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Biomedical subjects

H B Matthews

Publications and source records attributed to H B Matthews.

At least 127 records · Page 7Linked to original sources
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Toxicity and distribution of 2,3,7,8-tetrachlorodibenzofuran in male guinea pigs.

The toxicity of 2,3,7,8-tetrachlorodibenzofuran (TCDF) was studied in male Hartley guinea pigs after single or multiple oral treatment. In each animal studied, adipose tissue, liver, and skin were the major depots of TCDF and accounted for 50-74% of the total dose. The whole-body half-life of TCDF in guinea pigs was estimated to be approximately 40 d. This slow clearance of TCDF by guinea pigs may explain the high toxicity of TCDF for this species even when very low repeated doses were administered. Intervals of 1, 2, or 4 wk between doses had little effect on TCDF lethality, but did have an effect on the pattern of toxicity. Treatment of mature animals with high single doses of TCDF (10 or 15 micrograms/kg body weight) resulted in the immediate loss of weight and the eventual death of all treated animals within 2-4 wk after the loss of approximately 35% of their initial body weight. Treatment of immature animals with low multiple doses totaling cumulative doses of between 4 and 12 micrograms/kg resulted in the death of 75% of these animals, with the deaths occurring between 7 and 19 d after the initial appearance of quantitative toxic symptoms (loss of weight); however, weight loss was less dramatic following repeated low doses than after acute high doses. Concentration of TCDF in adipose tissue was generally proportional to dose of TCDF. With increasing time after dosage, there was a shift in distribution from adipose tissue to liver.

Adipose Tissue↗
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Analysis of dimethyl hydrogen phosphite and its stability under simulated physiological conditions.

In a study by the National Toxicology Program, dimethyl hydrogen phosphite (DMHP) was shown to cause dose-related neoplastic lesions in the lungs and forestomachs of Fischer 344 rats. This investigation was carried out to study the stability of this carcinogen under conditions similar to those that the chemical may encounter in the physiological environment. To carry out these studies, capillary gas chromatography was utilized to analyze DMHP. The method was linear over a range of 10 to at least 1000 ng. High-performance liquid chromatography (HPLC) also was used to analyze DMHP and its degradation products. In aqueous solutions, DMHP was stable for a period of time before degradation began. Once the process began, degradation continued until 10-20% of the original concentration was reached and further decomposition was minimal. At 10% concentration in 0.1M phosphate buffer, pH 7.4, DMHP was stable for 3.6 h at 37 degrees C. This stability period increased at lower temperature, at lower DMHP concentration, and in slightly more alkaline buffer (pH 8). After the stability period, DMHP disappeared from the solution and this disappearance followed a first order kinetics with a rate dependent upon temperature, concentration of DHMP, and the pH of the solution. The half-time of disappearance of DMHP under the conditions mentioned above was 2.4 h, which increased at lower temperature, at lower DMHP concentration, and in slightly more alkaline buffer (pH 8). The decomposition products of DMHP were identified by HPLC and proton nuclear magnetic resonance (1H-NMR) spectroscopy as methanol, monomethyl hydrogen phosphite, and orthophosphorous acid.

Chemical Phenomena↗
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Demonstration of a temporal relationship between ethyl acrylate-induced forestomach cell proliferation and carcinogenicity.

Ethyl acrylate (EA) is a known forestomach carcinogen in both rats and mice. Recent work in this laboratory indicated that carcinogenic doses of EA administered by gavage for 13 wk resulted in a sustained increase in forestomach epithelial hyperplasia as long as exposure to EA continued. However, hyperplasia regressed and no forestomach neoplasms were seen after a 19-mo recovery period. Current studies were designed to further investigate the time required for sustained hyperplasia to lead to neoplasia as well as the organ specificity of EA-induced cell proliferation/hyperplasia vs carcinogenicity. EA was administered at 200 mg/kg (po) to male Fischer-344 rats, 5 days/wk. Squamous cell proliferation/hyperplasia was observed in the forestomach of all rats that received EA for 6 or 12 mo. Treatment of rats with EA for 12 mo followed by 2 mo of recovery resulted in the development of forestomach papillomas in 2 of 5 treated rats. Furthermore, animals treated for 12 mo and allowed 9 mo of recovery exhibited an increase in forestomach squamous cell carcinomas and papillomas at a combined incidence of 4 in 13. In contrast, animals treated with EA for 6 mo and allowed 2 or 15 mo of recovery exhibited a time-dependent regression of cell proliferation and did not develop forestomach neoplasms. No significant elevation in liver cell proliferation or neoplasia was seen at any time in any of the rats included in the present study, further confirming the organ specificity in the relationship between EA-induced cell proliferation and carcinogenicity. In conclusion, EA resulted in increased cell proliferation in the target organ of carcinogenicity (forestomach) but not in nontarget organs such as the liver. This work indicates that cell proliferation, sustained for a sufficient period of time, results in the development of neoplasia despite cessation of chemical administration. Furthermore, a temporal relationship exists between EA-induced epithelial cell proliferation and forestomach carcinogenicity.

Acrylates↗
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Brain distribution and fate of tris(2-chloroethyl) phosphate in Fischer 344 rats.

Tris(2-chloroethyl) phosphate (TRCP) is a flame retardant that has a wide variety of industrial applications. In subchronic studies, oral administration of TRCP to rats and mice has been reported to produce dose-, sex-, and species-dependent lesions in the hippocampal brain region. The present investigation has examined the metabolism, elimination, and regional brain distribution of [14C]TRCP in male and female rats. [14C]TRCP was administered by gavage (0, 175, 350, or 700 mg/kg) and urine, feces, exhaled volatiles, CO2, and selected tissues were collected. Regional brain distribution of 14C was determined 2 hr following single doses of TRCP to male and female rats, and 24 hr after a single dose and the last of 14 daily doses of TRCP to female rats. Results of these studies indicate that TRCP is readily absorbed from the gastrointestinal tract, distributed to all brain regions, and that metabolism and excretion are nearly complete in 72 hr. Most of the TRCP-derived radioactivity was excreted in urine (up to 85%), with feces, volatiles, and CO2 combined accounting for less than 10% of the dose. Predominant signs of toxicity associated with TRCP administration (350 and 700 mg/kg) were seizures within 2 hr of treatment, when most of the TRCP-derived radioactivity present in brain tissue was in the form of the parent compound. Traces of inextractable 14C were detected at later times, but this material was not concentrated in brain relative to other tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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Metabolism of tris(2-chloroethyl) phosphate in rats and mice.

Tris(2-chloroethyl) phosphate (TRCP), a flame retardant, produces a dose-, sex-, and species-dependent lesion in the hippocampal region of the brain following subchronic oral administration. This lesion is more common and more severe in female F344 rats than in male F344 rats, and is not observed in B6C3F1 mice. The present investigation of the metabolism of TRCP was designed to detect sex and species variations that might account for differences in toxicity. Elimination of TRCP-derived radioactivity was more rapid in mice, which excreted greater than 70% of an oral dose of 175 mg/kg in urine in 8 hr vs. approximately 40% for male or female rats. However, the metabolic profile of TRCP-derived radioactivity in urine was similar for both species. The major metabolite in female rat urine was identified as bis(2-chloroethyl) carboxymethyl phosphate. This metabolite co-chromatographed with the major metabolite found in both male rat and mouse urine. Two additional metabolites identified in female rat urine were bis(2-chloroethyl) hydrogen phosphate and the glucuronide of bis(2-chloroethyl) 2-hydroxyethyl phosphate. These metabolites also cochromatographed with metabolites found in male rat and mouse urine. TRCP metabolism in rats was not induced or inhibited by nine daily 175 mg/kg doses. Toxicity, as evidenced by seizures, was potentiated in male rats pretreated with inhibitors of aldehyde dehydrogenase.

Animals↗
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Metabolism and disposition of diethylene glycol in rat and dog.

The disposition of carbon-14-labeled diethylene glycol (DEG) was determined in rats after oral, iv, and dermal administration, and in dogs after oral administration. Oral administration of DEG to rats was by gavage of 50 or 5000 mg/kg doses, or by provision of 0.3 1.0, and 3.0% in drinking water. Oral doses were well absorbed and excreted primarily (approximately 80%) in urine within 24 hr of administration. Greater than half of the dose was excreted unchanged, with 10-30% of the dose appearing as a single metabolite. The metabolite was isolated and characterized by 13C-NMR to be 2-(hydroxy) ethoxyacetic acid (HEAA). Confirmation of identity was provided by synthesis of HEAA and comparison of its NMR spectra and chromatographic behavior with those of the metabolite. Intravenous doses (50 mg/kg) were eliminated by the same routes and at the same rates as those administered orally and exhibited the same metabolic profile. The fate of oral doses of DEG administered to dogs (500 mg/kg) was similar to that of DEG in rats, with about 30% of the administered dose being excreted in urine as HEAA. DEG slowly penetrated the skin of rats after application of 50 mg to a 12-cm2 area. Only about 10% of the dose was absorbed in 72 hr of exposure, and the absorbed dose appeared to have the same fate as doses administered iv or orally. In all studies with rats, excretion of radiolabel in feces and persistence in tissues were low. The highest percentage of conversion to 14CO2 was 7%, found for doses of 0.3% DEG in drinking water.

Acetates↗
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A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat.

A mathematical model is presented to describe the kinetics of distribution, metabolism, and excretion of 4-chloro-, 4,4'-dichloro-, 2,2',4,5,5'-pentachloro-, and 2,2',4,4',5,5'-hexachlorobiphenyl in rats given an intravenols dose of 0.6 mg/kg. A modified flow-limited model simulates the penta- and hexachlorobiphenyl data for periods up to 96 hr but underestimates the mono- and dichlorobiphenyl data beyond 48 hr. The rate constant for metabolism by the liver decreases as degree of chlorination increases such that the rate constant is 200 times smaller for the hexachlorobiphenyl than for the monochlorobiphenyl. The value of the biliary clearance of metabolites is nearly the same for each chlorinated biphenyl, whereas the value of the urinary clearance decreases with increasing degree of chlorination, being 10 times smaller for hexachlorobiphenyl than for monochlorophenyl. The distribution coefficients between most tissues and blood are larger for each parent compound than for its metabolites. Hexachlorobiphenyl has the largest distribution coefficient of all the chlorinated biphenyls in each tissue, whereas the mono-, di-, and pentachlorobiphenyls show no consistent variation. For each compound the distribution coefficient is greater in the fat than in any other tissue. Changes in the fat volume of the growing rats were incorporated into the model in order to simulate the hexachlorobiphenyl concentrations in blood and fat for 42 days.

Animals↗
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Pharmacokinetics of 3,3',5,5'-tetrachlorobiphenyl in the male rat.

The pharmacokinetics of 3,3',5,5'-tetrachlorobiphenyl (4-CB) was studied to determine the importance of chlorine position to the kinetics of polychlorinated biphenyl (PCB) distribution, metabolism, and excretion by the rat. Tissue samples and excreta were collected at times ranging from 2 hr to 42 days after intravenous injection of a single 0.6-mg/kg dose of 14C-labeled 4-CB. The relative fractions of 4-CB and its metabolites were determined in selected samples, and 4-hr bile cannulations were performed to establish the rate of biliary excretion. A mathematical model description of PCB kinetics in the rat was defined here for 4-CB and used to generate tissue and excretion concentration-time profiles for both the parent compound and its metabolites. Model predictions were in good agreement with the experimental data, and showed how the individual pharmacokinetics of 4-CB compared to several other PBC's. The rate of 4-CB metabolism and excretion was slower than would be predicted according to its degree of chlorination. The relative rates of metabolism for 4-CB and five other differently chlorinated biphenyls could be ordered according to the number of adjacent unsubstituted carbon-atom pairs they contained. It appears that chlorine position is more important than degree of chlorination because the former can alter the availability of vicinal hydrogens thought to facilitate rapid PCB metabolism by mammals.

Animals↗
PubMedDate not supplied

The distribution and excretion of 2,4,5,2',5'-pentachlorobiphenyl in the rat.

Rats received single intravenous doses (0.6 or 6.0 mg/kg) of 2,4,5,2',5'-pentachlorobiphenyl-14C (5-CB). The distribution and ecretion of 5-CB-derived material were investigated at periods ranging from 10 min to 42 days after administration and found to be first-order rate processes in the dose range studied. Blood, liver, muscle, skin, and adipose tissues were found to be the most important tissues to the distribution of this compound. More than 90% of the total dose was removed from the blood within 10 min after administration. Most of the radioactivity was initially deposited in the liver and muscle, and then translocated to the skin and adipose tissue. The decay rate of radioactivity from each of the tissues could be described by the sum of two or more exponentials. Metabolism to more polar compounds appears to be a prerequisite to excretion, and most of the radioactivity was excreted in the bile and ultimately in the feces. Excretion in the urine accounted for less than 7% of the total dose and ceased at approximately 8 or 9 days after 5-CB-administration. Studies of the distribution and excretion of 5-CB-derived material over extended periods of time, 1-42 days, demonstrated the importance of the adipose tissue and skin as long-term storage sites, and demonstrated that the decay rate of 5-CB from the tissues paralleled the decreasing rate of excretion in the feces.

Adipose Tissue↗
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Metabolism, disposition, and mutagenicity of 2,6-diaminotoluene, a mutagenic noncarcinogen.

2,6-Diaminotoluene (2,6-DAT) is a major industrial chemical; approximately 100 million pounds are used annually in the synthesis of 2,6-toluene diisocyanate. 2,6-DAT is mutagenic in Salmonella typhimurium TA98 requiring metabolic activation, but has been previously shown to be a noncarcinogen in male and female F344 rats and male and female 86C3F1 mice dosed orally in 2-year bioassays. 2,6-DAT was rapidly and extensively absorbed following oral administration, indicating that its lack of carcinogenicity is not due to poor absorption from the gastrointestinal tract. 2,6-DAT was also rapidly excreted, with 85% of 2,6-DAT-associated radioactivity being recovered in the urine within 24 hr. Resolution of the urine by reverse phase HPLC demonstrated the presence of four metabolites, but none of the parent 2,6-DAT. Therefore, the lack of carcinogenicity of 2,6-DAT is not due to lack of biotransformation in vivo. Following separation by HPLC, the metabolites were analyzed by electron impact and fast atom bombardment mass spectroscopy and by NMR spectroscopy. The metabolites were identified as a) 3-hydroxy-2,6-DAT, b) 4-hydroxy-2-acetylamino-6-aminotoluene, c) 2-acetylamino-6-aminotoluene, and d) 2,6-di(acetylamino)-toluene. Metabolites b and d were found to be mutagenic in Salmonella typhimurium TA98 and then only in the presence of an activation system. Results of this study indicate that 2,6-DAT, which is a mutagen in in vitro tests, is also metabolized by the rat to compounds which are proximate mutagens.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Absorption, distribution, metabolism, and excretion of 1,2-dihydro-2,2,4-trimethylquinoline in the male F344 rat.

1,2-Dihydro-2,2,4-trimethylquinoline (TMQ), an antioxidant used in the rubber industry, was readily absorbed from the gastrointestinal tract of the male Fischer 344/N rat and rapidly distributed throughout the body tissues. Absorption, distribution, metabolism, and excretion were not significantly affected by dose in the range 11.5-1150 mumol/kg. Following iv administration, the greatest amounts of TMQ-derived radioactivity were present in the high volume tissues including muscle, adipose, skin, liver, and blood. TMQ had no particular affinity for any tissue. TMQ-derived radioactivity was excreted primarily in urine (60-70%) and feces (20-30%) within 3 days after administration. Greater than 99% of the TMQ dose excreted in urine and feces was in the form of metabolites. Urine contained two major and ten minor metabolites while feces contained two major and four minor metabolites. The two major TMQ metabolites in urine were identified by NMR and mass spectroscopy as the O-sulfate conjugate of 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline and the monosulfate conjugate of 1,2-dihydro-1,6-dihydroxy-2,2,4-trimethylquinoline. In vitro studies with liver subcellular fractions suggest that most of the metabolites present in urine, feces, and bile are the products of mixed function oxidase activity and conjugates of these metabolites. Multiple exposure of rats to high TMQ doses (1150 mumol/kg) resulted in some bioaccumulation of TMQ-derived radioactivity in all tissues examined, but these residues did not persist when dosing was discontinued.

Animals↗
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Metabolism and disposition of ethylene glycol monobutyl ether (2-butoxyethanol) in rats.

Ethylene glycol monobutyl ether (2-butoxyethanol, BE) is a major industrial chemical with multiple and diverse uses that may result in significant risk of human exposure and environmental contamination. The current studies were undertaken to investigate the metabolism and disposition of this chemical in male F344 rats. Data presented in this report showed that BE is rapidly absorbed after gavage administration, metabolized, and eliminated. Tissue distribution of BE revealed that BE is distributed to all tissues with the highest levels (determined 48 hr after dosing) detected in the forestomach followed by the liver, kidney, spleen, and the glandular stomach. However, the increase in the tissue concentration in rats treated with 500 mg/kg (as compared to that in rats treated with 125 mg/kg BE) was not proportional to the increase in BE dose. The major route of BE elimination was in the urine, followed by 14CO2 exhalation. The portion of the BE dose eliminated in urine or as 14CO2 was significantly higher in rats treated with 125 mg/kg than in the rats treated with 500 mg/kg. This may indicate that saturation of BE-metabolizing enzymes occurs at the high dose. A small portion (8%) of the administered dose (500 mg/kg) was excreted in the bile in 8 hr after dosing. Qualitative and quantitative HPLC analysis of the urinary and biliary metabolites of BE revealed that the major urinary metabolite, butoxyacetic acid (BAA), accounted for more than 75% of the radioactivity excreted in the urine. The second major metabolite in urine was the glucuronide conjugate of BE (BEG).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Metabolism and disposition of n-butyl acrylate in male Fischer rats.

Butyl acrylate (BA) is one of the major monomers used in the manufacture of polymers and resins. Because little is known regarding its metabolic fate in animals, it was of interest to study the metabolism and disposition of BA in the rat. After oral administration, butyl [2,3-14C]acrylate was rapidly absorbed and metabolized. The acrylate moiety was metabolized primarily to CO2, accounting for elimination of up to 75% of the administered radiolabel. Elimination in urine and feces accounted for approximately 10 and 2% of the dose, respectively. Initial clearance of radioactivity from the tissues was very rapid and then decreased to a negligible rate 2 hr after iv administration. Total radioactivity in the major tissues was relatively constant from 2 to 24 hr. The majority of the radioactivity in the blood at 24 hr was found to be covalently bound to the protein fraction of the red blood cell membranes. There was some evidence of a first-pass effect when BA was administered by gavage because iv administration resulted in less metabolism to CO2 and quantitative differences in urinary metabolites. The two major metabolites in urine were identified as N-acetyl-S-(2-carboxyethyl)cysteine and N-acetyl-S-(2-carboxyethyl)cysteine-S-oxide. Results of this study indicated that the major portion of a BA dose was hydrolyzed to acrylic acid, which was further metabolized to compounds available for oxidative metabolism. Radiolabeled carbons from the BA molecule were excreted as CO2 or incorporated in trace amounts into lipids, proteins, and other products of de novo synthesis. A smaller portion of the BA dose was conjugated with endogenous glutathione.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylates↗
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Methyl carbamate. Species-dependent variations in metabolism and clearance in rats and mice.

Studies of the chronic toxicity and carcinogenicity of methyl carbamate (MC) in F344 rats and B6C3F1 mice indicate that this compound is more toxic to rats than mice. MC was also a carcinogen for rats but not a carcinogen for mice even when administered at a higher dose. The present study of the comparative metabolism and disposition of MC in these two species was conducted to determine possible sources of these varying responses. Results of this study indicate that, although the initial distribution of MC in the two species is similar, the mouse metabolizes and clears MC much more rapidly than does the rat. In the mouse, clearance was primarily by metabolism to CO2 and elimination in exhaled air, which accounted for approximately 70% of the dose in 48 hr. On the other hand, the rat eliminated approximately 18% of the dose as CO2 in 48 hr and a similar amount in urine. The parent compound accounted for approximately 90% of the material excreted in urine of both rats and mice. Only the parent compound was detected in tissues of either species. Less than 4% of the dose was excreted in feces of either species. The lesser ability of the rat to metabolize and eliminate MC as CO2 results in bioaccumulation of this compound on repeat exposure. Therefore, bioaccumulation of MC by the rat on chronic exposure probably results in both greater total exposure and higher peak exposure of most rat tissues vs. those of mice and may thus account for the greater toxicity and possibly carcinogenicity of MC to rats.

Animals↗
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Use of a physiological compartmental model for the rat to describe the pharmacokinetics of several chlorinated biphenyls in the mouse.

The feasibility of extrapolating the pharmacokinetics of some chlorinated biphenyl congeners (PCB's) from one animal species to another was investigated. The fate of four differently chlorinated biphenyls previously studied in the rat was determined in the mouse The experimental tissue level, metabolism, and excretion data were then used to evaluate results predicted for each PCB after a physiological compartmental model for the rat was scaled to the mouse. Pharmacokinetic parameter values were also obtained from data in the mouse for further evaluations, and to determine whether the congener-dependent relationships previously observed in the rat were present in the mouse. The pharmacokinetics predicted by the scaled model and the results obtained when model parameters were derived from mouse data were equally descriptive of the experimental tissue distribution and excretion kinetics of the PCB's studied. Congener-dependent relationships among the PCB model parameters for the mouse were more varied than for the rat. The accuracy of the pharmacokinetic model predictions extrapolated from the rat to the mouse was primarily a function of their similar congener-dependent rates of PCB metabolism.

Animals↗
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Disposition of 4,4'-thiobis(6-t-butyl-m-cresol) in rats.

The absorption, distribution, metabolism, and excretion of 14C-labeled 4,4'-thiobis(6-t-butyl-m-cresol) (TBBC) was studied in male rats. Oral treatment showed a dose-related decrease in the rate of absorption due to a dose-related increase in retention time in the stomach. TBBC was incompletely absorbed after oral treatment, although the rate of absorption was proportional to the dose once the compound reached the small intestine. TBBC was rapidly distributed throughout the body with the liver being the major tissue depot. Significant amounts of the compound were also present in blood, muscle, skin, and adipose tissue. TBBC was initially rapidly cleared from all tissues except adipose, although a small percentage of the total dose tended to persist in liver and skin. Over half of the compound was excreted the first day, primarily via the bile into the feces. Little TBBC-derived radioactivity appeared in the urine. Metabolites of TBBC were present in the tissues at early times after administration, but were rapidly excreted. The major metabolite(s) appeared to be glucuronide conjugates of the parent compound. Thus, TBBC, an important antioxidant in the rubber and plastic industries, would tend to accumulate in liver and lipid-rich tissues upon chronic exposure, which if by the oral route, could also result in direct damage to the gastrointestinal tract.

Animals↗