Prediction of carcinogenic potential of chemicals using repeated-dose (13-week) toxicity data.
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.
TNO Innovation for Life, P.O. Box 360, 3700 AJ, Zeist, The Netherlands; Division of Toxicology, Wageningen University and Research Centre, P.O. Box 8000, 6700 EA, Wageningen, The Netherlands. Electronic address: ruud.woutersen@tno.nl.
Ruud A
RA
Woutersen
Division of Toxicology, Wageningen University and Research Centre, P.O. Box 8000, 6700 EA, Wageningen, The Netherlands.
Ans E M F
AE
Soffers
TNO Innovation for Life, P.O. Box 360, 3700 AJ, Zeist, The Netherlands.
E Dinant
ED
Kroese
TNO Innovation for Life, P.O. Box 360, 3700 AJ, Zeist, The Netherlands; University of Applied Sciences Utrecht, Institute for Life Sciences & Chemistry, P.O. Box 12011, 3501 AA, Utrecht, The Netherlands.
Cyrille A M
CA
Krul
Medicines Evaluation Board, Section on Pharmacological, Toxicological and Biotechnological Assessment, P.O. Box 8275, 3503 RG, Utrecht, The Netherlands.
Jan Willem
JW
van der Laan
National Institute for Public Health and the Environment (RIVM), Centre for Health Protection, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.
Jan
J
van Benthem
National Institute for Public Health and the Environment (RIVM), Centre for Health Protection, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.
Mirjam
M
Luijten
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage* / Q000633:toxicity*; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D009369:Neoplasms / Q000139:chemically induced*; D051381:Rats; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors
D002273:Carcinogens
Carcinogenicity; Non-genotoxic carcinogens; Predictivity; Preneoplastic lesions; Rat; Risk assessment; Sub-chronic toxicity; Tumours