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

This article has been made available through the Brunel Open Access Publishing Fund.Many xenobiotics have been identified as in vitro androgen receptor (AR) antagonists, but information about their ability to produce combined effects at low concentrations ismissing. Such data can reveal whether joint effects at the receptor are induced at low levels andmay 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). Chemicalswere combined at threemixture 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 froma 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

Introduction: Endocrine Disruptors—Exposure Assessment, Novel End Points, and Low-Dose and Mixture Effects

With the aim of discussing new research findings about chemicals able to interfere with the endocrine system, so-called endocrine disruptors, an international workshop was held in Prague, Czech Republic, 10–12 May 2005. The workshop was organized jointly by the EDEN project (Endocrine Disrupters: Exploring Novel Endpoints, Exposure, Low-Dose and Mixture-Effects in Humans, Aquatic Wildlife and Laboratory Animals; http://www.edenresearch.info) and the FIRE project (Risk Assessment of Brominated Flame Retardants as Suspected Endocrine Disrupters for Human and Wildlife Health; http://www.rivm.nl/fire), both large-scale consortia funded by the European Union (EU). The meeting was attended by more than 170 scientists from academia, industry, government agencies, and other organizations

Extending the applicability of the dose addition model to the assessment of chemical mixtures of partial agonists by using a novel toxic unit extrapolation method

This article has been made available through the Brunel Open Access Publishing Fund.Dose addition, a commonly used concept in toxicology for the prediction of chemical mixture effects, cannot readily be applied to mixtures of partial agonists with differing maximal effects. Due to its mathematical features, effect levels that exceed the maximal effect of the least efficacious compound present in the mixture, cannot be calculated. This poses problems when dealing with mixtures likely to be encountered in realistic assessment situations where chemicals often show differing maximal effects. To overcome this limitation, we developed a pragmatic solution that extrapolates the toxic units of partial agonists to effect levels beyond their maximal efficacy. We extrapolated different additivity expectations that reflect theoretically possible extremes and validated this approach with a mixture of 21 estrogenic chemicals in the E-Screen. This assay measures the proliferation of human epithelial breast cancers. We found that the dose-response curves of the estrogenic agents exhibited widely varying shapes, slopes and maximal effects, which made it necessary to extrapolate mixture responses above 14% proliferation. Our toxic unit extrapolation approach predicted all mixture responses accurately. It extends the applicability of dose addition to combinations of agents with differing saturating effects and removes an important bottleneck that has severely hampered the use of dose addition in the past. © 2014 Scholze et al

Declining semen quality and polybrominated diphenyl ethers (PBDEs): Review of the literature to support the derivation of a reference dose for a mixture risk assessment

Appendix A. Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijheh.2022.113953.Copyright © 2022 The Authors. To support a mixture risk assessment for chemicals that interfere with male reproductive health, we reviewed the literature to identify studies of polybrominated diphenyl ethers (PBDEs) and poor semen quality. Several epidemiological studies have shown associations of PBDE exposures with declining semen quality, non-descending testes and penile malformations. In rodent studies, poor semen quality, changes in testosterone levels and reproductive tissues have been observed. In vitro studies with reporter gene constructs show PBDE congeners as androgen receptor antagonists, and mixture studies in these systems have demonstrated that PBDE congeners act together with other androgen receptor antagonists. These observations led us to attempt the estimation of reference doses for specific PBDE congeners that can be used in a future mixture risk assessment for deteriorations of semen quality. While epidemiological studies provide support for such associations, they were uninformative for derivations of reference doses, due to the incompatibility of dose metrics used in exposure assessments. We therefore based our estimates on animal studies. Using a rigorous confidence rating approach, we found robust evidence that BDE-47 produced reductions in semen quality. We identified only one high confidence study of BDE-99 and accordingly evaluated the strength of evidence as moderate. One high confidence, and several medium confidence experimental studies observed declines in semen quality after BDE-209 exposure. Using established risk assessment procedures, we estimated that BDE-47 exposures below 0.15 μg/kg/d are unlikely to lead to reductions in semen quality. The corresponding exposures for BDE-99 and BDE-209 are 0.003 μg/kg/d and 1000 μg/kg/d. It is planned to use these estimates as reference doses in a mixture risk assessment of deteriorations in semen quality, involving multiple other chemicals also contributing to poor semen quality.This work was conducted with funding from the European HBM4EU project (www.hbm4eu.eu), contract number 733032, Horizon 2020 programme, which is gratefully acknowledged

Systematic review of associations of polychlorinated biphenyl (PCB) exposure with declining semen quality in support of the derivation of reference doses for mixture risk assessments

Background: Mixture risk assessments require reference doses for common health endpoints of all the chemicals to be considered together. In support of a mixture risk assessment for male reproductive health, we conducted a sys tematic review of the literature on associations between exposures to Polychlorinated Biphenyls (PCBs) and declines in semen quality. PCBs can act as Aryl-hydrocarbon Receptor (AhR)-agonists and Androgen Receptor (AR)-antagonists, both mechanisms which can afect sperm parameters. PCBs and other AR-antagonists can produce additive combi nation efects. Based on these observations our objective was to systematically gather data from animal and human studies to derive a reference dose for declines in semen quality for individual PCB. Methods: We systematically reviewed and evaluated the evidence in human epidemiological and experimental ani mal studies on associations between PCBs and deteriorations in semen quality. Human data and fndings from animal studies with PCB mixtures were considered as supporting evidence. Information for individual congeners from animal studies was required for inclusion in mixture risk assessment. Using a robust confdence rating approach, we identi fed suitable studies to derive reference doses for individual PCB congeners. Results: Evaluation of human epidemiological studies revealed several reports of adverse efects on sperm param eters linked to PCB exposures, although some studies reported improved semen quality. Our review of experimental animal studies found that treatments with PCBs afected semen quality, in most cases adversely. We found robust evi dence that PCB-118 and -169 were linked to declines in semen quality. Evidence for adverse efects of PCB-126, -132, -149, and -153 was moderate, whereas for PCB-77 it was slight and for PCB-180 indeterminate. Using widely accepted risk assessment procedures, we estimated reference dose values of 0.0029 µg/kg/day for PCB-118 and 0.00533 µg/kg/ day for PCB-169. In addition, we derived values for PCB-126: 0.000073 µg/kg/day, PCB-132: 0.0228 µg/kg/day, PCB-149: 0.656 µg/kg/day, and PCB-153: 0.0058 µg/kg/day. Conclusions: We found robust evidence for links between PCB exposure and deteriorations in semen quality, and derived reference doses for a set of congeners. We intend to use these values in combination with congener-specifcEuropean Joint Programme on Human Biomonitoring, HBM4EU (www.hbm4eu.eu), contract number 733032, Horizon 2020 programme

Migration of Interplanetary Dust

We numerically investigate the migration of dust particles with initial orbits close to those of the numbered asteroids, observed trans-Neptunian objects, and Comet Encke. The fraction of silicate asteroidal particles that collided with the Earth during their lifetime varied from 1.1% for 100 micron particles to 0.008% for 1 micron particles. Almost all asteroidal particles with diameter d>4 microns collided with the Sun. The peaks in the migrating asteroidal dust particles' semi-major axis distribution at the n:(n+1) resonances with Earth and Venus and the gaps associated with the 1:1 resonances with these planets are more pronounced for larger particles. The probability of collisions of cometary particles with the Earth is smaller than for asteroidal particles, and this difference is greater for larger particles.Comment: Annals of the New York Academy of Sciences, 15 pages, 8 Figures, submitte

Dynamics of two planets in co-orbital motion

We study the stability regions and families of periodic orbits of two planets locked in a co-orbital configuration. We consider different ratios of planetary masses and orbital eccentricities, also we assume that both planets share the same orbital plane. Initially we perform numerical simulations over a grid of osculating initial conditions to map the regions of stable/chaotic motion and identify equilibrium solutions. These results are later analyzed in more detail using a semi-analytical model. Apart from the well known quasi-satellite (QS) orbits and the classical equilibrium Lagrangian points L4 and L5, we also find a new regime of asymmetric periodic solutions. For low eccentricities these are located at $(\sigma,\Delta\omega) = (\pm 60\deg, \mp 120\deg)$, where \sigma is the difference in mean longitudes and \Delta\omega is the difference in longitudes of pericenter. The position of these Anti-Lagrangian solutions changes with the mass ratio and the orbital eccentricities, and are found for eccentricities as high as ~ 0.7. Finally, we also applied a slow mass variation to one of the planets, and analyzed its effect on an initially asymmetric periodic orbit. We found that the resonant solution is preserved as long as the mass variation is adiabatic, with practically no change in the equilibrium values of the angles.Comment: 9 pages, 11 figure

The generation of DNA single-strand breaks during the reduction of chromate by ascorbic acid and/or glutathione in vitro.

The potential role of iron and copper and the involvement of hydroxyl radicals in the DNA cleavage caused by chromate and glutathione (GSH) has been investigated. We have also studied the ability of chromate, on reaction with ascorbate as well as in mixed solutions of ascorbate and GSH, to cause DNA strand breaks. In both fully demetalated and conventional (i.e., metal contaminated) systems, chromate and GSH induced similar numbers of DNA strand breaks. This observation suggests that traces of iron or copper contaminating the reaction mixtures do not play a major role in the DNA cleavage caused by chromate and GSH. A series of hydroxyl radical scavengers exhibited a protective influence on the induction of DNA strand breaks. However, glucose and sucrose, both strong hydroxyl radical scavengers, showed no concentration-dependent inhibition of DNA cleavage. Competition kinetics studies yielded apparent rate constants that were not consistent with hydroxyl radicals being the species responsible for DNA strand breaks. Ascorbate in combination with chromate was also found to induce strand breaks in DNA; this damage could be attributed to reactive intermediates generated during the reduction. When mixed systems of ascorbate and GSH in the presence of chromate were investigated, there were clearly interactions between the two reductants

Assessing binary mixture effects from genotoxic and endocrine disrupting environmental contaminants using infrared spectroscopy

Benzo[a]pyrene (B[a]P), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are persistent contaminants and concern has arisen over co-exposure of organisms when the chemicals exist in mixtures. Herein, attenuated total reflection Fouriertransform infrared (ATR-FTIR) spectroscopy was used to identify biochemical alterations induced in cells by single and binary mixtures of these environmental chemicals. It was also investigated as a method to identify if interactions are occurring in mixtures and as a possible tool to predict mixture effects. Mallard fibroblasts were treated with single and binary mixtures of B[a]P, PCB126, PCB153, BDE47 and BDE209. Comparison of observed spectra from cells treated with binary mixtures with expected additive spectra, which were created from individual exposure spectra, indicated that in many areas of the spectrum, less-than-additive binary mixture effects may occur. However, possible greater-than-additive alterations were identified in the 1650-1750 cm-1 lipid region and may demonstrate a common mechanism of B[a]P and PCBs or PBDEs, which can enhance toxicity in mixtures

Ten Years of Mixing Cocktails: A Review of Combination Effects of Endocrine-Disrupting Chemicals

In the last 10 years, good evidence has become available to show that the combined effects of endocrine disruptors (EDs) belonging to the same category (e.g., estrogenic, antiandrogenic, or thyroid-disrupting agents) can be predicted by using dose addition. This is true for a variety of end points representing a wide range of organizational levels and biological complexity. Combinations of EDs are able to produce significant effect, even when each chemical is present at low doses that individually do not induce observable effects. However, comparatively little is known about mixtures composed of chemicals from different classes of EDs. Nevertheless, I argue that the accumulated evidence seriously undermines continuation with the customary chemical-by-chemical approach to risk assessment for EDs. Instead, we should seriously consider group-wise regulation of classes of EDs. Great care should be taken to define such classes by using suitable similarity criteria. Criteria should focus on common effects, rather than common mechanisms. In this review I also highlight research needs and identify the lack of information about exposure scenarios as a knowledge gap that seriously hampers progress with ED risk assessment. Future research should focus on investigating the effects of combinations of EDs from different categories, with considerable emphasis on elucidating mechanisms. This strategy may lead to better-defined criteria for grouping EDs for regulatory purposes. Also, steps should be taken to develop dedicated mixtures exposure assessment for EDs