Superfund Research Program

Biomarkers of Human Susceptibility to Vinyl Chloride

Project Leaders: David G. Kaufman, Howard L. Liber (Massachusetts General Hospital)
Grant Number: P42ES005948
Funding Period: 1995 - 2000

Project-Specific Links

Final Progress Reports

Year:   1999 

In the last year, Project 2 investigators focused on determining whether lymphoblastoid lines from French workers with high HPRT mutant frequencies in blood lymphocytes displayed a defect in DNA repair. A flow cytometric assay was used that quantifies the accumulation of cells in G2 after damaging DNA with ionizing radiation. This assay was shown to be capable of detecting the DNA repair defect in ataxia telangiectasia, and it correctly identified a repair defect in 3 of 4 heterozygous carriers of mutant ATM alleles. When applied to 28 lymphoblastoid lines from people exposed to varying levels of vinyl chloride, 10 lines (36%) displayed radiation hypersensitivity with enhanced accumulation in G2 characteristic of ATM heterozygotes. The proportion of samples with the trait of hypersensitivity was 31% among those from people with low HPRT mutant frequency and 62% among those with high mutant frequency. Due to the small sample size these fractions were not significantly different. Mutagen hypersensitivity of the type detected by the flow cytometric assay did not appear to account for the apparent enhanced sensitivity to mutation induction by vinyl chloride seen in about 15% of people. Other studies showed that ATM does protect against genotoxicity by chloroethylene oxide, the genotoxic metabolite of vinyl chloride. Moreover, an ATM-wildtype lymphoblastoid line displayed extreme hypersensitivity to chloroethylene oxide, suggesting that genes other than ATM also protect against genotoxicity of vinyl chloride.