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Correlations between different endpoints in repeated dose toxicity studies: Occurrence of dependent and independent effects at equal dose levels in the RepDose and the "ELINCS" database

: Batke, Monika; Bitsch, Annette; Gundert-Remy, Ursula; Gütlein, Martin; Kramer, Stefan; Partosch, Falko; Seeland, Madeleine; Stahlmann, Ralf

Naunyn-Schmiedebergs archives of pharmacology 387 (2014), Supplement 1, pp.S28, A108
ISSN: 0028-1298
ISSN: 1432-1912
Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie (Annual Meeting) <80, 2014, Hannover>
Journal Article, Conference Paper
Fraunhofer ITEM ()

The data basis for this analysis consists of two independent data bases containing results from repeated toxicity studies (RepDose and ELINCS). To have a consistent data set out of these both databases all data that are suitable with respect to reliability, route, species and study duration have been extracted in a so called homogenous subset.
The data set contains in total more than 2000 studies for 1046 chemicals, most of them industrial chemicals. Endpoints that do not have a clear organ attribution such as clinical chemistry have been subdivided and related to the specific organ such as clinical chemistry related to hepatotoxicity and clinical chemistry related to nephrotoxicity. The min LOEL values for each endpoint were used for further analyses.
In the present evaluation LOELs of single endpoints were analysed by Pearson correlation. The results are near to 1 for highly correlated LOELs, about 0 if no correlation of LOELs is given and <0 for inverse correlation of LOELs. With the correlation matrix effects that occur at similar dose levels are compared. Thus, the correlations are supposed to give a first input about toxicity profiling or toxicological pathways.
The matrix enables analyses for different aspects: 1) correlations of effects in different target organs, 2) correlations of different effects in one target organ (i.e. weight changes and histopathology for the male reproductive system) and 3) correlations of clinical chemistry with other effects in specific target organs.
Out of the various effects in clinical chemistry some profiles could be defined/proven as pathways for hepatotoxicity i.e. decreased cholesterol and increased ASAT/GOT as indicators of liver damages with histopathological changes (e.g.cirrhosis) or increased Bilirubin, ALAT and AP as indicators of cholestasis.
Furthermore, the analyses show that often effects may be elicited by different doses ("difference in sensitivity") indicating dose dependent disturbance of different steps in a pathway as further effects in the same target organ can be observed only at higher dose levels. Thus, it seems that the scope of examination and dose regime of a study is crucial for the outcome of possible correlations i.e. between clinical chemistry endpoints and organ toxicity.
All in all, this kind of correlation matrices on a reliable data basis can give important input in the knowledge on underlying mechanisms by elucidating relations/connections between toxic effects.