Evaluation of subchronic toxicity data using the benchmark dose approach

We used the benchmark dose (BMD) methodology devised by Crump (Fundam. Appl . Toxicol. 4, 854-871, 1984) to estimate BMDs for 90-day toxicological data and several fabricated data sets. From a toxicological perspective, dose-r esponse modeling offers certain advantages over using a point estimate, suc h as the currently used no-observable-adverse-effect level (NOAEL) approach . However, there are many variables associated with the BMD that could be s et to produce unreasonable BMD estimates. Some of these variables and decis ions are examined in this study. BMDs were calculated for discrete and cont inuous endpoints using a variety of different variables (e.g., maximum like lihood estimates [MLEs], lower-confidence limits [LCLs], and different risk levels). In addition, the fabricated data sets were manipulated (i.e., dos e groups eliminated) and the BMDs recalculated. This process tested how the BMD estimates varied using different forms of the data. For the 90-day tox icological studies, the BMDs were typically within an order of magnitude of the NOAEL for discrete endpoints, For the discrete endpoints, the MLEs wer e typically greater than the NOAEL and the LCLs were typically less than th e NOAEL. The BMD was insensitive to changes in the data points one to two d ose groups beyond the NOAEL/LOAEL. With the continuous data, the ratios of MLEs and LCLs to the NOAEL were highly variable, and no general trend could be determined. The BMD methodology offers potential improvements in the ri sk assessment process since dose-response characteristics are used to calcu late the BMD. Depending upon how the BMD is defined, i.e., the form of the dose-response model, and how the BRID is used in the risk assessment proces s, BMD estimates may produce reference doses/concentrations that are more o r less conservative than the NOAEL approach. Active involvement in discussi ons with regulatory agencies is needed to ensure that inappropriate models and unreasonable BMDs are not used. In addition, further discussions on how BMDs should be used in the risk assessment process are needed. (C) 2001 Ac ademic Press.