gene polymorphisms in the paraoxonase I gene (PON1) and the resulting differential response to organophosphate pesticides typify the type of genetic markers of toxic response that are likely to surface during the next decade (see Box 6-1).

Another potential impact arising from toxicogenomics is the development of new classifications of disease subgroups. Most adverse reactions to chemical or therapeutic compounds have been classified by biochemical or clinical markers (frequently based on histopathologies). New molecular classifications of disease are likely to arise as researchers better understand the genomic, transcriptomic, proteomic, and metabonomic characteristics of disease.

Finally, new knowledge about genetics and human variability in response is expected to enable greater tailoring of existing pharmaceuticals to patients to reduce toxicities and to better design new pharmaceuticals that produce fewer toxicities.

STATE OF THE ART IN ASSESSMENT OF INDIVIDUAL VARIATION

Toxicogenomic studies relevant to understanding human variability encompass various technologies and study designs. These range from investigations of variability in human gene expression profiles in responseto chemicals to large population-based cohort studies focused on identifying the genetic variations that influence sensitivity to chemicals. Dynamic modification of gene expression patterns without modification of the sequence, known as epigenetic phenomena, are also becoming better understood and characterized. This chapter reviews the state of the art in these areas and assesses future needs and challenges.

Variation in Gene Sequence

Gene-environment interactions refer to effects in which human genetic variability governs differential responses to environmental exposures such as the examples already discussed in this chapter. In this section, this concept is explored through a review of recent studies that identify genetic mutations associated with differential response to cigarette smoke and its association with lung cancer (Box 6-2). This study indicates that smoking is protective in some genotypic subgroups, which raises multiple ethical and policy related issues (see Chapter 11) yet typifies how gene-environment interactions may often appear counterintuitive with respect to our current knowledge base. This type of study also demonstrates the increased information provided by jointly examining the effects of multiple mutations on toxicity-related disease. Studies of polymorphisms in genes involved in Phase II metabolism (GSTM1, GSTT1, GSTP1) have also demonstrated the importance of investigating the combined effects of these variants (Miller et al. 2002).



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