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DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENT TOXICITY: II. COMPARISON OF GENERIC BENCHMARK DOSE ESTIMATES WITH NO OBSERVED ADVERSE EFFECT LEVELS
Citation:
Allen, B., R. Kavlock, C. Kimmel, AND E. Faustman. DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENT TOXICITY: II. COMPARISON OF GENERIC BENCHMARK DOSE ESTIMATES WITH NO OBSERVED ADVERSE EFFECT LEVELS. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-95/060.
Description:
Developmental toxicity risk assessment currently relies on the estimation of reference doses (RfDDTS) or reference concentrations (RfCDTS) based on the use of no observed adverse effect levels (NOAELS) divided by uncertainty factors (UFs)The benchmark dose (BUD) has been proposed as an alternative basis for reference value calculations. arge database of 246 developmental toxicity experiments representing 1825 endpoints related to dead implants or malformed fetuses has been compiled for use in evaluating alternative approaches to developmental toxicity risk assessment. sing this database we have compared two approaches for BMD estimation with each other and with corresponding statistically derived NOAEL.S. Comparisons have been based on proportion of affected litters Bitters with one or more affected offspring, a quantal response variable) and on the proportion of affected offspring within each litter (a continuous response variable). uantal Weibull model was used to calculate generic BMDs for the quantal response variable (QBMDs) and a continuous power model was used to calculate generic BMDs for the continuous response variable (CBMDS) at three levels of additional risk (10, 5, and 1%). BMD05 (continuous benchmark doses for 5% risk) and CNOAELs (statistically derived NOAELs based on the continuous response variable) were similar, with over 98% of the data subsets having CBMD, and CNOAEL values that differed by less than an order of magnitude. n contrast, QNOAELs.tended to be greater than corresponding QBMD10s. he observed conservatism of the QBMD values relative to the corresponding CBMD values was attributed to two factors, lower maximum likelihood estimates for the quantal model and wider confidence intervals found the maximum likelihood estimates, compared to the continuous model. omparisons of different quantitative dose-response assessments for developmental toxicity experiments should help to identify appropriate risk assessment approaches for developmental toxicity risk assessment.