disease should evaluate animal well-being at appropriate intervals. Clinical symptoms could involve such diverse markers as musculoskeletal abnormalities (tremor, reduced ambulation, and paralysis), decreased appetite (anorexia or aphagia), adipsia, signs of pain, fever, seizures, disorientation, and/or self-mutilation.
Before initiation of the research project, the research team, in consultation with the veterinary staff, should determine a course of clinical intervention or management based on the observed or expected clinical signs (see Table 6-1). The clinical plan should prevent the development of unintended pain and distress; but in instances where pain and/or distress is an intended outcome (as in pain research), the adverse consequences to the animal should be minimized as much as possible without jeopardizing the research goals. Potential interventions include the provision of easy access to water and perhaps to highly palatable food, promotion of urination and defecation, avoidance of decubital ulceration, maintenance of fluid balance, administration of appropriate analgesic or tranquilizing drugs, and, for some species, human contact to soothe and comfort the animal. Close clinical observation may also be necessary during periods of disease exacerbation. For example, in studies of seizure induction or treatment, continuous animal observation during the seizure is essential to prevent injury to the animal, although the seizure itself may not be painful.
The duration and severity of the condition should be managed within predetermined limits (humane endpoints) that reflect experimental goals. For example, studies of the mechanisms of disease development might require a shorter post-procedural duration than would studies of treatment interventions. Endpoints should be defined in terms of both the experimental goals (such as development of the syndrome or recovery of function according to some objective or subjective standard) and animal well-being (such as clinical deterioration that indicates that euthanasia is warranted). Endpoints applied to a specific model can be modified as more is learned about the model. For example, although death was used as an endpoint in some early studies of tumor metastasis in mice, later studies used hind limb paralysis to indicate that euthanasia should be performed, because paralysis was shown to be a valid indicator of death (Huang et al., 1993, 1995). Seizure studies should be designed to minimize the number, duration, and severity of seizures, without jeopardizing the scientific goals of the study.
The production of some animal disease models requires the use of substances that pose health risks to humans. They include neurotoxins (such as MPTP), infectious agents (such as prions, bacterial, and viral pathogens), human cell lines, and noise exposure (free field). Appropriate risk assessment and the development of safe standard operating procedures is essential for the review and use of these models.