Review of reproductive and developmental toxicity of 1,3-butadiene

Toxic doses of 1,3-butadiene (BD) have been reported to cause reproductive and/or developmental toxicity. Regardless of the strain used, mice were always affected by BD at lower doses than rats, an expected observation, based on well recognized differences in pharmacokinetic (PK) parameters in these two species. Because the mouse is particularly sensitive to BD in comparison with other laboratory species, and there are important functional and anatomical differences between humans and mice, the NOELs and LOELs identified for BD for various reproductive endpoints in mice may not be relevant to human reproductive risk. In mice, the LOELs for reproductive endpoints include developmental toxicity at 200 ppm, genotoxic effects at 500 ppm (mouse spot test), ovarian atrophy in females at 6.25 ppm (carcinogenicity study), reduced testicular weights at 200 ppm and testicular atrophy at 625 ppm BD in males (carcinogenicity studies), low incidences of abnormal sperm heads at 1000 and 5000 ppm BD (sperm head morphology study), small reversible increases in resorption at 1250/1300 ppm or 5000 ppm (dominant lethal studies), and other possible sequelae of genotoxicity resulting from exposure of male mice at 12.5 ppm BD and higher (dominant lethal study). When available, the much higher NOELs and LOELs of other species tested for the same endpoints should be considered. For example, maternal and developmental NOELs for BD in the rat were 200 and 1000 ppm, respectively, and 40 ppm in the mouse. Likewise, exposure of cohabited pairs of rats, guinea pigs and rabbits or of female dogs to BD concentrations as high as 6700 ppm for 8 months did not impair fertility or cause testicular or ovarian atrophy in these species. Thus, consideration of these remarkable species-dependent differences in toxicity is necessary. In addition, there are alternative scientific interpretations for some of the mouse studies and this review attempts to address these areas. For example, it may be incorrect to categorize results indicating weak in vivo genotoxic effects in male mice (sperm head morphology and dominant lethal studies) at 12.5 ppm BD and higher as reproductive effects because concentrations of BD as high as 5000 ppm did not affect mating, fertility or live litter sizes, even in this sensitive species. Similarly, it may be inappropriate to identify the ovary as a target organ for reproductive risk since the ovarian atrophy in mice was identified after completion of the normal reproductive life and after more than 15 months of exposure. Neither ovarian nor testicular atrophy occurred in Sprague-Dawley rats after exposure to BD concentrations as high as 8000 ppm for 105 (females) or 111 (males) weeks.