Inhaled crocidolite mutagenicity in lung DNA

We used transgenic mice carrying the lad reporter gene to study the mutagen esis potential of asbestos crocidolite. The animals were exposed by nose-on ly inhalation to an aerosol containing 5.75 mg/m(3) crocidolite dust for 6 hr/day and 5 consecutive days. After 1, 4, and 12 weeks, we examined four e nd points: the cytology of bronchoalveolar lavage, the lung load of crocido lite, the hydrophobic DNA adducts, and the mutations in the lacI reporter g ene. Twelve weeks after exposure, nearly 10% of the inhaled fibers remained in the lung (227 +/- 103 ng/mg lung). There was evidence of a typical infl ammatory response consisting of multinucleate macrophages at weeks 4 and 12 , whereas immediately after the exposure, we observed numerous polymorphonu clear neutrophils. The mutant frequency significatively increased during th e fourth week after the exposure: 13.5 x 10(-5) in the exposed group versus 6.9 x 10(-5) in the control group. The induction factor, defined by the ra tio of checked mutants of exposed mice to checked mutants of control mice, was 1.96. The mutation spectrum of control lung DNA and exposed lung DNA wa s similar, suggesting the possible involvement of a DNA repair decrease in crocidolite-treated animals. We used the (32)p- postlabeling method and did not detect any increase of either 5 mC or bulky adduct in treated mice. Th is is the first study that demonstrates asbestos mutagenicity in vivo after a nose-only inhalation.