Keratin adducts as biomarkers for dermal exposure to jet fuel JP-8 in the U.S. Air Force fuel cell maintenance personnel.

摘要

Jet propulsion fuel, JP-8, is the fuel of choice for all military operations in the United States and the North Atlantic Treaty Organization. Dermal exposure to jet fuel JP-8, along with inhalation exposure, has been observed to contribute significantly to the total body burden in the U.S. Air Force fuel-cell maintenance personnel. However, current dermal exposure assessment methodologies are either qualitative or reflect only acute exposure scenarios occurring during the day of sampling. A quantitative method that measures the long-term, cumulative dermal exposure is needed. In order to improve the current dermal exposure assessment methodologies, I developed four polyclonal antibodies to four hypothetical synthetic keratin adduct epitopes and validated enzyme-linked immunosorbent assays to quantitatively detect naphthyl-keratin adducts (NKA) predicted to be formed in the stratum corneum upon exposure to naphthalene-containing JP-8. I also demonstrated the existence of xenobiotic metabolism and dose-related induction in mRNA transcripts for various xenobiotic-metabolizing enzymes in the three-dimensional (3D) reconstructed human skin exposed to naphthalene. Most importantly, I demonstrated the dose-related NKA formation consistent with the hypothetical synthetic epitopes both in vitro in the 3D reconstructed human skin using in situ immuofluorescence and in vivo in skin samples collected from the fuel-cell maintenance workers exposed to naphthalene-containing JP-8. The measured total NKA (TNKA) levels were affected by exposure time, dermal naphthalene level, and worker's age. A significant association was observed between TNKA and urine naphthalene levels, which indicates a contribution of dermal metabolism to systemic exposure. In addition to the TNKA level, post-exposure breath naphthalene level, as well as the presence of GSTT1-plus (++/+-) and CYP2E1*6 wild-type (DD at the DraI restriction site of intron 6) significantly influenced urine naphthalene levels. This research is the first to confirm that naphthalene is readily metabolized and that reactive naphthalene metabolites form keratin adducts in the human skin, both in vitro and in vivo. Further, this research demonstrates the potential utility of using NKAs as biomarkers of cumulative dermal exposure to JP-8. These keratin adducts can also be utilized as biomarkers of exposure in occupational and environmental exposure settings where naphthalene can be used as a marker of exposure to complex mixtures (e.g., PAH exposure).