Keys D A, Wallace D G, Kepler T B, Conolly R B
Department of Statistics, North Carolina State University, Raleigh 27695, USA.
Toxicol Sci. 2000 Feb;53(2):173-84. doi: 10.1093/toxsci/53.2.173.
Phthalate esters are ubiquitous, low-level environmental contaminants that induce testicular toxicity in laboratory animals. The diester is rapidly metabolized in the gut to the monoester, which causes the testicular toxicity. Several physiologically based pharmacokinetic (PBPK) model structures have been evaluated for di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate (MEHP). The objective of this study was to test these PBPK models for a less lipophilic phthalate diester, di(n-butyl) phthalate (DBP), and monoester, mono(n-butyl) phthalate (MBP). Alternate models describing enterohepatic circulation, diffusion-limitation, tissue pH gradients (pH trapping), and a simpler, flow-limited model were evaluated. A combined diffusion-limited and pH trapping model was also tested. MBP tissue:blood partition coefficients were similar when determined either experimentally by a nonvolatile, vial equilibration technique or algorithmically. All other parameters were obtained from the literature or estimated from MBP blood concentrations following intravenous or oral exposure to DBP or MBP. A flow-limited model was unable to predict MBP blood levels, whereas each alternative model had statistically better predictions. The combined diffusion-limited and pH trapping model was the best overall, having the highest log-likelihood function value. This result is consistent with a previous finding that the pH trapping model was the best model for describing DEHP and MEHP blood dosimetry, though it was necessary to extend the model to include diffusion-limitation. The application of the pH trapping model is a step toward developing a generic model structure for all phthalate esters, though more work is required before a generic structure can be identified with confidence. Development of a PBPK model structure applicable to all phthalate esters would support more realistic assessments of risk to human health from exposure to one or more members of this class of compounds.
邻苯二甲酸酯是普遍存在的低水平环境污染物，可在实验动物中诱发睾丸毒性。二酯在肠道中迅速代谢为单酯，后者会导致睾丸毒性。已对几种基于生理学的药代动力学（PBPK）模型结构进行了评估，用于邻苯二甲酸二（2-乙基己基）酯（DEHP）和邻苯二甲酸单（2-乙基己基）酯（MEHP）。本研究的目的是测试这些PBPK模型对亲脂性较低的邻苯二甲酸二正丁酯（DBP）及其单酯邻苯二甲酸单正丁酯（MBP）的适用性。评估了描述肠肝循环、扩散限制、组织pH梯度（pH捕获）的替代模型以及一个更简单的流量限制模型。还测试了一个结合扩散限制和pH捕获的模型。通过非挥发性小瓶平衡技术实验测定或通过算法确定时，MBP的组织：血液分配系数相似。所有其他参数均从文献中获取或根据静脉内或口服DBP或MBP后MBP的血药浓度估算。流量限制模型无法预测MBP的血药水平，而每个替代模型在统计学上都有更好的预测。结合扩散限制和pH捕获的模型总体上是最佳的，具有最高的对数似然函数值。这一结果与之前的一项发现一致，即pH捕获模型是描述DEHP和MEHP血液剂量学的最佳模型，尽管有必要扩展该模型以纳入扩散限制。pH捕获模型的应用是朝着为所有邻苯二甲酸酯开发通用模型结构迈出的一步，不过在能够确定一个可靠的通用结构之前，还需要开展更多工作。开发适用于所有邻苯二甲酸酯的PBPK模型结构将有助于更实际地评估接触此类化合物中的一种或多种对人类健康造成的风险。
