ECOs, FOBs, and UFOs: Making sense of observational data

Systematic observations of rat behavior are required for both standard subc hronic safety studies and for neurotoxicity studies. The requirements speci fy subjective out-of-cage observations (eg, posture, gait, and reactivity t o various stimuli such as, auditory, tactile, and noxious) using defined sc ales. Measurement of forelimb/hind limb grip strength, landing foot splay, and locomotor activity ore also required. The observational endpoints are o rganized into a battery, eg, the Environmental Protection Agency functional observational battery (FOB) or expanded clinical observations (ECO). Funct ional and neuropathologic data are most easily integrated when the function al endpoints are organized as a neurologic exam (ie, each endpoint has a kn own anatomical basis and there are sufficient endpoints to cover the nervou s system). Current batteries do not constitute a neurologic exam. Although ECOs and FOBs contain some components of a neurologic exam (ie, observation s of gait, response to pinch), the anatomic basis for other components (eg, hind limb splay) is poorly defined. And although some functions (eg, somat omotor) are well characterized by current batteries, others (eg, vision, so matosensation) are evaluated less effectively. The measurement of locomotor activity in a novel environment is one of the most problematic parts of cu rrent functional testing batteries, although contemporary technology may pr ovide opportunities for improving this test. The influence of inherent limi tations of functional test methods is magnified by factors associated with testing for neurotoxicant-related effects during safety studies. First, mos t personnel at contract laboratories have little or no formal training in c onducting and interpreting a neurologic examination. Second, most neurotoxi cant-related lesions are bilateral, which paradoxically may produce more su btle effects than unilateral lesions. Third, most chemicals will bet tested only once, and sponsors are reluctant to evaluate results in "real time" a nd amend protocols to add endpoints (eg, neurophysiological tests) to clari fy functional effects. Pathologists should have realistic expectations abou t the opportunities for integrating functional and neuropathologic findings .