Biomedical subjects

S Muralidhara

Publications and source records attributed to S Muralidhara.

30 records · Page 2Linked to original sources

PubMed1994

Use of a physiologically based model to predict systemic uptake and respiratory elimination of perchloroethylene.

The pharmacokinetics of inhaled perchloroethylene (PCE) were studied in male Sprague-Dawley rats to characterize the pulmonary absorption and elimination of the volatile organic chemical (VOC). The direct measurements of the time course of PCE in the blood and breath were used to evaluate the ability of a physiologically based pharmacokinetic (PBPK) model to predict systemic uptake and elimination of PCE. Fifty or 500 ppm PCE was inhaled for 2 hr through a miniaturized one-way breathing valve by unanesthetized male Sprague-Dawley rats of 325-375 g. Serial samples of the inhaled and exhaled breath streams, as well as arterial blood, were collected during and following PCE inhalation and analyzed by headspace gas chromatography. PCE-exhaled breath concentrations increased rapidly to near steady state (i.e., within 20 min) and were directly proportional to the inhaled concentration. Uptake of PCE into the blood was also rapid, but blood levels continued to increase progressively over the course of the 2-hr exposure at both exposure levels. Cumulative uptake, or total absorbed dose, was not proportional to the exposure level. A PBPK model was developed from in vivo parameters determined from tissue concentration-time data in a companion ia study (Dallas et al., 1994, Toxicol. Appl. Pharmacol. 128, 50-59). PCE concentrations in the blood and exhaled breath during and following PCE inhalation were well predicted by the PBPK model. Despite species differences in blood:air and lung:air partition coefficients, the model was used to account for similar levels of PCE and other VOCs in the expired air of rats and humans. The model also accurately simulated percentage uptake and cumulative uptake of PCE over time. The model's ability to predict systemically absorbed doses of PCE under a variety of exposure scenarios should be useful in assessment of risks in occupational and environmental settings.

Absorption↗

PubMed1994

The pharmacokinetics of inhaled 1,1,1-trichloroethane following high milk intake in mice.

In the evaluation of lipophilic halocarbons for neurobehavioral toxicity in operant testing, animals often receive large amounts of milk as a behavioral reinforcer over time. If this increase of fat in the diet sufficiently impacted the lipid depots of the animal, the pharmacokinetics of lipophilic test compounds might be significantly affected and thus obscure the accompanying neurobehavioral effects. The effects of milk intake, comparable to what was consumed as behavioral reinforcer during operant behavioral sessions, on the pharmacokinetics of inhaled 1,1,1-trichloroethane (TRI) were therefore examined in the blood and nine organ tissues of mice. Male CD-1 mice were food restricted so that their body weights would be reduced to and maintained at 80% of their original, and received a single gavage dose of 1.0 ml evaporated milk daily for three weeks. A control group with similar food restrictions was dosed with the same volume of water. Inhalation exposures to 3500 ppm TRI for 100 minutes were conducted at the end of the treatment period. Blood and nine organ tissues were sampled at a series of time points, and their TRI contents were analyzed by headspace gas chromatography. The uptake of TRI was rapid, with near steady state approached in blood and most tissues after 40-60 minutes of exposure. All of the tissues except fat had similar TRI time-concentration profiles, while TRI concentrations in fat tissue were about 20-30 times higher than in other tissues. There was no statistically significant difference in the tissue concentrations between the milk-dosed group and water-dosed group at all of the time points for all tissues measured. Therefore, it appears unlikely that this level of milk intake as a reinforcer in behavioral studies will affect the results of operant testing evaluations by altering the pharmacokinetics of lipophilic halocarbons such as TRI.

Administration, Inhalation↗

PubMed1993

Analyses of volatile C2 haloethanes and haloethenes in tissues: sample preparation and extraction.

A tissue extraction procedure was developed which minimized loss of readily volatilizable compounds for subsequent quantification by headspace gas chromatography, and evaluated for perchloroethylene (PER), 1,1,1-trichloroethane, 1,1,2,2-tetrachloroethane, and 1,1,2-trichloroethylene. Of the procedures evaluated, joint isooctane and saline tissue homogenization had the most efficient recovery, ranging from 73 to 104% for the four halocarbons from seven different rat tissues. PER concentrations were also determined in tissues of rats following in vivo halocarbon administration. Recovery did not appear to be tissue-dependent, but did vary somewhat with test chemical, with the least volatile, most lipophilic compounds exhibiting the highest recovery.

Animals↗

PubMed1991

Physiological pharmacokinetic modeling of inhaled trichloroethylene in rats.

The pharmacokinetics of trichloroethylene (TCE) was characterized during and following inhalation exposures of male Sprague-Dawley rats. The blood and exhaled breath TCE time-course data were used to formulate and assess the accuracy of predictions of a physiologically based pharmacokinetic (PB-PK) model for TCE inhalation. Fifty or 500 ppm of TCE was inhaled by unanesthetized rats of 325-375 g for 2 hr through a miniaturized one-way breathing valve. Repetitive samples of the inhaled and exhaled breath streams, as well as arterial blood, were collected concurrently during and for 3 hr following the exposures and analyzed for TCE by headspace gas chromatography. Respiratory rates and volumes were continuously monitored and used in conjunction with the pharmacokinetic data to delineate uptake and elimination profiles. Levels of TCE in the exhaled breath attained near steady-state soon after the beginning of exposures, and were then directly proportional to the inhaled concentration. Exhaled breath levels of TCE in rats were similar in magnitude to values previously published for TCE inhalation exposures of humans. Levels of TCE in the blood of the 50 ppm-exposed animals also rapidly approached near steady-state, but blood levels in the 500 ppm-exposed animals rose progressively, reaching concentrations 25- to 30-fold higher than in the 50 ppm group during the second hour of exposure. The 10-fold increase in inhaled concentration resulted in an 8.7-fold increase in cumulative uptake, or total absorbed dose. These findings of nonlinearity indicate that metabolic saturation ensued during the 500 ppm exposure. The PB-PK model was characterized as blood flow-limited with TCE eliminated unchanged in the exhaled breath and by saturable liver metabolism. The uptake and elimination profiles were accurately simulated by the PB-PK model for both the 50 and 500 ppm TCE exposure levels. Such a model may be quite useful in risk assessments in predicting internal (i.e., systemically absorbed) doses of TCE and other volatile organics under a variety of exposure scenarios.

Administration, Inhalation↗

PubMed1989

The uptake and elimination of 1,1,1-trichloroethane during and following inhalation exposures in rats.

The pharmacokinetics of 1,1,1-trichloroethane (TRI) was studied in male Sprague-Dawley rats in order to characterize and quantify TRI uptake and elimination oby direct measurements of the inhaled and exhaled compound. Fifty or 500 ppm TRI was inhaled for 2 hr through a one-way breathing valve by unanesthetized rats of 325-375 g. Repetitive samples of the separate inhaled and exhaled breath streams, as well as arterial blood, were collected concurrently both during and following TRI inhalation and analyzed for TRI by gas chromatography. Respiratory rates and volumes were continuously monitored during and following exposure and were used in conjunction with the pharmacokinetic data to characterize profiles of uptake and elimination. TRI was very rapidly absorbed from the lung, in that substantial levels were present in arterial blood at the first sampling time (i.e., 2 min). Blood and exhaled breath concentrations of TRI increased rapidly after the initiation of exposure, approaching but not reaching steady state during the 2-hr exposures. The blood and exhaled breath concentrations were directly proportional to the exposure concentration during the exposures. Percentage uptake of TRI decreased 30-35% during the first hour of inhalation, diminishing to approximately 45-50% by the end of the exposure. Total cumulative uptake in the 50 and 500 ppm groups over the 2-hr inhalation exposures was determined to be 6 and 48 mg/kg body wt, respectively. By the end of the exposure period, 2.1 and 20.8 mg, respectively, of inhaled TRI was eliminated from rats inhaling 50 and 500 ppm TRI. A physiological pharmacokinetic model for TRI inhalation was utilized to predict blood and exhaled breath concentrations for comparison with observed experimental values. Overall, values predicted by the physiological pharmacokinetic model for TRI levels in the blood and exhaled breath were in close agreement with measured values both during and following TRI inhalation.

Administration, Inhalation↗

PubMed1989

Oral toxicity of 1,2-dichloropropane: acute, short-term, and long-term studies in rats.

The objective of this investigation was to characterize the acute and short- and long-term toxic potency of orally administered 1,2-dichloropropane (DCP). In the acute and short-term studies, male rats of 250-300 g were gavaged with 0, 100, 250, 500, or 1000 mg DCP/kg in corn oil once daily for up to 10 consecutive days. Although ingestion of DCP caused body weight loss and CNS depression, few other toxic effects were manifest 24 hr after a single dose of the chemical. Morphological changes were limited to liver centrilobular cells in 500 and 1000 mg/kg rats. Similarly, elevated activity of some serum enzymes occurred only at these two highest dose levels. Hepatic nonprotein sulfhydryl (NPS) levels were decreased and renal NPS levels increased at 24 hr. In the short-term study resistance developed to DCP hepatotoxicity over the 10 consecutive days of exposure, as reflected by progressively lower serum enzyme levels and by decreases in the severity and incidence of toxic hepatitis and periportal vacuolization. Nucleolar enlargement in hepatocytes, however, was observed at all dosage levels at 5 and 10 days. There were a number of manifestations of hemolytic anemia, including erythrophagocytosis in the liver, splenic hemosiderosis and hyperplasia of erythropoietic elements of the red pulp, renal tubular cell hemosiderosis, and hyperbilirubinemia. Urinalyses and histopathology revealed no evidence of nephrotoxicity. In the long-term study, male rats initially weighing 180-200 g were gavaged five times weekly for up to 13 weeks with 0, 100, 250, 500, or 750 mg DCP/kg. As over one-half the 750 mg/kg group died within 10 days, the survivors were sacrificed. Histopathological changes in the 750 mg/kg animals included mild hepatitis and splenic hemosiderosis, as well as adrenal medullary vacuolization and cortical lipidosis, testicular degeneration and a reduction in sperm, and increased number of degenerate spermatogonia in the epididymis in some members of the group. Similar testicular and epididymal degenerative change also were observed in some 500 mg/kg animals after 13 weeks of dosing. There was a progressive increase in the number of deaths in the 500 mg/kg group, such that more than 50% were dead by 13 weeks. No deaths occurred in the 100 or 250 mg/kg groups. The DCP dosage regimen also produced a dose-dependent decrease in body weight gain. DCP exhibited very limited hepatotoxic potential and no apparent nephrotoxic potential in the long-term study. Slight elevations in serum ornithine-carbamyltransferase activity, periportal vacuolization, and active fibroplasia in the liver were seen in the 500 mg/kg animals.

Administration, Oral↗

PubMed1986

Oral toxicity of carbon tetrachloride: acute, subacute, and subchronic studies in rats.

This investigation was conducted to characterize the acute, subacute, and subchronic toxic potency of ingested carbon tetrachloride (CCl4). In the first acute and subacute toxicity study, male Sprague-Dawley rats of 300-350 g were gavaged with 0, 20, 40, or 80 mg CCl4/kg once daily for 5 consecutive days, rested for 2 days, and dosed once daily for 4 additional days. Rats of 200-250 g were gavaged with 0, 20, 80, or 160 mg CCl4/kg according to the same dosage regimen in the second acute and subacute study. In the first and second studies one group of rats at each dosage level was sacrificed for clinical chemistry and histopathological evaluation at 24 hr, 4 days, and 11 days after initiation of dosing. Single 20- and 40-mg/kg doses had no apparent toxic effect at 24 hr, although 80 mg/kg caused mild hepatic centrilobular vacuolization and significant increases in some serum enzyme levels. In general, there was progressively severe hepatic injury at each dosage level over the 11-day period. CCl4 was more hepatotoxic to the 200-250-g rats than to the 300-350-g rats. In the subchronic study, rats initially 200-250 g were gavaged 5 times weekly for 12 weeks with 0, 1, 10, or 33 mg CCl4/kg. Body weight and clinical chemistry indices were monitored during the 12 weeks of dosing and 2 weeks after cessation of dosing. A dose of 1 mg/kg had no apparent adverse effect; 10 mg/kg produced slight, but statistically significant increases in sorbitol dehydrogenase activity and mild hepatic centrilobular vacuolization; 33 mg/kg caused marked hepatotoxicity. Serum enzyme levels remained elevated during the 12-week dosing period, but returned toward normal within 13 days of cessation of CCl4 exposure. Microscopic examination of livers of the 33-mg/kg rats revealed cirrhosis, characterized by bile duct proliferation, fibrosis, lobular distortion, parenchymal regeneration, hyperplastic nodules, and single-cell necrosis. The fibrosis was not reversed within the 13-day recovery period.

Alanine Transaminase↗

PubMed1982

A simple method for repetitive blood sampling from rats.

A convenient, reliable method for obtaining serial blood samples from rats is described. A simple cannula device is maintained in the ventral caudal artery of lightly etherized rats. Sequential blood samples of desired volume can be taken as frequently as needed without wastage. The technique is minimally traumatic to the animal and does not require extensive preparatory time. Since airtight blood samples can be taken, the technique can be used for pharmacokinetic studies of volatile compounds.

Animals↗

PubMed1982

Mammalian toxicity of Technical X-factor I. An acute oral study.

Intragastric administration of acute doses of Technical X-factor (beta-isomer free BHC, a byproduct obtained during separation of Lindane from Tech. BHC) carried in peanut oil elicited typical signs of central nervous system depression in adult rats. The computed oral LD50 values of X-factor were 4174 and 5673 mg/kg. body weight for male and female rats respectively indicating that its acute toxicity was of relatively low order compared to Tech. BHC. It is suggested that the low acute mammalian toxicity of X-factor could possibly be due to a direct antagonism of the delta isomer (present in larger proportion in X-factor) with the gamma isomer.

Animals↗

PubMed1981

Acute oral toxicity of hexachlorocyclohexane and X-factor to poultry Gallus domesticus.

Twelve week old male birds (Gallus domesticus) were intragastrically administered technical grade samples of Benzene hexachloride (gamma-isomer: 13%) and X-factor (gamma-isomer: 16%) [a by-product obtained during separation of gamma-isomer from (BHC)] in capsules with a view of establishing oral LD50 values. The computed oral LD50 values for BHC and X-factor were 596.8 and 589.5 mg/kg body weight, respectively, indicating no variation in their susceptibility to these pesticides. observations on symptoms, feed intake, body weight gain, organ weights, and microscopic examination of vital organs are reported.

Animals↗

PubMedDate not supplied

Schedule-controlled operant behavior of rats during 1,1,1-trichloroethane inhalation: relationship to blood and brain solvent concentrations.

The central nervous system is the principal target of 1,1,1-trichloroethane (TRI), and several studies of this volatile solvent have demonstrated effects on learned animal behaviors. There have been few attempts, however, to quantitatively relate such effects to blood or target organ (brain) solvent concentrations. Therefore, Sprague-Dawley rats trained to lever-press for evaporated milk on a variable interval 30-s reinforcement schedule were placed in an operant test cage and exposed to clean air for 20 min, followed by a single concentration of TRI vapor (500-5000 ppm) for 100 min. Additional rats were exposed to equivalent TRI concentrations for 10, 20, 40, 60, 80, or 100 min to determine blood and brain concentration vs. time profiles. Inhalation of 1000 ppm slightly increased operant response rates, whereas 2000, 3500, and 5000 ppm decreased operant response rates in a concentration- and time-dependent manner. Accumulation of TRI in blood and brain was rapid and concentration dependent, with the brain concentration roughly twice that of blood. Plots of blood and brain TRI concentrations against operant performance showed responding in excess of control rates at low concentrations, and decreasing response rates as concentrations increased. Linear regression analyses indicated that blood and brain concentrations, as well as measures of time integrals of internal dose, were strongly correlated with operant performance. Neurobehavioral toxicity in laboratory animals, as measured by changes in operant performance, can therefore be quantitatively related to internal measures of TRI exposure to enhance its predictive value for human risk assessment.

Animals↗

PubMedDate not supplied

Lack of volatilization and escape of orally administered trichloroethylene from the gastrointestinal tract of rats.

It is possible that a substantial portion of orally administered volatile organic chemicals (VOCs) may volatilize within the warm environment of the gastrointestinal (GI) tract and escape via the esophagus before being absorbed. The objective of this study was to test this hypothesis with a representative VOC, 1,1,2-trichloroethylene (TCE). Upon hepatic portal vein (PV) injection, complete systemic absorption of TCE was assumed. Thus, exhaled TCE after PV injection should originate only from pulmonary exhalation. In contrast, TCE volatilized in the gut may also contribute to the amounts of TCE exhaled by orally (PO) dosed animals. Male Sprague-Dawley rats (320-380 g) were given 8 or 16 mg TCE/kg bw in an aqueous Alkamuls emulsion (RhonePoulenc, Cranbury, New Jersey). For the PO groups both doses were given by gavage, and for the PV groups the lower dose was injected into the PV as a bolus and the higher dose given as a 20 mm infusion. Serial blood samples were taken from an indwelling carotid arterial cannula and analyzed for their TCE content by headspace gas chromatography (GC), so that the areas-under-blood-concentration-versus-time curves (AUCs) could be determined. Serial exhaled air samples were collected from a sampling port in a miniaturized one-way breathing value and TCE measured by GC analysis to delineate exhaled breath concentration-versus-time-curves (EAUCs). Exhaled breath levels of TCE paralleled blood levels of TCE throughout the monitoring periods. Evidence against the aforementioned hypothesis was provided by comparison of ratios of blood AUCs and exhaled breath EAUCs: values for ratios of AUCPO/AUCPV and EAUCPO/EAUCPV were the same, as were EAUC/AUC ratios for the PO and PV groups. The EAUCs in the PO groups should have been higher, had there been substantial extrusion of volatilized TCE fronm the GI tract.

Administration, Oral↗