Department of Biosciences, Università degli Studi di Milano, via Celoria 26, 20133, Milan, Italy.
International Centre for Pesticides and Health Risk Prevention (ICPS), University Hospital Luigi Sacco, via G.B Grassi 74, 20157, Milan, Italy.
Arch Toxicol. 2013 Nov;87(11):1989-1997. doi: 10.1007/s00204-013-1048-y. Epub 2013 Apr 4.
The effect of mixtures of azole fungicides on development of postimplantation rat whole-embryos cultured in vitro has been tested. On the basis of bench mark dose (BMD) modeling of the in vitro effect in rat embryo, the potency of 7 azoles was determined and compared. Then, relative potency factors have been derived based on either the NOAEL or on the BMD curve. Alternatively, each compound was used as index compound (IC), and IC-equivalent concentrations have been calculated for each mixture. Expected effects of such IC-equivalent concentrations of the mixture were derived from the appropriate BMD curve. Test mixture includes the agrochemicals triadimefon and imazalil (MIX2) or triadimefon, imazalil, and the clinically used fluconazole (MIX3) at their previously determined no-effect concentration, corresponding to approximately a benchmark response of 5-10 %. Subsequently, we tested the effect of a mixture of the agrochemicals triadimefon, imazalil, triadimenol, cyproconazole, tebuconazole, and flusilazole (MIX6) at concentration levels derived from their established human acceptable daily intake. MIX6 was also added with fluconazole at concentration levels indicated as the minimum therapeutically effective plasmatic concentration (MIX7A) or ten times this level (MIX7B). Generally, the experimental response was higher than the estimated one, by a factor of 2-6. Our data suggest that it is in principle correct to assume that azoles act as teratogens via a common mode of action and therefore should be grouped together for risk assessment. The synergistic effect needs to be confirmed with more combinations of concentrations/compounds in vitro and with specific in vivo experiments.
已测试唑类杀菌剂混合物对体外培养的植入后大鼠全胚胎发育的影响。基于大鼠胚胎体外效应的基准剂量 (BMD) 建模，确定并比较了 7 种唑类化合物的效价。然后，基于 NOAEL 或 BMD 曲线推导了相对效价因子。或者，将每种化合物用作指示化合物 (IC)，并计算了每种混合物的 IC 等效浓度。混合物的这种 IC 等效浓度的预期效应源自适当的 BMD 曲线。测试混合物包括农用化学品三唑酮和咪鲜胺（MIX2）或三唑酮、咪鲜胺和临床上使用的氟康唑（MIX3），其无效应浓度先前已确定，对应于基准反应约为 5-10%。随后，我们测试了农用化学品三唑酮、咪鲜胺、三唑醇、环丙唑醇、戊唑醇和氟硅唑混合物（MIX6）在其确定的人类可接受日摄入量衍生的浓度水平下的作用。MIX6 还添加了氟康唑，浓度水平为最低治疗有效血浆浓度（MIX7A）或该水平的 10 倍（MIX7B）。通常，实验反应比估计值高 2-6 倍。我们的数据表明，原则上可以假设唑类通过共同作用模式作为致畸物，因此应将它们分组进行风险评估。协同作用需要通过更多的体外浓度/化合物组合和特定的体内实验来证实。
