Interactions in developmental toxicology: a literature review and terminology proposal

Developmental toxicologists have investigated the interactive effects from concurrent exposures to a variety of chemical and physical agents, including therapeutic drugs, industrial agents, and some biological organisms or their toxins. Of approximately 160 reports of concurrent exposures reviewed in this paper, about one third report no interactive effects (including additive effects--usually referring to response--as opposed to dose-additivity); another one third report antagonistic effects, and the final third report potentiative or synergistic effects. The quality of the studies is highly variable. Frequently, only small numbers of animals were included, and very few dose levels were evaluated. Maternal toxicity was rarely discussed. Time-effect relationships were examined infrequently. In addition, these studies are also inconsistent in the use of terms to describe interactive effects, and more than 90% of the terms were not in harmony with currently accepted definitions in toxicology. Because interaction studies will continue to be important in the future, this paper proposes uniform usage of terms for additivity and interactions in developmental toxicology: additivity (the combined effect of two or more developmental toxicants approximates the sum of the effects of the agents administered separately); antagonism (the combined effect of two or more agents, one or more of which are present at doses that would be developmentally toxic if given individually, is significantly less than the sum of the effects of the agents administered separately); potentiation (the increased effect of a developmental toxicant by concurrent action of another agent at a dose that is not developmentally toxic); synergism (the combined effect of two or more developmental toxicants is significantly greater than the sum of the effects of each agent administered alone); and, interaction if more precise terminology does not apply.