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Journal of Applied Toxicology : JAT 1994
Review
Topics: Animals; Carcinogens; Humans; Mutagens; Nervous System; Reproduction; Toxicity Tests; Vinyl Chloride
PubMed: 7963245
DOI: 10.1002/jat.2550140411 -
Journal of Hepatology Dec 2009Vinyl chloride monomer is a known cause of angiosarcoma of the liver. It also has other toxic effects on the liver, and it has recently been suggested that exposure to... (Review)
Review
Vinyl chloride monomer is a known cause of angiosarcoma of the liver. It also has other toxic effects on the liver, and it has recently been suggested that exposure to vinyl chloride also causes hepatocellular carcinoma. However, the data on which this conclusion is based is incomplete. There is inadequate ascertainment of unequivocal diagnoses. In the largest studies lack of data meant that confounding diseases such as viral hepatitis or alcoholic liver disease could not be assessed. At best, the increase in risk is minimal, based on more than 22,000 exposed workers and more than 640,000 person years of observation. However, based on the available data the hypothesis that vinyl chloride causes or contributes to the development of hepatocellular carcinoma remains unproven.
Topics: Animals; Carcinoma, Hepatocellular; Hemangiosarcoma; Humans; Liver; Liver Cirrhosis; Liver Neoplasms; Mutagens; Occupational Exposure; Risk Factors; Vinyl Chloride
PubMed: 19836850
DOI: 10.1016/j.jhep.2009.09.012 -
Critical Reviews in Toxicology 2005The carcinogenicity of vinyl chloride in humans was recognized in 1974 based on observations of hepatic angiosarcomas in highly exposed workers. A multiplicity of... (Review)
Review
The carcinogenicity of vinyl chloride in humans was recognized in 1974 based on observations of hepatic angiosarcomas in highly exposed workers. A multiplicity of endpoints has been demonstrated. The primary target organ, the liver, displays differential susceptibilities of hepatocytes and sinusoidal cells, which are modified by factors of age and dose. There is consistency in organotropism between experimental animals and humans. Vinyl chloride is a pluripotent carcinogen, predominantly directed toward hepatic endothelial (sinusoidal) cells, and second toward the parenchymal cells of the liver. The similarity of results between experimental animals and humans is a solid basis of an amalgamation of experimental and epidemiological risk estimates. Vinyl chloride requires metabolic activation for carcinogenicity and mutagenicity, and toxicokinetics are a key to interpret the dose response. Practically the entire initial metabolism of vinyl chloride is oxidative. At higher exposure concentrations this is nonlinear, and metabolic saturation of metabolism in rats is reached at about 250 ppm. This is consistent with the plateau of hepatic angiosarcoma incidence in rat bioassays. Physiologically based pharmacokinetic/toxicokinetic (PBPK) models have been developed and successfully applied within the frame of human cancer risk assessments. The major DNA adduct induced by vinyl chloride (approximately 98% of total adducts in rats), 7-(2-oxoethyl)guanine, is almost devoid of promutagenic activity. The clearly promutagenic "etheno" adducts N2,3-ethenoguanine and 3,N4-ethenocytosine each represent approximately 1% of the vinyl chloride DNA adducts in rats, and 1,N6-ethenoadenine is found at even lower concentrations. Etheno adducts appear to have a long persistence and are repaired by glycosylases. Vinyl chloride represents a human carcinogen for which a series of mechanistic events connects exposure with the carcinogenic outcome. These include (1) metabolic activation (to form chloroethylene oxide), (2) DNA binding of the reactive metabolite (to exocyclic etheno adducts), (3) promutagenicity of these adducts, and (4) effects of such mutations on protooncogenes/tumor suppressor genes at the gene and gene product levels. In rat hepatocytes, a further event is a biomarker response. Cancer prestages (enzyme-altered foci), as quantitative biomarkers, provide a tool to study dose response even within low dose ranges where a carcinogenic risk cannot be seen in cancer bioassays directly. Such biomarker responses support a linear nonthreshold extrapolation for low-dose assessment of carcinogenic risks due to vinyl chloride. Published risk estimates based on different sets of data (animal experiments, epidemiological studies) appear basically consistent, and on this basis an angiosarcoma risk of approximately 3 x 10(-4) has been deduced by extrapolation, for exposure to 1 ppm vinyl chloride over an entire human working lifetime. An important point that should be considered in regulatory standard settings is the presence of a physiological background of those etheno DNA adducts, which are also produced by vinyl chloride. Likely reasons for this background are oxidative stress and lipid peroxidation. In essence, fundamentals of the hepatocarcinogenicity of vinyl chloride appear now well established, providing a solid scientific basis for regulatory activities.
Topics: Animals; Carcinogens; DNA; DNA Repair; Humans; Inhalation Exposure; Mutagens; Occupational Exposure; Risk Assessment; Vinyl Chloride
PubMed: 15989139
DOI: 10.1080/10408440490915975 -
Environmental Toxicology Feb 2022Vinyl chloride (VC) is an organochlorine mainly used to manufacture its polymer polyvinyl chloride, which is extensively used in the manufacturing of consumer products....
Vinyl chloride (VC) is an organochlorine mainly used to manufacture its polymer polyvinyl chloride, which is extensively used in the manufacturing of consumer products. Recent studies suggest that chronic low dose VC exposure affects glucose homeostasis in high fat diet-fed mice. Our data suggest that even in the absence of high fat diet, exposure to VC (0.8 ppm, 6 h/day, 5 day/week, for 12 weeks) induces glucose intolerance (1.0 g/kg, i.p.) in male C57BL/6 mice. This was accompanied with the depletion of hepatic glutathione and a modest increase in lung interstitial macrophages. VC exposure did not affect the levels of circulating immune cells, endothelial progenitor cells, platelet-immune cell aggregates, and cytokines and chemokines. The acute challenge of VC-exposed mice with LPS did not affect lung immune cell composition or plasma IL-6. To examine the effect of VC exposure on vascular inflammation and atherosclerosis, LDL receptor-KO mice on C57BL/6 background maintained on western diet were exposed to VC for 12 weeks (0.8 ppm, 6 h/day, 5 day/week). Unlike the WT C57BL/6 mice, VC exposure did not affect glucose tolerance in the LDL receptor-KO mice. Plasma cytokines, lesion area in the aortic valve, and markers of lesional inflammation in VC-exposed LDL receptor-KO mice were comparable with the air-exposed controls. Collectively, despite impaired glucose tolerance and modest pulmonary inflammation, chronic low dose VC exposure does not affect surrogate markers of cardiovascular injury, LPS-induced acute inflammation in C57BL/6 mice, and chronic inflammation and atherosclerosis in the LDL receptor-KO mice.
Topics: Animals; Cardiovascular Diseases; Diet, High-Fat; Liver; Male; Mice; Mice, Inbred C57BL; Vinyl Chloride
PubMed: 34717031
DOI: 10.1002/tox.23394 -
Chemico-biological Interactions Jul 1978Vinyl chloride and vinyl benzene (styrene) are mutagenic in microbial tests, in Drosophila, in yeast, and in mammalian cells. Reports from various countries have shown... (Review)
Review
Vinyl chloride and vinyl benzene (styrene) are mutagenic in microbial tests, in Drosophila, in yeast, and in mammalian cells. Reports from various countries have shown an excess of chromosomal aberrations in the lymphocytes of workers exposed to vinyl chloride monomer when the workers were compared with controls. Workers occupationally exposed to styrene also revealed a clear increase in the rate of chromosome aberrations in their lymphocytes. Both chloroethylene oxide and styrene oxide, the primary biotransformation products of vinyl chloirde and styrene respectively, bind covalently to cellular macromolecules. Vinyl chloride is a carcinogen in both animals and man. Styrene is currently being tested in animals. These findings, the demonstration of mutagenic response via microbial and other test systems and with observations of significant excesses of chromosomal aberrations among workers exposed to these agents, raise scientific and health oriented concern about the possible genetic risks of vinyl chloride and styrene to man.
Topics: Animals; Biotransformation; Carcinogens; Chromosome Aberrations; Female; Humans; Mutagens; Occupational Diseases; Rats; Styrenes; Vinyl Chloride; Vinyl Compounds
PubMed: 357035
DOI: 10.1016/0009-2797(78)90155-2 -
Food and Chemical Toxicology : An... Feb 1987There is little doubt that exposure to high levels of VCM as a consequence of occupation can result in an increased incidence of ASL. A review of 20 epidemiological... (Review)
Review
There is little doubt that exposure to high levels of VCM as a consequence of occupation can result in an increased incidence of ASL. A review of 20 epidemiological studies involving about 45,000 workers occupationally exposed to VCM showed that neoplasms of the liver showed an increase in incidence in the majority of studies. For brain cancer the association between exposure to VCM and an increased incidence was less clear because of the lower relative risk. Neoplasms of the respiratory tract, digestive system, lymphatic and haemopoietic system, buccal cavity, and pharynx, cardiovascular system and colon/stomach were reported to show an increased incidence in one or more studies, but to show no increase, or in some cases a decrease, in incidence in other studies. In view of the increased incidence of breast neoplasms in rodents exposed to VCM, the studies of Chaizze et al. (1980), who did not confirm these findings in humans, are of importance. The register of ASL cases now contains records of 99 persons with confirmed ASL and occupational exposure to VCM. The average latent period between first exposure to VCM and death from ASL is 21.9 years. The majority of cases occurred in autoclave workers, who are recognized as having been exposed to extremely high levels. Although precise estimates of exposure are not available for the periods of most interest, the pattern of cases roughly suggests that extremely high exposures were necessary for the induction of ASL. For example, ASL cases tended to occur in larger numbers in some plants than in others, a finding that can be explained most easily by differences in exposure patterns. There is an extensive series of animal studies on the carcinogenicity of VCM. Some of these precede the epidemiological studies confirming the association between VCM exposure and ASL in man. ASL and neoplasms of a number of other organs have been induced in laboratory rodents by VCM. Estimation of the exposure levels likely to cause a lifetime risk of ASL of 10(-6) on the basis of these data give extremely low levels (down to 3.9 X 10(-7) ppb) which appear to be unrealistic estimates for man. Part of the reason for this is that laboratory studies have shown that VCM is metabolized in the liver (and elsewhere in the body) to the reactive metabolites chloroethylene oxide and chloroacetaldehyde. The rate of conversion is limited at high levels of exposure giving inaccurate estimates of the slope of the dose-response relationship.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Air Pollutants, Occupational; Animals; Dose-Response Relationship, Drug; Environmental Exposure; Female; Hemangiosarcoma; Humans; Kinetics; Liver Neoplasms; Male; Occupational Diseases; Registries; Risk; Vinyl Chloride; Vinyl Compounds
PubMed: 3549485
DOI: 10.1016/0278-6915(87)90153-0 -
Journal of Toxicology and Environmental... Sep 1975
Review
Topics: Aerosols; Animals; Biotransformation; Bone Diseases; Carcinogens; Chemical Phenomena; Chemistry; Chick Embryo; Dogs; Drug Hypersensitivity; Environmental Exposure; Guinea Pigs; Humans; Mutagens; Occupational Diseases; Occupational Medicine; Rabbits; Rats; Vinyl Chloride; Vinyl Compounds
PubMed: 1102724
DOI: 10.1080/15287397509529308 -
Proceedings of the Royal Society of... Apr 1976
Review
Topics: Adenoma; Animals; Ear Neoplasms; Guinea Pigs; Hemangiosarcoma; Liver Neoplasms; Lung Neoplasms; Mice; Neoplasms, Experimental; Rats; Thymus Neoplasms; Vinyl Chloride; Vinyl Compounds; Wilms Tumor
PubMed: 177986
DOI: No ID Found -
General Pharmacology 1978
Review
Topics: Animals; Dose-Response Relationship, Drug; Humans; Kinetics; Models, Biological; Vinyl Chloride; Vinyl Compounds
PubMed: 350701
DOI: 10.1016/0306-3623(78)90006-x -
International Archives of Occupational... 1983In a plant producing vinyl chloride by the emulsion method 200 workers who were exposed to vinyl chloride for 1 to 25 yr (mean 14), 58 (i.e. 29%) were free of complaints...
In a plant producing vinyl chloride by the emulsion method 200 workers who were exposed to vinyl chloride for 1 to 25 yr (mean 14), 58 (i.e. 29%) were free of complaints and nervous disturbances. An astheno-autonomic syndrome was found in 54 (i.e. 27%) and in 88 (i.e. 44%) in combination with positive neurological findings, i.e. pyramidal syndromes (in 52), cerebellar disturbances (in 38), trigeminal neuropathy (in 24) and extrapyramidal symptoms (in 3), in various combinations - pyramidal + cerebellar in 12, trigeminal + pyramidal in 7, trigeminal + cerebellar in 5. Headaches (48%), nervousness (26%), decrease in physical strength (16%), loss of memory (14%), sleeping disturbances and somnolence were the most frequent complaints. Scleroderma-like skin changes were found in ten subjects, but only six of them had any neurological disturbances. Occupational exposure to vinyl chloride was lower in workers without neurological findings. Frequency of the arterial hypertension was the same in both groups, whereas acroparesthesias, Raynaud's syndrome, and increased gamma GTP serum activity were significantly more frequent in workers with neurological disturbances. Sixty-two per cent of the neurologically positive group and only 24% of the negative group reported euphoric or narcotic states after exposure. This probably indicates episodic exposures to high concentrations of vinyl chloride. This difference points to a possibility that neurological disturbances may be related to short exposures to peak concentrations. The neurological injury may be both a direct neurotoxic effect of vinyl chloride and secondary to vascular disorders.
Topics: Adult; Air Pollutants, Occupational; Alcoholism; Blood Proteins; Female; Humans; Male; Middle Aged; Nervous System Diseases; Occupational Diseases; Smoking; Trigeminal Nerve; Vinyl Chloride; Vinyl Compounds
PubMed: 6629505
DOI: 10.1007/BF00405418