The carcinogenic mechanisms of asbestos fibers are not well understood. Although there is clear evidence that asbestos causes chromosomal mutations (aneuploidy and aberrations) in various in vitro and in vivo systems, previous mutagenesis data, based on the HGPRT locus system, have concluded that mineral fibers are non-mutagenic. On the other hand, recent studies by the applicant using the human-hamster hybrid [AL] cells have shown that chrysotile fibers can induce a dose-dependent mutagenicity at the a1 locus, but induce no significant number of HGPRT- mutants. This raises the question: Can the negative mutagenic findings be attributed, at least in part, to large multilocus damages induced by the fibers that are incompatible with survival of the mutants in the test systems used? To examine this question, it is proposed to examine the mutagenic effects of various mineral fibers including asbestos, glass and man-made ceramic fibers at the a1, a2, HGPRT and the Na+ K 4+ ATPase loci (OuaR) in the same cell population. The AL system can measure both small and large mutations, scored in an antibody-complement mediated cytotoxic assay, as loss of lethal surface markers located on a non-essential human chromosome [no.11] with remarkable specificity and quantification. This cell system overcomes the problem inherent in some assays in which many large mutational events such as deletions and loss of chromosomes are unable to be scored because they are lethal. By using specific DNA probes mapped on human chromosome 11, the molecular mechanisms of mutation in the AL cells can also be examined. Since the AL cells contain the HGPRT gene, an analysis of genetic damage associated with specific fiber-induced mutation on an essential [-X] vs a non-essential chromosome [human chromosome 11] will provided useful information on the types and sizes of molecular changes induced by the various fiber treatments. The measurement of mutation at the Oua locus, an essential gene that measures primarily base-pair changes, will further ascertain the deletion damages proposed for fibers since other inactivating mutations in this locus can eliminate enzyme activity and be fatal.
