Mumtaz M M, De Rosa C T, Groten J, Feron V J, Hansen H, Durkin P R
Division of Toxicology, Agency for Toxic Substances and Disease Registry, Atlanta, GA 30329-2238, USA.
Environ Health Perspect. 1998 Dec;106 Suppl 6(Suppl 6):1353-60. doi: 10.1289/ehp.98106s61353.
The Agency for Toxic Substances and Disease Registry (ATSDR), in collaboration with the Dutch Organization for Applied Scientific Research (TNO) Nutrition and Food Research Institute, is conducting studies to evaluate the role of chemical interactions in the expression of toxicity from low-level exposure to combinations of chemicals. The goal of this collaborative effort is to use a weight-of-evidence (WOE) approach to estimate joint toxicity of some simple chemical mixtures and to compare the estimations with test results from animal toxicity studies. The WOE approach uses individual chemical dose-response assessments and algorithms that incorporate various assumptions regarding potential chemical interactions. Qualitative evaluations were prepared for binary combinations of chemicals for the effect of butyl hydroxyanisole on di(2-ethylhexyl)phthalate, the effect of stannous chloride on Cd chloride (CdCl2), and the effect of CdCl2 on loperamide. Analyses of these evaluations and their comparison with the conclusions of laboratory animal experiments indicate that the WOE approach can be used to estimate qualitatively the joint toxicity of such simple mixtures. To further test the utility of the WOE approach, qualitative and semiquantitative evaluations were prepared for two chemical mixtures--one with similarly acting halogenated aliphatics (trichloroethylene, tetrachloroethylene, hexachloro-1,3-butadiene[HCBD], and 1,1,2-trichloro-3,3,3-trifluoropropene [TCTFP]) and the other with dissimilarly acting nephrotoxic components (mercuric chloride, lysinolalanine, D-limonene, and HCBD). These two sets of data were used to estimate the overall toxicities of the mixtures using the WOE algorithm for the mixture. The comparison of the results of the estimated toxicity with experimentally determined toxicity of the mixture of similarly acting nephrotoxicants demonstrated that the WOE approach correctly adjusted for the observed interactions in experimental animal studies. However, this was not true for the mixture of dissimilarly acting nephrotoxicants. This could be attributed to the fact that WOE evaluations are based on dose additivity that postulates that all chemicals in a given mixture act in the same way--by the same mechanism--and differ only in their potencies. In these cases the WOE approach evaluations, based on consideration of common mechanisms for simple chemical mixtures, can lead to better estimates of joint toxicity of chemical mixtures than the default assumption of dose additivity. The results also show that the WOE evaluations should be target-organ specific because none of the models tested could approximate the observed responses in organs other than the target organs in the laboratory animal studies.
美国有毒物质与疾病登记署（ATSDR）与荷兰应用科学研究组织（TNO）营养与食品研究所合作，正在开展研究，以评估化学物质相互作用在低水平接触化学物质组合所产生毒性表达中的作用。这项合作努力的目标是采用证据权重（WOE）方法来估计一些简单化学混合物的联合毒性，并将这些估计值与动物毒性研究的测试结果进行比较。WOE方法使用个体化学物质剂量反应评估以及纳入有关潜在化学物质相互作用各种假设的算法。针对化学物质的二元组合，就丁基羟基茴香醚对邻苯二甲酸二（2-乙基己基）酯的影响、氯化亚锡对氯化镉（CdCl2）的影响以及CdCl2对洛哌丁胺的影响进行了定性评估。对这些评估结果及其与实验动物实验结论的比较分析表明，WOE方法可用于定性估计此类简单混合物的联合毒性。为进一步测试WOE方法的实用性，针对两种化学混合物进行了定性和半定量评估——一种含有作用相似的卤代脂肪族化合物（三氯乙烯、四氯乙烯、六氯-1,3-丁二烯[HCBD]和1,1,2-三氯-3,3,3-三氟丙烯[TCTFP]），另一种含有作用不同的肾毒性成分（氯化汞、赖氨酰丙氨酸、D-柠檬烯和HCBD）。利用WOE算法对混合物的这两组数据进行分析，以估计混合物的总体毒性。将估计毒性结果与作用相似的肾毒性物质混合物的实验测定毒性进行比较，结果表明WOE方法在实验动物研究中正确地对观察到的相互作用进行了调整。然而，对于作用不同的肾毒性物质混合物而言并非如此。这可能归因于WOE评估基于剂量相加性这一事实，该假设假定给定混合物中的所有化学物质以相同方式——通过相同机制——起作用，只是效力不同。在这些情况下，基于考虑简单化学混合物共同机制的WOE方法评估，相比默认的剂量相加性假设，能够更好地估计化学混合物的联合毒性。结果还表明，WOE评估应针对特定靶器官，因为在实验动物研究中，所测试的模型均无法近似靶器官以外其他器官观察到的反应。
