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The addition of an achiral crown ether (18-crown-6) to a cyclodextrin-based separation can significantly affect the capillary electrophoresis (CE) enantioresolution of organic racemates that contain a primary amine functional group. In most cases an enhancement of the enantioseparation was observed. However, there are also cases where the addition of 18-crown-6 was detrimental to a cyclodextrin-based CE enantioseparation. The effect of concentration of the two complexing additives as well as the effect of pH and added potassium ion were examined. A specific three-body complex involving simultaneous, dual inclusion complex formation can be used to explain both the enhanced and diminished enantioselectivities observed when 18-crown-6 is added to the run buffer.

Rats were subjected to chronic exposure to low levels of halothane (10 and 500 ppm for 8 and 4 weeks, respectively). The ultrastructural changes in the kidneys were studied. Animals exposed to 10 ppm halothane demonstrated chronic degenerative changes in the proximal convoluted tublues, including proliferation and membranous whirling of the basal infoldings of some epithelial cells and membranous degeneration of the mitochondria to form membranous bodies within the cellular cytoplasm. These pathologic changes were even more extensive and exaggerated in animals exposed to 500 ppm halothane. Fusion of the membranous bodies to form large membranous plaques and coalescence of lysosomes to form irregulary shaped cytoplasmic dense bodies were frequently found. Swelling of the mitochondria and areas of focal cytoplasmic degradation were also observed. Extrustions of large cytoplasmic masses containing mitochondria. clusters of smooth endoplasmic retriculum and ribosomes into the tubular lumen were frequently observed. Accumulation of spherical microparticles within the tubular basement membranes were also a prominent finding. The present investigation clearly indicated that halothane is nephrotoxic and may be considered as an occupational hazard.

Young adult BALB/c mice were administered trimethyltin chloride (TMT) at a dosage of 3.0 mg TMT/kg body wt. Animals displayed severe toxic signs (tremor and aggression) within 24 hr and were sacrificed at 48 and 72 hr postinjection. The brain stems of these animals were examined with light and electron microscopy. Degenerative and vacuolar changes were observed in many large brain stem neurons, especially those in the mesencephalic trigeminal nuclei. These neurons acquired a chromatolytic character with eccentric nuclei, loss of Nissl substance, and hyalinoid cytoplasm. Extensive vacuolation was also found in these nerve cells. Electron microscopy examination revealed progressive loss of the Nissl substance (rough endoplasmic reticulum) and distention of the cytoplasmic membranes (endoplasmic reticulum and Golgi complex). Severe distention of these membranes resulted in large membrane-limited vacuoles within these nerve cells. This intraneuronal vacuolation reflects an intracellular edema condition of these nerve cells and is potentially reversible. Mitochondrial damage in these neurons was only moderate. Further investigation is needed to elucidate the full toxic impact and pathogenetic mechanisms of TMT in the nervous system.

Chronic administration of cadmium chloride to B10-A-2R mice was discovered to severely depress the numbers and to delay the onset of appearance of splenic IgG and IgM plaque-forming cells (PFC) following injection of sheep erythrocytes. A recovery period of at least 1 month following cessation of administration of CdCl2 resulted in no increase in IgM PFC and only a minimal increase in IgG PFC. An apparent cadmium-induced splenomegaly was also noted in the intoxicated mice. Application of immune adherence and rosetting techniques as well as immunofluorescence to study the cellular morphology of these spleens indicated that the cell type most responsible for the increased spleen size had Fc and complement receptors as well as surface or cytoplasmic immunoglobulins. Populations of polymorphs and macrophages were not found to significantly contribute to the hyperplasia observed.

The protective effect of vitamin E on the neurotoxicity of methylmercury was investigated by means of light and electron microscopy. Young male golden hamsters were exposed to 2.0 ppm methylmercury chloride with or without concurrent administration of vitamin E (2.0 ppm). No toxic symptoms were observed in the vitamin E-protected animals while all the animals given methylmercury alone developed severe symptoms of methylmercury poisoning. Light microscopy revealed no significant neural damage by mercury in those animals exposed to methylmercury/vitamin E while significant neuronal necrosis could be demonstrated in both the cerebellum and calcarine cortex of the methylmercury-treated animals. Besides some accumulation of lysosomes, electron microscopy also demonstrated remarkable intactness of the cellular organelles in the nerve cells without neuronal necrosis. It appears that vitamin E has a strong protective potential against the toxicity of methylmercury.

Young C57BL/6N mice were injected (ip) with trimethyltin chloride at a dosage of 3.0 mg/kg body wt. Animals were sacrificed between 48 to 72 hr postinjection by means of intracardial perfusion of saline solution followed by 2.5% buffered glutaraldehyde. For light microscopy, the cords were further fixed in 10% buffered formalin and embedded in Paraplast. For electron microscopy, tissue samples were obtained from the cord levels at L1-L4, further fixed in glutaraldehyde and osmium tetroxide, and embedded in Epon. Chromatolytic and vacuolar changes involving neurons mainly in the medial and lateral motor nuclei of the anterior horns were observed. Electron microscopy revealed lysosomal accumulation and extensive dilatation of the cytoplasmic membrane systems (endoplasmic reticulum, Golgi complex). Large intraneuronal vacuoles were formed as a result of extensive intraneuronal edema. Progressive distention of the cytoplasmic membranes resulted in severe vacuolation, disintegration, and total breakdown of the neurons.

A battery of monitoring tests that could indicate genetic damage was used to investigate occupational formaldehyde exposure in a population of a hospital autopsy service workers. 11 exposed individuals and 11 matched controls were evaluated for sperm count, abnormal sperm morphology and 2F-body frequency. Subjects were matched for sex, age and customary use of alcohol, tobacco and marijuana. Additional information was collected on health, medications and other exposures to toxins. 10 subjects were employed for 4.3 months (range 1-11 months) prior to the first sample and 1 was employed for several years. Formaldehyde exposures were episodic but with a time weighed average between 0.61 and 1.32 ppm (weekly exposure range 3-40 ppm X h). Exposed and control subjects were sampled 3 times at 2-3 month intervals. Sperm morphology was also evaluated in B6C3F1 mice after 5 daily oral doses of 100 mg/kg formalin. No increase in abnormal morphology was detected in the treated animals. In humans, no statistically significant differences were observed between the exposed and control groups for the observed variables. Reduced sperm count correlated with increased abnormal morphology and 2F-body frequency in the exposed group but not in the control group. Evaluation of the impact of incidental exposures suggests a reduced count with marijuana use and increased abnormal morphology with medications used by controls. No effects on sperm were seen from formaldehyde or its metabolites in this population after occupational exposure, nor in mice following a high acute exposure. It is possible that minor effects might have occurred. The lack of an effect in this study may be due to a lack of statistical power to detect effects at this exposure level.

The interrelationship of alpha 1-antitrypsin (alpha 1-AT) or serum trypsin inhibitor capacity (TIC) level and cadmium exposure in the induction of pulmonary lesions was investigated. Sprague-Dawley rats were exposed to CdCl2, galactosamine, or galactosamine + CdCl2 for 24 hr. Biochemical study indicated a 20% reduction of serum TIC in animals exposed to galactosamine. A marked, 50%, reduction of serum TIC was induced in animals exposed to galactosamine + CdCl2. Histopathological study revealed no major morphological lesions in lungs of animals exposed to either CdCl2 or galactosamine. However, extensive lesions, including polymorphonuclear leukocyte (PMN) infiltration, distortion and distention of the alveolar spaces, and massive hemorrhages were observed in the lungs of animals exposed to galactosamine + CdCl2. It is believed that cadmium can induce rapid lesions in the pulmonary tissues when the alpha 1-AT is significantly suppressed. The present investigation has provided direct evidence on the importance and interrelationship of cadmium and alpha 1-AT in pulmonary lesion development.

The products of the covalent binding of chloroform to rat hemoglobin during microsomal metabolism were isolated and identified by gas chromatography (GC) and mass spectroscopy (MS). After isolation by Proteinase K hydrolysis, amino acid analysis and cellulose thin-layer chromatography (TLC), the major product was identified by GC/MS as N-hydroxymethyl cysteine and a minor product as 2-hydroxythiazolidine-4-carboxylic acid. N-Hydroxymethyl cysteine is proposed to be formed during isolation from the 2-oxothiazolidine-4-carboxylic acid present in the intact hemoglobin.

The alkylation of hemoglobin is a proposed dose monitor for chemical carcinogens and mutagens. The binding of fifteen chemical carcinogens and mutagens to rat hemoglobin was determined. Direct acting carcinogens and indirect acting carcinogens including aromatic amines, halogenated hydrocarbons, nitrosamines, polycyclic aromatic hydrocarbons, aflatoxin B1 and benzene bound hemoglobin. The efficiency of carcinogen and mutagen hemoglobin was dose dependent and ranged from 0.007 to 2.3% of an oral dose. The binding of chemical carcinogens and mutagens to hemoglobin would appear to be generic so that it could be developed into a dose monitor for a large number of known carcinogens and mutagens.

The covalent binding of chemical carcinogens and mutagens to hemoglobin has been proposed as a dose monitor for environmental exposure. The binding of chloroform to hemoglobin in rats was demonstrated to result from the formation of addition adducts to amino acids in the globin. The altered amino acids were isolated with an amino acid analyzer employing ion exchange chromatography. The covalent binding of orally-administered [14C]chloroform to rat hemoglobin reached a peak within 10 h. Afterwards, the amount of chloroform bound decreased slowly with half remaining at 7 weeks. The extent of chloroform binding was linearly dependent upon dose between 0.1 and 100 mumol/kg. Above 100 mumol/kg chloroform the binding to hemoglobin increased at a reduced rate. The extent of [14C]chloroform binding resulting from either 10 daily doses of 0.1 mumol/kg or a single 1.0 mumol/kg was similar. The binding to hemoglobin in three strains of mice and rats varied from 85 +/- 7 mumol/g Hb for Swiss (CFN) mice to 152 +/- 14 for Fisher-344 rats. We have demonstrated that the binding of chloroform to hemoglobin appears to have the following attributes of a dose monitor: (1) easily accessible from laboratory animals (and humans); (2) dose dependent; (3) stability, so that exposure can be determined weeks after it has ceased; (4) integration of low exposures which individually would be undetectable.

The effects of corn oil on rat dorsal root ganglia (DRG) were examined by both light and electron microscopy. Rats were fed corn oil via intubation 5 days per week for 7 weeks. No apparent morphological lesion was observed in the DRG by means of light microscopic examination. However, various cytological changes were revealed by electron microscopy. The most prominent change was the extensive and severe edematous condition in the interstitial space. After 7 weeks of treatment, the interstitial space between neurons and nerve fibers was distended by proteinaceous edematous fluid and collagen fibers. Distention of the intercellular space between the ganglion neurons and their surrounding satellite cell sheaths also occurred. Proliferation of the supporting cells, especially the satellite cells and Schwann cells, producing long and complex networks of cellular processes in the distended interstitial space was also evident. It is believed that chronic ingestion of corn oil by rats has an adverse effect on the endothelial system leading to an increased fluid permeability and edematous condition.