Fasano William J, McDougal James N
The DuPont Company, Haskell Global Centers for Health & Environmental Sciences, Newark, DE 19714-0050, USA.
Regul Toxicol Pharmacol. 2008 Jul;51(2):181-94. doi: 10.1016/j.yrtph.2008.04.005. Epub 2008 May 22.
In 2004, the United States Environmental Protection Agency (USEPA) published a final test rule in the US Federal Register requiring in vitro dermal penetration rate testing for selected industrial chemicals. The test rule described procedures for determining a permeability coefficient (Kp) and two short-term dermal absorption rates at 10 and 60min using human cadaver skin mounted in an in vitro diffusion cell model. According to the USEPA announcement, the selected chemicals were to be spiked with their radiolabeled form and tested in either water, isopropyl myristate (IPM) or neat depending on their physical character at room temperature, their aqueous solubility, their potential to damage the skin and their ability to achieve the study endpoints as prescribed. Overall, and for the majority of chemicals, the short-term absorption rates were higher at 10min than at 60min and the portion of applied dose remaining in the skin at the end of the exposure period was greater than the portion of dose that had penetrated through the skin and was detected in the receptor solution. In contrast to this, the amount of chemical in the receptor solution at study termination for the Kp (steady-state) experiments was greater than the amount remaining in the skin. For the Kp experiments, which lasted from 2 to 48h, a majority of skins exposed to neat chemical exhibited a reduced barrier function. However, integrity was mostly unaltered for skins from the short-term experiments and Kp experiments using chemicals applied either in water or IPM. Quantitative structure activity relationship (QSAR) model-predicted Kp values were in fair agreement with experimental data for those chemicals that were applied in a water vehicle when the integrity of the skin was not compromised. However, QSAR-derived Kp values were not predictive for those chemicals when applied in IPM vehicle or neat. Absorption predictions, based on the measured Kp and steady-state flux data for chemicals applied in water or neat, respectively, were comparable to measured values at both 10 and 60min. Kp data for chemicals applied in water and the flux values for neat chemicals will be useful for making estimates of skin absorption in occupational settings. Kp measurements for chemicals applied in IPM vehicle are not envisioned to provide useful data for estimating the risk from dermal exposure to chemicals in the workplace. When available, in vitro dermal flux measurements should be combined with toxicity information in order to improve the utility of chemical skin notations.
2004年,美国环境保护局(USEPA)在美国联邦公报上发布了一项最终测试规则,要求对选定的工业化学品进行体外皮肤渗透速率测试。该测试规则描述了使用安装在体外扩散池模型中的人体尸体皮肤来确定渗透系数(Kp)以及在10分钟和60分钟时的两个短期皮肤吸收率的程序。根据USEPA的公告,选定的化学品要用其放射性标记形式进行加标,并根据它们在室温下的物理特性、水溶性、对皮肤的潜在损害以及达到规定研究终点的能力,在水、肉豆蔻酸异丙酯(IPM)或纯物质中进行测试。总体而言,对于大多数化学品,10分钟时的短期吸收率高于60分钟时的,并且在暴露期结束时留在皮肤中的施用剂量部分大于穿透皮肤并在受体溶液中检测到的剂量部分。与此相反,在Kp(稳态)实验结束时受体溶液中的化学物质含量大于留在皮肤中的含量。对于持续2至48小时的Kp实验,大多数暴露于纯化学物质的皮肤表现出屏障功能降低。然而,对于短期实验以及使用在水中或IPM中施用的化学品的Kp实验,皮肤的完整性大多未改变。当皮肤完整性未受损害时,定量结构活性关系(QSAR)模型预测的Kp值与在水载体中施用的那些化学品的实验数据相当吻合。然而,当在IPM载体或纯物质中施用时,QSAR得出的Kp值对那些化学品没有预测性。分别基于在水中或纯物质中施用的化学品的测量Kp和稳态通量数据的吸收预测,在10分钟和60分钟时都与测量值相当。在水中施用的化学品的Kp数据以及纯化学品的通量值将有助于估计职业环境中的皮肤吸收情况。预计在IPM载体中施用的化学品的Kp测量值不会为估计工作场所皮肤接触化学品的风险提供有用数据。如有可用,体外皮肤通量测量应与毒性信息相结合,以提高化学皮肤标记的实用性。