Suchergebnisse

Recent EU legislation for chemical substances requires a particular assessment of endocrine disrupting properties that may cause adverse effects in humans. Especially for pesticidal active substances, measures concerning specific scientific criteria for the determination of endocrine disrupting properties should have been presented by the European Commission until December 2013. But presently, no specific science-based approach for the assessment of these substances has been agreed upon. This paper is discussing common scientific principles for the evaluation and grouping of substances with endocrine disrupting properties that may cause adverse effects in humans. A matrix-based approach is proposed to be applied in various fields of scientific evaluation of chemical substances, which is based on a scientific evaluation of all available data that may contribute to ensure a high level of protection of human health. This evaluation is expected to be proportionate, consistent and predictable to support administrative decisions in regulatory toxicology. However, a scientifically based categorisation in a decision matrix as a backbone for specific and legally binding rules should be performed according to the relevant EU regulations for the aforementioned groups of substances. Considering the complexity of the matter, it appears appropriate to base possible categorisation on considerations in a decision matrix, which take into account severity, reversibility, potency and consistency of an adverse effect. Based on this decision matrix it should be possible to allocate substances falling under the WHO/IPCS definition to categorise as endocrine disruptors (EDs) or even dispense such substances from categorisation.

Consumers are exposed to multiple residues of different pesticides via the diet. Therefore, EU legislation for pesticides requires the evaluation of single active substances as well as the consideration of combination effects. Hence the analysis of combined effects of substances in a broad dose range represents a key challenge to current experimental and regulatory toxicology. Here we report evidence for additive effects for (tri)azole fungicides, a widely used group of antifungal agents, in the human placental cell line Jeg-3. In addition to the triazoles cyproconazole, epoxiconazole, flusilazole and tebuconazole and the azole fungicide prochloraz also pesticides from other chemical classes assumed to act via different modes of action (i.e., the organophosphate chlorpyrifos and the triazinylsulfonylurea herbicide triflusulfuron-methyl) were investigated. Endpoints analysed include synthesis of steroid hormone production (progesterone and estradiol) and gene expression of steroidogenic and non-steroidogenic cytochrome-P-450 (CYP) enzymes. For the triazoles and prochloraz, a dose dependent inhibition of progesterone production was observed and additive effects could be confirmed for several combinations of these substances in vitro. The non-triazoles chlorpyrifos and triflusulfuron-methyl did not affect this endpoint and, in line with this finding, no additivity was observed when these substances were applied in mixtures with prochloraz. While prochloraz slightly increased aromatase expression and estradiol production and triflusulfuron-methyl decreased estradiol production, none of the other substances had effects on the expression levels of steroidogenic CYP-enzymes in Jeg-3 cells. For some triazoles, prochloraz and chlorpyrifos a significant induction of CYP1A1 mRNA expression and potential combination effects for this endpoint were observed. Inhibition of CYP1A1 mRNA induction by the AhR inhibitor CH223191 indicated AhR receptor dependence of this effect.

There is growing concern that environmental substances with a potential to modulate the hormonal system may have harmful effects on human health. Consequently, a new EU regulation names endocrine disrupting properties as one of the cut-off criteria for the approval of plant protection products, although it currently fails to provide specific science-based measures for the assessment of substances with such properties. Since specific measures are to be presented by the European Commission in 2013 the development of assessment and decision criteria is a key challenge concerning the implementation of this new EU regulation. Proposals of such decision criteria for substances with potential endocrine disrupting properties in human health risk assessment were developed by the German Federal Institute for Risk Assessment (BfR) and discussed at an expert workshop in November 2009. Under consideration of the requirements laid down within the new plant protection product legislation and the scientific discussions during the workshop, a conceptual framework on evaluation of substances for endocrine disrupting properties in a regulatory context is presented in this paper. Central aspects of the framework include assessment of adversity of effects, establishment of a mode/mechanism of action in animals, considerations concerning the relevance of effects to humans and two options for a regulatory decision.