Harold S. Weiss

Peripheral Nerve Changes Induced by Methyl n-Butyl Ketone and Potentiation by Methyl Ethyl Ketone

A study of the sequential morphological changes in the peripheral nerve induced by experimental inhalation exposure of methyl n-butyl ketone (MBK) revealed that the earliest change was an increase in the number of neurofilaments in the large myelinated nerve fibers. This change occurred prior to axonal swelling or myelin thinning. As the duration of exposure lengthened the number of neurofilaments gradually increased and ultimately produced axonal swelling with secondary thinning of the myelin sheath. This appears to be the pathogenesis of the “giant axonal” neuropathy. Another change observed early in this neuropathy was the presence of inpouchings of the myelin sheath, which also increased in number in parallel to the duration of exposure. A careful study of the sequential changes in the entire motor unit did not show a predilection for early morphological changes at the axon terminal. Abnormalities at the neuromuscular junction occurred only after a full spectrum of changes were seen in the main nerve trunk, nerve roots and intramuscular nerves. An important observation was the marked potentiation of peripheral neuro-toxicity observed when animals were exposed to MBK in combination with methyl ethyl ketone (MEK) at a ratio of 1:5, MBK:MEK. The latter solvent showed no neurotoxic effect alone. This might help explain a recent outbreak of a polyneuropathy affecting many workers. One further observation was that the sural nerve of a patient with prolonged exposure to MBK showed changes similar to those induced experimentally.

Toxic Polyneuropathy Produced by Methyl N-Butyl Ketone

A polyneuropathy affecting a large number of workers was recently observed at a plant producing plastic-coated and color-printed fabrics. Epidemiological data suggested strongly that methyl N-butyl ketone (MBK) was responsible for the outbreak. This hypothesis is now supported by the development of a peripheral neuropathy in chickens, rats, and cats exposed to MBK at atmospheric concentrations of 200 to 600 parts per million, 24 hours per day, 7 days per week. Although the animals were exposed continuously and the affected workers were exposed intermittently, the averages of the total number of hours of exposure for development of the peripheral neutropathy in the animals and workers were remarkably close.

Alterations of fast axoplasmic transport in experimental methyl n-butyl ketone neuropathy

Methyl n-butyl ketone (MBK) is known to produce a giant axonal neuropathy in man and experimental animals characterized pathologically by a gradual increase in the number of neurofilaments which become associated with focal areas of axonal swelling and thinning of the myelin sheath. Fast axoplasmic transport was studied in rats exposed to MBK. In 10 severely paralyzed rats exposed to MBK there was a significant impediment of fast axoplasmic transport following dorsal root ganglion injections (x +/- S.D. = 283.2 +/- 20.34 mm/day) compared to normal controls (417.6 +/- 23.78 mm/day). In rats undergoing injections into the ventral horn of the spinal cord there was a gradual impairment of the mean down flow rate for transport of [3H]leucine which correlated with the severity of the MBK induced neuropathy. Quantitative morphological determinations showed that the total number of neurotubules per unit cross-sectional myelin area and the number of neurotubules associated with mitochondria in swollen axons was unchanged from normal. The total number of mitochondria in randomly sampled axons varied significantly from controls but the absolute number of mitochondria associated with neurotubules was unchanged from normal. The results of these studies suggest that the impediment of fast axoplasmic transport may be related to the increased neurofilaments producing focal areas of axonal blockage.

The influence of inhaled ketone solvent vapors on hepatic microsomal biotransformation activities.

Abstract In studies conducted to determine the effects of inhaled ketone (methyl n-butyl ketone, MBK; methyl ethyl ketone, MEK) solvent vapors on hepatic microsomal oxidative and reductive enzyme activities in rats, groups of young male Wistar rats were housed in environmental chambers and exposed to solvent vapors (MBK, 225 ppm; MEK, 750 ppm; MBK, 225 ppm/MEK, 750 ppm). Hexobarbital sleep times were significantly reduced following exposure to MBK/MEK or MEK, but MBK exposure did not alter sleep time measurements. Aniline hydroxylase, aminopyrine demethylase, Neoprontosil reductase, and p-nitrobenzoate reductase activities were significantly enhanced two- to threefold over control values.

Starvation on compliance and surfactant of the rat lung

Abstract Air and saline P-V curves were run on the excised lungs of rats starved 1–4 days. Stability estimates based on % of maximum volume retained on deflation tended toward decreases, but atelectasis was not increased according to buoyancy measurements. Compliance was not significantly affected, with whatever trend existed being toward increases. Average air P-V curves for day 3 and 4 of starvation were essentially superimposable on control curves. Surface tension of lung lavage fluid was measured (Surfactometer) during cyclic compression and expansion of the film. Min and max γ were elevated, and the activity index (s) depressed, but the area of the hysteresis loop was relatively unchanged. It is concluded that despite increases in γ of lung washings, pulmonary mechanics was little affected by 1–4 days of food deprivation. The effects on surface tension may be due to a decrease in quantity of surfactant extractable, without any change in composition.

Pulmonary Compliance: Alteration during Infection

Lungs excised from rats infected with Mycoplasma pulmonis are more difficult to inflate with air than those from uninfected animals; they show no significant differences from controls inflated with saline. The altered pulmonary function in lungs from infected rats is attributed to an increase in surface forces, implying disruption of the lung surfactant system.

Thermal responses of man during rest and exercise in a helium oxygen environment.

Thermal responses of man during rest and exercise in helium oxygen environment for various temperatures

Mortality and histopathology of germ-free rats and mice exposed to 100 percent oxygen.

Summary Germ-free rats and mice tended to die sooner and within a narrower time span than conventional animals on exposure to 100% O2, suggesting that chronic respiratory conditions may increase resistance to O2 toxicity. Lung pathology of germ-free animals dying in O2 appeared much like that of chronic respiratory infection, indicating that inflammatory cell infiltration of the alveolar wall can occur in animals presumed free of disease.

Compliance and stability of excised mouse lungs

Abstract o 1. Static air and saline volume-pressure (V-P) curves were obtained from lungs of the mouse, mus musculus. Air curves were similar for lungs in situ or excised. 2. Continuous filling (5 ml/min) gave V-P curves as sensitive to changes in the lung as stepwise filling (1 min pause/5 cm H2O), but were simpler and quicker to run. 3. Total lung compliance was evaluated from various parts of the air V-P curve in the 0–30 cm H2O range. The slope of a tidal volume loop (8–15 cm H2O) gave the most consistent results. 4. Compared to Na pentobarbital, cervical dislocation and decapitation produced lungs with low compliance. 5. Per cent maximum volume retained at 10 cm H2O (V% 10) was as satisfactory as the more complicated index “L” for measuring lung stability. 6. Static total compliance of the excised lung of the 28 g female mouse averaged 37 ± 2·5 μl/cm H2O (n = 42).

Embryogenesis in 100% O2 at reduced pressure.

Fertile chicken eggs were incubated in an altitude chamber in a near 100% O2 atmosphere at 225 torr. Both N2 and CO2 were kept under 0.5%. Temperature was a standard 37.5° but a high relative humidity of 90% was required to prevent dehydration. In ten trials involving 382 eggs, hatchability averaged 21% of controls and weight of chicks was 11% less than controls, but embryo mortality was distributed similarly. Low pressureper se and small differences in O2 tension may have affected the results, but similarities to incubation in 21% O2-79% He call attention to absence of nitrogen as a possible explanation.