Comparison of the fate of vinyl chloride following single and repeated exposure in rats

Watanabe, P.G.; Zempel, J.A.; Gehring, P.J.

doi:10.1016/0041-008x(78)90199-0

Cited by 17 publications

(5 citation statements)

References 13 publications

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“…In addition, chloroacetaldehyde (and possibly also chlorooxirane) interacts difunctionally, losing both the chlorine and the oxygen and forming bonds to two sites on the substrate, yielding such products as ethenoadenine and ethenocytosine [23-261. In view of these observations, it is reasonable to anticipate that chlorooxirane and chloroacetaldehyde will alkylate cellular macromolecules, including DNA, and to suggest that some reaction of this sort may be the basis for the mutagenic and carcinogenic activity of vinyl chloride [16][17][18]. Indeed, evidence that vinyl chloride metabolites do alkylate cellular macromolecules has been reported [21,27,28]. Accordingly, both chlorooxirane and chloroacetaldehyde have been proposed as possible ultimate carcinogens, responsible for the carcinogenic action of vinyl chloride [ll, 13, 16, 18,251; it now appears to be most likely, however, that chlorooxirane, but not chloroacetaldehyde, is a carcinogenically reactive form of vinyl chloride [29,30].…”

Section: Metabolic Behavior Of Vinyl Chloridementioning

confidence: 99%

Calculated properties of some possible vinyl chloride metabolites

Politzer

Proctor

1982

Int J of Quantum Chemistry

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There is considerable evidence indicating that the carcinogenic action of vinyl chloride involves metabolic conversion to the epoxide (chlorooxirane) as the initial step. In order to learn more about its subsequent behavior, we have computed structures, energies and other properties for two different protonated forms of the epoxide, and also for two possible rearrangement products, chloroacetaldehyde and acetyl chloride. An ab initio SCF-MO procedure (GAUSSIAN 70) was used. Oxygen protonation is found to weaken both C -0 bonds, the effect being greater for the bond involving the carbon bearing the chlorine. Chlorine protonation leads to a marked weakening of the C-CI bond; this suggests a possible loss of HCI, leaving behind a carbonium ion (and possible alkylating agent or rearrangement precursor). Thus, while C-0 bond breaking is doubtless an important reaction pathway for chlorooxirane, our results indicate that attention should also be focused upon the C-CI bond; its rupture may conceivably be a key step in the biological action of vinyl chloride.

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Section: Metabolic Behavior Of Vinyl Chloridementioning

confidence: 99%

Calculated properties of some possible vinyl chloride metabolites

Politzer

Proctor

1982

Int J of Quantum Chemistry

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“…The relationship between TCDD (dioxin) exposure (measured in the plasma of the exposed workers) and total mortality from cancer 3 shows a plateauing of the curve, i.e., an effect that is proportionally greater at lower levels of exposure. Other examples are liver tumours and vinyl chloride in rats 4 or lung cancer and arsenic in humans. 5 However, it should be noted that these are heterogeneous situations, concerning both mutagens like vinyl chloride and chemicals like TCDD and arsenic that have multiple mechanisms of action, such as Ah receptor induction or DNA repair inhibition.…”

mentioning

confidence: 99%

Dose‐response relationship in tobacco‐related cancers of bladder and lung: A biochemical interpretation

Víneis

Alavanja

Garte

2003

Intl Journal of Cancer

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The purpose of our study is to address the challenge of evaluating carcinogenic effects at low levels of exposure to carcinogens. We examine the shape of the dose-response relationship between tobacco smoking and cancers of the bladder and lung, and the implications for the evaluation of the effects of exposure at lower levels, for example, environmental tobacco smoke (ETS). DOSE-RESPONSE RELATIONSHIPS IN TOBACCO CARCINOGENESIS: BLADDER AND LUNG CANCERThe fact that low doses of tobacco may have a carcinogenic effect proportionally greater than high doses is suggested by the study of dose-response relationships. A previous study, based on the re-analysis of a multicenter case-control study on lung cancer and of several studies on bladder cancer, 1 suggested that the dose-response relationship between cigarette smoking and cancer risk tends to level off after a dose of approximately 20 -25 cigarettes/day. A few explanations were put forward to explain leveling off, including bias (less accurate reporting by heavy smokers with cancer), lower inhalation at high doses or genetic heterogeneity of the population, with a "depletion of susceptibles" at low-dose levels. To test the latter hypothesis, we have reviewed the recent studies on smoking and bladder cancer, a type of tumour that is particularly well studied from a biochemical-molecular point of view (Tables I and II).We have identified all the cohort or case-control studies on smoking and bladder cancer published from 1985 to 2002 (those published before were reviewed in the IARC Monograph on tobacco smoking 2 ). We have considered men only because data for women tended to be unstable. We have extracted dose-response data, showing odds ratios and 95% confidence intervals whenever possible. Table I shows the results of case-control studies, and Table II those of cohort studies. Virtually all studies, except 1 case-control (Momas et al., 1994) and 2 cohort studies (Engeland et al., 1996;Tulinius et al., 1997), show a leveling off after 20 -30 cigarettes/day. Engeland et al. (1996) and Tulinius et al. (1997) show an attenuation of the slope but not a clear leveling off. The consistency between the 2 different designs suggests that we are observing a real phenomenon and not an artifact because different types of bias occur in case-control and in cohort investigations. In fact, only the former design is prone to retrospective recall bias, with underestimation of heavy consumption by cancer cases.There are other examples in the literature in which the shape of the dose-response relationship levels off. The relationship between TCDD (dioxin) exposure (measured in the plasma of the exposed workers) and total mortality from cancer 3 shows a plateauing of the curve, i.e., an effect that is proportionally greater at lower levels of exposure. Other examples are liver tumours and vinyl chloride in rats 4 or lung cancer and arsenic in humans. 5 However, it should be noted that these are heterogeneous situations, concerning both mutagens like vinyl chloride and chemicals like...

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“…Generally, as the dose increases, the proportion of unchanged vinyl chloride exhaled also increases. 43 At low exposure levels, the majority (ca.70% of the vinyl chloride is excreted in the urine.3y…”

Section: Absorption-metabolism+xcretionmentioning

confidence: 99%