Moser Virginia C, Simmons Jane Ellen, Gennings Chris
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory/Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Toxicol Sci. 2006 Jul;92(1):235-45. doi: 10.1093/toxsci/kfj189. Epub 2006 Apr 11.
The estimation of risk following exposure to mixtures is an important feature of pesticide risk assessment. Also of concern is the potential for increased sensitivity of the young to pesticide toxicity. We have conducted interaction studies using a mixture of five organophosphorus (OP) pesticides (chlorpyrifos, diazinon, dimethoate, acephate, and malathion) in both adult (published previously) and preweanling rats using a fixed-ratio ray design. In the present study, cholinesterase inhibition and behavioral changes (motor activity, gait, and tail-pinch response) were measured in 17-day-old Long-Evans male rats following acute exposure to the OPs. The ratio of pesticides in the mixture reflected the relative dietary exposure estimates projected by the U.S. Environmental Protection Agency Dietary Exposure Evaluation Model. Dose-response data were collected for each OP alone, which were used (alone or in conjunction with the mixture data) to build an additivity model to predict the effects of the pesticide mixture along a ray of increasing total doses, using the same fixed ratio of components. The mixture data (full ray) were similarly modeled and statistically compared to the additivity model along the ray. Since malathion has been shown to produce synergistic interactions with certain OPs, it was of interest to evaluate the influence of malathion in this study. A second pesticide mixture, without malathion (reduced ray), was tested using the same dose levels of the remaining four OPs. Analysis of the full ray revealed significant greater-than-additive responses for all endpoints. The magnitude of this shift ranged from two- to threefold for estimates of the ED(20) and ED(50). The deviation from additivity was also detected in the reduced ray for all but two endpoints (motor activity and tail-pinch response); however, for all endpoints, the reduced ray was significantly different from the full ray. Thus, greater-than-additive responses were detected in preweanling rats with this OP mixture, and this effect can only partially be attributed to the malathion in the mixture.
接触混合物后的风险评估是农药风险评估的一个重要特征。同样令人关注的是，幼龄动物对农药毒性的敏感性可能会增加。我们使用固定比例射线设计，对成年大鼠（此前已发表）和断奶前大鼠进行了五种有机磷（OP）农药（毒死蜱、二嗪农、乐果、乙酰甲胺磷和马拉硫磷）混合物的相互作用研究。在本研究中，对17日龄的Long-Evans雄性大鼠急性暴露于有机磷农药后，测量了胆碱酯酶抑制和行为变化（运动活性、步态和夹尾反应）。混合物中农药的比例反映了美国环境保护局膳食暴露评估模型预测的相对膳食暴露估计值。单独收集每种有机磷农药的剂量反应数据，并将其（单独或与混合物数据结合使用）构建一个相加模型，以预测沿着总剂量增加射线的农药混合物的效应，使用相同的固定成分比例。混合物数据（完整射线）也进行了类似建模，并与沿射线的相加模型进行了统计比较。由于马拉硫磷已被证明与某些有机磷农药产生协同相互作用，因此在本研究中评估马拉硫磷的影响很有意义。使用其余四种有机磷农药的相同剂量水平，测试了第二种不含马拉硫磷的农药混合物（减少射线）。对完整射线的分析显示，所有终点的反应均显著大于相加反应。对于ED(20)和ED(50)的估计，这种变化幅度在两倍至三倍之间。除两个终点（运动活性和夹尾反应）外，在减少射线中也检测到与相加性的偏差；然而，对于所有终点，减少射线与完整射线显著不同。因此，在断奶前大鼠中使用这种有机磷农药混合物检测到大于相加的反应，但这种效应只能部分归因于混合物中的马拉硫磷
