thought to be near levels associated with key precursor events in the carcinogenic process, and (2) by using nonlinear slopes at low doses when there are enough data to determine the mode of action and conclude the dose-response relationship is not linear or an agent is not mutagenic at low doses.

Because of their ability to detect more subtle changes at the molecular level than those detected by traditional high-dose animal studies, toxicogenomic studies, properly designed and interpreted, can provide greater insight into dose-response relationships with respect to low-dose effects and mode of action (which affects the assumed shape of the dose-response relationship). However, similar to traditional toxicology assays, most toxicogenomic investigations to date have used relatively high doses and conventional end points.

These studies assume that many of the differentially regulated genes are associated with the observed toxic effect. For example, Gant et al. (2003) identified genes induced during chronic liver injury, Amin et al. (2004) investigated renal toxicity, and Hamadeh et al. (2004) identified furan-mediated hepatotoxicity. Moggs et al. (2004) identified the genes and molecular networks associated with the uterotrophic response to estrogens. Such studies are critical for proof of concept, but, ultimately, toxicogenomic technologies will most benefit risk assessments when they provide insight into responses that occur at doses at or near anticipated population exposures—modeling at such low doses is always a challenge. Several illustrations of the potential implications of toxicogenomics for exploring dose-response issues are provided in the following sections.

Low-Dose Responses

When looking at gene expression over a range of doses, some altered genes may reflect homeostatic responses, others may be “early responders” inherent to the ultimate toxic response, and still others may represent perturbations in vital cell pathways resulting from adverse effects. To elucidate quantitative dose-response relationships, the observed changes in gene expression need to predict the toxic response and distinguish it from nontoxic responses. Although this is inherently difficult in complex biologic systems, several concepts have been proposed to help distinguish low-dose effects that predict toxicity from those that do not. They include emphasizing perturbations in critical cellular systems, such as stress responses, apoptosis, and energy production as well as assessing the magnitude of gene expression changes and the number of genes affected as doses increase (Heinloth et al. 2004).

Often a dose increase does not simply increase the magnitude of expression change in the same set of genes but also influences which genes are affected; that is, the dose increase shifts the response profile. For example, Andrew et al. (2003) compared the effects of low noncytotoxic doses with higher cytotoxic doses of arsenic on human bronchial epithelial cells and reported the expression of almost completely nonoverlapping sets of genes. There appeared to be a threshold switch from a “survival-based biologic response at low doses



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