Thomaseth K, Salvan A
Institute of Systems Science and Biomedical Engineering (LADSEB-CNR), National Research Council, Padova, Italy.
Environ Health Perspect. 1998 Apr;106 Suppl 2(Suppl 2):743-53. doi: 10.1289/ehp.98106743.
In this study we investigated estimation of occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on a minimal physiologic toxicokinetic model in humans. Our purpose was to obtain a mathematical tool for dose-response studies based on human data. We first simplified an existing model of TCDD kinetics in humans and estimated its parameters (i.e., liver elimination and background input of TCDD) using repeated measures of serum dioxin taken in Vietnam veterans (Ranch Hand data and data from an unexposed reference group). We carried out computer simulation and estimation of the model parameters both under a nonlinear weighted least-squares model (naive pooled data approach) and under a nonlinear mixed-effects model. The best parameter estimates were obtained with log-transformed data under a mixed-effects model: liver elimination parameter kf = 0.022 days-1 (95% confidence interval [CI] = 0.020, 0.024), and background input rate input = 0.1251 pg/kg/day (95% CI = 0.071, 0.179). The dioxin kinetic model and its estimated parameters were then used to provide dose estimates for a cohort of workers with exposure to TCDD at chemical plants in the United States. First, the model was used to estimate the rate of occupational intake of TCDD in a subset of the cohort consisting of 253 subjects for whom one measure of serum TCDD was available. A model of change in body-mass index over time was also identified for this subsample. The occupational exposure rate was estimated by linear regression using the above values of kinetic parameters and assuming an initial condition for serum TCDD of 7 ppt, i.e., the average level found in unexposed workers. The estimate of the occupational exposure parameter was 232.7 pg/kg/day (95% CI 192, 273). This value can be applied to the full cohort to obtain for each cohort member the time course of serum dioxin concentration from which exposure indices can be derived. Sensitivity coefficients to model parameters (background input, kf, occupational exposure, and the assumed TCDD concentration at hire) allow for a convenient recalculation of the serum TCDD curve and of the derived exposure indices for different assumed values of the model parameters.
在本研究中，我们基于人类最小生理毒物动力学模型，对职业性接触2,3,7,8 - 四氯二苯并 - p - 二噁英（TCDD）进行了研究。我们的目的是获得一个基于人类数据的剂量反应研究的数学工具。我们首先简化了现有的人类TCDD动力学模型，并使用越南退伍军人血清二噁英的重复测量值（“牧场工人”数据和未接触参考组的数据）估计其参数（即肝脏消除率和TCDD的背景输入率）。我们在非线性加权最小二乘模型（朴素合并数据方法）和非线性混合效应模型下进行了计算机模拟和模型参数估计。在混合效应模型下，对数据进行对数转换后获得了最佳参数估计值：肝脏消除参数kf = 0.022天⁻¹（95%置信区间[CI] = 0.020, 0.024），背景输入率input = 0.1251 pg/kg/天（95% CI = 0.071, 0.179）。然后，二噁英动力学模型及其估计参数被用于为美国化工厂中接触TCDD的一组工人提供剂量估计。首先，该模型用于估计该队列中一个子集（由253名有一次血清TCDD测量值的受试者组成）的TCDD职业摄入量。还为该子样本确定了体重指数随时间变化的模型。通过线性回归，使用上述动力学参数值并假设血清TCDD的初始条件为7 ppt（即未接触工人中发现的平均水平），估计职业接触率。职业接触参数的估计值为232.7 pg/kg/天（95% CI 192, 273）。该值可应用于整个队列，以获得每个队列成员血清二噁英浓度随时间的变化过程，从中可以得出接触指数。对模型参数（背景输入、kf、职业接触以及雇佣时假设的TCDD浓度） 的敏感性系数允许方便地重新计算血清TCDD曲线以及针对模型参数的不同假设值得出的接触指数。
