Species differences in acrylonitrile metabolism and toxicity between experimental animals and humans based on observations in human accidental poisonings

The high acute toxicity of acrylonitrile may be a result of its intrinsic b iological reactivity or of its metabolite cyanide. Intravenous N-acetylcyst eine has been recommended for treatment of accidental intoxications in acry lonitrile workers, but such recommendations vary internationally. Acrylonit rile is metabolized in humans and experimental animals via two competing pa thways; the glutathione-dependent pathway is considered to represent an ave nue of detoxication whilst the oxidative pathway leads to a genotoxic epoxi de, cyanoethylene oxide, and to elimination of cyanide. Cases of acute acry lonitrile overexposure or intoxication have occurred within persons having industrial contact with acrylonitrile; the route of exposure was by inhalat ion and/or by skin contact. The combined observations lead to the conclusio n of a much higher impact of the oxidative metabolism of acrylonitrile in h umans than in rodents. This is confirmed by differences in the clinical pic ture of acute life-threatening intoxications in both species, as well as by differential efficacies of antidotes. A combination of N-acetylcysteine wi th sodium thiosulfate seems an appropriate measure for antidote therapy of acute acrylonitrile intoxications. Clinical observations also highlight the practical importance of human individual susceptibility differences.. Furt hermore, differential adduct monitoring, assessing protein adducts with dif ferent rates of decay, enables the development of more elaborated biologica l monitoring strategies for the surveillance of workers with potential acry lonitrile contact.