Tilson H A, Cabe P A
Environ Health Perspect. 1978 Oct;26:287-99. doi: 10.1289/ehp.7826287.
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.
行为神经毒理学这一不断发展的学科面临的关键问题之一是动物模型中普遍缺乏试验验证。本文旨在提供一种解决这一重要问题的策略。建议通过在一系列试验中评估已知神经毒素来完成试验验证，这些试验旨在根据报告的人类中毒症状，在动物模型中评估广泛的影响。我们建议测量笼内持续的运动活动、食物消耗、水消耗、泥土消耗（以及这些指标的昼夜循环）、神经/生理指标（反射、自主神经体征、平衡/步态、平衡、震颤、反应性和肌肉力量），以及涉及内源性和外源性（感觉）反应控制的认知和联想行为方面。将采用一个综合、高效的方案，涵盖90天的化学处理和30天的给药后恢复期。选择要评估的化学物质时考虑到了代表神经毒性作用的类别。对于初步研究，选择三乙锡作为导致神经脱髓鞘的试剂，丙烯酰胺作为导致“逆行性”神经病变的试剂，甲基汞作为导致中枢和外周混合性神经病变的试剂。由于已知效应缺乏物种普遍性、目前缺乏适当的暴露设施或其他问题，在本研究的第一阶段将不评估攻击神经系统特定部位的试剂和导致缺氧的试剂。此外，将研究两种药物（苯丙胺和水杨酸钠）以支持测试程序的通用性。通过将动物模型中神经毒素的观察结果与基于报告的人类症状预测的效应进行比较，将对每个程序的有效性做出一些决策。预计行为神经毒理学中使用的试验验证将允许对更复杂的问题进行有意义的评估，例如神经毒素作用的机制。
