Inhalation Study on Exposure to Bitumen Fumes: Formation of DNA Adducts in Various Rat Tissues Following Nose-only Inhalation

Genevois-charmeau, Carole; Binet, Stéphane; Bonnet, Pierre; Lafontaine, Michel; Brandt, H.; Kriech, Anthony J.; Groot, P.C. de; Wissel, Herbert L.; Garren, Liliane; Moréle, Yves; Nunge, Hervé; Castegnaro, M.

doi:10.1080/10406630108233819

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…Furthermore, no DNA adducts were identified in the lung in the low-dose exposure groups (4 mg/m 3 ). This agreed well with findings by Genevois-Charmeau et al (55) who exposed rats for 5 days to bitumen fumes and coal-tar at 5.4 and 4 mg/m3, BSM (benzene soluble particulate), respectively, but did not detect any adducts in lung and WBC. They also exposed rats to 50 mg/m 3 BSM for 5 days and detected one DNA adduct in the lung.…”

Section: Genotoxicity Of Bitumen Fumessupporting

confidence: 93%

“…Future studies will need to focus on chemical characterization of bitumen fumes to identify DNA-binding species. As recently reported by Genevois-Charmeau et al (55) sulfur-containing polycyclic aromatic compounds were considered to be genotoxic in an inhalation study with rats exposed to bitumen fumes.…”

Section: Identification Of Pahs and Metabolites In Urinementioning

confidence: 77%

“…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: 94%

“…We did not detect DNA adducts at 20 mg/m 3 THC in the lung of exposed animals after five days of treatment, whereas in the high-dose group (100 mg/m 3 ) DNA adducts were visible at this early time point. Due to differences in the experimental design and materials used the study of Genevois-Charmeau et al (55) and our own investigation cannot be directly compared. The metric system differed between Genevois-Charmeau et al (55) and our study (benzene soluble particulate versus THC).…”

Section: Genotoxicity Of Bitumen Fumesmentioning

confidence: 96%

“…Due to differences in the experimental design and materials used the study of Genevois-Charmeau et al (55) and our own investigation cannot be directly compared. The metric system differed between Genevois-Charmeau et al (55) and our study (benzene soluble particulate versus THC).…”

Section: Genotoxicity Of Bitumen Fumesmentioning

confidence: 96%

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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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Section: Genotoxicity Of Bitumen Fumessupporting

confidence: 93%

Section: Identification Of Pahs and Metabolites In Urinementioning

confidence: 77%

Section: Genotoxicity Of Bitumen Fumesmentioning

confidence: 94%

Section: Genotoxicity Of Bitumen Fumesmentioning

confidence: 96%

Section: Genotoxicity Of Bitumen Fumesmentioning

confidence: 96%

See 3 more Smart Citations

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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Bitumen (Dampf und Aerosol bei der Heißverarbeitung) [MAK value documentation in German language, 2019]

Hartwig

Arand

2019

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the classification of bitumen [ 8052‐42‐4 ; 64741‐56‐6 ; 64742‐93‐4 ] in Carcinogen Category 2 considering all toxicological endpoints. New data allowed a separate assessment of the harmful properties of vapours and aerosols from high‐temperature processing of two bitumen groups. Straight‐Run and Air‐Rectified Bitumen For the derivation of a maximum concentration at the workplace (MAK value), a 2‐year inhalation study in rats exposed to vapours and aerosols from a mixture of straight‐run and air‐rectified bitumen is used. Due to an increased incidence of bronchioalveolar hyperplasia in the lungs and of inflammatory cells in the nasal epithelium, the study resulted in a NOAEC of 6 mg/m 3 . Taking into account the extrapolation from an animal study and the increased respiratory volume at the workplace compared with the exposure of the animals at rest, a MAK value of 1.5 mg/m 3 (sum of vapour and inhalable fraction) is derived for straight‐run and air‐rectified bitumen based on bitumen condensate standard. The MAK value is one‐third of the mean concentration at which three out of 12 inflammation markers are elevated in the sputum of exposed workers. However, the clinical relevance of this finding is unclear and the margin to the MAK value is considered sufficient. The effects on the lung is the most sensitive endpoint, so vapours and aerosols of bitumen are assigned to Peak Limitation Category II with an excursion factor of 2. All in all, the investigated straight‐run and air‐rectified bitumens did not exhibit distinct genotoxic or carcinogenic properties. However, due to the wide range in the chemical composition, harmful emissions of carcinogenic and mutagenic substances during high‐temperature processing cannot be completely excluded. Therefore, vapours and aerosols of straight‐run and air‐rectified bitumens, as commonly used in road paving, are regarded as suspicious carcinogens and classified in Carcinogen Category 3 B. As no data are available for developmental toxicity they are assigned to Pregnancy Risk Group D. Skin contact may contribute significantly to systemic toxicity and the “H” notation is confirmed. Sensitization is not expected from the available data. Oxidized Bitumen There are no inhalation studies available for evaluation of the carcinogenicity of oxidized bitumen (“Roofing Bitumen”). The new animal studies published since 2001 and most of the previous studies show the carcinogenicity of condensates of vapours and aerosols of oxidized bitumens in skin painting studies in mice, so that a significant number of tested oxidized bitumens must be considered carcinogenic. The positive animal experiments on the carcinogenicity are consistent with the results of a genotoxicity study in roofing workers with increased DNA strand break rates. Vapours and aerosols of oxidized bitumen are classified in Carcinogen Category 2. A MAK value could not be derived. Mutations in bacteria and higher levels of benzo[a]pyrene in oxidized bitumen condensates compared to those of straight‐run and air‐rectified bitumen and the systemic availability of inhaled vapours and aerosols of oxidized bitumen support suspicion of germ cell mutagenicity. Therefore, vapours and aerosols of oxidized bitumen are classified in Category 3 B for germ cell mutagens. Skin contact may contribute significantly to systemic toxicity and the “H” notation is confirmed. Sensitization is not expected from the available data.

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Effects of paving asphalt fume exposure on genotoxic and mutagenic activities in the rat lung

Zhao

Yin

Frazer

et al. 2004

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Inhalation Study on Exposure to Bitumen Fumes: Formation of DNA Adducts in Various Rat Tissues Following Nose-only Inhalation

Cited by 9 publications

References 28 publications

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

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

Bitumen (Dampf und Aerosol bei der Heißverarbeitung) [MAK value documentation in German language, 2019]

Effects of paving asphalt fume exposure on genotoxic and mutagenic activities in the rat lung

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