The relationship of vehicle to target organ toxicology induced by the naturally occurring nitrile 1-cyano-2-hydroxy-3-butene

Abstract

The effects of gavage vehicle on the acute toxicity of the naturally occurring nitrile 1-cyano-2-hydroxy-3-butene (CHB) were investigated by oral administration of 200 mg/kg body wt/day CHB to male CDF ( F-344 Crl BR) rats for 2 days. The vehicles studied here were distilled water, 5% aqueous Tween 20, and corn oil. Liver, kidney, and pancreas were examined histologically and the differences in lesion incidence and severity were assessed. The effects of gavage vehicle on nitrile-induced elevations of daily urinary thiocyanate excretion and tissue glutathione concentrations were also assessed. The pancreatotoxicity of CHB was present regardless of vehicle and consisted of apoptosis of pancreatic acinar cells, infiltration of pancreatic lobules by macrophages, and acinar atrophy and disorganization. CHB in water alone was associated with the least pancreatotoxic effect, whereas the aqueous Tween vehicle was associated with more severe CHB-induced pancreatic lesions. CHB-induced elevations of tissue nonprotein thiol and glutathione concentrations occurred in all treatment groups, but the values were elevated significantly less in the pancreata of CHB/Tween-treated rats than in those of rats given CHB in water or corn oil. By contrast, the greatest elevation in daily urinary thiocyanate excretion occurred in rats given CHB in aqueous Tween, indicating increased biotransformation of CHB to cyanide when Tween 20 was used as a vehicle. These results illustrate the difficulty of identifying suitable vehicles for administration of lipophilic compounds in toxicology studies.