Use of real-time breath analysis and physiologically based pharmacokinetic modeling to evaluate dermal absorption of aqueous toluene in human volunteers.
Use of real-time breath analysis and physiologically based pharmacokinetic modeling to evaluate dermal absorption of aqueous toluene in human volunteers.
复制标题
使用实时呼吸分析和基于生理学的药代动力学模型来评估人类志愿者对甲苯水溶液的皮肤吸收。
DOI：
10.1093/toxsci/68.2.280
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Woodstock,AngelaD
中科院分区：
文献类型：
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作者：
Thrall,KarlaD;Weitz,KarlK;Woodstock,AngelaD
甲苯是一种普遍存在的化学品，因其溶剂性质而常用于工业和制造业，并且是许多油漆产品的组分。虽然人类接触甲苯最有可能是通过吸入，但甲苯也存在于井水和地表水中。因此，评估皮肤对甲苯总吸收的贡献有助于了解人体接触情况。为了评价这些暴露的显著性，使用实时呼气分析和基于生理学的药代动力学（PBPK）建模相结合的方法，在人类志愿者中评估了甲苯的皮肤吸收。将穿着泳衣的人类志愿者浸没在含有约500 μg/l甲苯初始浓度的不锈钢水疗浴缸中的温自来水中至颈部水平。向志愿者提供净化的呼吸空气以消除吸入暴露，并在暴露前、暴露期间和暴露后连续分析呼出气，以真实的时间跟踪化合物的吸收和随后的消除。使用PBPK模型来估计皮肤渗透系数（Kp），以描述来自4-6名人类志愿者的每组呼出气数据。发现平均Kp值为0.012 ± 0.007 cm/h，与所有数据集拟合良好。志愿者还参加了第二个研究阶段，其中允许受试者在浸泡期间呼吸室内空气，因此发生了皮肤和吸入暴露于甲苯。呼气分析显示，同时吸入挥发的甲苯导致呼气峰值水平瞬时增加100 ppb，或比仅皮肤研究中观察到的呼气水平增加约50%。从长远来看，与口服2升含甲苯的洗澡水浓度相关的甲苯总摄入量估计比洗澡引起的皮肤贡献大30倍以上。
Toluene is a ubiquitous chemical that is commonly used for its solvent properties in industry and manufacturing, and is a component of many paint products. Although human exposure to toluene is most likely to be through inhalation, toluene is also found in well and surface water. Therefore, an assessment of the dermal contribution to total toluene uptake is useful for understanding human exposures. To evaluate the significance of these exposures, the dermal absorption of toluene was assessed in human volunteers using a combination of real-time exhaled breath analysis and physiologically based pharmacokinetic (PBPK) modeling. Human volunteers wearing swimsuits were submerged in warm tap water to neck level in a stainless steel hydrotherapy tub containing an initial concentration of approximately 500-μg/l toluene. Volunteers were provided purified breathing air to eliminate inhalation exposures, and exhaled breath was continually analyzed before, during, and post exposure to track the absorption and subsequent elimination of the compound in real time. A PBPK model was used to estimate the dermal permeability coefficient (Kp) to describe each set of exhaled breath data from 4–6 human volunteers. An average Kpvalue of 0.012 ± 0.007 cm/h was found to provide a good fit to all data sets. Volunteers also participated in a second study phase, in which the subject was allowed to breathe the room air during immersion, thus both dermal and inhalation exposures to toluene occurred. Exhaled breath analyses revealed that concurrent inhalation of volatilized toluene resulted in a transient increase in the peak exhaled-breath level by 100 ppb, or an approximate 50% increase over breath levels observed in dermal-only studies. For perspective, the total intake of toluene associated with oral consumption of 2 liters of water containing toluene at bath water concentrations were estimated to be more than 30 times greater than the dermal contribution due to bathing.