Comparative chronic toxicity and carcinogenicity of acrylonitrile by drinking water and oral intubation to Spartan Sprague-Dawley rats.
Groups of 100 male and 100 female Spartan Sprague-Dawley rats were administered lifetime oral doses of Acrylonitrile (AN) by one of two routes of dosing, either at 0.1 or 10 mg/kg per day, 7 day per week by intubation or continually at 1 or 100 ppm AN in their drinking water. The doses selected were designed to approximate the same daily intake of AN in each of two separate studies, whether by a single bolus dose (intubation) or a more continuous dosing regimen in drinking water. Each study had its own untreated control group of 100 rats per sex. In the drinking water study, the equivalent mean dosage of AN administered to males and females were 0, 0.09, and 0.15 mg/kg per day, respectively, at the 1 ppm level, and 0, 8.0 and 10.7 mg/kg per day, respectively, for 100 ppm dose groups. In both studies, groups of ten rats per sex were sacrificed at 6, 12 and 18 months and at study term. Ophthalmoscopic, hematological, clinical biochemistry, urinalysis and full histopathological exams were performed on control and high dose groups of rats in each study. Similar tests were done in lower dose groups, as required, to define dose-responses of observed effects. All animals were necropsied and underwent microscopic examination of target tissues, including brain, ear canal, stomach, spinal cord and any observable tissue masses. High dose male and female rats in both studies exhibited statistically decreased body weights. Food consumption and water intake were reduced only in the drinking water study. Due to increased deaths in groups of high dose rats of both studies receiving AN, all intubation test groups were terminated after 20 months of treatment. Surviving males and females in the drinking water study were terminated after 22 and 19 months, respectively. Small, sometimes statistically significant, reductions in hemoglobin, hematocrit and erythrocyte count were observed in male and female rats in both high dose (10 mg/kg per day intubation and 100 ppm drinking water) groups from both studies. There were increases in absolute or relative organ weight ratios for liver and adrenal in the high dose intubation study groups, but could not be correlated with AN toxicity in the absence of adverse clinical biochemistry or microscopic findings. Similar organ weight findings were not observed in the drinking water study. Again, there were no changes in clinical biochemistry or microscopic findings in these tissues. Absolute kidney weights were increased in high dose male and female rats in the intubation study and high dose female rats only in the drinking water study. Male and female rats from high dose groups in each study had a higher incidence of palpable masses of the head and the nonglandular stomach and, in females only, the mammary region. In both sexes, treatment-related tumors of the central nervous system (brain, spinal cord), ear canal, and gastrointestinal tract, and in females only, the mammary gland (intubation only) were observed in rats administered either 10 mg/kg per day by intubation or 100 ppm in drinking water. Animals from the intubation study had a substantially higher incidence of AN-related site-specific tumors than did their drinking water study counterparts. While a similar spectrum of tumors was produced by both oral dosing regimens, there were some notable differences in organ-specific incidence of tumors. Astrocytomas of the brain and spinal cord were found at a higher incidence in those rats exposed continuously to AN administered in the drinking water versus bolus dosing by intubation. Conversely, a higher incidence of squamous cell carcinomas/papillomas of the forestomach and adenocarcinomas of the intestine and, in females only, carcinomas of the mammary gland were observed in high dose rats receiving AN by intubation. An increase in the degree of severity of forestomach hyperplasia was observed in all high dose groups of animals, irrespective of mode of administration. These effects were more pronounced, were correlated with a much higher incidence of forestomach tumors, and were identified earlier (12 months) in the intubation study in which there was direct tissue contact with a more concentrated AN solution. Elevations in epidermal cysts in high dose males and females in the intubation study and renal hyperplasia in high dose animals of both sexes in both studies may have a treatment relationship. All other clinical and microscopic findings were considered unremarkable. There were no discernable non-neoplastic effects attributable to treatment in groups of low dose male and female rats given AN by intubation at 0.1 mg/kg per day or 1 ppm in drinking water. The results of this study indicate a consistent spectrum of neoplastic and non-neoplastic effects produced by AN in the same rat strain, whether administered orally by bolus or by continuous dosing in the drinking water. While the spectrum of tumors and target organ toxicity produced was similar, bolus dosing clearly increased tumors associated with the gastrointestinal tract. Neoplasms found in several other tissues were most prominently displayed in groups of more continuously dosed rats.
Johannsen
Frederick R
FR
Environmental, Safety and Health, Solutia Inc., 575 Maryville Center Drive, St. Louis, MO 63141, USA. frjoha@solutia.com
Levinskas
George J
GJ
D000181:Acrylonitrile / Q000008:administration & dosage / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005260:Female; D007441:Intubation, Gastrointestinal; D008297:Male; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D013995:Time; D018675:Toxicity Tests; D014867:Water / Q000008:administration & dosage
D002273:Carcinogens; D014867:Water; D000181:Acrylonitrile