Use of the benchmark dose approach in risk assessment Guidance of the Scientific Committee
Use of the benchmark dose approach in risk assessment Guidance of the Scientific Committee
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DOI：
10.2903/j.efsa.2009.1150
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发表时间：
2009-06-01
期刊：
影响因子：
3.3
通讯作者：
Vannier, Philippe
中科院分区：
文献类型：
--
作者：
Barlow, Susan;Chesson, Andrew;Vannier, Philippe
考虑到 EFSA 科学委员会和科学小组在评估风险时需要使用透明且科学合理的方法，EFSA 要求科学委员会评估关于基准剂量 (BMD) 方法实用性的现有信息，作为传统使用的 NOAEL 方法的替代方案，并就 EFSA 是否应使用 BMD 方法以及在什么情况下使用该方法是适当的提出建议。科学委员会还被要求就如何使用 BMD 方法分析实验研究的剂量反应数据提供一些指导，并研究这种方法对观察性流行病学研究数据的可能应用。最后，科学委员会被要求就在使用 BMD 方法推导参考点时是否需要选择适当的不确定性因素提出建议。传统上，当实验动物数据用于食品中非遗传毒性和致癌物质的风险评估时，关键的未观察到不良影响水平 (NOAEL) 和/或最低观察到不良影响水平 (LOAEL) 物质的影响，形成了推导基于健康的指导值的参考点，例如可接受的每日摄入量（ADD）。然而，虽然这种方法可以利用定性信息，但它不使用定量方式可用的数据。相反，BMD方法广泛使用来自实验动物研究或观察性流行病学研究的剂量反应数据，以更好地描述和量化潜在风险。EFSA尚未系统地使用 到目前为止，BMD 方法虽然一些 EFSA 科学小组偶尔也应用 BMD 方法。此外，计算BMD的实验数据也会不时提交。 EFSA 的科学委员会还在之前的意见中建议使用 BMD 方法来推导参考点，以估计具有遗传毒性和致癌性的物质的暴露幅度。在比较了强度和致癌性之后， 鉴于 BMD 和 NOAEL 方法推导风险评估参考点的缺点，科学委员会得出结论认为，BMD 方法是比 NOAEL 推导参考点方法更科学先进的方法，因为它广泛使用了现有的剂量反应数据，并提供了剂量反应数据中不确定性的量化。由于指定的结果，使用 BMD 方法还会产生更一致的参考点 基准响应。虽然目前有可用于 BMD 分析的软件，但科学委员会指出，这种情况正在不断发展，预计中期内将出现重大发展，例如模型平均，连续数据分析。科学委员会还认为，当毒性测试指南，例如修订了 OECD 指南，考虑了 BMD 方法的具体方面。可以预期使用 BMD 方法得出基于健康的指导值 与 NOAEL 方法一样具有保护性，即根据大量风险评估得出的平均值。因此，当前应用的不确定性因素的默认值仍然是适当的，不需要任何额外的不确定性因素。科学委员会认为没有必要重复使用 BMD 方法进行的所有先前评估，因为平均而言，BMD 和 NOAEL 方法给出了可比较的结果。当认为有必要对先前的风险评估进行细化时，例如，当人类 如果暴露量接近 ADI，则 BMD 方法的应用将具有特别的价值。BMD 方法适用于食品中的所有化学品，无论其类别或来源如何，例如：农药、添加剂或污染物。 BMD 方法对于以下情况特别有价值：i) NOAEL 的识别不确定的情况，ii) 为具有基因毒性和毒性的物质的暴露裕度提供参考点。 致癌性，以及 iii) 观察流行病学数据的剂量反应评估。在短期内，强烈鼓励 EFSA 科学小组和单位对上述情况采用 BMD 方法。从长远来看，科学委员会预计 BMD 方法将被用作确定参考点的方法，以得出基于健康的指导值和暴露幅度。为此，认识到在 EFSA 中引入和更广泛使用该软件存在实际考虑，并认识到其应用需要一定水平的专家判断和建模专业知识，科学委员会建议向科学小组和 EFSA 部门的专家提供剂量反应建模和软件使用方面的培训。科学委员会将在两年后审查 EFSA 工作中 BMD 方法的实施情况、经验和可接受性。
Considering the need for transparent and scientifically justifiable approaches to be used when risks are assessed by the Scientific Committee and the Scientific Panels of EFSA, the Scientific Committee was requested by EFSA to assess the existing information on the utility of the benchmark dose (BMD) approach, as an alternative to the traditionally used NOAEL approach, and to make recommendations on whether EFSA should use the BMD approach and under which circumstances this use would be appropriate. The Scientific Committee was also asked to provide some guidance on how to use the BMD approach for analysing dose-response data from experimental studies, and to look at the possible application of this approach to data from observational epidemiological studies. Finally, the Scientific Committee was asked to advise on whether the selection of appropriate uncertainty factors are needed when using the BMD approach for deriving the Reference Point.Traditionally, when experimental animal data are used for risk assessment of substances in food, which are not genotoxic and carcinogenic, the No-Observed-Adverse-Effect-Level (NOAEL) and/or the Lowest-Observed-Adverse-Effect-Level (LOAEL) for the critical effect of a substance, forms the Reference Point for deriving health-based guidance values, such as an Acceptable Daily Intake (ADD. However, while this approach may utilise qualitative information, it does not use the data available in a quantitative way. In contrast, the BMD approach makes extended use of the dose-response data from studies in experimental animals or from observational epidemiological studies to better characterise and quantify potential risks.EFSA has not systematically used the BMD approach so far, although some EFSA Scientific Panels have been applying the BMD approach occasionally. Moreover, experimental data from which a BMD has been calculated are submitted from time to time. EFSA's Scientific Committee has also proposed in a previous Opinion to use the BMD approach for deriving the Reference Point for the estimation of Margins of Exposure for substances that are both genotoxic and carcinogenic.After comparing the strengths and weaknesses of the BMD and NOAEL approaches for deriving Reference Points for risk assessment, the Scientific Committee concludes that the BMD approach is a scientifically more advanced method to the NOAEL approach for deriving a Reference Point, since it makes extended use of available dose-response data and it provides a quantification of the uncertainties in the dose-response data. Using the BMD approach also results in a more consistent Reference Point, as a consequence of the specified benchmark response.Whilst software is currently available for BMD analysis, the Scientific Committee notes that this is evolving and significant developments are anticipated in the medium term, e.g. model averaging, analysis of continuous data.The Scientific Committee also considers that when toxicity test guidelines, e.g. OECD guidelines, are revised, specific aspects of the BMD approach are taken into account.Health-based guidance values derived using the BMD approach can be expected to be as protective as those derived from the NOAEL approach, i.e. on average over a large number of risk assessments. Therefore the default values for uncertainty factors currently applied remain appropriate and there is no need for any additional uncertainty factor.The Scientific Committee does not consider it necessary to repeat all previous evaluations using the BMD approach, because, on average, the BMD and NOAEL approaches give comparable results. Where refinement of previous risk assessments is considered necessary, for instance where the human exposure is close to the ADI, application of the BMD approach would be of particular value.The BMD approach is applicable to all chemicals in food, irrespective of their category or origin, e.g. pesticides, additives or contaminants. The BMD approach is of particular value for i) situations where the identification of a NOAEL is uncertain, ii) providing a Reference Point for the Margin of Exposure in case of substances that are both genotoxic and carcinogenic, and iii) dose-response assessment of observational epidemiological data. In the short term, the EFSA Scientific Panels and Units are strongly encouraged to adopt the BMD approach to situations such as those described above.In the longer term, the Scientific Committee anticipates that the BMD approach will be used as the method of choice for the determination of the Reference Points for deriving health-based guidance values and margins of exposure. To that end, recognising that there are practical considerations regarding its introduction and wider use in EFSA, and recognising that its application requires a level of expert judgement and modelling expertise, the Scientific Committee proposes that training in dose-response modelling and the use of the software be offered to experts in the scientific Panels and EFSA Units. The Scientific Committee would then like to review the implementation, experience and acceptability of the BMD approach in EFSA's work in two years time.