INVESTIGATION OF THE POTENTIAL IMPACT OF BENCHMARK DOSE AND PHARMACOKINETIC MODELING IN NONCANCER RISK ASSESSMENT

Abstract

There has been relatively little attention given to incorporating knowledge of mode of action or of dosimetry of active toxic chemical to target tissue sites in the calculation of noncancer exposure guidelines. One exception is the focus in the revised reference concentration (RfC) process on delivered dose adjustments for inhaled materials. The studies reported here attempt to continue in the spirit of the new RfC guidelines by incorporating both mechanistic and delivered dose information using a physiologically based pharmacokinetic (PBPK) model, along with quantitative dose-response information using the benchmark dose (BMD) method, into the noncancer risk assessment paradigm. Two examples of the use of PBPK and BMD techniques in noncancer risk assessment are described: methylene chloride, and trichloroethylene. Minimal risk levels (MRLs) based on PBPK analysis of these chemicals were generally similar to those based on the traditional process, but individual MRLs ranged from roughly 10-fold higher to more than IO-fold lower than existing MRLs that were not based on PBPK modeling. Only two MRLs were based on critical studies that presented adequate data for BMD modeling, and in these two cases the BMD models were unable to provide an acceptable fit to the overall dose-response of the data, even using pharmacokinetic dose metrics. A review of 10 additional chemicals indicated that data reporting in the toxicological literature is often inadequate to support BMD modeling. Three general observations regarding the use of PBPK and BMD modeling in noncancer risk assessment were noted. First, a full PBPK model may not be necessary to support a more accurate risk assessment; often only a simple pharmacokinetic description, or an understanding of basic pharmacokinetic principles, is needed. Second, pharmacokinetic and mode of action considerations are a crucial factor in conducting noncancer risk assessments that involve animal-to-human extrapolation. Third, to support the application of BMD modeling in noncancer risk assessment, reporting of toxicity results in the toxicological literature should include both means and standard deviations for each dose group in the case of quantitative endpoints, such as relative organ weights or testing scores, and should report the number of animals affected in the case of qualitative endpoints.