Increased thermal stability of collagen after 2,5-hexanedione intoxication in rats.

The present study examined the ability of 2,5-hexanedione (2,5-HD) to cross-link the fibrillary protein, collagen, in vivo. The thermal stability of collagen measured as the isometric contraction-relaxation force was studied in tail tendons from rats, receiving 2,5-HD intraperitoneally for 2 or 6 weeks (1 g/kg/week, divided into 3 doses). The maximum contraction force was significantly increased after 6 weeks of intoxication as compared to controls, indicating an increase in covalent cross-linking between collagen molecules. Likewise, in vitro incubation of rat tail tendons in 2,5-HD for 24 hr induced an increase in thermal isometric contraction force.

Cell body responses to axonal injury: traumatic axotomy versus toxic neuropathy.

To compare the evolution of cell body responses to two different types of axonal injuries--sciatic nerve crush (axotomy) and chronic 2,5-hexanedione-induced neuropathy--we studied rat lumbar dorsal root ganglion neurons with light microscopy and morphometry. Compared with control neurons, axotomized cells showed early (1 day) increases in the frequencies of two responses, nuclear eccentricity and Nissl body displacement, and later (4 day) increases in average satellite cell nuclei and decreases in perikaryal diameters. In toxin-induced axonal degeneration, there were similar patterns of defined alterations, although the evolution progressed over weeks and the response magnitudes were smaller. We conclude that the two experimental conditions show basic morphologic similarities, implying cell body reorganization in toxic axonopathy may be a response to axonal dysfunction or degeneration.

Neurotoxicity of certain environmental substances.

Lead, aluminum, mercury, and ketones and related solvents are discussed because they represent common problems in the environment and because they demonstrate selective vulnerability, selectively attacking some portions of the nervous system, sparing others. The absorption, excretion, distribution, and toxicologic effects of these chemicals and the diseases they are associated with are reviewed, as is the accuracy of screening procedures for detection of these chemicals.

[An experimental study on electrophysiological and histopathological changes in 2,5-hexanedione-intoxicated rats].

An experimental study of neuropathy due to 2,5-hexanedione (2,5-HDione) was performed in rats by using simultaneously both electrophysiological and histopathological methods. Seven rats were given subcutaneously five days a week 200 mg/kg of 2,5-HDione for first 3 weeks and then 300 mg/kg for the next 5 weeks. Nerve conduction velocities in the tail were measured every week and after the respective measurement times one animals was sacrificed for histological study. At the 2nd week of the experiment, 2,5-HDione-treated rat showed a slight morphological changes with swollen axons in the posterior spinal root fiber and tail nerve. A slowing of motor and sensory conduction velocity (MCV and SCV) in the tail was observed in the treated group at the 4th week. Weakness of hindlimbs was apparently seen at the 5th week. At the 6th and 7th week, histological changes including giant axonal swelling, fiber loss, thinning of myelin and demyelination, were prominent in the various regions of the peripheral nervous system. Additionally, degenerative changes of the spermatogenic cells, especially the formation of multinucleated giant spermatids, were markedly observed in the treated rats at the 6th and 7th week.

Toxicity and metabolism of the neurotoxic hexacarbons n-hexane, 2-hexanone, and 2,5-hexanedione.

Human exposure to hexacarbon compounds is quite pervasive, including occupational exposures to industrial solvents as well as unintentional and sometimes deliberate exposures to hexacarbon solvents contained in innumerable commercial products. The exact mechanism of hexacarbon neurotoxicity has not yet been identified, but an interference with neuronal axoplasmic flow seems most likely. Metabolism of n-hexane and 2-hexanone to 2,5-hexanedione is a prominent feature which appears to be causally related to the neuropathologic syndrome, and mixed solvent effects have been noted in regard to potentiation of hexacarbon neurotoxicity. Continued effort in investigating the chemically induced peripheral neuropathy is essential not only to define the precise molecular mechanism, but to advance our basic understanding of other polyneuropathies as well. Ultimately, progress in these areas should yield such benefits as early diagnosis of potential neuropathology, better measures for the prevention of neurotoxicities, and more effective modalities of treatment. Indeed, sustained research efforts are imperative in maintaining human health and safety throughout our current era of advancing global technology.

Efficacy of sodium diethyldithiocarbamate (dithiocarb) in acute nickel carbonyl poisoning.

A brief historical resume is presented on the use of dithiocarbamates for the treatment of persons exposed to nickel carbonyl. The specificity of the treatment is demonstrated in an industrial accident in which four men were simultaneously exposed to nickel carbonyl vapors. Three of the men received dithiocarb within 24 hours after exposure and the fourth was hospitalized by his family physician and treated for bronchopneumonia with antibiotics and without benefit of dithiocarb. The three workmen who received dithiocarb became symptomless and returned to work within 72 hours after exposure. The fourth man who had not received dithiocarb died within five days after exposure.

Function of peripheral nerves and signs of polyneuropathy in solvent-exposed workers at a Swedish steelworks.

A field study was performed at a Swedish steelworks concerning symptoms and signs of polyneuropathy in 42 workers exposed to organic solvents at the plastic coating line of the plant. Examination was done clinically and by simple electrophysiological methods. The workers were exposed to a mixture of solvents, including methyl ethyl ketone (MEK) and trichloroethyelen. Nosed to a mixture of solvents, including methyl ethyl ketone (MEK) and trichloroethylene. None of the solvents used are known to cause peripheral neuropathy. At times very high vapour concentrations of solvents in the air were attained. The exposed workers were compared with at group of reference subjects sampled from other sections of the steelworks, matched for sex, age and duration of employment. Among the exposed workers one plausible and two suspected cases of polyneuropathy were found. None of the reference subjects showed signs of polyneuropathy. Statistical assessment provided some evidence, though weak, of a connection between the exposure to organic solvents and the observed abnormalities. A brief review is made of the present state of knowledge about hazards to the peripheral nervous system from the solvents in question.

"Giant axonal neuropathy" caused by industrial chemicals: neurofilamentous axonal masses in man.

Symmetrical polyneuropathy developed in two patients after they had been in contact with acrylamide and methyl n-butyl ketone, respectively. In sural nerve biopsy material from both patients, electron microscopy showed frequent focal axonal swellings containing masses of neurofilaments. Some axons undergoing axonal degeneration also were seen. These morphologic features are identical to those produced in experimental animals after exposure to these chemicals and are similar to those found in n-hexane neuropathy and in the three reported cases of giant axonal neuropathy. Sural nerve biopsy is an important diagnostic test in identifying cases of peripheral neuropathy caused by these chemicals.

Experimental neuropathy produced by 2,5-hexanedione--a major metabolite of the neurotoxic industrial solvent methyl n-butyl ketone.

Chronic exposure of rats to 2,5-hexanedione (CH3COCH2CH2COCH3), a major metabolite of the neurotoxic industrial solvent methyl n-buryl ketone (CH3COCH2CH2CH2CH3), has been shown to cause a clinical peripheral neuropathy with dying-back peripheral and central nervous system degeneration characterized by giant axonal swellings filled with neurofilaments. This pattern of disease is similar to that produced by methyl n-butyl ketone.

Toxic polyneuropathy due to methyl n-butyl ketone. An industrial outbreak.

Cases of toxic distal polyneuropathy have been studied in a plant producing plastic-coated and color-printed fabrics. After the screenig of 1,157 employees, a total of 86 verified cases were detected. Of these, 11 were moderate to severe in intensity and usually with motor and sensory involvement; 38 were mild, with sensory signs prevailing; and 37 were minimal, but with characteristic electro-diagnostic abnormalities. Muscle weakness and electromyographic abnormalities were predominantly distal. Reflex loss was minimal. Sensory deficits were distal and limited to pain, touch, and temperature discrimination with occasional loss of vibration sense. The distribution of involvement severity of the disorder, and temporal course of the outbreak correlated with exposure with methyl n-butyl ketone. After elimination of this agent improvement was noted in the majority of cases.