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DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENTAL TOXICITY: I. CHARACTERIZATION OF DATA BASE AND DETERMINATION OF NO OBSERVED ADVERSE EFFECT LEVELS
Citation:
Faustman, E., B. Allen, R. Kavlock, AND C. Kimmel. DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENTAL TOXICITY: I. CHARACTERIZATION OF DATA BASE AND DETERMINATION OF NO OBSERVED ADVERSE EFFECT LEVELS. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-95/113.
Description:
Developmental toxicity risk assessment currently relies on the estimation of reference doses or references concentrations based on the use of no-observed-adverse-effect-levels (NOAELs) and uncertainty factors. The benchmark dose (BMD) has been proposed as an alternative basis for reference value calculations. A large database of 246 developmental toxicity experiments (Segment II-type studies) representing 1825 data subsets for various endpoints was compiled for use in comparing NOAEL and BMD approaches to developmental toxicity risk assessment. This paper describes the characteristics of the database used and the estimation of NOAELs using several approaches. For each endpoint evaluated, two NOAELs were calculated using the NOSTASOT procedure Tukey et al., 1985). The first NOAEL calculation, the QNOAEL, was based on a quantal response where a litter was defined as "affected" if one or more fetuses in the litter had the endpoint of interest. The second NOAEL calculation, the CNOAEL, was based on the proportion of fetuses affected within each litter and was treated as a continuous response variable. Although the NOAELs tended to be the same for the two approaches, the continuous approach appeared to be more powerful in detecting dose-related toxicity. Compilation and characterization of such a large database of Segment II developmental toxicity experiments provides us with an opportunity to evaluate new quantitative approaches for developmental toxicity risk assessment.