Abstract
One of the critical issues confronting the evolving discipline of behavioral and neurological toxicology is the general lack of test validation in animal models. This paper seeks to provide a strategy aimed at resolving this important problem. It is proposed that test validation be accomplished by evaluating known neurotoxins in a battery of tests chosen to assess in animal models a wide range of effects on the basis of reported human toxicosis symptomatology. We propose to measure ongoing home cage motor activity, food consumption, water consumption, clay consumption (and the diurnal cycling of these), neurological/physiological indices (reflexes, autonomic signs, equilibrium/gait, balance, tremor, reactivity, and muscular strength), and aspects of cognitive and associative behavior involving both endogenous and exogenous (sensory) control of responding. An integrated, time-efficient scheme, covering 90 days of chemical treatment and 30 days of post-dosing recovery will be used. Chemical substances to be evaluated were chosen with the view of representing classes of neurotoxic effects. For initial study, triethyltin was chosen as an agent producing demyelination of nerves, acrylamide as an agent producing "dying-back" neuropathy, and methylmercury as an agent producing mixed central and peripheral neuropathies. Agents which attack specific loci in the nervous system and those producing anoxia will not be assessed in the first stages of this research due to lack of species generality of known effects, present lack of appropriate exposure facilities, or other problems. In addition, two drugs (amphetamine and sodium salicylate) will be investigated to support the generality of the testing procedures. By comparing the observed results of the neurotoxins in the animal models with the predicted effects based on reported human symptomatology, some decision concerning the validity of each procedure will be made. It is expected that the validation of tests to be used in behavioral and neurological toxicology will permit the meaningful assessment of more complex issues, such as the mechanisms by which neurotoxins act.