Plowchalk D R, Andersen M E, Bogdanffy M S
E. I. du Pont de Nemours and Co., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware 19714, USA.
Toxicol Appl Pharmacol. 1997 Feb;142(2):386-400. doi: 10.1006/taap.1996.8052.
Chronic inhalation exposure to vinyl acetate (VA) causes lesions in the nasal cavity of the rat. This effect appears to be related to tissue exposure to either acetaldehyde (AAld) or acetic acid (AA) metabolites of VA or both. A physiologically based pharmacokinetic model was constructed to describe the deposition of VA in the nasal cavity of the rat and provide estimates of regional tissue exposure to VA, AAld, and AA. Since formation of AA in the nasal tissue should cause intracellular acidification, a submodel which describes free intracellular hydrogen ion concentration and intracellular pH (pHi) changes was linked to the VA model. The dosimetry model was applied to data from a series of experiments designed to measure the uptake and metabolism of VA in the isolated upper respiratory tract of the rat at exposure concentrations ranging from 73 to 2190 ppm. Extraction of VA from the nasal cavity was nonlinear with respect to exposure concentration and ranged from 36 to 94%, with the greatest deposition occurring at the lowest VA concentrations. Pretreatment with bis(p-nitrophenyl)phosphate, an inhibitor of carboxylesterases, significantly reduced fractional deposition of VA compared to naive rats exposed to similar VA concentrations. The best model fits for VA extraction and AAld appearance were achieved when a second carboxylesterase isozyme, with high-affinity characteristics, was included. Simulations of 6-h inhalation exposures to VA predicted that the order of nasal tissue exposures will be to AA > AAld > VA. In addition, based on measured tissue hydrolysis rates, sufficient acid should be formed by the metabolism of VA to cause significant changes in pHi. VA exposures of 200 and 600 ppm were predicted to result in a pHi of less than 7.2 and 6.7, respectively. This model provides nasal dosimetry estimates needed to develop mechanistically based risk assessment approaches for human exposures to VA vapor.
长期吸入乙酸乙烯酯（VA）会导致大鼠鼻腔出现病变。这种效应似乎与组织暴露于VA的乙醛（AAld）或乙酸（AA）代谢产物或两者有关。构建了一个基于生理学的药代动力学模型，以描述VA在大鼠鼻腔中的沉积情况，并提供对VA、AAld和AA区域组织暴露量的估计。由于鼻腔组织中AA的形成会导致细胞内酸化，因此将一个描述游离细胞内氢离子浓度和细胞内pH（pHi）变化的子模型与VA模型相连接。该剂量学模型应用于一系列实验的数据，这些实验旨在测量大鼠离体上呼吸道在73至2190 ppm暴露浓度下对VA的摄取和代谢情况。VA从鼻腔的提取相对于暴露浓度是非线性的，范围从36%至94%不等，在最低VA浓度下沉积量最大。与暴露于相似VA浓度的未处理大鼠相比，用羧酸酯酶抑制剂双（对硝基苯基）磷酸酯预处理可显著降低VA的分数沉积。当纳入具有高亲和力特征的第二种羧酸酯酶同工酶时，可实现对VA提取和AAld出现的最佳模型拟合。对VA进行6小时吸入暴露的模拟预测，鼻腔组织暴露的顺序将是AA＞AAld＞VA。此外，根据测得的组织水解速率，VA代谢应形成足够的酸，从而导致pHi发生显著变化。预计200 ppm和600 ppm的VA暴露分别会导致pHi低于7.2和6.7。该模型提供了鼻腔剂量学估计值，这对于制定基于机制评估人类暴露于VA蒸气风险的方法是必要的。
