A unified approach to risk assessment for cancer and noncancer endpoints based on benchmark doses and uncertainty safety factors
A unified approach to risk assessment for cancer and noncancer endpoints based on benchmark doses and uncertainty safety factors
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DOI：
10.1006/rtph.1998.1279
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发表时间：
1999-04-01
影响因子：
3.4
通讯作者：
Krewski, D
中科院分区：
文献类型：
--
作者：
Gaylor, DW;Kodell, RL;Krewski, D
毒理学的一个基本目标是确定人类接触有毒物质的安全水平。由于缺乏信息来建立人类通常经历的低暴露水平下的剂量-反应关系，高剂量到低剂量的线性外推法通常用于估计致癌风险，而未观察到的不良反应水平除以不确定性（安全）因素被广泛用于制定人类非癌症影响的暴露指南。对这种二分法的基础和影响进行了检验和质疑。建议采用统一的方法来建立癌症和非癌症终点的人类暴露指南。建议使用估计在人体研究中10%的个体或实验室实验中10%的动物中产生过量不良健康影响发生率的剂量的较低置信限作为起点。这一剂量将除以适当的不确定因素，以建立人类接触准则。对于严重的不可逆转的不利健康影响，我们建议动物数据的总默认不确定性因子（除数）为10,000数量级，这与目前的指导方针相当。对于可逆的生物效应，可以采用较小的默认不确定性因子，约为1000。这与目前通常使用的除数相当，当出发点是最低观察到的不利影响水平时。有人断言，一般可获得的毒理学资料不能保证对人体低水平接触的风险进行数值估计。相反，我们支持对基准剂量除以适当的不确定性因素的所有不利健康影响采取统一方法，以建立人类接触有毒物质的准则。(C) 1999学术出版社。
A fundamental goal of toxicology is to determine safe levels of human exposure to toxic substances. In the absence of information to establish dose-response relationships at low exposure levels generally experienced by humans, high-dose to low-dose linear extrapolation is generally used for estimating carcinogenic risks and the no-observed-adverse-effect-level divided by uncertainty (safety) factors is widely used for establishing human exposure guidelines for noncancer effects. The basis and impact of this dichotomy is examined and questioned. It is proposed that a unified approach be adopted for establishing human exposure guidelines for both cancer and noncancer endpoints. It is suggested that a lower confidence limit on the dose estimated to produce an excess incidence of adverse health effects in 10% of the individuals in a human study or 10% of the animals in laboratory experiments be used as a point-of-departure. This dose would be divided by appropriate uncertainty factors to establish human exposure guidelines. For severe irreversible adverse health effects we suggest a total default uncertainty factor (divisor) for animal data on the order of 10,000, which is comparable to current guidelines. For reversible biological effects a smaller default uncertainty factor on the order of 1000 may be employed. This is comparable to the divisor often used currently when the point-of-departure is the lowest-observed-adverse-effect-level. It is asserted that the toxicological information generally available does not warrant numerical estimates of risk at low levels of human exposure. Rather, we support a unified approach for all adverse health effects of dividing a benchmark dose by appropriate uncertainty factors to establish guidelines for human exposures to toxic substances. (C) 1999 Academic Press.