Effect of oral dosing vehicles on the acute hepatotoxicity of carbon tetrachloride in rats

Kim, H.J.; Odend'hal, Stewart; Bruckner, James V.

doi:10.1016/0041-008x(90)90081-5

Cited by 35 publications

(28 citation statements)

References 21 publications

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“…We anticipated that the threshold dosage, 10 mg/kg, would be quite sensitive to any effects of Emulphor. The second CCL, dosage, 180 mg/kg, was chosen because it is known to be moderately toxic (Kim et al, 1990a). An emulsifier-induced increase or decrease in liver damage should be apparent in rats receiving such a dose.…”

Section: Discussionmentioning

confidence: 99%

“…Analytical-grade CCU (•!• T. Baker Chemical Co., Phillipsburg, NJ) was administered by gavage as a single oral bolus of 10 or 180 mg/kg bw. Previous experiments (Kim et al, 1990a) have shown 10 mg/kg to be a threshold dose and 180 mg/kg to be moderately hepatotoxic in fasted male Sprague-Dawley rats. Emulphor EL-620 (GAF Corp., New York, NY), was used in concentrations of 1, 2.5, 5, and 10* to prepare an aqueous emulsion of CCU in 0.9% saline.…”

Section: Animal Preparationmentioning

confidence: 99%

“…Each blood sample was quickly transferred to a headspace vial, capped with a PFTE-lined butyl rubber septum and aluminum lid, and tightly crimped. Measurement of the CCl» content in each vial was performed by the method of Kim et al (1990a). Briefly, the vials were placed into an autosampler of a Sigma 300 GC (Perkin-Elmer, Nonvalk, CT), where they were heated to a preset temperature by a thermostat A precise volume of the vapor was then injected automatically into the GC column for analysis.…”

Section: Time (Min)mentioning

confidence: 99%

“…Briefly, the vials were placed into an autosampler of a Sigma 300 GC (Perkin-Elmer, Nonvalk, CT), where they were heated to a preset temperature by a thermostat A precise volume of the vapor was then injected automatically into the GC column for analysis. The column and GC operating conditions are described by Kim et al (1990a). The concentration of CCU in the blood samples was determined from a standard curve generated from control blood specimens, which were spiked with standard solutions prepared by diluting known amounts of CCU in toluene.…”

Section: Time (Min)mentioning

confidence: 99%

“…Emulphor has been reported to be cytotoxic in vitro, at concentrations >0.125%, when added to isolated hepatocytes (O'Hara et al, 1989). Although low doses of Emulphor do not appear to be hepatotoxic or to alter the hepatotoxic potency of halocarbons in vivo (Merrick et al, 1989;Kim et al, 1990a;Borzelleca et al, 1990), a comprehensive evaluation of the ability of a wide range of doses of Emulphor to alter the kinetics or toxicity of a halocarbon or other VOC could not be located in the literature.…”

mentioning

confidence: 99%

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Effect of Emulphor, an Emulsifier, on the Pharmacokinetics and Hepatotoxicity of Oral Carbon Tetrachloride in the Rat

SANZGIRI¹,

BRUCKNER²

1997

Toxicol Sci

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Emulphor, a polyethoxylated vegetable oil, is now being used widely to incorporate volatile organic compounds (VOCs) and other lipophilic compounds into aqueous solutions for biochemical, pharmacokinetic, and toxicological studies. Previous work in this laboratory demonstrated that 0.25% Emulphor did not alter the kinetics or hepatotoxicity of low doses of CCL, compared to when the halocarbon was given to rats orally in water. The present study was undertaken as there was concern that higher concentrations of Emulphor (necessary to maintain lipophilic VOCs in stable aqueous emulsions for extended periods) might alter the VOCs' absorption, disposition, and/or toxidty. Dosages of 10 and 180 mg CCU/kg bw were given, as an aqueous emulsion using 1, 2.5, 5, or 10% Emulphor, by gavage to fasted male Sprague-Dawley rats. Serial microsamples of blood were collected from an indwelling cannula in unanesthetized, freely moving rats at intervals of 2-60 min for up to 12 hr. The samples' CCL, content was measured by headspace gas chromatography. Thereby, it was possible to obtain blood CCL, concentration-versus-time profiles. Animals were euthanized 24 hr postdosing and blood was collected for measurement of serum enzymes as indices of hepatotoxicity. No toxicologically significant differences in pharmacokinetic parameters as a function of Emulphor concentration were found. Similarly the hepatotoxic potency of 10 and 180 mg/kg CCL,, as reflected by elevation in serum enzyme activities, did not vary significantly with the concentration of Emulphor utilized. Hence, it can be concluded that Emulphor, in concentrations as high as 10% (equivalent to 260 mg Emulphor/kg bw) in aqueous emulsions, does not significantly affect the absorption, disposition, or acute hepatotoxicity of CCL, in male Sprague-Dawley rats, o iw sod«y of To

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Section: Discussionmentioning

confidence: 99%

Section: Animal Preparationmentioning

confidence: 99%

Section: Time (Min)mentioning

confidence: 99%

Section: Time (Min)mentioning

confidence: 99%

mentioning

confidence: 99%

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Effect of Emulphor, an Emulsifier, on the Pharmacokinetics and Hepatotoxicity of Oral Carbon Tetrachloride in the Rat

SANZGIRI¹,

BRUCKNER²

1997

Toxicol Sci

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Peroral Toxicity

Brock¹

2009

General, Applied and Systems Toxicology

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Numerous factors will affect the passage of drugs and chemicals through the gastrointestinal tract and into systemic circulation. These factors involve anatomical and physiological features, species differences and biochemical features, including intestinal metabolism and effects on transporters. With regard to assessing potential risk of humans to chemicals, these features will need to be considered as there will be differences between experimental animals and humans. The cellular environment of the gastrointestinal tract and the molecular mechanisms of absorption will have a major influence on the bioavailability of drugs and chemicals. The pH of the local cell environment will affect the ionization status of the compound, whereas a drug may inhibit cellular transport of other substances, for example, nutrients, potentially having an affect on the nutritional status of the animal. Moreover, there has been demonstrated evidence that some xenobiotics will affect the metabolic status of the gastrointestinal tract. Cytochrome P450 3A is the more common form of cytochrome isoforms found in the intestine, but there are numerous examples that can inhibit, or induce, metabolism much in the same way that hepatic metabolism is affected by chemicals. In addition, the bacterial content of the gastrointestinal tract can affect the absorption of substances primarily by bacterial metabolism. The fasting status of the animal also will affect absorption, and is probably one the more important considerations in the design of a toxicology study. It has been clearly shown that absorption occurs more readily in the fasted animal, and that toxicity may be enhanced since there is a greater surface area of the gastrointestinal tract available for absorption. Finally, chemical interactions will potentially modify absorption through binding of the compound or changing the local cellular environment. From a practical perspective, oral administration of compounds is the most common method for compound administration in toxicology studies. In oral toxicity studies, one will need to consider the drug formulation and the potential effects of the vehicle on the stability as well as the potential toxicity of the vehicle. For the most part, a majority of the vehicles being used currently in laboratories have a long history of use such that toxicity of the vehicle does not become too much of a concern, but the principle of toxicology, the dose makes the poison, should always be a consideration.

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Organic Solvents

Bruckner

2015

Mammalian Toxicology

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Effect of oral dosing vehicles on the acute hepatotoxicity of carbon tetrachloride in rats

Cited by 35 publications

References 21 publications

Effect of Emulphor, an Emulsifier, on the Pharmacokinetics and Hepatotoxicity of Oral Carbon Tetrachloride in the Rat

Effect of Emulphor, an Emulsifier, on the Pharmacokinetics and Hepatotoxicity of Oral Carbon Tetrachloride in the Rat

Peroral Toxicity

Organic Solvents

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