Different people respond differently to pharmaceuticals and environmental and occupational chemicals. Some people are sensitive to the adverse side effects from pharmaceuticals, while most have no reaction. Some people get lung cancer from cigarette smoking and others don't. Diethylstilbestrol exposure of fetuses in utero resulted in the development of cancer later in life, although equivalent exposures in adults does not cause a detectable increase in cancer. This list could go on and on, but the point is that we are beginning to recognize and understand some of the molecular and biological determinants of susceptibility to chemically mediated disease and the role that individual differences play. Unfortunately, regulatory policy has not kept pace with research advances.
Risk estimates are usually based on predicted effects in 70-kilogram young-adult males. To account for interindividual differences in response, a 10-fold safety factor is often applied to a given risk estimate. This safety factor is likely to be high for some chemicals and probably much too low for others. All parties engaged in science policy have stated a need to identify sensitive subpopulations so that regulations can be based on a more realistic range of expected risks. A number of issues need to be addressed regarding sensitive subpopulations, including genetic differences that predispose an individual to risk, gender, age, diet, preexisting disease conditions, and exposure to mixtures of chemicals.
Research in the area of genetic susceptibility includes differences in drug metabolism, DNA repair capabilities, and inherited mutations in critical target genes. Numerous reports in the scientific literature have established the presence of polymorphisms in drug-metabolizing enzymes such as the cytochrome P450 isozymes, glutathione transferase, and N-acetyltransferase. Polymorphisms in these metabolizing enzymes exert a profound effect on the rate of activation or detoxification of toxic chemicals such as benzene, polycyclic aromatic hydrocarbons, and arylamines. For example, a recent study by Douglas Bell and Jack Taylor of the NIEHS have shown that a polymorphism (gene deletion) in a glutathione transferase isozyme significantly increases the risk of bladder cancer from cigarette smoking and may account for 25% of all bladder cancers worldwide.
Genetic differences in DNA repair capacity are emerging as a key determinant in some environmental diseases. As we learn more about the genes that control DNA repair rates and specificity, we undoubtedly will uncover many polymorphisms in DNA repair pathways that could increase or decrease risk.
Recent characterizations of the breast cancer and colon cancer susceptibility genes have shown that a mutation in a critical target gene may drastically increase cancer risk. For example, 85% of the women who harbor the BRCA1 (breast cancer 1) gene will develop the disease. Once the function of susceptibility genes is known, effective molecular blocks could possibly be designed to prevent the development of cancers caused by their expression. Further study of interactions between susceptibility genes and environmental chemicals is crucial. We also need to further our understanding of ethnic differences that predispose to risk. Recent discoveries of polymorphisms in drug-metabolizing enzymes specific to African-Americans may be related to differences in environmentally related cancers such as lung and bladder cancers.
The most compelling issue in distribution of risk is age-dependent differences. Fetuses and children are not just small adults; their differentiating and developing systems may be especially sensitive to toxic insult. Some effects caused by newborn or in utero exposure to chemicals such as PCB-induced behavioral disturbances may not be manifested until much later in life. This issue is of special concern in the case of environmental chemicals that mimic or block the actions of naturally occuring hormones that are essential for normal development. One route of exposure to such chemicals may be through breast milk. It is estimated that infants can be exposed to approximately 50-80 picograms per kilogram body weight per day of dioxinlike compounds in breast milk from women exposed to only 4 picograms per kilogram per day of these compounds. This does not recommend against breastfeeding, though, because of its many benefits, but it demonstrates that infants may receive much higher doses of some chemicals compared to adults, at a time in their life when they are most sensitive.
Women's health issues, inadequately addressed until recently, have raised our consciousness of gender and hormonal influences on susceptibility to disease. There are numerous diseases of concern for women, with breast cancer and endometriosis as two of the most devastating examples. There is growing evidence of an environmental component of these diseases, yet the mechanisms responsible remain unknown.
Diet exerts a dramatic influence on environmental causes of disease. The food we eat changes the way we metabolize chemicals, the pattern of mutations in selected genes, and the capacity of our immune systems to combat disease. Clearly, diet is in part responsible for differences in breast cancer rates observed between Japan and the United States. Also, changes in diet affect the results of animal bioassays for cancer. For example, a recent National Toxicology Program study showed that several chemicals which increased cancer rates in animals fed ad libitum had no detectable effect when animals were subjected to diet restriction.
Preexisting diseases and accompanying changes in physiology and biochemistry must certainly change the way humans respond to chemicals. Little is known about the impact of common diseases on sensitive subpopulations, so this issue remains a priority research question. Regulatory agencies need to begin developing strategies to evaluate chemical risks under chronic disease conditions.
We are exposed to a sea of chemicals in day-to-day living. The interactions of these chemicals at the molecular and biological levels may lead to antagonism, potentiation, or synergism. How to develop scientifically sound yet economically practical risk assessment strategies for mixtures is one of the most challenging problems confronting regulatory agencies.
Proponents of environmental justice have raised numerous issues concerning the inequities of chemical exposure. Clearly, where a person lives will determine the pattern and magnitude of chemical contaminants in his or her body. Strategies need to be developed to understand the consequences of these exposures and their relationship to the identification of sensitive subpopulations.
I strongly encourage attempts to identify subpopulations who are especially sensitive to the adverse health consequences of chemical exposure. What must follow is the use of this information by regulatory agencies in making decisions that consider all of the social and scientific factors involved while protecting against the range of expected risks based on the growing scientific knowledge of the mechanisms and situations responsible for the distribution of risk.
George W. Lucier
Co-Editor in Chief
Last Update: May 21, 1998
