BIOLOGICALLY-BASED DOSE-RESPONSE MODEL FOR HEPATIC TOXICITY - A MECHANISTICALLY BASED REPLACEMENT FOR TRADITIONAL ESTIMATES OF NONCANCER RISK

Uncertainty in risk assessment can be reduced by increasing the use of relevant data specific to the particular xenobiotic and exposed organ ism. We describe the development of a preliminary, mechanism-based exp osure response model for chloroform hepatotoxicity consisting of toxic okinetic (TR) and toxicodynamic (TD) submodels. The TK submodel is bas ed on an existing physiologically based toxicokinetic (PBTK) model for chloroform. The TD submodel consists of an empirical function linking tissue dose, defined by the PBTK model, with hepatocyte killing and s ubsequent regenerative cellular replication. Chloroform-induced cell k illing was inferred quantitatively from dose-response hepatic labellin g index studies conducted in female B6C3F1 mice and male F344 rats. Th e overall model was scaled to humans by conventional scaling of the TK submodel and by using the TD submodel as is, i.e. as developed from t he rodent data. The resulting human model was used to analyze a case o f human poisoning which developed after repeated ingestion of large do ses of cough syrup containing chloroform and alcohol. The model predic ted the observed toxic response after the capacity for chloroform meta bolism was increased by a factor of 3 from the value estimated using h uman liver microsomes. This is an acceptable adjustment of this parame ter, given the uncertainty associated with the extrapolation from micr osomes and the coexposure to alcohol. This preliminary result is encou raging, suggesting that the model, at its current stage of development , is able to approximate actual human risks of hepatotoxicity from chl oroform exposure. The extensive use of data on chloroform TK and cytol ethality-induced regenerative cellular replication for model developme nt suggests that the model has reduced uncertainty relative to the cur rent U.S. EPA oral reference dose (RfD) calculation for chloroform, wh ich does not use any mechanistic or dose-response data.