Case study on the impact of the source of metabolism parameters in next generation physiologically based...

Physiologically based pharmacokinetic (PBPK) models are a means of making important linkages between exposure assessment and in vitro toxicity. A key constraint on rapid application of PBPK models in risk assessment is traditional reliance on substance-specific in vivo toxicokinetic data to evaluate model quality. Bounding conditions, in silico, in vitro, and chemical read-across approaches have been proposed as alternative sources for metabolic clearance estimates. A case study to test consistency of predictive ability across these approaches was conducted using trimethylbenzenes (TMB) as prototype chemicals. Substantial concordance was found among TMB isomers with respect to accuracy (or inaccuracy) of approaches to estimating metabolism; for example, the bounding conditions never reproduced the human in vivo toxicokinetic data within two-fold. Using only approaches that gave acceptable prediction of in vivo toxicokinetics for the source compound (1,2,4-TMB) substantially narrowed the range of plausible internal doses for a given external dose for occupational, emergency response, and environmental/community health risk assessment scenarios for TMB isomers. Thus, risk assessments developed using the target compound models with a constrained subset of metabolism estimates (determined for source chemical models) can be used with greater confidence that internal dosimetry will be estimated with accuracy sufficient for the purpose at hand.