Cox L A, Bird M G, Griffis L
Cox Associates, Denver, Co 80218, USA.
Toxicology. 1996 Oct 28;113(1-3):263-72. doi: 10.1016/0300-483x(96)03455-5.
Most statistical risk assessment models assume that equal, measured on scale such as mg/kg/day, create equal tumor risks. This equivalent dose metric (EDM) hypothesis allows risks to be extrapolated from high concentrations to low-concentrations and from and species, sex, and strain to another, since it implies that all administered dose histories corresponding to the same total dose create the same risk. This paper tests the EDM hypothesis using data on tumor rates in B6C3F mice administered isoprene via inhalation. Its major conclusion is that the EDM hypothesis does not hold for isoprene. For example, it appears that exposure concentration has a greater impact on tumor rates than weeks of exposure. To predict tumor probabilities, the time pattern of dose administration must be considered. The asymmetric effects of concentration, hours-per-day, and number of days of exposure on tumor risks imply that complex dynamic risk models may be needed to accurately describe dose-time-response relations. The traditional concept of a dose-response relation as a static curve relating a numerical summary of dose to a numerical summary of response probability is probably not predictively useful for chemicals such as isoprene, and extrapolations of risk based on the EDM hypothesis could be misleading for such chemicals.
大多数统计风险评估模型假定，以毫克/千克/天等单位衡量的相等剂量会产生相等的肿瘤风险。这种等效剂量度量（EDM）假说使得风险能够从高浓度外推至低浓度，以及从一个物种、性别和品系外推至另一个物种、性别和品系，因为这意味着所有对应于相同总剂量的给药剂量历程都会产生相同的风险。本文利用通过吸入给予异戊二烯的B6C3F小鼠的肿瘤发生率数据对EDM假说进行了检验。其主要结论是，EDM假说对于异戊二烯并不成立。例如，暴露浓度似乎比暴露周数对肿瘤发生率的影响更大。为了预测肿瘤发生概率，必须考虑给药的时间模式。浓度、每天的小时数以及暴露天数对肿瘤风险的非对称影响意味着，可能需要复杂的动态风险模型来准确描述剂量-时间-反应关系。将剂量-反应关系视为将剂量的数值汇总与反应概率的数值汇总相关联的静态曲线这一传统概念，对于异戊二烯这类化学物质可能在预测方面并无用处，并且基于EDM假说进行的风险外推对于这类化学物质可能会产生误导。
