Toxicity, Mutagenicity, and Mutational Spectra of Vinyl Chloride, 2-Chloroethylene Oxide, and Chloracetaldehyde in a Human Lymphoblastoid Line Expressing Cytochrome P450IIE1

摘要

Vinyl Chloride Monomer is one of the few chemical s identified as a humancarcinogen. In this report, the toxicity and mutagenicity of VCM and its two metabolic products, 2-chloroethylene oxide (CEO and 2-chloroacetaldehyde (CAA) were studied in a human B-lymphoblastoid line containing cloned cytochrome P450IIE1. Cytochrome P450IIE1 is capable of metabolizing VCM to CEO which non-enzymatically rearranges to CAA. Toxicity was determined by plating cells immediately after exposure and comparing their clone-forming ability to that of untreated cells. Mutagenicity at the hprt locus was determined by plating cells in the presence of the selective agent 6-thioguanine. Delivered doses of 25 um to 400 um VCM x 24 hours produced no measureable toxicity but resulted in induced mutation frequencies that ranged from 0.5x10 EXP-6 to 5.6x10 EXP-6. Although increases in mutation frequency were consistently seen, a clear dose-response was not apparent. Dose dependent increases in toxicity and mutagenicity were observed with both CEO and CAA. Treatments of 25 um CEO x 24 hours resulted in survival of 0.82 and induced mutation frequency of 8x10-6, while similar treatments with CAA produced a survival of 0.06 and induced mutation frequency of 9x10 exp-6. Comparison of mutation frequency/survival ratios for three compounds at the same induced mutation frequency suggest the majority of mutations induced by VCM must be produced by CEO. Denaturing gradient gel electrophoresis (DGGE) was used to identify unique VCM, CEO, and CAA mutations in exon 3 of the hprt gene.