ToxSci Advance Access published online on July 26, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm190
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Published by Oxford University Press 2007.
Disposition of Bromodichloromethane in Humans Following Oral and Dermal Exposure
* U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Human Studies Division, Chapel Hill, NC 27599; Present address: The Hamner Institutes for Health Sciences, Research Triangle Park, NC, 27709; email: tleavens{at}thehamner.org
The Centers for Disease Control and Prevention, Atlanta, GA 30341; email: bkb3{at}cdc.gov
U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Environmental Carcinogenesis Division, Research Triangle Park, NC 27711; email: demarini.david{at}epa.gov
U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Human Studies Division, Chapel Hill, NC 27599; email: madden.michael{at}epa.gov
¶ U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Human Studies Division, Chapel Hill, NC 27599; Present address: Merck & Co., West Point, PA, 19486; email: john_valentine{at}merck.com
|| U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Human Studies Division, Chapel Hill, NC 27599; email: case.martin{at}epa.gov
11 The Centers for Disease Control and Prevention, Atlanta, GA 30341; email: zox1{at}cdc.gov
111 U.S. EPA, National Health and Environmental Effects Research Laboratory, Environmental Carcinogenesis Division, Research Triangle Park, NC 27711; email: warren.sarah{at}epa.gov
# U.S. EPA, National Health and Environmental Effects Research Laboratory, Environmental Carcinogenesis Division, Research Triangle Park, NC 27711; email: hanley.nancy{at}epa.gov
** To whom correspondence should be addressed at U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Experimental Toxicology Division, MD-B143-01, Research Triangle Park, NC 27711; email: pegram.rex{at}epa.gov; Phone: 919-541-0410; Fax: 919-541-4284
Received May 1, 2007; revision received July 16, 2007; accepted July 18, 2007
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Abstract |
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Exposure to bromodichloromethane (BDCM), one of the most prevalent disinfection byproducts in drinking water, can occur via ingestion of water and by dermal absorption and inhalation during activities such as bathing and showering. The objectives of this research were to assess BDCM pharmacokinetics in human volunteers exposed percutaneously and orally to 13C-BDCM and to evaluate factors that could affect disposition of BDCM. Among study subjects, CYP2E1 activity varied 4-fold; 20% had the glutathione S-transferase theta (GSTT1-1) homozygous null genotype; and body fat ranged from 7 to 22%. Subjects were exposed to 13C-BDCM in water (target concentration of 36 µg/L) via ingestion and by forearm submersion. Blood was collected for up to 24 h and analyzed for 13C-BDCM by solid-phase microextraction and high-resolution GC-MS. Urine was collected before and after exposure for mutagenicity determinations in Salmonella. After ingestion (mean dose = 146 ng/kg), blood 13C-BDCM concentrations peaked and declined rapidly, returning to levels near or below the limit of detection (LOD) within 4 h. The Tmax for the oral exposure ranged from 5 to 30 min, and the Cmax ranged from 0.4 to 4.1 ng/L. After the one hour dermal exposure (estimated mean dose = 155 ng/kg), blood concentrations of 13C-BDCM ranged from 39 to 170 ng/L, and decreased to levels near or below the LOD by 24 h. Peak post-dose urine mutagenicity levels that were at least twice that of the predose mean level occurred in 6 of 10 percutaneously exposed subjects and 3 of 8 orally exposed subjects. These results demonstrate a highly significant contribution of dermal absorption to circulating levels of BDCM and confirm the much lower oral contribution, indicating that water uses involving dermal contact can lead to much greater systemic BDCM doses than water ingestion. These data will facilitate development and validation of physiologically based pharmacokinetic models for BDCM in humans.
Key Words: bromodichloromethane; pharmacokinetics; dermal absorption; oral absorption.
Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.