Chronic toxicity and oncogenic dose–response effects of lifetime oral acrylonitrile exposure to Fischer 344 rats

Abstract

Acrylonitrile (AN) was administered in the drinking water for approximately 2 years to groups of 100 male and 100 female Fischer 344 rats at nominal concentrations of 1, 3, 10, 30, and 100 ppm. Two groups, each of 100 males and 100 females, were used as untreated controls. Average daily intake was 0.1, 0.3, 0.8, 2.5 or 8.4 mg AN per kg body weight per day, respectively, for treated male rats and 0.1, 0.4, 1.3, 3.7, or 10.9 mg AN per kg per body weight per day, respectively, for dosed females. Clinical biochemistry, interim necropsies, organ weights and microscopic evaluation of tissues and organs were performed on groups of ten rats per sex per group at months 6, 12, and 18 and at study termination. Females were sacrificed in the 24th month and males were terminated after 26 months of dosing. A consistent decrease in survival, lower body weight and reduced water intake, as well as small reductions in hematological parameters, were observed in both sexes of the 100 ppm group. Elevated numbers of early deaths were observed in groups of males receiving 10 ppm AN and females receiving 30 ppm AN. Organ:body weight ratios at various study intervals were consistently elevated in the high dose group and likely were related to lower body weights. At these same intervals, mean absolute weights were either comparable to controls or only slightly elevated and few changes in weight ratios were seen when organ weights were compared with brain weights. No biochemical changes suggested a treatment-related effect. An increase in urine specific gravity in 100 ppm male rats was reflective of a decrease in liquid intake at this level. The only significant non-neoplastic finding observed histologically was a dose-related increase in hyperplasia/hyperkeratosis in squamous cells of the forestomach in male and female rats given 3 ppm and higher AN. This observation correlated with the induction of treatment-related squamous cell tumors (papillomas and carcinomas) of the forestomach seen primarily in rats at 3 ppm AN and higher. Mammary gland carcinomas were observed only in female groups. Both sexes given 10 ppm AN or more in their drinking water for their lifetime had astrocytomas of the brain/spinal cord and adenomas/carcinomas of the Zymbal's gland.