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How pharmacokinetic modeling could improve a risk assessment for manganese
Citation:
BOYES, W. K. AND E. M. KENYON. How pharmacokinetic modeling could improve a risk assessment for manganese. Presented at Society of Risk Analysis 2009 Annual Meeting, Baltimore, MD, December 06 - 09, 2009.
Impact/Purpose:
This symposium will discuss the testing program and the risk assessment of manganese. This specific talk will discuss how this new data and the new models could be useful for a manganese risk assessment.
Description:
The neurotoxicity of manganese (Mn) is well established, yet the risk assessment of Mn is made complex by certain enigmas. These include apparently greatertoxicity via inhalation compared to oral exposure and greater toxicity in humans compared to rats. In addition, until recently there. was little information regarding potential gender-or age-related differences in response to Mn. The limitations of the data led to' the application of default uncertainty factors in prior risk assessments. Development of more detailed knowledge of the pharmacokinetics of Mn in multiple species via oral and inhalation exposure across lifestage; together with incorporation of these data in pharmacokinetic (PBPK) models 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 exposure conditions and for subjects of different age, gender and species. In addition, incorporation of specific biological mechanisms that control tissue disposition of Mn as a consequence its function as an essential element provide greater biological plausibility for these models. The performance of the PBPK models can be assessed using recent data collected under an alternative tier II test rule established by EPA under section 211(b) of the Clean Air Act, dealing with fuels and fuel additives and a proposal to register use of a Mn-containing fuel additive (MMT). 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. New PBPK models are available that consider gender as a factor as well as prenatal and lactation exposures. 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