| 1. |
- Nielsen, Frederik Knud, et al.
(author)
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Mixture effects of 3 mechanistically different steroidogenic disruptors (prochloraz, genistein, and ketoconazole) in the H295R cell assay
- 2015
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In: International journal of toxicology. - 1091-5818 .- 1092-874X. ; 34:6, s. 534-542
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Journal article (peer-reviewed)abstract
- Mixture effects of 3 model endocrine disruptors, prochloraz, ketoconazole, and genistein, on steroidogenesis were tested in the adrenocortical H295R cell line. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone, and 17β-estradiol) were analyzed using gas chromatography and tandem mass spectrometry (GC-MS/MS) to investigate the effects throughout the steroidogenic pathway. Current modeling approaches often rely on models assuming compounds acting independently and that the individual effects in some way can be summarized to predict a mixture effect. In H295R cells with an intact steroidogenic pathway, such assumptions may not be feasible. The purpose of this study was therefore to evaluate whether effects of a mixture with differing modes of action followed or deviated from additivity (concentration addition) and whether the H295R cell line was suitable for evaluating mixture toxicity of endocrine disruptors with different modes of action. The compounds were chosen because they interfere with steroidogenesis in different ways. They all individually decrease the concentrations of the main sex steroids downstream but exert different effects upstream in the steroidogenic pathway. Throughout the study, we observed lowest observed effect concentrations of mixtures at levels 2 to 10 times higher than the predicted EC50, strongly indicating antagonistic effects. The results demonstrate that chemical analysis combined with the H295R cell assay is a useful tool also for studying how mixtures of endocrine disruptors with differing modes of action interfere with the steroidogenic pathway and that existing models like concentration addition are insufficient in such cases. Furthermore, for end points where compounds exert opposite effects, no relevant models are available.
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| 2. |
- Nielsen, Frederik Knud, et al.
(author)
-
Mixture effects of 3 mechanistically different steroidogenic disruptors (prochloraz, genistein, and ketoconazole) in the H295R cell assay
- 2015
-
In: International Journal of Toxicology. - : SAGE Publications Inc.. - 1091-5818 .- 1092-874X. ; 34:6, s. 534-542
-
Journal article (peer-reviewed)abstract
- Mixture effects of 3 model endocrine disruptors, prochloraz, ketoconazole, and genistein, on steroidogenesis were tested in the adrenocortical H295R cell line. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone, and 17β-estradiol) were analyzed using gas chromatography and tandem mass spectrometry (GC-MS/MS) to investigate the effects throughout the steroidogenic pathway. Current modeling approaches often rely on models assuming compounds acting independently and that the individual effects in some way can be summarized to predict a mixture effect. In H295R cells with an intact steroidogenic pathway, such assumptions may not be feasible. The purpose of this study was therefore to evaluate whether effects of a mixture with differing modes of action followed or deviated from additivity (concentration addition) and whether the H295R cell line was suitable for evaluating mixture toxicity of endocrine disruptors with different modes of action. Thecompounds were chosen because they interfere with steroidogenesis in different ways. They all individually decrease the concentrations of the main sex steroids downstream but exert different effects upstream in the steroidogenic pathway. Throughout the study, we observed lowest observed effect concentrations of mixtures at levels 2 to 10 times higher than the predicted EC50, strongly indicating antagonistic effects. The results demonstrate that chemical analysis combined with the H295R cell assay is a useful tool also for studying how mixtures of endocrine disruptors with differing modes of action interfere with the steroidogenic pathway and that existing models like concentration addition are insufficient in such cases. Furthermore, for end points where compounds exert opposite effects, no relevant models are available.
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| 3. |
- Rudén, Christina
(author)
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Scrutinizing three trichloroethylene carcinogenicity classifications in the European Union - Implications for the risk assessment process
- 2002
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In: International journal of toxicology. - : SAGE Publications. - 1091-5818 .- 1092-874X. ; 21:6, s. 441-450
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Journal article (peer-reviewed)abstract
- In this paper, carcinogenicity classifications of the chlorinated solvent trichloroethylene (TCE) made by the European Union Commission Expert Groups in 1976, 1988, and 2001 are scrutinized and alternative classifications are proposed. It is argued that the TCE database at these three points in time could have been interpreted to fulfill the criteria for stricter classifications than those actually made. Implications of this for the classification process are discussed.
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