Ethical, Legal, and Social Issues (2024)

Research Priorities

One myth about scientific research is that science is value neutral—that new scientific understandings await discovery, that these discoveries have no independent moral significance, and that they take on moral significance only when individuals and groups of individuals assign weight to scientific findings. One flaw in this argument is that there are seemingly limitless areas for scientific inquiry, yet there are finite numbers of scientists and limited resources to pursue research. Therefore, scientists and society must set priorities for research, and those priorities are a function of societal values. Even though scientists often make adventitious discoveries, they generally discover what they are looking for, and what they look for are the things that science and society value discovering.

Pharmacogenomics provides a good illustration. Pharmaceutical researchers may discover numerous polymorphisms in the gene for a particular drug target. Before spending tens or hundreds of millions of dollars on studying a particular polymorphism, any revenue-conscious biotech or pharmaceutical company will try to ascertain the population frequency of these drug targets. Consequently, initial drug development does not focus on genetic variations found most often among individuals in developing countries, where most people do not have the money to pay for basic medicines, let alone expensive new products that treat persons with particular genotypes. Even in developed countries, without some external support from government or private sources, developing drugs directed at rare genotypes is not cost-effective.

Another way to set research priorities is to focus on the nature of the harm to be prevented. It has been asserted that a disproportionate share of health resources (research and treatment) are directed at specific diseases simply because of the effectiveness of advocacy groups working on behalf of affected individuals (Greenberg 2001). Similarly, environmental policy may be influenced by considering certain environmental risks to be of greater societal concern than others. For example, it has been argued that U.S. environmental policy is flawed because we spend millions of dollars on a relatively few Superfund sites in need of remediation but insufficient sums on air and water pollution, which is a more widespread threat to public health (Breyer 1995). Undoubtedly, the targets of toxicogenomic research will be influenced by a myriad of social factors, and priority setting will be influenced by economic and political concerns.

The Federal Rule for the Protection of Human Subjects

The federal Rule for Protection of Human Subjects (45 C.F.R. Part 46, Subpart A) is usually referred to as the Common Rule, because most federal agency sponsors of research in addition to the Department of Health and Human Services (DHHS) have adopted it (DHHS 1997). The Common Rule describes basic procedures and principles for conducting federally sponsored research on human subjects. It applies to researchers who receive federal financial support from a signatory federal agency, research conducted in contemplation of a submission to the Food and Drug Administration (FDA) for approval, and research conducted by an institution that has signed a “multiple project assurance” with DHHS promising to comply with the Common Rule in all research, regardless of the funding source. As a result, the Common Rule applies to much, but not all, research involving human subjects in the United States.

The Common Rule is designed to safeguard the welfare of human subjects of research, and therefore an important preliminary matter is to define “research.” The Common Rule defines it as “a systematic investigation, including research development, testing, and evaluation designed to develop or contribute to generalizable knowledge” (45 C.F.R. § 102[d]). Research also includes the development of repositories for future research (DHHS 1997).

The Common Rule does not apply to research conducted on specimens or health records that are not individually identifiable. According to a guidance document issued by the Office for Human Research Protections (OHRP), private information and specimens are not “individually identifiable when they cannot be linked to specific individuals by the investigator(s) either directly or through coding systems” (DHHS 2004). The guidance further provides that research involving only coded private information or specimens does not involve human subjects if the investigator cannot “readily ascertain” the identity of the individual because the key was destroyed before the research began, the key holder has agreed not to release the key to investigators under any circ*mstances, there are Institutional Review Board (IRB)-approved written policies prohibiting release of the key until the individuals are deceased, or other legal requirements prohibit releasing the key to the investigators until the individuals are deceased. Neither the OHRP guidance nor other authoritative policies address all the major issues surrounding specimen collection and use, including identifiability (McGuire and Gibbs 2006) and the potential for group harm (Foster and Sharp 2002). It is also possible that definitions of “readily identifiable” will need to change with the incorporation of large amounts of polymorphism and similar data in databases.

Health Insurance Portability and Accountability Act

HIPAA (42 U.S.C. §§ 300gg-300gg-2) contains a section called “Administrative Simplification” (Title II, subtitle F, §§ 261-264), which commits the United States to more efficient health claim processing through standard electronic transactions. To protect the confidentiality of protected health information, DHHS was directed to promulgate Standards for Privacy of Individually Identifiable Health Information (Privacy Rule) (45 C.F.R. Parts 160, 164). The Privacy Rule applies to three classes of covered entities: health care providers, health plans, and health clearinghouses. The covered entities under the Privacy Rule and the Common Rule overlap to a great extent (for example, both cover large academic medical center institutions), but they are not of equal scope. The Privacy Rule and the Common Rule also differ on other key issues, including reviews preparatory to research, research involving health records of deceased individuals, and revocation of consents and authorizations (Rothstein 2005a).

Biorepositories

Biorepositories are repositories of human biologic materials collected for research. According to the most recent and widely cited estimate, more than 300 million specimens are stored in the United States, and the number grows by 20 million per year (Eiseman and Haga 1999). Because the ability to access large numbers of well-characterized and annotated samples is an essential part of new genomic research strategies (see Chapter 10), biorepositories are increasingly important (Andrews 2005; Clayton 2005; Deschênes and Sallée 2005; Janger 2005; Knoppers 2005; Majumder 2005; Malinowski 2005; Palmer 2005; Rothstein 2005b). Although biorepositories raise numerous issues involving research ethics and social policy, three issues are especially important to toxicogenomics, pharmacogenomics, and related research.

First, biorepositories collect samples and data for unspecified, unknown, future research and thereby differ from traditional biomedical research, which generally contemplates a single, discrete project for which a single process of informed consent is used. Thus, the question that arises is whether it is permissible under the Common Rule for researchers to obtain informed consent for future uses of specimens collected by a biorepository. Under the Common Rule, a research subject may consent to future, unspecified research. Nevertheless, IRBs generally do not approve “blanket consent” for all possible research on the grounds that consent about unknown future uses by definition is not “informed” (Strouse 2005). Using “tiered” or “layered” consent, research subjects are presented with a menu of possible future research categories, such as cancer research, AIDS research, and genetic research. They can then indicate for which types of research it is permissible to use their sample (NBAC 1999). Because of the growth of biorepositories and new methods of informed consent, researchers need to monitor the understanding of research subjects and the effectiveness of the informed consent process to determine whether changes or improvements in the informed consent process are needed.

Under the HIPAA Privacy Rule, however, each new research project requires a new authorization. Thus, tiered consent does not satisfy the Privacy Rule. Although researchers can obtain a waiver of the authorization requirement (meaning that the researchers do not need to recontact each sample donor for each new research project) (45 C.F.R. §164.512[l][2][ii]), a separate waiver from an IRB or Privacy Board is needed for each proposed new use. Therefore, the inconsistency between the Common Rule and the Privacy Rule complicates compliance for researchers, especially when toxicogenomic research may involve large repositories of individually identifiable specimens that may be used for multiple research projects (Rothstein 2005a).

A second key ethical issue about biorepositories concerns if or when researchers have a duty to recontact sample donors to notify them that research using their samples has identified health risk information of clinical or social significance to them or their relatives (Rothstein 2005b; Bookman et al. 2006; Renegar et al. 2006). If the samples are deidentified, it will be impossible to notify any individual of sample-specific research findings, but there still may be a duty to notify all sample donors of the overall conclusions of the study and the potential desirability of consulting a physician. The greatest challenge, however, involves individually identifiable samples. Because it is too late to develop a recontact policy after a discovery has been made, the most prudent course is for researchers to ask sample donors at the time of sample collection if they want to be recontacted in certain circ*mstances (for example, when there is a predictive test or therapy) and, if so, whether the contact should be through their physician or personally.

A third set of issues on which there has been considerable debate in the bioethics literature, is who owns the property rights to tissue samples and whether researchers have a duty to undertake any type of “benefit sharing” with individual donors or groups of donors (Andrews 2005; Marchant 2005). For example, over and above informed consent, who ultimately controls the use, distribution, and disposal of donated tissue samples? In one of the first judicial decisions to address this issue, a federal district court recently held that the research institute, not the individual researcher or tissue donor, “owns” donated tissue samples (Washington University v. Catalona, 2006 U.S. Dist. LEXIS 22969 [E.D. Mo. 2006]). Some tissue donors, especially those who are members of identifiable groups such as Native Americans, are now insisting that they retain the property rights in their donated tissues as a precondition for providing samples for research (Marchant 2005).

A related question concerns those instances in which research on biorepository samples has led to commercially valuable discoveries: are sample donors entitled to some share of the proceeds (see Greenberg v. Miami Children’s Hospital Research Institute, Inc., 264 F. Supp. 2d 1064 [S.D. Fla. 2003]; Moore v. Regents of Univ. of Cal., 793 p.2d 479 (Cal. 1990)? There have been a few documented cases in which one individual’s sample has been extremely valuable in developing cell lines or other research products (Moore v. Regents of Univ. of Cal., 793 p.2d 479 [Cal. 1990]; Washington 1994). It is far more likely, however, for analyses of numerous samples to be needed for development of any commercially viable finding. Whether it is ethical for individual research subjects to waive all their interests in the products of discovery remains unclear, although it is common for informed consent documents to so provide. Regardless of the language in the informed consent document, the principle of benefit sharing would be satisfied if researchers declare in advance that they will set aside a small percentage of revenues derived from commercialization for dona tion to a charitable organization that, for example, provides health care to indigent individuals with the condition that is the target of the research (HUGO 2000; Knoppers 2005).

Intellectual Property

The development, exploitation, and protection of intellectual property are important elements of contemporary research strategy. Many of the contentious intellectual property issues, such as publication, timing of filing, ownership, and licensing, arise “downstream,” after the discovery of a patentable invention. These issues are not unique to toxicogenomic and pharmacogenomic research. Nevertheless, because many toxicogenomic applications involve assays that produce large amounts of data, often involving large numbers of genes or proteins, obtaining intellectual property rights to all the materials used in an assay could be particularly burdensome and problematic for researchers and platform manufacturers in the field of toxicogenomics (NRC 2005b).

An important, “upstream” issue, and one that needs to be addressed specifically in the context of toxicogenomic and pharmacogenomic research, is whether to have an “open access” policy to raw samples and data and, if so, how open it should be and how it would work. Traditionally, both toxicologic and pharmaceutical research have been undertaken with closed access, with private companies maintaining proprietary control over their research until a patent has been filed or a company has decided to disclose information for some other reason. Increasingly, however, there is pressure to make preliminary data from government-funded (and even some privately funded) research more widely available to researchers in general. For example, the Human Genome Project (public), the Pharmacogenetics Research Network (public), and the SNP Consortium (private) have adopted the policy of making research findings available online promptly for other researchers to use.

The Committee on Emerging Issues and Data on Environmental Contaminants of the National Research Council held a Workshop on Intellectual Property in June 2006 at the National Academies. Among other issues, the workshop discussed the position of the National Institutes of Health (NIH) in support of immediate (or prompt) release of and free access to human genome sequence data. These policies, embodied in the so-called Bermuda Principles, have been endorsed by the International Human Genome Organization and other organizations (HUGO 1997). They also have been applied more broadly, and they form the basis of the National Human Genome Research Institute’s policies of prompt or immediate disclosure of genomic information generated by NIH-supported research or collected in NIH-supported repositories.

No standard policy for data release has been developed for toxicogenomic and pharmacogenomic research. In the absence of such a policy, the default position is nondisclosure. Consequently, affirmative steps should be undertaken to ensure that toxicogenomic and pharmacogenomic data are promptly and freely made available to all researchers whenever possible.

Conflicts of Interest

Environmental, pharmaceutical, and occupational health research often is sponsored or undertaken by entities with an economic interest in the outcome of the study. Especially for sensitive research, such as genetic research involving vulnerable populations, concerns about the investigators’ actual or perceived conflicts of interest will be magnified. Transparency, informed consent, and external oversight are essential (Rothstein 2000a). Even with such precautions, conflicts may arise with regard to what actions to take on the basis of the study.

Privacy and Confidentiality

Privacy has many dimensions. In the information sense, privacy is the right of an individual to prevent the disclosure of certain information to another individual or entity (Allen 1997). Increasingly, the bioethics literature also has recognized a negative right of informational privacy—that is, the right “not to know” certain information about oneself (Chadwick 2004). Toxicogenomics affects both of these aspects of privacy. Individuals may want to restrict the disclosure of their toxicogenomic or pharmacogenomic information that was obtained in a research, clinical, workplace, or other setting. They also may not want to know of certain risks, especially when nothing can be done to prevent the risk of harm (for example, where there was past occupational or environmental exposure).

Confidentiality refers to a situation in which information obtained or disclosed within a confidential relationship (for example, physician-patient) generally will not be redisclosed without the permission of the individual (Rothstein 1997). With regard to toxicogenomics, the most important relationship is the physician-patient relationship. Restrictions on redisclosure are an important ethical precept of health care professionals, and maintaining the confidentiality of health information is important in preventing intrinsic and consequential harm to individuals (Orentlicher 1997). Although toxicogenomic and pharmacogenomic information would be covered under the “genetic privacy” laws several states have enacted (NCSL 2005a), these laws afford limited and inconsistent protection.

It should also be noted that DHHS is taking the lead in promoting widespread adoption of electronic health records and creation of a national infrastructure to support a system of interoperable, longitudinal, comprehensive health records (NCVHS 2006). In such an environment, privacy and confidentiality protections are even more important because detailed health information can be disclosed to numerous sources instantaneously (Rothstein and Talbott 2006).

Although it is important to safeguard the security of health records to prevent unauthorized disclosure of information, breaches of confidentiality through authorized disclosures may be an even greater problem. For example, in health care settings, not all employees (for example, billing clerks, meal service employees, maintenance employees) need the same degree of access to patient health records. Thus, the degree of access needs to comport with the need to know about protected health information. “Role-based access restrictions” help to limit the scope of disclosure.

In non-health care settings, individuals often are required to execute an authorization for disclosure of their medical records as a condition of employment or insurance. Development and application of “contextual access criteria” will help to limit these disclosures to the health information relevant to the purpose of the disclosure (for example, ability to perform a job) (Rothstein and Talbott 2006).

Socially Vulnerable Populations

Many genetic loci of actual or potential significance to toxicogenomics and pharmacogenomics have a differential allelic frequency in discrete subpopulations. Due to ancestral patterns of endogamy (marrying within a social group), migration, geographic isolation, and other elements of ancestral origins, some genetic traits have a higher frequency among subpopulations socially defined by race or ethnicity. Thus, there is great potential for stigma when an increased risk of a particular undesirable health condition is associated with a particular population group, especially when the group is a racial or ethnic minority in a society. These population groups are then said to be “vulnerable” with respect to a particular health condition.

A socially vulnerable population also can be based on shared somatic mutations. For example, workers with an acquired mutation or biomarker based on a particular occupational exposure or residents of a certain area with toxic exposures who demonstrated the subclinical effects of a particular exposure may also be said to be socially vulnerable populations. These polymorphisms may not be phenotypically obvious and often do not correlate with race, ethnicity, and other traditional social categories.

The notion of vulnerable populations based on toxicogenomics and pharmacogenomics raises numerous ethical concerns, including the ethical principles of justice, respect for persons, and beneficence. Because of the social risks to vulnerable populations from research, special efforts are needed to obtain infor mation about community interests and concerns. Community engagement and consultation are essential elements of ethical research (Foster and Sharp 2002). In addition, if environmental or pharmaceutical exposures have already adversely affected a subpopulation or a subpopulation has been identified to be at greater risk, ethical considerations might require that vulnerable populations have fair access to health care for diagnostic and treatment measures; that steps be taken to prevent unfair discrimination in employment, insurance, and other opportunities; that there is adequate compensation for harms; that feasible remediation be undertaken; and that effective protections are in place for protecting privacy and confidentiality (Weijer and Miller 2004).

Health Insurance Discrimination

The leading concern among individuals at a genetically increased risk of illness is that they will be unable to obtain or retain their health insurance (Rothstein and Hornung 2004). In the United States, individuals obtain health care coverage mostly through government-funded programs (for example, Medicare, Medicaid) or employer-sponsored group health insurance. A relatively small percentage (about 10%) of those with health coverage have individual health insurance policies. Although this group is the only one in which individual medical underwriting takes place, individuals who currently have group coverage might be legitimately concerned that if they lost their job and their group health insurance, they would need to obtain individual health insurance.

To address the concern about discrimination in health insurance, nearly every state has enacted a law prohibiting genetic discrimination in health insurance (NCSL 2005b). These laws have a fatal flaw: they prohibit discrimination only against individuals who are asymptomatic. If an individual later becomes affected by a condition, he or she is no longer protected by the law and is at risk of rate increases or even cancellation in accordance with general provisions of state insurance law (Rothstein 1998).

Health insurance discrimination is very difficult to resolve. As long as a key element of our system of health care finance is individually underwritten, optional, health insurance, then it will contain less favorable access for individuals at an increased risk of future illness. Meaningful reform would require major changes in health care financing.

Employment Discrimination

Employers have two concerns about employing individuals who are at a genetic risk of future illness. First, employee illness and disability of any etiology represents significant costs in terms of lost productivity, lost work time, high turnover, and increased health care costs. Genetic testing makes it possible to predict future risks and would make it more attractive for employers to exclude at-risk individuals from their workforces. To combat such discrimination, about two-thirds of the states have enacted laws prohibiting genetic discrimination in employment (NCSL 2005c). These laws are seriously deficient because, although they make discrimination based on genetic information illegal, they do not prohibit employers from lawfully obtaining genetic information contained within the comprehensive health records that employers may require individuals to disclose as a condition of employment. Consequently, at-risk individuals, who might benefit from genetic testing, are often reluctant to do so because a future employer can lawfully obtain the results (Rothstein and Hornung 2004).

Second, employers may be reluctant to hire or assign individuals to work where they are at an increased risk of occupational illness because of their genetics. In addition to the employers’ illness concerns listed above, occupational illness could result in additional costs based on workers’ compensation, compliance with the Occupational Safety and Health Act of 1970, personal injury litigation, and reduced employee morale. With regard to toxicogenomics in the workplace, is it lawful or ethical for employers to request or require workers to undergo genetic testing? See Box 11-1 for additional discussion on toxicogenomic research in the workplace.

There are two ethical cross-currents in the laws regulating the workplace: paternalism and autonomy. Much workplace health and safety regulation may be characterized as paternalistic, including child labor laws, minimum wage laws, and the Occupational Safety and Health Act. A greater appreciation for worker autonomy in the workplace is reflected in the Supreme Court’s leading decision in International Union, UAW v. Johnson Controls, Inc. (1991). The Court held that the employer discriminated on the basis of sex, in violation of Title VII of the Civil Rights Act of 1964 (42 U.S.C. § 2000e), by excluding all fertile women from jobs with exposure to inorganic lead because of concerns that a woman could become pregnant and give birth to a child with deformities caused by maternal workplace exposures. According to the Court: “Congress made clear that the decision to become pregnant or to work while being either pregnant or capable of becoming pregnant was reserved for each individual woman to make for herself” (499 U.S. at 206).

A middle position between permitting employers to mandate genetic testing and prohibiting all employee genetic testing is that a worker who is currently capable of performing the job should have the option of learning whether he or she is at increased risk of occupational disease based on genetic factors. Optional genetic testing would be conducted by a physician or laboratory of the individual’s choice; the testing would be paid for by the employer; and the results would be available only to the individual. The individual would then have the option of deciding whether to assume any increased risk of exposure (Rothstein 2000b). Only if employment of the individual created a direct and immediate threat of harm to the individual or the public would the employer be justified in excluding the individual based on future risk (Chevron U.S.A. Inc v. Echazabal 2002). See Box 11-2 for additional discussion on genetic screening in the workplace.

Individual Responsibility

To what extent should individuals have a responsibility to learn if they are at increased risk from certain exposures, to avoid those exposures, and to deal with the consequences of illness caused by those exposures? To what extent does society have a duty to respect the autonomy of individuals to decline to learn of possible increased risks or to accept those risks? To what extent is society obligated to provide special protections for such individuals and health care if they become sick?

Several of these policy choices have been settled in the workplace setting for some time. Under workers’ compensation law, an employer “takes the employee as is,” and therefore it is no defense that the individual was at an increased risk of illness (Perry v. Workers’ Comp. App. Bd. 1997). Under the Occupational Safety and Health Act, health standards, at least in theory, are designed to protect all workers (29 U.S.C. § 655 [c][5]). Under HIPAA, employer-sponsored group health plans may not charge employees different rates or have different levels of coverage based on their health status, including genetic predisposition (42 U.S.C. § 300gg-1[a] and [b]). Nevertheless, even with regard to employment, many issues remain to be resolved, including the role of individual variation in setting permissible exposure levels.

It may be even more difficult to develop rules of general applicability beyond the workplace setting. Both scientific evidence (for example, absolute risk, relative risk, severity, latency, treatability) and context-specific social conceptions of reasonable conduct in the face of increased risk are likely to affect the development of public policy. For example, if members of a low-income family with a genetic predisposition to illness and with few options of places to live “voluntarily” agree to accept the increased risk of living in the vicinity of toxic emissions, it is doubtful that society would shift the moral blame from the polluter to the individuals harmed by the pollutants. On the other hand, if toxicogenomic testing indicated that a particular individual would be much more likely to suffer serious harm from exposure to tobacco smoke and the individual started smoking or made no effort to stop, it is likely that at least some of the moral blame would shift to the cigarette smoker (Christiani et al. 2001).

Race and Ethnicity

Concerns about race and ethnicity are subsumed under the heading of “socially vulnerable populations,” discussed above, but they are raised in distinctive ways by pharmacogenomics. All humans are genetically 99.9% alike. There is more genetic diversity within certain socially defined groups (for example, race, ethnicity) than between groups (Ossorio and Duster 2005). The individual and group differences, however, are measurable and may be significant. Among the traits for which subpopulation variance has been observed are those dealing with pharmaco*kinetics and pharmacodynamics (Rothstein and Epps 2001a).

Although pharmacogenomics holds great promise for increasing drug efficacy and decreasing adverse drug events, there is a risk of “racializing” medicine. It is facile to rely on race as a surrogate for genotype, but the social cost of doing so may be high. “By heedlessly equating race with genetic variation and genetic variation with genotype-based medications, we risk developing an oversimplified view of race-specific medications and a misleading view of the scientific significance of race” (Rothstein 2003, p. 330). The controversy surrounding the FDA’s approval of the drug BiDil in 2005 for self-identified African Americans demonstrates the currency of the issue (Saul 2005). See Box 11-3.

Implementation Issues

Traditionally, pharmaceutical companies have searched for new blockbuster drugs to provide effective treatments for common conditions, such as hypertension, hypercholesterolemia, and musculoskeletal pain. A single product is designed to be safe and effective for substantially all members of the adult population. With pharmacogenomics, however, the potential market is segmented by genotype and many different companies may develop products for each affected population. Although virtually every biotech and pharmaceutical company is using genomic technologies in researching new products, whether “personalized medicine” will prove to be a viable business model remains to be seen (Reeder and Dickson 2003; Royal Society 2005; Ginsburg and Angrist 2006).

Once medications that target people with particular genotypes are developed, it is not clear how widely they will be adopted. Targeted medications may eliminate the costly trial and error of current prescribing and dosing, but the substantial research and development costs almost certainly will result in more expensive medications. Whether private and public payers will include these therapies on their formularies will depend on several factors, including the condition being treated, the relative improvement in safety and efficacy over standard therapies, and cost (La Caze 2005). Patient demand produced by direct-to-consumer advertising (Ausness 2002) and provider concerns about potential liability (Palmer 2003) undoubtedly will increase adoption of the new products.

New technologies will also expand the responsibilities of physicians, nurses, pharmacists, and other health care providers to use genetic information in prescribing, dispensing, and administering medications (Rothstein and Epps 2001b). Professionals not only will need to integrate genetic information into their practices, they also will need to become competent in genetic counseling (Clayton 2003). In addition, even though genetic testing for medication purposes is more limited in scope than genetic tests for assessment or prediction of health status, the test results will still contain sensitive genetic information. For example, identifying someone as being more difficult or expensive to treat could lead to discrimination in employment or insurance. Consequently, pharmacogenomics could increase the demand for new protections for the confidentiality of health information.

Defining New Adverse Effects

Many regulatory requirements are based on a finding of “adverse effect.” For example, national ambient air-quality standards set under the Clean Air Act are set at a level that protects against adverse effects in susceptible populations. Some subclinical effects (for example, changes in erythrocyte protoporphyrin concentration in blood) have been found to be adverse effects under this statutory provision and have required more stringent standards to prevent such effects from occurring in exposed populations (Lead Industry Association v. EPA 1980). Furthermore, many EPA regulations for noncarcinogenic substances are based on the reference concentration (RfC) or reference dose (RfD). Some gene expression or other changes measured with toxicogenomic technologies may constitute new adverse effects under these programs and thus lower the RfDs and RfCs, resulting in more stringent regulations. Manufacturers of pesticides and toxic chemicals are required to notify the EPA of new scientific findings about adverse effects associated with their products. In pharmaceutical regulation, the detection of a biomarker that suggests an adverse effect may likewise trigger additional regulatory scrutiny or restrictions.

Therefore, a critical issue in the regulatory application of toxicogenomics will be determining whether and when a change constitutes an adverse effect. Many changes in gene expression, protein levels, and metabolite profiles will be adaptive responses to a stimulus that are not representative or predictive of a toxic response. Other toxicogenomic changes may be strongly indicative of a toxic response. Therefore, it will be important to distinguish true biomarkers of toxicity from reversible or adaptive responses and to do so in a way that is transparent, predictable, and consistent for the affected entities (Gallagher et al. 2006). At least initially, phenotypic anchoring of toxicogenomic changes to well-established toxicologic end points will likely be necessary to identify toxicologically significant markers.

Regulatory Decisions Based on Screening Assays

The availability of relatively inexpensive and quick toxicogenomic assays that can be used for hazard characterization of otherwise untested materials offers a number of potential regulatory opportunities (Gallagher et al. 2006). Full toxicologic characterization of the approximately 80,000 chemicals in commerce using a battery of traditional toxicology tests (for example, chronic rodent bioassay) is not economically or technologically feasible in the foreseeable future. Screening with a toxicogenomic assay, such as a gene expression analysis that classifies agents based on transcript profiles, might be useful to quickly screen chemicals for prioritizing substances for further investigation and possible regulation (see Chapter 5). Another possibility is to require the manufacturer of a new chemical substance, or an existing substance that will be used in a new application, to include the results of a standardized toxicogenomic assay as part of a premanufacturing notice required under section 5 of the Toxic Substances Control Act (Marchant 2003a).

Protection of Genetically Susceptible Individuals

Many regulatory programs specifically require protection of susceptible individuals. For example, the Clean Air Act requires that national ambient air-quality standards be set at a level that protects the most susceptible subgroups within the population. Under this program, the EPA focuses its standard-setting activities on susceptible subgroups such as children with asthma. Recent studies indicate a significant genetic role in susceptibility to air pollution (Kleeberger 2003), which may lead to air-quality standards being based on the risks to genetically susceptible individuals (Marchant 2003b; Grodsky 2005). Regulations under other environmental statutes, such as pesticide regulations under the Food Quality Protection Act and drinking water standards under the Safe Drinking Water Act, may likewise focus on genetically susceptible individuals in the future, as might occupational exposure standards promulgated by the Occupational Safety and Health Administration. Likewise, pharmaceutical approvals may require considering and protecting individuals with genetic susceptibilities to a particular drug.

The identification of genetic susceptibilities to chemicals, consumer products, pharmaceuticals, and other materials raises a number of regulatory issues. One issue is the question of the feasibility of protecting genetically susceptible individuals. On the one hand, protecting the most susceptible individuals in society may be extremely costly, and perhaps even infeasible without major, formidable changes in our industrial society. On the other hand, the concept of government regulators leaving the health of some individuals unprotected, who through no fault of their own are born with a susceptibility to a particular product or chemical, also seems politically and ethically infeasible (Cranor 1997). As more information on individual genetic susceptibility becomes available, regulators and society generally will confront difficult challenges in deciding whether and how to protect the most genetically vulnerable citizens in our midst (Grodsky 2005).

A related set of issues will involve the extent to which we rely on societal regulation versus individual self-help in protecting genetically susceptible individuals. All regulatory programs confront choices between societal regulation and targeting high-risk individuals (Rose 1994), but these choices will be heightened by the identification of genetic susceptibilities to specific products or substances. For example, should products be labeled to warn people with particular genotypes to avoid using the product, just as diet sodas are labeled to warn people with the genetic disease phenylketonuria that the product contains phenylalanine? Should regulators approve for sale pharmaceuticals that are effective only for individuals with compatible genotypes and are ineffective or even hazardous for other people? Under what conditions and with what types of warnings? Will workers with genetic susceptibilities to specific workplace hazards be precluded from working in those jobs, or will they be required to accept personal responsibility for any harms that result? In all these scenarios relying on self-help, how will susceptible individuals discover they carry a particular genetic susceptibility? How will the privacy and confidentiality issues associated with such genetic knowledge be addressed? How well will people understand and adapt their behavior appropriately to information on their genetic susceptibilities? Policymakers, scientists, regulators, and other interested parties will need to address these and other questions raised by new knowledge about genetic susceptibilities.

Generic Regulatory Challenges

Several generic issues will confront all regulatory programs that use toxicogenomic data. One issue will be ensuring that toxicogenomic data are adequately validated (see Chapter 9). Each agency has its own procedures and criteria for ensuring data quality. In deciding whether and when toxicogenomic data are ready for “prime time” application in formulating federal regulations, agencies must balance the risk of premature use of inadequately validated data versus the harm from unduly delaying the use of relevant data by overly cautious policies. Agencies such as the EPA have been criticized for being too conservative in accepting new types of toxicologic data (NRC 1994).

Another trade-off that agencies must face involves whether and when to standardize toxicogenomic platforms and assays (Gallagher et al. 2006). On the one hand, standardization is important in that it facilitates comparison between datasets (see Chapter 3) on different substances and ensures consistent treatment of different substances. On the other hand, standardization runs the risks of prematurely freezing technology before it has fully matured.

A related issue is how regulatory agencies can encourage or require private parties to generate and submit toxicogenomic data. Many product manufacturers are likely to be concerned that toxicogenomic markers may detect biologic effects from their products or emissions at lower doses that may lead to increased regulatory scrutiny. To address such disincentives, agencies have adopted different approaches to encourage data submission. The FDA has adopted an approach under which the voluntary submission of certain types of toxicogenomic data will be for informational purposes only to help regulators and regulated parties better understand toxicogenomic responses, with an assurance that the data will not be used for regulatory purposes (Salerno and Lesko 2004). The EPA has adopted an interim policy that it will not base regulatory decisions solely on genomic data, alleviating concerns that a new regulatory requirement may be imposed based solely on a toxicogenomic finding when no other indication of toxicity is present (EPA 2002).

Proving Exposure

Many toxic tort claims involving exposures to environmental pollutants fail because the plaintiffs are unable to adequately demonstrate and quantify their exposure to a toxic agent. Individuals exposed to contaminated drinking water, hazardous chemicals in the workplace, or toxic releases from an environmental accident often lack access to objective environmental monitoring data that can be used to quantify their exposures. In such cases, courts often dismiss claims because the plaintiffs are unable to prove sufficient exposure with objective data (Wright v. Willamette Indus 1996). Some courts have endorsed, in principle, the possibility of using genetic biomarkers (for example, chromosomal aberrations) rather than environmental monitoring data to demonstrate and even quantify exposure (in re TMI litigation, 193 F. 3d 613, 622-623 [3d Cir. 1999] cert. denied, 530 U.S. 1225 [2000]).

Toxicogenomic data may be able to help prove or disprove exposure in appropriate cases. If a particular toxic agent creates a chemical-specific fingerprint of DNA transcripts, protein changes, or metabolic alterations, those biomarkers potentially could be used to demonstrate and perhaps even quantify exposure. Alternatively, a defendant could argue that the lack of a chemical-specific toxicogenomic marker in an individual proves that there was not sufficient exposure. However, a number of technical obstacles and data requirements need to be addressed before toxicogenomic data can be used reliably in this manner (see Chapter 4). The chemical-specific attribution of the toxicogenomic change would need to be validated, as would the platform used to quantify the changes. The potential variability in expression between cell types and individuals would also need to be addressed. Perhaps most significantly, the time course of toxicogenomic changes during and after exposure would need to be understood to correctly extrapolate an individual’s exposure history from after-the-fact measurements of toxicogenomic changes (Marchant 2002).

Causation

The other major evidentiary challenge that plaintiffs in toxic exposure cases must overcome is to prove causation. Plaintiffs bear the burden of proof to demonstrate both general causation and specific causation. General causation involves whether the hazardous agent to which the plaintiff was exposed is capable of causing the adverse health effect the plaintiff has incurred. Specific causation concerns whether the exposure did in fact cause the health effect in that particular plaintiff. Courts generally consider these questions separately, and both inquiries frequently suffer from a lack of direct evidence, resulting in outcomes that are highly uncertain, speculative, and often unfair. Toxicogenomic data have potential applications for both general causation and specific causation.

General causation determinations are impaired by “toxic ignorance” (NRC 1984; EDF 1997), in which valid scientific studies do not exist for many combinations of toxic substances and specific health end points. The lack of a valid published study evaluating whether the agent to which the plaintiff was exposed can cause the plaintiff’s health condition will generally bar tort recovery for failure to demonstrate general causation. Toxicogenomic assays that can reliably be used for hazard identification may provide a relatively inexpensive and quick test result that could be used to fill the gaps in general causation. For example, a gene expression assay that can identify a particular type of carcinogen might be used to classify a chemical as a carcinogen (and hence establish general causation) in the absence of a traditional chronic rodent bioassay for carcinogenicity.

Toxicogenomic data can also play a role in proving or disproving specific causation. Current toxicologic methods are generally incapable of determining whether a toxic agent caused an adverse health effect in a specific individual for all but so-called “signature diseases” that usually have a single cause (for example, mesothelioma and asbestos; diethylstilbestrol and adenocarcinoma) (Farber 1987). Lacking any direct evidence of specific causation, courts generally adjudicate specific causation based on a differential diagnosis by an expert or based on epidemiologic evidence showing a relative risk greater than 2.0, which suggests that any individual plaintiff’s disease was more likely than not caused by the exposure under study (Carruth and Goldstein 2001). Such methods are very imprecise and prone to under- and overcompensation depending on the facts of the case. A toxicogenomic marker could provide direct evidence of specific causation if an individual who develops a disease is shown to have the specific molecular signature of toxicity attributable to a specific agent.

Duty of Care

Toxic tort litigation involves judgments about the duty of care by an actor who creates risks to those who may be injured by those risks. Toxicogenomic data could affect or shift those judgments about duty of care in a number of con texts. For example, the finding that some members of the population may have a genetic susceptibility that makes them particularly sensitive to a product may impose new duties on the product manufacturer with regard to testing, labeling, and selling that product. Some individuals who alleged they had been harmed by the Lyme disease vaccine Lymerix brought lawsuits claiming that the vaccine manufacturer had a legal duty to warn vaccine users to obtain a genetic test for a polymorphism that allegedly affected the user’s propensity to develop serious side effects from the vaccine (Noble 2000). The litigation settled before a judgment was issued but likely contributed at least indirectly to the vaccine being removed from the market and was the first of what will likely be a new trend of plaintiffs claiming that a product manufacturer has additional duties to protect individuals genetically susceptible to their products. Alternatively, under the “idiosyncratic defense doctrine,” defendants may be able to argue in some cases that they have no duty to protect individuals with a rare genetic susceptibility to a product. Under this line of cases, courts have held that a product manufacturer can be reasonably expected to ensure the safety of “normal” members of the population and not individuals with an unusual susceptibility to the agent in question (Cavallo v. Star Enterprise 1996; Marchant 2000).

The detection of toxicogenomic changes in exposed individuals using toxicogenomic technologies may also result in lawsuits seeking damages for an increased risk of disease or for medical monitoring. Historically, courts have been reluctant to award damages for an increased risk of disease that has not yet manifested in clinical symptoms, but courts in some states have recognized such a claim if the at-risk individual can sufficiently quantify a substantial increased risk of disease (Klein 1999). It is possible that toxicogenomic data could support such a claim (Marchant 2000). A related type of claim is for medical monitoring, now recognized by more than 20 states, which requires a defendant responsible for a risk-creating activity to pay for periodic medical testing of exposed, at-risk individuals (Garner et al. 2000). Toxicogenomic assays could be used to identify at-risk individuals who would be entitled to ongoing medical evaluations, or the assays could serve as a periodic medical test for people who incurred a hazardous exposure.

Damages

Toxicogenomic data may also be relevant in the damages stage of toxic tort litigation. A defendant who is liable for a plaintiff’s injuries may seek to undertake genetic testing of the plaintiff to identify potential predispositions to disease that might have contributed to his or her disease or that might otherwise reduce the plaintiff’s life expectancy (Rothstein 1996). Either of these findings could reduce the damages the defendant would be ordered to pay to the plaintiff. Although the plaintiff’s genetic predispositions to disease may sometimes be pertinent (and may be used to benefit the plaintiff in some situations), there is a danger that defendants will undertake “fishing expeditions” in the plaintiff’s genome that may reveal sensitive and private personal information and potentially violate the plaintiff’s right not to know (Chadwick 2004).

Legal, Policy, and Ethical Aspects of Toxic Tort Applications

The many potential applications of toxicogenomic data in toxic tort litigation raise a number of scientific, legal, policy, and ethical issues. One central concern is the potential for premature use of toxicogenomic data (Marchant 2000). Unlike regulatory agencies, which generally consider new types of data cautiously and deliberately, toxic tort litigants are unlikely to show similar restraint. A toxic tort case is a one-time event often involving large stakes that, once filed, tends to move forward expeditiously toward a decision under a court-ordered schedule. Therefore, toxic tort litigants have every incentive to use any available data that may help them prevail, regardless of how well those data have been considered and validated by the scientific community. Premature use of toxicogenomic data should obviously be discouraged, but it is important to note that current scientific evidence on issues in litigation such as causation are often inadequate, and toxicogenomic data have enormous potential to make the resolution of toxic tort litigation more scientifically informed, consistent, and fair.

The reliability of toxicogenomic data introduced in a court proceeding will be evaluated under the standards for admissibility of scientific evidence. In federal courts and many state courts, the evidence will be evaluated under the criteria for scientific evidence announced by the U.S. Supreme Court in the 1993 Daubert decision (Daubert v. Merrell Dow 1993). Under that standard, the trial judge is to serve as a gatekeeper for scientific evidence to ensure that any such evidence presented to a jury is both relevant and reliable. The Supreme Court identified the following four nonexclusive criteria that courts can use to evaluate the reliability of scientific evidence: (1) whether the evidence can and has been empirically tested, (2) whether it has a known rate of error, (3) whether it has been peer reviewed and published, and (4) whether it is generally accepted within the relevant scientific field. These criteria are consistent with general criteria used to validate toxicologic tests and, if applied rigorously, should help ensure against the premature or inappropriate use of toxicogenomic data in toxic tort litigation.

Specifically, a court might want to consider the following factors in deciding whether to admit toxicogenomic data in a toxic tort lawsuit.

1. Has the toxicogenomic response been shown to be associated with or predictive of a traditional toxicologic end point (for example, cancer, toxicity)?

2. Are there data showing that the observed toxicogenomic response is characteristic of exposure to the specific toxic agent at issue, with a similar time course of exposure as experienced by the plaintiff?

3. Have the data used or relied on for making the above determinations been published in peer-reviewed scientific journals?

4. Have one or more other laboratories replicated the same or similar results under similar conditions?

5. Has the toxicogenomic platform used been shown to provide consistent results to the platform used in any other studies relied on?

Ideally, all these questions would be answered affirmatively before toxicogenomic data were introduced into evidence. Given that it is not reasonable to impose greater barriers to the introduction of toxicogenomic data than other types of toxicologic evidence used in toxic tort litigation, data satisfying most of the above criteria would likely be sufficiently reliable to be admitted.

The use of toxicogenomic data in toxic tort litigation raises a series of other issues. For instance, the capability of lay jurors to adequately understand and apply toxicogenomic data in their decision making will present challenges. The potential privacy and confidentiality issues raised by genetic testing of plaintiffs create another set of concerns. Protective orders that protect sensitive information used at trials from being publicly disclosed will be needed to help protect the confidentiality of personal genetic information.

Product manufacturers may have concerns about future liabilities associated with toxicogenomic biomarkers. For example, a manufacturer may sponsor a study that detects a biomarker of unknown toxicologic significance today but that years later may become established as a validated biomarker of toxicity. The use of such data to impose liability retroactively could raise fairness concerns and may deter manufacturers from conducting toxicogenomic studies. At the same time, shielding manufacturers from such liability could create the wrong incentives by deterring them from investigating the risks of their products and taking appropriate mitigation measures and may deprive injured product users from being compensated for their injuries. These countervailing factors demonstrate the complex and sensitive role that potential liability can exert on scientific research and applications of toxicogenomics.