Inhalation toxicity of ribavirin in suckling ferrets

Ribavirin is a broad-spectrum antiviral agent useful for treatment of infants. To study the effects in developing mammalian lungs, four groups of jill ferrets and their litters were given whole body inhalation exposures for 6 h a day for 10 or 30 consecutive days to concentrations of 0 (vehicle control), 162, 355 or 620 mg/m3. The effects, including special lung observations in suckling kits, were evaluated after exposures at weaning and at puberty. First the high dose, then the mid dose jills developed lactation failure. Probably due to nutritional deficiency, approximately half of the mid dose and three quarters of the high dose kits were found dead or killed whilst moribund. There were no test compound-related deaths in the control or low dose level groups. Reductions in body weight gain were observed in both 10 and 30 day exposed kits, and high dose kits actually lost weight as exposure continued. Some recovery was apparent in survivors. Some discoloration of the liver was seen in malnourished kits at necropsy. There were no gross or histopathologic lesions in the lungs or tracheas of suckling ferrets attributable to the test material. Ribavirin exposure had no effect on the lavageable cell pool, while lung DNA to protein ratios showed a mild, reversible, proliferative response in smaller kits. There were no differences in lung function between controls and low dose kits of either group. Effects seen in the higher dose groups are due to differences in size. While there may have been a real dose-related enlargement of alveolar diameters at 40 days of age, this disappeared in males by puberty and did not seem toxicologically significant in females. The low dose, which corresponds to an exposure dose 4 to 6 times that used clinically, appeared to be a no-effect level.