The interactions between the nervous and immune systems have been recognized in the development of neurodegenerative disease. This can be exploited through detection of the immune response to autoantigens in assessing the neurotoxicity of environmental chemicals. To test this hypothesis, the following questions were addressed. a) Are autoantibodies to nervous system (NS) antigens detected in populations exposed to environmental or occupational chemicals? In sera of male workers exposed to lead or mercury, autoantibodies, primarily IgG, to neuronal cytoskeletal proteins, neurofilaments (NFs), and myelin basic protein (MBP) were prevalent. These findings were confirmed in mice and rats exposed to either metal. b) Do autoantibodies to NS antigens relate to indices of exposure? In humans exposed to either metal, and similarly in exposed rats, titers of lgG against NFs and MBP significantly correlated with blood lead or urinary mercury, the typical indices of exposure. c) Do autoantibodies correlate with sensorimotor deficits? In workers exposed to lead or mercury, a significant correlation was observed between lgG titers and subclinical deficits. Doses of metals used in rat exposures were subclinical, suggesting that autoantibodies may be predictive of neurotoxicity. d) Is the detection indicative of nervous system pathology? In rats exposed to metals, histopathology indicated central nervous system (CNS) and peripheral nervous system (PNS) damage. In addition there was evidence of astrogliosis, which is indicative of neuronal damage in the CNS, and the presence of lgG concentrated along the blood-brain barrier, as indicated by immunostaining for antibodies. e) Are immune responses to NS antigens pathogenic? Immunoglobulin fractions from rat and human sera interfered with neuromuscular function. These studies suggest that the detection of autoantibodies to NS-specific antigens may be used to monitor the development of neurotoxicity to environmental chemicals and that immune mechanisms may be involved in the progression of neurodegeneration.