Carcinogenicity of Epoxides, Lactones, and Peroxy Compounds. III. Biological Activity and Chemical Reactivity

Duuren, Benjamin L. Van; Goldschmidt, B. M.

doi:10.1021/jm00319a020

Cited by 51 publications

(34 citation statements)

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“…2) indicate that although mortality due to exposure to 1,3-butadiene was concentration related, the multiple of exposure concentration times duration of exposure (CT) did not predict the probability of survival. Mortalities occurred at a greater rate for male mice exposed to 625 ppm 1,3-butadiene for 26 weeks, compared to 312 ppm for 52 weeks (equivalent total exposure), and for male mice exposed to 625 ppm for 13 weeks, compared to 200 ppm for 40 weeks.…”

Section: Introductionmentioning

confidence: 92%

Inhalation Toxicology and Carcinogenicity of 1,3-Butadiene in B6C3F 1 Mice Following 65 Weeks of Exposure

Melnick¹,

Huff²,

Roycroft³

et al. 1990

Environmental Health Perspectives

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1,3-Butadiene, a large-production volume chemical used mainly in the manufacture of synthetic rubber, was found to induce multiple-organ carcinogenicity in male and female B6C3F1 mice at exposure concentrations (625 and 1250 ppm) equivalent to and below the OSHA standard of 1000 ppm. Since this study was terminated after 60 weeks of exposure because of reduced survival due to fatal tumors, and because dose-response relationships for 1,3-butadiene-induced neoplastic and nonneoplastic lesions were not clearly established, a second long-term inhalation study of 1,3-butadiene in B6C3F1 mice was conducted at lower exposure concentrations, ranging from 6.25 to 625 ppm. Both the histopathological findings from animals dying through week 65 and the results of evaluations of animals exposed for 40 and 65 weeks are presented in this report. Exposure to 1,3-butadiene caused a regenerative anemia at concentrations of 62.5 ppm and higher. Testicular atrophy was induced at 625 ppm, and ovarian atrophy was observed at 20 ppm and higher. During the first 50 weeks of the study, lymphocytic lymphoma was the major cause of death of mice exposed to 625 ppm 1,3-butadiene. Neoplasms of the heart, forestomach, lung, Harderian gland, mammary gland, ovary, and liver were frequently observed in 1,3-butadiene-exposed mice that died between week 40 and week 65 of the study. Studies in which exposure to 1,3-butadiene was stopped after limited periods were also included to assess the relationship between exposure levels and duration of exposures on the outcome of 1,3-butadiene-induced carcinogenicity. In these studies, lymphocytic lymphomas were induced in male mice exposed to 625 ppm 1,3-butadiene for only 13 weeks. The incidence of lymphocytic lymphoma in male mice exposed to 625 ppm 1,3-butadiene for 26 weeks was two times that in mice exposed to 625 ppm for 13 weeks. However, when the exposure concentration was reduced by half to 312 ppm and the exposure duration extended to 52 weeks, the incidence of lymphocytic lymphoma was reduced by 90%. Thus, the multiple of the exposure concentration times the exposure duration did not predict the incidence of lymphocytic lymphoma in mice. The early mortalities resulting from lymphocytic lymphomas in male mice exposed to 625 ppm 1,3-butadiene limited the expression of tumors at other sites. A clearer dose-response for 1,3-butadieneinduced neoplasia should be apparent from experiments in mice exposed to lower concentrations of this chemical for 2 years.

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Section: Introductionmentioning

confidence: 92%

Inhalation Toxicology and Carcinogenicity of 1,3-Butadiene in B6C3F 1 Mice Following 65 Weeks of Exposure

Melnick¹,

Huff²,

Roycroft³

et al. 1990

Environmental Health Perspectives

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“…The butadiene metabolites epoxybutene and diepoxybutane are also carcinogenic and genotoxic in vivo (21)(22)(23)(24)(25). Diepoxybutane is a more potent carcinogen in mice than epoxybutene (21) and is nearly 100 times more mutagenic on a molar basis than epoxybutene in mammalian systems (26).…”

Section: Introductionmentioning

confidence: 99%

“…Diepoxybutane is a more potent carcinogen in mice than epoxybutene (21) and is nearly 100 times more mutagenic on a molar basis than epoxybutene in mammalian systems (26). Diepoxybutane also induces genetic damage in vitro in mammalian cells (Chinese hamster ovary cells and human peripheral blood lymphocytes) at lower concentrations than epoxybutene (27,28 appear to play major roles in the overall metabolism of butadiene: cytochrome P450 monooxygenase, epoxide hydrolase, and glutathione (GSH) S-transferase.…”

Section: Introductionmentioning

confidence: 99%

Biomonitoring of 1,3-butadiene and related compounds.

Osterman-Golkar

Bond²

1996

Environ Health Perspect

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The 1990 Clean Air Act Amendments list several volatile organic chemicals as hazardous air pollutants, including ethylene oxide, butadiene, styrene, and acrylonitrile. The toxicology of many of these compounds shares several common elements such as carcinogenicity in laboratory animals, genotoxicity of the epoxide intermediates, involvement of cytochrome P450 for metabolic activation (except ethylene oxide), and involvement of at least two enzymes for detoxication of the epoxides (e.g., hydrolysis or conjugation with glutathione). These similarities facilitate research strategies for identifying and developing biomarkers of exposure. This article reviews the current knowledge about biomarkers of butadiene. Butadiene is carcinogenic in mice and rats, which raises concern for potential carcinogenicity in humans. Butadiene is metabolized to DNAreactive metabolites, including 1,2-epoxy-3-butene and diepoxybutane. These epoxides are thought to play a critical role in butadiene carcinogenicity. Butadiene and some of its metabolites (e.g., epoxybutene) are volatile. Exhalation of unchanged butadiene and excretion of butadiene metabolites in urine represent major routes of elimination. Therefore, biomonitoring of butadiene exposure could be based on chemical analysis of butadiene in exhaled breath, blood levels of butadiene epoxides, excretion of butadiene metabolites in urine, or adducts of butadiene epoxides with DNA or blood proteins. Mutation induction in specific genes (e.g., HPRT) following butadiene exposure can be potentially used as a biomarker. Excretion of 1,2-dihydroxy-4-(N-acetylcysteinyl-S)butane or the product of epoxybutene with N-7 in guanine in urine, epoxybutene-hemoglobin adducts, and HPRT mutation have been used as biomarkers in recent studies of occupational exposure to butadiene. Data in laboratory animals suggest that diepoxybutane may be a more important genotoxic metabolite than epoxybutene. Biomonitoring methods need to be developed for diepoxybutane and other putative reactive butadiene metabolites. With butadiene and related compounds, the ultimate challenge is to identify useful biomarkers of exposure in which quantitative linkages between exposure and internal dose of the important DNA-reactive metabolites are established. Environ Health Perspect 104(Suppl 5): 907-915 (1996)

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“…The original comparative carcinogenicity data from 3 laboratories showed that K region epoxides were less potent than the parent hydrocarbons either when applied topically or when administered subcutaneously (Boyland and Sims, 1967;Sims, 1967;Miller and Miller, 1967;Van Duuren et al, 1967). More recent studies with epoxides in 2 in vitro transformation systems (Berwald and Sachs, 1963;Chen and Heidelberger, 1969) have demonstrated that several K region derivatives are more active than the corresponding hydrocarbons in inducing malignant transformation Marquardt et al, 1972;Huberman et al, 1972), but others are not (Marquardt et al, 1974).…”

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confidence: 99%

The carcinogenicity of polycyclic hydrocarbon epoxides in newborn mice

Grover¹,

Sims²,

Mitchley³

et al. 1975

Br J Cancer

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Summary.-Benz(a)anthracene injected subcutaneously during the first 3 days of life caused a dose related increase in the incidence of liver and lung tumours in Swiss mice but over a similar dose range, the K region epoxide of benz(a)anthracene was less effective. Neonatally injected 7-methylbenz(a)anthracene was considerably more active than its K region epoxide in increasing the incidence of liver tumours in males. Both the parent compound and the epoxide slightly raised the incidence of lung tumours. Both chrysene and its K region epoxide increased liver tumour incidence but not lung tumour incidence. The K region epoxides of dibenz(a,h) -anthracene and 3-methylcholanthrene were without apparent effect on the incidence of liver, lung or other tumours despite indications from previously reported studies that the parent hydrocarbons are active at the same dose levels. The K region epoxide of phenanthrene had no effect on the incidence of any kind of neoplasm.THE HYPOTHESIS that the carcinogenicity of polycyclic hydrocarbons is associated with the formation of epoxide metabolites (Grover, Hewer and Sims,

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Carcinogenicity of Epoxides, Lactones, and Peroxy Compounds. III. Biological Activity and Chemical Reactivity

Cited by 51 publications

References 1 publication

Inhalation Toxicology and Carcinogenicity of 1,3-Butadiene in B6C3F 1 Mice Following 65 Weeks of Exposure

Inhalation Toxicology and Carcinogenicity of 1,3-Butadiene in B6C3F 1 Mice Following 65 Weeks of Exposure

Biomonitoring of 1,3-butadiene and related compounds.

The carcinogenicity of polycyclic hydrocarbon epoxides in newborn mice

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