Interactions in developmental toxicology: A literature review and terminology proposal

Abstract

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.

Developmental Toxicity Interactions of Methanol and Radiofrequency Radiation or 2-Methoxyethanol in Rats

“…Effects of 2ME, methanol, their interaction, and separation of exposures on resorptions in maternal rats exposed on day 13 simplest way to detect interactions is to administer the agents when at least one of the teratogens exerts its maximal effect (Nelson 1994). We used resorptions, external malformations, and fetal weights as our measures of developmental toxicity.…”

“…This lack of effect, however, should not be construed to suggest that temperature effects may not play a signi cant role in interactions. The literature is replete with studies which implicate altered body temperature as a primary interacting agent with toxic (e.g., Keplinger, Lanier, and Deichmann 1959;Weihe 1973) and teratogenic agents (e.g., Ferm and Kilham 1977;Ferm and Ferm 1979;Hanlon and Ferm 1986;Shiota et al 1988;Nelson 1994). It should also be noted that (apparently) nonthermic levels of magnetic radiation from video display terminals reportedly enhanced the developmental toxicity of cytosine arabinoside in mice (Chiang et al 1995;cf., Marcickiewicz et al 1986).…”

DNA alkylation studies of combined treatment with methylnitrosourea and ethylmethanesulfonate in mice

“…The literature on combined effects in teratology has been discussed in earlier publications [9,13]. Reviews were written by Wilson in 1964, Fraser in 1973, and more recently by Nelson in 1994 [14][15][16]. Generally, all types of interactions were found.…”

Effect of environmental temperature on the interactive developmental toxicity of radiofrequency radiation and 2-methoxyethanol in rats

“…In addition to RF radiation, many workers can be concurrently exposed to various chemicals±some of which could be teratogenic at certain levels (Goldstein et al 1976;Cox and Conover 1981;Stewart and Elkington 1985;Cone 1986;Schardein 1993). Concurrent exposures to various agents can sometimes produce developmental toxicity that is very dierent from that seen with individual exposures (e.g., Fraser 1977;Nelson 1994Nelson , 1997.…”