Mixture effects at very low doses with combinations of anti-androgenic pesticides, antioxidants, industrial pollutant and chemicals used in personal care products

Abstract

Many xenobiotics have been identified as in vitro androgen receptor (AR) antagonists, but information about their ability to produce combined effects at low concentrations is missing. Such data can reveal whether joint effects at the receptor are induced at low levels and may support the prioritisation of in vivo evaluations and provide orientations for the grouping of anti-androgens in cumulative risk assessment. Combinations of 30 AR antagonists from a wide range of sources and exposure routes (pesticides, antioxidants, parabens, UV-filters, synthetic musks, bisphenol-A, benzo(a)pyrene, perfluorooctane sulfonate and pentabromodiphenyl ether) were tested using a reporter gene assay (MDA-kb2). Chemicals were combined at three mixture ratios, equivalent to single components' effect concentrations that inhibit the action of dihydrotesterone by 1%, 10% or 20%. Concentration addition (CA) and independent action were used to calculate additivity expectations. We observed complete suppression of dihydrotestosterone effects when chemicals were combined at individual concentrations eliciting 1%, 10% or 20% AR antagonistic effect. Due to the large number of mixture components, the combined AR antagonistic effects occurred at very low concentrations of individual mixture components. CA slightly underestimated the combined effects at all mixture ratios. In conclusion, large numbers of AR antagonists from a wide variety of sources and exposure routes have the ability of acting together at the receptor to produce joint effects at very low concentrations. Significant mixture effects are observed when chemicals are combined at concentrations that individually do not induce observable AR antagonistic effects. Cumulative risk assessment for AR antagonists should apply grouping criteria based on effects where data are available, rather than on criteria of chemical similarity.

Cumulative effects of antiandrogenic chemical mixtures and their relevance to human health risk assessment

“…Both of these pathways converge on several common reproductive tissues and results from this initial study support the conclusions reached by the NAS panel in 2008 which recommended considering all chemicals that affect a common tissue in a cumulative assessment (National Academies of Science, 2008). Furthermore, the laboratories of Ulla Hass and Andreas Kortenkamp have corroborated our observations that dose addition accurately predicts the effects of mixtures of antiandrogenic chemicals on androgen-dependent reproductive development, regardless of whether the individual chemical share a mechanism of action or not (Christiansen et al, 2009; Hass et al, 2007; Metzdorff et al, 2007; Orton et al, 2014; Orton et al, 2012). They also report that mixtures of endocrine disrupting chemicals combined at environmentally-relevant dose levels induce effects greater than expected based on individual chemical doses levels (Axelstad et al, 2014; Isling et al, 2014).…”

Proposal to optimize ecotoxicological evaluation of wastewater treated by conventional biological and ozonation processes

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Associations of persistent organic pollutants in serum and adipose tissue with breast cancer prognostic markers

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