Evaluation of data relevance, reliability and contribution to uncertainty is crucial in regulatory health risk assessment if robust conclusions are to be drawn. Whether a specific study is used as key study, as additional information or not accepted depends in part on the criteria according to which its relevance and reliability are judged. In addition to GLP-compliant regulatory studies following OECD Test Guidelines, data from peer-reviewed scientific literature have to be evaluated in regulatory risk assessment of pesticide active substances. Publications should be taken into account if they are of acceptable relevance and reliability. Their contribution to the overall weight of evidence is influenced by factors including test organism, study design and statistical methods, as well as test item identification, documentation and reporting of results. Various reports make recommendations for improving the quality of risk assessments and different criteria catalogues have been published to support evaluation of data relevance and reliability. Their intention was to guide transparent decision making on the integration of the respective information into the regulatory process. This article describes an approach to assess the relevance and reliability of experimental data from guideline-compliant studies as well as from non-guideline studies published in the scientific literature in the specific context of uncertainty and risk assessment of pesticides.
Teratogenicity can be predicted in vitro using the embryonic stem cell test (EST). The EST, which is based on the morphometric measurement of cardiomyocyte differentiation and cytotoxicity parameters, represents a scientifically validated method for the detection and classification of chemicals according to their teratogenic potency. Furthermore, an abbreviated protocol applying flow cytometry of intracellular marker proteins to determine differentiation into the cardiomyocyte lineage is available. Although valproic acid (VPA) is in worldwide clinical use as antiepileptic drug, it exhibits two severe side effects, i.e., teratogenicity and hepatotoxicity. These limitations have led to extensive research into derivatives of VPA. Here we chose VPA as model compound to test the applicability domain and to further evaluate the reliability of the EST. To this end, we study six closely related congeners of VPA and demonstrate that both the standard and the molecular flow cytometry-based EST are well suited to indicate differences in the teratogenic potency among VPA analogs that differ only in chirality or side chain length. Our data show that identical results can be obtained by using the standard EST or a shortened protocol based on flow cytometry of intracellular marker proteins. Both in vitro protocols enable to reliably determine differentiation of murine stem cells toward the cardiomyocyte lineage and to assess its chemical-mediated inhibition.
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