Abstract
Polycyclic aromatic hydrocarbons (PAH) are ubiquitous pollutants, among which benzo[a]pyrene (B[a]P) is the only compound classified carcinogenic to humans. Besides pulmonary uptake, skin is the major route of PAH absorption during occupational exposure. Health risk due to PAH exposure is commonly assessed among workers using biomonitoring. A realistic human ex vivo skin model was developed to explore B[a]P diffusion and metabolism to determine the most relevant biomarker following dermal exposure. Three realistic doses (0.88, 8.85 and 22.11 nmol/cm2) were topically applied for 8, 24, and 48 h. B[a]P and its metabolites were quantified by liquid chromatography coupled with fluorimetric detection. The impact of time, applied dose, and donor age were estimated using a linear mixed-effects model. B[a]P vastly penetrated the skin within 8 h. The major metabolites were 3-hydroxybenzo[a]pyrene (3-OHB[a]P) and 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P-tetrol). This latter predominantly derives from the most carcinogenic metabolite of B[a]P, benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), as well as benzo[a]pyrene-9,10-diol-7,8-epoxide (reverse-BPDE). Benzo[a]pyrene-trans-7,8-dihydrodiol (B[a]P-7,8-diol) was a minor metabolite, and benzo[a]pyrene-trans-4,5-dihydrodiol (B[a]P-4,5-diol) was never quantified. Unmetabolized B[a]P bioavailability was limited following dermal exposure since less than 3% of the applied dose could be measured in the culture medium. B[a]P was continuously absorbed and metabolized by human skin over 48 h. B[a]P-tetrol production became saturated as the applied dose increased, while no effect was measured on the other metabolic pathways. Age had a slight positive effect on B[a]P absorption and metabolism. This work supports the relevance of B[a]P-tetrol to assess occupational exposure and carcinogenic risk after cutaneous absorption of B[a]P.
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Acknowledgements
This work was funded by the French National Institute of Health and Medical Research (INSERM) (Grant Number ENV201412) and Plan Cancer. The authors wish to thank the team “Service de Chirurgie Plastique et Maxillo-faciale CHU Grenoble Alpes” for their help in skin sample collection.
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Experiments were conducted in accordance with the article L1245-2 of the French Public Health Code on the use of surgical wastes for research purposes. Collection, storage, and use of human skin samples were made anonymously, declared to the French authorities, and validated in the CODECOH DC-2008-444 document.
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Bourgart, E., Barbeau, D., Marques, M. et al. A realistic human skin model to study benzo[a]pyrene cutaneous absorption in order to determine the most relevant biomarker for carcinogenic exposure. Arch Toxicol 93, 81–93 (2019). https://doi.org/10.1007/s00204-018-2329-2
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DOI: https://doi.org/10.1007/s00204-018-2329-2