Solvent neurotoxicity.

Our present understanding of the way certain aliphatic hydrocarbons adversely affect the nervous system has been one of the outstanding achievements in the field of neurotoxicology in recent years. The initial description of the neuropathy in workers exposed to fumes of n-hexane by Japanese observers' was followed by other case reports both in America2 and in Europe.3 A similar syndrome was described in workers in a factory employing methyl n-butyl ketone,4 and experimental studies on rats and in cats showed that the essential pathological change was gross focal swellings of the axon from accumulations of apparently normal 10 nm intermediate filaments (neurofilaments). s "Giant axonal neuropathy," as it came to be termed, was also noted in subjects addicted to the inhalation of solvents used for domestic glues and other preparations.6 These cases showed the same slowly developing motor and sensory neuropathy with reduced conduction velocity and very slow rate of recovery once exposure had ceased. The signs and symptoms were always distal in distribution, and ataxia and involvement of cranial nerves were not part of the syndrome. From the metabolic studies of DiVincenzo et al7 and of Couri et ar and their colleagues it became plain that an essential element in the story was the step-wise transformation in the tissues of n-hexane and of methyl n-butyl ketone to 2,5-hexanedione. Analogues, such as methyl ethyl ketone, that did not proceed to this product were non-toxic, although they might have the capacity to enhance the conversion of the toxic compounds by stimulating the metabolic processes involved in the transformations. The essential feature to the transformation is the production of the y-diketone, a necessary structural component for the toxic effect since synthesised 2,5-heptanedione and 3,6-octanedione are also toxic, and so is 5-nonanone when given in large enough doses. O' Donohue and Krasavage have suggested from this that a better and more precise term would be "y-diketone intoxication. "9 We owe it to Graham and his associates for taking the next step in the solution of this problem. '°0" From their reflections on the remarkable yellow staining of the fur of the groins and around the mouth of animals dosed with hexacarbons or their metabolites, they showed that the y-diketone derivative had the capacity to combine with the lysyl residues in proteins and, after a final oxidation step, to produce a stable pyrrhol ring configuration that was not only responsible for the chromogenic change but also for cross linked proteins. The evidence is now fairly strong that 2,5-hexanedione or its precursors are either capable of entering axons or of being metabolised in the cells to produce the toxic product and thus directly cross link the neurofilaments. A major outcome of this is that the normal structural role of the neurofilaments in the cytoskeleton of the nerve fibre is interfered with and the capacity of the long protein filaments to slip smoothly down the axon at the rate of 1 mm a day is impaired. Masses of filaments become held up at the constriction of the axons at nodes of Ranvier, the nodes become disorganised and the myelin sheath overlying the axonal swellings becomes greatly attenuated, with consequent impairment of the axon's conducting capacity. Wallerian degeneration follows as the filamentous masses block the normal supply of materials to the axon downstream. This is certainly an intriguing story, but how far can we generalise to other solvent intoxications? Has this tale any meaning for CS2, trichlorethylene, or toluene intoxication? The answer is "yes" so far as CS2 is concerned but distinctly "no" with regard to the others. In CS2, throughout the nervous system, filament masses occur within axons in exactly the same way as in y-diketone intoxication, despite the fact that this compound clearly cannot form the same chemical configuration, although the same cross linking process must occur. This probably takes place through the active sulphur released during the metabolism of CS2 to COS and then to CO2. The transformation of CS2 to diethyldithiocarbamate (DDC), which also occurs, probably has no relevance to the development of the filament accumulations. The question of the chemical mechanism of neurofilament change that goes on to the neurological damage is thus still quite open. The other solvents are other kettles of fish. There are strong suggestions that two solvents-namely, trichlorethylene and toluene-can cause damage to I the nervous system, but the others, such as white spirit and perhaps styrene, are still in the realms of clinical appraisal. Trichlorethylene is both puzzling as to its toxic process and unique in its presentation. After inhalation the minimal signs are of sensory disturbances and anaesthesia in the trigeminal (Vth cranial nerve) area. These may become permanent and indeed it was once recommended as a treatment for the debilitating condition trigeminal neuralgia. In more severe cases of exposure the change may spread to other cranial nerves, both motor and sensory, and