Hattis Dale, Baird Sandra, Goble Robert
Center for Technology, Environment, and Development, George Perkins Marsh Institute, Clark University, 950 Main Street, Worcester, MA 01610, USA.
Drug Chem Toxicol. 2002 Nov;25(4):403-36. doi: 10.1081/dct-120014793.
This paper discusses the merits and disadvantages of a specific proposal for a numerical calculation of the reference dose (RfD) with explicit recognition of both uncertainty and variability. It is suggested that the RfD be the lower (more restrictive) value of: The daily dose rate that is expected (with 95% confidence) to produce less than 1/100,000 incidence over background of a minimally adverse response in a standard general population of mixed ages and genders, or The daily dose rate that is expected (with 95% confidence) to produce less than a 1/1000 incidence over background of a minimally adverse response in a definable sensitive subpopulation. Developing appropriate procedures to make such estimates poses challenges. To be a viable replacement for current RfDs, a numerical definition needs to be A plausible representation of the risk management values that both lay people and "experts" believe are intended to be achieved by current RfDs, (while better representing the "truth" that current RfDs cannot be expected to achieve zero risk with absolute confidence for a mixed population with widely varying sensitivities), Estimable with no greater amount of chemical specific information than is traditionally collected to estimate current RfD values, Subjected to a series of comparisons with existing RfDs to evaluate overall implications for current regulatory values, A more flexible value in the sense of facilitating the development of procedures to allow the incorporation of more advanced technical information--e.g., defined data on human distributions of sensitivity; information on comparative pharmacokinetic and/or pharmacodynamics in humans vs. test species, etc. The discussion evaluates the straw man proposal in the light of each of these points, and assesses the risks and uncertainties inherent in present RfDs by applying existing distributional information on various uncertainty factors to 18 of 20 randomly-selected entries from IRIS. The analysis here suggests that current RfDs seem to meet the 1/100,000 risk criterion with only somewhat better than 50% confidence. However, the current RfDs appear to generally fall short of the goal of meeting this risk criterion with 95% confidence, typically by an order of magnitude in dose or somewhat more. The single most important uncertainty is the extent of human interindividual variability in the doses of specific chemicals that cause adverse responses. Our major conclusion is that with some important assumptions, it is currently feasible to both specify quantitative probabilistic performance objectives for RfDs and to make tentative assessments about whether specific current RfDs for real chemicals seem to meet those objectives. Similarly it is also possible to make preliminary estimates of how much risk is posed by exposures in the neighborhood of current RfDs, and what the uncertainties are in such estimates. It is therefore possible to harmonize cancer and noncancer risk assessments by making quantitative noncancer risk estimates comparable to those traditionally made for carcinogenic risks. The benefits from this change will be an increase in the candor of public discussion of the possible effects of exposures to chemicals posing non-cancer risks, and encouragement for the collection of better scientific information related to toxic risks in people--particularly the extent and distributional form of interindividual differences among people in susceptibility.
本文讨论了一项关于参考剂量（RfD）数值计算的特定提议的优缺点，该提议明确认识到不确定性和变异性。建议RfD为以下两者中的较低（更严格）值：在年龄和性别混合的标准普通人群中，预期（95%置信度）产生低于背景下最低不良反应发生率十万分之一的每日剂量率；或在可定义的敏感亚人群中，预期（95%置信度）产生低于背景下最低不良反应发生率千分之一的每日剂量率。制定合适的程序进行此类估计具有挑战性。要成为当前RfD的可行替代方案，数值定义需要是：对风险管理值的合理表述，普通民众和“专家”都认为当前RfD旨在实现该值（同时更好地体现“真相”，即对于敏感性差异很大的混合人群，不能期望当前RfD能绝对确定地实现零风险），在估计时所需的化学物质特定信息不超过传统上收集用于估计当前RfD值的量，与现有RfD进行一系列比较以评估对当前监管值的总体影响，在促进开发允许纳入更先进技术信息的程序方面更具灵活性——例如，关于人类敏感性分布的定义数据；人类与试验物种的比较药代动力学和/或药效学信息等。讨论根据这些要点对这个稻草人式提议进行了评估，并通过将关于各种不确定性因素的现有分布信息应用于IRIS中随机选择的20个条目中的18个，评估了当前RfD中固有的风险和不确定性。这里的分析表明，当前的RfD似乎仅以略高于50%的置信度满足十万分之一的风险标准。然而，当前的RfD似乎总体上未达到以95%置信度满足该风险标准的目标，通常在剂量上相差一个数量级或更多。唯一最重要的不确定性是导致不良反应的特定化学物质剂量在人群个体间的变异程度。我们的主要结论是，在一些重要假设下，目前既可以为RfD指定定量概率性能目标，也可以初步评估实际化学物质的特定当前RfD是否似乎满足这些目标。同样，也可以初步估计当前RfD附近的暴露所带来的风险有多大，以及此类估计中的不确定性是什么。因此，通过使定量非癌症风险估计与传统上对致癌风险所做的估计具有可比性，可以协调癌症和非癌症风险评估。这一变化的好处将是增加公众对接触具有非癌症风险的化学物质可能产生的影响进行讨论的坦诚度，并鼓励收集与人群中毒性风险相关的更好的科学信息——特别是人群个体间易感性差异的程度和分布形式。
