Vinyl chloride: An assessment of the risk of occupational exposure

Purchase, I. F. H.; Stafford, Jason; Paddle, G.M.

doi:10.1016/0278-6915(87)90153-0

Cited by 31 publications

(11 citation statements)

References 30 publications

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“…Over the years, the vinyl chloride case has also been developed as a key example for the integration of mechanistic data and other biological information into human cancer risk assessment (Anderson et al, 1980;Purchase et al, 1987;Chen and Blancato, 1988;Green, 1990;Whysner et al, 1996;Albertini et al, 2004;Streffer et al, 2004).…”

mentioning

confidence: 98%

Vinyl Chloride—A Classical Industrial Toxicant of New Interest

Bolt

2005

Critical Reviews in Toxicology

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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 physiolo...

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confidence: 98%

Vinyl Chloride—A Classical Industrial Toxicant of New Interest

Bolt

2005

Critical Reviews in Toxicology

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“…For example, the number of workers exposed to VC has been estimated to be approximately 80 (Table 3). Some VC workers, autoclave cleaners in particular, were estimated to be exposed to as much as 1,000 ppm (2,600 mg/m3) in the 1950s and earlier (85)(86)(87)(88)(89).…”

Section: Occupational Exposure Levelsmentioning

confidence: 99%

Vinyl Chloride: Still a Cause for Concern

Kielhorn¹,

Melber²,

Wahnschaffe³

et al. 2000

Environmental Health Perspectives

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“…Vinyl chloride is a known human and rodent carcinogen and causes hepatic angiosarcomas (1,2). It is metabolized by the human liver P450 system (3) to the reactive unstable intermediate chloroethylene oxide, which rearranges rapidly to the more stable bifunctional carcinogen chloroacetaldehyde (CAA) (4).…”

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confidence: 99%

All four known cyclic adducts formed in DNA by the vinyl chloride metabolite chloroacetaldehyde are released by a human DNA glycosylase.

Dosanjh

Chenna

Kim

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

149

100

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We have previously reported that human cels and tissues contain a 1,N-ethenoadenine (EA) binding protein, which, tuh glycosylase activity, releases both 3-ethyladine (m3A) and eA from DNA treated with methylating agents or the vinyl chloride metabolite chloroacetaldehyde, respectively. We now find that both the partially purified human eA-binding pren and cell-free extracts contaiing the cloned human m3A-DNA glycosylase release all four cyclic etheno adducts-namely eA, 3,N4-ethenoCyte (eC), N2,3-ethen aine (N2,3-eG), and l,N2-ethenoguanine (1,N2-eG). Base

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Vinyl chloride: An assessment of the risk of occupational exposure

Cited by 31 publications

References 30 publications

Vinyl Chloride—A Classical Industrial Toxicant of New Interest

Vinyl Chloride—A Classical Industrial Toxicant of New Interest

Vinyl Chloride: Still a Cause for Concern

All four known cyclic adducts formed in DNA by the vinyl chloride metabolite chloroacetaldehyde are released by a human DNA glycosylase.

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