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FP5

ACE Sintesi della relazione

Project ID: EVK1-CT-2001-00100
Finanziato nell'ambito di: FP5-EESD
Paese: Germany

Evaluation of the impact of toxic pollutants on the apparent activity of estrogenic chemicals and the predictability of the joint action of estrogens

The interaction between toxic and estrogenic substances has been studied in a modified Yeast Estrogen Screen, the so-called 2-phase-YES (2P-YES) and the E-Screen assay. We investigated to which extent the apparent estrogenicity of a chemical or a chemical mixture can be masked or enhanced by the simultaneous presences of a non-estrogenic toxicant and whether this is dependent on the molecular mechanism of action of the toxicant. Furthermore, the impact of toxic confounders on the predictability of the joint action of estrogens by the concept of Concentration Addition was analysed. We selected heavy metals (Mercury, Lead), two organic solvents (DMSO, 2,4-Dinitroanline), a surfactant (LAS) and a specifically acting antibiotic (Cycloheximide) as toxicants. Estrogens were selected from a variety of substances, mainly comprising of natural and synthetic estrogens such as 17ß-Estradiol, Estrone or Ethinylestradiol.

Concentrations that provoked severe toxic effects if applied singly always also clearly diminished the apparent estrogenicity of both, single substances and mixtures. That is, the maximum observable estrogenic effect is lowered if a toxicant is present simultaneously to the estrogen(s) and effect concentrations such as the EC50 values are shifted to the right (i.e., the cells seem to react less sensitive to the estrogens). This pattern was observed in both assays (E-Screen and 2P-YES) and with all test chemicals. Additionally, the impacts of low concentrations of toxicants, that do not provoke any visible effects if applied singly, were also investigated n the 2P-YES. A clear dependence on the specifically applied test substance became apparent here. The apparent estrogenic activity was reduced in the presence of low non-toxic concentrations of 2,4-Dinitroaniline and Cycloheximide, but was enhanced by the presence of low concentrations of LAS or DMSO.

The apparent estrogenicity of the mixtures of estrogens was affected in direct proportion to the single chemicals. Consequently the predictability of the joint action by Concentration Addition was compromised, if the presence of confounder was not already accounted for on the level of single substances. Both under- and overestimations by Concentration Addition occurred, depending on the impact on the apparent estrogenicity of the mixture components. As soon as this is accounted for, i.e. the toxic confounders are present in equal amounts during the single substance and the mixture experiments; predictability by Concentration Addition is restored.

These results clearly show that toxic confounders need to be considered during the assessments of the estrogenic potential of any substance, chemical mixture of complex environmental sample. Otherwise there is a severe risk of over- or underestimating its "true" estrogenicity. This could for example lead to the seemingly contradictory situation that the estrogenicity of an environmental sample is higher after a remediation than before - due to a decrease in the concentration of a toxic confounder. It has to be pointed out that at the moment no model is at hand that could quantitatively predict the impact that a given concentration of a toxic confounder has. Hence, it is of paramount importance to carefully consider the presence of toxic confounders while testing any sample for estrogenicity. For this purpose suitable toxicity indicators are needed.

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Thomas BACKHAUS, (Scientist)
Tel.: +49-042-12184208
Fax: +49-042-12184920
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