Asphalt fume dermal carcinogenicity potential: II. Initiation-promotion assay of Type III built-up roofing asphalt.

Clark et al. (accepted for publication) reported that a sample of field-matched fume condensate from a Type III built-up roofing asphalt (BURA) resulted in a carcinogenic response in a mouse skin bioassay, with relatively few tumor-bearing animals, long tumor latency and chronic skin irritation. This mouse skin initiation/promotion study was conducted to assess possible mechanisms, i.e., genotoxic initiation vs. tumor promotion subsequent to repeated skin injury and repair. The same Type III BURA fume condensate sample was evaluated in groups of 30 male Crl:CD1® mice by skin application twice per week (total dose of 50 mg/week) for 2 weeks during the initiation phase and for 26 weeks during the promotion phase. Positive control substances were 7,12-dimethylbenz(a)anthracene (DMBA, 50 µg applied once) as an initiator and 12-O-tetradecanoyl-13-acetate (TPA, 5 µg, applied twice weekly) during the promotion phase. During the 6 months of study with the asphalt fume condensate, eight skin masses were observed when tested for initiation, five of which were confirmed microscopically to be benign squamous cell papillomas. Only two papillomas were observed when tested for promotion. There was no apparent relationship between skin irritation and tumor development in this study. These results are more indicative of genotoxicity rather than a non-genotoxic mode of action.

Asphalt fume dermal carcinogenicity potential: I. dermal carcinogenicity evaluation of asphalt (bitumen) fume condensates.

Asphalt (bitumen) fume condensates collected from the headspace above paving and Type III built up roofing asphalt (BURA) tanks were evaluated in two-year dermal carcinogenicity assays in male C3H/HeNCrl mice. A third sample was generated from the BURA using a NIOSH laboratory generation method. Similar to earlier NIOSH studies, the BURA fume condensates were applied dermally in mineral oil twice per week; the paving sample was applied 7 days/week for a total weekly dose of 50 mg/wk in both studies. A single benign papilloma was observed in a group of 80 mice exposed to paving fume condensate at the end of the two-year study and only mild skin irritation was observed. The lab generated BURA fume condensate resulted in statistically significant (P<0.0001) increases in squamous cell carcinomas (35 animals or 55% of animals at risk). The field-matched BURA condensate showed a weaker but significant (P=0.0063) increase (8 carcinomas or 13% of animals) and a longer average latency (90 weeks vs. 76 for the lab fume). Significant irritation was observed in both BURA condensates. It is concluded that the paving fume condensate was not carcinogenic under the test conditions and that the field-matched BURA fume condensate produced a weak tumor response compared to the lab generated sample.

Marginal biotin deficiency is teratogenic in ICR mice.

The incidence of marginal biotin deficiency in normal human gestation is approximately one in three. In ICR mice, maternal biotin deficiency results in cleft palate, micrognathia, microglossia and limb hypoplasia. However, the relationships among the severity of maternal biotin deficiency, fetal biotin status and malformations have not been reported. This study utilized validated indices of biotin status to investigate the relationships among maternal biotin status, fetal biotin status and the rate of fetal malformations in ICR mice. Biotin status was controlled by feeding diets with varying egg white concentration. In dams and fetuses, biotin status was assessed by hepatic biotin content and hepatic activity of the biotin-dependent enzyme propionyl-CoA carboxylase; in dams, status was also assessed by urinary excretion of biotin and 3-hydroxyisovaleric acid. Malformations were assessed morphologically. Biotin was measured by HPLC/avidin-binding assay. Propionyl-CoA carboxylase (PCC) activity was determined by H(14)CO(3) incorporation. 3-Hydroxyisovaleric acid concentration was determined by GC/MS. Although no overt signs of deficiency appeared, metabolic disturbances caused by biotin deficiency were detectable in dams and fetuses. These disturbances increased with increasing egg white. Fetal biotin status correlated significantly with maternal biotin status (fetal vs. dam hepatic biotin, r = 0.671; fetal vs. dam PCC activity, r = 0.70). The incidences of malformations were strikingly dependent on egg white concentration. We conclude that in ICR mice, marginal maternal biotin deficiency causes fetal biotin deficiency. We speculate that the fetal malformations are primarily the consequence of fetal biotin deficiency. Because murine malformations appeared at degrees of biotin deficiency that are similar to those in human gestation, we speculate that some human fetal malformations may be caused by biotin deficiency.