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The assessment of joint endocrine effects of multi-component mixtures of food contaminants and additives

Project Code: T01045;
Publication:

Ermler, S., Scholze, M., Kortenkamp, A. (2010) The sensitivity of the MDA-kb2 cell in vitro assay in detecting anti-androgenic chemicals – identification of sources of variability and estimation of statistical power. Toxicology in vitro 24, 1845-1853
Evans, R.M., Rahte, S., Kortenkamp, A. (2010) Inability to confirm estrogenicity of the heterocyclic amine PhIP in two in vitro assays. Toxicology in vitro 24, 1757-1763

09/02/2011

University of London
Kortenkamp, A ; Ermler, S; Evans, R; Scholze, M

The chemicals studied in this project were potential endocrine disrupting chemicals (EDCs) known to be found in food which had data available on their levels in humans. The project investigated dose-response relationships for these relevant individual chemicals, and then tested these chemicals in a series of mixtures. Three in vitro assays were used: The ER-CALUX assay, which detects chemicals that act on the estrogen receptor; the MCF-7 cell proliferation assay, which detects chemicals that stimulate cell division; and the AR-Luc assay, which detects chemicals that act on the androgen receptor.

Fifty different mixtures containing up to 31 individual chemicals were tested in vitro for endocrine disrupting effects. When mixtures of ten or more active chemicals (i.e. those chemicals that exhibited activity in the in vitro test system when tested alone) were evaluated, the combined effect could usually be predicted using the concept of Concentration Addition. The mixtures were also assessed using an alternative model known as, Independent Action, (whereby the effect, or response, for the mixture is obtained by applying stochastic principles). Using the concept of Independent Action resulted in an underestimation of the observed effects.

When mixtures were tested in combination with chemicals that do not induce positive effects in the in vitro assays, most did not affect the response to the mixtures of active compounds they were tested against, however three chemicals, PCB126, benzo(a)pyrene and cadmium chloride did induce negative estrogenic effects.

Concentration Addition was reasonably predictive of the combined effects of the active chemicals when testing mixtures constructed to reflect levels of chemicals predicted to be found in human tissue. The project team noted that a small number of the individual chemicals appeared to account for the majority of the combined effects observed.

The results of this study support the use of the Concentration Addition approach to predict the effects of mixtures, when the chemicals in the mixture have similar structures and/or act via similar mechanisms. However, the authors note that in vitro observations cannot necessarily be readily extrapolated to an in vivo situation.

The outcomes from this project provide support for the methodology the Agency’s currently uses when conducting risk assessments of mixtures of chemicals acting on the same receptor.

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