Neglect of function and obsession with structure in toxicity testing
The discrimination against the use of functional measurements in favour of pathomorphological investigations goes back to the very beginnings of drug toxicology studies. Since pharmacologists had the lead in drug development, they kept for themselves most of the activities necessary in the preparation of therapeutic trials, and only delegated to the toxicologists those safety studies required to exclude organdirected, cumulative adverse effects. Originally, these consisted of repeated-dose experiments with special attention to haematology, autopsy and histopathological examination of the organs. Later, an ever growing battery of clinical pathological tests was added. Together, these investigations resulted in a dossier of impressive dimensions which inspired confidence, not only because of its sheer size, but also because of the nature of the data, which could be easily compared with those usually obtained in patients. Pharmacologists still maintained an interest in acute disturbances of organ functions, but gladly relinquished the responsibility for long-term safety testing to toxicologists.
KeywordsFunctional Disturbance Reproductive Toxicity Functional Safety Central Nervous System Side Effect Safety Pharmacology
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- CHEN, G. & ENSOR, C.R. (1953). The combined anticonvulsant activity and toxicity of dilantin and N-methyl-5-phenylsuccinimide. J. Lab. din. Med., 41, 78–83.Google Scholar
- DETWEILER, D.K. (1981a). The use of electrocardiography in toxicological studies in beagle dogs. In Cardiac Toxicology, Balazs, T.(ed.), pp 33–82, Boca Raton FL: CRC Press Inc.Google Scholar
- DETWEILER, D.K. (1981b). The use of electrocardiography in toxicological studies with rats. In The Rat Electrocardiogram in Pharmacology and Toxicology, Budden, R., Detweiler, D.K. & Zbinden, G., (eds), pp 83–115, Oxford: Pergamon Press.Google Scholar
- ELSNER, J., LOOSER, R. & ZBINDEN, G. (1979). Quantitative analysis of rat behavior patterns in a residential maze. Neurobeh. Toxicol., 1, Suppl. 1, 163–174.Google Scholar
- FROMTLING, R.A. & GADESBUSCH, H.H. (1983). Ethanolcephalosporin antibiotic interactions: an animal model for detection of disulfiram (antabuse)-like effects. Meth. Find. exp. clin. Pharmac., 5, 595–600.Google Scholar
- LEHMAN, A.J., PATTERSON, W.I., DAVIDOW, B., HAGAN, E.C., WOODARD, G., LAUG, E.P. & 6 OTHERS. (1955). Procedures for the appraisal of the toxicity of chemicals in foods, drugs and cosmetics. Food Drug Cosmetic Law J., 10, 679–748.Google Scholar
- ZBINDEN, G. (1966). Toxicology of new drugs. In Handbook of Biochemistry and Biophysics, Damm, H.C., Besch, P.K. & Goldwyn, A.J. (eds), pp 495–511, Cleveland & New York: The World Publishing Co.Google Scholar
- ZBINDEN, G. (1981). Assessment of cardiotoxic effects in subacute and chronic rat toxicity studies. In Cardiac Toxicity, Balazs, T. (ed.) vol.Ill, pp 7–32, Boca Raton, FL: CRC Press Inc.Google Scholar
- ZBINDEN, G., ELSNER, J. & BOELSTERLI, U.A. (1984). Toxicological screening. Regulat. Toxicol. Pharmac. (in press).Google Scholar
- ZBINDEN, G. & GROSS, F. (1979). Pharmacological Methods in Toxicology, Oxford: Pergamon Press.Google Scholar