Implications of Developmental Toxicity Study Design for Quantitative Risk Assessment

Standard experimental designs for conducting developmental toxicity studies typically include three‐ or four‐dose levels in addition to a control group. Some researchers have suggested that designs with more exposure groups would improve dose‐response characterization and risk estimation. Such proposals have not, however, been supported by the results of simulation studies, which instead back the use of fewer dose levels. This discrepancy is partly due to using a known dose–response pattern to generate data, making model choice obvious. While the carcinogenicity literature has explored implications of different study designs, little attention has been given to the role of design in developmental toxicity risk assessment (or noncancer toxicology in general). In this research, we explore the implications of various experimental designs for developmental toxicity by resampling data from a large study of 2,4,5‐trichlorophenoxyacetic acid in mice. We compare the properties of benchmark dose (BMD) estimation for different design strategies by randomly selecting animals within particular dose groups from the entire 2,4,5‐T database of over 77,000 birth outcomes to create smaller “pseudo‐studies” that are representative of standard bioassay sample sizes. Our results show that experimental designs which include more dose levels have advantages in terms of risk characterization and estimation.