Influence of Experimental Factors on the Mutagenicity of Vinylic Monomers

Poncelet, F.; Meester, Conrad De; Bogaert, M. Duverger-van; Lambotte-Vandepaer, M.; Roberfroid, Marcel; Mercier, Michel

doi:10.1007/978-3-642-67729-8_14

Cited by 21 publications

(3 citation statements)

References 4 publications

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“…1,3-Butadiene has been shown to be genotoxic in the Salmonella mutation assay (18)(19)(20) and in vivo in mice (21)(22)(23); it is, however, negative in rats (21). Since 1,3-butadiene must be metabolized to exhibit genotoxicity (19), the metabolic competence of different species may determine the putative hazard in that species.…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Genotoxicity of 1,3-Butadiene and Metabolites

Arce¹,

Vincent²,

Cunningham³

et al. 1990

Environmental Health Perspectives

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1,3-Butadiene and two major genotoxic metabolites 3,4-epoxybutene (EB) and 1,2:3,4-diepoxybutane (DEB) were used as model compounds to determine if genetic toxicity findings in animal and human cells can aid in extrapolating animal toxicity data to man. Sister chromatid exchange (SCE) and micronucleus induction results indicated 1,3-butadiene was genotoxic in the bone marrow of the mouse but not the rat. This paralleled the chronic bioassays which showed mice to be more susceptible than rats to 1,3-butadiene carcinogenicity. However, 1,3-butadiene did not induce unscheduled DNA synthesis (UDS) in the rat or mouse hepatocytes following in vivo exposure. Likewise, UDS in rat and mouse hepatocytes in vitro was not induced by EB or DEB. Salmonella typhimurium gene mutation (Ames) tests of 1,3-butadiene using strains TA1535, TA97, TA98, and TA100 and employing rat, mouse, and human liver S9 metabolic systems were barely 2-fold above background only in strain TA1535 at 30%o 1,3-butadiene in air with induced and uninduced rat S9 and mouse S9 (uninduced). 1,3-Butadiene was negative in in vitro SCE studies in human whole blood lymphocytes cultures treated in the presence of rat, mouse, or human liver S9 metabolic activation. In general, 1,3-butadiene is genotoxic in vivo but is a weak in vitro genotoxin.

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Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Genotoxicity of 1,3-Butadiene and Metabolites

Arce¹,

Vincent²,

Cunningham³

et al. 1990

Environmental Health Perspectives

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“…Studies on the genotoxicity of 1,3-butadiene have indicated that 1,3-butadiene itself is not mutagenic in bacteria (27,28). Both of its putative metabolites, 3,4-epoxybutene and 1,2:3,4-diepoxybutane, however, are (29-32).…”

Section: Genotoxicity Of 13-butadienementioning

confidence: 99%

Assessment of the Potential Risk to Workers from Exposure to 1,3-Butadiene

Turnbull¹,

Rodricks²,

Brett³

1990

Environmental Health Perspectives

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The available epidemiologic data provide equivocal evidence that 1,3-butadiene is carcinogenic in humans; some available studies suggest that the lymphopoietic system is a target, but there are inconsistencies among studies in the types of tumors associated with 1,3-butadiene exposure, and there is no evidence of a relationship between length of exposure and cancer risk, as one might expect if there was a true causal relationship between 1,3-butadiene exposure and cancer risk. The available chronic animal studies, however, show an increase in tumor incidence associated with exposure to high concentrations of 1,3-butadiene. In addition to the general uncertainty ofthe relevance of animal data to humans, there are several additional reasons why the National Toxicology Program's mouse study may not be appropriate for assessing possible human risks. These include: a) the possible involvement of a species-specific tumor virus (MuLV) in the response in mice; b) apparent differences between mice and humans in the rate of metabolism of 1,3-butadiene to reactive epoxides that may be proximate carcinogens; c) use of high dose levels that caused excess early mortality; and d) exposure of animals to 1,3-butadiene for only about half their lifetime. While recognizing the uncertainty in using the available animal data for risk assessment, we have performed low-dose extrapolation ofthe data to examine the implications of the data if humans were as sensitive as rats or mice to 1,3-butadiene, and to examine how the predictions of the animal data compare to that observed in the epidemiologic studies. With the mouse data, because the study was of less than lifetime duration, we have used the Hartley-Sielken time-to-tumor model to permit estimation of lifetime risk from the less than lifetime exposure of the study. With the rat data, we have used three plausible models for assessing low-dose risk: the multistage model, the Weibull model, and the Mantel-Bryan probit model. With both the rat and mouse data, we used information on how much 1,3-butadiene is retained by animals exposed to various concentrations of the chemical. This improves the accuracy of the low-dose extrapolation. When extrapolated to low-dose levels, mice appear to be at greater risk (by a factor of 5-fold to 40-fold) than rats. Some of this difference (a factor 3-fold to 5-fold) may be due to the faster rate of metabolism of 1,3-butadiene to, and higher blood levels of, epoxide derivatives in mice than in rats. If humans, rats, and mice were at equal risk from equal average lifetime daily doses of retained 1,3-butadiene, the mouse and rat data would predict risks to occupationally exposed humans that are statistically inconsistent at the 95% level with the results of the available human data, unless human exposure in the past was very much lower than is believed to have been the case.

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“…BD displays mutagenic activity in Salmonella typhimurium, but only in the presence of hepatic 9000g supernatant (11)(12)(13), indicating that BD is not mutagenic but that its metabolites, possibly 1,2-epoxybut-3-ene (butadiene monoepoxide; BMO) and/or butadiene diepoxide (BDE), are responsible for the observed bacterial mutagenicity. BD is also genotoxic in vivo, inducing chromosome aberrations and sister chromatid exchanges in bone marrow cells and micronucleus formation in peripheral blood of male B6C3F1 mice (14,15), but not in Sprague-Dawley rats (15).…”

Section: Introductionmentioning

confidence: 99%

1,3-Butadiene: linking metabolism, dosimetry, and mutation induction.

Bond

Csanády

Gargas

et al. 1994

Environ Health Perspect

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There is increasing concern for the potential adverse health effects of human exposures to chemical mixtures. To better understand the complex interactions of chemicals within a mixture, it is essential to develop a research strategy which provides the basis for extrapolating data from single chemicals to their behavior within the chemical mixture. 1,3-Butadiene (BD) represents an interesting case study in which new data are emerging that are critical for understanding interspecies differences in carcinogenic/genotoxic response to BD. Knowledge regarding mechanisms of BD-induced carcinogenicity provides the basis for assessing the potential effects of mixtures containing BD. BD is a multisite carcinogen in B6C3F1 mice and Sprague-Dawley rats. Mice exhibit high sensitivity relative to the rat to BD-induced tumorigenesis. Since it is likely that BD requires metabolic activation to mutagenic reactive epoxides that ultimately play a role in carcinogenicity of the chemical, a quantitative understanding of the balance of activation and inactivation is essential for improving our understanding and assessment of human risk following exposure to BD and chemical mixtures containing BD. Transgenic mice exposed to 625 ppm BD for 6 hr/day for 5 days exhibited significant mutagenicity in the lung, a target organ for the carcinogenic effect of BD in mice. In vitro studies designed to assess interspecies differences in the activation of BD and inactivation of BD epoxides reveal that significant differences exist among mice, rats, and humans. In general, the overall activation/detoxication ratio for BD metabolism was approximately 10-fold higher in mice compared to rats or humans. A preliminary physiological dosimetry model was developed for BD. The model simulations for the in vitro Vmax and Km for BD oxidation compare favorably with the metabolic rate constants that were determined from the in vitro studies when the in vitro values were adjusted to account for microsomal content and liver weight in the intact animal. This favorable comparison suggests that in vitro biochemical parameters derived for BD could be used to predict in vivo metabolism. Using the physiological dosimetry model developed for BD, potential interactions of BD with other chemicals in the workplace (e.g., BD/styrene), the environment (e.g., BD/benzene), or through certain dietary influences (e.g., BD/ethanol) were explored. The three examples of simulations of BD chemical mixtures suggest two important general points regarding chemical interactions. The first relates to extrapolations from high to low doses. Due to the saturable enzyme systems that metabolize most toxic organic chemicals, it cannot be assumed that the inhibition effects demonstrated at high exposure concentrations will be proportional, or even significant, at low exposure concentrations. Second, patterns of enzyme induction determined in vitro may not exhibit the same magnitude of effect in the intact animal. Delivery of the chemical to the site of the enzyme chemical interaction may be, i...

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Influence of Experimental Factors on the Mutagenicity of Vinylic Monomers

Cited by 21 publications

References 4 publications

In Vitro and In Vivo Genotoxicity of 1,3-Butadiene and Metabolites

In Vitro and In Vivo Genotoxicity of 1,3-Butadiene and Metabolites

Assessment of the Potential Risk to Workers from Exposure to 1,3-Butadiene

1,3-Butadiene: linking metabolism, dosimetry, and mutation induction.

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