Overview of Reproductive and Developmental Toxicity Studies of 1,3-Butadiene in Rodents

A series of studies to further evaluate the developmental and reproductive toxicity of inhaled 1,3-butadiene was sponsored by the National Toxicology Program. Pregnant Sprague-Dawley rats (24-28/group) and Swiss (CD-1) mice (18-22/group) were exposed to atmospheric concentrations of 0, 40, 200, or 1000 ppm 1,3-butadiene for 6 hr/day on days 6 through 15 of gestation (dg) and killed on dg 18 (mice) or dg 20 (rats). Subsequently, the uterine contents were evaluated; individual fetal body weights were recorded; and external, visceral, and skeletal examinations were performed. In rats, maternal toxicity was observed in the 1000-ppm group in the form of reduced extragestational weight gain and, during the first week of treatment, decreased body weight gain. Under these conditions, there was no evidence of developmental toxicity in rats. In contrast, results of the mouse developmental toxicity study indicated that the fetus may be more susceptible than the dam to inhaled 1,3-butadiene. Maternal toxicity was observed in mice at the 200- and 1000-ppm 1,3-butadiene exposure levels, whereas 40 ppm and higher concentrations of 1,3-butadiene caused significant exposure-related reductions in the mean body weights of male fetuses. Mean body weights of female fetuses were also reduced at the 200- and 1000-ppm exposure levels. No increased incidence of malformations was observed in either study. Other studies addressing male reproductive and mutagenesis end points were performed with B6 C3 F1mice (sperm-head morphology) and Swiss (CD-1) mice (dominant lethal study). In both studies, groups of 20 male mice were exposed to atmospheric concentrations of 0, 200, 1000, or 5000 ppm 1,3-butadiene 6 hr/day for 5 consecutive days. There were small concentration-related increases in abnormal sperm morphology 5 weeks following exposure (the only time of examination). Sequential postexposure examinations to determine the effect of 1,3-butadiene on all stages of gamete development were not performed. In the dominant lethal study, there were indications that exposure of males to levels as low as 200 ppm 1,3-butadiene caused an increase in the percentage of females with two or more dead implants in the first week following exposure. In both the first and second weeks following exposure, there were increases in the number of dead implantations (early), although strict atmospheric concentration-response relationships were not observed. These results suggest that more mature cells (spermat