Physiologically-Based Pharmacokinetic/Pharmacodynamic Modeling: Preliminary Evaluation and Case Study for the N-Methyl Carbamate Pesticides

摘要

EPA is in the early stages of developing a strategy for incorporating physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) models into its cumulative risk assessments. PBPK/PD models are very powerful tools that can account for anatomic structure and physiological and biochemical processes. They 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 Agency in developing its strategy for using PBPK/PD models in cumulative risk assessments. The following document provides the preliminary model structure for two separate PBPK/PD models being developed in addition to the biological basis for their structure. These models are being developed in separate programming languages (ACSL and MCSim).