Mixture Effects of Estrogenic Pesticides at the Human Estrogen Receptor α and β

Seeger, Bettina; Klawonn, Frank; Bekale, Boris Nguema; Steinberg, Pablo

doi:10.1371/journal.pone.0147490

Cited by 23 publications

(17 citation statements)

References 33 publications

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“…The usage of receptor-based reporter assays has been established for the quantitative assessment of chemical mixture effects, especially for substances binding to hormone receptors, by means of concentration addition for substances sharing a mode of action (MoA) or independent action for substances with dissimilar MoA (Orton et al 2014;Seeger et al 2016). This system has also been used in the present study and was again capable of showing that the substances used follow the DA/CA model.…”

Section: Relevance Of Omics Data For Risk Assessment Of Pesticide MIXmentioning

confidence: 99%

Assessment of mixture toxicity of (tri)azoles and their hepatotoxic effects in vitro by means of omics technologies

et al. 2019

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Consumers are constantly exposed to chemical mixtures such as multiple residues of different pesticides via the diet. This raises questions concerning potential combination effects, especially because these substances are tested for regulatory purposes on an individual basis. With approximately 500 active substances approved as pesticides, there are too many possible combinations to be tested in standard animal experiments generally requested for regulatory purposes. Therefore, the development of in vitro tools and alternative testing strategies for the assessment of mixture effects is extremely important. As a first step in the development of such in vitro tools, we used (tri)azoles as model substances in a set of different cell lines derived from the primary target organ of these substances, the liver (human: HepaRG, rat: H4IIE). Concentrations were reconciled with measured tissue concentrations obtained from in vivo experiments to ensure comparable effect levels. The effects of the substances were subsequently analyzed by transcriptomics and metabolomics techniques and compared to data from corresponding in vivo studies. The results show that similar toxicity pathways are affected by substances and combinations, thus indicating a similar mode of action and additive effects. Two biomarkers obtained by the approach, CAR and Cyp1A1, were used for mixture toxicity modeling and confirmed the concentration-additive effects, thus supporting the selected testing strategy and raising hope for the development of in vitro methods suitable to detect combination effects and prioritize mixtures of concern for further testing.

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Section: Relevance Of Omics Data For Risk Assessment Of Pesticide MIXmentioning

confidence: 99%

Assessment of mixture toxicity of (tri)azoles and their hepatotoxic effects in vitro by means of omics technologies

et al. 2019

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“…One focus of research on mixture effects of pesticides has been endocrine disruption (Hass et al 2012 ; Orton et al 2011 ; Seeger et al 2016 ). Since the liver is the main target organ of many pesticides, potential hepatotoxic mixture effects are of high relevance.…”

Section: Introductionmentioning

confidence: 99%

Hepatotoxic combination effects of three azole fungicides in a broad dose range

et al. 2017

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Single active substances of pesticides are thoroughly examined for their toxicity before approval. In this context, the liver is frequently found to be the main target organ. Since consumers are generally exposed to multiple residues of different active substances via the diet, it is important to analyse combinations of active substances for potential mixture effects. For the (tri-)azoles, a group of agricultural fungicides and antifungal drugs, combination effects on the liver are likely because of a similar mode of action. Hepatotoxic effects of mixtures of two triazoles (cyproconazole and epoxiconazole) and an imidazole (prochloraz) were investigated in a 28-day feeding study in rats at three dose levels ranging from a typical toxicological reference value to a clear effect dose. Test parameters included organ weights, clinical chemistry, histopathology and morphometry. In addition, molecular parameters were investigated by means of pathway-focused gene expression arrays, quantitative real-time PCR and enzyme activity assays. Effects were compared to those caused by the individual substances as observed at the same dose levels in a previous study. Mixture effects were substantiated by increases in relative and absolute liver weights, histopathological findings and alterations in clinical chemistry parameters at the top dose level. On the molecular level also at lower dose levels, additive effects could be observed for the induction of several cytochrome P 450 enzymes (Cyp1a1, Cyp2b1, Cyp3a2), transporters (Abcb1a, Abcc3) and of genes encoding for enzymes involved in fatty acid or phospholipid metabolism (Ppargc1a, Sc4 mol). In most cases, treatment with mixtures caused a more pronounced effect as compared to the individual substances. However, the assumption of dose additivity was in general sufficiently conservative to cover mixture effects observed under the conditions of the present study.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-017-2087-6) contains supplementary material, which is available to authorized users.

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“…A dramatic enhancement of endocrine effects not predicted from tests on individual compounds (Rajapakse et al, 2002;Silva et al, 2002Silva et al, , 2011 has been observed for some estrogenic chemicals. When three estrogenic test systems were used (Seeger et al, 2016), similar outcomes on mixtures of endocrinedisrupting pesticides were confirmed. The additive/synergistic behavior of endocrine disruptors is likely to be the case with glyphosate and additives in glyphosate-based formulations.…”

Section: The Underlying Principles Of Adjusting Glyphosate Adi Valuesmentioning

confidence: 76%

Hypothetical adjustment of the acceptable daily intake and correction of the underrated risk: A case study of glyphosate-based herbicides

Ibrahim¹

2016

J. Toxicol. Environ. Health Sci.

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Following the introduction of genetically-engineered glyphosate-resistant (GEGR) crops, commercially known as Roundup Ready (RR), no pesticide's active principle has been used as much as glyphosate; yet its safety measures have been sternly disputed. After its classification by the International Agency for Research on Cancer (IARC) as probably carcinogenic to humans in 2015, scientists, activists, regulators and the general public revisited voluminous studies that outweighed the risk of this herbicide and raised ferocious concerns that warranted serious attention. Recently published studies on glyphosate established at least four toxicological principles. First, glyphosate exhibited severe mammalian toxicity at concentrations orders of magnitude lower than its regulatory-promulgated 'No Observed Adverse Effect Level' (NOAEL) or even its 'Chronic Reference Dose' (cRfD) and 'Acceptable Daily Intake' (ADI). Second, even though not transparently scrutinized or officially required for toxicological testing and risk assessment, glyphosate co-formulants and glyphosate-based herbicides (GBHs) are orders of magnitude more toxic than the principle active ingredient alone. Third, glyphosate and GBHs are cytotoxic and endocrine disruptors, and the latter explains why ultra low concentrationsyet environmentally relevant-cause severe chronic toxicity. Fourth, the endocrine disruption likely leads to epigenotoxicity that may be extended to offspring and unexposed descending generations. Taken all together, it can be fairly said that confidence in the regulatory-certified ADI values is highly eroded. To resolve the paradoxical discrepancy between regulatory safety measures and elicited toxicities at concentrations far below these measures, ADI was refined using two safety or adjustment factors. Together, these two factors scale down ADI by four orders of magnitude and bring it to an Adjusted ADI (AADI) value of 2.5 ng/kg bw/day. Contrary to regulatory ADI, the new AADI successfully explains many research findings which demonsted severe mammalian toxicity at concentrations in the neighborhood of nanograms a.i./kg bw/day. This distills confidence in the new AADI value, as well as the magnitude of the proposed safety factors. Glyphosate uses as per human capita, in two countries representing the extremes of adopting RR crops (the USA) or not-adopting these crops (Egypt), were compared. The comparison confirms the association between growing RR crops and the escalated use of glyphosate, and shows that the American public is likely exposed to glyphosate residue at forty times higher levels than the Egyptian public.

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Mixture Effects of Estrogenic Pesticides at the Human Estrogen Receptor α and β

Cited by 23 publications

References 33 publications

Assessment of mixture toxicity of (tri)azoles and their hepatotoxic effects in vitro by means of omics technologies

Assessment of mixture toxicity of (tri)azoles and their hepatotoxic effects in vitro by means of omics technologies

Hepatotoxic combination effects of three azole fungicides in a broad dose range

Hypothetical adjustment of the acceptable daily intake and correction of the underrated risk: A case study of glyphosate-based herbicides

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