Human cancer risk and exposure to 1,3-butadiene - a tale of mice and men

Lt, Stayner; Da, Dankovic; Rj, Smith; Sj, Gilbert; Bailer, A. John

doi:10.5271/sjweh.549

Cited by 11 publications

(13 citation statements)

References 25 publications

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“…Although DEB is a relatively minor metabolite of BD, it is hypothesized to be the ultimate carcinogenic species of BD based on its proven genotoxic potency and the ability to induce bifunctional DNA adducts (7,42–44). In previous studies, we have identified three types of DEB-specific DNA adducts, bis -N7G-BD, N7G-N1A-BD, and 1,N 6 -HMHP-dA (9,10,12,20), and developed quantitative HPLC-ESI-MS/MS methods for their analyses in tissues of laboratory rodents treated with BD by inhalation (13,14,16).…”

Section: Discussionmentioning

confidence: 99%

Persistence and Repair of Bifunctional DNA Adducts in Tissues of Laboratory Animals Exposed to 1,3-Butadiene by Inhalation

Goggin

Sangaraju

Walker

et al. 2011

Chem. Res. Toxicol.

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1,3-butadiene (BD) is an important industrial and environmental chemical classified as a human carcinogen. The mechanism of BD-mediated cancer is of significant interest because of the widespread exposure of humans to BD from cigarette smoke and urban air. BD is metabolically activated to 1,2,3,4-diepoxybutane (DEB), which is a highly genotoxic and mutagenic bis-alkylating agent believed to be the ultimate carcinogenic species of BD. We have previously identified several types of DEB-specific DNA adducts, including bis-N7-guanine cross-links (bis-N7-BD), N6-adenine-N7-guanine cross-links (N6A-N7G-BD), and 1,N6-dA exocyclic adducts. These lesions were detected in tissues of laboratory rodents exposed to BD by inhalation (Goggin et al. Cancer Res. 2009;69:2479–2486). In the present work, persistence and repair of bifunctional DEB-DNA adducts in tissues of mice and rats exposed to BD by inhalation were investigated. The half-lives of the most abundant cross-links, bis-N7G-BD, in mouse liver, kidney, and lungs were 2.3–2.4 days, 4.6–5.7 days, and 4.9 days, respectively. The in vitro half-lives of bis-N7G-BD were 3.5 days (S,S isomer) and 4.0 days (meso isomer) due to their spontaneous depurination. In contrast, tissue concentrations of the minor DEB adducts, N7G-N1A-BD and 1,N6-HMHP-dA, remained essentially unchanged during the course of the experiment, with an estimated t 1/2 of 36–42 days. No differences were observed between DEB-DNA adduct levels in BD-treated wild type mice and the corresponding animals deficient in methyl purine glycosylase or the Xpa gene. Our results indicate that DEB-induced N7G-N1A-BD and 1,N6-HMHP-dA adducts persist in vivo, potentially contributing to mutations and cancer observed as a result of BD exposure.

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Section: Discussionmentioning

confidence: 99%

Persistence and Repair of Bifunctional DNA Adducts in Tissues of Laboratory Animals Exposed to 1,3-Butadiene by Inhalation

Goggin

Sangaraju

Walker

et al. 2011

Chem. Res. Toxicol.

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“…The discrepancy will be even larger if mortality due to the eVect of the exposure of interest on other causes of death is high. Since calculation of life table risk is straightforward and available (e.g., Steenland et al, 1998), this is the preferred method and is therefore presented as the only possible approach in many reports (e.g., Canadian Environmental Protection Act, 2000; Stayner et al, 1995Stayner et al, , 2000Thomas et al, 1992). Nevertheless, life table risk can be replaced by conditional risk if the background rate of the disease and the potency of the substance are low or if the age for which the risk is considered relevant is relatively young (<70 years).…”

Section: Step 3: Converting the Rr To An Elr As Function Of Exposure mentioning

confidence: 99%

“…For example, the US EPA establishes an eVective dose (ED), which is the level of exposure associated with a speciWed level of excess risk in the range of observations (e.g., 10, 1, or 0.1%) (U.S. Environmental Protection Agency, 2005). Through linear extrapolation, i.e., by connecting the observed ED with the origin (no exposure/no excess risk), the risk per unit of exposure can be derived (e.g., Stayner et al, 2000). In general, the risk assessor has to decide from which point in the curve such extrapolation has to be carried out.…”

Section: Step 3: Converting the Rr To An Elr As Function Of Exposure mentioning

confidence: 99%

Risk estimation for carcinogens based on epidemiological data: A structured approach, illustrated by an example on chromium

Goldbohm

Tielemans

Heederik

et al. 2006

Regulatory Toxicology and Pharmacology

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“…It is also an environmental toxin present in automobile exhaust and in cigarette smoke (2,3). BD is classified as a human carcinogen based on laboratory animal data linking it to the formation of tumors, human epidemiology data revealing increased incidence of leukemia and lymphohematopoietic cancers in occupationally exposed workers, and genotoxicity data for laboratory animals demonstrating the induction of point mutations, large deletions, and chromosomal aberrations following exposure to BD (4–8). Due to the ubiquitous human exposures to BD, there is a pressing need to identify biomarkers of BD exposure for use in quantitative risk assessment.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dosimetry of 1,2,3,4-Diepoxybutane–Induced DNA-DNA Cross-Links in B6C3F1 Mice and F344 Rats Exposed to 1,3-Butadiene by Inhalation

et al. 2009

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Abstract1,3-Butadiene (BD) is an important industrial and environmental chemical classified as a human carcinogen based on epidemiologic studies in occupationally exposed workers and animal studies in laboratory rats and mice. BD is metabolically activated to three epoxides that can react with nucleophilic sites in biomolecules. Among these, 1,2,3,4-diepoxybutane (DEB) is considered the ultimate carcinogen due to its high genotoxicity and mutagenicity attributed to its ability to form DNA-DNA cross-links. Our laboratory has developed quantitative high-performance liquid chromatography-MESI + -tandem mass spectrometry methods for two DEB-specific DNA-DNA cross-links, 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) and 1-(guan-7-yl)-4-(aden-1-yl)-2,3-butanediol (N7G-N1A-BD). This report describes molecular dosimetry analysis of these adducts in tissues of B6C3F1 mice and F344 rats exposed to a range of BD concentrations (0-625 ppm). Much higher (4-to 10-fold) levels of DEB-DNA crosslinks were observed in mice compared with rats exposed to the same BD concentrations. In both species, bis-N7G-BD levels were 1.5-to 4-fold higher in the liver than in other tissues examined. Interestingly, tissues of female animals exposed to BD contained higher concentrations of bis-N7G-BD adducts than tissues of male animals, which is in accord with previously reported differences in tumor incidence. The molecular dosimetry data presented herein suggest that species and gender differences observed in BD-induced cancer are directly related to differences in the extent of BD metabolism to DEB. Furthermore, a rat model of sensitivity to BD may be more appropriate than a mouse model for assessing human risk associated with BD exposure, because rats and humans seem to be similar with respect to DEB formation.

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Human cancer risk and exposure to 1,3-butadiene - a tale of mice and men

Cited by 11 publications

References 25 publications

Persistence and Repair of Bifunctional DNA Adducts in Tissues of Laboratory Animals Exposed to 1,3-Butadiene by Inhalation

Persistence and Repair of Bifunctional DNA Adducts in Tissues of Laboratory Animals Exposed to 1,3-Butadiene by Inhalation

Risk estimation for carcinogens based on epidemiological data: A structured approach, illustrated by an example on chromium

Molecular Dosimetry of 1,2,3,4-Diepoxybutane–Induced DNA-DNA Cross-Links in B6C3F1 Mice and F344 Rats Exposed to 1,3-Butadiene by Inhalation

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