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Data-derived uncertainty factor approach in the revised N-methyl carbamate risk assessment.
Citation:
LOWIT, A., E. REAVES, W. SETZER, V. C. MOSER, AND D. H. MILLER. Data-derived uncertainty factor approach in the revised N-methyl carbamate risk assessment. Presented at Society of Toxicology, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
This data-derived approach to applying uncertainty and extrapolation factors represents a major advance in improving the scientific basis for risk extrapolation with pesticide chemicals.
Description:
EPA completed its Revised Cumulative Risk Assessment (CRA) of the N-methyl Carbamate (NMC) Pesticides in 2007. This assessment evaluated the joint risk to 10 pesticides from food, water, and residential exposure. NMCs share the ability to inhibit acetylcholinesterase (AChE) via carbamylation of the active site leading to accumulation of acetylcholine and ultimately clinical signs. Adult rat brain data provided the basis for relative potency factors and points of departure in the NMC CRA. The Agency used a data-derived uncertainty factor approach to evaluate both the interspecies (animal to human) factor and the FQPA 10X factor specific to infants and children. Where there were no human study or comparative sensitivity data for individual NMCs, respective factors remained 10X. Data from toxicity studies with human subjects were used to quantify the interspecies factor for three pesticides (aldicarb, methomyl, oxamyl). These studies were evaluated by the Human Studies Review Board in 2006 and considered appropriate for purposes of risk assessment. A sensitivity analysis was performed where a 3X factor for interspecies extrapolation was applied to the other NMCs without data in human subjects. This 3X factor was used instead of the typical 10X factor based on the assumption of pharmacodynamic equivalence for interspecies extrapolation. Data collected in comparative AChE studies where adult and post-natal day 11 or 17 pups were exposed via gavage were used to inform the magnitude of the FQPA 10X factor for infants and children. In order to provide a uniform measure of comparison for these factors, a benchmark dose approach was used. The BMD10 or the dose expected to cause 10% inhibition in AChE was estimated for adult rat, adult human, and juvenile rat AChE data. This data-derived approach to applying uncertainty and extrapolation factors represents a major advance in improving the scientific basis for risk extrapolation with pesticide chemicals.