Risk of angiosarcoma in workers exposed to vinyl chloride as predicted from studies in rats

Gehring, P.J.; Watanabe, P.G.; Park, C.N.

doi:10.1016/0041-008x(79)90271-0

Cited by 55 publications

(18 citation statements)

References 12 publications

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“…The metabolism/pharmacokinetics of VC by inhalation has been extensively studied (Bolt et al, 1977Withey, 1976;Bolt, 1979, 1981;Watanabe et al, 1976Watanabe et al, , 1978aGehring et al, 1978Gehring et al, , 1979. It has been shown (Withey, 1976;Bolt et al, 1977) that rats exposed to VC in air (I00 to 7,000 ppm) for 5 hours rapidly reached air/blood equilibrium within 15 to 30 minutes, and the blood concentration of VC declined Gehring et al (1978).…”

Section: Pb-pk Modeling For Vcmentioning

confidence: 99%

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Incorporation of biological information in cancer risk assessment: Example ? Vinyl chloride

Chen

Blancato

1989

Cell Biol Toxicol

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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.

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Section: Pb-pk Modeling For Vcmentioning

confidence: 99%

“…The fate of VC and its metabolites following inhaled lac-vc at various exposure concentrations in rats had been investigated by Watanabe et al (1976) and Gehring et al (1978Gehring et al ( , 1979. Table 1 gives the total amount of the dose metabolized at various exposure concentrations by inhalation.…”

Section: Pb-pk Modeling For Vcmentioning

confidence: 99%

Incorporation of biological information in cancer risk assessment: Example ? Vinyl chloride

Chen

Blancato

1989

Cell Biol Toxicol

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“…An increasing fraction is exhaled because the oxidation pathway responsible for the activation of vinyl chloride to a chemically active metabolite becomes saturated. When the fraction of animals with angiosarcoma was plotted as a function of the metabolite concentration, an apparently linear relationship (without saturation) was obtained, although Gehring et al (51,52) report that this effective dose versus response plot was also consistent with a probit formula. However, the concentration of active metabolite may or may not be linear with applied dose at low doses, for no adequate measurements of the metabolite at exposures comparable to environmental exposures have been made.…”

mentioning

confidence: 97%

“…Gehring et al (51,52) used animal data to estimate the relationship between the amount of vinyl chloride entering the body and the amount of active (carcinogenic) metabolite formed, that is an ef- Table 16. Osteosarcomas in female mice after ID injections of "4Ra (188 (Weeks) i (36) detailed multistage model (Eq.…”

Section: Large Experimentsmentioning

confidence: 99%

Dose-response relationships for carcinogens: a review.

Zeise

Wilson

Crouch

1987

Environ Health Perspect

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We review the experimental evidence for various shapes of dose-response relationships for carcinogens and summarize those experiments that give the most information on relatively low doses. A brief review of some models is given to illustrate the shapes of dose-response curve expected from them. Our major interest is in the use of dose-response relationships to estimate risks to humans at low doses, and so we pay special attention to experimentally observed and theoretically expected nonlinearities. There are few experimental examples of nonlinear dose-response relations in humans, but this may simply be due to the limitations in the data. The several examples in rodents, even though for high dose data, suggest that nonlinearity is common. In some cases such nonlinearities may be rationalized on the basis of the pharmacokinetics of the test compound or its metabolites. IntroductionThe primary reason for the authors' interest in doseresponse relationships for carcinogens is the need to estimate human risks at low doses. Typically, the only data available are the results of animal experiments at high doses, perhaps augmented by scanty epidemiological information (together with test results from a battery of short-term tests, which are not considered further here). Conclusive demonstration of the existence or nonexistence of certain aspects of dose-response relationships for carcinogens would greatly ease the task of risk assessment, in turn making regulation of carcinogens, and the explanation of such regulation, simpler. For example, if a threshold dose, below which there is no response, exists, then exposure up to that threshold would clearly pose no risk. Evidently, there are many other reasons for study of dose-response relationships at all doses, but in this review we concentrate on the lowest doses that give experimentally measurable response. In particular, we are interested in the extent to which measurable dose-response curves for cancers .deviate from linearity.This review surveys the relevant human ("Human Studies") and whole animal ("Animal Studies") experimental data on carcinogenesis at relatively low doses, with an outline of theories that have been advanced and remain consistent with this data ("Dose-Response For- mulae"). Of special interest are the observed nonlinearities in dose-response relationships, and the possible explanations for them.Most models of the cancer process are constructed by describing (mathematically) a set of elementary biological processes which are supposed to be fundamental. The effect of doses of carcinogens on these elementary processes is generally assumed to be the simplest possible (e.g., described by a chemical reaction rate), but the dose-response relationship for the whole model will usually be as arbitrary as the assumptions made for these elementary processes. Many of the mathematical models suggested are expressions of the biological idea of a multistage process. We demonstrate how many different dose-response formulae can be obtained within this one framework, ...

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“…While toxicologists must face the dangerous business of extrapolation from animals studies to man, the epidemiologist is never certain about exposure levels and the many variables which may have been overlooked. Despite such difficulties a variety of models for data analysis have been proposed and used in toxicological as well as epidemiological studies (1,2). Assuming for a moment that such models permit us to extrapolate from toxicological data obtained in long-term chronic studies (2) within reason-and it looks that way-the long-term chronic study remains to be done.…”

Section: Introductionmentioning

confidence: 99%

Dose-response analysis in animal studies: prediction of human responses.

Alarie¹

1981

Environ Health Perspect

126

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An animal bioassay has been used to evaluate a series of airborne chemicals for their sensory irritating properties to the upper respiratory tract. Teh results obtained can be used to rank their potency. An attempt has been made to predict "safe" levels of exposure for humans on the basis of this short-term assay. A good correlation was obtained between the predicted "safe" levels of exposure and current Threshold Limit Values established for industrial exposures.

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Risk of angiosarcoma in workers exposed to vinyl chloride as predicted from studies in rats

Cited by 55 publications

References 12 publications

Incorporation of biological information in cancer risk assessment: Example ? Vinyl chloride

Incorporation of biological information in cancer risk assessment: Example ? Vinyl chloride

Dose-response relationships for carcinogens: a review.

Dose-response analysis in animal studies: prediction of human responses.

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