Prediction and assessment of the effects of mixtures of four xenoestrogens.

Abstract

The assessment of mixture effects of estrogenic agents is regarded as an issue of high priority by many governmental agencies and expert decision-making bodies all over the world. However, the few mixture studies published so far have suffered from conceptual and experimental problems and are considered to be inconclusive. Here, we report the results of assessments of two-, three- and four-component mixtures of o,p'-DDT, genistein, 4-nonylphenol, and 4-n-octylphenol, all compounds with well-documented estrogenic activity. Extensive concentration-response analyses with the single agents were carried out using a recombinant yeast screen (yeast estrogen screen, YES). Based on the activity of the single agents in the YES assay we calculated predictions of entire concentration-response curves for mixtures of our chosen test agents assuming additive combination effects. For this purpose we employed the models of concentration addition and independent action, both well-established models for the calculation of mixture effects. Experimental concentration-response analyses revealed good agreement between predicted and observed mixture effects in all cases. Our results show that the combined effect of o,p'-DDT, genistein, 4-nonylphenol, and 4-n-octylphenol in the YES assay does not deviate from expected additivity. We consider both reference models as useful tools for the assessment of combination effects of multiple mixtures of xenoestrogens.

Understanding the endocrine disruption of chiral pesticides: The enantioselectivity in estrogenic activity of synthetic pyrethroids

“…The E 2 was employed as a positive control and yielded a maximal absorbance at 10 9 mol L 1 with an EC 50 of 10 10.1 mol L 1 (data not shown), which was consistent with previous observation [28]. Enantioselective estrogenic activity was popular at this testing system for each SPs and their isomers, albeit only the stereo-structure was asymmetric among them.…”

Toxic masking and synergistic modulation of the estrogenic activity of chemical mixtures in a yeast estrogen screen (YES)

“…However, sensitivity of the 2P-YES in terms of EC50 values for estrogens seems to be lower. While we found a mean value of 2.35 nmol/L, typical EC50 data of E2 published for the original YES range from 0.13 to 0.4 nmol/L (Beresford et al 2000;Payne et al 2000;Rajapakse et al 2001;Miller et al 2001;Schultis and Metzger 2004). Variability behind these values may be high, as De Boever et al (2001) reported a 95% confidence interval of one order of magnitude (0.14-1.1 nmol/L).…”

The risky cocktail: what combination effects can we expect between ecstasy and other amphetamines?

“…Based on the complete concentration-response curves of the single agents, the overall effect of each mixture with defined composition was predicted applying both CA and IA models, as described in Payne et al (2000). Quantitative GC/MS analysis was performed with a Varian CP-3800 gas chromatograph (USA) equipped with a VARIAN Saturn 4000 Ion Trap (IT) mass selective detector (USA) and a Saturn GC/IT-MS workstation software version 6.8.…”

“…Over the last decades, several studies on mixture toxicology have compared two well-established models for the calculation of expected additive mixture effects (Drescher and Boedeker 1995;Payne et al 2000;Rajapakse et al 2001;Silva et al 2002;Pavlaki et al 2011): concentration addition (CA), first defined by Loewe and Muchnik (1926), and independent action (IA) as described by Bliss (1939). The concept of CA is based on the assumption that the mixture constituents have similar modes of action, which means that any component can be replaced partially or totally with another without changing the overall mixture effect.…”