**2.7 Gene-environment interactions**

496 Toxicity and Drug Testing

new exposures that may be potential reproductive toxicants. New technologies such as geographic information systems (GIS) allow mapping of industries and specific chemical exposures. Use of GIS to identify geographic areas with high volume of use of suspect chemicals might be an effective method of identifying populations with greater potential occupational and environmental exposures. Biomonitoring is a valuable tool for estimating occupational exposure. The National Report on Human Exposure to Environmental Chemicals is a new and ongoing assessment of the U.S. population's exposure to environmental chemicals. The first edition of the report presents levels of 27 environmental chemicals, including metals (e.g., lead, mercury, and uranium), cotinine (a marker of tobacco smoke exposure), organophosphate pesticide metabolites, and phthalate metabolites. This is a significant step forward in assessing the potential human toxicity of a class of chemicals known to be reproductive and developmental toxicants in rodents. Improved methods for analysis of exposure, especially of age and time effects, are likely to impact the characterization of occupational exposure in these studies (Richardson and Wing 1998). Current research approaches usually consider the action of single, unique toxicants on outcomes of interest, creating yet another challenge to drafting a reproductive hazards agenda. The more common human exposure scenario is to mixtures of toxicants at low concentrations, episodically and over the long term. Attention to cumulative exposure over years of a working lifetime and total aggregate exposure to toxicants from multiple exposure sources, as well as classical considerations of exposure routes, must also be addressed. Methodologic approaches must enlarge and mature to consider the effects and modulation of effects mediated by both exposure to mixtures of toxicants and the

complexities of exposure mode at low dose and over prolonged duration.

Understanding mechanisms of action of toxicants is important for a number of reasons, including *a*) supporting the biologic plausibility of an observed association between chemical exposure and adverse outcome; *b*) uncovering common pathways of actions of different agents; *c*) extrapolating across species for risk assessment; *d*) improving the predictability of human morbidity from responses of model species; and *e*) predicting responses to mixed exposures (Lawson et al., 2003). Mechanistic studies are not new in toxicology; however, new tools in genomics, proteomics, and bioinformatics present unprecedented opportunities to advance our understanding of toxicant action at a molecular level. Genomic information and the ability to screen most or all of the genome of an increasing number of organisms for changes in gene expression are revolutionizing the way in which biologic effects data are gathered. It is now possible to determine the effects of a toxicant exposure on gene expression of most of the genome of mice and rats. This will allow us to generate testable hypotheses about the mechanism of action of toxicants. It will also open up the possibility of identifying markers of exposure or effect specific to a particular insult that can be used in field studies. As with any new technology, a number of problems will need to be overcome for the promise of genomics to be realized. The first will be to manage the large volume of information produced by gene expression experiments. Gene chips may contain thousands or tens of thousands of sequences. Experience shows that any perturbation in a biologic system leads to numerous changes in gene expression. An entire field of bioinformatics is being developed to help collect, organize, and manage

**2.6 Mechanistic research** 

Reproductive toxicants can affect human populations over the total life span, including the *in utero* and perinatal periods, childhood, puberty, and adulthood. Thus, extending research efforts to address stage-specific sensitivity is recommended. Another emerging approach allows the identification of populations at potentially increased risk from toxicant exposure by characterizing genetic polymorphisms of metabolizing enzymes in exposed cohorts. Such methods may identify vulnerable subpopulations on the basis of inherent (genetic) differences in their ability to metabolize a toxicant.
