Induction of DNA adducts in vivo in rat lung cells by fume condensates of roofing asphalt

Qian, Honglan; Ong, T.; Nath, J.; Whong, Wen‐Zong

doi:10.1002/(sici)1520-6866(1998)18:3<131::aid-tcm4>3.0.co;2-h

Cited by 17 publications

(5 citation statements)

References 29 publications

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“…There are a variety of possible explanations for these effects. First, WBCs might not be a suitable target cell for bitumen effects as shown in experimental animals where bitumen condensate binds covalently to DNA in lung cells but not in WBCs of rats (16). Second, these unspecific DNA adducts might represent other influences than occupational exposure, such as physical activity, during work.…”

Section: Discussionmentioning

confidence: 99%

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Assessment of DNA Damage in WBCs of Workers Occupationally Exposed to Fumes and Aerosols of Bitumen

Marczyński

Raulf‐Heimsoth²,

Preuss³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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We conducted a cross-shift study with 66 bitumen-exposed mastic asphalt workers and 49 construction workers without exposure to bitumen. Exposure was assessed using personal monitoring of airborne bitumen exposure, urinary 1-hydroxypyrene (1-OHP), and the sum of 1-, 2 + 9 -,3-,4-hydroxyphenanthrene (OHPH). Genotoxic effects in WBC were determined with nonspecific DNA adduct levels of 8-oxo-7, 8-dihydro-2V-deoxyguanosine (8-oxodGuo) and the formation of DNA strand breaks and alkali-labile sites. Concentration of fumes and aerosols of bitumen correlated significantly with the concentrations of 1-OHP and OHPH after shift (r s = 0.27; P = 0.03 and r s = 0.55; P < 0.0001, respectively). Bitumen-exposed workers had more DNA strand breaks than the reference group (P < 0.0001) at both time points and a significant correlation with 1-OHP and OHPH in the postshift urines (r s = 0.32; P = 0.001 and r s = 0.27; P = 0.004, respectively). Paradoxically, we measured higher levels of DNA strand breaks, although not significant, in both study groups before shift. 8-OxodGuo adduct levels did not correlate with DNA strand breaks. Further, 8-oxodGuo levels were associated neither with personal exposure to bitumen nor with urinary metabolite concentrations. Significantly more DNA adducts were observed after shift not only in bitumen-exposed workers but also in the reference group. Only low-exposed workers had significantly elevated 8-oxodGuo adduct levels before as well as after shift (P = 0.0002 and P = 0.02, respectively). Our results show that exposure to fumes and aerosols of bitumen may contribute to an increased DNA damage assessed with strand breaks.

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Section: Discussionmentioning

confidence: 99%

“…In experimental animals, exposure to asphalt fume was genotoxic to alveolar macrophages, as revealed by DNA migration in the Comet assay, but no micronuclei formation was detected (15). Further, bitumen condensate binds covalently to DNA in lung cells but not in WBCs of rats (16).…”

Section: Introductionmentioning

confidence: 94%

Assessment of DNA Damage in WBCs of Workers Occupationally Exposed to Fumes and Aerosols of Bitumen

Marczyński

Raulf‐Heimsoth²,

Preuss³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Likewise, in the study by Qian et al (56) and in the investigation by GenevoisCharmeau et al (55) DNA adducts could not be identified in WBC therefore demonstrating a significant limitation in the use of WBC instead of target tissue for the study of genotoxicity. Noteworthy, in humans no increase in WBC DNA-adduct is common for many PAHs and along with our own data suggests WBC to be a poor surrogate for the target tissue in human biomonitoring.…”

Section: Genotoxicity Of Bitumen Fumesmentioning

confidence: 98%

Importance of DNA-Adduct Formation and Gene Expression Profiling of Disease Candidate Genes in Rats Exposed to Bitumen Fumes

Halter

Hansen

Seidel

et al. 2007

Journal of Occupational and Environmental Hygiene

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The equivocal experimental and epidemiological evidence of bitumen fumes and the possible mechanisms of toxicity remain uncertain. This study therefore aimed at investigating the genotoxicity of bitumen fumes, the biotransformation and urinary excretion of PAHs, and altered expression of a selected number of genes in lung, nasal epithelium, and white blood cells of rats. Animals were exposed to three different concentrations (low: 4 mg/m 3 ; medium: 20 mg/m 3 ; high: 100 mg/m 3 ) of bitumen fume condensate for 5 days, 30 days, and 12 months (6 hours per day) or ambient air. Notably, no dose-related signs of intolerance were observed throughout the inhalation period but dose dependent uptake of bitumen fumes was observed based on urinary excretion of PAHs and metabolites. At best, measurements of naphthols enabled an estimate of dose-dependent body burden. Excretion of 1-hydroxy-and 2-hydroxyphenanthrene was dose dependent and their production is catalyzed by the CYP1A1 monooxygenase which we found to be strongly induced upon exposure to bitumen fumes. Furthermore, pyrene, a minor component in bitumen fumes, produced hydroxypyrene levels close to the detection limit in rat urine. We additionally determined DNA adduct formation by the 32 P-postlabelling assay and observed a dose and time dependent increase of 3 to 4 stable DNA adducts in lung, nasal, and alveolar epithelium. DNA adduct levels were highest in nasal epithelium, the relative adduct level (RAL) being 450 adducts per 10 9 nucleotides. For lung and alveolar epithelium the RAL was 114 and 76 adducts per 10 9 nucleotides, respectively. However, we did not observe micronucleated red blood cells of the peripheral blood or with polychromatic erythrocytes of the bone marrow (after 12 months). It is important to note that erythrocyte cell count in bone marrow smears was reduced in four out of six animals after 12 months of exposure, clearly demonstrating that components of bitumen fume had reached the bone marrow. Finally, we investigated by reverse transcription polymerase chain reaction regulation of genes with known functions in inflammation, asthma and other pulmonary diseases. Gene expression changed during the time of exposure. With the monooxygenases CYP1A1 and CYP2G1 we observed dose dependent regulation in nasal and lung tissue. We also observed significant, but dose independent, regulation of cathepsin K and D, cadherin 22, platelet activating factor acetylhydrolase isoform 1b alpha subunit and the regulator of G-protein signalling in nasal epithelium of male rats after exposure to bitumen fumes. We found bitumen fumes to be genotoxic in target tissue of exposure and observed altered regulation of genes involved in the metabolic activation of polycyclic aromatic hydrocarbons and cellular inflammatory processes. These findings are consistent with the histopathology observed in the respiratory tract of rats chronically exposed to bitumen fume. An understanding of the regulation of suspected disease candidate genes in target tissues of exposure will be a...

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“…Genies et al 2013 Qian et al (1996Qian et al ( , 1998Qian et al ( , 1999 identified genetic effects from exposure to type I or type III roofing bitumen emissions generated at 316 C which had been employed by Sivak et al 1997 to induce tumors in mouse skin painting studies. Exposure caused increased micronuclei formation in Chinese hamster V79 cells (Qian et al 1996(Qian et al , 1999) and dose-dependent increases in DNA adducts in lung cells of male rats exposed by intratracheal instillation (Qian et al 1998). No adducts were seen in blood lymphocytes.…”

Section: Experimental Genetic Toxicity (In Vitro and In Vivo Mammalian)mentioning

confidence: 99%

Assessing cancer hazards of bitumen emissions – a case study for complex petroleum substances

Kriech¹,

Schreiner²,

Osborn³

et al. 2017

Critical Reviews in Toxicology

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When assessing cancer hazard and risk associated with a complex petroleum substance, like bitumen emissions, there are often conflicting results related to human, animal and mechanistic studies. Validation of the complex composition to assure that it matches real-world exposures and control of confounders are pivotal factors in study design to allow the necessary read-across during assessments. Several key studies on bitumen emissions in two-year dermal cancer assays reported variable outcomes ranging from high cancer incidence to no cancer incidence. Here, we synthesize findings from published studies to explain the differences and discuss critical factors in cancer hazard evaluation for complex petroleum substances. Using these critical factors, we reviewed relevant human genetic toxicity, mammalian toxicity and mechanistic studies with bitumen to understand the divergence in results. We assess the most reliable and scientifically supported information on the potential carcinogenic hazards of bitumen emissions and comment on quality and completeness of data. Human hazard data are typically considered highest priority because they eliminate the need for interspecies extrapolation and reduce the range of high -to low-dose extrapolation during the risk assessment process. Finally, two well-conducted comprehensive animal studies are discussed that have well-defined test material, exposure concentration and composition representative of worker exposure, evidence of systemic uptake, no confounding exposures and provide consistency across all elements within both studies. Studies that allow effective read-across from human, animal and mechanistic components, control for confounders and are well-validated analytically against workplace exposures, provide the strongest evidence base for evaluating cancer hazard. ARTICLE HISTORY

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Induction of DNA adducts in vivo in rat lung cells by fume condensates of roofing asphalt

Cited by 17 publications

References 29 publications

Assessment of DNA Damage in WBCs of Workers Occupationally Exposed to Fumes and Aerosols of Bitumen

Assessment of DNA Damage in WBCs of Workers Occupationally Exposed to Fumes and Aerosols of Bitumen

Importance of DNA-Adduct Formation and Gene Expression Profiling of Disease Candidate Genes in Rats Exposed to Bitumen Fumes

Assessing cancer hazards of bitumen emissions – a case study for complex petroleum substances

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