The utility of PBPK in the safety assessment of chloroform and carbon tetrachloride

Occupational exposure Limits (OELs) for individual substances are establish ed on the basis of the available toxicological information at the time of t heir promulgation, expert interpretation of these data in light of industri al use, and the framework in which they sit. In the United Kingdom, the est ablishment of specific OELs includes the application of uncertainty factors to a defined starting point, usually the NOAEL from a suitable animal stud y. The magnitude of the uncertainty factors is generally determined through expert judgment including a knowledge of workplace conditions and manageme nt of exposure. PBPK modeling may help in this process by informing on issu es relating to extrapolation between and within species. This study was the refore designed to consider how PBPK( modeling could contribute to the esta blishment of OELs, PBPK models were developed for chloroform (mouse and hum an) and carbon tetrachloride (rat and human). These substances were chosen for examination because of the extent of their toxicological databases and availability of existing PBPK models. The models were exercised to predict the rate (chloroform) or extent (carbon tetrachloride) of metabolism of the se substances, in both rodents and humans. Monte Carlo analysis was used to investigate the influence of variability within the human and animal model populations. The ratio of the rates/extent of metabolism predicted for hum ans compared to animals was compared to the uncertainty factors involved in setting the OES, Predictions obtained from the PBPK( models indicated that average rat and mouse metabolism of carbon tetrachloride and chloroform, r espectively, are much greater than that of the average human. Application o f Monte Carlo analysis indicated that even those people who have the fastes t rates or most extensive amounts of metabolism in the population are unlik ely to generate the levels of metabolite of these substances necessary to p roduce overt toxicity in rodents. This study highlights the value that the use of PBPK modeling may add to help inform and improve toxicological aspec ts of a regulatory process. (C) 2000 Academic Press.