FUNCTION IN NEUROTOXICITY - INDEX OF EFFECT AND ALSO DETERMINANT OF VULNERABILITY

1. In neurotoxicity, functional indices may be the only available meas ures of effect, as many potent neurotoxic agents produce no morphologi cal change. Examples of these are strychnine, dieldrin and pyrethroids , which produce excitation but no pathology, and barbiturates, xylene and lithium, which produce depression hut no pathology. 2. In other ca ses where both functional and morphological effects are seen, function al measures often produce the most convenient, if not always the most specific, indices of toxicity. Appropriate functional measures can be highly sensitive, both in humans and in experimental animals, and can also give vital mechanistic information. However, it is essential that functional measures are reproducible and interpretable (some behaviou ral measures are not) and also provide a reasonably exacting test of f unction (passive observation of resting behaviour can miss many effect s). 3. In addition to their use as an index of toxicity, changes in fu nction, even within the normal range, can themselves influence suscept ibility to toxins. Tissue perfusion can determine delivered dose and i s influenced by function, while metabolic transformation is modified b y nutritional state. Nutritional state can also influence absorption, with anaemia enhancing manganese toxicity and calcium deficiency enhan cing lead toxicity. Functional activity can influence target susceptib ility directly: thus, noise exposure enhances the ototoxicity of carbo n monoxide, toluene or aminoglycoside antibiotics; noise, motor activi ty or anaesthesia all influence the central neurotoxicity of dinitrobe nzene or metronidazole; motor activity enhances the peripheral nerve t oxicity of lead or thallium; and nerve regeneration enhances the toxic ity of hexane. These functional factors can be very important in deter mining individual susceptibility.