Dose-rate effects of ethylene oxide exposure on developmental toxicity

In risk assessment, evaluating a health effect at a duration of exposure th at is untested involves assuming that equivalent multiples of concentration (C) and duration (T) of exposure have: the same effect. The limitations of this approach (attributed to F. Haber, Zur Geschichte des Gaskrieges [On t he history of gas warfare], in Funf Vortrage aus den Jahren 1920-1923 [Five lectures from the years 1920-1923], 1924, Springer, Berlin, pp. 76-92), ha ve been noted in several studies. The study presented in this paper was des igned to specifically look at dose-rate (C x T) effects, and it forms an id eal case study to implement statistical models and to examine the statistic al issues in risk assessment. Pregnant female C57BL/6J mice were exposed, o n gestational day 7, to ethylene oxide (EtO) via inhalation for 1.5, 3;, or 6 h at exposures that result in C x T multiples of 2100 or 2700 ppm-hi EtO was selected because of its short half-life, documented developmental toxi city, and relevance to exposures that occur in occupational settings. Concu rrent experiments were run with animals exposed to air for similar periods. Statistical analysis using models developed to assess dose-rate effects re vealed significant effects with respect to fetal death and resorptions, mal formations, crown-to-rump length, and fetal weight. Animals exposed to shor t, high exposures of EtO on day 7 of gestation were found to have more adve rse effects than animals exposed to the same C x T multiple but at longer, lower exposures. The implication for risk assessment is that applying Haber 's Law could potentially lead to an underestimation of risk at a shorter du ration of exposure and an overestimation of risk at a longer duration of ex posure. Further research, toxicological and statistical, are required to un derstand the mechanism of the dose-rate effects, and how to incorporate the mechanistic information into the risk assessment decision process.