Mixture effects of two plant protection products in liver cell lines

Food Chem Toxicol. 2018 Feb;112:299-309. doi: 10.1016/j.fct.2017.12.067. Epub 2017 Dec 30.


Pesticide products contain one or more active substances as well as adjuvants, which are added for example as solvents or antioxidants. Nevertheless, only the active substances are evaluated with a comprehensive battery of mammalian toxicity tests. However, in some cases mixture effects of active substances and adjuvants may occur, leading to increased toxicity of the products. To address this issue, we investigated effects of active substances with known hepatotoxicity and two commonly used fungicides: Priori Xtra® and Adexar®. For this purpose, respective active substances individually and in combination as well as the products were applied to two human hepatoma cell lines (HepaRG and HepG2) in a broad dose range. The results of cytotoxicity analysis, nuclear receptor transactivation (AhR, CAR, PXR), mRNA and protein expression of xenobiotic metabolizing enzymes (CYP1A1, CYP2B6 and CYP3A4) allow the conclusion that active substances and plant protection products differ in terms of their in vitro toxicity. The products activate AhR, while the individual active substances as well as the combination of the active substances have no or only minor effects. The present results support the hypothesis that plant protection products may have a modified toxicity as compared to active substances alone, consequently requiring more comprehensive testing.

Keywords: Hepatotoxicity; In vitro; Mixture effects; Pesticides; Triazoles.

MeSH terms

  • Cell Line
  • Cytochrome P-450 CYP1A1 / antagonists & inhibitors
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1A1 / metabolism
  • Fungicides, Industrial / chemistry
  • Fungicides, Industrial / toxicity*
  • Hep G2 Cells
  • Humans
  • Liver / drug effects*
  • Liver / enzymology
  • Protective Agents / chemistry
  • Protective Agents / pharmacology*
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism


  • Fungicides, Industrial
  • Protective Agents
  • Receptors, Cytoplasmic and Nuclear
  • Cytochrome P-450 CYP1A1