Strategy for and Experience with Neurotoxicity Testing of New Pharmaceuticals

Abstract

In response to present and anticipated regulatory needs for routine screening of pharmaceuticals for assessment of their neurotoxic potential, a primary tier screen for rodents, consisting of a functional observational battery (FOB) and an automated test of motor activity, has been developed at Searle. Additionally, an FOB for dogs currently is being developed. The rodent FOB assess such functions as home cage and open field activity, stimulus reactivity, and neuromuscular function. The dog FOB emphasizes evaluation of gait, postural reactions, and reflex function. The strategy taken has been to incorporate the primary rodent tier screen into repeated dose preclinical studies. Positive findings would trigger a secondary tier of testing, which would involve the use of more complex and integrated tests of neurobehavioral function. The methodologies for both rodent and nonrodent primary tier screens, validation study results, and the scientific criteria that would trigger secondary tier testing are discussed.

References

1. Settee, W.F. (1991). Pesticide Assessment Guidelines, Subdivision F, Hazard Evaluation, Addendum 10, Neurotoxicity, Series 81, 82, and 83. Published by U.S. Department of Commerce, National Technical Information Service, Springfield, VA (publication #PB91–154617).

2. Leukroth Jr., R.W. , ed. (1986). Predicting Neurotoxicity and Behavioral Dysfunction from Preclinical Toxicologic Data. Life Sciences Research Office. Federation of American Societies for Experimental Biology, Wash. DC.

3. Gad, S.C. (1982). A neuromuscular screen for use in industrial toxicology. J. Toxicol. Environ. Health 9, 691–704.

4. Haggerty, G.C. , Kurtz, P.J. , and Armstrong, R.D. (1986). Duration and intensity of behavioral change after sublethal exposure to soman in rats. Neurobehav. Toxicol. Teratol. 8, 695–702.

5. Irwin, S. (1968). Comprehensive observational assessment: Ia. A systematic quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia (Berl.) 13, 222–257.

6. Moser, V.C. , Mccormick, J.P. , Creason, J.P. , and Mcphail, R.C. (1988). Comparison of chlordimeform and carbaryl using a functional observational battery. Tox. Appl. Pharm. 11, 189–206.

7. Meyer, O.A. , Tilson, H.A. , Byrd, W.C. , and Riley, M.T. (1979). A method for the routine assessment of fore- and hindlimb grip strength of rats and mice. Neurobeh. Toxicol. Teratol. 1, 233–239.

8. Haggerty, G.C. , Morton, S. , Levin, S. , Ruben, Z. , and Gad, S.C. (1990). Neurotoxic profile induced by subchronic exposure to trimethyltin in sprague dawley (SD) rats. Toxicologist 10, 110.

9. Reiter, L.W. and Ruppert, P.H. (1984). Behavioral toxicity of trialkyltin compounds: A review. Neurotoxicology 5, 177–186.

10.

10. Weiner, N. (1985). Norepinephrine, epinephrine, and the sympathomimetic amines. In: Goodman, A.G. , Goodman, L.S. , Rall, T.W. , and Murad, F. eds. The Pharmacologic Basis of Therapeutics, New York: Macmillan, pp. 145–180.

11.

11. Inversen, S.D. and Iversen, L.L. (1981). Drugs with antipsychotic or psychotomimetic properties. In: Behavioral Pharmacology, New York: Oxford University Press, pp. 248–277.

12.

12. Ritchie, J.M. (1985). The aliphatic alcohols. In: Goodman, A.G. , Goodman, L.S. , Rall, T.W. , and Murad, F. eds. The Pharmacologic Basis of Therapeutics. New York: Macmillan, pp. 372–386.

13.

13. Fortemps, E. , Amand, G. , Lauwerys, R. , and Laterre, E.C. (1978). Trimethyl tin poisoning: Report of two cases. Int. Arch. Occup. Environ. Health 41, 1–6.

14.

14. Chang, L.W. and Dyer, R.S. (1983). A time-course study of trimethyl tin induced neuropathology in rats. Neurobehav. Toxicol. Teratol. 5, 443–459.

15.

15. Chang, L.W. (1986). Neuropathology of trimethyl tin: A proposed pathogenetic mechanism. Toxicol. Appl. Pharmacol. 6, 217–232.

16.

16. Haggerty, G.C. , Morton, S. , Levin, S. , and Gad, S.C. (1991). Evaluation of the neurotoxic potential of two alkyltin compounds in the rat. Toxicologist 11, 120.