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8 Setting Air Quality Standards in the Postgenomic Era
- Johns Hopkins University Press
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C H A P T E R 8 Setting Air Quality Standards in the Postgenomic Era GARY E. MARCHANT The sequencing of the human genome revealed that humans are more genetically homogeneous than previously appreciated. Any two humans differ on average only once in every thousand DNA base pairs, representing a striking 99.9 percent genetic alikeness (Venter et al., 2001). Notwithstanding this overall genetic homogeneity, one category of genes that are highly variable (“polymorphic”) between individual humans are those coding for enzymes involved in the metabolism of foreign substances entering our bodies, including infectious agents, foods, drugs, and chemicals. Such variations likely represent the evolutionary vestige of trade-offs in seeking the optimal adaptation to the various environments, diseases, and diets that are present in different parts of the world (Nebert, 2000; Kalow, 2002). In the past few years, considerable progress has been made in understanding the genetic basis of human variability in susceptibility to environmental exposures. Genes have been identified and mapped affecting susceptibility to virtually every major environmental pollutant (Marchant , 2003). The Environmental Genome Project, sponsored by the National Institute of Environmental Health Sciences, identified a working list of more than 550 genes affecting variable response to environmental exposures and is in the process of characterizing variants of those genes (Wakefield, 2002; Wilson and Olden, 2004). These genetic variants affect all aspects of the body’s handling of foreign substances, including metabolism , detoxification, DNA repair, receptors, and cell cycle controls. The genes affecting variable susceptibility to environmental agents generally have several important features in common. First, unlike disease susceptibility genes such as the BRCA1 and BRCA2 breast cancer predisposition genes, which increase risks for everyone who has the gene, most environmental susceptibility genes increase risks only when both the gene and the corresponding environmental agent are present. This relationship between the gene and the agent has been described as being “similar to that of a loaded gun and its trigger. A loaded gun by itself causes no harm; only when the trigger is pulled is the potential for harm released or initiated. Likewise, one can inherit a predisposition for a devastating disease, yet never develop the disease unless exposed to the environmental trigger(s)” (Olden and Guthrie, 2001, pp. 3–4). Environmental susceptibility genes are generally neither sufficient nor necessary to cause environmentally induced disease; they merely increase the risk. Second, the effect for the individual of any environmental susceptibility gene is rather modest, as most of the genes seem to increase risk by at most a fewfold over background rates, compared with some disease genes that generally increase risks much more dramatically (Caporaso and Goldstein, 1995; Garte et al., 2001). From a population perspective, however, many of these environmental susceptibility genes are important because they are very prevalent and thus may increase or decrease population risk substantially (Kelada et al., 2003). Third, genetic susceptibility to environmental agents is likely to account for an increasing proportion of environmentally induced illnesses as environmental exposures are progressively reduced by regulatory and other initiatives. Some commentators have suggested that, following the major reductions that have been made in exposures to many environmental pollutants, the remaining adverse health impacts from residual pollutant levels are likely to be heavily or even almost exclusively concentrated in people with genetic and other susceptibilities to the relevant pollutants (Eaton et al., 1998; Olden and Guthrie, 2001). Many genetic susceptibilities to environmental pollutants are most significant S E T T I N G A I R Q U A L I T Y S T A N D A R D S I N T H E P O S T G E N O M I C E R A 117 [3.82.58.213] Project MUSE (2024-03-29 12:06 GMT) at lower exposure levels, because higher exposure levels are likely to overwhelm defense mechanisms even in people with the most resilient genotypes. Fourth, genes explain only some of the differences in individual susceptibility to environmental agents. Other genes and other environmental exposures, health conditions, age, and nutrition can also affect susceptibility, and moreover these types of susceptibility are likely to interact in complex ways with genetic susceptibilities. The result is that each individual, through the combination of his or her own mix of intrinsic and extrinsic factors, will be uniquely susceptible (or nonsusceptible ) to the myriad of environmental agents to which we are all exposed. These types of susceptibility-susceptibility interactions make the study of genetic...