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Physiologically-Based Pharmacokinetics/Pharmacodynamic Modeling and Cumulative Risk Assessment: Case Study for the N-Methyl Carbmate Pesticides

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Abstract: The Food Quality Protection Act of 1996 [PL 104-170: 110 STAT. 1513] requires EPA to consider potential cumulative human health risks resulting from aggregate exposure to pesticide chemicals acting through a common mechanism of toxicity. This includes all anticipated dietary exposures and all other exposure for which there is reliable information. In 2001, EPA established the N-methyl carbamate pesticides as a common mechanism group based on their structural characteristics and also similarity and shared ability to inhibit acetylcholinesterase (AChE) by carbamylation of the serine hydroxyl group located in the active site of the enzyme. The Office of Pesticide Programs (OPP) expects to release a preliminary cumulative risk assessment for this group in the spring of 2005. OPP is currently evaluating which method or methods will be used to estimate cumulative risk. A collaborative research effort to develop a physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model for the N-methyl carbamate pesticides has been undertaken by the OPP, ORD's National Health and Environmental Effects Laboratory (NHEERL) and National Exposure Research Lab (NERL), and the CIIT Centers for Health Research. PBPK/PD models are very powerful tools that can account for anatomic structure and physiological and biochemical processes. These models can be used to estimate internal exposure dose or concentrations of parent compounds and/or active metabolites at the target site(s) and also toxicologically relevant effects. Typically, inhibition of AChE is fairly rapid (within hours) for members of the N-methyl carbamate common mechanism group. The time dependant relationship between exposure and effect for this group make the N-methyl carbamates a good case study to aid the EPA in developing a multi-chemical, multi-pathway PBPK/PD models for evaluating cumulative risk.
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Citation:Lowit, A., C. C. Dary, F. W. Power, J. Blancato, R. W. Setzer, R. Conolly, and M. Seaton. Physiologically-Based Pharmacokinetics/Pharmacodynamic Modeling and Cumulative Risk Assessment: Case Study for the N-Methyl Carbmate Pesticides. Presented at EPA Science Forum 2004, Washington, DC, June 1-3, 2004.
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Contact: Liz Hope - (919) 541-2785 or hope.elizabeth@epa.gov
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Division: Human Exposure & Atmospheric Sciences Division
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Branch: Exposure & Dose Research Branch
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Product Type: Abstrct/Oral
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Presented: 06/02/2004
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Related Entries:
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Bullet Item Models and Modeling Methods for Assessing Human Exposure and Dose to Toxic Chemicals and Pollutants
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Last Updated on Monday, October 22, 2007
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