From the article: Abstract Sub-chronic toxicity studies of 163 non-genotoxic chemicals were evaluated in order to predict the tumour outcome of 24-month rat carcinogenicity studies obtained from the EFSA and ToxRef databases. Hundred eleven of the 148 chemicals that did not induce putative preneoplastic lesions in the sub-chronic study also did not induce tumours in the carcinogenicity study (True Negatives). Cellular hypertrophy appeared to be an unreliable predictor of carcinogenicity. The negative predictivity, the measure of the compounds evaluated that did not show any putative preneoplastic lesion in de sub-chronic studies and were negative in the carcinogenicity studies, was 75%, whereas the sensitivity, a measure of the sub-chronic study to predict a positive carcinogenicity outcome was only 5%. The specificity, the accuracy of the sub-chronic study to correctly identify non-carcinogens was 90%. When the chemicals which induced tumours generally considered not relevant for humans (33 out of 37 False Negatives) are classified as True Negatives, the negative predictivity amounts to 97%. Overall, the results of this retrospective study support the concept that chemicals showing no histopathological risk factors for neoplasia in a sub-chronic study in rats may be considered non-carcinogenic and do not require further testing in a carcinogenicity study.
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Introduction: To reduce continuously increasing costs in drug development, adverse effects of drugs need to be detected as early as possible in the process. In recent years, compound-induced gene expression profiling methodologies have been developed to assess compound toxicity, including Gene Ontology term and pathway over-representation analyses. The objective of this study was to introduce an additional approach, in which literature information is used for compound profiling to evaluate compound toxicity and mode of toxicity. Methods: Gene annotations were built by text mining in Medline abstracts for retrieval of co-publications between genes, pathology terms, biological processes and pathways. This literature information was used to generate compound-specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes after compound administration. To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with 11 hepatotoxicants. Results: Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat aspecific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. A more detailed analysis of the keyword profiles of diethylhexylphthalate, dimethylnitrosamine and methapyrilene (MPy) showed that the differences in the keyword fingerprints of these three compounds are based upon known distinct modes of action. Visualization of MPy-linked keywords and MPy-induced genes in a literature network enabled us to construct a mode of toxicity proposal for MPy, which is in agreement with known effects of MPy in literature. Conclusion: Compound keyword fingerprinting based on information retrieved from literature is a powerful approach for compound profiling, allowing evaluation of compound toxicity and analysis of the mode of action. © 2007 Future Medicine Ltd.
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Background: Particulate matter (PM) exposure is an important health risk, both in daily life and in the workplace. It causes respiratory and cardiovascular diseases and results in 800,000 premature deaths per year worldwide. In earlier research, we assessed workers’ information needs regarding workplace PM exposure, the properties and effects of PM, and the rationale behind various means of protection. We also concluded that workers do not always receive appropriate risk communication tools with regards to PM, and that their PM knowledge appears to be fragmented and incomplete. Methods: We considered several concepts for use as an educational material based on evaluation criteria: ease of use, costs, appropriateness for target audiences and goals, interactivity, implementation issues, novelty, and speed. We decided to develop an educational folder, which can be used to inform employees about the properties, effects and prevention methods concerning PM. Furthermore, we decided on a test setup of a more interactive way of visualisation of exposure to PM by means of exposimeters. For the development of the folder, we based the information needs on our earlier mental models-based research. We adjusted the folder based on the results of ten semi-structured interviews evaluating its usability. Results: The semi-structured interviews yielded commentaries and suggestions for further improvement, which resulted in a number of alterations to the folder. However, in most cases the folder was deemed satisfactory. Conclusion: Based on this study, the folder we developed is suitable for a larger-scale experiment and a practical test. Further research is needed to investigate the efficacy of the folder and the application of the exposimeter in a PM risk communication system.
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