Bolt H M, Mumtaz M M
Institut für Arbeitsphysiologie, Universität Dortmund, Germany.
Food Chem Toxicol. 1996 Nov-Dec;34(11-12):1179-81. doi: 10.1016/s0278-6915(97)00096-3.
Basic concepts of 'dose/concentration additivity' and 'response addition/independence' may be applied to evaluate chemical mixtures in human toxicology, as well as in ecotoxicology. In the case of compounds that cause the same toxicological effect by the same mechanism, 'dose addition' is a more plausible form of joint action than 'response addition'. Data on the effects of halogenated hydrocarbons on the kidney, the effects of organic solvents on the central nervous system, and the effects of organophosphates on cholinesterase, are the basis of this assumption. For such compounds, response addition will generally underestimate risk. None the less, both dose addition and response addition are 'non-interactive' forms of joint action. As such, neither additivity assumption will accurately predict risk for compounds that exhibit toxicological interactions regardless of the primary mechanism(s) of toxicity. More often, the additivity approach overestimates the risk of a combination of chemicals. From a public health perspective, such results over-protect the public; hence this approach can be used for standard setting. The introduction of a special safety factor of 10 for the standard setting for mixtures in addition to those normally used for deriving acceptable daily intakes, reference doses or minimal risk levels is not supported by data. Instead, each exposure scenario should be considered on a case-by-case basis. Furthermore, considerations of multiple endpoints, including multiple organs, multiple effects, multiple mechanisms and potential interactions between such mechanisms, are very desirable for overall toxicity and risk assessment of chemical mixtures. In conclusion, additivity could be used to estimate potential risks for a combination of chemicals: only if scientific data support independence of effects can response independence be used as an alternative for standard setting.
“剂量/浓度相加”和“反应相加/独立”的基本概念可应用于评估人类毒理学以及生态毒理学中的化学混合物。对于通过相同机制产生相同毒理学效应的化合物，“剂量相加”是比“反应相加”更合理的联合作用形式。关于卤代烃对肾脏的影响、有机溶剂对中枢神经系统的影响以及有机磷酸酯对胆碱酯酶的影响的数据，是这一假设的基础。对于此类化合物，反应相加通常会低估风险。尽管如此，剂量相加和反应相加都是联合作用的“非交互性”形式。因此，对于表现出毒理学相互作用的化合物，无论毒性的主要机制如何，这两种相加假设都无法准确预测风险。更常见的情况是，相加方法会高估化学物质组合所带来的风险。从公共卫生的角度来看，这样的结果过度保护了公众；因此，这种方法可用于标准制定。在推导可接受的每日摄入量、参考剂量或最小风险水平时，除了通常使用的安全系数外，为混合物标准制定引入一个特殊的10倍安全系数是没有数据支持的。相反，应该根据具体情况对每个暴露场景进行逐一考虑。此外，对于化学混合物的整体毒性和风险评估，考虑多个终点，包括多个器官、多种效应、多种机制以及这些机制之间的潜在相互作用，是非常有必要的。总之，相加性可用于估计化学物质组合的潜在风险：只有在科学数据支持效应独立性的情况下，反应独立性才能用作标准制定的替代方法。
