Slide 1. Research on the relationship between inheritance and environmental exposures is enhancing understanding of a variety of human diseases and conditions. In fact, the age-old question, "nature vs nurture?" in many cases no longer seems relevant. Rather, each person's genetic makeup and environment interact in complex and important ways.
Slide 2. Research in what may be termed "environmental genetics" suggests that common complex medical problems, such as heart disease and breast cancer, tend to become manifest when there is a genetic predisposition combined with certain environmental conditions. In addition, even medical problems once considered to be strictly 'environmental', such as infectious diseases (including AIDS) and adverse drug effects, seem to be influenced by genetics. For example, human host defense mechanisms are clearly important in determining how sick different individuals get when they are infected by the same pathogen.
Slide 3a. Taking a leadership role in understanding gene-environment interactions, the National Institute of Environmental Health Sciences created the Environmental Genome Project (EGP). Its primary goal is to identify functionally significant DNA polymorphisms in environmental response genes that may influence disease risks from environmental exposures.
Slide 3b. Practically speaking, the EGP seeks to identify "at risk" groups of individuals, better understand the etiology of environmental and genetic components of human diseases, and discover molecular indicators of exposure to environmental toxins.
Slide 4a. Despite the promises of environmental genetics research, and the extensive resources being devoted to it, it is associated with a range of ethical issues. Addressing these may help ensure both the protection of the rights and interests of the research participants, as well as the appropriate application of the research findings.
Slide 4b. While many of the ethical issues encountered in environmental genetics research are similar to those encountered in other population-based genetic research (see Module #1 in this series), the issues sometimes manifest in unique ways. Therefore, this module presents ethical issues that may be encountered when doing environmental genetics research as well as those associated with applying research findings.
Slide 4c. The ethical issues raised by environmental genetics research itself include concerns related to: determining disease susceptibility, the personal and social harms associated with performing extensive evaluations of environmental exposures, and interventions over a long period of time. The ethical issues raised in applying environmental genetics research include the harms caused by use in the legal system and workplace.
Slide 5. Therefore, by the end of this module, you should be able to (1) recognize some of the major ethical issues that can be encountered in environmental genetics research; and (2) describe ways of minimizing harms related to these issues.
Slide 6a. Environmental genetics research raises ethical questions related in large part to the research methods and approaches being employed to enhance current understanding in the field. These include: determining susceptibility to disease, obtaining extensive data regarding environmental exposures, having continual access to personally identifiable information, conducting environmental intervention research, and continuing research across the life span.
Slide 6b. Related forms of research not described in this module are intentional human dosing studies, in which participants are exposed to toxins, such as pesticides, to help determine appropriate safety standards.
Slide 6c. Here a set of critical questions must be addressed regarding the acceptability of exposing participants to harmful substances without offsetting personal benefit for the sake of science. (See http://books.nap.edu/books/0309091721/html/index.html.)
Slide 7a. The environmental role of some genetic diseases is sometimes quite clear. For example, in phenylketonuria, or PKU, individuals with a particular genetic trait can avoid developing a disease by maintaining a diet free of phenylalanine. However, the role of the environment may be less clear for common diseases such as breast cancer.
Slide 7b. While it is clear that environmental influences matter, because populations from different regions and with different exposures have different incidence rates, determining what those influences are, how they work, and the role of genes in determining risk are largely unknown. Thus, although there may be some predictive value to a genetic susceptibility to breast cancer, it can be difficult or impossible to suggest what types of environmental modifications may decrease the risk of developing the disease. Thus, persons may be left with potentially upsetting information with uncertain prognostic value and no means of taking reasonable action, raising the question about whether providing this information is appropriate. Even when the scientific uncertainties are minimal, communicating the concept of susceptibility can be complicated and easily misunderstood, perhaps resulting in psychological harms. Finally, susceptibility alone might pose a risk of social or economic harms (such as in the workplace or for insurance purposes) for participants, reinforcing the need for close attention to protecting privacy and confidentiality.
Slide 8a. Standard epidemiologic surveys, which are often based on participants' self-reports and memories of environmental exposures, can be imprecise at characterizing lifelong environmental exposures and perhaps lead to recall bias and other confounders[1]. Many existing prospective epidemiologic studies capture only a portion of an individual's life -- and usually only portions of the adult part, potentially missing important environmental exposures that occur prenatally and in childhood[2].
Slide 8b. Therefore, efforts are now focusing on developing means to assess the "complete lifetime environment" (eg, the physical surroundings, social factors, behavioral influences, and geographic location, among others) of study participants, sometimes referred to as the "envirome"[3].
Slide 9. While important to the science, this approach raises some important ethical issues. For instance, privacy and confidentiality protections will take on new importance if an individual's "envirome" is known since it will likely contain information of sufficient breadth and detail to allow individual identification. In addition, respect for privacy may be more crucial than when obtaining conventional information about environmental exposures, because of the potentially sensitive questions that are asked. For example, such as those related to illicit drugs.
Slide 10. Similarly, to answer relevant and important scientific questions, researchers in environmental genetics may need continued access to participants' medical and research data, thereby making it impractical or inappropriate to de-link or anonymize personally identifiable information about participants from research data as a means of protecting their privacy in the context of research. Some have suggested that individuals need less protection in environmental genetics research because of the common nature of relevant polymorphisms and the ubiquitous environmental exposures. Nonetheless, this issue remains unsettled. In the meantime, it is critical to ensure that secure databases are established, and consideration needs to be given in advance to when and how informed consent to continuous or periodic access to medical and genetic information will be accomplished.
Slide 11. In addition to obtaining more detailed information about environmental exposures, environmental genetics research may move beyond discovering associations to testing cause-and-effect hypotheses with various pharmacologic and behavioral interventions in randomized clinical prevention trials. Such intervention research will raise substantial questions[5]. These include: What justifies the use (or on the other hand, the denial) of environmental interventions during a study that is attempting to collect good epidemiologic data? Does it matter if the environment is a potentially beneficial one, as opposed to a noxious one? In HIV prevention trials, researchers increasingly recognize a duty to provide practical and effective means to prevent HIV transmission -- in spite of the fact that such measures may make hypotheses more difficult to test[6]. These cases lead one to question when observation alone may be insufficient for the protection of research participants. That is, if there is sufficient evidence suggesting that a particular environmental exposure is harmful and preventable, when do researchers have an obligation to intervene rather than simply study it? Furthermore, how far ought such research go in requiring individuals to modify their behaviors or environments for the sake of verifying genetic hypotheses? Addressing these questions explicitly at the outset of research will be an important first step in ensuring the appropriate protection of the rights and interests of participants.
Slide 12a. As discussed earlier, environmental genetics research has been constrained by information that is limited to particular periods of the lives of participants. Nevertheless, environmental exposures span a lifetime, calling for long-term studies.
Slide 12b. However, such studies pose a range of logistical challenges for researchers, including the availability of funding, the willingness to pursue questions that exceed their own professional careers, and maintaining contact with mobile participants.
Slide 12c. Ethical questions about privacy obviously exist for participants who might need to live with continual observation and monitoring. In addition, there will likely be important implications related to participants' desires to leave the research, or refuse consent to continued observation. Developing methods to accommodate such requests will be critical both to protecting participants as well as to ensuring the generation of useful data.
Slide 13a. The National Children's Study Interagency Committee has proposed a birth to age 21 cohort study involving approximately 100,000 children, termed the National Children's Study (NCS)[7]. (See http://nationalchildrensstudy.gov.)
Slide 13b. Although beyond the scope of this module, studies such as these raise questions about the appropriateness of conducting research involving children, especially when interventions may be risky and there may not be a prospect of benefit to them. In addition, such a study that begins data collection prenatally and continues through adulthood raises key issues about the evolving ability and expectation of participants to take part in the informed consent process. (See http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm.)
Slide 14a. The powerful findings of environmental genetics research are exciting, in part, because of their potential applications in many settings, including clinical care, the workplace, the court room, and in public health.
Slide 14b. While as in other areas of scientific research, such as behavioral genetics (See Module #2 in this series), these applications can sometimes be harmful.
Slide 14c. Nonetheless, much can be learned from this experience to minimize future harms resulting from both future applications and ongoing environmental research.
Slide 14d. Five topics related to applying the results of environmental genetics research will be discussed here: pharmacogenomics, race and ethnicity, toxicogenomics (including legal applications in toxic torts and genetic screening in the workplace), personal responsibility, and public health genetics.
Slide 15. Pharmacogenomic (and pharmacogenetic) research is seen by some as the environmental analogue to the study of complex, common diseases[9]. That is, drugs are the environmental exposure used in individuals with different genetic make-ups. Pharmacogenomics research has the potential to improve clinical trial groups by selecting those most likely to benefit from the drug being studied (perhaps resulting in cheaper, faster, and smaller clinical trials) and to reduce toxic side effects from medications[10]. Ultimately, this may be the first application of personalized medicine, with targeted drug therapies that maximize benefit and safety. Difficulties remain, however. For instance, if clinical trials are smaller, the chance of detecting some adverse events, especially rare ones, may be reduced[11]. Therefore, these adverse events may be revealed only after the drug is marketed. While good surveillance studies conducted after marketing is one approach to finding this information, patients may experience such events in the less-controlled setting of clinical practice compared to research. In addition, it is unclear if there will be detrimental effects if those with a less-common genetic make-up lack access to safe and effective medications[12]. While ethical questions such as these are being addressed and policy solutions being offered, for the purposes of this module it is important to recognize these issues as they relate to environmental genetics research more broadly.
Slide 16a. All population-based genetics research continues to struggle with the notions of race and ethnicity[13, 14, 15, 16, 17, 18, 19, 20]. In environmental genetics research this can be especially problematic since exposures to some agents are associated with socioeconomic status and with "race." If an association is found between a genotype and a biomarker of exposure or a bad outcome, is that due to the genotype or (more likely) to something with which it is associated (like living near a toxic waste dump, being poor, having poor access to care)? It is a conceptual mistake to leap from genotype association to genetic cause.
Slide 16b. Suppose a study discovers a particular genetic polymorphisms that is associated with a particular pharmaceutical response, as well as with a particular race or ethnicity[21]. Should researchers then recommend that clinicians use race or ethnicity to infer the presence of the polymorphisms and prescribe accordingly? Much depends on the validity of the pharmacogenetic data, how well it correlates with the way patients are assigned racial or ethnic labels, and the risk and magnitude of any harm that might occur if the inference is mistaken. If self-reported or clinician-judged race is only a poor proxy for the genetic polymorphisms in question, using race to infer the presence of the genetic polymorphisms and to prescribe a drug accordingly stands on questionable scientific ground and risks injuring the patients.
Slide 17. Toxicogenomics profiles gene expression as well as the metabolic constituents of cells. It also creates the potential for molecular fingerprints of toxin exposure or toxicological response to specific classes of substances[23]. A "molecular fingerprint" in this context is a change in DNA or DNA expression that is specifically associated with particular substances. In the legal setting, toxicogenomics is tied to toxic torts and workplace genetic screening.
Slide 18. Private citizens file "tort lawsuits" against other persons or institutions requesting compensation for an injury allegedly caused by the other's wrongful act. When this act involves or results in exposure to a toxic agent, the tort claim is a "toxic tort." Toxicogenomics could make this sort of litigation more fair and efficient by helping to refine the association between the putative agent and the particular harm, especially if a molecular fingerprint exists. More than likely, however, this evidence will be introduced into courtrooms before all scientific uncertainties are resolved, making scientific and legal interpretation crucial[24]. Thus, although toxicogenomics might improve toxic tort litigation by helping to ensure validity of cases both for citizens and those against whom such cases are brought, it can do so only with a sound scientific basis.
Slide 19a. Similar issues are related to the genetic screening of workers[25, 26]. As Omenn[27] points out, the Occupational Safety and Health Act (OSHA) of 1970 requires that "no worker" suffers adverse effects, even at the maximum exposure level to environmental threats. It also requires testing of workers who come into contact with workplace toxins -- but should this include genetic testing or molecular fingerprinting? In addition, the 1996 Food Quality Protection Act includes the explicit need to address the risks for particularly vulnerable or exposed subgroups of the population[5].
Slide 19b. In favor of genetic testing, such tests may help protect the employee's health and aid the employer's obligation to ensure a safe working environment[28]. Another aim could be to avoid employing a worker who is likely to develop an illness, potentially leading to higher employer healthcare costs.
Slide 19c. Alternatively, a case might be made for banning genetic testing in the workplace. First, there is a potential to inappropriately discriminate against individuals. Second, it diminishes attention to creating a safe work environment for all. Thus, with such competing approaches, the role of toxicogenomics with respect to workplace testing remains quite unclear.
Slide 20. Environmental genetics research raises important questions about personal responsibility to avoid environmental exposures that pose heightened risk of harm to the individual. Does having a known genetic susceptibility to disease in a particular setting increase one's personal responsibility because she or he "should have known better?" Or does it decrease responsibility because she or he "cannot help it?" Recent research even suggests that arming individuals with susceptibility information may not matter. These issues have important policy implications. For example, imagine a situation where insurance cost and coverage (health, life, or disability) are partially determined by willingness to modify one's environment based on genetic risk profiles. Some worry that emphasis on genetics may cause society to lose sight of other more important but perhaps more complicated ways of improving health, eg, via social institutions, lifestyle and environment[34]. Others disagree[35, 36, 37, 38]. This is a debate that is likely to continue.
Slide 21a. The application of research findings in environmental genetics research intersects the field of public health genetics. "Public Health Genetics"[39] involves public health epidemiology, biostatistics, environmental health sciences, health sciences research, and clinical prevention trials necessary for an appropriate application of genetic knowledge[40].
Slide 21b. Some cite the success of newborn genetic screening programs as evidence of public health's contribution to genetics[41], while others voice caution, wondering whether public health's newborn screening paradigm is generally applicable in all contexts[42, 43].
Slide 21c. Efforts have been made to incorporate the core functions of public health (assessment, policy development, and assurance[44]), with genetic testing and an understanding of how genes interact with modifiable risk factors[45]. To date, however, none of the Human Genome Epidemiology Network (HuGENet) reviews have shown a significant public health application for genetic information, although more reviews are needed in the area of environmental genetics interactions[46]. Other recent public health guidelines note the broad absence of evidence (utilizing scientific evidence, risk/benefit analyses, the need for counseling and informed consent, costs and resources required, and social issues) that would support public health applications for adult-onset conditions[47].
Slide 21d. Finally, defining the meaning and scope of public health in genetics may be crucial, because this has an impact on what public health can and should do. For example, the scope of public health helps determine when coercive measures on the part of the government are justifiable. If population health is defined with an emphasis on individuals and their health actions (with a greater emphasis on individual medical responsibility), rather than merely the population as a whole, such measures may be less easily justified[52].
Slide 22. This module has summarized some of the key ethical issues associated with environmental genetics research and its application. Raising awareness of these issues will hopefully help prepare those involved with this research and its oversight to help mitigate them, primarily by promoting the protection of the rights and interests of research participants.
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