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

There has been relatively little attention given to incorporating know ledge of mode of action or of dosimetry of active toxic chemical to ta rget tissue sites in the calculation of noncancer exposure guidelines. One exception is the focus in the revised reference concentration (Rf C) process on delivered dose adjustments for inhaled materials. The st udies reported here attempt to continue in the spirit of the new RfC g uidelines by incorporating both mechanistic and delivered dose informa tion 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 example s of the use of PBPK and BMD techniques in noncancer risk assessment a re 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 MRL s ranged from roughly 10-fold higher to more than IO-fold lower than e xisting MRLs that were not based on PBPK modeling. Only two MRLs were based on critical studies that presented adequate data for BMD modelin g, and in these two cases the BMD models were unable to provide an acc eptable fit to the overall dose-response of the data, even using pharm acokinetic dose metrics. A review of 10 additional chemicals indicated that data reporting in the toxicological literature is often inadequa te to support BMD modeling. Three general observations regarding the u se of PBPK and BMD modeling in noncancer risk assessment were noted. F irst, a full PBPK model may not be necessary to support a more accurat e risk assessment; often only a simple pharmacokinetic description, or an understanding of basic pharmacokinetic principles, is needed. Seco nd, pharmacokinetic and mode of action considerations are a crucial fa ctor in conducting noncancer risk assessments that involve animal-to-h uman extrapolation. Third, to support the application of BMD modeling in noncancer risk assessment, reporting of toxicity results in the tox icological literature should include both means and standard deviation s for each dose group in the case of quantitative endpoints, such as r elative organ weights or testing scores, and should report the number of animals affected in the case of qualitative endpoints.