Sanner T, Dybing E, Willems M I, Kroese E D
Department of Environmental and Occupational Cancer, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo.
Pharmacol Toxicol. 2001 Jun;88(6):331-41.
This report provides guidance for using the dose-descriptor T25 from animal studies as a basis for quantitative risk characterisation of non-threshold carcinogens. T25 is presently used within the European Union for setting specific concentration limits for carcinogens in relation to labelling of preparations (formulations). The T25 is defined as the chronic dose rate which will give 25% of the animals tumours at a specific tissue site, after correction for spontaneous incidence, within the standard life-time of that species. The T25 is converted to the corresponding human dose descriptor, HT25, by dividing it with the appropriate scaling factor for interspecies dose scaling based on comparative metabolic rates. Subsequently, the human dose (expressed in mg per kg body-weight per day) is calculated from the available exposure data. The corresponding human life-time cancer risk is then obtained by using linear extrapolation by dividing the exposure dose with the coefficient (HT25/0.25). The results with this new method, which can easily be calculated without computer programmes, are in excellent agreement with results from computer-based extrapolation methods such as the linearised multistage model and the benchmark method using LED10, even though the present method only takes into consideration one single dose-response point. To overcome possible shortcomings of the present method, the estimated life-time risks are proposed to be accompanied by a commentary statement giving an overall evaluation of data that may have bearing on the carcinogenic risk and that may indicate whether the real human risk is likely to be higher or lower than the calculated life-time risk. By using the present guidance and a harmonized set of criteria and default values, the calculation of life-time cancer risk should be transparent and easy to comprehend.
本报告为使用动物研究中的剂量描述符T25作为非阈值致癌物定量风险特征描述的基础提供了指导。T25目前在欧盟范围内用于设定与制剂（配方）标签相关的致癌物特定浓度限值。T25定义为在该物种的标准寿命内，经自发发病率校正后，能使特定组织部位25%的动物发生肿瘤的慢性剂量率。通过将T25除以基于比较代谢率的种间剂量缩放的适当缩放因子，将其转换为相应的人类剂量描述符HT25。随后，根据可用的暴露数据计算人类剂量（以每天每千克体重毫克数表示）。然后，通过线性外推法，将暴露剂量除以系数（HT25/0.25），得到相应的人类终身癌症风险。即使本方法仅考虑单个剂量反应点，但使用这种无需计算机程序就能轻松计算的新方法得到的结果，与基于计算机的外推方法（如线性化多阶段模型和使用LED10的基准方法）的结果非常吻合。为克服本方法可能存在的缺点，建议在估计的终身风险后附上一份评论声明，对可能与致癌风险相关的数据进行全面评估，并指出实际人类风险可能高于或低于计算出的终身风险。通过使用本指南以及一套统一的标准和默认值，终身癌症风险的计算应具有透明度且易于理解。
