Prediction of carcinogenic potential of chemicals using repeated-dose (13-week) toxicity data

• Published in: Regulatory toxicology and pharmacology 2016-11, Vol.81, p.242-249
• Main Authors: Woutersen, Ruud A., Soffers, Ans E.M.F., Kroese, E. Dinant, Krul, Cyrille A.M., van der Laan, Jan Willem, van Benthem, Jan, Luijten, Mirjam
• Format: Article
• Language: English
• Subjects: Animals; Carcinogenicity; Carcinogenicity Tests; Carcinogens - administration & dosage; Carcinogens - toxicity; Databases, Factual; Dose-Response Relationship, Drug; Neoplasms - chemically induced; Non-genotoxic carcinogens; Predictivity; Preneoplastic lesions; Rat; Rats; Retrospective Studies; Risk assessment; Risk Factors; Sub-chronic toxicity; Time Factors; Tumours
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2016.09.003

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. •The whole animal negative predictivity hypothesis has been evaluated using data of 202 chemicals.•The accuracy of sub-chronic studies to correctly identify non-carcinogens was 90%.•Cellular hypertrophy appeared to be an unreliable predictor of carcinogenicity.•Non-genotoxic chemicals showing no putative neoplasia in a 13-week study need no further testing.