抄録
A 90-day toxicity inhalation study was conducted in Wister WU rats with bitumen fumes. The composition of the fume was aimed to be similar to the exposure atmosphere released during road paving. The objective of this study was to determine the concentration levels and maximally tolerated dose for a future carcinogenicity study. Male and female rats, approx. 10 weeks old, were exposed to clean air, or to target concentrations of 4, 20, and 100mg/m3 THC (total hydrocarbon), 6 hrs/day, 5 days/week for 14 weeks. In the male hight dose group a decrease of body weight up to 10% versus controls was observed. Milder effects on body weight (approx. 5%) were noted in all female bitumen groups. A statistically significant lower food consumption was noted in the male high dose group.Statistically significant test substance-related changes were only observed in histopathology, i.e. the nasal and paranasal cavities from rats of the bitumen high dose group. Eosinophilic cytoplasmic inclusions (hyalinosis) were found exclusively in nasal epithelial cells of the high dose group. In addition, degenerative hyalinosis associated with focal/multifocal basal cell hyperplasia was observed in the olfactory/respiratory transition areas of high-dosed males. Other significant treatment-related changes were multifocal mucous (goblet) cell hyperplasia and multifocal mucosal inflammatory cell infiltration.Under the conditions of this subchronic study an NOAEL of 20mg/m3 THC was derived for bitumen fumes. Thus, target concentrations of 4, 20, and 100mg/m3 THC were defined for a chronic study focussing on examination of potential carcinogenicity; further endpoints are BAL and cell proliferation measurements of nose and lungs. In addition, as mechanistic endpoints the analysis of DNA adduct formation and gene expression profiling have been included.Results of the chronic study, together with epidemiological data, may allow the definition of a health-based threshold value for bitumen road paving workplaces. These studies are sponsored by ARBIT, Hamburg, Germany.
