The results of studies investigating interactive effects in developmental toxicology in mammalian species were reviewed. The studies were identified from a search of the published literature using 34 terms such as teratology, developmental toxicology, developmental toxicity, reproductive toxicity, postnatal, prenatal, gestational, birth defects, organogenesis, synergistic, additive, and antagonistic. Altogether, 160 studies which reported more than 600 combined doses of test agents were identified. The test agents included chemicals, physical agents such as ionizing radiation and hyperthermia, and therapeutic agents. The quality of the studies was highly variable, many using only small numbers of animals and testing few dose levels. Few studies examined time/effect relationships or evaluated maternal toxicity. The studies also showed inconsistencies in the use of terminology, more than 90% of the terms used not having a precisely defined toxicological meaning. In the studies, approximately 44% of the doses produced less than additive effects and 36% produced greater than additive effects. Of those showing synergistic effects, 16% of the dose combinations produced increases of more than 200% over additive. The author concludes that concurrent exposure to two or more exogenous agents can clearly cause pronounced decreases or increases in developmental toxicity. To promote clear use of terminology, precise definitions for use in developmental toxicity are proposed for the terms additivity, antagonism, potentiation, synergism, and interaction.
B. K. Nelson, CDC, NIOSH, DBBS (C-24), 4676 Columbia Parkway, Cincinnati, OH 45226