GENETICS AND ENVIRONMENT IN HUMAN HEALTH

All living things interact with multiple environments, both physical and biological. With regard to the flourishing of plants and animals, environmental features such as temperature, humidity, sunlight, and altitude often set boundaries crucial to development. Biological interactions between living things frequently are another major factor in growth and survival, for example, where parasites and predators cause illness or injure plants and animals. So it is with human health and flourishing as well, where environmental hazards and infectious diseases account for the vast majority of illnesses resulting in death.

The publication of Rachel Carson's Silent Spring (1962) and the subsequent emergence of a worldwide environmental movement has raised social awareness of the dangers to human health posed by industrial chemicals. Of the several million chemicals listed by the American Chemical Society, about 75,000 are used as pesticides, cosmetics, pharmaceuticals, food additives, or industrial agents. Most new chemicals must be tested for potential toxicity to humans and other living things before they can be approved for sale. In the United States, the Food and Drug Administration (FDA) requires extensive animal and clinical testing of new drugs, vaccines, and approved drugs proposed for new uses, as well as animal testing for food additives and cosmetics. Under various pesticide laws, including the Toxic Substances Control Act of 1976, the U.S. Environmental Protection Agency (EPA) also requires toxicity testing of new chemicals before they are brought to market. In addition, the Occupational Safety and Health Administration, Consumer Product Safety Commission, Department of Agriculture, Department of Transportation, and their state and local counterparts, each have additional responsibilities regarding the control of chemical agents.

These regulatory policies have done much to improve environmental quality and protect humans from industrial hazards. Nonetheless, individuals do not bear the burdens of environmental risk equally and vary remarkably in their responses to chemical exposures and pharmaceuticals. Such variation may reflect differences in sex, age, nutrition, lifestyle decisions to smoke cigarettes or drink alcoholic beverages, recreational exposures to similar chemicals, concurrent occupational exposures, and use of protective gear or medicines. In addition, variation in individual response may reflect inherited differences in a person's ability to metabolize specific chemicals, thus affecting individual risks of disease and other adverse effects.

The products of the Human Genome Project are allowing new investigations of these inherited differences that appear to make some individuals more vulnerable to specific environmental exposures or more susceptible to environmentally-induced diseases. The study of these inherited differences and their potential influence on individual response to environmental agents is the subject of the field of ecogenetics.

Ecogenetics: Individual Variation in Susceptibility to Environmental and Chemical Agents

Ecogenetics examines how genes and environmental factors interact with each other to affect human health and disease. Genes are sequences of DNA in humans' twenty-three pairs of chromosomes in each nucleated cell. Genes specify the sequence of proteins, which are the main effector molecules of cells, serving as enzymes (catalysts), structural molecules (like collagen), antibodies to fight off infections, and binders of oxygen or xenobiotics (including pharmaceuticals or chemicals in the environment). Environmental factors include social and familial environment, intrauterine environment, cigarette smoking, alcohol, other substance abuse, stress, and exposures to chemical, physical, and biological agents. Some environmental exposures such as ultraviolet light, X rays, and certain industrial chemicals cause damage to DNA (genetic mutations), which alter gene function as well as the structure and function of the protein specified by that gene. Although many such mutations appear to be of little consequence, some may lead to disease.

There are many examples of gene-environment interactions combining to affect human health. Body weight and obesity, for example, appear to be the result of food intake, energy expenditure, and various genetic determinants. For infectious diseases such as malaria and tuberculosis, genetic features appear to affect both individual susceptibility and the severity of the illness. Another example is response to pharmaceutical products, where some drugs with limited side effects (at usual doses in most individuals) may cause severe problems for persons with genes associated with decreased capacity to metabolize the drug. Without exposure to the drug, however, these genetic variants may be innocuous. For example, cytochrome P450 enzymes form a family of dozens of related enzymes with distinct and overlapping characteristics. One specific P450 enzyme, debrisoquine 4-hydroxylase, has been associated with marked variation in the metabolism of more than thirty drugs.

Biochemical and molecular techniques are being used to develop new genetic markers of host susceptibility to environmental and chemical agents. To cause poor health, many chemicals must be activated by enzymes to intermediates that attack DNA (as appears to be the case in many environmentally-induced cancers and birth defects). Other enzyme systems detoxify potentially toxic compounds, and variation in the genes that specify the sequence of enzymes involved in these biotransformation steps can result in people with similar exposures having very different disease risks.

An example of this type of gene-environment interaction affecting health outcomes is deficiency in the enzyme glutathione S-transferase (GST), which is believed to be an important predisposing factor in the development of some environmentally-induced cancers. About 45 percent of persons of European ancestry lack detectable activity of a particular form of GST. Several studies examining GST levels in lung tissue suggest that GST-deficient smokers are at higher risk of developing lung cancer, presumably because this enzyme detoxifies carcinogenic chemicals. Thus, GST-normal smokers are partially protected against lung cancer. In addition, high GST activity is an important protective factor against liver cancer resulting from exposure to aflatoxin (a toxin from fungi that grow on peanuts and corn).

An additional example of this type of ecogenetic phenomenon is provided by variation in the liver enzyme N-acetyl transferase (NAT), which has been associated with marked differences in blood levels of several drugs, including the anti-tuberculosis drug isoniazid (at standard doses). Roughly 50 percent of individuals of European or African ancestry have the slow acetylator phenotype (the form of the gene and enzyme with lower metabolic activity) associated with higher levels of still-active drug and a propensity to adverse effects. The same detoxification mechanism metabolizes several other chemicals, including the human bladder carcinogens beta-naphthylamine, benzidine, and 4-amino-biphenyl—all former mainstays of the dyestuff industry worldwide. People who are slow acetylators are at higher risk for bladder cancer, as expected from the hypothesis that they would be less able to detoxify these potent carcinogens by acetylation to inactive products. DNA probes are available to assay this kind of genetic variation in peripheral blood cells, rather than having to administer a test drug and measure metabolites in urine.

Gene-environment interactions also can be seen in many other kinds of diseases, not just cancers. For example, the common organophosphorus pesticide, parathion, is converted to its toxic intermediate, paraoxon, by the P450 system and then inactivated by a circulating plasma enzyme, paraoxonase. About half of individuals of European descent have low paraoxonase activity. For similar exposures, people with lower activity of this enzyme are likely to be at higher risk for neurologic toxicity and take longer to recover. High blood cholesterol levels are related both to diet and to inherited variation in several genes affecting the proteins that carry fat (lipoproteins) and their cell receptors. Cholesterol- and fat-reducing diets and drugs can reduce coronary heart disease deaths and heart attacks; however, responses to diet and drugs appear to differ among people with different genetic causes of high levels of fat components in the blood. Chronic anemias due to iron deficiency are a major health problem throughout the world. Although iron can be supplied inexpensively by fortification of flour, a small percentage of individuals carry genes (for types of anemia called thalassemias or for an iron metabolism disorder known as hemochromatosis) that cause these individuals to absorb iron excessively. These people might be injured by additional dietary intake of iron.

Integrating Genetic and Environmental Information in Clinical Research

The risks posed by exposure to chemical and environmental agents are related to the level of exposure, the intrinsic potency of the agent, and the susceptibility of the person exposed. In general, the highest exposures are in patients receiving potent drugs or radiation as medical treatments and in workers manufacturing or cleaning up chemicals in various operations. Therefore, it is logical and efficient to investigate potential risks to human health in patients and in workers with known exposures to specific agents. Studies of risks to the general population from contamination of groundwater or from air pollution, consumer products, or hazardous waste sites are far more difficult to conduct because the levels of exposure are typically much lower and thus the likelihood of identifying adverse effects is significantly reduced. In addition, although chemical exposures may cause immediate toxicity to the skin, eyes, lungs, heart, liver, nervous system, reproductive organs, or other target sites in the body, some effects may be unrecognized at first, including mutations in specific genes that may eventually lead to cancer or birth defects. Repeated exposures at relatively low doses also may have cumulative toxic effects that are difficult to identify. The challenge of establishing that impairment of brain function can result from lead exposure, for example, illustrates the difficulty of assessing the role of chronic, low-level environmental exposures in disease.

These considerations highlight the importance of ecogenetic research combining careful exposure-assessment studies with investigations of genetic influences on disease. Such a multidisciplinary approach is being explored in a coordinated manner through the Environmental Genome Project (EGP), a research initiative supported by the National Institute of Environmental Health Sciences, a component of the National Institutes of Health. The goals of the EGP are to: (1) identify some of the more common genetic differences between individuals that appear to affect response to environmental hazards; (2) conduct epidemiological studies investigating the role of gene-environment interactions in the development of common diseases like asthma, cancer, and heart disease; and (3) promote the use of information regarding gene-environment interactions in public health initiatives.

The EGP will develop in several stages. In the first phase of the project, experts will identify a set of approximately 500 genes that appear to play a role in the development of environmentally-induced diseases. These will include xenobiotic metabolism and detoxification genes, DNA repair genes, signal transduction genes, and genes involved in oxidative processes. Having identified a set of genes that appear to be involved in environmental response, the second phase of the project will catalogue common genetic differences in these genes—differences that may affect the functioning of the associated enzymes. Finally, in the third phase of the EGP, researchers will study the biological implications of these genetic differences using functional assays and population-based studies of gene-environment interactions. Organizers of the project expect that the first two phases of the EGP will be completed in late 2004. The third phase of the project will require significantly more time to complete, however, and will involve numerous epidemiological studies conducted over the next ten to twenty years.

Since many of the genes believed to play an important role in how humans respond to environmental hazards appear to affect health only in the presence of specific environmental exposures, deciphering the relationships that exist between genetic variants and individual response has the potential to improve public health significantly. Identifying those persons most at risk, for example, and encouraging them to avoid those environmental hazards to which they are most susceptible, may help prevent or delay disease onset in large segments of the population without pharmacological interventions. In addition, projects like the EGP might eventually lead to:

1. more accurate estimates of disease risks;
2. targeted disease-prevention strategies or medicalmonitoring programs to detect disease earlier;
3. pharmaceutical products with fewer adverse effects; and
4. a better understanding of biological mechanisms of disease.

A great deal of work will need to be done to elucidate specific genetic risk profiles for environmentally-induced diseases as we move into the era of genetic medicine. In the meantime, both the population-wide approach that emphasizes environmental measures and the genetic approach that aims to identify individuals at increased risk are likely to be advocated. It is certainly prudent, for example, that everyone follow a diet that avoids excess fat, cholesterol, and salt. At the same time, genetic tests may soon be able to identify those persons at highest risk of developing coronary heart disease and high blood pressure. Taken together, these two strategies may provide a powerful approach to encouraging individuals to change their diets and lifestyles in ways that promote good health.

Ethical Issues in Ecogenetics

Although ecogenetics is still in its infancy as a scientific field, a number of important ethical considerations can be anticipated and should be addressed before genetic tests are used to screen individuals or populations for inherited susceptibilities to chemical or environmental agents. For example, long before the development of molecular genetics, J.B.S. Haldane suggested in Heredity and Politics (1938) that it might be reasonable to exclude persons who are susceptible to potter's bronchitis (a common problem among British potters at the time) from work in that occupation. Since workplace exclusion, stigmatization, and discrimination can result from knowledge of genetic risk factors for disease, studies of gene-environment interactions raise a number of ethical and social issues of great importance.

How one defines the extent of an individual's risk, for example, is an issue deserving of attention. Susceptibility to one kind of chemical may not predict susceptibility to chemicals with unrelated metabolism or structure. Thus, no one should be branded as "hypersusceptible" to chemical exposures on the basis of being identified as vulnerable to a specific environmental hazard or chemical. Since much confusion often surrounds the interpretation of genetic information, with laypersons frequently overstating the predictive value of a test, educational programs that aim to improve public understanding of ecogenetic tests will be critical to the long-term success of this new field.

Another issue that will be important to clarify for the general public is that, even after a genetic risk factor has been identified and is well characterized, the cause of disease in a specific individual often will be unclear. The well-recognized interaction of cigarette smoking with workplace asbestos exposure in causing lung cancer reveals some of the scientific uncertainties and ethical problems associated with assignments of disease causation in individual cases. The mere fact that a person has a gene that predisposes him or her to a specific disease—and then goes on to develop that disease—does not establish that the genetic susceptibility was the cause of the disease. Other genetic or environmental factors, for example, may have contributed substantially to the outcome.

Another ethical consideration is that since genetic differences sometimes occur with markedly different frequencies across racial or ethnic groups, targeted genetic testing programs could place disproportional burdens on members of some racial or ethnic groups. Related to this is the problem of group stigmatization, where social disadvantage results from the general association of a susceptibility gene with a particular racial or ethnic group.

Although tests for genetic predispositions to chemical and environmental agents could lead to targeted preventive approaches and improved assessments of individual risk, it is important that the future availability of such techniques does not diminish the commitment to eliminate hazardous environmental exposures. For example, the ability to identify genetic sensitivities to toxins in the workplace may inadvertently shift the focus of risk-management efforts away from the improvement of unhealthy environmental conditions if employers find it less costly to dismiss genetically sensitive workers than to eliminate workplace hazards.

In addition, the potential geneticization of environmental disease may inappropriately place unreasonable expectations on those persons with known genetic sensitivities. Individuals known to be particularly susceptible to the harmful effects of a particular chemical agent, for example, may face social pressures to remove themselves from those environments in which that chemical is found (e.g., to move to a different neighborhood or change jobs). Ironically, if we are successful in reducing environmental exposures to levels sufficient to protect most of the population, genetic differences between individuals will account for a larger proportion of the remaining risk among those exposed. This possibility could foster more deterministic attitudes regarding the significance of genetic information, for example, resulting in research funding being diverted from traditional preventive strategies for improving public health to approaches stressing genetic causes of disease.

Lastly, while genetic markers of susceptibility are being developed for use in healthcare settings, it is important to be mindful of the possibility that information about gene-environment interactions may be used in other contexts before those associations are well validated. In this regard, a recent Equal Employment Opportunity Commission (EEOC) claim brought forth against the Burlington Northern Santa Fe Railroad Company illustrates the potential for not-yet-validated associations to be used inappropriately. The EEOC dispute in question involved the railroad company testing workers for an alleged genetic predisposition to carpel tunnel syndrome. Although the extent to which the gene in question may be a predisposing factor in the development of carpel tunnel syndrome is largely unknown, that did not prevent the company from attempting to use this information in their efforts to avoid responsibility for workers' compensation claims. Whether other employers will adopt similar practices based on new ecogenetic information is a matter to watch carefully in the coming years.

gilbert s. omenn

arno g. motulsky (1995)

revised by richard r. sharp

SEE ALSO: Genetic Counseling, Ethical Issues in; Genetic Counseling, Practice of; Genetic Discrimination; Genetics and Human Self-Understanding; Genetic Testing and Screening; Health and Disease; Health Insurance

BIBLIOGRAPHY

Andrews, Lori B.; Fullarton, J. E.; Holtzman, N. A.; and Motulsky, A. G. 1994. Assessing Genetic Risks: Implications for Health and Social Policy. Washington, D.C.: National Academy Press.

Carson, Rachel. 1962. Silent Spring. Boston: Houghton Mifflin.

Draper, Elaine. 1991. Risky Business: Genetic Testing and Exclusionary Practices in the Hazardous Workplace. New York: Cambridge University Press.

Eaton D. L., and Bammler, T. K. 1999. "Concise Review of the Glutathione S-Transferases and Their Significance to Toxicology." Toxicological Science 49: 156–164.

Grandjean, Philippe. 1991. Ecogenetics: Genetic Predisposition to the Toxic Effects of Chemicals. New York: Routledge, Chapman, and Hall/World Health Organization.

Guttmacher, A. E., and Collins, F. S. 2002. "Genomic Medicine—A Primer." New England Journal of Medicine 347: 1512–1520.

Haldane, John Burdon Sanderson. 1938. Heredity and Politics. New York: Norton.

Holtzman, Neil A. 1989. Proceed with Caution: Predicting Genetic Risks in the Recombinant DNA Era. Baltimore: John Hopkins University Press.

International Agency for Research on Cancer, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans.1987. Overall Evaluation of Carcinogenicity: An Updating of IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vols. 1–42, suppl. 7. Lyons, France: Author.

Khoury, M. J.; Adam, M. J.; and Flanders, W. D. 1988. "An Epidemiologic Approach to Ecogenetics." American Journal of Human Genetics 42: 89–95.

Motulsky, Arno G. 1978. "Bioethical Problems in Pharmacogenetics and Ecogenetics." Human Genetics Supplement 1: 185–192.

Nebert, D. W., and Russell, D. W. 2002. "Clinical Importance of the Cytochromes P450." Lancet 360: 1155–1162.

Olden, Kenneth, and Wilson, Samuel. 2000. "Environmental Health and Genomics: Visions and Implications." Nature Reviews Genetics 1: 149–153.

Omenn, Gilbert S. 2000. "Public Health Genetics: An Emerging Interdisciplinary Field for the Post-Genomic Era." Annual Review of Public Health 21: 1–13.

Omenn, Gilbert S., and Motulsky, Arno G. 1978. "'Eco-genetics': Genetic Variation in Susceptibility to Environmental Agents." In Genetic Issues in Public Health and Medicine, ed. Bernice H. Cohen, Abraham M. Lilienfeld, and Pien-Chien Huang. Springfield, IL: Charles C. Thomas.

Sharp, Richard R. 2001. "The Evolution of Predictive Genetic Testing: Deciphering Gene-Environment Interactions." Jurimetrics 41: 145–163.

Sharp, Richard R., and Barrett, J. Carl. 1999. "The Environmental Genome Project and Bioethics." Kennedy Institute of Ethics Journal 9: 175–188.

U.S. Congress, Office of Technology Assessment. 1983. The Role of Genetic Testing in the Prevention of Occupational Disease. Washington, D.C.: U.S. Government Printing Office.

U.S. Congress, Office of Technology Assessment. 1991. Medical Monitoring and Screening in the Workplace. Washington, D.C.:U.S. Government Printing Office.

Weber, Wendell W. 1997. Pharmacogenetics. New York: Oxford University Press.