Disposition of bromodichloromethane in humans following oral and dermal exposure
Disposition of bromodichloromethane in humans following oral and dermal exposure
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DOI：
10.1093/toxsci/kfm190
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发表时间：
2007-10-01
影响因子：
3.8
通讯作者：
Pegram, Rex A.
中科院分区：
文献类型：
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作者：
Leavens, Teresa L.;Blount, Benjamin C.;Pegram, Rex A.
接触到饮用水中最常见的消毒副产品之一的溴二氯甲烷(BDCM)可通过摄入水以及在洗澡和淋浴等活动中通过皮肤吸收和吸入发生。本研究的目的是评估经皮和口服~(13)C-BDCM的人体志愿者体内BDCM的药代动力学，并评估可能影响BDCM处置的因素。在被研究的受试者中，细胞色素P450_2E_1活性变化四倍；20%的人具有谷胱甘肽S转移酶theta1-1纯合子零基因；体脂含量从7%到22%。受试者通过摄入和前臂浸泡的方法暴露于水中(目标浓度为36微克/L)。采血24小时后，用固相微萃取和高分辨GC-MS分析(13)C-BDCM。在暴露前和暴露后收集尿液进行沙门氏菌的致突变性检测。血中C-BDCM浓度在摄入(平均剂量5146 ng/kg)后迅速达到峰值并迅速下降，在4h内恢复到接近或低于检出限(LOD)的水平。经口接触的T(Max)为5~30min，C(Max)为0.4~4.1 ng/L。~(13)C-BDCM的血药浓度范围为39~170 ng/L，24 h后降至接近或低于LOD的水平。10名经皮接触者中有6名和8名经口接触者中有3名出现了剂量后尿致突变峰值，至少是剂量前均值的两倍。这些结果表明皮肤吸收对BDCM循环水平的贡献非常显著，并证实了口服贡献要低得多，表明涉及皮肤接触的水使用可以导致比水摄入更大的全身BDCM剂量。这些数据将促进BDCM在人体内基于生理的药代动力学模型的开发和验证。
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 (13)C-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 (13)C-BDCM in water (target concentration of 36 mu g/l) via ingestion and by forearm submersion. Blood was collected for up to 24 h and analyzed for (13)C-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 5 146 ng/kg), blood (13)C-BDCM concentrations peaked and declined rapidly, returning to levels near or below the limit of detection (LOD) within 4 h. The T(max) for the oral exposure ranged from 5 to 30 min, and the C(max) ranged from 0.4 to 4.1 ng/l. After the 1 h dermal exposure (estimated mean dose 5 155 ng/kg), blood concentrations of (13)C-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.