Dose-response assessments for developmental toxicity. IV. Benchmark doses for fetal weight changes.
Recently, most attention on the application of benchmark dose (BMD) techniques to toxicology data has focused on quantal measures of response. Before the advantages of the BMD approach can be exploited in the risk assessment process, it is important that continuous measures of response also be modeled appropriately. In this study, we examined a variety of approaches to estimating BMDs for a change in fetal weight following chemical exposure from a total of 85 developmental toxicity experiments. We modeled the change in the mean fetal weight of a litter in response to treatment using a continuous power model, as well as reductions in the weight of individual fetuses within litters (defined as falling below a preset level) using a log-logistic model which incorporates litter size as a covariable and considers intralitter correlations. For the litter-based approach, several methods of defining a benchmark effect (BME) were considered, including a percentage change in mean litter weight, a change in mean litter weight relative to variability in the control group, and a reduction in the mean litter weight to some point on the control group distribution curve. For the fetus-based approach, we examined several BME options on the cumulative frequency distribution of the control fetuses for defining a low weight fetus and calculated several levels of additional risk. BMDs for four litter-based BMEs (a difference of 5% in mean fetal weight, a decrease to the 25th percentile mean weight of control litters, a decrease in the mean weight by 2 standard errors, and a decrease of 0.5 standard deviation units) and two fetus-based BMEs (a 5% added risk of weighing less than the 5th percentile of control weights and a 10% added risk of weighing less than the 10th percentile) showed strong similarities to each other and to statistically derived NOAELs. In addition to providing comparison with the NOAEL as a reference value, these analyses provided confirmation of the advantages of the BMD approach over the NOAEL in terms of the influence of dose spacing and dose selection. Combined with our previous analyses of quantal endpoints of fetal effects, this information provides a firm basis upon which to implement the benchmark dose concept in developmental toxicity risk assessments.
Kavlock
R J
RJ
Developmental Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Allen
B C
BC
Faustman
E M
EM
Kimmel
C A
CA
D000818:Animals; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D008098:Litter Size / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D011817:Rabbits; D051381:Rats; D018570:Risk Assessment
D004364:Pharmaceutical Preparations