Exposure routes extrapolating across species

The greater the depth of understanding of toxicity and agent deposition in animals and humans, the less is the uncertainty that attends extrapolation across species and routes of exposure. When such pharmacokinetic studies are done, apparent species differences in susceptibility are often found to result from differences in absorption, fate, or elimination of the potential toxic agent rather than to biological differences in susceptibility (Renwick 1993). 

Present-day risk assessment methodologies have an increasing emphasis on physiologically based pharmacokinetics (PBPK) or toxicokinetic models and mode of action (MOA). Snch models have been developed to predict exposure levels in target tissues for a large number of agents. PBPK models are especially useful in the risk assessment context because they allow data to be extrapolated across species, dose levels, and routes of exposure. 

In the absence of definitive human data, risk assessment may have to depend on the results of cancer bioassays in laboratory animals, short-term tests, or other experimental methods. Hence the following issues must be addressed under such circumstances the ability of the test system to predict risks for man (quantitatively as well as qualitatively) the reproducibility of test results the influence of species differences in pharmacokinetics, metabolism, homeostasis, repair rates, life span, organ sensitivity, and baseline cancer rates extrapolation across dose and dose rates, and routes of exposure the significance of benign tumors fitting models to the data in order to characterize dose-incidence relationships and the significance of negative results. 

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Additionally, in some situations extrapolation across exposure routes is not recommended at all. For example, we know that metals often have different target organs depending on how exposure occurred (e.g., breathing versus eating or drinking). For metals where we do not have toxicity data for both exposure routes, there is no way to accurately predict if toxicity will be the same or different. Therefore, extrapolation across exposure routes is not typically performed for metals. For most environmentally important metals, toxicity information has been compiled for multiple routes of exposure, which obviates the need for such extrapolation. The same process is typically used for extrapolation to wildlife species. 

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