The choice of vehicle for administration of water-insoluble xenobiotics in toxicology studies has become of concern since there is evidence that vehicles originally thought to be biologically inactive have been shown to influence uptake, distribution, pharmacokinetics and toxicity of chemicals. For example corn oil, one of the most common vehicle used for administration of water-insoluble agents, alters the uptake and fate of short chain halogenated aliphatic compounds and has enhancing effect on their toxicity. Corn oil also promote carcinogenesis and alters nutritional intake, microsomal enzyme activities and gastrointestinal physiology. Such behavior of vehicles further complicates interpretation of bioassays and toxicological data. The objective of this investigation is to elucidate the relationship of vehicle to toxicity and metabolic fate of selected unsaturated nitriles. The selection of nitriles stems from the fact that nitriles are very important monomers used in the polymer, plastic, synthetic fiber, resin, dyestuff, pharmaceutical and vitamin industries and they also exist as naturally occurring substances. The nitriles selected for this study possess similarity in their chemical structure, toxicity and metabolic fate. The vehicles selected for this study include corn oil, olive oil, safflower oil, mineral oil, and the Tweens. The actual studies planned involve treatment of vertebrate animals (rats and mice) with the selected vehicles alone and the nitriles prepared in those vehicles and observation of typical signs of toxicity of these nitriles. Two routes of administration (oral and intraperitoneal) will be sought. Metabolic parameters to be investigated include liberation of cyanide, excretion of thiocyanate and interaction of these nitriles with glutathione. The experiments proposed in this application will serve as a pilot study and provide vital information on the effect of vehicles on the toxicity and metabolic fate of nitriles and hopefully a better understanding for the selection of a vehicle for oral and intraperitoneal toxicity studies of structurally related compounds.
| Farooqui, M Y; Ybarra, B; Piper, J et al. (1995) Effect of dosing vehicle on the toxicity and metabolism of unsaturated aliphatic nitriles. J Appl Toxicol 15:411-20 |
