The hypothesis that neurotoxins may play a role in neurodegenerative disorders remains an elusive one, given that epidemiologic studies often provide conflicting results. Although these conflicting results may result from methodological differences within and between studies, the complexity of chemical disruption of the central nervous system cannot be ignored in attempts to evaluate this hypothesis in different neurodegenerative disorders. Spencer provides a detailed review of the complex processes involved in defining the neurotoxic potential of naturally occurring and synthetic agents. Even concepts such as exposure and dose, as often reported in studies attempting to evaluate the risk imparted by a potential compound, can be deceptive. For example, although dose reflects "that amount of chemical transferred to the exposed subject", factors such as time and concentration in the organism, the ability to access the central nervous system, and how a compound reaches the central nervous system (routes of administration) or secondarily affects other organ systems leading to central nervous system disruption are clearly important to the concept of neurotoxic risk in neurodegenerative disorders. These factors would appear to explain the observed disagreements between studies using animal or neuronal models of neurotoxicity and population-based studies in humans. The importance of these factors and how a potential neurotoxin is investigated are clearly seen in the data on AD and aluminum. In contrast, the impact of MTPT on the central nervous system is more direct and compelling. Added complexity in the study of neurotoxins in human neurodegeneration is derived from data showing that agents may have additive, potentiating, synergistic, or antagonistic effects. Therefore, data from studies evaluating EMF risks could be readily confounded by the presence or absence of heavy metals (eg, arc welding). Other factors that may conceal neurotoxic causes for a given disorder focus on additional features such as genetic predispositions, physiologic changes that occur in aging, and even nutritional status that can support or hinder the affect of a given agent on the central nervous system. Finally, many studies that investigate exposure risk do not readily incorporate the five criteria proposed by Schaumburg for establishing causation. For example, if we apply Schaumburg's first criterion, epidemiologic studies often determines the presence of an agent through history, yet they cannot readily confirm exposure based on environmental or clinical chemical analyses to fulfill this criterion for causation. Additional limitations in research design along with the populations and methods that are sued to study neurotoxins in human neurodegenerative disorders often fail to meet other criteria such as linking the severity and onset with duration and exposure level. Therefore, although studies of agents such as MTPT provide compelling models of neurotoxins and neurodegeneration in humans, disorders such as ALS, PD, and particularly AD will require additional effort if research is to determine the contribution (presence or absence) of neurotoxins to these neurologic disorders.