Disposition of Bromodichloromethane in Humans Following Oral and Dermal Exposure

• Published in: Toxicological sciences Vol. 99; no. 2; pp. 432 - 445
• Main Authors: Leavens, Teresa L., Blount, Benjamin C., DeMarini, David M., Madden, Michael C., Valentine, John L., Case, Martin W., Silva, Lalith K., Warren, Sarah H., Hanley, Nancy M., Pegram, Rex A.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.10.2007
• Subjects: Administration, Cutaneous; Administration, Oral; Area Under Curve; bromodichloromethane; Cytochrome P-450 CYP2E1 - physiology; dermal absorption; Glutathione Transferase - physiology; Half-Life; Humans; Models, Biological; oral absorption; pharmacokinetics; Salmonella; Trihalomethanes - administration & dosage; Trihalomethanes - pharmacokinetics; pharmacokinetics; dermal absorption; bromodichloromethane; oral absorption
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfm190

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 fourfold; 20% had the glutathione S-transferase theta 1-1 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 1 h 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 postdose 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.