The inability or failure to consider and control for other relevant genetic polymorphisms that interact with the susceptibility variant being studied may also explain some of the divergent results.⁶²

Even when a susceptibility genetic marker has been unambiguously identified, its effects can vary across individuals for a variety of reasons.⁶³ Some increases in susceptibility are dose-dependent, in that they primarily increase an individual's susceptibility to a toxic agent relative to the general population only at low doses in some cases or high doses in others.⁶⁴ Some susceptibility genes have effects [33 ELR 10646] that are gender-specific, likely due to interactions between the environmental agent, the genetic polymorphism, and hormones.⁶⁵ Certain associations appear to be ethnic-dependent, in that the susceptibility associated with a particular gene variant appears to be limited to particular ethnic groups and is not seen in other groups even when the same variant is present.⁶⁶ The distribution of gene frequencies also varies significantly between different ethnic groups.⁶⁷ Among other things, these ethnic differences in susceptibility suggest the need for caution in extrapolating risk findings between different populations.⁶⁸

Yet another complication is that genetic susceptibilities operate in conjunction with other types of individual susceptibility from factors such as age, infections or disease, previous toxic exposures, diet, weight, and lifestyle.⁶⁹ Many of these "acquired" susceptibilities fluctuate over a person's lifetime, and thus even the same person becomes more or less susceptible to toxicity at different times.⁷⁰ It is the interaction of acquired susceptibilities, inherited genetic susceptibilities, and environmental exposures that therefore determine an individual's risk.⁷¹ Finally, individual susceptibility to potentially toxic agents is rarely determined by a single genetic locus, but rather is the combined influence of many different genes.⁷² Some of these gene-gene interactions are simply additive,⁷³ while others exhibit a more synergistic (or greater than additive) interaction.⁷⁴ Thus, even if testing identifies a specific gene variant with a significant effect on individual susceptibility to a particular environmental toxicant, the magnitude and nature of the susceptibility conferred by the gene may vary depending on the other gene variants present in a given individual.⁷⁵

Notwithstanding these complications, as the most serious environmental exposures continue to be reduced by government regulation and technology improvements, genetic susceptibility likely accounts for a growing proportion of the residual environmental risks.⁷⁶ Perhaps even more important than the knowledge of the existence of common genetic polymorphisms within the population is the increasing capability to identify individuals who are more or less genetically susceptible.⁷⁷ Based on these developments, the paradigm [33 ELR 10647] of toxicology has been shifted irrevocably from "the dose makes the poison"⁷⁸ to "the dose and individual make the poison."⁷⁹ This shift in focus has led to what has been described as a "new era in toxicology."⁸⁰ It will likewise lead to new eras in toxic torts and environmental regulation.

Toxic Tort Applications

Both plaintiffs and defendants are likely to try to utilize data on genetic susceptibility to environmental exposures in a number of different ways.

Proving or Disproving Causation

Plaintiffs in toxic tort lawsuits have the burden to prove that a defendant's product or activity caused their illness. A plaintiff's genetic susceptibility may be relevant to this question of causation. For example, some (but not all) courts require that plaintiffs prove that the defendant's action doubled the background risk, i.e., relative risk > 2.0, for contracting the injury incurred by the plaintiff in order to satisfy the "more likely than not" standard of causation.⁸¹ Relatively few toxic substances cause a doubling of the background risk for commonly occurring health effects such as lung cancer or birth defects.⁸²

Until recently, epidemiology studies have generally measured the increase in relative risk from exposure to a toxic agent for an entire exposed cohort, without segmenting the population into subgroups based on differences in genetic susceptibility. With the advent of molecular or genetic epidemiology, it is increasingly common for epidemiology studies to stratify exposed groups by genetic and other forms of susceptibility.⁸³ A genetically susceptible plaintiff may be able to use such data to show that even if the relative risk for the general population from a particular exposure is less than two, the relative risk for people with the genetic polymorphism carried by the plaintiff exceeds two.⁸⁴ Thus, even though an "average" person may not be able to meet the doubling of background risk causation criteria, individuals with a relevant genetic susceptibility might.

Plaintiffs in several lawsuits have already sought to use this susceptible genotype argument to try to circumvent large epidemiology studies showing relative risks for the general public less than two. Examples include lawsuits brought by breast implant recipients claiming connective tissue disease⁸⁵ and thyroid cancer victims residing near the Hanford nuclear facility.⁸⁶ To date, these claims have usually involved reference to scientific studies indicating that genetic susceptibility to the agent in question may exist within the general population,⁸⁷ but without any test data or other specific evidence showing that particular plaintiffs did in fact carry the relevant gene.⁸⁸ While such unsupported claims have occasionally been successful,⁸⁹ they have in most part been rejected by courts for failure to introduce specific evidence showing that the individual plaintiffs are genetically susceptible.⁹⁰

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With the rapidly expanding capability to test individuals for genetic polymorphisms affecting susceptibility to particular toxicants, it is now technically possible to genetically profile the potential chemical susceptibilities of individual plaintiffs. The genetic testing of plaintiffs to discover their potential genetic susceptibilities may carry other risks, however. The genetic information uncovered by testing may be obtained and used against the plaintiff's interests by parties outside the litigation, such as an employer or insurer.⁹¹ The genetic testing may also reveal information about the plaintiff's own predispositions and risks that he or she may prefer not to know.⁹² Protective orders and similar measures may be able to limit these risks, but not completely.⁹³

Of course, if the genetic testing determines that the plaintiff is not genetically susceptible, the defendant will be able to discover this information and use it to argue against causation. A defendant may also seek to test the plaintiff for other genetic variants that provide increased resilience to the toxic agent at issue, which would make that person less susceptible than the average person and thus even less likely to be able to prove that the defendant's actions doubled the individual's background risk.

A defendant could also argue that the plaintiff's disease resulted solely from his or her genetic predisposition, which caused the disease to develop independent of any exposure to the defendant's product. This alternative causation defense based on inherited susceptibility has been asserted in many cases, but its success has been limited by the inability to demonstrate with specific evidence that the plaintiff had a genetic predisposition to the condition that has now manifested. There are, however, a few reported examples where defendants have sought genetic testing of plaintiffs for the purpose of showing potential alternative causes of the claimants' condition.⁹⁴ As testing for genetic predispositions becomes more available, at least one medical expert has suggested that it should become "standard practice" for defendants to seek genetic testing of plaintiffs in order to identify potential alternative causes.⁹⁵ With both plaintiffs and defendants potentially benefitting from genetic susceptibility data in appropriate cases, it is likely that such evidence will increasingly be introduced in future toxic tort cases.

Duty to Protect Genetically Susceptible Plaintiffs?

Defendants could also seek to exploit evidence showing that a plaintiff is genetically susceptible to argue that they have no duty to protect such hypersensitive individuals. In particular, defendants could assert what has sometimes been described as the "idiosyncratic response" defense.⁹⁶ This defense protects from liability a defendant whose product or activity is harmless to the general public but may injure a small number of individuals with a unique and unusual susceptibility.⁹⁷ This defense has generally been applied in cases where a plaintiff developed a rare allergenic response to a cosmetic or similar product, but the defense would presumably also apply to cases where a plaintiff was harmed due to a rare genetic susceptibility to a product that is otherwise harmless to the general population.⁹⁸

The formal justification for this defense is that the hypersusceptibility of the plaintiff, rather than some defect in the product, is the proximate cause of the plaintiff's injury.⁹⁹ As one court stated: "A manufacturer has no duty to withhold its product from the market merely because the product may pose a risk to certain hypersensitive individuals."¹⁰⁰ It remains [33 ELR 10649] to be seen how the idiosyncratic response doctrine will apply to individuals genetically susceptible to toxic exposures, but the application may turn in particular cases on factors such as the prevalence of the susceptibility in the population,¹⁰¹ the type and nature of the product,¹⁰² and whether the manufacturer had a reasonable basis for predicting the presence of the susceptibility.¹⁰³

Duty to Warn and Test

Does a product manufacturer have a duty to provide a specific warning for individuals who are genetically susceptible to its product? Product manufacturers currently have a duty to warn of potential side effects that occur only in a relatively small percentage of product users. This duty to warn should not be diminished just because it is now possible to identify in advance those genetically susceptible persons who are most likely to develop the adverse side effect.¹⁰⁴ Indeed, to the extent that susceptible individuals have the capability to self-identify their predisposition,¹⁰⁵ the case for requiring a warning becomes stronger because those individuals are better positioned to take preventive action.¹⁰⁶

If the general rule is that a manufacturer must provide reasonable warnings to susceptible individuals, the parameters of this duty remain to be worked out for genetic susceptibilities. For example, what is the threshold, if any, that makes a susceptibility so rare that no warning is required? What level of knowledge about susceptibilities should be imputed to the product manufacturer?¹⁰⁷ Should a product manufacturer be expected to proactively test its products for all potential genetic susceptibilities?¹⁰⁸ Given the number of potential susceptibility genes in the population, this obligation could be almost unlimited.

It is likely that courts would apply a "reasonable foreseeable" standard similar to that used in many failure-to-warn cases,¹⁰⁹ and thus require manufacturers to provide warnings only for susceptibilities that are reasonably foreseeable at the time the product was manufactured.¹¹⁰ Such a rule would almost certainly lead to many factual disputes about whether a manufacturer should have foreseen that a particular susceptibility would apply to its products. The number of people susceptible to the product may also be a relevant factor, given existing precedent that a manufacturer need only provide a warning when a "substantial" number of the population are susceptible,¹¹¹ another ambiguous standard that [33 ELR 10650] invites dispute. Another issue will be whether a manufacturer need only warn of the existence of a genetic susceptibility, or should go further and recommend that a product user be genetically tested before using the product.¹¹² Finally, warnings about genetic susceptibilities will be further complicated by the numerous gene-gene, gene-environment, and dose-effect interactions that can occur, which will dilute the accuracy and utility of genetic susceptibility warnings.¹¹³

These issues are being addressed for the first time in pending lawsuits against the manufacturer of the LYMErix vaccine, the only vaccine that has been approved in the United States to protect against Lyme disease. In one such case, a group of over 100 plaintiffs have filed a class action lawsuit claiming that the vaccine causes a chronic autoimmune reaction described as "treatment-resistant Lyme arthritis" in people carrying the HLA-DR4+ gene variant, which is found in approximately 30% of the general population.¹¹⁴ The lawsuit claims that the manufacturer should be held liable for failing to warn consumers who carry the HLA-DR4+ gene variant of the increased risk of treatment-resistant Lyme arthritis and for failing to recommend that LYMErix users first be tested to determine if they carry the HLA-DR4 gene.¹¹⁵ Although both pre-marketing and post-marketing analyses by federal agencies have failed to confirm any increased risk from LYMErix,¹¹⁶ the vaccine was removed from the market in February 2002 as a result of plummeting sales that likely resulted from the controversy surrounding the lawsuits.¹¹⁷

This lawsuit, and similar suits that inevitably will follow against manufacturers of other products that allegedly injure genetically susceptible subgroups, will determine the existence and nature of a manufacturer's duty to warn genetically susceptible individuals.¹¹⁸ The LYMErix example also suggests that the potential for genetic susceptibility opens a new dimension in product safety, one that is likely to be characterized by considerable uncertainty and contention. As LYMErix demonstrates, allegations of genetic susceptibility to a product, even if not supported by compelling scientific support, have the potential to adversely affect the sales of a product, and potentially drive it off the market.

If a defendant properly warns of a genetic susceptibility to its products, an individual who nevertheless voluntarily assumes the risk of the product may be precluded from recovery if he or she subsequently gets sick as a result of exposure to the product. An analogy is provided by court decisions finding assumption of risk or contributory negligence when a plaintiff fails to follow the manufacturer's recommendation to take a "patch test" for allergic reactions to a cosmetic product.¹¹⁹ Genetic tests to determine susceptibility to certain groups of compounds will soon be commercially available.¹²⁰ The availability of such tests will open the door to more frequent assertion of a defense of contributory or comparative negligence (or assumption of risk), depending on the jurisdiction.¹²¹ A defendant could argue that a plaintiff knew, or should have known, that she was genetically susceptible to a particular agent and accordingly should have taken greater precautions to avoid exposure.¹²²

These issues are at the cutting edge of a fundamental transition from a market premised on a one-size-fits-all paradigm to an era of personalized products and risks based on individual genetic predispositions. This change is occurring first in the pharmaceutical industry, where the use of genotype-based product testing and custom-tailored medicine has already begun.¹²³ For example, the breast cancer drug Herceptin is only prescribed for the approximately 30% of breast cancer patients who over-express a particular protein (HER2) that allows them to benefit from the medication.¹²⁴ [33 ELR 10651] Before children with acute lymphocytic leukemia are treated with standard chemotherapeutic drugs such as mercaptopurine, they are genetically tested for deficiencies in the thiopurine S-transferase gene, as conventional dosage regimes can be fatal to the 1 in 300 patients that have two nonfunctional copies of the gene.¹²⁵ Other drugs currently under development will likewise be targeted for individuals with particular genetic traits.¹²⁶

Many of the same genetic polymorphisms affecting the safety and efficacy of pharmaceuticals will also affect susceptibility to chemicals and other commercial products, which may in the future also require labels warning genetically susceptible consumers.¹²⁷ New rules will be required to guide manufacturers with respect to testing their products for effects on genetically susceptible individuals, providing warnings to susceptible consumers, and perhaps even recommending that product users obtain a genetic test before using the product.¹²⁸

Certification of Genetically Heterogeneous Class

The genetic heterogeneity of a putative class of plaintiffs with respect to their susceptibility to a toxic substance may provide defendants with a potent weapon for opposing class certification. One requirement for certification of a class of plaintiffs is that the issues in common within the class must "predominate" over individual issues.¹²⁹ Defendants in toxic tort cases frequently oppose class certifications based on differences within the proposed class with respect to factors such as exposure levels, health status, and often a vague reference to inherited differences. Even when not supported by specific evidence showing genetic differences in susceptibility within the class, such assertions have sometimes been successful in opposing class certification.

For example, a New Jersey court denied the certification of a proposed class consisting of all New Jersey smokers in a suit against the tobacco industry, in part because the determination of whether smoking caused a smoker's illness will require an assessment of each individual smoker's medical and genetic history.¹³⁰ A California court denied class certification for medical monitoring claims brought by residents allegedly put at increased risk from chemical contamination of groundwater, in part because of potential individual differences in health backgrounds of the plaintiffs, including genetic predispositions.¹³¹ Other courts have likewise cited genetic heterogeneity as a factor for denying class certification in cases involving toxic injury.¹³² As genetic susceptibilities to toxic substances are increasingly identified and characterized, this argument against class certification will likely become more frequent and compelling.

Discounting Damages for Plaintiff's Genetic Predispositions

A defendant that has been found liable for a plaintiff's injuries may seek to discount the damages payable based on the plaintiff's genetic susceptibility. The strongest form of such an argument is when the plaintiff incurred the identical disease for which she or he was genetically predisposed. The defendant will likely try to argue that it was this genetic predisposition and not defendant's actions that caused the disease, but even if that argument is unsuccessful, the defendant may be able to argue that the damages should be discounted based on the likelihood that the plaintiff would have eventually developed the same condition in the absence of defendant's actions. Under this argument, the damages should be discounted to compensate the plaintiff only for the period from the time the plaintiff did develop the condition to the estimated time that the plaintiff would likely have developed the condition but for defendant's actions.¹³³

A more aggressive form of the same argument would be for the defendant to seek to uncover any genetic predisposition in the plaintiff that would reduce his or her life expectancy, thus resulting in a concomitant reduction in damages. This type of argument could involve a very broad and intrusive search into the plaintiff's medical and genetic history, and perhaps even comprehensive genetic testing. Such "fishing expeditions" have been criticized on the ground that they represent excessive intrusion into the personal privacy of the plaintiff, with the potential to unveil genetic information that the plaintiff may not want to know or which may be used by insurers or employers to discriminate against the plaintiff in the future.¹³⁴ Yet, courts have allowed defendant's to require testing of plaintiffs for human immunodeficiency virus (HIV) for the purpose of reducing damages based on the plaintiff's diminished life expectancy due to acquired immune deficiency syndrome (AIDS).¹³⁵ [33 ELR 10652] It remains to be seen how lenient courts will be in allowing defendants to obtain genetic testing of plaintiffs for the purpose of calculating life expectancy for damages assessment.¹³⁶

Environmental Regulatory Applications

Incorporating Susceptibility Into Risk Assessment

The U.S. Environmental Protection Agency (EPA) addresses susceptible subpopulations differently in risk assessment for carcinogens and noncarcinogens. For noncarcinogens, EPA generally applies a standard tenfold uncertainty factor for inter-individual (or intraspecies) variation in susceptibility in calculating a reference dose (RfD) or reference concentration (RfC).¹³⁷ RfCs and RfDs are considered to be the de facto "safe" level of a noncarcinogen, and are defined as "an estimate (with uncertainty spanning perhaps an order of magnitude)" of an ongoing exposure "to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime."¹³⁸ EPA calculates the RfC or RfD for a chemical by applying a series of uncertainty factors, including the tenfold factor for intraspecies variation, to the no observed adverse effect level (NOAEL), or in the absence of a NOAEL, the lowest observed adverse effect level (LOAEL).

The default tenfold uncertainty factor for intraspecies variation has no specific scientific justification—it is simply a policy assumption in the absence of available data. A number of published studies have attempted to evaluate the sufficiency of this default safety factor to account for actual intraspecies variation in susceptibility, and have generally found that a factor of 10 does adequately protect most of the population for most chemicals, but for some substances appeared to be either too large or too small.¹³⁹ With the expanding characterization of genetic polymorphisms affecting susceptibility to environmental agents, for many chemicals it may be possible to replace default assumptions for intraspecies variability with science-based data, which is sometimes referred to as a chemical-specific adjustment factor (CSAF).¹⁴⁰

There is some confusion in the literature on how to measure whether the tenfold default uncertainty factor is adequate. Assume, for example, that genetic studies indicate two relevant genotypes affecting the metabolism of a particular noncarcinogenic chemical. Assume also that the data indicates that there is a twentyfold difference in susceptibility to that chemical, i.e., individuals with genotype A generally develop a toxic response at a concentration twentyfold lower than individuals with genotype B. How should EPA use this data to calculate an RfD or RfC? If EPA decides that the data are robust enough to replace the default uncertainty factor, there are at least two possible perspectives on the new uncertainty factor that should be applied. The first view is that the current default factor is underprotective because it only covers a tenfold difference in susceptibility, whereas the new data indicates that there is a twentyfold difference in susceptibility within the population. This perspective assumes that susceptibility has a bimodal distribution within the population, with one peak consisting of the normal population (genotype B), and the other peak consisting of susceptible individuals (genotype A).¹⁴¹ In the hypothetical, the people at the susceptible tail of the distribution (genotype A) are 20 times more susceptible than the rest of the population with the "normal" susceptibility (genotype B). Under this view, a larger uncertainty factor, i.e., 20, is warranted.

The alternative view is that the tenfold uncertainty factor actually covers a 100-fold difference in susceptibility within the human population, because it extends on both sides of the median. If we assume that differences in susceptibility are multimodal and distributed on either side of the "average" person, and that the tenfold uncertainty factor is applied to the response of that "average" person, then the tenfold uncertainty factor actually encompasses a 100-fold difference in susceptibility between the most susceptible, i.e., 10 times more susceptible than the average, and least susceptible, i.e., 10 times less than the average, individuals in the population.¹⁴² According to this view, the data showing [33 ELR 10653] a twentyfold difference between the most and least susceptible groups in the population therefore suggests that the default tenfold uncertainty factor is overprotective, and that a smaller uncertainty factor (in the range of fivefold) is justified.

There are some data suggesting that the distribution of genetic susceptibility generally follows a more complex pattern than the simple bimodal distribution consisting of a "normal" and susceptible subtype. For example, one common cytochrome p450 polymorphism involves a deficiency of the gene for the CYP2D6 enzyme, which is known to be involved in the metabolism of over 30 widely used therapeutic agents, e.g., codeine.¹⁴³ Individuals can be divided into three distinct groups depending on whether they have two copies (poor metabolizers), one copy (extensive metabolizers), or zero copies (ultrarapid metabolizers) of the deficient mutation.¹⁴⁴ Similarly, there are at least three different genotypes in the population for the enzyme serum paraoxonase (PON1), which plays a central role in the metabolism of organophosphate pesticides.¹⁴⁵ Sensitivity to cancer from exposure to ionizing radiation also appears to vary significantly across the population with a range of different susceptibilities that appear to follow a normal distribution.¹⁴⁶ The gene-gene interaction between different susceptibility genes further suggests that susceptibility will be distributed continuously, with some individuals more susceptible and others less susceptible than the "average" person.¹⁴⁷

Even if the default tenfold uncertainty factor adequately protects the vast majority of the population, there are likely to be some outlier genotypes that are not protected by the tenfold uncertainty factor. The discovery of such genetic variations affecting susceptibility may undermine one of the assumptions underlying the current approach to risk assessment and regulation of noncarcinogenic chemicals. The current approach assumes that there is a threshold level below which no adverse effects occur. While the existence of a threshold may be realistic for a specific individual, the implication of genetic heterogeneity is that there is no threshold that is applicable to the entire population.¹⁴⁸ In the absence of a scientifically definable threshold for the population, the approach of establishing RfDs and RfCs at levels that will protect the entire population is no longer plausible, to the extent that was the initial objective.¹⁴⁹ With the increased knowledge of the existence and consequences of genetic variations in susceptibility, regulators will be faced with making explicit policy and social judgments about what percentage of the population should be protected.

Most RfCs and RfDs are based on NOAELs or LOAELs in animal studies, but for those derived from human studies, genetic susceptibility factors will play an even more critical role in the development of the RfC or RfD. In its 1995 Guidance for Risk Characterization, EPA states that if reliable data on sensitive human populations are available, then the RfD is to be set at a level at which no adverse effects are observed in the sensitive human population.¹⁵⁰ In other words, the RfC or RfD is based exclusively on the most susceptible subgroup within the population. The Guidance for Risk Characterization lists the fluoride and nitrite RfDs as examples of this approach.¹⁵¹ As more human genetic susceptibilities to toxic chemicals are characterized, an increasing number of RfDs and RfCs will be based on the response of those sensitive subgroups. Environmental standards based on those RfCs and RfDs will become more stringent, in some cases by orders of magnitude in order to protect the most genetically vulnerable groups. As the most susceptible of the susceptible are identified, the costs of protection could rise exponentially. At some point, the difficult question of how much we are prepared to pay (or are capable of paying) to protect the most susceptible individuals in society will need to be confronted. It may be that there is no satisfactory answer to that question, in which case regulatory agencies will face an intractable dilemma.

Unlike the practice for noncarcinogens, EPA has traditionally not adjusted its risk assessment for carcinogens to account for susceptible subpopulations.¹⁵² EPA's carcinogen risk assessment guidelines direct agency risk assessors to identify susceptible subpopulations as part of the characterization of risk for carcinogens, and if possible to calculate separate risk estimates for susceptible populations, but do not otherwise require any additional safety factor or other way of taking into account differential susceptibility in calculating cancer risks.¹⁵³

[33 ELR 10654]

EPA's strategy of producing separate risk estimates for different susceptible populations may be useful in certain cases where the population can be subdivided into discrete subgroups with substantially different susceptibilities to a particular agent based on a well-characterized genetic polymorphism.¹⁵⁴ Probabilistic risk analysis methods such as Monte Carlo analysis could then be used to produce population risk estimates that take into account the frequency and differential susceptibility of the various genotypes in the population.¹⁵⁵ Separate risk estimates for susceptible subgroups may also be helpful in identifying the existence of unacceptably high risks for individuals with a particular genetic trait, which may not be apparent from a population risk estimate that does not take into account differential genetic susceptibility.¹⁵⁶ On the other hand, stratified risk assessment that produces separate risk estimates for different genetic subpopulations is likely to be limited by inadequate susceptibility data in many cases, as well as the practical effects of increased costs, delays, and complexity in producing and utilizing stratified risk assessments for regulatory decisionmaking.¹⁵⁷

Another approach that has been suggested for addressing differential genetic susceptibility in carcinogen risk assessment is to use safety factors to account for intraspecies variability, similar to the approach used in non-cancer risk assessment. In 1994, the National Research Council issued a congressionally mandated report on EPA's risk assessment policies which recommended EPA adopt a "default susceptibility factor" to account for differences in susceptibility in calculating cancer risks.¹⁵⁸ In response, EPA considered but elected not to adopt a default factor for human differences in susceptibility generally, concluding that the default linear, no-threshold default assumption used in carcinogen risk assessment, as well as the practice of basing such risk assessments on the response of the most sensitive species and sex of animals tested, already provides adequate protection for susceptible groups.¹⁵⁹

In response to strong pressure from environmental organizations and some scientists, EPA recently proposed providing an additional uncertainty factor in carcinogen risk assessment for one susceptible subgroup—children. Unless early-life data for the specific agent under consideration is available, EPA has proposed to increase risk estimates for exposures to children under 2 years of age by a factor of 10 and for children between 2 and 15 years by a factor of 3 in calculating cancer risks from exposure to potential carcinogens known to have a mutagenic mode of action.¹⁶⁰ This approach could establish a precedent that potentially could be applied to genetically susceptible subpopulations in the future, assuming sufficient data were available and warranted such a default adjustment factor. Applying such an uncertainty factor to genetically susceptible subgroups would be much more complicated than the proposed adjustment factor for children because of the number and variety of genes affecting susceptibility, the interaction between such genes as well as interactions with non-genetic factors affecting susceptibility, and the existence of genes that provide increased resilience in addition to those that increase susceptibility.¹⁶¹ While the incorporation of genetic susceptibility into risk assessment will be complex and challenging, such efforts are likely to be worthwhile given the potential of susceptibility data to make risk assessment more precise and informed.¹⁶²

[33 ELR 10655]

Health-Based Standards

The text or legislative history of several federal environmental statutes expressly require EPA to consider susceptible subpopulations.¹⁶³ While it has always been assumed that the population contains individuals with different genetic susceptibilities to environmental exposures, regulatory agencies have been permitted to, and as a practical matter have had little alternative but to, disregard these differences in promulgating regulatory standards because of the lack of usable data on genetic susceptibility.¹⁶⁴ This lack of adequate data will progressively be resolved as a result of the rapid advancement of scientific understanding of differential genetic susceptibility to environmental toxicants, and over the next few years regulatory agencies will be forced to consider the relevance of these data in setting standards under a variety of regulatory programs that are intended to protect susceptible individuals.

For example, § 108(f)(1)(C) of the Clean Air Act (CAA) requires the EPA Administrator to provide to federal, state, and local regulators information on "measures which may be employed to reduce the impact on public health or protect the health of sensitive or susceptible individuals or groups."¹⁶⁵ Although this particular statutory provision has not had much practical impact to date, the protection of susceptible subgroups has played a major role in the establishment of national ambient air quality standards (NAAQS) under § 109 of the CAA. Under this section, EPA is directed to set NAAQS at a level which are "requisite to protect the public health" with "an adequate margin of safety."¹⁶⁶ Although the statutory language does not refer explicitly to susceptible subgroups, the Senate Report for the legislation adopted in 1970 requires the Agency to protect such subgroups:

The Committee emphasizes that included among those persons whose health should be protected by the ambient standard are particularly sensitive citizens such as bronchial asthmatics and emphysematics who in the normal course of daily activity are exposed to the ambient environment. In establishing an ambient standard necessary to protect the health of these persons, reference should be made to a representative sample of persons comprising the sensitive group rather than to a single person in such a group.

Ambient air quality is sufficient to protect the health of such persons whenever there is an absence of adverse effect on the health of a statistically related sample of persons in sensitive groups from exposure to the ambient air. An ambient air quality standard, therefore, should be the maximum permissible ambient air level of an air pollution agent or class of such agents (related to a period of time) which will protect the health of any group in the population.

For purposes of this description, a statistically related sample is the number of persons necessary to test in order to detect a deviation in the health of any person within such sensitive group which is attributable to the condition of the ambient air.¹⁶⁷

The U.S. Court of Appeals for the D.C. Circuit has construed this legislative history to require EPA to set NAAQS "at a level at which there is an absence of adverse effect on … sensitive individuals," and therefore "if a pollutant adversely affects the health of these sensitive individuals, EPA must strengthen the entire national standard."¹⁶⁸

Consistent with this directive to protect sensitive individuals, EPA has promulgated NAAQS which are intended to protect identifiable susceptible subgroups within the population, such as children with asthma. Not surprisingly, the level of protection needed to protect sensitive subgroups becomes the determinative factor in setting air quality standards, and EPA's risk assessment and regulatory analysis tend to focus primarily on such susceptible subgroups.¹⁶⁹ Recent studies have identified genes conferring susceptibility to criteria air pollutants such as particulate matter¹⁷⁰ and ozone.¹⁷¹ As these genetic variants conferring susceptibility to air pollutants become better characterized, ambient air quality standards will likely be based on protecting people with such genetic susceptibilities.

To consider a specific example, people who are carriers of the serum [alpha] 1-antitrypsin deficiency are at increased risk of developing emphysema from pollutant exposure.¹⁷² Approximately 3% of Caucasians carry this allele, which is not found in African Americans or Asian Americans.¹⁷³ A [33 ELR 10656] NAAQS standard would almost surely need to be set at zero (or at least background levels) to protect this susceptible subpopulation. Similarly, recent data suggest that individuals carrying a combination of two different gene variants, which occur in combination in as much as one-third of the population,¹⁷⁴ experience effects from ozone exposure at levels that do not appear to affect people with other genotypes.¹⁷⁵ The ozone standard would presumably need to be significantly tightened to protect this susceptible subpopulation.

As early as 1981, the president of the Conservation Foundation, William Reilly, who would later become the Administrator of EPA, recognized the looming dilemma posed by differential susceptibility to air pollutants:

The [CAA] incorporates the notion of threshold values of pollutants, levels below which there are presumed to be no adverse health effects, and requires that standards be set on the basis of the threshold, with a margin of safety. But the concept of a threshold becomes increasingly difficult to deal with scientifically when we try to reconcile it with what we know about the heterogeneity of the population. As the definition of the sensitive population to be protected is increasingly refined, the threshold level becomes increasingly tighter, inevitably approaching zero…. Hence, in a heterogeneous population it is unlikely that, for any pollutant, there will be a single scientifically defensible threshold applicable to all people. Instead there will be a series of thresholds for different sensitive populations and a threshold of zero for some people.

In the absence of a scientifically definable threshold, the decision makers responsible for establishing a standard are inescapably forced to make social, not scientific, judgments. Any standard above zero might cause injury to some people. But a zero standard might wreak economic havoc—a zero level for almost any of the major air pollutants would virtually halt industrialization.¹⁷⁶

As former Administrator Reilly predicted, EPA will face difficult issues in determining how to adequately protect genetically susceptible subgroups in setting air quality standards. An initial issue is whether genetically susceptible individuals were intended to be included within the protection given to sensitive subgroups by the statute. There is no official or standard definition of "susceptibility" for purposes of setting air quality standards, and different unofficial definitions have been offered or assumed.¹⁷⁷ The key legislative history cited above gives as examples of sensitive subgroups that must be protected persons with asthma and emphysema.¹⁷⁸ Other statements in that same Senate Report, however, suggest that susceptibility should be construed more broadly than existing respiratory diseases. For example, the report states that protection from air pollution "must extend beyond 'normal' segments of the population to effects on the very young, the aged, the infirm, and other susceptible individuals."¹⁷⁹ There is no obvious reason or evidence that genetically susceptible individuals should be excluded from the catchall category "other susceptible individuals."

EPA's regulatory construction of the term "susceptible" appears to incorporate genetic susceptibility. In promulgating an air quality standard for lead in the late 1970s, for instance, EPA staff stated that the statute is intended to protect people at high risk from air pollutants due to either "inherent susceptibility" or unique exposure situations.¹⁸⁰ EPA defined "inherent susceptibility" as "a host characteristic or status that predisposes the host to a greater risk of heightened response to an external stimulus or agent."¹⁸¹ Genetic susceptibility would clearly fit within this definition. In more recent NAAQS rulemakings, EPA has discussed the possible existence of genetically susceptible subgroups, but has so far concluded that such susceptibilities are not sufficiently characterized to be used for standard-setting.¹⁸²

Assuming genetic susceptibilities should be included within the definition of sensitive groups, the second question is whether all genetically susceptible individuals qualify as sensitive subpopulations that must be protected by air quality standards. The legislative history of the CAA indicates that EPA is required to protect the most susceptible "groups" and not necessarily the most susceptible individual.¹⁸³ But what constitutes a sensitive "group"?¹⁸⁴ EPA has not issued any guidance or criteria on how to incorporate susceptibility data into NAAQS decisions, having relied to date on case-by-case determinations of susceptible subgroups. This approach may have worked in the past when the critical susceptible subgroups were large groups such as the elderly or asthmatic children, but as genetic susceptibilities are identified and become the driving factor for setting such standards, more complex issues are likely to be faced. For example, if only 1,000, or 100, or even 10 people in the entire nation have a particularly severe genetic susceptibility [33 ELR 10657] to ozone pollution, must the national standard for ozone be based solely on that small subgroup?

EPA has in the past characterized a sensitive subgroup as a "defined population" with "significantly higher probability of developing a condition, illness, or other abnormal status" from pollutant exposure.¹⁸⁵ At a minimum, it is likely that the characterization of the increased risk associated with a genetic polymorphism, and quite likely the frequency of the polymorphism within the population, would be prerequisites to recognizing a "defined population" consisting of people carrying that genetic trait.¹⁸⁶ It is likely that the issue of when a genetically susceptible subgroup becomes adequately "defined" will be a contentious issue that might allow the agency to postpone basing its standards on some genetically susceptible groups, but given the rapid development of scientific understanding of such susceptibilities, such delays will necessarily be of limited duration.¹⁸⁷

A third set of issues relates to what level of protection EPA must provide to a genetically susceptible subgroup that qualifies as a sensitive population under the statute. Is EPA required to establish a standard that will fully protect the health of every single individual within the susceptible subgroup? The legislative history directs EPA to establish air quality standards at a level that will ensure "an absence of adverse effect on the health of a statistically related sample" from the susceptible subpopulation.¹⁸⁸ A "statistically related sample" is defined as "the number of persons necessary to test in order to detect a deviation in the health of any person within such sensitive group."¹⁸⁹ Despite the reference to sampling, this definition appears to require full protection of every individual within the susceptible subgroup, by requiring a sample large enough to detect an effect in "any person" within the group, and then mandating an "absence of adverse effect" in that sample.¹⁹⁰

In the few cases where EPA has addressed this issue explicitly, the Agency has in fact not attempted to protect the most sensitive individuals within susceptible subgroups. In revising the ozone air quality standard in 1979, for example, EPA and its scientific experts focused "not only on the most sensitive population group, but also on a very sensitive portion of that group (specifically, those persons who are more sensitive than 99[%] of the sensitive group, but less sensitive than 1[%] of that group)."¹⁹¹ In other words, the most sensitive 1% of the most susceptible subgroup would not be protected by the standard. In promulgating its lead air quality standard in 1978, EPA likewise set a level that would protect 99.5% of children, who had been designated the most susceptible subgroup.¹⁹²

The identification of genetically susceptible subgroups within the population will force policymakers to grapple with this difficult issue of when and to what extent does society have a duty to provide special protections for vulnerable individuals. As susceptible people become individually identified, the public may be willing to expend greater resources to protect the health of these individuals because of what is known as the "identifiable victim effect."¹⁹³ Thomas Schelling encapsulated this phenomenon with the phrase "the more we know, the more we care," and gave the following illustration:

There is a distinction between an individual life and a statistical life. Let a 6-year-old girl with brown hair need thousands of dollars for an operation that will prolong her life until Christmas, and the post office will be swamped with nickels and dimes to save her. But let it be reported that without a sales tax the hospital facilities of Massachusetts will deteriorate and cause a barely perceptible increase in preventable deaths—not many will drop a tear or reach for their checkbooks.¹⁹⁴

The identifiable victim effect appears to be primarily related to the size of the at-risk group and the percentage of the at-risk group that can be saved, rather than the absolute number of lives saved.¹⁹⁵ These findings suggest that the [33 ELR 10658] public would attach greater importance to "a group of 10 randomly distributed 'vaccine sensitive' people who are at risk of death from a flu vaccine, but who cannot be identified beforehand," than "a situation in which 10 random people will be killed by the same vaccine."¹⁹⁶ In a similar manner, the public is likely to give greater prominence to an environmental risk that may result in the deaths of one-half of 500 genetically susceptible people in the population than to an exposure that imposes a risk of 1 in 1,000,000 on the entire U.S. population, even though the total expected number of deaths from the two risks are comparable. While such distinctions may not be rational, they are nonetheless an important aspect of public perceptions, and suggest that there may be strong public support for protecting genetically susceptible subgroups, even (and maybe especially) if they constitute only a minute sliver of the overall population, in setting environmental standards.¹⁹⁷

Notwithstanding public perceptions, the identification and characterization of genetic variations conferring susceptibility to pollutants will present daunting economic and policy challenges for environmental decisionmaking. Protecting 99% or 99.5% of the most genetically susceptible individuals to air pollutants has the potential to impose enormous costs on the nation, and may even be infeasible. Yet, the U.S. Supreme Court has recently interpreted the CAA to preclude any consideration of costs or feasibility in promulgating standards that will adequately protect public health, including susceptible subgroups.¹⁹⁸ As the genetic basis of susceptibility differences to air pollutants is better characterized, EPA may be forced to adopt standards that could impose unprecedented regulatory costs on society, if it adheres strictly to the statutory mandate to protect genetically susceptible subgroups regardless of cost.

The statute may need to be revised, but that would not avoid the need to address the central issue—can EPA or the U.S. Congress decide, as either a legal or ethical matter, that some groups of citizens through no fault of their own, are so susceptible that they are too expensive to protect under our environmental statutes, and thus must fend for themselves?¹⁹⁹ The unfortunate reality is that we probably cannot afford to provide full protection to the most susceptible genotypes in the population, and indeed such protection may not even be possible. Yet, there are enormous political and moral impediments to facing this reality and making decisions based on it. Genetic susceptibility information may be in that rare category of unwanted information that we would be more comfortable not knowing,²⁰⁰ but once we have the information, we cannot ignore it, and are forced to make difficult choices based on it.

Shift to Self-Help Measures

A central issue in public health and disease prevention is whether to focus interventions on a relatively small number of "high risk" individuals or rely on measures that apply to the entire population.²⁰¹ Genetic information on susceptibility to environmental toxicants could shift the focus of many environmental regulatory programs from the entire population to certain high-risk subgroups. As the largest sources of pollution continue to be controlled, genetic susceptibilities to environmental exposures will account for an increasing proportion of remaining environmental risks.²⁰² Because many environmental susceptibility genes only increase risks in the presence of the relevant environmental exposures, there is much potential for preventing disease associated with such genes by eliminating or minimizing exposures to genetically susceptible individuals.²⁰³

A key prerequisite for interventions focused on genetically susceptible individuals is the capability to identify those high-risk individuals. We are on the eve of a new era in which widespread testing for various genetic susceptibilities and predispositions, conducted either by a physician or through home-test kits, will become commonplace.²⁰⁴ For example, the British company Sciona provides such a genotyping service, which was initially offered directly to the public over the Internet.²⁰⁵ For a fee, the company offered to send a kit, called: "You and Your Genes," along with instructions for consumers to procure a sample of their DNA by brushing a cotton swab across the inside of the cheek.²⁰⁶ The returned sample was then genetically tested for mutation polymorphisms of nine common genes, such as some of the cytochrome p450 enzyme genes, that affect susceptibility [33 ELR 10659] to foods, medicines, alcohol, and other substances. A total of 19 different mutations are tested for, each of which is present in between 20% and 40% of the population, with the average person carrying 5 or 6 of the mutations.²⁰⁷ Based on the genetic test results and a lifestyle questionnaire completed by the customer, the company then provided the subject a 60-page personalized report that included "food, lifestyle, vitamins, and supplemental recommendations to help keep your body working at an optimum level."²⁰⁸

While some scientists and public interest groups criticized Sciona for exaggerating the strength of the relationship between the genetic polymorphisms and lifestyle risks, as well as for privacy concerns about the DNA samples,²⁰⁹ over 600 people purchased the genetic testing in the first few months of its commercial availability.²¹⁰ In response to criticism from the British government, however, Sciona announced in early 2003 that it would only market its genotyping service through physicians, rather than direct-to-consumer.²¹¹ As of April 2003, Sciona's website was offering three different batteries of genetic polymorphism tests relating to lifestyle—described as a "NutritionScreen," "AlcoholScreen," and "DrugScreen"—that were available through a licensed physician.²¹² Each battery of tests includes several genes that allegedly affect one's susceptibility to various foods, alcohol, and pharmaceuticals, respectively.²¹³

Several other companies are now preparing to market similar over-the-counter genetic test kits directly to consumers in the United States.²¹⁴ Quick and relatively inexpensive genetic testing services for the general public are now technologically feasible. Consumer demand will determine if they will be commercially feasible. As the potential health benefits of preventative actions based on genotype become better validated and known, the demand for such testing is likely to be significant.²¹⁵

The capability to identify individuals who are genetically susceptible to a particular product or chemical creates the potential for a paradigmatic shift in environmental regulation from protecting the entire population with a generic standard toward more individualized interventions that emphasize appropriate warnings and self-help measures.²¹⁶ This approach is already being considered in the pharmaceutical sector, where instead of banning drugs that may injure a small percentage of the population that is genetically susceptible to the product, the product will be allowed to remain on the market with warnings that consumers should be genetically tested before taking the product to ensure that they are not genetically susceptible.²¹⁷

The same warning and testing approach may apply to some chemical products where the remaining risks are primarily due to genetic susceptibility. If most risks from a particular chemical product can be attributed to genetic susceptibility in some proportion of the public, then appropriate warnings to, and avoidance behavior by, susceptible [33 ELR 10660] individuals may be the most cost-effective measure to prevent risk.²¹⁸ Indeed, this approach is already being used for some products. For example, diet soda cans provide a warning such as "Phenylketonurics: Contains Phenylalanine." This warning is intended to alert individuals with the genetic disease phenylketonuria (PKU) that the product contains a chemical (the amino acid phenylalanine produced by the metabolism of the artificial sweetener aspartame) that they should avoid because of their genetic condition. Of course, this approach assumes that exposure is a matter of individual choice, which may be the case for some commercial products but not for many ubiquitous environmental pollutants.

In addition to warnings on product labels, there are other potential approaches for providing information on genetic susceptibility to prompt self-help measures for minimizing or preventing environmental risks. Consider, for example, the widely used industrial solvent trichloroethylene (TCE). Individuals with a particular variant of one of the cytochrome p450 genes (CYP2E1) appear to be more susceptible to cancer from TCE exposure, and this risk is exacerbated significantly when the individual also consumes ethanol, which is metabolized using some of the same enzymes as TCE.²¹⁹ For at least those uses of TCE where exposure is voluntary, an effective risk management strategy may be to warn individuals to avoid TCE if they carry the particular CYP2E1 genetic variant that confers susceptibility, and certainly to avoid drinking alcohol if they may be exposed to TCE.²²⁰

Genetic susceptibility information may also influence where people choose to reside. For example, individuals carrying a particular genetic variation are at a substantially increased risk of developing chronic beryllium disease (CBD) from exposure to beryllium.²²¹ Beryllium is a commercially important metal that is highly valued in the computing, space, and other high tech industries because of its unique set of properties including its high strength, light weight, and thermal and electric conductivity.²²² Genetic tests for beryllium sensitivity have now been developed and are being offered on a voluntary basis to beryllium-exposed workers.²²³ The test has low predictive value, in that the majority of workers who test positive for the genetic susceptibility do not develop disease even when exposed to beryllium.²²⁴ Studies have nevertheless suggested that genetic screening and exclusion of genetically susceptible workers may provide the most cost-effective approach for preventing CBD in the workplace.²²⁵ While the focus of genetic screening for beryllium susceptibility has to date focused on workers, some residents living near beryllium processing plants have reportedly developed CBD.²²⁶ Even though air emissions of beryllium are tightly controlled, individuals with a genetic susceptibility may be at risk even at very low ambient levels near a beryllium-processing facility.²²⁷ Assuming such risks are significant, residents living near such a facility who have the genetic susceptibility to beryllium may be advised to consider relocating away from the plant (or better yet, not locating near the plant in the first place). While this type of action clearly raises important fairness and social justice issues, such as who should bear the cost of the relocation, it may nevertheless represent a prudent and cost-effective measure to prevent serious beryllium disease in the general population.

In addition to self-help avoidance measures, there may be other available measures to target environmental protection resources on genetically susceptible subgroups. For example, identification of susceptible individuals may facilitate a medical monitoring program designed for early detection of adverse health effects, which could facilitate prompt preventive and treatment options.²²⁸ Lifestyle modifications, such as changes in diet, may help to protect against some toxic risks in genetically susceptible individuals.²²⁹ The use of chemopreventive agents, other pharmacological interventions, or prophylactic treatments may be used to mitigate any present injury and protect against future injury.²³⁰ Further [33 ELR 10661] into the future, it may be possible for gene therapy to protect susceptible individuals.²³¹

The potential enhanced role for self-help measures to protect genetically susceptible individuals in environmental protection raises two major normative issues: (i) whether it is fair to require individuals to assume the burden of protecting themselves from environmental toxicants; and (ii) whether reliance on self-help measures will be effective.²³² On the fairness issue,²³³ one might take the position that it is the responsibility of industry as the generators of pollution and government as the regulators of pollution to ensure that all citizens are safe, and this obligation should not be relegated to particularly vulnerable members of the public.²³⁴ This position is supported, for example, by a deontological or rights-based approach to environmental policy, under which citizens have a right against being exposed to significant pollution risks.²³⁵ Such an argument is most powerful for involuntary exposures over which exposed individuals have little or no control.²³⁶ "Privatizing" risk by requiring susceptible individuals to bear the burden of avoiding such exposures would in effect be blaming the victims for their own innate vulnerabilities.²³⁷

A rights-based approach to risk has two components. First, it argues for reducing overall risks as low as possible, while recognizing that the complete elimination of risk is not feasible. Second, it argues that no individual or subgroup should be subjected to an unfair share of the remaining risk. It is this second prong that is most relevant to the issue of genetically susceptible subgroups. Some claim that there is a right of equal protection from pollution that requires that we ensure the same level of environmental protection for genetically susceptible groups as the rest of the population.²³⁸ The immutability of genetic susceptibility is said to provide a particularly compelling case for equal protection given that an individual's susceptibility is something they were born with and over which they obviously have no control.²³⁹

Yet, society often does leave citizens with immutable susceptibilities to fend for themselves against certain risks. For example, even though over 3,000,000 Americans are allergic to peanuts, and over 100 people are killed each year by anaphylactic reactions attributed to such allergies, peanuts are not banned or otherwise restricted.²⁴⁰ Instead, we leave it to allergic individuals to take appropriate steps to avoid peanuts, such as by carefully reading food labels and avoiding high-risk situations such as foods in buffets and unlabeled desserts, and to be prepared to manage the early stages of an anaphylactic reaction from inadvertent and unanticipated exposures.²⁴¹ Similarly, rather than banning perfumes, cleaning solutions, new furniture, and a multitude of other common products which sicken those with multiple chemical sensitivity (MCS), we leave those people to fend for themselves even though in many cases it largely forces their withdrawal from society.²⁴² To be sure, the lack of scientific proof and consensus on the existence or nature of MCS may [33 ELR 10662] explain, at least in part, why regulators have not taken regulatory action to protect individuals claiming to suffer from this condition.²⁴³ Even if compelling proof of MCS became available tomorrow, it is highly unlikely that society would ban or restrict the large number of consumer products that cause or aggravate MCS.²⁴⁴

Moreover, existing pollution control programs already rely to some extent on individual self-help measures to protect sensitive individuals. For example, in promulgating NAAQS, EPA has acknowledged that some susceptible individuals will not be fully protected, and thus the standards should be supplemented by a pollution warning system known as the Air Quality Index to "allow particularly sensitive individuals to take appropriate action."²⁴⁵ Similarly, the federal government is distributing gas masks to 35,000 people who live near an incinerator in Anniston, Alabama, so that the citizens can take their own precautionary measures when the government destroys nerve gas from a chemical weapons stockpile at a nearby incinerator.²⁴⁶

Even if it may be appropriate to place the responsibility on the susceptible individual to avoid exposure in some circumstances, there is likely to be much controversy over which circumstances justify such a shift in the burden from industry and government to the individual.²⁴⁷ Clearly, the case for reliance on self-help measures is strongest when such measures are more effective than traditional regulatory approaches for reducing risks, in that they reduce or eliminate some risks that are intractable using traditional broad-based regulations. The cost-effectiveness of self-help measures versus regulation will also be a critical factor. The magnitude of the risk and the proportion of the population that are susceptible may also be relevant factors.²⁴⁸ The relative difficulty and costs of risk avoidance by susceptible individuals may be another relevant factor,²⁴⁹ as is the availability and cost of a reliable genetic test to detect susceptible individuals.²⁵⁰ Focusing on high-risk individuals will be most useful when almost all the societal risk is concentrated in the susceptible subgroup, because otherwise even a small risk to the "non-susceptible" majority of the population may produce more disease cases than a high risk to a small number of susceptible individuals.²⁵¹

Another concern is that if the burden is placed on the individual, what happens when the susceptible individual fails to take the appropriate preventive or avoidance measures?²⁵² Can insurers refuse to reimburse recalcitrant susceptible individuals for their health expenses on the grounds that they failed to take appropriate avoidance measures and thus knowingly placed themselves at risk?²⁵³ Can a susceptible individual file a tort suit against the product manufacturer, or should private liability suits be preempted when there has been a regulatory judgment that the individual rather than the manufacturer should bear the burden of avoiding exposure or harm? These questions will no doubt be highly controversial, and unlikely to have simple solutions given the diversity of actual exposure and susceptibility scenarios.

The second major question is whether self-help measures by genetically susceptible individuals will be effective in reducing risk.²⁵⁴ As discussed above, self-help measures targeted at high-risk groups will be most effective when most of the population risk is concentrated in the susceptible subgroup, because otherwise measures directed at the entire population are likely to provide greater overall health benefits because of the large number of people involved, even if the risk to any one individual is relatively small.²⁵⁵ Assuming this and other factors that justify focusing on high-risk individuals apply, are there available measures which can effectively target and reduce the risks of high-risk individuals?

An initial question is whether health care professionals, who will often be the gatekeepers for an individual patient's access to genetic information, are prepared to fully utilize genetic susceptibility data by identifying and then notifying [33 ELR 10663] susceptible patients of available avoidance and preventive measures. The actions of health care professionals to date suggest that genetic information is likely to be underutilized, as physicians have been reluctant to use readily available genetic information to safeguard susceptible patients. As two U.S. Food and Drug Administration officials recently wrote, "we continue to be concerned that despite the widespread availability of simple tests to determine a patient's phenotype and/or genotype with regard to polymorphism in drug metabolizing enzymes, there has been little use of this information to tailor drug doses and dosing regimes to individual patient subgroups in clinical practice before using the drug."²⁵⁶

From the perspective of the at-risk individual, learning of one's own unique susceptibly to a particular risk may provide strong motivation to undertake behavioral changes that will reduce exposures and risk.²⁵⁷ Most people suffer from "optimism bias," in which they believe that they are some-how more resilient or fortunate than the average.²⁵⁸ Providing individual-specific information on genetic susceptibilities may help overcome this bias, as virtually every theory on health behavior suggests that behavioral change is strongly influenced by an individual's perception of their own susceptibility.²⁵⁹

On the other hand, there are few precedents in which communication of individual risk information has been successful in appreciably reducing risk-incurring behavior and associated disease.²⁶⁰ With respect to genetic risk information specifically, the increased risks associated with most genetic susceptibilities to environmental agents are relatively modest (generally no more than a fewfold increase),²⁶¹ and thus may not be dramatic enough to stimulate a strong behavioral response.²⁶² In addition, the uncertainties and inaccuracies in predicting individual genetic susceptibility due to the complex gene-gene and gene-environment interactions that exist will further dilute the effectiveness of any program based on risk communication and individual self-help measures. Finally, the anxiety that will often be associated with genetic profiling indicating increased risk may have direct adverse health effects, or may produce self-defeating or nonadaptive behaviors, that offset the health benefits of targeted behavioral modification programs based on genetic susceptibilities.²⁶³

One recent review of the limited data available on the behavioral response to genetic risk concluded that providing people with genetic information about their health risks does not appear to increase motivation to change behavior and may even reduce motivation in some people because of a feeling of inevitability given what are apparently immutable genetic risks.²⁶⁴ Another review found that providing biomarker data (including genetic information) to subjects did generally increase motivation for behavior change, but the study lacked data on whether this increased motivation led to actual behavioral change.²⁶⁵ These and other studies caution that knowledge of one's own genetic susceptibility may have a net detrimental effect if it leads to a sense of genetic fatalism or inevitability.²⁶⁶

Most of the limited data that are available to date on the effects of genetic susceptibility information on avoidance behavior have been developed in the context of genetic susceptibility to tobacco smoke. In one published study, two groups of smokers were given either quit-smoking counseling or quit-smoking counseling along with information on their personal genetic susceptibility to tobacco smoke.²⁶⁷ [33 ELR 10664] The genetic susceptibility polymorphism used in this study was present in approximately 90% of the population.²⁶⁸ After two months of follow-up, the group receiving information that they carried the genetic susceptibility gene had on average a sixfold greater increase in perceived risk, a 4.2-fold greater perceived benefit from quitting smoking, and a 4.7-fold greater effect in fear arousal than the group given counseling information only.²⁶⁹ Yet, the genetic information had only a marginal, nonstatistically significant effect on actual quitting smoking within the first 30 days.²⁷⁰ Although they had no appreciably higher avoidance behavior, the group who had been provided information on their genetic susceptibility had higher levels of post-treatment fear and depressive symptoms.²⁷¹ This led the authors of the study to caution that "if excessive distress or fear is generated, yet self-efficacy is not sufficiently high, genetic susceptibility feedback could backfire."²⁷²

A one-year follow-up of the same study found that smokers who were informed of their genetic susceptibility were more than twice as likely to have attempted to quit smoking than the other study participants, but had no higher rate of actual smoking cessation.²⁷³ This result suggests that provision of genetic susceptibility data may indeed have a beneficial effect on a subject's motivation to undertake appropriate behavior change, but that this motivation is not strong enough to overcome the addictive effects of smoking.²⁷⁴ It may be that genetic information could have a stronger outcome on changing behaviors that do not have such a strong addictive characteristic. The one-year follow-up also found no difference in depressive symptoms or other indications of psychological distress in subjects who were informed of their genetic susceptibility.²⁷⁵ The initial increases in depressive symptoms observed after two months therefore appeared to be temporary, and were not sustained after 12 months.

Another study looked at the effect of including genetic feedback as part of a multicomponent smoking cessation program.²⁷⁶ The genetic trait examined was one of the glutathione S-transferase (GSTM1) genes that is deleted in approximately 35% of the population, and individuals with this trait are at an increased risk of lung cancer from smoking relative to people who have at least one normal copy of the GSTM1 gene.²⁷⁷ Individuals who were informed that they carried the genetic susceptibility had significantly greater rates of smoking cessation after six months than subjects who were given no genetic information, but there was no statistically significant difference in smoking cessation between the two groups at 12 months of follow-up.²⁷⁸ Unlike the previous study, no differences in risk perception or levels of depression were observed as a result of provision of personal genetic susceptibility information. Also notable was that subjects who were informed that they did not carry the genetic susceptibility to cancer from smoking had the same cessation rate as the other groups, alleviating concerns that people with reduced genetic risk would engage in more high-risk behaviors.²⁷⁹ The authors suggested that the demographics of this study population, which consisted of low-income smokers recruited at an inner-city community health clinic, may have influenced the study results given that 45% of the subjects indicated in follow-up interviews that they did not fully understand the genetic test results.²⁸⁰

These limited findings suggest that provision of individual susceptibility data may have some beneficial effect on behavior, although the existence and strength of this effect needs to be tested in nonsmoking contexts where addiction is less of an issue. In addition, the available studies confirm that the psychological impact of providing personal genetic information is potentially important, but that such information appears to produce at most only a short-term temporary increase in depression and a sense of fatalism. Any proposed intervention strategy that includes communicating genetic susceptibility data must therefore take careful consideration of the effect of providing genetic information on actual behavior, as well as what additional steps can be taken to maximize the beneficial and appropriate use of that information.

Environmental Justice

Many of the genetic polymorphism affecting susceptibility to environmental exposures vary in frequency between different ethnic groups.²⁸¹ Some of these frequency differences are dramatic. An extreme example is one variant of the CYP1A1 gene which has been found in approximately 8% of African Americans but not at all in Caucasians or Asian Americans.²⁸² The CYP1A1 gene codes for one of the cyto-chrome p450 enzymes that catalyzes the first step in the metabolism of polycyclic aromatic hydrocarbons, such as those found in tobacco smoke.²⁸³

Ethnic differences in the frequency of genetic susceptibility genes may raise environmental justice issues. Yet, application of environmental justice to genetic susceptibility would involve several shifts from the traditional environmental justice paradigm. The traditional environmental justice focus has been on minority or low-income populations that have been exposed to disproportionate risks due to higher exposures to environmental contaminants. The higher exposure typically occurs to the population of concern clustered in a specific geographical area.

[33 ELR 10665]

One difference from this traditional paradigm is that genetically susceptible individuals will usually not be concentrated geographically into a local community, but rather may be dispersed throughout the general population.²⁸⁴ Application of environmental justice principles to dispersed populations would not be without precedent. For example, EPA's National Environmental Justice Advisory Committee has recently been evaluating environmental justice issues with regard to fish consumption by subsistence fishermen and Indian tribes, which are not always concentrated in a particular location.²⁸⁵ On the other hand, environmental justice is not just concerned about some people having greater risk than others, but it also has a social component in that it focuses on those communities with disproportionate exposures who are also disadvantaged and disempowered because of race or poverty, and therefore may be unable to protect their rights through the normal democratic process.²⁸⁶ This view of environmental justice would accord less priority to genetically susceptible individuals scattered throughout the population than to a geographically concentrated community of disadvantaged people.²⁸⁷

A second issue is whether environmental justice applies to disproportionate risk or disproportionate exposure. As discussed above, the traditional environmental justice paradigm addresses the unfairness of inequitable exposure to toxic substances by poor or minority groups due to factors such as their lack of empowerment to resist polluting facilities. Should environmental justice also apply to people who are not exposed to higher levels than the general population, but who are at an elevated risk from that exposure? One could argue that there is a right to equal protection against environmental harm,²⁸⁸ and that protection is best determined by focusing on risk rather than exposure. On the other hand, disproportionate exposure may invoke stronger considerations of unfairness and culpability that might justify stronger regulatory or legal remedies.

Finally, to the extent that environmental justice applies to genetically susceptible subgroups, should it apply only to those genetic susceptibilities that are disproportionately concentrated in particular ethnic groups? Do they have to be disadvantaged ethnic groups? Because race itself has no direct causal role in the higher risks that genetically susceptible groups may face,²⁸⁹ it makes little policy sense to apply environmental justice to those genetic susceptibilities that are clustered in particular racial groups but not to genetic susceptibilities more evenly spread throughout the entire population. Some commentators have argued that environmental justice principles, and presumably legal protections, should also apply to all genetically susceptible subgroups, regardless of their ethnic distribution.²⁹⁰ Such application of environmental justice policies would be consistent with the ethical principle that individuals should not be exposed to disproportionate environmental risk based on intrinsic factors beyond their control.²⁹¹ Yet, both the legal and policy underpinnings of environmental justice policies are based primarily on race, and thus would appear to be inapplicable to race-neutral genetic susceptibilities.²⁹²

Americans With Disability Act

The implications of genetic susceptibilities to toxicants under the Americans With Disability Act (ADA) have primarily focused on workers to date,²⁹³ but the ADA may also apply to some environmental exposures for genetically susceptible individuals. Specifically, genetic susceptibilities to environmental pollutants may be used to support legal actions under Title II of the ADA to require additional pollution reductions beyond those required by environmental statutes. Title II of the ADA provides that no "public entity" may "exclude from participation in or deny the benefits of the services, programs, or activities of a public entity," or "subject to discrimination by any such entity," any "qualified person with a disability."²⁹⁴ A public entity is required [33 ELR 10666] to make "reasonable modifications in policies, practices, or procedures" to accommodate individuals with disabilities, unless the entity can demonstrate that such modifications would "fundamentally alter" the nature of the service, program, or activity.²⁹⁵

A threshold definitional issue is whether a person carrying a genetic susceptibility to environmental pollutants is "disabled" under the ADA. The statute defines "disability" as (i) "a physical or mental impairment that substantially limits one or more of the major life activities"; (ii) "a record of such an impairment"; or (iii) "being regarded as having such an impairment."²⁹⁶ In 1995, the Equal Employment Opportunity Commission (EEOC) issued an interpretation in which it concluded that an asymptomatic genetically susceptible worker was "disabled'" under the "regarded as" prong of the disability definition.²⁹⁷ However, this "regarded as" prong is unlikely to apply in the context of environmental susceptibilities under Title II of the ADA, since this provision is primarily directed at employers who discriminate against workers who are perceived as disabled.²⁹⁸ A public entity is unlikely to be required under the ADA to take additional environmental protective measures based on perceived rather than actual disabilities.

The courts have generally defined "disability" narrowly. For example, the U.S. Supreme Court has held that a disability can exist "only where an impairment 'substantially limits' a major life activity, not where it 'might,' 'could,' or 'would' be substantially limiting."²⁹⁹ Thus, a plaintiff asserting an ADA claim against an environmental exposure would need to have an existing genetic disease or such a strong predisposition that the individual could not engage in a major life activity. Despite this hurdle, there has already been some limited success in applying Title II of the ADA to environmental pollution to protect susceptible individuals. In 1999, an organization called "Save Our Summers" filed a lawsuit under the ADA claiming that the statute applied to environmental programs.³⁰⁰ The lawsuit contended that a permit issued under the CAA by the Washington Department of Ecology violated the ADA because it authorized burning of wheat stubble which produced smoke that prevented two children who lived nearby, one with asthma and one with cystic fibrosis, from availing themselves of public facilities such as schools, roads, and parks. Washington State defended the case by arguing that the ADA did not apply to activities regulated and permitted under the CAA. After the U.S. district court denied the plaintiff's motion for a preliminary injunction based on its preliminary conclusion that the ADA claims were foreclosed by the comprehensive regulatory scheme of the CAA, the U.S. Department of Justice (DOJ) filed an amicus curiae brief arguing that the ADA and CAA could be read harmoniously.³⁰¹

According to the DOJ, ADA claims against polluting activities are not barred by environmental statutes such as the CAA, and the ADA requires reasonable modifications of regulated environmental activities to protect disabled persons, "but do not require modifications that would constitute a fundamental alteration of an existing program."³⁰² The DOJ argued that "what constitutes reasonable modifications is highly fact-specific, requiring case-by-case inquiry,"³⁰³ but the government refused to take a position on any proposed modifications in the Save Our Summers³⁰⁴ case. The DOJ brief did suggest, however, that remedies that were "localized, site-specific, and carefully tailored for the affected individuals" would be more likely to be legally acceptable and not represent a fundamental alteration of the CAA. Based in large part on this argument by the federal government, the district court declined to dismiss the case,³⁰⁵ which then settled prior to trial.³⁰⁶

Persons with a strong genetic susceptibility to an environmental pollutant may therefore argue that the ADA requires more stringent environmental protection, at least where such added protection would not fundamentally alter the existing environmental statutory scheme. It will be up to regulatory agencies in the first instance, and to the courts ultimately, to determine whether and how the ADA applies to environmental regulation. If the ADA is indeed held by the courts to apply to environmental exposures, it has the potential, as one commentator recently noted, "to become the nation's most stringent and comprehensive environmental statute."³⁰⁷ Data on genetic susceptibility to environmental pollutants are likely to provide much of the fuel for any such environmental lawsuits under the ADA in the future.

[33 ELR 10667]

Caveats and Limitations

The potential application of genetic susceptibility data in both litigation and regulatory contexts has important scientific and ethical limitations. As discussed above, most genes conferring susceptibility to environmental toxicants have several complicating features, including a relatively modest increase in risk that may be affected by other genes, other types of susceptibility, ethnicity, and dose.³⁰⁸ The accurate isolation and quantification of the effects of such genes on susceptibility will require large epidemiology studies that stratify the population studies by genotype.³⁰⁹ Even when such studies have been completed, there will remain many uncertainties and technical complexities in applying such data, especially to the individual. Another problem is that when the population is subdivided into many different subgroups based on genotypes, there is a higher chance of spurious associations being reported solely as a result of chance.³¹⁰

Even more significant will be the many critical social, policy, ethical, and legal issues associated with the collection and application of genetic susceptibility data. These issues include the individual's right to privacy and confidentiality with respect to their genetic information, and minimizing the risks of discrimination from the potential misuse of such information. Other issues that will apply in both the litigation and regulatory contexts are respecting an individual's right not to know about certain genetic propensities or traits, and assuring appropriate informed consent for the collection and use of an individual's genetic information. Finally, safeguards, including appropriate genetic counseling, will be needed to protect against stigmatizing individuals based on their genetic susceptibility information, and minimizing and managing the psychological stress associated with finding out one's own susceptibilities and vulnerabilities.³¹¹

Notwithstanding the importance of providing these protections for the individual to guard against the misuse of their genetic information, overemphasis on the potential pitfalls of genetic technology may impede many of the important benefits it offers. Many consumers are likely to be deterred from obtaining and utilizing their genetic information if they are convinced that such actions will expose them to potential discrimination by third parties.³¹² The preoccupation with the risks of genetic discrimination by many journalists, policymakers, and commentators may be providing consumers with an exaggerated perception of the risks of genetic discrimination, perhaps frightening much of the public away from benefitting from genetic information. Some legislative protection against discrimination may help to allay such fears, but there are concerns in the research community that many of the restrictions being enacted or proposed in state and federal legislation will unnecessarily impede genetic research and foreclose many of the potential environmental health benefits of genetic susceptibility data.³¹³

Conclusion

Genetic technologies will fundamentally transform both environmental regulation and toxic torts over the next decade. These technologies and the data they will provide have the potential to make toxics regulation and litigation more informed, effective, and fair. At the same time, genetic approaches will present a major challenge to existing institutions for managing toxic risks. As two commentators recently warned, "this is clearly a situation where rapid scientific and technological advance could outrun our institutional capabilities and test our moral fabric."³¹⁴ To prevent this from occurring, it is imperative that we begin addressing now the legal, policy, and ethical issues that genomics will present for the management of toxic risks, before this rapidly advancing technology makes such discussions moot.

1. International Human Genome Sequencing Consortium, Initial Sequencing and Analysis of the Human Genome, 409 NATURE 860, 911 (2001).

2. The terms genetic "susceptibility" and genetic "sensitivity" are often used interchangeably to refer to a genetic predisposition to disease from exposure to one or more toxic agents. Some authors distinguish the two terms, however, and limit the term genetic "susceptibility" to a predisposition to a certain type of adverse health effect, such as breast cancer. In contrast, genetic "sensitivity" is used to refer to a vulnerability to exposure to a particular environmental agent or exposure. See, e.g., R. Julian Preston, Interindividual Variations in Susceptibility and Sensitivity: Linking Risk Assessment and Risk Management, 111 TOXICOLOGY 331, 332 (1996). In other words, "susceptibility" is in reference to a health outcome, while "sensitivity" applies to an environmental agent. While this distinction is important yet subtle, most of the scientific and policy literature uses the term "susceptibility" to both refer to a predisposition to a particular disease and a sensitivity to a particular type of exposure. This Article will accordingly follow that trend and refer to susceptibility to environmental exposures, while noting the potential for some confusion.

3. See, e.g., Kenneth Olden & Janet Guthrie, Genomics: Implications for Toxicology, 473 MUTATION RES. 3, 3-4 (2001); William W. Au et al., Usefulness of Genetic Susceptibility and Biomarkers for Evaluation of Environmental Health Risk, 37 ENVTL. & MOLECULAR MUTAGENESIS 215 (2001); N. Rothman et al., The Use of Common Genetic Polymorphisms to Enhance the Epidemiologic Study of Environmental Carcinogens, 1471 BIOCHICA BIOPHYSICA ACTA C1 (2001).

4. EDWARD J. CALABRESE, ECOGENETICS: GENETIC VARIATION IN SUSCEPTIBILITY TO ENVIRONMENTAL AGENTS (1984); E.S. Vesell, Pharmacogenetic Perspectives on Susceptibility to Toxic Industrial Chemicals, 44 BRIT. J. IND. MED. 505, 506 (1987). As two environmental health scientists from the federal government write,

it is well known that not all smokers develop lung cancer, most females exposed in utero to diethylstilbestrol never develop vaginal or cervical cancer, and the overwhelming majority of individuals exposed to dust mites and cockroach allergens never develop asthma. So, the answer to the most common question asked of physicians, i.e., "Why me, Doc?" … will not be answered by looking only at the environment. One answer to these questions is that genetically-determined differences in susceptibility may be at least partly responsible.

Olden & Guthrie, supra note 3, at 5.

5. See E. Dybing et al., Hazard Characterization of Chemicals in Food and Diet: Dose Response, Mechanisms, and Extrapolation Issues, 40 FOOD & CHEM. TOXICOLOGY 237, 248 (2002). The fact some individuals but not others appeared to have an inherent susceptibility to fava beans was known as far back as 510 B.C., when Pythagoras made this observation. See Mary H.H. Ensom et al., Pharmacogenetics: The Therapeutic Drug Monitoring of the Future?, 40 CLINICAL PHARMACOKINETICS 783, 785 (2001).

6. Dybing et al., supra note 5, at 248.

7. David N. Irani & Richard T. Johnson, Diagnosis and Prevention of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease, 54 ANN. REV. MD. 305, 314 (2003) (100% of people suffering from vCJD carry a specific genetic mutation that is present in approximately 40% of the general population); Carolyn Abraham, Mad-Cow Victims Share Genetic Trait, GLOBE & MAIL, Aug. 10, 2002, at A1 ("All 135 people on the planet who have contracted the human form of so-called mad-cow disease have carried a specific genetic trait.").

8. See generally William E. Evans & Julie A. Johnson, Pharmacogenomics: The Inherited Basis for Interindividual Differences in Drug Response, 2 ANN. REV. HUM. GENETICS 9 (2001); Lars Noah, The Coming Pharmacogenomics Revolution: Tailoring Drugs to Fit Patients' Genetic Profiles, 42 JURIMETRICS 1 (2002).

9. Early in the 20th century, Sir Archibald Garrod, the discoverer of several inborn errors of metabolism, made this very observation: "In every case of every malady there are two sets of factors at work in the formation of the morbid picture, namely internal or constitutional factors, inherent in the sufferer and usually inherited from his forebearers, and external ones which fire the train." Quoted in David L. Eaton et al., Genetic Susceptibility, in ENVIRONMENTAL AND OCCUPATIONAL MEDICINE 209, 209 (William N. Rom ed., 3d ed. 1998).

10. A "polymorphism" is generally defined as a genetic variant that is present in the human gene pool at a frequency of at least 1%. See Evans & Johnson, supra note 8, at 14. Many other genetic variants are present at lower frequencies.

11. In addition, the same susceptibility information may have many other important applications in addition to toxic torts and environmental protection, such as in occupational health and safety, pharmaceutical regulation, and public health. These applications are also outside the scope of this Article.

12. Emile F. Nuwaysir et al., Microarrays and Toxicology: The Advent of Toxicogenetics, 24 MOLECULAR CARCINOGENESIS 153, 158 (1999); Richard J. Albertini, Developing Sustainable Studies on Environmental Health, 480-81 MUTATION RES. 317, 323 (2001).

13. Gary E. Marchant, Genomics and Toxic Substances: Part I—Toxicogenomics, 33 ELR 10071 (Jan. 2003).

14. See Seymour Garte et al., Metabolic Gene Polymorphism Frequencies in Control Populations, 10 CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION 1239, 1239 (2001); Olden & Guthrie, supra note 3, at 5; David C. Christiani et al., Applying Genomic Technologies in Environmental Health Research: Challenges and Opportunities, 43 J. OCCUPATIONAL ENVTL. MED. 526-33 (2001); Edward J. Calabrese, Biochemical Individuality: The Next Generation, 24 REG. TOXICOLOGY & PHARMACOLOGY S58, S63-S64 (1996) (listing many of the genetic polymorphisms affecting susceptibility and the environmental agents which increase risk for each polymorphism).

15. A comprehensive listing of such polymorphisms identified as of 1999 is provided in INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC), METABOLIC POLYMORPHISMS AND SUSCEPTIBILITY TO CANCER, IARC SCIENTIFIC PUBLICATIONS NO. 148 (P. Vineis et al. eds., 1999) [hereinafter IARC METABOLIC POLYMORPHISMS].

16. See Daniel W. Nebert, Drug-Metabolizing Enzymes, Polymorphisms, and Interindividual Response to Environmental Toxicants, 38 CLINICAL CHEM. LAB. MED. 857, 860 (2000); Werner Kalow, Both Populations and Individuals Are Evolutionary Targets: Pharmacogenomic and Cultural Indicators, 2 PHARMACOGENOMICS J. 12 (2002).

17. The "p" in cytochrome p450 stands for protein, and the "450" identifies the wavelength of the light they absorb. Each cytochrome p450 enzyme is designated by the generic term "CYP" and then a three digit identifier, such as 1A1, 2E1, or 3A4.

18. See Evans & Johnson, supra note 8, at 15; Daniel W. Nebert & Amy L. Roe, Ethnic and Genetic Differences in Metabolism Genes and Risk of Toxicity and Cancer, 274 SCI. TOTAL ENV'T 93, 95 (2001).

19. For example, the CYP2A6 enzyme, a member of the cytochrome p450 family, activates several parental compounds (often referred to as "procarcinogens") such as aflotoxin and 1,3-butadiene into carcinogenic intermediates. See Masami Miyamoto et al., CYP2A6 Gene Deletion Reduces Susceptibility to Lung Cancer, 261 BIOCHEMICAL & BIOPHYSICAL RES. COMMUNICATIONS 658, 658 (1999). Individuals with two nonfunctional copies of the gene coding for this enzyme deleted have a risk of lung cancer that is only 25% of the rate in people carrying two normal copies of the gene, presumably because such individuals are less able to convert procarcinogens into their carcinogenic metabolites. Id. at 659.

20. When the parent compound is the toxic agent, the reverse will apply. "Slow metabolizer" variants will increase risk, and "rapid metabolizer" variants will decrease risk. See Dybing et al., supra note 5, at 242; Nebert & Roe, supra note 18, at 95. These same cytochrome p450 enzymes play a similar role in determining both the efficacy and toxicity of pharmaceuticals. If the metabolite is the active pharmaceutical agent, then a genetic variant that increases metabolism will produce too much of the active agent, potentially resulting in adverse side-effects. A variant that decreases metabolism will result in too little of the active component being formed, and standard dosage of the drug may be ineffective in such persons.

21. See Eaton et al., supra note 9, at 210.

22. See F. Peter Guengerich, Pharmacogenomics of Cytochrome p450 and Other Enzymes Involved in Biotransformation of Xenobiotics, 49 DRUG DEV. RES. 4, 5 (2000).

23. See Kaname Kawajira, CYP1A1, in IARC, METABOLIC POLYMORPHISMS, supra note 15, at 159. Consistent with scientific convention, the name of enzymes will be given in normal font capital letters, while the gene with the same name that codes for that enzyme will be shown in italicized capitals.

24. See J.A. Indulski & W. Lutz, Metabolic Genotype in Relation to Individual Susceptibility to Environmental Carcinogens, 73 INT'L ARCHIVES OCCUPATIONAL ENVTL. HEALTH 71, 72-74 (2000).

25. See Douglas A. Bell et al., Genetic Risk and Carcinogen Exposure: A Common Inherited Defect of the Carcinogen-Metabolism Gene Glutathione S-Tranferase M1 (GSTM1) That Increases Susceptibility to Bladder Cancer, 85 J. NAT'L CANCER INST. 1159, 1162 (1993); Radim J. Sram, Effect of Glutathione S-Transferase M1 Polymorphisms on Biomarkers of Exposure and Effects, 106 (Suppl. 1) ENVTL. HEALTH PERSP. 231, 231-32 (1998); Lawrence S. Engel et al., Pooled Analysis and Meta-Analysis of Glutathione S-Transferase M1 and Bladder Cancer: A HuGE Review, 156 AM. J. EPIDEMIOLOGY 95 (2002); William P. Bennett et al., Environmental Tobacco Smoke, Genetic Susceptibility, and Risk of Lung Cancer in Never-Smoking Women, 91 J. NAT'L CANCER INST. 2009 (1999).

26. The null genotype for GSTT1 is found in approximately 64% of Chinese, 60% of Koreans, 15% to 24% in different Caucasian populations, 20% to 24% of African Americans, and just under 10% of Mexican Americans. See Stefano Landi, Mammalian Class Theta GST and Differential Susceptibility to Carcinogens: A Review, 463 MUTATION RES. 247, 260-61 (2000); Hisham A. El-Masri et al., Effects of Glutathione Transferase Theta Polymorphism on the Risk Estimates of Dichloromethane to Humans, 158 TOXICOLOGY & APPLIED PHARMACOLOGY 221, 222 (1999).

27. See Dybing, supra note 5, at 260; El-Masri et al., supra note 26, at 230.

28. K.T. Kelsey et al., Sister-Chromatid Exchanges, Glutathione S-Transferase Theta Deletion and Cytogenetic Sensitivity to Diepoxybutane in Lymphocytes From Butadiene Monomer Production Workers, 335 MUTATION RES. 267 (1995); Eaton et al., supra note 9, at 213-14; Landi, supra note 26, at 247.

29. Two types of susceptibility genes can be distinguished. See Neil Caporaso & Alisa Goldstein, Cancer Genes: Single and Susceptibility: Exposing the Difference, 5 PHARMACOGENETICS 59 (1995). One category, which includes genes such as BRCA1 which predispose the carrier to breast cancer, increase the risk of one or more diseases independent of any environmental exposure. Environmental or other genetic factors may modify the risks associated with these genes, but some appreciable and often large risk exists regardless of environmental exposures. These susceptibility genes tend to occur at low frequency but adversely affect a high percentage of the individuals carrying the genes, and are therefore often referred to as high penetrance genes. The second category of susceptibility genes, which are the primary focus of this Article, are those that increase the risk of disease from exposure to particular toxic agents. These genes tend to occur at high frequencies in the population but involve only a modest increase in risk for any one individual, and thus are sometimes described as low penetrance genes. Of course, the degree of penetrance for both types of susceptibility genes varies along a continuum, but this categorization into two general types is useful for distinguishing those genes for which environmental exposures are critical for determining risk versus those where environmental exposures have only a minor modifying effect. Id.; Lisbeth E. Knudsen et al., Risk Assessment: The Importance of Genetic Polymorphisms in Man, 482 MUTATION RES. 83, 84 (2001); Peter G. Shields & Curtis C. Harris, Cancer Risk and Low-Penetrance Susceptibility Genes in Gene-Environment Interactions, 18 J. CLINICAL ONCOLOGY 2309, 2309 (2000).

30. See, e.g., Knudsen et al., supra note 29, at 84-85 (people carrying a polymorphism of an N-acetyltransferase gene have an elevated risk of bladder cancer among smokers, but have no increased risk in nonsmokers); Matthew B. Schabath et al., A Myeloperoxidase Polymorphism Associated With Reduced Risk of Lung Cancer, 37 LUNG CANCER 35, 38 (2002) (polymorphism in gene for enzyme myeloperoxidase has protective effect against lung cancer in smokers but no impact in nonsmokers).

31. Kenneth Olden & Samuel Wilson, Environmental Health and Genomics: Visions and Implications, 1 NATURE REV. GENETICS 149, 149 (2000).

32. As discussed above, individuals lacking both copies of the GSTT1 gene are more resilient to methylene chloride, but more sensitive to butadiene or ethylene oxide exposures. See supra notes 27-28 and accompanying text.

33. See Frederica P. Perera, Molecular Epidemiology: Insights Into Cancer Susceptibility, Risk Assessment, and Prevention, 88 J. NAT'L CANCER INST. 496, 502 (1996); Wolfgang Hoffmann et al., "Host Factors"—Evolution of Concepts of Individual Sensitivity and Susceptibility, 204 INT'L J. HYGIENE & ENVTL. HEALTH 5, 11 (2001).

34. William W. Au et al., Genetic Susceptibility to Environmental Disease and Its Impact on Quality of Life, in HUMAN MONITORING AFTER ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO CHEMICAL AND PHYSICAL AGENTS 312, 313 (Diana Anderson et al. eds., 2000).

35. Seymour Garte, Metabolic Susceptibility Genes as Cancer Risk Factors: Time for a Reassessment? 10 CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION 1233, 1233 (2001).

36. See Christiani et al., supra note 14, at 530 ("Each of us carries dozens of such risk-conferring polymorphisms."); Hoffmann et al., supra note 33, at 12 ("Susceptibility is not a problem of a genetically underprivileged minority but a general principle that likely concerns almost everybody and relates to almost any exposure situation …."); Perera, supra note 33, at 505 ("factors known or believed to affect susceptibility are not rare events in the human population. Thus, there are few cases where the risk is likely to be confined to a few 'outliers'").

37. See Eaton, supra note 9, at 214 ("Because biotransformation of xenobiotics is usually a multistep pathway involving both activation and detoxification steps, one might expect that certain combinations of genotypes could be especially predisposing to chemical-induced disease."); Paul D.P. Pharoah et al., Polygenic Susceptibility to Breast Cancer and Implications for Prevention, 31 NATURE GENETICS 33, 35 (2002) (polygenic approach can identify high-risk individuals for particular type of risk); Ari Hirvonen, Combination of Susceptible Genotypes and Individual Responses to Toxicants, 105 (Suppl. 4) ENVTL. HEALTH PERSP. 755, 756 (1997) ("Given the number and variability in expression of carcinogen-metabolizing enzymes and the complexity of chemical exposures, assessment of a single polymorphic genotype cannot be expected to be sufficient for evaluating individual susceptibility to environmental agents. Establishment of a broader risk profile [based on the combination of susceptible genotypes] for each individual or subtype is required."); Garte, supra note 35, at 1234-35.

38. See Jocelyn Kaiser, Environment Institute Lays Plans for Gene Hunt, 278 SCIENCE 569, 569 (1997); Olden & Wilson, supra note 31, at 151; Richard R. Sharp & J. Carl Barrett, The Environmental Genome Project and Bioethics, 9 KENNEDY INST. ETHICS J. 175 (1999).

39. Press Release, National Institute of Environmental Health Sciences, Environmental Health Institute Announces Advances in Genomics (Apr. 16, 2003), available at http://www.niehs.nih.gov/oc/news/genev3.htm. See also Jocelyn Kaiser, Tying Genetics to the Risk of Environmental Diseases, 300 SCIENCE 563 (2003); National Inst. of Health (NIH), Environmental Health Prevention Research, Prepared Testimony of Kenneth Olden, Director of the National Institute of Environmental Health Sciences, Before the Subcomm. on Public Health, Senate Comm. on Health, Education, Labor, and Pensions, at 8 (Mar. 6, 2002); Susan M. Booker, Environmental Genome Project: A Positive Sequence of Events, 109 ENVTL. HEALTH PERSP. A22 (2001). See also Frederica Gemignani et al., A Catalogue of Polymorphisms Related to Xenobiotic Metabolism and Cancer Susceptibility, 12 PHARMACOGENETICS 459 (2002) (identifying 313 known experimentally confirmed polymorphisms in 54 candidate genes affecting cancer susceptibility from exposure to toxic substances).

40. Rothman et al., supra note 3, at C3; Olden & Wilson, supra note 31, at 152; Paul Brennan, Gene-Environment Interaction and the Aetiology of Cancer: What Does It Mean and How Can We Measure It?, 23 CARCINOGENESIS 381, 381 (2002).

41. See Brennan, supra note 40, at 381; Hidemi Ito et al., Monoamine Oxidase Polymorphisms and Smoking Behavior in Japanese, 13 PHARMACOGENETICS 73 (2003) (some people predisposed to tobacco addiction by polymorphisms in gene for the enzyme monoamine oxidase, which affects a smoker's requirement for nicotine); Chun Xu et al., CYP2A6 Genetic Variation and Potential Consequences, 54 ADVANCED DRUG DELIVERY REV. 1245, 1251 (2002) (variations in gene CYP2A6 affect nicotine metabolism and smoking behavior); Caryn Lerman et al., Pharmacogenetic Investigation of Smoking Cessation Treatment, 12 PHARMACOGENETICS 627 (2002) (variations in CYP2B6 affect cravings for nicotine and relapse rates in smoking cessation programs); Caryn Lerman & Wade Berrettini, Elucidating the Role of Genetic Factors in Smoking Behavior and Nicotine Dependence, 118 AM. J. MED. GENETICS 48-54 (2003) (review of data suggesting genetic role in smoking behavior).

42. See infra note 171.

43. See infra note 170.

44. Xiaobin Wang et al., Genetic Susceptibility to Benzene and Shortened Gestation: Evidence of Gene-Environment Interaction, 152 AM. J. EPIDEMIOLOGY 693, 698-99 (2000) (women with a specific variant of a cytochrome p450 gene and a glutathione S-transferase gene have shortened gestation period relative to other genotypes in response to benzene exposures); Daniel W. Nebert et al., NAD(P)H:quinone Oxidoreductase (NQO1) Polymorphism, Exposure to Benzene, and Predisposition to Disease: A HuGE Review, 4 GENETICS MED. 62 (2002) (common genetic polymorphism resulting in negligible activity of enzyme NAD(P)H:quinone results in increased risk of cancer from benzene exposure).

45. Landi, supra note 26, at 265-66.

46. El-Masri et al., supra note 26, at 222.

47. Marie Vahter, Genetic Polymorphism in the Biotransformation of Inorganic Arsenic and Its Role in Toxicity, 112-113 TOXICOLOGY LETTER 209, 213-14 (2000); Hung-Yi Chiou et al., Arsenic Methylation Capacity, Body Retention, and Null Genotypes of Glutathione S-Transferase M1 and T1 Among Current Arsenic-Exposed Residents in Taiwan, 386 MUTATION RES. 197 (1997).

48. Matthew B. Schabath et al., Association Between Asbestos Exposure, Cigarette Smoking, Myeloperoxidase (MPO) Genotypes, and Lung Cancer Risk, 42 AM. J. IND. MED. 29 (2002); A. Hirvonen et al., Inherited GSTM1 and NAT2 Defects as Concurrent Risk Modifers in Asbestos-Related Human Malignant Mesothelioma, 55 CANCER RES. 2981 (1995); C. Mark Smith et al., Inherited Glutathione-S-Transferase Deficiency Is a Risk Factor for Pulmonary Asbestosis, 3 CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION 461 (1994).

49. Ruey-Hong Wong et al., XRCC1 and CYP2E1 Polymorphisms as Susceptibility Factors of Plasma Mutant p53 Protein and Anti-p53 Antibody Expression in Vinyl Chloride Monomer-Exposed Polyvinyl Chloride Workers, 11 CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION 475, 481 (2002).

50. Walter F. Stewart et al., ApoE Genotype, Past Adult Lead Exposure, and Neurobehavioral Function, 110 ENVTL. HEALTH PERSP. 501 (2002).

51. Klaus Golka et al., The Enhanced Bladder Cancer Susceptibility of NAT2 Slow Acetylators Towards Aromatic Amines: A Review Considering Ethnic Differences, 128 TOXICOLOGY LETTER 229 (2002); David W. Hein, N-Acetyltransferase Genetics and Their Role in Predisposition to Aromatic and Heterocylic Amine-Induced Carcinogenesis, 112-113 TOXICOLOGY LETTER 349 (2000).

52. Ricarda Thier et al., Influence of Polymorphisms of the Human Glutathione Transferases and Cytochrome P450 2E1 Enzyme on the Metabolism and Toxicity of Ethylene Oxide and Acrylonitrile, 482 MUTATION RES. 41 (2001).

53. Id.

54. Gina M. Pastino et al., Human Variability and Susceptibility to Trichloroethylene, 108 (Suppl. 2) ENVTL. HEALTH PERSP. 201 (2000).

55. Luca Richeldi et al., HLA-DPB1 Glutamate 69: A Genetic Marker of Beryllium Disease, 262 SCIENCE 242 (1993) (97% of the workers tested who developed chronic beryllium disease carry a specific genetic susceptibility gene consisting of a specific mutation in the HLA-DPB1 marker); Zaolin Wang et al., Differential Susceptibilities to Chronic Beryllium Disease Contributed by Different Glu69 HLA-DPB1 and -DPA1 Alleles, 163 J. IMMUNOLOGY 1647 (1999); Erin C. McCanlies et al., HLA-DPB1 and Chronic Beryllium Disease: A HuGE Review, 157 AM. J. EPIDEMIOLOGY 388 (2003).

56. Bennett et al., supra note 25, at 2012.

57. Olden & Guthrie, supra note 3, at 5. The susceptibility genes are therefore different than deterministic disease-causing genes such as those that cause cystic fibrosis, Tay-Sachs disease, or Huntington's disease.

58. See Brennan, supra note 40, at 384; Olden & Wilson, supra note 31, at 150; Caporaso & Goldstein, supra note 29, at 60; Garte et al., supra note 14, at 1240.

59. See Brennan, supra note 40, at 382; Olden & Wilson, supra note 31, at 150; Garte, supra note 35, at 1234; Eaton et al., supra note 9, at 209. Preliminary data suggests that individuals with susceptible variants of metabolic genes are underrepresented in senior citizens populations, suggesting that such individuals may have a shorter life-span. Au et al., supra note 34, at 316-17. One study estimated that the deletion of the GSTM1 gene in approximately one-half of the population is responsible for 25% of all bladder cancers, which represents 12,550 of the 50,200 new bladder cancer cases diagnosed each year in the United States. Bell et al., supra note 25, at 1163.

60. See Garte, supra note 35, at 1233 ("when one surveys the literature (especially in the last five years) on metabolic gene variants as cancer risk factors, it is apparent that the most striking feature of the published studies is the heterogeneity of the results"); Garte et al., supra note 14, at 1239; Au et al., supra note 3, at 217; Hein, supra note 51, at 350-51 (attributing some of the inconsistent results to the failure to accurately distinguish the large number of different alleles of highly polymorphic metabolic genes such as the N-acetyltransferases).

61. See Brennan, supra note 40, at 384; Garte et al., supra note 14, at 1240; Robert Milliken, The Changing Face of Epidemiology in the Genomics Era, 13 EPIDEMIOLOGY 472, 475 (2002).

62. Hirvonen, supra note 37, at 755.

63. See Susan R. Poulter, Genetic Testing in Toxic Injury Litigation: The Path to Certainty or a Blind Alley, 41 JURIMETRICS 211, 221-31 (2001).

64. See Kei Nakachi et al., Polymorphisms of the CYP1A1 and Glutathione S-Transferase Genes Associated With Susceptibility to Lung Cancer in Relation to Cigarette Dose in a Japanese Population, 53 CANCER RES. 2994 (1993) (the combined effect of two susceptibility genotypes (GST1 and CYP1A1) resulted in a 41-fold increase of risk at low-dose levels but only a twofold risk increase at high doses); Bennett et al.; supra note 25, at 2012 (increased risk from tobacco smoke in people with GSTM1 gene deficiency occurs primarily at low-exposure levels); Schabath, supra note 10, at 38 (variant of gene for enzyme myeloperoxidase has protective effect against lung cancer in light smokers but not moderate or heavy smokers); Hirvonen et al., supra note 48, at 2981 (increased risk from GSTM1 and NAT2 susceptible genotypes occurs primarily in high exposure groups). See generally E. Taioli et al., Models of Interaction Between Metabolic Genes and Environmental Exposures in Cancer Susceptibility, 106 ENVTL. HEALTH PERSP. 67 (1998); Eino Hietanen et al., Interaction Bewteen Dose and Susceptibility to Environmental Cancer: A Short Review, 105 (Suppl. 4) ENVTL. HEALTH PERSP. 763-66 (1997).

65. See Schabath et al., supra note 10, at 38-39 (finding that genetic polymorphism for enzyme myeloperoxidase has protective effect against lung cancer in male smokers but not females, and noting that similar gender differences are observed for other genetic polymorphisms including many of cytochrome p450 polymorphisms).

66. Au et al., supra note 3, at 217; Nebert & Roe, supra note 18, at 100; Seymour Garte, The Role of Ethnicity in Cancer Susceptibility Gene Polymorphisms: The Example of CYP1A1, 19 CARCINOGENESIS 1329, 1330 (1998). For example, the GSTM1 null allele was strongly associated with the development of lung cancer in Chinese, Finnish, Japanese, and Slovakian populations, but no such association was found in American, English, Portugese, and Spanish populations. Au et al., supra note 34, at 313. It is unlikely that the same gene has different functions in different ethnic groups, and thus the discrepant effects of some genetic susceptibilities in different ethnic groups is likely due to one or both of two possible explanations. The first is that the known differences in frequencies of these alleles between ethnic groups may make it more difficult to obtain a statistically significant association in those ethnic groups where the allele frequency is lower. Garte, supra, at 1331. A second possible explanation is that the differential susceptibility is affected (or determined solely) by one or more other genes closely linked to the gene being evaluated, and that the linkage patterns differ between ethnic groups. Id.

67. Garte et al., supra note 14, at 1240 ("It has been demonstrated in many studies that allele frequencies of the metabolic genes are not randomly distributed throughout the human population but follow diverse ethnic and/or geographic-specific patterns."); Au et al., supra note 3, at 217-19; Nebert & Roe, supra note 18, at 97-99; Wendell W. Weber, Populations and Genetic Polymorphisms, 4 MOLECULAR DIAGNOSIS 299, 304-05 (1999); Heather H. Nelson et al., Ethnic Differences in the Prevalence of the Homozygous-Deleted Genotype of Glutathione S-Transferase Theta, 16 CARCINOGENESIS 1243 (1995). For example, approximately 50% of many Asiatic populations lack a functional gene for the enzyme aldehyde dehydrogenase 2 (ALDH2), which plays a key role in the metabolism of ethanol as well as chemicals such as toluene, whereas this deficiency is much less common in Caucasian populations. This genetic variation results in many Asian people being unable to metabolize alcohol, which builds up in the body and causes nausea, face flushing, and other symptoms. See Sofia Pavanello & Erminio Clonfero, Biological Indicators of Genotoxic Risk and Metabolic Polymorphisms, 463 MUTATION RES. 285, 286 (2000).

68. For example, a study in Taiwan found that deletions of the genes for two glutathione S-transferases (GSTM1 and GSTT1) appeared to play a role in arsenic toxicity observed in populations in that country. Chiou et al., supra note 47, at 205. Fifty-nine percent of the Taiwanese population included in this study carried the null genotype for GSTM1 and 26% had the null genotype for GSTT1. Id. Other populations have much lower frequencies of these genetic polymorphisms, and thus may exhibit strikingly different risk levels to the same pollutant.

69. See Vesell, supra note 4, at 505; Perera, supra note 33, at 503-04; William W. Au, Life Style Factors and Acquired Susceptibility to Environmental Disease, 204 INT'L J. ENVTL. HEALTH 17 (2001). For example, individuals infected with the parasite Schistosoma, cells pre-treated with ionizing radiation, or individuals who smoke cigarettes, are all more susceptible to subsequent environmental exposures. Id. Similarly, the increased risk from solvents such as trichloroethylene in individuals with a common variant of the CYP2E1 metabolic gene is exacerbated by alcohol consumption. Pastino et al., supra note 54, at 204.

70. See Vesell, supra note 4, at 505.

71. Au, supra note 69, at 21. But see Olden & Guthrie, supra note 3, at 5 ("It is well documented that genetic variability in several super-families of xenobiotic metabolizing enzymes … is the major determinant of host-specific chemical susceptibility.").

72. See Hirvonen, supra note 37, at 755; Wendell W. Weber, Effect of Pharmacogenetics on Medicine, 37 ENVTL. & MOLECULAR MUTAGENESIS 179, 182 (2001); Au et al., supra note 3, at 217; Nebert & Roe, supra note 18, at 98; Pharoah et al., supra note 37, at 36.

73. See Wei Zhou et al., Genetic Polymorphisms in N-Acetyltransferase-2 and Microsomal Epoxide Hydrolase, Cumulative Cigarette Smoking, and Lung Cancer, 11 CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION 15, 20 (2002) (N-acetyltransferase-2 (NAT2) and epoxide hydrolase (mEH) genetic polymorphisms confer independent and additive increases in risk of lung cancer in smokers).

74. See Perera, supra note 33, at 502.

75. See Knudsen et al., supra note 29, at 86 (combination of both glutathione S-transferase M1 null allele and N-acetyltransferase slow acetylator genotype produced greatest increase in level of chromosomal aberrations in nonsmoking bus drivers and mail carriers).

76. See Olden & Guthrie, supra note 3, at 4 ("Particularly in the case of low-dose toxicants, the interactions of susceptibility genes with specific environmental factors are probably the dominant cause of any resultant human illness."); Eaton et al., supra note 9, at 209 ("As we reduce harmful exposures in the workplace and the environment more generally, genetic variations could account for a larger proportion of the remaining risk of adverse health effects from chemical and other exposures.").

77. See Weber, supra note 72, at 179; Michael F.W. Festing, Experimental Approaches to the Determination of Genetic Variability, 120 TOXICOLOGY LETTER 293, 294 (2001) ("Genotyping of individuals from a sample of DNA is becoming increasingly easy so that already it is possible to genotype people for loci that are thought to control susceptibility to those xenobiotics to which they are likely to be exposed."). DNA microarrays or "gene chips" create the potential to rapidly characterize the genotype (genetic complement) of an individual by hybridizing the individual's DNA to the DNA microarray. See Francis S. Collins, Microarrays and Macroconsequences, 21 (Suppl.) NATURE GENETICS 2, 2 (1999) ("Applied to mutation screening of disease genes with pronounced allelic heterogeneity, the use of microarrays is likely to move the possibility of genetic testing for disease susceptibility of individuals, or even entire populations, into the realm of practical reality."); Christiani et al., supra note 14, at 526-27 (microarrays "will allow large-scale, low-cost genotyping of both individuals and populations"). Some industry laboratories routinely analyze 5,000 genotypes per day using DNA microarrays, and this capacity will soon increase to 100,000 genotypes per day using automated microarray systems. See Howard L. McLeod & William E. Evans, Pharmacogenomics: Unlocking the Human Genome for Better Drug Therapy, 41 ANN. REV. PHARMACOLOGY & TOXICOLOGY 101, 103 (2001). By way of comparison, it would have taken a laboratory over 20 years to conduct a similar analysis of the genes of a single individual using pre-microarray technology. Id. at 102.

78. One of the central tenets of toxicology, first attributed to Paracelsus in the 16th century, is that the dose makes the poison. See M. ALICE OTTOBONI, THE DOSE MAKES THE POISON 30-31 (2d ed. 1991). Paracelsus wrote: "What is it that is not poison? All things are poison and nothing is without poison. It is the dose only that makes a thing not a poison." Quoted in id. at 31.

79. See Hoffmann, supra note 33, at 6 (describing shift from "exposure-causes-effect" paradigm to a more complex approach that incorporates host factors, i.e., individual susceptibility).

80. Ricarda Thier & Hermann M. Bolt, The New Era of Toxicology, 11 TRENDS PHARMACOLOGICAL SCI. 549, 549 (2001).

81. E.g., Daubert v. Merrell Dow Pharmaceuticals, Inc., 43 F.3d 1311, 1321, 25 ELR 20856, 20860 (9th Cir. 1995); Hall v. Baxter Healthcare Corp., 947 F. Supp. 1387, 1403-04 (D. Or. 1996); Allison v. McGhan Med. Corp., 184 F.3d 1300, 1315 (11th Cir. 1999). Other courts have rejected the requirement to show a doubling of relative risk. See generally Russellyn S. Carruth & Bernard D. Goldstein, Relative Risk Greater Than Two in Proof of Causation in Toxic Tort Litigation, 41 JURIMETRICS 195 (2001).

82. See Frederica P. Perera, Environment and Cancer: Who Are Susceptible?, 278 SCIENCE 1068, 1072 (1997) ("In epidemiology, it has been difficult to detect relative risks of 1.5 or even 2.0."); Gary Taubes, Epidemiology Faces Its Limits, 269 SCIENCE 164, 165 (1995) (noting only a handful of carcinogenic agents have produced relative risk greater than 2.0 in epidemiology studies).

83. See, e.g., Peter G. Shields & Curtis C. Harris, Molecular Epidemiology and the Genetics of Environmental Cancer, 266 J. AM. MED. ASS'N 681 (1991); Ofer Shpilberg et al., The Next Stage: Molecular Epidemiology, 50 J. CLINICAL EPIDEMIOLOGY 633 (1997).

84. Some courts have already hinted at such an approach. See, e.g., Hall, 947 F. Supp. at 1398 n.26 (even when statistical study shows relative risk less than 2, some plaintiffs may still recover if they can "demonstrate that they differ in some significant way from the subjects of the statistical study"); Daubert, 43 F.3d at 1321 n.16, 25 ELR at 20861 n.16 ("A statistical study showing a relative risk of less than two could be combined with other evidence to show that it is more likely than not that the accused cause is responsible for as particular plaintiff's injury," but in that particular case the "plaintiffs' experts did not seek to differentiate these plaintiffs from the subjects of the statistical studies.").

85. See Ernest H. Hornsby & Dianna Pendleton, Plaintiffs' Mounting Case Against Silicone Gel Breast Implants, MEDICAL-LEGAL ASPECTS OF BREAST IMPLANTS, Mar. 1998, at 5; Gary E. Marchant, Genetic Susceptibility and Biomarkers in Toxic Injury Litigation, 41 JURIMETRICS 67, 91-92 (2000).

86. In re Hanford Nuclear Reservation Litig., No. C Y-91-3015-AAM, 1998 WL 775340 (E.D. Wash. 1998), rev'd on other grounds, 292 F.3d 1124 (9th Cir. 2002). See Marchant, supra note 85, at 90-91.

87. E.g., V. Leroy Young et al., HLA Typing in Women With Breast Implants, 96 PLASTIC & RECONSTRUCTIVE SURGERY 1497, 1508 (1995) (study suggesting that some women may carry a genetic susceptibility to silicone). See Hall, 947 F. Supp. at 1456 (court-appointed expert summarizes plaintiffs' evidence of genetic susceptibility to silicone breast implants but concludes that the existing data is conflicting and "too small to draw meaningful conclusions").

88. But see Woolf v. Consolidated NDE, Inc., 796 A.2d 906, 908, 912 n.1 (N.J. Super. Ct. 2001) (worker's compensation claimant successfully demonstrated that occupational exposures most likely caused his leukemia in part by showing that he carried a chromosomal abnormality known as a "Philadelphia chromosome" which made him genetically predisposed to developing leukemia).

89. See, e.g., Collins v. Hygenic Corp. of Or., 739 P.2d 1073, 1076-77 (Or. Ct. App. 1987) (worker recovers for injury allegedly caused by chemical exposure two orders of magnitude lower than safe level for average person based on expert's testimony of a "high clinical suspicion" that the plaintiff was unusually susceptible to the chemical).

90. E.g., In re Hanford Nuclear Reservation Litig., 1998 WL 775340, at *70 (use of susceptibility factor to calculate plaintiffs' risk from radiation exposure must be rejected because "of the present reality that there is no way to identify persons who are allegedly more susceptible to radiation-induced thyroid cancer, nor can alleged differences in susceptibility be quantified."); Hall, 947 F. Supp. at 1456 (rejecting introduction of evidence of genetic susceptibility to silicone because the breast implant plaintiffs had failed to show that they carried the specific genes allegedly conferring susceptibility).

91. See generally GENETIC SECRETS: PROTECTING PRIVACY AND CONFIDENTIALITY IN THE GENETIC ERA (Mark A. Rothstein ed., 1997).

92. See Ronald M. Green & A. Mathew Thomas, DNA: Five Distinguishing Features for Policy Analysis, 11 HARV. J.L. & TECH. 571, 572 (1998) (describing "informational risks" from finding out genetic information about one's self that a person may prefer not to know).

93. See Marchant, supra note 85, at 106-08; Anthony S. Niedwiecki, Science Fact or Science Fiction? The Implications of Court-Ordered Genetic Testing Under Rule 35, 34 U.S.F. L. REV. 295, 345-46 (2000).

94. For example, a chemical company defendant successfully obtained a court order to genetically test a mentally retarded child who claimed that his mother's workplace exposure to solvents caused his condition. See Sally Lehrman, Pushing Limits of DNA Testing: Suit Prompts Study Into Whether a Birth Defect Was Inherited or Caused by Toxics, S.F. EXAMINER, June 5, 1994, at A1; Marchant, supra note 85, at 99-100. In another high-profile case, the Burlington-Northern Railway secretly genetically tested workers for a genetic trait that allegedly could be an alternative cause of the workers' carpal tunnel syndrome. See Equal Employment Opportunity Comm'n v. Burlington Northern Santa Fe R.R., No. C01-4013 MWB, settlement reached (N.D. Iowa, Apr. 17, 2001); Tamar Lewin, Commission Sues Railroad to End Genetic Testing in Work Injury Cases, N.Y. TIMES, Feb. 10, 2001, at A7. See also Bourkney v. New York Infirmary-Beekman Downtown (N.Y. Sup. Ct. Nov. 19, 2002), reported at 228 N.Y.L.J. 18 (Nov. 19, 2002) (granting defendant hospital's motion to compel genetic testing of plaintiff in medical malpractice case).

95. Diane E. Lewis, Under a Genetic Cloud: The Benefits of DNA Testing Come With a Potential for Abuse, BOSTON GLOBE, Aug. 14, 1994, at A1 (quoting Philip Reilly).

96. See Marchant, supra note 85, at 80-84; John Gerald Gleeson, Idiosyncrasy: A Developing Defense in Drug and Hazardous Substances Litigation, FOR THE DEFENSE, Apr. 1989, at 9; Joseph J. Ortego et al., Idiosyncratic Reactions: A Limitation on the Duty to Warn, MEALEY'S LITIG. REP.: TOXIC TORTS, Oct. 20, 1999, at 29.

97. For example, in Cavallo v. Star Enterprise, 100 F.3d 1150, 27 ELR 20428 (4th Cir. 1996), a homeowner claimed to be "highly susceptible" to fuel vapors to support her claim that she had been injured by inhaling fuel vapors from a spill at a nearby petroleum distribution terminal. The U.S. Court of Appeals for the Fourth Circuit held that only those adverse effects that would be suffered by a "normal" person are cognizable, and thus plaintiff's own allegation that she was "highly susceptible" to fuel vapors precluded her recovery. Id. at 1154, 27 ELR at 20429.

98. An alternative approach that arguably might apply is the "eggshell skull" doctrine, which holds a tortfeasor liable for all damages to an unusually fragile plaintiff, even if those damages were far in excess of what would be expected in a "normal" person. See Vosburg v. Putney, 50 N.W. 403, 404 (Wis. 1891) ("the rule of damages in actions for torts … [is] that the wrongdoer is liable for all injuries resulting directly from the wrongful act, whether they could or could not have been foreseen by him."). See also Gary L. Bahr & Bruce N. Graham, The Thin Skull Plaintiff Concept: Evasive or Persuasive?, 15 LOY. L.A. L. REV. 409 (1982). The eggshell skull doctrine applies only where the defendant has been negligent, and does not apply in strict liability cases. Id. at 409; Dahlen v. Gulf Crews, Inc., 281 F.2d 487, 495 (5th Cir. 2002). The eggshell skull doctrine will therefore have limited application to genetically susceptible plaintiffs in toxic tort cases which are primarily based on strict liability, as discussed further in Marchant, supra note 85, at 81-84.

99. See Adelman-Tremblay v. Jewel Cos., 859 F.2d 517, 522 (7th Cir. 1988). This justification is inconsistent with the modern toxicological understanding that all toxic responses involve the interaction of environmental factors with host factors.

100. Bingham v. Terminix Int'l Co., 896 F. Supp. 642, 645 (S.D. Miss. 1995).

101. The idiosyncratic response doctrine has generally only applied to rare hypersentitivities that are much less prevalent than many of the more important genetic polymorphisms that are relatively common in the general population. See Marchant, supra note 85, at 81 n.73 (the most commonly occurring susceptibility to which the idiosyncratic response doctrine has been applied in a published decision is present in the population at a frequency of 1 in 2000 people). Some of the major genetic polymorphisms affecting susceptibility to environmental exposures, which are present in from 1% to 50% of the population, therefore may be too prevalent to trigger the idiosyncratic response defense. See Perera, supra note 33, at 505 (given the frequency of many susceptibility factors in the population, "there are few cases where the risk is likely to be confined to a few 'outliers'"). The idiosyncratic defense therefore may be limited in its application to less common genetic variants.

102. Some courts have limited the idiosyncratic response defense to generally safe over-the-counter products such as cosmetics, and have relaxed "the rule of nonliability" for products such as pharmaceuticals, vaccines, and industrial chemicals with "dangerous propensities." Presbrey v. Gillette Co., 435 N.E.2d 513, 513 (Ill. App. Ct. 1982); Goldman v. Walco Tool & Eng'g Co., 614 N.E.2d 42, 49 (Ill. App. Ct. 1993). It is difficult to conceive of a clear rule separating products with "dangerous propensities" from those without such potential risks given that any substance has the potential to harm some individuals at some dose levels. See John D. Graham, Historical Perspective on Risk Assessment in the Federal Government, 102 TOXICOLOGY 29, 31 (1995):

Toxicity, the capacity of a substance to produce serious bodily injury or death, is an inherent property of every chemical substance. Even those substances which we ordinarily think of as non-toxic, such as sugar, salt or water, possess the inherent capacity to produce serious bodily injury or death, but to a slight degree relative to other substances which are ordinarily considered toxic.

103. See, e.g., Griggs v. Combe, Inc., 456 So. 2d 790, 792 (Ala. 1984) (idiosyncratic response defense applies when defendant "could have no foreknowledge of this type of injury" and "it was not negligent in marketing the product").

104. The "identifiable victim effect," discussed infra at notes 193-197 and accompanying text, suggests that then public would attach greater not lesser importance to susceptible individuals who can be identified relative to statistical risks for the entire population.

105. See infra notes 204-215 and accompanying text.

106. Some courts have expressly based their decision on whether a susceptibility warning is required on whether or not susceptible individuals are "identifiable" and therefore can presumably take appropriate avoidance action if warned. See, e.g., Adelman-Tremblay v. Jewel Cos., 859 F.2d 517, 517 (7th Cir. 1988) (requiring warning if there is an "identifiable class of sensitive users"). Conversely, if the susceptible individuals cannot be identified, no warning is required. See Kaempfe v. Lehn & Fink Prods., 249 N.Y.S.2d 840, 845-46 (1964) ("in the case of a useful and reasonably safe product, in general use, the supplier owes no special duty of warning to the unknown few who constitute a mere microscopic fraction of potential users who may suffer some allergic reaction not common to the ordinary or normal person") (emphasis added).

107. For example, the Restatement (Second) of Torts requires a warning only if a manufacturer knows or should know there is a special danger. RESTATEMENT (SECOND) TORTS § 492A cmt. j.

108. Courts have imposed a general duty on manufacturers to adequately test their products. E.g., Borel v. Fibreboard Paper Prods. Corp., 493 F.2d 1076, 1090 (5th Cir. 1973), cert. denied, 419 U.S. 869 (1974) ("[A] manufacturer has a duty to test and inspect his product."); RESTATEMENT (THIRD) OF TORTS: PRODUCTS LIABILITY § 2 cmt. m (1997) ("[A] seller bears responsibility to perform reasonable testing prior to marketing a product and to discover risks and risk-avoidance measures that such testing would reveal."). The issue of whether and to what extent a manufacturer must test its product in susceptible subgroups has yet to be defined, however.

109. The recently enacted Restatement (Third) of Torts provides that a manufacturer may be liable for failure to warn "when the foreseeable risks of harm posed by the product could have been reduced or avoided by the provision of reasonable instructions or warnings …." RESTATEMENT (THIRD) OF TORTS: PRODUCTS LIABILITY § 2(c) (1998). See also Hawkinson v. A.H. Robins Co., 595 F. Supp. 1290, 1308 (Colo. 1984) (describing standard as that of a "reasonably prudent" manufacturer); W. PAGE KEETON ET AL., PROSSER AND KEETON ON THE LAW OF TORTS § 99, at 697 (5th ed. 1984) ("there will be no liability unless manufacturer failed to take the precautions that a reasonable person would take in presenting the product to the public"); Oakes v. E.I. Dupont de Nemours & Co., 272 Cal. App. 2d 645, 651 (Cal. Ct. App. 1969) ("To exact an obligation to warn the user of unknown and unknowable allergies, sensitivities and idiosyncracies would be for the courts to recast the manufacturer in the role of an insurer ….").

110. See Mark A. Rothstein & Phyllis Griffin Epps, Ethical and Legal Implications of Pharmacogenomics, 2 NATURE GENETICS 228, 230-31 (2001) (a drug manufacturer is likely to be held liable for failing to warn about a genetic susceptibility "that was knowable in the light of generally recognized and prevailing best scientific and medical knowledge available at the time of manufacture and distribution").

111. For example, the Restatement (Second) of Torts requires a manufacturer of a product to warn of allergic reactions to its product when such reactions are reasonably foreseeable to the manufacturer, not generally known to the consumer, and affect "a substantial number of the population." RESTATEMENT (SECOND) OF TORTS § 402A cmt. j.

112. See John A. Robertson et al., Pharmacogenetic Challenges for the Health Care System, 21 HEALTH AFF. 155, 160-61 (2002):

As the predictive power and reliability of PGx [pharmacogenetic] tests increases, it is likely that a drug's labeling will contain information about what PGx tests are desirable before a drug is prescribed …. In the future, lawsuits for failure to give a test or properly interpret it will occur, both reflecting and reinforcing acceptance of PGx testing as an ordinary part of medical practice.

113. See supra notes 66-67, 69-75 and accompanying text.

114. Amended Complaint, Class Action, P10, Cassidy v. SmithKline Beecham (Court of Common Pleas, Chester County, Pa.) (No. 99-10423). See Holcomb B. Noble, Concerns Grow Over Reactions to Lyme Shots, N.Y. TIMES, Nov. 21, 2000, at S1 (class-action lawsuits have also been filed in New Jersey and New York in addition to the original Pennsylvania suit).

115. Amended Complaint, PP38, 48, Cassidy (No. 99-10423).

116. Centers for Disease Control & Prevention, Recommendations for the Use of Lyme Disease Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 48 (No. RR-7) MORBIDITY & MORTALITY WKLY. REP. 1, 8 (June 4, 1999) (recognizing potential for autoimmune arthritis reaction in some patients but finding no evidence of such a response in premarketing clinical studies); Sarah L. Lathrop et al., Adverse Event Reports Following Vaccination for Lyme Disease: December 1998-July 2000, 20 VACCINE 1603-08 (2002) (Centers for Disease Control and Prevention post-marketing analysis found no increase in adverse reactions from LYMErix vaccine).

117. See Manufacturer Discontinues Only Lyme Disease Vaccine, FDA CONSUMER, May 2002, at 5 ("Initially, hundreds of thousands of people received the vaccine. However, sales plummeted after highly publicized reports that some users suffered arthritis-like symptoms, muscle pain and other ailments following vaccination.").

118. Physicians, pharmacists, and other health professionals may also face liability for prescribing or dispensing drugs to patients with a genetic susceptibility to the prescribed product. See Wolfgang Sadee, Pharmacogenomics, 319 BRIT. MED. J. 1, 3 (1999); Ensom et al., supra note 5, at 787; Rothstein & Epps, supra note 110, at 230.

119. E.g., Quiroz v. Max Factor, Inc., 264 So. 2d 263, 266 (La. Ct. App. 1972); Thomas v. Gillette Co., 230 So. 2d 870, 876 (La. Ct. App. 1970), cert. denied, 233 So. 2d 249 (1970); Arata v. Tonegato, 314 P.2d 130, 133 (Cal. Ct. App. 1957).

120. See infra notes 204-215 and accompanying text.

121. For a discussion of the current status of the assumption of risk defense, and its merger into comparative fault doctrine in most (but not all) jurisdictions, see Kenneth W. Simons, Reflections on Assumption of Risk, 50 UCLA L. REV. 481 (2002).

122. See Gary E. Marchant, Genetics and Toxic Torts, 31 SETON HALL L. REV. 949, 968-69 (2001).

123. See Evans & Johnson, supra note 8, at 20 (discussing a new "paradigm" of drug development in which labeling and pretreatment testing will be required in order to target the medication for certain genotypes that can most benefit from the medication); Guengerich, supra note 22, at 8 (genotyping of patients in clinical trials for drug safety is "generally in practice already with p450 2D6 in many pharmaceutical companies"); Rothstein & Epps, supra note 110, at 228 ("Pharmacogenomics is changing the way that drugs are developed, approved, marketed and prescribed.").

124. See ROBERT BAZELL, HER-2: THE MAKING OF HERCEPTIN, A REVOLUTIONARY TREATMENT FOR BREAST CANCER (1998); L.J. Lesko & J. Woodcock, Pharmacogenomic-Guided Drug Development: Regulatory Perspective, 2 PHARMACOGNEOMIC J. 20, 23 (2002). Herceptin does not actually involve a genetic test, but rather a test for protein expression, but nevertheless demonstrates the importance of molecular tests to differentiate otherwise indistinguishable conditions.

125. See Sadee, supra note 118, at 1; Ensom et al., supra note 5, at 790. Children with the genetic deficiency can be safely treated with much lower doses (tenfold to fifteenfold lower) of the same drugs. Id.

126. See, e.g., Gautam Naik, Rx4U: Drug Firms Get Personal, WALL ST. J., Mar. 25, 2002, at B1; Lesko & Woodcock, supra note 124, at 21-23; Ensom et al., supra note 5, at 790-94.

127. See Andrew Pollack, New Era of Consumer Genetics Raises Hope and Concerns, N.Y. TIMES, Oct. 1, 2002, at 5 ("Mass market products like corn flakes may one day come in different varieties, geared to different subsets of people based on their genes.").

128. The U.S. Food and Drug Administration (FDA) is currently grappling with precisely these issues with respect to pharmaceuticals. Lesko & Woodcock, supra note 124, at 22. See also Robertson et al., supra note 112; Rothstein & Epps, supra note 110. A critical issue in determining whether a manufacturer should have a duty to warn susceptible individuals and perhaps recommend genetic testing prior to product use is the cost-effectiveness of such a screening program. See Ensom et al., supra note 5, at 794-95 (suggesting that some pre-prescribing pharmacogenetic screening may not be justified by cost-effectiveness considerations).

129. Fed. R. Civ. P. 23(b)(3).

130. Opinion of Plaintiffs' Motion for Reconsideration of Class Certification, Cosentino v. Philip Morris Inc. (N.Y. Super. Ct. Feb. 11, 1999) (No. MID-L-5135-97).

131. Lockheed Martin Corp. v. Superior Court, 94 Cal. Rptr. 2d 652, 657, 658 (Cal. Ct. App. 2000), petition for review granted, 4 P.3d 264 (Cal. 2000).

132. Mahoney v. R.J. Reynolds Tobacco Co., 204 F.R.D. 150, 157 (S.D. Iowa 2001) (denying certification to class of long-time smokers with lung cancer); Reed v. Philip Morris Inc., Civil No. 96-5070, 1997 WL 538921 (D.C. Cir., Aug. 18, 1997) (denying class certification of all District of Columbia smokers).

133. E.g., Kegel v. United States, 289 F. Supp. 790 (D. Mont. 1968) (after finding that the plaintiff would have developed the same condition within two years because of a preexisting condition, the court discounted the plaintiff's recovery to the lost income and pain and suffering that the plaintiff will incur in the two-year period immediately following the accident).

134. Mark A. Rothstein, Preventing the Discovery of Plaintiff Genetic Profiles by Defendants Seeking to Limit Damages in Personal Injury Litigation, 71 IND. L.J. 877, 900-01 (1996).

135. Pettyjohn v. Goodyear Tire & Rubber Co., No. Civ. A. 91-CV-2681, 1992 WL 105162 (E.D. Pa. Apr. 29, 1992) (ordering HIV testing); Agosto v. Trusswal Sys. Corp., 142 F.R.D. 118 (E.D. Pa. 1992) (ordering disclosure of HIV test results). See also Niedwiecki, supra note 93, at 295 (discussing court-ordered HIV and genetic testing).

136. A trial judge has the discretion to order genetic testing of a plaintiff under Rule 35 of the Federal Rules of Civil Procedure if good cause for such testing is shown. Niedwicki, supra note 93, at 299-309; Rothstein, supra note 134, at 889-91; Marchant, supra note 85, at 106-07.

137. U.S. EPA, METHODS FOR DERIVATION OF INHALATION REFERENCE CONCENTRATIONS AND APPLICATION OF INHALATION DOSIMETRY (1994); Donald G. Barnes & Michael Dourson, Reference Dose (RfD): Description and Use in Health Risk Assessments, 8 REG. TOXICOLOGY & PHARMACOLOGY 471 (1988).

138. U.S. EPA, INTEGRATED RISK INFORMATION SYSTEM, GLOSSARY OF IRIS TERMS (rev. 1999), available at http://www.epa.gov/iris/gloss8.htm.

139. A.G. Renwick & N.R. Lazarus, Human Variability and Noncancer Risk Assessment—An Analysis of the Default Uncertainty Factor, 27 REG. TOXICOLOGY & PHARMACOLOGY 3, 15 (1998); G.J. Burin & D.R. Saunders, Addressing Human Variability in Risk Assessment—The Robustness of the Intraspecies Uncertainty Factor, 30 REG. TOXICOLOGY & PHARMACOLOGY 209 (1999); P. Robinan Gentry et al., An Approach for the Quantitative Consideration of Genetic Polymorphism Data in Chemical Risk Assessment: Examples With Warfarin and Parathion, 70 TOXICOLOGICAL SCL 120-39 (2002); Edward J. Calabrese, Uncertainty Factors and Interindividual Variation, 5 REG. TOXICOLOGY & PHARMACOLOGY 190 (1985); M.L. Dourson & J.F. Stara, Regulatory History and Experimental Support of Uncertainty (Safety) Factors, 3 REG. TOXICOLOGY & PHARMACOLOGY 224 (1983); Dale Hattis et al., Distributions of Individual Susceptibility Among Humans for Toxic Effects: How Much Protection Does the Traditional Tenfold Provide for What Fraction of Which Kinds of Chemicals and Effects?, 95 ANN. N.Y. ACAD. SCL 286 (1999).

140. See INTERNATIONAL PROGRAM ON CHEMICAL SAFETY (IPCS), GUIDANCE DOCUMENT FOR THE USE OF DATE IN DEVELOPMENT OF CHEMICAL-SPECIFIC ADJUSTMENT FACTORS (CSAF) FOR INTERSPECIES DIFFERENCES AND HUMAN VARIABILITY IN DOSE/CONCENTRATION RESPONSE ASSESSMENT (World Health Organization 2001), available at http://www.ipcsharmonize.org; L.T. Haber et al., Genetic Polymorphisms in Assessing Interindividual Variability in Delivered Dose, 35 REG. TOXICOLOGY & PHARMACOLOGY 177, 178 (2002); Renwick & Lazarus, supra note 139, at 16. Regulatory agencies such as EPA have generally been moving toward replacing default tenfold safety factors with data-derived safety factors in specific cases where adequate data to characterize human variability exists. Haber et al., supra, at 178; A.G. Renwick, Data-Derived Safety Factors for the Evaluation of Food Additives and Environmental Contaminants, 10 FOOD ADDITIVES & CONTAMINANTS 275 (1993).

141. See NATIONAL RESEARCH COUNCIL (NRC), SCIENCE AND JUDGMENT IN RISK ASSESSMENT 206 (1994) ("EPA and the research community have thought almost exclusively in terms of a bimodal type of variation, with a normal majority and a hypersusceptible minority.").

142. See Haber et al., supra note 140, at 177 (noting that some authors suggesting that the tenfold default factor is inadequate to cover actual variations in human susceptibility "evaluated the total range of human variability, rather than considering that the uncertainty factor of 10 is applied to account for the degree of variability from the population average to the sensitive human").

143. See Weber, supra note 17, at 301-02.

144. Id. at 301, 304. See also Fred F. Kadlubar, Biochemical Individuality and Its Implications for Drug and Carcinogen Metabolism: Recent Insights From Acetyltransferase and Cytochrome P4501A2 Phenotyping and Genotyping in Humans, 26 DRUG METABOLISM REV. 37, 42-43 (1994) (finding a similar trimodal distribution of susceptibility for polymorphisms of the CYPIA2 gene).

145. C.E. Furlong et al., Genetic Factors in Susceptibility: Serum PONI Variation Between Individuals and Species, 8 HUMAN & ECOLOGICAL RISK ASSESSMENT 31, 38 (2002).

146. See Kenneth L. Mossman, Radiation Protection of Radiosensitive Populations, 72 HEALTH PHYSICS 519, 520 (1997).

147. See Dybing et al., supra note 5, at 242 ("A number of phase I and phase II enzymes display genetic polymorphisms, so that the distribution of xenobiotic metabolising capacity and thus potential toxicity, is not unimodal."). Yet another complication is that genetic polymorphisms are only one source of variation in human susceptibility. Other factors affecting susceptibility include age, gender, nutritional status, preexisting health conditions, and past occupational and environmental exposures.

148. Werner K. Lutz, Susceptibility Differences in Chemical Carcinogenesis Linearize the Dose-Response Relationship: Threshold Doses Can Be Defined Only for Individuals, 482 MUTATION RES. 71 (2001); William E. Bishop et al., The Genomic Revolution: What Does It Mean for Risk Assessment?, 21 RISK ANALYSIS 983, 986 (2001).

149. See Bishop et al., supra note 148, at 986; Lorenz R. Rhomberg, It's Time for Risk Assessment to Step Up to the Challenge of Informing Benefits Analysis, RISK POL'Y REP., Feb. 19, 2002, at 35, 36 (arguing that risk assessment of noncarcinogens must move beyond estimation of fictional human no-effect doses to an emphasis on estimation of acceptable risk due in part to the genetic differences in susceptibility within the population). The absence of a population threshold for any toxicant because of genetic heterogeneity in the population also subverts the historical risk assessment distinctions between carcinogenic and noncarcinogenic agents and even between genotoxic and nongenotoxic carcinogens. In both cases, the two types of agents were regulated differently because the former type of agent was assumed to have no population threshold while the latter did, a distinction which is now questionable.

150. U.S. EPA, SCIENCE POLICY COUNCIL, GUIDANCE OF RISK CHARACTERIZATION 18 (1995).

151. Id.

152. See NRC, supra note 141, at 207 ("EPA's guidelines are silent regarding person-to-person variations in susceptibility, thereby treating all humans as identical, despite substantial evidence and theory to the contrary. This is an important 'missing default' in the guidelines.").

153. U.S. EPA, Proposed Guidelines for Carcinogen Risk Assessment, 61 Fed. Reg. 17960, 17991 (Apr. 23, 1996) [hereinafter U.S. EPA, Proposed Carcinogen Guidelines] ("the hazard characterization routinely includes … identification of any subpopulations believed to be more susceptible to the hazard than the general population"); U.S. EPA, DRAFT FINAL GUIDELINES FOR CARCINOGEN RISK ASSESSMENT 3-21 (2003) (EPA/630/P-03/001A), available at http://www.epa.gov/ncea/raf/cancer2003.htm) [hereinafter U.S. EPA, DRAFT FINAL CARCINOGEN GUIDELINES] ("When there is an epidemiologic study or an animal bioassay that reports quantitative results for susceptible individuals, the data should be analyzed to provide a separate risk estimate for those who are susceptible.").

154. See Perera, supra note 33, at 505:

Wherever possible, risk assessments should explicitly account for the range of human susceptibility among the population. By presenting the distribution of risks across the population, as well as the estimated risks to specific groups known or likely to be most sensitive to the exposure in question …, risk assessment can be far more effective in shaping public policy that is both preventive and fair.

155. See generally Susan R. Poulter, Monte Carlo Simulation in Environmental Risk Assessment—Science, Policy, and Legal Issues, 9 RISK: HEALTH, SAFETY & ENV'T 7 (1998).

156. Some commentators argue that EPA's assumption that the population is biologically homogenous results in underestimation of the risks to sensitive subgroups, and hence underprotection of these groups in environmental standards. See Frederica P. Perera, Molecular Epidemiology: On the Path to Prevention?, 92 J. NAT'L CANCER INST. 602, 608 (2000):

Risk assessments by agencies such as the U.S. Environmental Protection Agency have assumed that the population is biologically homogeneous in response to carcinogens. This default assumption can lead to underestimates of risk to the population and to sensitive subgroups, leading to standards and policies that are not adequately health protective or equitable.

See also Perera, supra note 33, at 497-98.

157. See Carl F. Cranor, Eggshell Skulls and the Loss of Hair From Fright: Some Moral and Legal Principles That Protect Susceptible Populations, 4 ENVTL. TOXICOLOGY & PHARMACOLOGY 239, 244 (1997) (taking individual susceptibilities into account in risk assessments "will make the assessments more complicated and slower than they already are").

158. NRC, supra note 141, at 208. The NRC report suggested that this "default susceptibility factor" could be in the form of an extra safety factor that would increase estimated risks by a factor of 10 (or some other factor determined to be appropriate), or alternatively as a default assumption that risk assessors use the 95th or 99th percentile of risk in risk assessments. Id. at 208-09.

159. U.S. EPA, Proposed Carcinogen Guidelines, supra note 153, at 18004 (rejecting need for additional default factor for differential susceptibility because "in general, the EPA believes that the linear extrapolation is sufficiently conservative to protect public health"); U.S. EPA, DRAFT FINAL CARCINOGEN GUIDELINES, supra note 153, at A-8 ("EPA will assume that the linear default procedure adequately accounts for human variation unless there is case-specific information for a given agent that indicates a particularly susceptible subpopulation or lifestage, in which case the special information will be used."). See also Festing, supra note 77, at 293 (by basing cancer risk assessments on the most susceptible strain studied for a particular agent, regulatory agencies implicitly are providing some degree of protection for the most susceptible human subpopulations); Haber et al., supra note 140, at 178 ("Different strains of mice or rats differ dramatically in their response to specific carcinogens. It is not uncommon for a specific compound to "have little or no effect in one strain of rats or mice, but be highly toxic in another strain.").

160. U.S. EPA, SUPPLEMENTAL GUIDANCE FOR ASSESSING CANCER SUSCEPTIBILITY FROM EARLY-LIFE EXPOSURE TO CARCINOGENS 34-35 (2003) (EPA/630/R-03/003), available at http://www.epa.gov/ncea.raf/cancer2003.htm. EPA concluded that insufficient information was available to apply a similar adjustment factor for potential carcinogens that act by a nonmutagenic mode of action. Id. at 36.

161. See supra notes 57-75 and accompanying text.

162. See Olden & Wilson, supra note 31, at 152 ("Data on the prevalence and characteristics of susceptibility genes offers the potential to reduce the guesswork in risk assessment, and therefore it is likely that the ability to issue fair and appropriate regulations concerning environmental hazards will increase markedly.").

163. See generally Carl F. Cranor, Risk Assessment, Susceptible Subpopulations, and Environmental Justice, in THE LAW OF ENVIRONMENTAL JUSTICE 307, 312-17 (Michael B. Gerrard ed., 1999); ROBERT D. FRIEDMAN, SENSITIVE POPULATIONS AND ENVIRONMENTAL STANDARDS (Conservation Foundation 1981). For example, the 1996 Amendments to the Safe Drinking Water Act require EPA to "conduct a continuing program of studies to identify groups within the general population that may be at greater risk than the general population of adverse health effects from exposure to contaminants in drinking water." 42 U.S.C. § 300j-18(a)(1), ELR STAT. SDWA § 1458(a)(1). The statute expressly limits this undertaking to subpopulations that are "identified and characterized." Id.

164. For example, the Federal Communications Commission successfully defended its radiofrequency radiation standards for cell phones against a legal challenge claiming that the standards failed to adequately protect susceptible individuals by contending that there were insufficient reliable data to take interindividual differences in susceptibility into account in setting the standards. Cellular Phone Task Force v. Federal Comm'n Comm., 205 F.3d 82, 93 (2d Cir. 2000). The court and agency recognized that there were likely to be susceptible individuals within the population, but upheld the agency's determination that there "is presently inadequate knowledge to set firm standards" to protect such susceptible individuals. Id.

165. 42 U.S.C. § 7408(f)(1)(C), ELR STAT. CAA § 108(f)(1)(C).

166. Id. § 7409(b)(1), ELR STAT. CAA § 109(b)(1).

167. S. REP. No. 91-1196, at 10 (1970).

168. American Lung Ass'n v. EPA, 134 F.3d 388, 389, 28 ELR 20481, 20482 (D.C. Cir. 1998) (quotations omitted).

169. See, e.g., Lead Indus, Ass'n v. EPA, 647 F.2d 1130, 1141, 10 ELR 20643, 20654 (D.C. Cir.), cert. denied, 449 U.S. 1042 (1980) (endorsing EPA's position that "protection of the most sensitive groups within the population had to be a major consideration in determining the level at which the air quality standards should be set").

170. Yoshinori Ohtsuka et al., Genetic Linkage Analysis of Susceptibility to Particle Exposure in Mice, 22 AM. J. RESPIRATORY CELLULAR MOLECULAR BIOLOGY 574 (2000); GEORGE D. LEIKAUF ET AL., PATHOGENOMIC MECHANISMS FOR PARTICULATE MATTER INDUCTION OF ACUTE LUNG INJURY AND INFLAMMATION IN MICE, HEALTH EFFECTS INSTITUTE RESEARCH REP. No. 1065 (2001).

171. Steven R. Kleeberger et al., Linkage Analysis of Susceptibility to Ozone-Induced Lung Inflammation in Inbred Mice, 17 NATURE GENETICS 475 (1997); Enrico Bergamaschi et al., Polymorphism of Quinone-Metabolizing Enzymes and Susceptibility to Ozone-Induced Acute Effects, 163 AM. J. RESPIRATORY CRITICAL CARE MED. 1426 (2001); Massimo Corradi et al., Biomarkers of Oxidative Stress After Controlled Human Exposure to Ozone, 134 TOXICOLOGY LETTER 219 (2002); William F. McDonnell, Individual Variability in Human Lung Function Responses to Ozone Exposure, 2 ENVTL. TOXICOLOGY & PHARMACOLOGY 171, 175 (1996).

172. See Calabrese, supra note 14, at S62; Eaton et al., supra note 9, at 215-16.

173. Eaton et al., supra note 9, at 215-16.

174. Bergamaschi et al., supra note 171, at 1427. The susceptible subgroup carried two copies of the normal or "wild-type" version of the NAD(P)H:quinone oxidoreductase (NQO1) gene and contained two null variants of the glutathione-S-transferase [mu] -1 (GSTM1) gene.

175. Id. at 1429.

176. William K. Reilly, Forward to ROBERT D. FRIEDMAN, SENSITIVE POPULATIONS AND ENVIRONMENTAL STANDARDS vii, vii-viii (Conservation Foundation 1981).

177. See Rebecca T. Parkin & John M. Balbus, Can Varying Concepts of Susceptibility in Risk Assessment Affect Particulate Matter Standards?, 50 J. AIR & WASTE MANAGEMENT ASS'N 1417, 1422 (2000). Some key differences in the various definitions of susceptibility include whether only intrinsic host factors, e.g., health, age, genetics, should be considered or whether extrinsic factors such as exposure levels are also relevant, and whether susceptibility should be defined on an individual or population basis. Id. at 1419.

178. See text accompanying supra note 167 (quoting S. REP. No. 91-1196, supra note 167).

179. S. REP. No. 91-1196, supra note 167, at 7.

180. U.S. EPA, AIR QUALITY CRITERIA FOR LEAD 13-11 (1977) [hereinafter AIR QUALITY CRITERIA FOR LEAD].

181. Id.

182. See, e.g., 1 U.S. EPA, THIRD EXTERNAL REVIEW DRAFT OF AIR QUALITY CRITERIA FOR PARTICULATE MATTER E-19 (2002) ("Genetic susceptibility can plan (sic) a role in the response to inhaled or instilled particles.").

183. S. REP. NO. 91-1196, supra note 167, at 10 (air quality standards to be set at a level "which will protect the health of any group in the population") (emphasis added). Some judicial decisions have failed to recognize this distinction between protecting the most sensitive groups and most sensitive individuals. See, e.g., American Lung Ass'n v. EPA, 134 F.3d 388, 389, 28 ELR 20481, 20482 (D.C. Cir. 1998) (EPA required to protect the most "sensitive individuals"); Lead Indus. Ass'n v. EPA, 647 F.2d 1130, 1153, 10 ELR 20643, 20654 (D.C. Cir. 1980) (air quality standards are to "be set at a level at which there is 'an absence of adverse effect' on … sensitive individuals").

184. See FRIEDMAN, supra note 176, at 7 ("the choice of a sensitive population, although crucial in determining the level at which a standard will be set, is somewhat arbitrary").

185. AIR QUALITY CRITERIA FOR LEAD, supra note 180, at 13-11.

186. See FRIEDMAN, supra note 176, at 6 ("It might be argued from the legislative history [of the CAA] that Congress, in talking of sensitive populations, meant identifiable groups within the population."). In its 1978 rulemaking to establish a lead ambient air quality standard, EPA based the standard on children (aged one to five) as the relevant sensitive population, but various commentators suggested that EPA should focus instead on subgroups of children within that larger group with enhanced risk due to genetic conditions or other factors. U.S. EPA, National Primary and Secondary Ambient Air Quality Standards; for Lead; Final Rulemaking, 43 Fed. Reg. 46246, 46252 (Oct. 5, 1978) [hereinafter Lead Final Rulemaking]. EPA acknowledged "the higher risk status of such groups," but declined to base the standard on these susceptible subgroups of children because it lacked adequate information "for estimating a threshold for adverse effects [for such subgroups] separate from that of all young children." Similarly, in the preamble to the proposal for same standard, EPA stated that such sensitive subgroups could not be considered because of "insufficient data to determine the effects threshold for such groups or to accurately characterize such groups within the general population." U.S. EPA, Lead; Proposed National Ambient Air Quality Standard, 42 Fed. Reg. 63076, 63078 (Dec. 14, 1977). This precedent suggests that adequate information about the increased risk for a sensitive subgroup is a prerequisite for basing standards on such a group.

187. As mentioned above, see supra note 163, the SDWA expressly limits the focus on susceptible subgroups to those that are "identified and characterized." In its first report to Congress on susceptible subpopulations under the SDWA in December 2000, EPA concluded that because "genetic influences are complex and still poorly understood," it "is unclear to what extent individuals with heightened sensitivities due to genetic factors meet the statutory criterion of 'subpopulations that can be identified and characterized.'" OFFICE OF WATER, U.S. EPA, REPORT TO CONGRESS: EPA STUDIES ON SENSITIVE SUBPOPULATIONS AND DRINKING WATER CONTAMINANTS 4 (2000) (EPA 815-R-00-015).

188. S. REP. NO. 91-1196, supra note 167, at 10.

189. Id.

190. Cf. FRIEDMAN, supra note 176, at 8 ("This definition could reasonably be interpreted to mean that the single most sensitive individual of the most sensitive group is the benchmark of an adequate health standard. Conversely, choosing a sample from the sensitive group seems to imply focusing on some portion (e.g., 95%) of the most sensitive group.").

191. U.S. EPA, Revisions to the National Ambient Air Quality Standards for Photochemical Oxidants, Final Rulemaking, 44 Fed. Reg. 8202, 8215 (Feb. 8, 1979).

192. Lead Final Rulemaking, supra note 186, at 46249.

193. Karen E. Jenni & George Loewenstein, Explaining the "Identifiable Victim Effect," 14 J. RISK & UNCERTAINTY 235 (1997).

194. T.C. Schelling, The Life You Save May Be Your Own, in PROBLEMS IN PUBLIC EXPENDITURE ANALYSIS 127, 129 (Samuel B. Chase ed., 1968). A real-life example of the identifiable victim effect is the tremendous rescue effort and monetary donations when 18-month-old Jessica McClure was trapped in a well for 58 hours in 1987. See Jenni & Lowenstein, supra note 193, at 235. If those same resources had been expended on preventive health care for children, hundreds of children's lives could have been saved. Id.

195. Jenni & Lowenstein, supra note 193, at 235. For example, the public is willing to pay much more for a program that will eliminate all 25 fatalities that occur annually at a particular intersection than they will to fund a different program that will reduce the annual death toll of approximately 50,000 victims per year in automobile collisions nationally by the same 25 deaths prevented per year. Id. at 245.

196. Jenni & Lowenstein, supra note 193, at 254.

197. An alternative view would be that most people will support environmental protection policies if they and their families, friends and neighbors are at some risk, even if small, but may become less supportive if environmental risk is primarily clustered in a small group of susceptible individuals, with whom most people have no connection.

198. Whitman v. American Trucking Ass'n, 531 U.S. 457, 31 ELR 20512 (2001).

199. See, e.g., Cranor, supra note 157, at 245 ("Do we want to suggest that the most susceptible people in the community do not have sufficient moral standing to warrant protection, or that their standing to be protected is not equal to the healthy among us?"). EPA has already had to face such issues (at least subtlety) in deciding to set the ozone standard in the late 1970s at a level that would protect 99% of the most sensitive subgroup, rather than the most sensitive individual within that subgroup. EPA stated, somewhat defensively, that "it would be incorrect to interpret this [determination] as an indication of an utilitarian judgment to trade off the interests of 1[%] of a sensitive group against the interests of society as a whole." U.S. EPA, A METHOD FOR ASSESSING THE HEALTH RISKS ASSOCIATED WITH ALTERNATIVE AIR QUALITY STANDARDS FOR OZONE (1978), quoted in FRIEDMAN, supra note 176, at 9. EPA went on to say that "by redefining the threshold in terms of 0.005 or 0.05 [rather than 0.01] of the most sensitive group we can say that roughly half as many or five times as many people will be effected. So the somewhat arbitrary choice of 1[%] is not unimportant. But this kind of choice must be made." Id. A proliferation of data on genetic susceptibility to air pollutants is likely to bring these difficult issues to the forefront of NAAQS decisionmaking.

200. See Gregory S. Kavka, Some Social Benefits of Uncertainty, 15 MIDWEST STUD. PHIL. 311, 314 (1990) (some types of uncertainty, such as the inability to predict in advance which individuals will be affected as a result of the adoption of a given public policy, promote social cohesion and stability).

201. See GEOFFREY ROSE, THE STRATEGY OF PREVENTIVE MEDICINE 13-14 (1992); Harri Vainio & Kirtsi Husgafvel-Pursiainen, Elimination of Environmental Factors or Elimination of Individuals: Biomarkers and Prevention, 37 J. OCCUPATIONAL & ENVTL. MED. 12, 12 (1995).

202. See supra note 76 and accompanying text.

203. See Christiani et al., supra note 14, at 528.

204. See David Brown, P450: Enzymes With the Answers on Drug Risks, WASH. POST, Apr. 10, 2000, at A9 ("The day may not be far off when people know their p450 profiles the way they know their blood types."); Helen Pearson, At-Home DNA Test Kits Are Here, WALL ST. J., June 25, 2002, at D6.

205. See Pollack, supra note 127, at 5; see also http:///www.sciona.com/wellbeing/your_genes.htm (last visited Mar. 22, 2002).

206. See http:///www.sciona.com/wellbeing/guide.htm (last visited Mar. 22, 2002). See also Pollack, supra note 127, at 5

207. See Clive Cookson, Genome Project Comes to Rest on My Plate: Clive Cookson Took a Dietary Screening Test—and Was Told to Eat More Garlic and Onions, FIN. TIMES, Dec. 15, 2001, available at 2001 WL 31429423. The nine genes selected for the tests are those that affect susceptibility to many common chemicals, drugs, and foods, and were selected based on the company's conclusion that there was evidence that a change in diet or lifestyle based on the genetic information can have a benefit. Id. The company claimed it avoided including mutations that carry a high risk of developing a serious disease, e.g., breast cancer or early-onset Alzheimer's, on ethical grounds. Id. Sciona claims that it plans to expand the genetic screen from 19 to 40 polymorphisms in the near future. Id.

208. See http:///www.sciona.com/wellbeing/your_genes.htm (last visited Mar. 22, 2002).

209. See, e.g., James Meek, Genetic Testing Rules "Unenforceable"—Watchdog Calls for Suspension of Unusable Code of Practice, GUARDIAN (U.K.), June 4, 2002, at 7; Pearson, supra note 204.

210. See Pollack, supra note 127, at 5; Pearson, supra note 204, at D6; James Meek, Public "Misled by Gene Test Hype"—Scientists Cast Doubt on "Irresponsible" Claims for Checks Offered by Body Shop, GUARDIAN (U.K.), Mar. 12, 2002, at 9.

211. Pollack, supra note 127, at 8. Spurred by the controversy over Sciona's direct-to-consumer genetic tests, the United Kingdom's Human Genetics Commission issued a report in March 2003 recommending stricter controls on genetic tests marketed directly to consumers. HUMAN GENETICS COMM'N, GENES DIRECT: ENSURING THE EFFECTIVE OVERSIGHT OF GENETIC TESTS SUPPLIED DIRECTLY TO THE PUBLIC (2003), available at http://www.hgc.gov.uk/genesdirect/genesdirect_full.pdf.

212. See http://www.sciona.com/coresite/products.htm.

213. Id.

214. Pearson, supra note 204, at D6; see Pollack, supra note 127, at 5; Gail Vines, I See a Long Life and a Healthy One …, NEW SCIENTIST, Nov. 23, 2002, at 42. For example, one company is planning to soon sell a home test kit in drugstores and supermarkets that will allow consumers to test themselves to see if they carry one particular susceptibility polymorphism (a mutation of the gene coding for the cytochrome p450 2D6 enzyme) that is present in 7% to 10% of the population and results in improper metabolism of up to one-quarter of all drugs on the market, including many popular painkillers and cough medicines. See Wortman, infra note 217, at 78. A company called GeneLink is offering a series of genetic profiling test kits, including an "Oxidative Stress Profile (patent pending)" test that characterizes "an individual's inherent genetic capacity to combat oxidative stress." This profile can purportedly "measure a person's potential to efficiently control free radical damage … and destroy harmful environmental compounds," which among other things will "enable nutritional and skin care companies to recommend a specific and targeted regime of antioxidant vitamins, nutrients or skin-care formulations that have been specifically designed to compensate for predicted deficiencies." See http://www.bankdna.com/breakthrough_genetic_profiling.asp.

215. For example, a recent Harris poll found that 81% of surveyed adults would be likely, and 56% say they would be very likely, to take a genetic test that would determine whether they are at high risk for a serious disease, if there are treatments or other measures that could be taken to greatly reduce the risk of contracting the disease even if one is genetically susceptible. The Harris Poll(R) # 26, June 5, 2002, available at http://www.harrisinteractive.com/harris_poll/index.asp?PID=304. Privacy and confidentiality concerns are currently seen as an important impediment to public receptivity to genetic testing. See, e.g., Henry T. Greely, Genotype Discrimination: The Complex Case for Some Legislative Protection, 149 U. PA. L. REV. 1483, 1501 (2001) ("people who are afraid of genetic discrimination are afraid to take genetic tests that offer the possibility of improving their health"); Karen H. Rothenberg & Sharon F. Terry, Before It's Too Late—Addressing Fear of Genetic Information, 297 SCIENCE 196, 196 (2002). If proposals to strengthen genetic privacy laws are enacted and the health benefits of genetic testing become more concrete, it is likely that genetic testing will become more widespread.

216. See A. Dan Tarlock, Genetic Susceptibility and Environmental Risk Assessment: An Emerging Link, 30 ELR 10277, 10280 (Apr. 2000) ("The major policy long-run implication of the Environmental Genome Project is that it could shift the responsibility for risk minimization from society to the individual."); Olden & Wilson, supra note 31, at 152 ("Prevention, diagnosis and treatment will eventually become more individualized as differences in response to environmental stress or pharmaceutical interventions can be tailored to a patient's specific genotype."); Wendy Yap & David Rejeski, Environmental Policy in the Age of Genetics, ISSUES IN SCI. & TECH., Fall 1998, at 33, 34-35 (genetic technologies "could open up whole new avenues for prevention and allow us to custom-design individual strategies to reduce or avoid a person's exposure to environmental threats at a molecular level"); Christiani et al., supra note 14, at 531.

217. See Brown, supra note 204, at A9; Marc Wortman, Medicine Gets Personal, TECH. REV., Jan./Feb. 2001, at 72; Lesko & Woodcock, supra note 124, at 21-23; Robertson et al., supra note 112, at 159.

218. See Tarlock, supra note 216, at 10281 ("if certain at-risk groups can mitigate their exposure and risk through individual and group exposure avoidance, it might even be cheaper to subsidize these efforts than to require across the board pollutant reductions which create very low probability risks for the vast majority of a nongenetically susceptible population").

219. See Pastino et al., supra note 54, at 208-10.

220. Of course, this strategy assumes that individuals can easily ascertain their genotype for the CYP2E1 gene, which may soon be the case.

221. See supra note 55. Chronic beryllium disease, also sometimes known as berylliosis, is a debilitating and sometimes fatal respiratory disease caused by beryllium exposure. While efforts to control occupational exposures to beryllium have to date focused primarily on reducing exposures through engineering controls, work practices, and personal protective equipment, such measures are unlikely to eliminate the very low levels of beryllium dust that can cause CBD in genetically susceptible workers.

222. See Scott Fields, Toxic Beryllium: New Solutions to a Chronic Problem, 109 ENVTL. HEALTH PERSP. A74, A75 (2001). Beryllium is one-third lighter than aluminum, the next lightest metal, and six times stronger than steel. Id.

223. See Kristen Davenport, Lab Offers Genetic Testing to Beryllium Workers, SANTA FE NEW MEXICAN, Nov. 15, 2000, at A7 (describing voluntary genetic testing offered to workers exposed to beryllium at the Los Alamos National Laboratory); Stephanie Armour, Could Your Genes Hold You Back?, USA TODAY, May 5, 1999, at B1 (800 employees of largest beryllium supplier have voluntarily been tested as part of a genetic research program).

224. The majority of individuals with the genetic susceptibility gene for beryllium do not develop CBD when exposed to beryllium. Up to 30% of workers carry the susceptibility gene, but only 2% to 5% of exposed workers develop CBD. Lee S. Newman, To Be+ or Not to Be2+: Immunogenetics and Occupational Exposure, 262 SCIENCE 197, 198 (1993). Thus, the presence of the susceptibility gene signifies only an increased risk, and not the certainty, of being adversely affected by beryllium exposure.

225. Scott M. Bartell et al., Risk Estimation and Value-of-Information Analysis for Three Proposed Genetic Screening Programs for Chronic Beryllium Disease Prevention, 20 RISK ANALYSIS 87 (2000); Mark Nicas & Geoffrey P. Lomax, A Cost-Benefit Analysis of Genetic Screening for Susceptibility to Occupational Toxicants, 41 J. OCCUPATIONAL & ENVTL. MED. 535 (1999).

226. See Richard T. Sawyer et al., Chronic Beryllium Disease: A Model Interaction Between Innate and Acquired Immunity, 2 INT'L IMMUNOPHARMACOLOGY 249, 252 (2002); U.S. EPA, TOXICOLOGICAL REVIEW OF BERYLLIUM AND COMPOUNDS 16-17 (1998) (EPA/635/R-98/008).

227. See Fields, supra note 222, at A77; Henry H. Willis & H. Keith Florig, Potential Exposures and Risks From Beryllium-Containing Products, 22 RISK ANALYSIS 1019 (2002).

228. See Tarlock, supra note 216, at 10280.

229. For example, recent data suggests that increased dietary intake of antioxidants may reduce some of the increased risk of lung cancer in persons with the null GSTM1 genotype. See Christiani et al., supra note 14, at 529.

230. See Kenneth Olden et al., A Bold New Direction for Environmental Health Research, 91 AM. J. PUB. HEALTH 1964, 1966 (2001) (pharmacological intervention); Tarlock, supra note 216, at 10280 (noting possibility of prophylactic surgery to remove susceptible tissues).

231. See Sharp & Barrett, supra note 38, at 280 ("When certain genetic polymorphisms help protect against adverse exposures, individuals may wish to alter their genetic makeup to increase their tolerance to these exposures."); Olden et al., supra note 230, at 1966.

232. There are no doubt other ethical and policy issues associated with the identification of genetically susceptible individuals, including the confidentiality of such private information and the potential misuse of that information by employers, insurers, or other third parties. See Olden & Wilson, supra note 31, at 153.

233. There has been a long-standing debate on whether susceptible individuals should be excluded from the workplace or other areas or activities where they might be exposed to agents to which they are unusually sensitive. As long-ago as 1938, the famous geneticist J.B.S. Haldane wrote: "There are two sides to most of these questions involving unfavorable environments. Not only could the environment be improved, but susceptible individuals could be excluded." J.B.S. HALDANE, HEREDITY AND POLITICS 180 (1938), quoted in Calabrese, supra note 14, at S59. In June 2002, the Court held that an employer could exclude a vulnerable worker from the workplace to prevent a significant risk to the worker, even when the worker was willing to assume that risk. Chevron, U.S.A., Inc. v. Echazabal, 122 S. Ct. 2045 (2002).

234. As Alexander Hamilton proclaimed to the Constitutional Convention in 1787: "There can be no truer principle than this—that every individual of the community at large has an equal right to the protection of government." Alexander Hamilton, Address to the Constitutional Convention, June 29, 1787.

235. See, e.g., W. David Slawson, The Right to Protection From Air Pollution, 59 S. CAL. L. REV. 667 (1986); Sumudu Atapattu, The Right to a Healthy Life or the Right to Die Polluted?: The Emergence of a Human Right to a Healthy Environment Under International Law, 16 TUL. ENVTL. L.J. 65 (2002).

236. See Cranor, supra note 157, at 240. Of course, defining "voluntary" risks is not as black and white as it may first appear, in that there are varying shades of voluntariness and involuntariness. See Tarlock, supra note 216, at 10277 ("Air pollutants are the clearest example of involuntary exposure, but even in this case, those at risk could move to less polluted areas."); Cass R. Sunstein, A Note on "Voluntary" Versus "Involuntary" Risks, 8 DUKE ENVTL. L. & POL'Y F. 173, 176 (1997) ("the question whether a risk is run voluntarily or not is often not a categorical one but instead a question of degree, associated with information costs, risk-reduction costs, and the existence or not of accompanying benefits").

237. See Beverly Rockhill, The Privatization of Risk, 91 AM. J. PUB. HEALTH 365, 367 (2001); Scot D. Yoder, Individual Responsibility for Health: Decision, Not Discovery, HASTINGS CENTER REP., Mar./Apr. 2002, at 22, 27.

238. See, e.g., Cranor, supra note 157, at 239 ("all of us, even the most susceptible, have equal standing to be protected from harms from toxic substances"); id. at 240 ("since the EPA's charge is to protect the general public from exposure to toxic substances, this suggests that everyone in the public is entitled to such protections"); id. at 327 ("every person has the right to be free from exposure to toxic substances"). This view is similar to some of the broader conceptions of environmental justice discussed at infra note 290 and accompanying text.

239. Immutability has often been invoked to support for protection against genetic discrimination. See, e.g., Larry Gostin, Genetic Discrimination: The Use of Genetically-Based Diagnostic and Prognostic Tests by Employers and Insurers, 17 AM. J.L. & MED. 109, 111 (1991) (arguing for protection of people with genetic conditions because such conditions are "neither subject to the person's control, nor the result of willful behavior"). It is one thing to say that we will not discriminate against someone based on an innate characteristic, but it goes one step further, and a step that is likely to be more controversial, to suggest that there is an affirmative duty to provide more benefits or protection to someone because of an innate vulnerability. See generally ROBERT E. GOODIN, PROTECTING THE VULNERABLE: A REANALYSIS OF OUR SOCIAL RESPONSIBILITIES (1985) (discussing responsibilities toward vulnerable members of society).

240. See Hugh A. Sampson, Peanut Allergy, 346 N. ENG. J. MED. 1294, 1294 (2002).

241. Id. at 1295-96. The average patient with a peanut allergy has an allergic reaction from unanticipated or inadvertent exposure to peanuts on average once every three to five years. Id. at 1296.

242. While the etiology and even existence of MCS is controversial, it is not disputed that a relatively large number of people claim to suffer from this condition and are highly sensitive to many products used in daily life. See Robert S. Dyer & Ken Saxton, What Can Research Contribute to Regulatory Decisions About the Health Risks of Multiple Chemical Sensitivity?, 24 REG. TOXICOLOGY & PHARMACOLOGY S139, S139-40 (1996) ("There is no disagreement that a significant, albeit uncertain number of people suffer from a collection of symptoms referred to under the rubric of MCS."); Chris Winder, Mechanisms of Multiple Chemical Sensitivity, 128 TOXICOLOGY LETTER 85 (2002).

243. See Dyer & Saxton, supra note 242, at S142 ("But MCS is so ill-defined and indeterminate that it poses some special problems for regulatory decision makers.").

244. But see id. ("if MCS is found to be caused by exposures to extremely low levels of environmental chemicals, the ramifications for environmental health policy are potentially enormous. Legislators might revise existing laws to be more protective and regulators might promulgate more stringent health-based standards.").

245. U.S. EPA, National Ambient Air Quality Standards for Ozone and Particulate Matter; Advance Notice of Proposed Rulemaking, 61 Fed. Reg. 29719, 29721 (June 12, 1996); U.S. EPA, AIR QUALITY INDEX: A GUIDE TO AIR QUALITY AND YOUR HEALTH (2000) (EPA-454/R-00-005), available at http://www.epa.gov/airnow/aqibroch/.

246. Jay Reeves, U.S. Will Buy Safety Gear for Residents Near Ala. Incinerator, WASH. POST, Mar. 29, 2002, at A21.

247. See Tarlock, supra note 216, at 10277 (the long-standing assumption that "it would be unfair and inefficient to shift the burden of protection to individuals for a wide variety of pollution risks" is "open to question in light of advances in genetic research"); Cf. E. Donald Elliott, The Genome and the Law: Should Increased Genetic Knowledge Change the Law?, 25 HARV. J.L. PUB. POL'Y 61, 66-67 (2001):

We are going to have to develop new political justifications for equality before the law and, perhaps even more importantly, a new way of thinking about what equal rights before the law really mean for people who are born with different abilities and disabilities. There may even need to be an "unequal protection" right to be treated differently in light of our biological differences.

248. See Philippe Grandjean & Marja Sorsa, Ethical Aspects of Genetic Predisposition to Environmentally-Related Disease, 184 SCI. TOTAL ENV'T 37, 42 (1996) ("With relatively small excess risks and small proportions of the population involved, voluntary programs would be favored. When the risks are greater and may affect a larger proportion, paternalistic intervention could perhaps be better justified."); Patricia Danzon & Adrian Towse, The Economics of Gene Therapy and Pharmacogenetics, 5 VALUE HEALTH 5, 12 (2002) (the percentage of susceptible individuals, and the seriousness of the adverse reactions that can develop are relevant factors for determining whether genetic testing and targeted avoidance measures for individuals will be the socially optimal policy for pharmaceuticals); Joshua Graff Zivin & David Zilberman, Optimal Environmental Health Regulations With Heterogeneous Populations: Treatment versus "Tagging," 43 J. ENVTL. ECON. & MGMT. 455, 471 (2002) (the social optimality of "tagging," or targeting vulnerable subgroups of the population with special exposure-reducing treatments, depends on factors such as the size and sensitivity of the vulnerable population).

249. Sharp and Barrett raise the hypothetical of an individual genetically susceptible to low levels of direct sunlight, which the individual could avoid only with extraordinary measures. Sharp & Barrett, supra note 38, at 182.

250. Danzon & Towse, supra note 248, at 12.

251. See Vainio & Husgafvel-Pursiainen, supra note 201, at 13.

252. This issue is similar to an ongoing debate on whether and how patients should be held accountable for not complying with prescribed medical treatment. See Yoder, supra note 237, at 23.

253. See Sharp & Barrett, supra note 38, at 182.

254. See Yoder, supra note 237, at 29 (arguing that effectiveness should be a key consideration in assigning responsibility for health protection to the individual or to society more generally).

255. See supra note 251 and accompanying text.

256. Lesko & Woodcock, supra note 124, at 24.

257. See Garte, supra note 35, at 1236 ("Advisement that smoking cessation and changing dietary habits will reduce their relative cancer risk from 9 to 1.2 times that of the general population may be a strong motivation for behavior modification and lead ultimately to some degree of cancer risk reduction.").

258. See Neil Weinstein & William M. Klein, Unrealistic Optimism: Present and Future, 15 J. SOC. CLINICAL PSYCHOLOGY 1 (1996); Neil D. Weinstein, Mindset, Optimistic Bias About Personal Risk and Health-Protective Behavior, 4 BRIT. J. HEALTH PSYCHOLOGY 289 (1999).

259. Jennifer B. McClure, Are Biomarkers Useful Treatment Aids for Promoting Health Behavior Change? An Empirical Review, 22 AM. J. PREVENTIVE MED. 200, 200-01 (2002):

The health belief model, health decision model, protection motivation theory, theory of reasoned action, and dual process model all suggest that behavior change is in part induced by one's perceived susceptibility to disease …. Thus, increasing awareness that one has some personal risk of harm … may increase motivation for health behavior change.

260. See Rockhill, supra note 237, at 367:

There is little precedent for relying on communications about individual risk to meaningfully reduce chronic disease burden. Even a cursory reading of the history of chronic disease trends will demonstrate that favorable population-wide changes in risk factors, and resulting decreases in disease incidence, have rarely resulted from individual risk calculations made simultaneously by key "high-risk" individuals in the population.

261. See supra note 58 and accompanying text.

262. See Brennan, supra note 40, at 382. But see Pharoah et al., supra note 37, at 35 ("using combinations of risk factors may overcome many of the limitations of using single risk factors, which has caused skepticism regarding the usefulness of molecular genotyping for common, low-risk genes").

263. An example of such an effect is a Swedish program that sought to reduce smoking by parents of children with alpha-1 -antitrypsin deficiency, a genetic condition that predisposes individuals to pulmonary emphysema and premature death from smoke inhalation. The program involved mass screening of all new-born children in Sweden over a three-year period. While the program anticipated that early detection of susceptible children would encourage parents of such at-risk children to reduce smoking, the actual observed effect was an increase in smoking by parents of at-risk children relative to controls, perhaps due to the anxiety associated with knowing that one's child had the genetic predisposition. T. Thelin et al., Primary Prevention in a High-Risk Group: Smoking Habits in Adolescents With Homozygous Alpha-1-Antitrypsin Deficiency (ATD), 85 ACTA PAEDIATRICA 1207 (1996).

264. Theresa M. Marteau & Caryn Lerman, Genetic Risk and Behavioural Change, 322 BRIT. MED. J. 1056, 1057, 1058 (2001).

265. See McClure, supra note 259, at 205.

266. See id. at 206; Sharp & Barrett, supra note 38, at 182-83; Olden & Wilson, supra note 31, at 153 ("How will we deal with the concern that many, on learning that they carry a predisposing genotype, will develop a fatalistic attitude and assume that they can do nothing to prevent the disease?"). For example, one recent study looked at how parents responded to the results of neonatal genetic testing that revealed their child carried a genetic predisposition to familial hypercholesterolaemia, which increases the risk of cardiovascular disease. Parents who understood that the test was a genetic test reported stronger perceptions of inevitability and uncontrollability than parents of children with the same condition who believed the test detected increased levels of cholesterol without appreciating the genetic basis of the condition. Victoria Senior et al., Will Genetic Testing for Predisposition for Disease Result in Fatalism? A Qualitative Study of Parents Responses to Neonatal Screening for Familial Hypercholesterolaemia, 48 SOC. SCI. MED. 1857, 1859 (1999).

267. Caryn Lerman et al., Incorporating Biomarkers of Exposure to Genetic Susceptibility Into Smoking Cessation Treatment: Effects on Smoking-Related Cognitions, Emotions, and Behavior Change, 16 HEALTH PSYCHOLOGY 87 (1997).

268. The relevant gene was a common variant of the CYP2D6 gene that is present in approximately 90% of the population and causes faster metabolism of tobacco carcinogens, resulting in a twofold to three-fold increase in cancer risk. Id. at 88-89. With a gene present in 90% of the population, susceptible individuals may (correctly) perceive themselves at the same risk as most of the population, and therefore this information may not have the same impact as information showing that an individual carries a relatively rare genetic susceptibility.

269. Id. at 93-94.

270. Id. at 94, 95.

271. Id. at 96.

272. Id.

273. Janet Audrain et al., Genetic Susceptibility Testing in Smoking-Cessation Treatment: One-Year Outcomes of a Randomized Trial, 22 ADDICTIVE BEHAV. 741, 746, 748 (1997).

274. Id. at 749.

275. Id. at 749.

276. Colleen M. McBride et al., Incorporating Genetic Susceptibility Feedback Into a Smoking Cessation Program for African American Smokers With Low Income, 11 CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION 521 (2002).

277. Id. at 522.

278. Id. at 527.

279. Id.

280. Id.

281. See supra note 67 and accompanying text.

282. Eaton et al., supra note 9, at 210; Garte et al., supra note 14, at 1241; Garte, supra note 66, at 1330.

283. Garte, supra note 66, at 1329.

284. For genetic variants that are disproportionately represented in specific ethnic groups, there may be a geographical concentration of that genotype in a community that is primarily composed of the relevant ethnic group.

285. National Environmental Justice Advisory Committee, Fish Consumption and Environmental Justice (rev. Nov. 2002), available at http://www.epa.gov/compliance/resources/publications/ej/fish_consump_report_1102.pdf.

286. While the primary focus of many environmental justice theorists and activists is on racial minority and low-income communities for these reasons, EPA's environmental justice program has a broader focus that protects any racial group, not just minority communities. For example, EPA has granted the environmental justice petition submitted by a upper middle class community in Phoenix that consist primarily of Caucasians, who argued that they were not treated the same as some minority communities in the permitting process. Citizens Environmental Awareness League (CEAL) v. Maricopa County Environmental Services Dep't, Aug. 17, 2001, EPA Title VI Administrative Complaint 18R-00-R9.

287. See Jenni & Lowenstein, supra note 176, at 238 ("In general, people are more concerned about risks that are concentrated within a geographic region or population than about those that are dispersed.").

288. See Cranor, supra note 157, at 240 ("individuals with special sensitivities or susceptibilities to disease have moral standing equal to that of normally healthy people to warrant protection from toxic substances").

289. "No racial or ethnic group is uniformly at higher risk of cancer than another. Rather, each possesses a distinct mix of genetic traits with the potential to increase susceptibility to specific carcinogens." Perera, supra note 33, at 503.

290. See Cranor, supra note 157, at 310:

A broader conception of environmental justice aims to provide protections for all who are particularly vulnerable as a result of greater susceptibility, greater exposure, or both, whether or not they live in heavily impacted communities. Such a conception would provide protection to those individuals who may not be part of a particularly vulnerable organized community but who have intrinsic susceptibilities to disease (for example, genetic, metabolic, or gender-based vulnerabilities), …. The broader idea underlies the environmental justice movement, since its advocates have emphasized from the beginning that everyone is entitled to environmental health protections.

291. See Cranor, supra note 157, at 308 ("A principle underlying environmental justice is that every person, even the most susceptible, has a right to protection from invasion of his or her interests by environmental toxicants.").

292. Title VI of the Civil Rights Act of 1964 provides the primary legal basis for most federal environmental justice claims, but this statute only protects against disproportionate impacts based on "race, color, or national origin." 42 U.S.C. § 2000d.

293. See, e.g., Mark A. Rothstein, Genetic Discrimination in Employment and the Americans With Disabilities Act, 29 HOUS. L. REV. 23 (1992); Mark S. Dichter & Sarah E. Sutor, The New Genetic Age: Do Our Genes Make Us Disabled Individuals Under the Americans With Disabilities Act?, 42 VILL. L. REV. 613 (1997).

294. 42 U.S.C. § 12132. A "public entity" includes "any State or local government" and "any department, agency, special purpose district, or other instrumentality of a State or States or local government." Id. § 12131(1). A "qualified individual with a disability" is defined to mean

an individual with a disability who, with or without reasonable modifications to rules, policies, or practices, the removal of architectural, communication, or transportation barriers, or the provision of auxiliary aids and services, meets the essential eligibility requirements for the receipt of services or the participation in programs or activities provided by a public entity.

Id. § 12131(2).

295. 28 C.F.R. § 35.130(b)(7).

296. 42 U.S.C. § 12102(2).

297. Equal Employment Opportunity Commission, EEOC Compl. Man. (BNA) 902.89(a).

298. See Melinda B. Kaufman, Genetic Discrimination in the Workplace: An Overview of Existing Protections, 30 LOY. U. CHI. L.J. 393, 412 (1999). While there are various ways and reasons why employers might discriminate against workers they perceive as disabled, it is difficult to envision any scenario in which a "public entity" would act in such a way that discriminates against or exclude persons who it perceives as susceptible to environmental exposures, but who in fact are not.

299. Sutton v. United Air Lines, Inc., 527 U.S. 471, 482 (1999).

300. Save Our Summers v. Washington State Dep't of Ecology, 132 F. Supp. 2d 896 (E.D. Wash. 2000).

301. Brief Amicus Curiae of the United States at 2, Save Our Summers, 132 F. Supp. 2d at 896 (No. CS-99-269-RHW).

302. Id. at 11.

303. Id. at 17 (quoting Crowder v. Kitagawa, 81 F.3d 1480, 1486 (9th Cir. 1996)).

304. Brief Amicus Curiae of the United States at 27, Save Our Summers v. Washington State Dep't of Ecology, 132 F. Supp. 2d 896 (E.D. Wash. 2000) (No. CS-99-269-RHW).

305. Save Our Summers, 132 F. Supp. 2d at 896.

306. In another attempt to use the ADA to force more stringent environmental restrictions, a public interest group sued the Federal Communications Commission for failing to adopt more stringent health and safety standards for radiofrequency radiation to protect susceptible individuals. Cellular Phone Taskforce v. Federal Communications Comm'n, 205 F.3d 82 (2d Cir. 2000). The court dismissed the petitioner's claim that the ADA required such restrictions on exhaustion grounds because the issue had not been raised in the administrative proceedings below. Id. at 89. See also Heather K. v. City of Mallard, 887 F. Supp. 1249 (N.D. Iowa 1995) (issuing temporary restraining order under Title II of the ADA against city ordinance allowing open burning that would adversely affect susceptible children).

307. Michael S. Heyl, Circumventing Environmental Policy: Does the Americans With Disabilities Act Provide Protection Where Environmental Statutes Don't?, 18 J. CONTEMP. HEALTH L. & POL'Y 323, 357 (2001).

308. See supra notes 57-75 and accompanying text.

309. See Garte et al., supra note 14, at 1240; Garte, supra note 35, at 1236.

310. See Garte, supra note 35, at 1236; John P.A. Ioannidis, Genetic Associations: False or True?, 9 TRENDS MOLECULAR MED. 135, 136 (2003).

311. One recent review made the important point that almost all scholarship on genetic privacy to date has focused on the highly penetrant disease genes such as the BRCAI breast cancer gene or the Huntington's disease (HD) gene, with very little analysis of privacy issues associated with the low-penetrance environmental susceptibility genes that have been the focus of this Article. See Christiani et al., supra note 14, at 550. The authors suggest that because these genes are much less predictive of future disease, providing third-party access to information about such genes may be less controversial. Id.

312. See Greely, supra note 215, at 1501 ("people who are afraid of genetic discrimination are afraid to take genetic tests that offer the possibility of improving their health"); Gostin, supra note 239, at 113:

If fear of discrimination deters people from genetic diagnosis and prognosis, renders them less willing to confide in physicians and genetic counselors, and makes them more concerned with loss of a job or insurance than with care and treatment, the benefits of genetic data collection will not be fully achieved.

313. See Christiani et al., supra note 14, at 527 (many of the proposed regulations for protecting genetic information "could inadvertently curtail important epidemiologic studies employing genetic markers to examine gene-environment interactions").

314. Yap & Rejeski, supra note 216, at 36.

33 ELR 10641 | Environmental Law Reporter | copyright © 2003 | All rights reserved