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' ASBESTOS MEDITEXT ® - Medical Management Page 14 of 15

mesotheliomas in hamsters: soft chrysotile, harsh chrysotile, amosite, diatomaceous earth, crocidolite, and anthophyllite (Smith, 1984). C. LACK OF EFFECT 1. Chrysotile asbestos was not carcinogenic by the oral exposure route in hamsters when given at a level of 1 percent in the diet over the animals' lifetime (NTP, 1990).

3.22 GENOTOXICITY

3.22.2 DNA DAMAGE/REPAIR

A. Asbestos can induce DNA damage; its activity is enhanced several-fold by peroxides (Mahmood et al, 1993; Mahmood et al, 1994). Asbestos can form complexes with iron cations; iron-complexed asbestos reacts with peroxides to generate free radicals. The extent of DNA damage is proportional to the amount of active iron complexed with asbestos (Ohio et al, 1994; Lund et al, 1994). 1. Iron contained in ferruginous bodies can also induce DNA damage if it is in the ferrous form (Lund et al, 1994). B. A 2- to 4-fold elevation in double-stranded DNA breaks was seen in lymphocytes of persons occupationally exposed to asbestos, compared with non-exposed controls (Marczynski et al, 1994).

3.22.3 MUTAGENICITY

A. In general, asbestos has not been mutagenic in bacteria and is not clearly genotoxic in mammalian cells, except for some rodent cells in vitro (Daniel, 1983; Chamberlain & Tarmy, 1977; Daniel, 1983). Amosite, crocidolite, and chrysotile were not mutagenic in the HGPRTase assay in rat cells (Reiss et al, 1982). B. Developments in molecular genetics have enabled mutations induced by asbestos to be detected in mammalian cells. 1. Asbestos can induce multilocus deletions in human-hamster hybrid cells; these mutations are prevented by catalase, superoxide dismutase, or anti-oxidant enzymes (Hei et al, 1995). 2. Crocidolite, but not chrysotile, induced loss of heterozygosity in the HLA-A locus in human peripheral lymphocytes (Both et al, 1994). C. Induction of mutations in specific genes (oncogenes) is thought to be part of the mechanism of carcinogenesis for some cancers. 1. Lung tumor specimens from lung cancer patients showed a high frequency of a specific kind of ras oncogene mutation: 57 percent of the adenocarcinoma samples had K-ras mutations. K-ras mutations were elevated 4.9-fold in samples from heavy smokers and 2.2-fold with occupational exposure to asbestos. While the latter elevation was not statistically significant, it suggests that asbestos may play a role in inducing K-ras mutations (Husgafvelpursiainen et al, 1993).

3.22.4 CHROMOSOME ABERRATIONS

A. Sister chromatid exchange (SCE) frequency was increased in a sample of 22 asbestos cement workers compared to matched controls (Fatma et al, 1991). B. CYTOGENETIC ANALYSIS OF ASBESTOS-RELATED TUMORS - Seven mesothelial cell lines were established from clinical specimens from 5 patients with asbestos-related pleural

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