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Editorial and Guest Editorial

In this issue we publish a review of the evidence for an environmental factor in the causation of ALS. This has a long history. As in other disorders of unknown causation, and imperfectly understood pathogenesis, the suggestion that an environmental factor, or toxin, could lead to the disease, has an almost inevitable attraction. In considering the biological basis of a degenerative disease such as ALS, with variable pattern of onset and variable rate of progression, the possible inuences of genetic factors, of inherited susceptibility, and of acquired exposure to environmental or endogenous toxins are legitimate matters for debate. More importantly, these issues generate possible research approaches to the problem of understanding the disease, in order to derive ways to prevent, arrest, or cure the disease. The mechanism of action of riluzole, for example, is complex and far from fully understood. It is not unlikely that the action of riluzole on excitotoxic mechanisms, through its anti-glutamate action via inhibition of cellsurface glutamatergic receptors, and its effect on cytosolic processes, does not reect a basic pathogenic mechanism in the disease, but an effect on an epiphenomenon, conferred by some other underlying abnormal process. In the case of SOD1 mutations, as exemplied by the benecial effect of riluzole on life expectancy in SOD1 transgenic mice, this action is more clearly occurring in parallel to the underlying gain of function anomaly thought to underly the deleterious action of the abnormal gene. Since not all inherited ALS is associated with SOD1 mutations there must be other mutations, and much will no doubt be learned from study of these when their genetic loci have been revealed. An interaction with other genetic factors or, possibly, with environmental factors, can be inferred from the variable phenotypes of patients with familial ALS in affected SOD1 sibships. The data from study of potential environmental toxic factors are, however, largely derived from epidemiological studies. These suffer from the everpresent possibility of Type 2 errors in the interpretation of the statistics, a matter that always needs careful thought when considering the implications of epidemiological data in the pathogenesis of a disease of unknown causation. The example of the implications to be drawn from the relation of the Broad Street pump to a typhoid epidemic is unfortunately all too rare in modern epidemiological studies of neurodegenerative disease. Nonetheless, the issue of a possible environmental factor in triggering the onset of ALS, or in setting the scene that allows the disease to continue to progress, in the context of an inherited susceptibility, rather than familial ALS itself, is a problem that should continue to provide a source of inspiration for further epidemiological and experimental research. There are clues here that have not yet been thoroughly explored.