The developmental toxicity of inhaled methanol in the CD‐1 mouse, with quantitative dose—response modeling for estimation of benchmark doses

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Abstract
The developmental toxicity of the alternative motor vehicle fuel methanol was assessed in mice by the inhalation route. Pregnant CD‐1 mice were exposed to 1,000, 2,000, 5,000, 7,500, 10,000, or 15,000 ppm methanol for 7 hr/day on days 6–15 of gestation. Sham‐exposed controls were exposed to filtered air under similar conditions. Additional control groups were left in their home cages either unhandled or food‐deprived for 7 hr/day to match the food deprivation experienced by the exposed mice. Dams were observed twice daily and weighed on alternate days during the exposure period. Blood methanol concentrations were determined in some mice on gestation days 6, 10, and 15. On day 17, the remaining mice were weighed and killed and the gravid uteri removed. Implantation sites, live and dead fetuses and resorptions were counted, fetuses were examined externally and weighed as a litter. Half of each litter was examined for skeletal morphology and the other half of each litter was examined for internal soft tissue anomalies. One dam died in each of the 7,500, 10,000, and 15,000 ppm methanol exposure groups, but no dose–response relationship was evident for maternal death. The sham‐exposed and food‐deprived controls as well as all methanol exposed dams gained less weight than did unexposed dams fed ad libitum, but methanol did not exacerbate this effect. Significant increases in the incidence of exencephaly and cleft palate were observed at 5,000 ppm and above, increased embryo/fetal death at 7,500 ppm and above (including an increasing incidence of full‐litter resorptions), and reduced fetal weight at 10,000 ppm and above. A dose‐related increase in cervical ribs or ossification sites lateral to the seventh cervical vertebra was significant at 2,000 ppm and above. Thus, the NOAEL for the developmental toxicity in this study was 1,000 ppm. A log–logistic dose response model was applied to the incidence data for exencephaly, cleft palate, resorption and cervical rib, and maximum likelihood estimates (MLEs) and benchmark dosages (BDs, the lower 95% confidence interval of the MLEs) corresponding to 1% and 5% added risk above background were calculated. The MLE for 5% added combined risk of having either exencephaly or cleft palate or being resorbed was 3667 ppm, and the corresponding BD was 3,078 ppm. For cervical rib, the 5% added risk values for the MLE and BD were 824 and 305 ppm, respectively. The BDs for 1% added risk were 1915 ppm for exencephaly, cleft palate or resorption, and 58 ppm for cervical rib. Quantitative modeling of these dose‐response data for estimates of added risk offers more complete use of the data and less subjectivity than determining a NOAEL, and the lowest MLE for 5% added risk of developmental toxicity was in the dose range of the NOAEL. Litters of pregnant mice gavaged orally with 4 g methanolkg were examined for resorption, external defects (including cleft palate) and fetal weight. Incidences of adverse effects on these endpoints were similar to those seen in the 10,000‐ppm methanol inhalation exposure group. Published 1993 by Wiley‐Liss, Inc.