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PubMed1989

Incorporation of biological information in cancer risk assessment: example--vinyl chloride.

Vinyl chloride (VC) is used as an example to demonstrate how biological information can be incorporated into quantitative risk assessment. The information included is the pharmacokinetics of VC in animals and humans and the data-generated hypothesis that VC primarily affects the initiation stage of the multistage carcinogenesis. The emphasis in this paper is on the improvement of risk assessment methodology rather than the risk assessment of VC per se. Sufficient data are available to construct physiologically-based pharmacokinetic models for both animals and humans. These models are used to calculate the metabolized dose corresponding to exposure scenarios in animals and in humans. On the basis of the data on liver angiosarcomas and carcinomas in rats, the cancer risk per unit of metabolized dose is comparable, irrespective of routes (oral or inhalation) of exposure. The tumor response from an intermittent/partial lifetime exposure is shown to be consistent with that from a lifetime exposure when VC is assumed to affect the first (initiation) stage of the multistage carcinogenic process. Furthermore, the risk estimates calculated on the basis of animal data are shown to be consistent with the human experience.

Administration, Inhalation↗
PubMed2002

Mutation analysis of K-ras-2 in liver angiosarcoma and adjacent nonneoplastic liver tissue from patients occupationally exposed to vinyl chloride.

Vinyl chloride (VC) is a potent liver carcinogen that induces angiosarcomas in humans and animals. Recent evidence shows that liver tumors from patients with VC exposure may have a specific K-ras mutation pattern. This study was performed to determine the status of K-ras-2 in liver angiosarcomas (LAS) from workers occupationally exposed to VC. We examined the presence of K-ras-2 mutations in 15 LAS from patients with known exposure to VC (median exposure: 8,260 ppm [range 3,900- 21,000 ppm]]. In all cases, other risk factors for the development of LAS were excluded. Direct DNA sequencing after microdissection of the tumor cells was used for the analysis. Heterozygous mutations of K-ras-2 were detected in 8/15 LAS (53%). Five patients (33%) had a mutation of codon 12 and three of codon 13 (20%). The most common changes were G-->A transitions in five LAS which lead to the substitution of aspartic acid for glycine in the resulting p21 protein. In two patients (13%), mutations of the K-ras-2 gene were identified in the adjacent nonneoplastic liver tissue. These data indicate that VC induces a high frequency of G-->A transitions in human LAS. This mutation pattern is likely a consequence of VC-DNA-adduct formation.

Aged↗
PubMed1997

p53 gene mutation pattern in rat liver tumors induced by vinyl chloride.

Vinyl chloride (VC) induces angiosarcomas of the liver (ASL) and hepatocellular carcinomas (HCCs) in humans and rodents. We examined the presence of p53 gene mutations in ASL and HCC induced by VC in Sprague Dawley rats; 25 ASL and eight HCCs were analyzed for point mutations in exons 5-8, using PCR amplification, single-strand conformation polymorphism analysis, and direct DNA sequencing. Mutations were found in 11 (44%) of the ASL and in 1 HCC. A 12-base pair deletion was found in one tumor; all others were base pair substitutions. Nine of the point mutations were observed at A:T base pairs (5 A:T --> T:A; 2 A:T --> G:C, and 2 A:T --> C:G), and of three G:C --> A:T transitions, only one was at a CpG site. In ASL, four mutations were found in exon 5, two in exon 6, and six in exon 7; the base pair substitution found in one HCC was in exon 8. One ASL exhibited two point mutations, including a silent one. Two ASL exhibited the same mutation in codon 203 and two other samples in codon 253. Codon 235 was found to be mutated in three ASL. These data show that p53 is often mutated in ASL induced by VC in rats and, as observed in ASL in humans exposed to VC, the majority of the missense mutations involved A:T base pairs. The characteristic patterns of mutations found suggest that a common mechanism operates in VC-induced p53 mutagenesis in both species, and these mutations are consistent with the formation of DNA etheno adducts by VC in the liver. The A:T --> T:A transversion observed in the first nucleotide of codon 253 in two rat ASL is equivalent to the A:T --> T:A transversion characterized previously in codon 255 in one human ASL associated with VC exposure.

Animals↗
PubMed2001

Frequent k- ras -2 mutations and p16(INK4A)methylation in hepatocellular carcinomas in workers exposed to vinyl chloride.

Vinyl chloride (VC) is a know animal and human carcinogen associated with liver angiosarcomas (LAS) and hepatocellular carcinomas (HCC). In VC-associated LAS mutations of the K- ras -2 gene have been reported; however, no data about the prevalence of such mutations in VC associated HCCs are available. Recent data indicate K- ras -2 mutations induce P16 methylation accompanied by inactivation of the p16 gene. The presence of K- ras -2 mutations was analysed in tissue from 18 patients with VC associated HCCs. As a control group, 20 patients with hepatocellular carcinoma due to hepatitis B (n = 7), hepatitis C (n = 5) and alcoholic liver cirrhosis (n = 8) was used. The specific mutations were determined by direct sequencing of codon 12 and 13 of the K- ras -2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. The status of p16 was evaluated by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. All patients had a documented chronic quantitated exposure to VC (average 8883 ppmy, average duration: 245 months). K- ras -2 mutations were found in 6 of 18 (33%) examined VC-associated HCCs and in 3 cases of adjacent non-neoplastic liver tissue. There were 3 G --> A point mutations in the tumour tissue. All 3 mutations found in non-neoplastic liver from VC-exposed patients were also G --> A point mutations (codon 12- and codon 13-aspartate mutations). Hypermethylation of the 5' CpG island of the p16 gene was found in 13 of 18 examined carcinomas (72%). Of 6 cancers with K- ras -2 mutations, 5 specimens also showed methylated p16. Within the control group, K- ras -2 mutation were found in 3 of 20 (15%) examined HCC. p16 methylation occurred in 11 out of 20 (55%) patients. K- ras -2 mutations and p16 methylation are frequent events in VC associated HCCs. We observed a K- ras -2 mutation pattern characteristic of chloroethylene oxide, a carcinogenic metabolite of VC. Our results strongly suggest that K- ras -2 mutations play an important role in the pathogenesis of VC-associated HCC.

Adult↗
PubMed1986

Interaction of vinyl chloride with poly(vinyl chloride) by inverse gas chromatography: effect of monomer concentration, plasticizer content and temperature.

The interaction of vinyl chloride (VC) with poly(vinyl)chloride) (PVC) has been studied by inverse gas chromatography (IGC). The present work focusses on the effect of monomer concentration, temperature and plasticizer content. Values for thermodynamic parameters such as free energy (delta GS), excess free energy (delta GSXS), enthalphy (delta HS), entropy (delta SS) and activity coefficient (gamma S) corresponding to sorption of the monomer (VCM) by the polymer, have been calculated using chromatographic data. It was found that retention of VC by PVC is favored at lower monomer concentrations. Increase in temperature resulted in increase of delta GS, delta GSXS, and gamma S values corresponding to a less spontaneous process or a weaker interaction between VC and PVC. An increase in plasticizer content of the polymer resulted in an increase of degree of binding of the monomer. Data support the hypothesis that at significantly low concentrations of residual monomer, low storage temperatures and high concentrations of plasticizer, in the polymer, the probability of migration of VC from a plastics packaging material into a food contacting phase is markedly reduced.

Chromatography, Gas↗
PubMed1981

Worker exposure to vinyl chloride and poly(vinyl chloride).

The National Institute for Occupational Safety and Health (NIOSH) in early 1974 began industrial hygiene studies of vinyl chloride exposed workers. Three VC monomer plants, three VC polymerization plants, and seven PVC fabrication plants were surveyed. V polymerization plant workers and workers in one job category in VC monomer plants were exposed to average levels above 1 ppm. The highest average exposure was 22 ppm. NIOSH health hazard evaluation studies since these initial surveys have primarily shown nondetectable levels of vinyl chloride. A NIOSH control technology study in 1977 showed that exposure levels in VC polymerization plants had been drastically reduced but exposure levels above 1 ppm were still found in several cases.

Air Pollutants↗
PubMed2000

Deficiency of N-methylpurine-DNA-glycosylase expression in nonparenchymal cells, the target cell for vinyl chloride and vinyl fluoride.

The ability to repair promutagenic damage resulting from exposure to carcinogens is a critical factor in determining quantitative relationships in carcinogenesis, including the target cell for neoplasia. One major pathway for the repair of alkylating agent-induced DNA damage involves removal of alkylated bases by N-methylpurine-DNA-glycosylase (MPG), the first enzyme in base excision repair. We have measured the expression level of MPG mRNA in liver, lung, and kidney of Sprague-Dawley rats as a function of age. A quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) method was used to measure cellular MPG mRNA. MPG mRNA was readily detectable in each tissue analyzed and the age-dependent and tissue specific expressions were not statistically different. The lowest amount of mRNA was measured in preweanling liver and the highest amounts were found in preweanling lung and kidney. Since MPG is reported to be responsible for excision of 1,N(6)-ethenoadenine and N(2),3-ethenoguanine, two promutagenic DNA adducts of vinyl chloride (VC) and vinyl fluoride (VF), we examined the regulation of this enzyme after carcinogen exposure. Expression of MPG was induced in rat liver by these carcinogens. In order to determine the repair capacity in different cell populations of liver, we measured MPG gene expression in isolated hepatocytes and nonparenchymal cells (NPC). The amount of MPG mRNA was 4.5-5 times higher in hepatocytes than in NPC of control rats. Induction of MPG expression was observed in hepatocytes of VF exposed-rats but not in NPC. The expression of MPG in NPC was only 15% of that of the hepatocytes from exposed rats. Western blots of MPG protein confirmed the cell type differences, but did not show increased protein in exposed vs. control liver and hepatocytes. Since metabolism of VC and VF requires CYP2E1, an enzyme exhibiting much greater activity in hepatocytes, formation of etheno adducts preferentially occurs in hepatocytes. These data suggest that cellular differences in the repair of N-alkylpurines may be a critical mechanism in the development of cell specificity in VC carcinogenesis.

Aging↗
PubMed2002

Copolymerization studies of vinyl chloride and vinyl acetate with ethylene using a transition-metal catalyst.

Since the advent of Ziegler-Natta polymerization of ethylene, attempts have been made to extend coordination polymerization to commercially important monomers with polar functionality. In this study we examined the copolymerization of perdeuterated vinyl chloride (VC) and perdeuterated vinyl acetate (VA) with ethylene using a tridentate Fe(II) dichloride pyridine diimine metal catalyst. The resulting ethylene oligomers were examined by GC/MS and 2H NMR spectroscopy. It was shown that VC was inserted once for every approximately 180 ethylene monomers and VA was inserted once for every approximately 350 ethylene monomers. VC and VA behave as comonomers for coordination/insertion polymerizations with ethylene. However, we find that insertion with either monomer leads to termination of the growing chain via beta-elimination processes. The deuterium atoms are exclusively located at the olefin terminus for each of the monomers.

Journal Article↗
PubMed1987

Determination of vinyl chloride monomer residue in poly(vinyl chloride) at the parts-per-billion level with an automatic purge-and-trap technique.

A method for the determination of vinyl chloride residue in poly(vinyl chloride) using a commercial purge-and-trap ancillary unit has been developed. Concentrations lower than 10 ppb (10(9] with relative standard deviations in the region of 10% in up to 24 samples are detectable with fully automatic operation without operator attendance. With multiple extraction of the same sample an external standard is used; the matrix does not have any influence on the recovery of vinyl chloride.

Chromatography, Gas↗
PubMed2003

Polymorphisms for vinyl chloride metabolism in French vinyl chloride workers.

Genetic polymorphisms of aldehyde dehydrogenase 2 (ALDH2) and cytochrome P450 2E1 (CYP2E1) have been shown to influence the degree of genetic damage in Taiwanese workers exposed to the carcinogen - vinyl chloride(VC). Certain French VC workers have been found to express biomarkers of mutant forms of cancer-related proteins (ras-p21 and p53) that have been related to their exposure. ALDH2 and CYP2E1 polymorphisms were investigated in 211 of these workers in an attempt to correlate differences in VC metabolic capacity with differences in the presence of these biomarkers. All of the workers were found to have the normal, wild-type ALDH2 gene, and none of them were found to be homozygous for the variant CYP2E1 allele. Sixteen workers were found to be heterozygous for the variant CYP2E1 allele. After adjusting for age, smoking, drinking and cumulative VC exposure, the odds ratio for the presence of either the mutant ras-p21 or the mutant p53 biomarker in these heterozygous workers was found to be statistically significantly increased in comparison to their homozygous, wild-type counterparts (OR = 5.05; 95% CI = 1.10-23.25). However, as opposed to the case in Taiwanese workers, these polymorphisms are relatively uncommon, and thus differences in ALDH2 and CYP2E1 can account for only a small proportion of the variability in mutagenic response to VC exposure in a Caucasian population.

Adult↗
PubMed2002

[Determination of acetylene and vinyl chloride in hydrochloric acid from producing vinyl chloride by headspace gas chromatography].

A headspace gas chromatographic method was used for determining acetylene and vinyl chloride in hydrochloric acid from vinyl chloride production. Hydrogen chloride was neutralized by sodium hydroxide, so its effect on determining acetylene and vinyl chloride was eliminated. The headspace bottle was put in a water bath at 35 degrees C for 45 min. The GC column was a 2 m x 3 mm i.d. stainless steel tube packed with GDX-202 stationary phase. The column temperature was 140 degrees C. Injection volume was 1 mL. External standard method was used for quantitation. The relative standard deviation was 0.85% and the recoveries in the range of 30.0 micrograms/g-150 micrograms/g were 98.9%-103% for acetylene. The relative standard deviation was 1.4% and the recoveries in the range of 20.0 micrograms/g-100 micrograms/g were 98.8%-102% for vinyl chloride.

Acetylene↗
PubMed1981

[Biochemical changes in vinyl chloride poisoning. I. Effect of different conditions of vinyl chloride exposure on lipid metabolism in rats].

Lipids metabolism was evaluated in rats chronically exposed to vinyl chloride concentrations of 50, 500 and 20 000 ppm. The studies involved: 1) estimation of lipids content in serum; 2) estimation of cholesterol and triglycerides content in some tissues (liver, muscles, connective tissue, aortic wall), 3) evaluation of the rate of incorporating 14C-acetate into 14C-cholesterol in liver and the rate of its transition into blood. The studies were carried out after 1, 3, 6 and 10 months of vinyl chloride exposure. The results prove that under effects of vinyl chloride exposure some tendencies of an increase in the total and esterified cholesterol in serum vary with the magnitude of exposure (vinyl chloride airborne concentration, intoxication time). As to triglycerides and phospholipids at the final phase of intoxication (after 10 months) a significant increase in their serum content is found at the 20 000 ppm. concentration, whereas there are no changes in the free fatty acids level. As to the examined tissue only in liver some tendencies are found of a decrease in cholesterol content and much greater decrease in triglycerides level, which is progressing with intoxication time and exposure magnitude. No effect of vinyl chloride on the level of lipids in muscles, aortic wall and connective tissue were found. Studies of cholesterol synthesis in liver showed some increase in the rate of building 14C-acetate into cholesterol only in two highest vinyl chloride concentrations (500 and 20 000 ppm) after 10 months of exposure. The results demonstrate that chronic vinyl chloride exposure only slightly affects lipid metabolism. The most significant changes occur only after 10 months of exposure at the concentration of 20 000 ppm. It is supposed that the disturbances in lipid metabolism have no important contribution to vinyl chloride poisonings pathology.

Animals↗
PubMed1981

Results of sputum, cytology among workers exposed to vinyl chloride monomer and to poly(vinyl chloride).

The results of systematic cytological sputum examinations of 3,380 Italian VC-PVC industry workers and of 2,287 workers in other industries at different potential risk and chosen as control groups are reported. The results indicate an increase in cellular abnormalities and dysplasias in the epithelium of the respiratory tract among VC-PVC workers. These data are in line with experimental results showing that VC produces lung tumors in mice and with early epidemiological evidence among exposed workers.

Humans↗
PubMed2001

Formation of dioxins during the combustion of newspapers in the presence of sodium chloride and poly(vinyl chloride).

Exhaust gases from the combustion of newspaper alone, from branches of London plane tree alone, and from newspapers mixed with sodium chloride (NaCl), polyethylene, or poly(vinyl chloride) (PVC) were collected. The samples were analyzed for dioxins by gas chromatography/mass spectrometry. Total amounts of dioxins found in the samples were 0.186 ng/g from newspapers alone, 1.42 ng/g from the branches of London plane, 102 ng/g from newspapers impregnated with sodium chloride (CI wt % = 3.1), 101 ng/g from newspapers impregnated with sodium chloride mixed with PVC (Cl wt % = 2.6), and 146 ng/g from newspapers mixed with PVC (Cl wt % = 5.1). Samples with a higher chloride content produced more dioxins, and there is a clear correlation between dioxin formation and chloride content. The amount of dioxins formed in the samples according to the number of chlorides was Cl5 > Cl4 > Cl6 > Cl7 > Cl8 in PCDD isomers and Cl4 > Cl5 > Cl6 > Cl7 > Cl8 in PCDF isomers, except in the case of newspapers alone. Benzofurans composed 78-92% of the total dioxins formed in the exhaust gases. The higher the number of the chlorides, the lower the production of benzofuran observed. NaCl vaporized at the temperature of the flame used for combustion of the samples (760-1080 degrees C). The results indicate that NaCl and PVC contribute significantly to dioxin formation from waste materials combusted in incinerators.

Air Pollution↗