Occupational exposure to methyl isobutyl ketone causes lasting impairment in working memory.

The authors describe serial evaluations of a 44-year-old man who became cognitively impaired during a 6-year period of repeated exposure to high levels of methyl isobutyl ketone (MIBK). Neuropsychological tests administered six times over 10 years demonstrated a stable pattern of cognitive impairment. Dynamic imaging studies suggested persistent CNS dysfunction. The authors conclude that chronic, high-level, occupational MIBK exposure can cause a persistent cognitive syndrome best explained by impaired working memory.

Critical review of the toxicity of methyl n-butyl ketone: risk from occupational exposure.

Methyl n-butyl ketone (MBK) was considered rather harmless until an outbreak of peripheral neuropathy occurred in 1973 among workers exposed to MBK. MBK easily penetrates the skin; pulmonary retention is approximately 80-85% in man. Distribution is widespread with highest levels in blood and liver; MBK also reaches the fetal tissues. MBK metabolism probably depends on the route of exposure, and is very similar to that of n-hexane. The critical organ is the nervous system. These effects find expression as peripheral neuropathy, with potential for serious effects of the central nervous system. From the viewpoint of neurotoxicity, 2,5-hexanedione is the most important metabolite. The neurotoxicity is potentiated by several compounds, while MBK itself potentiates the toxicity of other chemicals. From animal experiments, a no-adverse-effect level (NAEL) could not be established. Peripheral neuropathy may develop in workers exposed to only a few ppm of MBK. The difference in the Occupational Exposure Limits for MBK and n-hexane, as established by several organizations, is questioned in view of the neurotoxic effects of these substances.

Motoneuron disease: a disorder secondary to solvent exposure?

There seems to be a statistically significant association between work in the leather industry and subsequent development of motoneuron disease. The reason for this association may be occupational exposure to solvents, which may damage motoneurons either directly or through activation of latent virus.

Environmental chemicals and nervous system dysfunction.

Selected examples of associations between nervous system diseases and exposures to occupational and environmental chemicals have been reviewed. Recent outbreaks of human neurotoxicity from both wellknown and previously unknown toxicants reemphasize the need for the medical community to give increased attention to chemical causes of nervous system dysfunction.

The effect of 2-hexanone and 2-hexanone metabolites on pupillomotor activity and growth.

Neurotoxic agents such as MBK (2-hexanone) and MBK metabolites were fed in drinking water to guinea pigs. Effects of these solvents on locomotor activity were studied. Dynamic pupillometry indicated that MBK, 2,5-hexanedione and 2-hexanol decreased pupillary response throughout the first five weeks; by the 24th week, all treatment groups showed a greatly impaired pupillary response. From biotransformation studies, it is possible that the 2-hexanol effect on pupillary response may be attributed to its conversion to MBK and/or 2,5-hexanedione. Each of the solvents increased body weight, but decreased locomotor activity. The pupillary changes reported here may serve as an index of solvent exposure in the work environment, if such measurements were to be conducted on workers.

Ultrastructural studies of the dying-back process. III. The evolution of experimental peripheral giant axonal degeneration.

The spatio-temporal evolution of peripheral giant axonal degeneration has been studied in rats during the development of concurrent peripheral (PNS) and central (CNS) nervous system dying-back disease after chronic intoxication with the neurotoxic hexacarbons n-hexane (CH3CH2CH2CH2CH2CH3), methyl n-butyl ketone (MBK) (CH3COCH2CH2CH2CH3), or 2,5-hexanedione (CH3COCH2CH2CHOCH3), a neurotoxic metabolite of MBK. Each compound caused animals insidiously to develop identical, symmetrical peripheral neuropathies characterized by eversion and drop of hindfeet, inability to extend hindlimbs and upper extremity weakness. Teased fiber studies demonstrated that giant axonal swellings first developed on the proximal sides of multiple paranodes sited in distal, non-terminal regions of large myelinated fibers. Later, swellings developed at internodal sites. Smaller myelinated and unmyelinated fibers also underwent multifocal, giant axonal swelling. In affected myelinated fibers, swollen nodal and paranodal axons were frequently associated with retracted paranodal myelin sheaths. Adjacent distal internodes were attenuated and corrugated. Demyelinated paranodes apparently underwent local shrinkage and remyelination before complete distal fiber breakdown commenced. The proximal limits of chains of homogeneous myelin ovoids were interfaced with proximal, preserved regions at sites of giant axonal swellings. Regeneration of myelinated axons also occurred during intoxication. Regenerating fibers wre composed of multiple, short, branched internodes which sometimes appeared multifocally swollen. Interfaces between regenerating and preserved portions of fibers were unswollen. Thick section studies showed that pronounced endoneurial edema accompanied fiber degeneration in peripheral nerve trunks. Ultrastructural studies revealed multifocal, giant axonal swellings containing masses of 10 nm neurofilaments and sometimes, clustered mitochondria, neurotubules and smooth endoplasmic reticulum. Enlarged granular mitochondria, interdigitated Schwann cell/axon networks and corrugated myelin sheaths were common findings. Dense granules, vesicles and hexagonal particles were also noted in the axoplasm. These findings provide new insights into the nature of the dying-back process: although there was a retrograde, temporal spread of axonal swelling up affected nerve trunks, axonal degeneration neither began in the nerve terminal nor spread seriatim centripetally along individual nerve fibers. The dying-back process was further examined in a companion study in this issue (32) which analyzed some of the factors determining the differential vulnerability of PNS and CNS fibers in animals intoxicated either with these neurotoxic hexacarbons or with acrylamide.

Ultrastructural studies of the dying-back process. IV. Differential vulnerability of PNS and CNS fibers in experimental central-peripheral distal axonopathies.

A companion paper in this issue (46) described the evolution of peripheral nervous system dying-back disease of the giant axonal type in animals chronically intoxicated with the neurotoxic hexacarbons n-hexane (CH3CH2CH2CH2CH2CH3), methyl n-butyl ketone or MBK (CH3COCH2CH2CH2CH3), and 2,5-hexanedione (CH3COCH2CH2COCH3). The present study compares the distribution and pattern of peripheral (PNS) and central nervous system (CNS) dying-back disease produced by these three neurotoxic hexacarbons with that produced by acrylamide (CH2CHCONH2), and, in addition, employs these compounds to address unresolved issues in the dying-back process. In the PNS, large myelinated fibers in tibial nerve branches supplying calf muscles were especially sensitive in rats intoxicated with hexacarbons. These nerve branches and sensory plantar nerves in the hindfeet were equally vulnerable in acrylamide-treated rats. In both conditions, fibers located at these sites commenced degeneration before the distal regions of much longer and smaller diameter nerve fibers in nerve branches supplying the flexor digitorum brevis muscle and, in rats intoxicated with hexacarbons, before equivalent regions of plantar sensory branches to the digits. Pacinian corpuscles sited in the hindfeet of intoxicated cats were much less vulnerable to MBK than to acrylamide. Rats and cats intoxicated with hexacarbons displayed giant axonal swellings in vulnerable regions of the PNS degeneration in these animals was accompanied by pronounced endoneurial edema. In the CNS, rostral regions of long, ascending tracts (dorso-spino-cerebellar, gracile and, later, the cuneate) and the caudal end of long, descending tracts (lateral colums, ventrolateral and ventromedial tracts) of hexacarbon-treated animals were especially vulnerable. After prolonged intoxication of cats with MBK, giant axonal swelling was also found in preterminal and terminal axons in Rexed laminae V-VII at spinal levels C4 through S3-Neurofilament proliferation without giant axonal swelling was seen in CNS fibers of rats intoxicated with acrylamide. Taken in concert, the findings underline the importance of axon diameter and length in determining the hierarchy of fiber vulnerability and indicate the common sensitivity of selected regions of the PNS and CNS. The term central-peripheral distal axonopathy is introduced to emphasize the widespread, distal distribution of disease in these and in similar experimental conditions. It is suggested that certain human neuropathies (toxic, nutritional, uremic, diabetic and some hereditary polyneuropathies, and the neuropathy associated with multiple myeloma) are additional examples of central-peripheral distal axonopathies.