Boyes William K, Bercegeay Mark, Ali Joseph S, Krantz Todd, McGee John, Evans Marina, Raymer James H, Bushnell Philip J, Simmons Jane Ellen
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Toxicol Sci. 2003 Nov;76(1):121-30. doi: 10.1093/toxsci/kfg213. Epub 2003 Aug 12.
Risk assessments often must consider exposures that vary over time or for which the exposure duration of concern differs from the available data, and a variety of extrapolation procedures have been devised accordingly. The present experiments explore the relationship(s) between exposure concentration (C) and time (t) to investigate procedures for assessing the risks of short-term solvent exposures. The first hypothesis tested was that the product of C x t would produce a constant health effect (Haber's rule). The second hypothesis tested was that exposure conditions produce effects in proportion to the tissue concentrations created. Awake, adult, male Long-Evans (LE) rats were exposed to trichloroethylene (TCE) vapor in a head-only exposure chamber while pattern onset/offset visual evoked potentials (VEPs) were recorded. Exposure conditions were designed to provide C x t products of 0 ppm/h (0 ppm for 4 h) or 4000 ppm/h created through four exposure scenarios: 1000 ppm for 4 h; 2000 ppm for 2 h; 3000 ppm for 1.3 h; or 4000 ppm for 1h (n = 9-10/concentration). The amplitude of the VEP frequency double component (F2) was decreased significantly by exposure; this decrease was related to C but not to t or to the C x t product, indicating that Haber's rule did not hold. The mean amplitude (+/- SEM in muV) of the F2 component in the control and treatment groups measured 4.4 +/- 0.5 (0 ppm/4 h), 3.1 +/- 0.5 (1000 ppm/4 h), 3.1 +/- 0.4 (2000 ppm/2 h), 2.3 +/- 0.3 (3000 ppm/1.3 h), and 1.9 +/- 0.4 (4000 ppm/1 h). A physiologically based pharmacokinetic (PBPK) model was used to estimate the concentrations of TCE in the brain achieved during each exposure condition. The F2 amplitude of the VEP decreased monotonically as a function of the estimated peak brain concentration but was not related to the area under the curve (AUC) of the brain TCE concentration. In comparison to estimates from the PBPK model, extrapolations based on Haber's rule yielded approximately a 6-fold error in estimated exposure duration when extrapolating across only a 4-fold change in exposure concentration. These results indicate that the use of a linear form of Haber's rule will not predict accurately the risks of acute exposure to TCE, nor will an estimate of AUC of brain TCE. However, an estimate of the brain TCE concentration at the time of VEP testing predicted the effects of TCE across exposure concentrations and durations.
风险评估常常必须考虑随时间变化的暴露情况，或者所关注的暴露持续时间与现有数据不同的情况，因此已经设计了各种外推程序。本实验探讨暴露浓度（C）与时间（t）之间的关系，以研究评估短期溶剂暴露风险的程序。所检验的第一个假设是C×t的乘积会产生恒定的健康效应（哈伯法则）。所检验的第二个假设是暴露条件产生的效应与所产生的组织浓度成比例。将成年雄性长 Evans（LE）大鼠在清醒状态下置于仅头部暴露的实验箱中暴露于三氯乙烯（TCE）蒸气中，同时记录模式起始/偏移视觉诱发电位（VEP）。暴露条件设计为通过四种暴露方案提供0 ppm/h（4小时0 ppm）或4000 ppm/h的C×t乘积：1000 ppm持续4小时；2000 ppm持续2小时；3000 ppm持续1.3小时；或4000 ppm持续1小时（每个浓度n = 9 - 10）。暴露显著降低了VEP频率双成分（F2）的幅度；这种降低与C有关，但与t或C×t乘积无关，表明哈伯法则不成立。对照组和处理组中F2成分的平均幅度（以μV为单位，±SEM）分别为4.4±0.5（0 ppm/4小时）、3.1±0.5（1000 ppm/4小时）、3.1±0.4（2000 ppm/2小时）、2.3±0.3（3000 ppm/1.3小时）和1.9±0.4（4000 ppm/1小时）。使用基于生理学的药代动力学（PBPK）模型来估计每种暴露条件下大脑中达到的TCE浓度。VEP的F2幅度随估计的大脑峰值浓度单调下降，但与大脑TCE浓度的曲线下面积（AUC）无关。与PBPK模型的估计相比，仅在暴露浓度有4倍变化时基于哈伯法则进行外推，在估计暴露持续时间时产生了约6倍的误差。这些结果表明，使用线性形式的哈伯法则不能准确预测急性暴露于TCE的风险，大脑TCE的AUC估计也不行。然而，VEP测试时大脑TCE浓度的估计预测了TCE在不同暴露浓度和持续时间下的效应。
