DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENTAL TOXICITY .2. COMPARISON OFGENERIC BENCHMARK DOSE ESTIMATES WITH NO OBSERVED ADVERSE EFFECT LEVELS

Developmental toxicity risk assessment currently relies on the estimat ion of reference doses (RfD(DT)s) or reference concentrations (RfC(DT) s) based on the use of no observed adverse effect levels (NOAELs) divi ded by uncertainty factors (UFs). The benchmark dose (BMD) has been pr oposed as an alternative basis for reference value calculations. A lar ge database of 246 developmental toxicity experiments representing 182 5 endpoints related to dead implants or malformed fetuses has been com piled for use in evaluating alternative approaches to developmental to xicity risk assessment. Using this database we have compared two appro aches for BMD estimation with each other and with corresponding statis tically derived NOAELs. Comparisons have been based on proportion of a ffected litters (litters with one or more affected offspring, a quanta l response variable) and on the proportion of affected offspring withi n each litter (a continuous response variable). A quantal Weibull mode l was used to calculate generic BMDs for the quantal response variable (QBMDs) and a continuous power model was used to calculate generic BM Ds for the continuous response variable (CBMDs) at three levels of add itional risk (10, 5, and 1%). CBMD(05)s (continuous benchmark doses fo r 5% risk) and CNOAELs (statistically derived NOAELs based on the cont inuous response variable) were similar, with over 98% of the data subs ets having CBMD(05) and CNOAEL values that differed by less than an or der of magnitude. In contrast, QNOAELs tended to be greater than corre sponding QBMD(10)s. The observed conservatism of the QBMD values relat ive to the corresponding CBMD values was attributed to two factors, lo wer maximum likelihood estimates for the quantal model and wider confi dence intervals around the maximum likelihood estimates, compared to t he continuous model. Comparisons of different quantitative dose-respon se assessments for developmental toxicity experiments should help to i dentify appropriate risk assessment approaches for developmental toxic ity risk assessment. (C) 1994 Society of Toxicology.