A functional observational battery for use in canine toxicity studies: development and validation

The most commonly used nonrodent species in regulatory toxicity and safety assessment studies has been and remains the dog, with the beagle being the standard breed employed. Although a standard functional observational battery (FOB) or neurobehavioral screen for use in rodents (primarily rats) has been incorporated into rodent studies since the late 1980s, this is not the case in nonrodents. In the pharmaceutical area (where repeat exposure nonrodent studies are generally required to develop a drug for humans), some work has been previously conducted towards developing a similar screen in the dog but progress has been limited. Given both the differential metabolism and sensitivity of the dog compared to rodents and the extreme desirability of having as complete a set of toxicity and/or functionality measures in the same species (to simplify and improve the accuracy of dose/response metrics) as possible, the need for such a standardized and validated methodology is clear. Study data from prior work establish the susceptibility of dogs to a wide variety of neurotoxic agents, including 6-aminonicotinamide (ANA), methanol, lasalocid, metronidazole, acrylamide, clinoquinol, organo tins, and mercury. Additionally, the dog is likewise well established as a sensitive model for a wide range of peripheral and central nervous system-active pharmacologic agents, as required by recent regulatory requirements for safety pharmacology evaluations. Here we report on a robust and yet sensitive noninvasive screening methodology for detecting and providing initial quantitation and characterization of such direct and indirect neurotoxic and neuropharmacologic effects that has been developed. Additionally, an analysis and interpretation component that allows differentiation of neurotoxic from neuropharmacologic activities has also been adapted from prior work by one of the authors. Comparative species difference in sensitivity to neuroactive agents are also discussed, as well as means for integrating this evaluation screen into existing standard design. Particularly, with the recent promulgation of safety pharmacology testing requirements (the in vivo cardiovascular component of which is performed in the dog), the availability of such an evaluation paradigm presents a valuable potential addition to existing study designs without increasing animal usage.