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Imprint
Mechanism of toxicity of triazole fungicides
Project
Project code: BfR-SiP-08-1322-552
Contract period: 01.03.2013
- 31.12.2016
Purpose of research: Applied research
The recent European Regulations for Biocides and Pesticides (Reg.(EC) No. 1107/2009 and 528/2012) foresee an assessment of risks for human health from combination effects of product ingredients. In addition to this, judgement of the relevance of (adverse) effect in laboratory animals requires an in-depth understanding of the mechanisms of toxicity. Finally, the decision about non-approval of active substances in reflection of findings that suggest endocrine disrupting potential (newly included in 1107/2009 and 528/2012) requires an understanding of the mechanisms involved in toxicity. Current research projects run at BfR have provided indications for new mechanisms involved in toxicity of fungicides frequently used in biocides and pesticides. An induction of ABCB1 gene expression in the liver of rats dosed for 28days implies an involvement of in ABC-Transporters (rf. to 2012 report on project 1322-499). A reduction of the expression of the Vitamin D receptor (VDR) - which is regulated homologously with calcitriol levels (if calcitriol, then VDR) - in all organs examined (Testes, adrenals, prostate), accompanied by an induction of CYP27B1 in the liver (activates Vitamin D3) further suggests an involvement of the Vitamin D3 homeostasis (rf. to 2012 report on projects 1322-456 and 499). It will be the objective of this project to follow-up on these indications for new but plausible mechanisms of action of the fungicides under investigation. This is to support the BfR activities in the risk assessment of biocides and pesticides and the corresponding activities by EU and OECD, which engaged in the development of Adverse Outcome Pathways (AOP).
Triazole fungicides show reprotoxic and carcionogenic properties, an influence on the endocrine system and may retard ossification in laboratoiry animals (e.g. EFSA (2010) and CA-Report Propiconazol acc. to 98/8/EC, RMS FI(2007)). Screening for gene expression changes in various organs of rats from a 28-day feeding study, indicated an involvement of Vitamin D signalling and homeostasis as well as an influence on ABC transporters (rf. to report on 1322-499), 2012). Therefore, further mechanistic studies were initiated to clarify the involvement of Vitamin D, its metabolism and transport proteins. Changes in gene expression levels of the transporters Abcb1a, Abcb1b und Slco1a2 and enzymes involved in xenobiotic as well as Vitamin D metabolism and function (Cyp3a, Ugt1a, Cyp2r1, Cyp27b1, Vdr) could be confirmed and were described in detail. Effects on serum PTH levels were measured by ELISA.
Section overview
Subjects
- Crop Protection
- Animal health
- Physiology of Nutrition
- Toxicology
