Byczkowski J Z, Fisher J W
ManTech Environmental Technology, Inc., Dayton, OH 45437, USA.
Comput Methods Programs Biomed. 1995 Feb;46(2):155-63. doi: 10.1016/0169-2607(94)01616-n.
The risk assessment process predicts the chances of adverse health effects that the toxicant possibly can do to the target organism under expected conditions of exposure. Regulators chose among several mathematical approaches to estimate the risk, but in each case it is necessary to link the dosemetrics of the toxicant with its predicted health effect. In this paper, a computer program is described that allowed us to link a physiologically based pharmacokinetic (PBPK) model for tetrachloroethylene (PCE) in the lactating mother with the estimate of extra cancer risk for breast-fed infants, according to the U.S. Environmental Protection Agency (EPA) methodology. When inhaled by a lactating woman, PCE may partition into breast milk and may be transferred to the breast-fed infant. We have developed and validated experimentally a PBPK model for lactational transfer of PCE in rats, including a quantitative description of a milk compartment and the nursing pup. Subsequently, the model has been scaled to describe human physiology, and was validated with literature data for human cases of PCE exposure. Finally, we linked the dosage predictions of the PBPK model with equations used by EPA to estimate the cancer risk from PCE. The model predictions are in good agreement with both the measured values and those reported in the literature for exposure to PCE. This comparison confirms the usefulness of PBPK modeling in risk assessments.
风险评估过程预测了在预期暴露条件下，有毒物质可能对目标生物体产生不良健康影响的几率。监管机构在几种数学方法中进行选择以估计风险，但在每种情况下，都有必要将有毒物质的剂量指标与其预测的健康影响联系起来。本文描述了一个计算机程序，该程序使我们能够根据美国环境保护局（EPA）的方法，将哺乳期母亲体内四氯乙烯（PCE）的基于生理的药代动力学（PBPK）模型与母乳喂养婴儿的额外癌症风险估计联系起来。当哺乳期妇女吸入PCE时，PCE可能会进入母乳并可能转移到母乳喂养的婴儿体内。我们已经开发并通过实验验证了大鼠中PCE乳汁转移的PBPK模型，包括对乳汁隔室和哺乳幼崽的定量描述。随后，该模型已按比例缩放以描述人体生理学，并用PCE暴露人类病例的文献数据进行了验证。最后，我们将PBPK模型的剂量预测与EPA用于估计PCE癌症风险的方程联系起来。模型预测与PCE暴露的测量值和文献报道值均吻合良好。这种比较证实了PBPK建模在风险评估中的有用性。
