Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University , Mississippi State, MS , USA .
Crit Rev Toxicol. 2014 Feb;44(2):176-210. doi: 10.3109/10408444.2013.855163. Epub 2013 Nov 25.
Conventional risk assessments for crop protection chemicals compare the potential for causing toxicity (hazard identification) to anticipated exposure. New regulatory approaches have been proposed that would exclude exposure assessment and just focus on hazard identification based on endocrine disruption. This review comprises a critical analysis of hazard, focusing on the relative sensitivity of endocrine and non-endocrine endpoints, using a class of crop protection chemicals, the azole fungicides. These were selected because they are widely used on important crops (e.g. grains) and thereby can contact target and non-target plants and enter the food chain of humans and wildlife. Inhibition of lanosterol 14α-demethylase (CYP51) mediates the antifungal effect. Inhibition of other CYPs, such as aromatase (CYP19), can lead to numerous toxicological effects, which are also evident from high dose human exposures to therapeutic azoles. Because of its widespread use and substantial database, epoxiconazole was selected as a representative azole fungicide. Our critical analysis concluded that anticipated human exposure to epoxiconazole would yield a margin of safety of at least three orders of magnitude for reproductive effects observed in laboratory rodent studies that are postulated to be endocrine-driven (i.e. fetal resorptions). The most sensitive ecological species is the aquatic plant Lemna (duckweed), for which the margin of safety is less protective than for human health. For humans and wildlife, endocrine disruption is not the most sensitive endpoint. It is concluded that conventional risk assessment, considering anticipated exposure levels, will be protective of both human and ecological health. Although the toxic mechanisms of other azole compounds may be similar, large differences in potency will require a case-by-case risk assessment.
传统的作物保护化学品风险评估将潜在的毒性（危害识别）与预期暴露进行比较。已经提出了新的监管方法，这些方法将排除暴露评估，而仅基于内分泌干扰来重点关注危害识别。本综述包括对危害的批判性分析，重点关注内分泌和非内分泌终点的相对敏感性，使用了一类作物保护化学品，唑类杀菌剂。选择这些杀菌剂是因为它们广泛用于重要作物（如谷物），因此可以接触靶标和非靶标植物，并进入人类和野生动物的食物链。羊毛甾醇 14α-脱甲基酶（CYP51）的抑制介导了抗真菌作用。其他 CYP 的抑制，如芳香酶（CYP19），可能导致许多毒理学效应，这些效应也明显存在于人类高剂量接触治疗性唑类药物的情况下。由于其广泛的用途和大量的数据，环氧康唑被选为代表性唑类杀菌剂。我们的批判性分析得出结论，预期人类接触环氧康唑将产生至少三个数量级的安全边际，以防止在假定为内分泌驱动的实验室啮齿动物研究中观察到的生殖效应（即胎儿吸收）。最敏感的生态物种是水生植物浮萍（浮萍），其安全边际对人类健康的保护作用不及对人类健康的保护作用。对于人类和野生动物来说，内分泌干扰不是最敏感的终点。结论是，考虑到预期的暴露水平，传统的风险评估将保护人类和生态健康。尽管其他唑类化合物的毒性机制可能相似，但效力的巨大差异将需要逐个进行风险评估。
