Rudolph J. Jaeger

Effect of 18 HR fast and glutathione depletion on 1,1-dichloroethylene-induced hepatotoxicity and lethality in rats

Abstract Four-hour inhalation exposure to 1,1-dichloroethylene (1,1-DCE, vinylidene chloride) was more injurious to 18-hr (overnight) fasted rats than to rats fed ad libitum. The estimated 24 hr LC50 for fed rats was 15,000 ppm while the same value for fasted rats was 600 ppm. The minimum lethal concentration was 200 ppm for fasted rats and 10,000 ppm for fed rats. Serum alanine α-ketoglutarate transaminase (AKT) elevation occurred at 150 ppm in fasted rats, but in the fed rats, a significant elevation was only seen at 2000 ppm and higher. Elevated serum AKT preceded hepatic necrosis and death. This fed-fasted difference in serum AKT elevation was also demonstrable in an isolated perfused rat liver system. The AKT elevation in perfusate from livers of fasted rats was consistent with the time course of injury seen in vivo. Increased susceptibility to hepatic injury appeared to be related to decreased hepatic glutathione concentration associated with fasting (18 hour). Diethylmaleate, a material which results in a decreased hepatic glutathione concentration was administered in vivo and in vitro. This treatment potentiated the hepatic injury in fed rats and in livers taken from fed rats and subsequently perfused.

Acute hepatotoxicity of ethylene, vinyl fluoride, vinyl chloride, and vinyl bromide after aroclor 1254 pretreatment☆

Abstract Male rats were pretreated by gavage with the polychlorinated biphenyl mixture (PCB) Aroclor 1254 (300 μmole of PCB/kg) for 3 consecutive days. On the fourth day these rats were exposed by inhalation (4 hr) to various concentrations of ethane, ethylene, fluoride monomer (VFM), vinyl chloride monomer (VCM), or vinyl bromide monomer (VBM). Animals were sacrificed 24 hr after exposure and acute hepatic responses were estimated by measurement of serum alanine-α-ketoglutarate transaminase (SAKT) and by light microscopy. All of the compounds tested, except ethane, caused significant elevations of SAKT and produced severe degeneration and necrosis of the liver. Typical SAKT values (milligrams of pyruvate per milliliter of serum per hour) were: absolute controls, 0.17 ± 0.01; PCB pretreated, not exposed, 0.19 ± 0.02; PCB and 50,000 ppm of ethane, 0.11 ± 0.02; PCB and 25,000 ppm of ethylene, 1.98 ± 0.61; PCB and 10,000 ppm of VFM 6.29 ± 0.99; PCB and 10,000 ppm of VCM 1.11 ± 0.32; and PCB and 33,000 ppm of VBM, 3.78 ± 2.28. The relative potencies of these compounds in elevating SAKT were similar and the spectrum of morphologic changes (e.g., midzonal ballooning of hepatocytes and centrolobular hemorrhagic necrosis) was the same. The acute hepatotoxicity of ethylene plus PCB and lack of effect from ethane plus PCB indicate a role for the double bond in these toxic interactions. With the exception of ethane the compounds tested are similar in acute toxicity after PCB pretreatment. This similarity of acute action, in light of the carcinogenicity of VCM, suggests that ethylene, VMF, and VBM should be evaluated for chronic effects.

Biochemical effects of 1,1-dichloroethylene in rats: Dissociation of its hepatotoxicity from a lipoperoxidative mechanism☆☆☆

Abstract The dose-response and time course of hepatic injury following orally administered doses of 1,1-dichloroethylene (1,1-DCE) were studied. The following parameters were measured: hepatic glucose-6-phosphatase (G6Pase), serum alanine-α-ketoglutarate transaminase (SAKT), hepatic triglyceride (HTG), and pentobarbital sleeping time (PST). A comparison was made between 1,1-DCE and carbon tetrachloride (CCl4) in terms of the ability of each to stimulate lipoperoxidation both in vitro and in vivo. The results indicate that 1,1-DCE causes G6Pase depression, SAKT and HTG elevation, and PST prolongation. Measurements of lipoperoxidative stimulatory activity indicated that 1,1-DCE was dissimilar to CCl4 in terms of a proposed lipoperoxidative mechanism.

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.

Chemical modification of acute hepatotoxicity of vinyl chloride monomer in rats.

Six-hour inhalation exposure of male rats to vinyl chloride monomer (VCM) was hepatotoxic as measured by elevated serum alanine-a-ketoglutarate transaminase (AKT) when the rats were pretreated with either sodium phenobarbital (0.1% in the drinking water, 7 days) or Aroclor 1254 (pretreatment doses given by gavage; 100, 200, or 300 μmol/kg/day for 3 days). Following Aroclor 1254 pretreatment and VCM exposure, serum AKT elevation was proportional to Aroclor 1254 dose as well as VCM concentration (range 12,500–50,000 ppm). In phenobarbital-pretreated rats, fasting, but not diethyl maleate, significantly potentiated VCM injury; SKF-525A (75 mg/kg, ip) given 30 min prior to exposure prevented liver injury produced by VCM. Both Aroclor 1254 and phenobarbital pretreatment increased in vitro liver hexobarbital oxidase activity in unexposed animals. Exposure to VCM caused hexobarbital oxidase activity to decrease in livers from both nonpretreated and pretreated rats. The decreases in activity did not correlate with injury as measured by serum AKT. Ethyl alcohol (3.33 ml/kg) given by gavage 30 min prior to VCM exposure in phenobarbital-pretreated rats was associated with a nonsignificant serum AKT increase when compared to controls not given ethanol. A larger dose of ethanol (5 ml/kg, po) given to Aroclor 1254-pretreated rats prior to VCM did not increase the serum AKT elevation compared to controls. Four doses of ethanol (5 ml/kg, po) given to phenobarbital-pretreated rats at 48, 42, 24, and 16 hr before VCM exposure did not potentiate the increase in serum AKT caused by VCM. Disulfiram (200 mg/kg, ip, or 1000 mg/kg, po) given prior to VCM exposure in Aroclor-pretreated rats produced a significant potentiation of VCM toxicity. The data suggest: first, that VCM is activated to a toxic intermediate and this activation is inducible; second, while ethyl alcohol per se does not appear to play a primary or modifying role in acute VCM hepatotoxicity, inhibitors of ethanol metabolism modify the toxicity of VCM.

Modification of 1,1-dichloroethylene hepatotoxicity by hypothyroidism

Abstract Exposure of fasted male rats for 4 hr to 2000 ppm of 1,1-dichloroethylene (1,1-DCE), which decreases hepatic contents of reduced glutathione (GSH), resulted in severe liver injury by 2 hr as manifested by morphologic and histochemical (i.e., Ca and glucose-6-phosphatase) alterations, elevation of serum alanine-α-ketoglutarate transaminase activity, increases in hepatic contents of Na and Ca, and decreases in K and Mg. Thyroidectomy, which increases hepatic amount of GSH, and, to a lesser extent, administration of antithyroid drugs minimized each parameter of liver injury while thyroxine injection to thyroidectomized animals restored susceptibility to 1,1-DCE. Three-day survival experiments demonstrated that thyroidectomy abolished the mortality and significantly decreased the total extent of hepatic necrosis caused by 1,1-DCE. Elevated concentrations of reduced GSH in the livers of the hypothyroid animals may be a factor in their resistance to this reactive molecule.

Isotopic Ratio Analysis in Residential Lead-Based Paint and Associated Surficial Dust

OBJECTIVES This investigation assessed the contribution of lead in lead-based paint (7 samples) to lead-laden dust (8 samples) in a single suburban vacant residence using isotopic ratio analysis. METHODS Interior/exterior lead-based paint surface concentration was measured by X-ray fluorescence while dust and scrapings were analyzed chemically for total lead content and by mass spectrometry for the associated isotopic ratios. RESULTS Four out of 5 comparisons of paint (7 samples) and dust (8 samples) for a given location did not match isotopically. In the one location where the isotopic ratio of the paint and dust samples matched closely, some portions of the paint were not intact. One explanation for the isotopic ratio match is that the dust sample may have actually been contaminated with paint flecks. This explanation appears likely since the isotopic ratio for the lead in the dust and paint sample were not in the modern average range of US environmental lead, strongly indicating a local point source of the lead in this dust sample, namely the paint at this location. Lead dust samples whose isotopic ratio lies in the modern average range for US environmental lead cannot be correlated to the paint which is beneath them, since the isotopic ratio of lead in the dust may actually be a composite of many sources of lead over time, as suggested by an isotopic ratio in the modern average range. CONCLUSIONS From the samples from this one house, the data dispute the contention that intact lead-based paint chalks and creates lead-contaminated dust on its surface. While leaded household dust may contribute to childrens lead exposure, intact paint need not contribute to surficial lead-laden dust. Isotopic ratio measurements can be useful for point-source determination by virtue of sample match and by placement of the ratio on the spectrum of isotopic ratio values for lead. Point-source assessment based on isotopic ratio was either strengthened or weakened by placement outside or within the average range for US environmental lead, respectively.

1,1‐Dichloroethylene hepatotoxic1ty: Effect of altered thyroid function and evidence for the subcellular site of injury

Male Sprague‐Dawley rats were exposed for 4 hr to 1,1‐dichloroethylene (1,1‐DCE) by inhalation following an 18 hr fast. They were killed at 6 hr. Under these circumstances, prior thyroidectomy caused a decrease in the severity of the injury as measured by elevation of serum alanine‐α‐ketoglutarate transaminase (AKT), while thyroxine pretreatment (50 \ig per rat sc for 7 days) enhanced the hepatotoxicity of 1,1‐DCE as measured by lethality and serum AKT elevation. Chemical thyroidectomy using either propylthiouracil (30 mg/kg po for 7 days) or methimazole (15 mg/kg po for 7 days) also provided a degree of protection. Thyroidectomy, surgical or chemical, was associated with an increase in hepatic glutathione concentration, while thyroxine decreased the hepatic concentration of this nucleophile. Livers from rats exposed to 1,1‐DCE were found to have decreased in vitro oxygen uptake when supplied with succinate and ADP. This form of injury preceded the elevation in serum AKT, which occurred at 4 hr. Subcellul...

Pulmonary mechanics in guinea pigs: Repeated measurements using a nonsurgical computerized method☆☆☆

Abstract A method of pulmonary mechanics measurement using plethysmography and esophageal pressure to determine tidal volume, compliance, resistance, frequency, and minute volume in guinea pigs is described. The procedure is not surgical, does not require anesthesia, and allows for repeated measurements in the same animals. Calculations based upon physiological data (esophageal pressure as a measure of transpleural pressure and plethysmograph pressure as a measure of tidal volume) are done in real time with a relatively low-cost (

Infusion of di-2-ethylhexylphthalate for neonates: a review of potential health risk.

12,000) digital computer that displays numerical results as well as stores data for later analysis. The results of this method are compared to the published results of others. Data on repeated measurements in two animals over a 2-week period and the pulmonary effects of exposure to combustion products of plastics at 1, 24, 48 hr postexposure are given.