US Environmental Protection Agency, Washington, DC 20460, USA.
Crit Rev Toxicol. 2010 Jan;40(1):16-23. doi: 10.3109/10408440903401529.
Prior to October 2007, the US Environmental Protection Agency (EPA) required both 13-week and 1-year studies in Beagle dogs be submitted in support of registration for pesticides. Following an extensive retrospective analysis, we (the authors) determined that the 1-year toxicity dog study should be eliminated as a requirement for pesticide registration. The present work presents this retrospective analysis of results from 13-week and 1-year dog studies for 110 conventional pesticide chemicals, representing more than 50 classes of pesticides. The data were evaluated to determine if the 13-week dog study, in addition to the long-term studies in two rodent species (mice and rats), were sufficient for the identification of no observed adverse effect levels (NOAELs) and lowest observed adverse effect levels (LOAELs) for the derivation of chronic reference doses (RfD). Only pesticides with adequate 13-week and 1-year duration studies were included in the present evaluation. Toxicity endpoints and dose-response data from 13-week and 1-year studies were compared. The analysis showed that 70 of the 110 pesticides had similar critical effects regardless of duration and had NOAELs and LOAELs within a difference of 1.5-fold of each other. For the remaining 40 pesticides, 31 had lower NOAELs and LOAELs in the 1-year study, primarily due to dose selection and spacing. In only 2% of the cases were additional toxic effects identified in the 1-year study that were not observed in the 13-week study and/or in the rodent studies. In 8% of the cases, the 1-year dog had a lower NOAEL and/or LOAEL than the 13-week study, but there would have been no regulatory impact if the 1-year dog study had not been performed because adequate data were available from the other required studies. A dog toxicity study beyond 13-weeks does not have significant impact on the derivation of a chronic RfD for pesticide risk assessment.
在 2007 年 10 月之前，美国环保署（EPA）要求在支持农药注册时提交 13 周和 1 年的犬类研究。经过广泛的回顾性分析，我们（作者）确定应取消 1 年毒性犬研究作为农药注册的要求。本工作回顾性分析了 110 种常规农药化学品的 13 周和 1 年犬研究结果，这些化学品代表了 50 多种农药类别。评估这些数据的目的是确定 13 周犬研究是否与两种啮齿动物（小鼠和大鼠）的长期研究一起足以确定无观察到不良影响水平（NOAEL）和最低观察到不良影响水平（LOAEL），以便推导出慢性参考剂量（RfD）。只有具有足够 13 周和 1 年持续时间研究的农药才包括在本评估中。将来自 13 周和 1 年研究的毒性终点和剂量反应数据进行了比较。分析表明，110 种农药中有 70 种具有相似的关键作用，无论持续时间如何，其 NOAEL 和 LOAEL 相差 1.5 倍。对于其余的 40 种农药，有 31 种在 1 年研究中具有较低的 NOAEL 和 LOAEL，主要是由于剂量选择和间隔。在 1 年研究中仅发现了 2%的情况下，在 13 周研究中未观察到的其他毒性作用，并且/或在啮齿动物研究中未观察到其他毒性作用。在 8%的情况下，1 年犬的 NOAEL 和/或 LOAEL 低于 13 周研究，但如果未进行 1 年犬研究，也不会对农药风险评估的慢性 RfD 的推导产生重大影响，因为其他所需研究中提供了足够的数据。超过 13 周的犬毒性研究对慢性 RfD 的推导不会对农药风险评估产生重大影响。
