Gradient, Cambridge, Massachusetts 02138, USA.
Crit Rev Toxicol. 2011 Nov;41(10):822-903. doi: 10.3109/10408444.2011.616877.
We used a hypothesis-based weight-of-evidence (HBWoE) approach to analyze the evidence regarding the hypothesis that chlorpyrifos can cause neurodevelopmental effects below the threshold for inhibition of acetylcholinesterase activity in the nervous system, which is an established mode of action for chlorpyrifos neurotoxicity. The epidemiology data do not consistently demonstrate associations between chlorpyrifos exposure and neurodevelopmental toxicity, and the animal toxicity data do not provide clear evidence that neurodevelopmental effects occur at doses below the threshold for acetylcholinesterase inhibition. The alternative mechanisms proposed to underlie potential neurodevelopmental effects in humans have been observed in the absence of acetylcholinesterase inhibition in a few in vitro studies but not in the developing brain in vivo. We provide perspective on the HBWoE approach compared with frameworks developed by the United States Environmental Protection Agency and the European Center for Ecotoxicology and Toxicology of Chemicals. We suggest that our HBWoE approach offers advantages over these frameworks in providing a better perspective on how to integrate all of the relevant data and how to use each line of evidence to inform the integration of other kinds of data or compare alternative hypotheses. Based on an HBWoE analysis, we conclude that a causal association between chlorpyrifos exposure and neurodevelopmental effects in the absence of acetylcholinesterase inhibition in the brain is not plausible in humans, and the few positive associations observed in epidemiology studies are most likely attributable to alternative explanations.
我们采用基于假设的证据权重（HBWoE）方法分析了以下假设的证据：毒死蜱可在神经系统中乙酰胆碱酯酶活性抑制阈值以下引起神经发育影响，而这是毒死蜱神经毒性的既定作用模式。流行病学数据并未一致表明接触毒死蜱与神经发育毒性之间存在关联，动物毒性数据也未提供明确证据表明神经发育影响发生在乙酰胆碱酯酶抑制阈值以下的剂量。在少数体外研究中观察到了一些潜在的神经发育影响的替代机制，但在体内发育的大脑中并未观察到。我们提供了与美国环境保护署和欧洲化学品生态毒理学和毒理学中心制定的框架相比，基于假设的证据权重方法的观点。我们认为，与这些框架相比，我们的基于假设的证据权重方法在如何整合所有相关数据以及如何使用每条证据线来提供更好的视角方面具有优势，还可以用来整合其他类型的数据或比较替代假设。基于基于假设的证据权重分析，我们得出结论，在人类中，没有大脑中乙酰胆碱酯酶抑制的情况下，接触毒死蜱与神经发育影响之间的因果关系是不合理的，流行病学研究中观察到的少数阳性关联很可能归因于替代解释。
