Fate of [14C]vinyl chloride after single oral administration in rats

Watanabe, P.G.; McGowan, G.R.; Gehring, P.J.

doi:10.1016/0041-008x(76)90013-2

Cited by 94 publications

(20 citation statements)

References 11 publications

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“…Alternatively, rapid in vivo approaches for determining metabolic constants can be used either based on steady-state (96) or gas uptake experiments (102-104, 106, 107). Determination of the total amount of chemical metabolized in a particular exposure situation can also be used to estimate metabolic parameters (109). In addition, determination of stable end-product metabolites after exposure can be a particularly attractive technique in some cases (108,110).…”

Section: Biochemical Parametersmentioning

confidence: 99%

Physiologically Based Pharmacokinetic/Toxicokinetic Modeling

Campbell

Clewell

Gentry

et al. 2012

Methods in Molecular Biology

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Physiologically based pharmacokinetic (PBPK) models differ from conventional compartmental pharmacokinetic models in that they are based to a large extent on the actual physiology of the organism. The application of pharmacokinetics to toxicology or risk assessment requires that the toxic effects in a particular tissue are related in some way to the concentration time course of an active form of the substance in that tissue. The motivation for applying pharmacokinetics is the expectation that the observed effects of a chemical will be more simply and directly related to a measure of target tissue exposure than to a measure of administered dose. The goal of this work is to provide the reader with an understanding of PBPK modeling and its utility as well as the procedures used in the development and implementation of a model to chemical safety assessment using the styrene PBPK model as an example.

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Section: Biochemical Parametersmentioning

confidence: 99%

Physiologically Based Pharmacokinetic/Toxicokinetic Modeling

Campbell

Clewell

Gentry

et al. 2012

Methods in Molecular Biology

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“…For animals administered 10 ppm within 6 hr, 68% of the 14C radioactivity was recovered from the urine and 2% in expired 14C-VCM. With single oral or intraperitoneal administration, low doses of VCM resulted in higher excretion of radioactivity in the urine and lower exhalation as 14C-VCM, while high dose levels resulted in the opposite pattern of elimination (17,18). Following a single intravenous injection of 250 uag/kg 14C-VCM, 80% of the radioactivity was detected within a few minutes in the exhaled air as unchanged VCM (18).…”

Section: Metabolismmentioning

confidence: 98%

“…Following a single intravenous injection of 250 uag/kg 14C-VCM, 80% of the radioactivity was detected within a few minutes in the exhaled air as unchanged VCM (18). Of the various tissues examined, the liver and skin retained the highest levels of radioactivity (16,17).…”

Section: Metabolismmentioning

confidence: 99%

“…The pharmacokinetics and tissue distribution of 14C-labeled VCM in rats exposed by various routes to different concentrations was reported by Watanabe et al (16,17). For animals exposed to 1000 ppm 14C-VCM for 6 hr, 56% of the radioactivity was excreted in urine, 12% was expired as VCM, 12% was expired as 14CO., and 4% was found in the feces within 72 hr.…”

Section: Metabolismmentioning

confidence: 99%

See 1 more Smart Citation

Mutagenicity and Metabolism of Vinyl Chloride and Related Compounds

Bartsch¹,

Malaveille²,

Barbin³

et al. 1976

Environmental Health Perspectives

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The various adverse biological effects of vinyl chloride appear to be dependent upon the metabolic conversion of this compound into chemically reactive metabolites. The metabolism of vinyl chloride in mammals and in man, including the formation of monochloroacetic acid and some identified sulfur conjugates is reviewed. Hepatic microsomal mixed function oxidases from rats, mice, and humans were equally effective in transforming vinyl chloride into alkylating agents in vitro. Two of the enzyme reaction products, i.e., chloroethylene oxide and 2-chloroacetaldehyde, showed potent genetic activity in microorganisms and Chinese hamster V79 cells. The role of liver microsomal enzymes in the generation of electrophilic mutagenic vinyl chloride metabolites is discussed.Chlorinated hydrocarbons, such as vinyl chloride (VCM) or vinylidene chloride, are widely used in the production of plastic resins and are present in the environment (1, 2). It is now recognized that VCM is responsible for various adverse biological effects which induce neoplastic and nonneoplastic diseases in man as well as in animals (2) and that these effects seem to be attributable not to VCM itself but to reactive metabolites formed by microsomal mixed-function oxidases. Many chemical carcinogens have been shown to exert a carcinogenic effect following their metabolic activation into elctrophilic metabolites which react readily with cellular macromolecules (3). This paper is a review of results obtained in our laboratory and by others concerning the mutagenicity of VCM and related compounds and the metabolism of some of these compounds. MutagenicityThe mutagenicity of VCM has been examined in various strains of S. typhimurium in which

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“…Results on exposure to low and high concentrations of VC and on pretreatment of the animals with metabolic inhibitors indicated that VC was metabolized by at least two pathways. More Table 1 shows the percentage of 14C-activity eliminated via various routes following different single oral doses of VC in corn oil to rats (2). The 14C-activity in urine, feces, and carcass and tissues represents nonvolatile metabolites of VC.…”

Section: Introductionmentioning

confidence: 99%

Dose-dependent fate of vinyl chloride and its possible relationship to oncogenicity in rats.

Watanabe¹,

Gehring²

1976

Environ Health Perspect

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Studies on the fate of 14C-labeled vinyl chloride (VC) following oral administration and inhalation exposure in rats demonstrated that the disposition of VC in the body is a function of the dose. More importantly, from the data available, it appears that a correlation exists between doses of VC which cause tumors and those that saturate metabolic or detoxifying pathways. Additional studies characterized the depression of liver nonprotein sulfhydryl content (primarily GSH) with the duration and concentration of exposure to VC. The results of these investigations indicate that statistical projections utilizing data collected from rats exposed to high doses of VC are invalid for predicting the hazard of low level exposure, because such projections violate the a priori assumption that the dynamics governing the fate of VC in the body are unaltered.

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Fate of [14C]vinyl chloride after single oral administration in rats

Cited by 94 publications

References 11 publications

Physiologically Based Pharmacokinetic/Toxicokinetic Modeling

Physiologically Based Pharmacokinetic/Toxicokinetic Modeling

Mutagenicity and Metabolism of Vinyl Chloride and Related Compounds

Dose-dependent fate of vinyl chloride and its possible relationship to oncogenicity in rats.

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