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DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENTAL TOXICITY I. CHARACTERIZATION OF DATABASE 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 DATABASE AND DETERMINATION OF NO OBSERVED ADVERSE EFFECT LEVELS. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-95/059, 1994.
Description:
Developmental toxicity risk assessment currently relies on the estimation of reference doses or reference concentrations based on no observed adverse effect levels (NOAELS) and uncertainty factors. he benchmark dose (BMD) has been proposed as an alternative basis for reference value calculations. arge database of 246 developmental toxicity experiments (Segment II-studies) representing 1825 data subsets for various endpoints was compiled for use in comparing NOAEL and BMD approaches to developmental toxicity risk assessment. his paper describes the database and the estimation of NOAELs using several approaches. or each endpoint evaluated, two NOAELs were calculated us-mg the NOSTASOT procedure. irst, the QNOAEL was based on a quantal response where a litter was defined as "affected" if one or more fetuses or implants in the litter had the endpoint of interest. econd, the CNOAEL was based on the proportion of fetuses or implants affected wi@ each lifter and was treated as a continuous response variable. 57% of the 246 experiments had at least one endpoint that showed a significant trend with dose. otal of 386 data s@ were significant with respect to both the quanta[ and continuous test of trend. n additional 44 data sets were identified with significant trend only by the quantal approach whereas 177 additional data sets were identified with significant trend tests only by the continuous approach. hus, the continuous approach appeared to be more powerful in detecting dose-related toxicity, but the patterns detected by the two approaches differed. NOAELs and CNOAELs were compared by ex g the degree to which they selected the same, dose group. or 98% of the 386 data sets with both significant continuous and quantal trend tests, the CNOAEL was wi@ one dose level of the QNOAEL. or data sets having significant continuous and/or quantal trend tests, 99% of the two NOAELs were within two dose levels. 20 of the NTP studies were reviewed for comparison of "expert" versus statistically derived NOAELS. ost of the 360 NOAELs derived were identical for these two approaches-, for the 8% that were different, approximately 80% were within one dose level. us, the statistically derived NOAELs that were used as the basis of our data comparisons were reflective of the typical methods used in deriving NOAELS.