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Biomedical subjects

R J Jaeger

Publications and source records attributed to R J Jaeger.

At least 73 records · Page 4Linked to original sources
PubMed1977

1,1-Dichloroethylene hepatotoxicity: proposed mechanism of action and distribution and binding of 14C radioactivity following inhalation exposure in rats.

1,1-Dichloroethylene is reported to produce renal tumors in male mice. It is an hepatotoxin in fasted rats after inhalation. We found that trichloropropane epoxide, an inhibitor of epoxide hydrase, enhances hepatic injury as measured by serum sorbitol dehydrogenase elevation. A significant elevation of hepatic citric acid concentration was seen in fasted but not fed rats. We hypothesized that mitochondrial injury was associated with inhibition of the tricarboxylic acid cycle and postulated that monochloroacetic acid was a toxic metabolite of 1,1-DCE. Fluoroacetic acid and chloroacetic acid were similar in their ability to inhibit oxygen uptake when pyruvic and malic acids were substrates in isolated mitochondria supplemented with adenosine diphosphate. In experiments where 1,1-DCE metabolism was estimated, no difference between the rate of uptake in a 2-hr period was detected between fed and fasted animals. Urinary output of radioactivity at 26 hr for fed and fasted rats was similar. Water-soluble (i.e. TCA-soluble) 1,1-DCE metabolites were found in tissues of fasted rats in excess of that seen in fed rats. The kidney had the largest concentration of total metabolites. Tissue-bound, or TCA-insoluble, radioactivity was associated with the mitrochondrial and microsomal fraction of fasted rats in excess of that seen in fed rats. The disappearance of TCA-insoluble radioactivity from the mitochondrial and microsomal fractions was comparable in rate between fed and fasted rats respectively. These results suggest that 1,1-DCE is metabolized quite rapidly in the organism to TCA-soluble components which are excreted by the kidneys. Metabolites of 1,1-DCE may enter the metabolic pool, since a reasonably short turnover of (14)C-labeled, bound material was observed. The metabolite of 1,1-DCE appears to inhibit the mitochondria so that citric acid accumulates. This may occur by a process of lethal synthesis.

Acetates↗
PubMed1977

Acute hepatotoxicity of ethylene and halogenated ethylenes after PCB pretreatment.

Previous studies from our laboratory have shown that ethylene, vinyl fluoride monomer (VFM), vinyl chloride monomer (VCM), and vinyl bromide monomer (VBM) are all acutely hepatotoxic in rats pretreated with polychlorinated biphenyl (PCB). The time course of hepatic injury development after exposure and several parameters, environmental and chemical, affecting this toxicity were evaluated in the work reported here. Liver injury, as measured by serum alanine-alpha-ketoglutarate transaminase (SAKT) or sorbitol dehydrogenase (SDH), develops progressively over a 24-hr period following a 4-hr inhalation exposure of PCB-pretreated rats to ethylene or VCM. Environmental temperature during exposure to VCM does not affect hepatotoxicity or mortality below 30.3 degrees C. At 33.8 degrees C, however, mortality and SAKT are dramatically increased. Overnight fasting, which depletes hepatic glutathione (GSH) of PCB-pretreated rats before exposure to ethylene or VCM, significantly increases the hepatotoxicity of these compounds as measured by SDH. The combined effects of fasting and of trichloropropane epoxide (TCPE), an inhibitor of epoxide hydrase (EH), were also examined. TCPE treatment of fasted PCB-pretreated rats immediately before exposure was synergistic in increasing the acute toxicity of ethylene and VCM. TCPE increased mortality in fed or fasted rats exposed to VFM, but there was no effect of fasting alone. Both fasting and TCPE increased the sensitivity of PCB-pretreated rats to VBM, but there was not a clearly synergistic effect of fasting plus TCPE. These data suggest that the acute toxicity of these compounds is mediated through epoxide intermediates.

Animals↗
PubMed1976

Training and performance of rhesus monkeys as operators in a compensatory manual control system.

Two rhesus monkeys were trained as operators in a compensatory manual control system similar to systems used in human studies. Training procedures used to shape compensatory tracking behavior included a multiple shock-avoidance technique, the gradual introduction of the system input, and sharpening visual stimulus control of tracking behavior. Time-on-target scores for the monkeys were 95% to 98% while responding to three different frequency bandwidths of the system input. As frequency bandwidth increased, no significant increase in error was noted, the monkeys returned the target element to the center target area at increasing rates, and the number of shocks delivered to each subject remained low. Bode plots and stripouts of input, output, and error signals resembled those typically obtained in human studies. Through extrapolations based on nonhuman primate performance, the conclusion was that the task development and training procedures of the present study provided a means for estimating human performance in manual control systems under environmental stress or in hazardous environments.

Animals↗
PubMed1976

Human and nonhuman operators in manual control systems.

The human operator in manual control systems is well known from a control theory point of view. The need for highly specialized data in an area which does not permit using human subjects resulted in the study of rhesus monkeys in manual control systems. The performances of monkey and human operators in a simple compensatory control system were similar.

Animals↗
PubMed1975

Short-term inhalation toxicity of halogenated hydrocarbons: effects on fasting rats.

Male rats, fasted overnight (18 hours), and exposed to various materials in inhalation were more sensitive to the hepatotoxic effects of carbon tetrachloride, 2-chlorobutadiene, 1,1-dibromoethylene, and 1,1-dichloroethylene (DCE). Vinyl chloride monomer and 1,1-difluoroethylene were not acutely hepatotoxic in fed or fasted rats at any concentration tested. Vinyl chloride monomer when administered simultaneously with DCE prevented the injury associated with DCE inhalation in fasted rats. This prevention of injury may be a result of a competitive interaction since the effect was concentration dependent.

Aerosols↗
PubMed1975

Biochemical toxicology of unsaturated halogenated monomers.

Previous inhalation toxicity studies from our laboratory have shown that 1,1-dichloroethylene (1,1-DCE), 1,1-dibromoethylene (1,1-DBE), and 2-chloro-1,3,-butadiene (2-CBD) are more toxic to fasted rats than to fed rats. Vinyl chloride monomer (VCM) and 1,1-difluoroethylene (1,1-DFE) were not acutely hepatotoxic at 46,500 and 82,000 ppm, respectively, in normal male rats, whether fed or fasted. On a molar basis, 1,1-DBE and 1,1-DCE have similar toxicities while 2-CBD is less toxic. All three compounds produce similar elevation of serum transaminase and bloody ascites, although at differing times following differing exposure concentrations. 1,1-DCE produces massive midzonal hepatic necrosis with hepatic thrombosis and chromatolysis within 2 hr after a 4 hr exposure of fasted rats to 200 ppm. Subsequent to formation of this midzonal lesion, the central portion of the lobule collapses, accompanied by congestion, ascites, and in increased hematocrit in the rat. Serum transaminase and sorbital dehydrogenase are greatly elevated at 6 hr. This effect in fasted rats is associated with glutathione (GSH) depletion. Diethyl maleate (DEM) which depletes GSH in fed rats potentiates the injury associated with 1,1-DCE exposure as well as that produced by 2-CBD. Rats fed ad libitum and exposed to 1,1-DCE or 2-CBD at night, a time of low hepatic GSH concentration, exhibit enhancement of hepatotoxic response when compared to animals exposed during the day when GSH is high.

Alanine Transaminase↗
PubMed1975

Acute liver injury by vinyl chloride: involvement of endoplasmic reticulum in phenobarbital-pretreated rats.

A single 6-hr exposure to vinyl chloride monomer (5%) produces extensive vacuolization of centrolobular liver parenchyma and focal midzonal necrosis in the hepatic lobuole in phenobarbital-pretreated rats. Ultrastructurally, vacuolization consists of dilation of cysternae of rough endoplasmic reticulum and in the same cells smooth endoplasmic reticulum coalesces into discreet aggregates resembling denatured membranes. The findings support the hypothesis that vinyl chloride is hepatotoxic because it is converted into a toxic metabolite by components of the mixed function oxidase system of liver endoplasmic reticulum.

Animals↗
PubMed1975

Vinyl chloride-induced deactivation of cytochrome P-450 and other components of the liver mixed function oxidase system: an in vivo study.

Liver microsomal enzyme activities were measured 24 hr after a 6 hr exposure to 5% vinyl chloride in male rats pretreated with phenobarbital, Aroclor 1254 or the control vehicle. Liver injury as indicated by serum transaminase elevations after vinyl chloride, was found only in phenobarbital and Aroclor 1254 animals while cytochrome P-450 contents and oxidative N-demethylation of aminoantipyrine and ethylmorphine were markedly decreased in all groups. Glucose-6-phosphatase, cytochrome b5 and NADPH and NADH cytochrome P-450 reductase were scarcely affected. This selective enzymatic deactivation is consistent with a cytochrome P-450 centered activation of vinyl chloride to a reactive electrophile.

Alanine Transaminase↗
PubMed1975

Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene. Role of mixed function oxidase system.

Vinyl chloride, an occupational carcinogen, produces acute liver injury in rats pretreated with phenobarbital or Aroclor 1254. Injury appears related to morphologic changes in the endoplasmic reticulum. The degree of injury, as indicated by elevation of serum enzymes derived from the liver, correlates with the magnitude of induction of cytochrome P-450 and its reduction by NADPH. Hepatic injury following 1,1-dichloroethylene exposure differs strikingly from that caused by vinyl chloride and appears to involve plasma membranes, mitochondria, and chromatin and spares endoplasmic reticulum. Induction of cytochrome P-450 appears to protect against 1,1-dichloroethylene but not vinyl chloride.

Animals↗