The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
Isoprene, a reactive, branched diene, is used in large quantities in manufacture of polyisoprene and as a copolymer in the synthesis of butyl rubber. The potential for isoprene to cause developmental toxicity was assessed in rodents, by exposing four groups each of Sprague-Dawley rats and Swiss (CD-1) mice to 0, 280, 1400, or 7000 ppm isoprene vapors, 6 hours per day, 7 days per week. Each treatment group consisted of 10 virgin females (for comparison), and ~ 30 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 gd. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects.
Exposure of pregnant rats to these concentrations of isoprene did not result in apparent maternal toxicity or in developmental toxicity. There were no treatment-related effects upon body weights or reproductive indices at any exposure level, nor was there a significant increase in the incidence of fetal malformations or variations. The only effect observed in the dams was an increased kidney to body weight ratio, and in the fetuses there was a slight, but not statistically significant, exposure-correlated increase in the incidence of reduced vertebral ossifications (centra) which suggests that the 7000-ppm exposure level may be at or near a developmental toxicity threshold.
Exposure of Swiss (CD-1) mice to isoprene resulted in (from 12 dg onward) significant reductions in maternal body weight, body weight gain during treatment and in uterine weight for the 7000-ppm group. Since neither the extragestational weight gain of the pregnant dams, nor the body weight gain of the virgin animals was affected, there was an indication of selective developmental toxicity at the 7000-ppm exposure level. Liver to body weight ratios for pregnant dams were significantly greater than the 0-ppm group for both the 1400 and 7000-ppm groups. Kidney to body weight ratios were significantly greater than the 0-ppm group for the 7000-ppm group. Developmental toxicity was further evident as an exposure-correlated reduction in fetal body weights which was statistically significant at the 280-ppm level (the lowest isoprene level) for female fetuses and at the 1400-ppm level for male fetuses. However, no embryotoxicity in the form of increased intrauterine death was present at any exposure level.
Fetuses of mice exposed to isoprene had an increased incidence of supernumerary ribs which was significantly correlated to increasing exposure concentration and was statistically significant for the 7000-ppm group. Although there was no significant increase in the incidence of malformations, two fetuses with cleft palate were found, one in each of the two highest exposure groups. Cleft palates were not detected in the 0-ppm group.
In summary, pregnant Sprague-Dawley rats and their offspring appeared to be relatively resistant to the toxic effects of isoprene at the exposure levels employed in this study. Swiss (CD-1) mouse dams exhibited significant toxic effects at the 7000-ppm level; however, the offspring of the mice exhibited significant signs of toxicity, including reductions in fetal body weight and ossification, at all the exposure concentrations employed. In light of the above results, the 7000-ppm isoprene level could be set as a no observable effect level in the Sprague-Dawley (CD) rat for both maternal and developmental toxicity. In the Swiss (CD-1) mouse, a no observable effect level of 1400 ppm could be set for maternal toxicity; however, a NOEL based on the results of this study cannot be assigned to the Swiss (CD-1) mouse for developmental toxicity.