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Collection of chemical-specific toxicological and pharmacokinetic data to improve risk assessments based on epidemiology: Example of Mn
Citation:
BOYES, W. K. Collection of chemical-specific toxicological and pharmacokinetic data to improve risk assessments based on epidemiology: Example of Mn. Presented at Society of Toxicology Annual Meeting, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
Development of both data and pharmacokinetic (PBPK) models of Mn in multiple species via oral and inhalation exposure and across ages can provide a biologically-informed basis for future risk assessment.
Description:
Data limitations led to the application of default uncertainty factors in prior risk assessments for Mn. These limitations were instrumental in the EPA generation of an alternative tier II test rule under section 211 (b) of the Clean Air Act, (fuels and fuel additives) regarding the proposed use a Mn-containing fuel additive (MMT). Development of both data and pharmacokinetic (PBPK) models of Mn in multiple species via oral and inhalation exposure and across ages can provide a biologically-informed basis for future risk assessment. Under the premise that target tissue dose is the key determinant of toxicity, the concentration of Mn in the brain can be estimated by PBPK models for a variety of conditions relevant to risk assessment. In addition, incorporation of specific biological mechanisms that control tissue disposition of Mn as an essential nutrient improves the biological plausibility of these models. The predicted levels from the PBPK models can be assessed using recent test rule data, in addition to other literature values. The PBPK models have the capability to consider Mn input by both oral and inhalation routes of exposure in a single evaluation, and resolve apparent route-dependent differences in toxicity, Species sensitivity differences are more complex and likely involve both pharmacodynamic and pharmacokinetic factors. Together this set of pharmacokinetic data and new PBPK models provide capabilities for comprehensive biologically based risk assessments of Mn that were not previously feasible. This abstract does not reflect EPA policy