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Biomedical subjects

H B Matthews

Publications and source records attributed to H B Matthews.

At least 73 records · Page 4Linked to original sources
PubMed1985

Ethyl acrylate-induced gastric toxicity. I. Effect of single and repetitive dosing.

Ethyl acrylate (EtAc) is widely used in the production of polymers and copolymers for use in the preparation of latex paints, textiles, paper coatings, and specialty plastics. EtAc caused squamous cell carcinomas and papillomas in the forestomach (nonglandular portion of the stomach) of both sexes of F344 rats and B6C3F1 mice when administered chronically by gavage. The current studies were undertaken to investigate and characterize the nature of the acute gastric toxicity caused by EtAc. Gavage administration of a single dose of 100, 200, or 400 mg/kg EtAc (in corn oil) to F344 male rats caused dose-and time-dependent mucosal and submucosal edema and vacuolization of the tunica muscularis in the forestomach and mild submucosal edema in the glandular stomach. Equivalent sc or ip doses did not produce similar gastric lesions. Treatment of rats with two or four consecutive oral daily doses (200 mg/kg each) of EtAc caused mucosal edema associated with vesicle formation, mucosal hyperplasia, submucosal edema and inflammation, and vacuolization of the tunica muscularis of the forestomach. Submucosal edema and inflammation were also observed in the glandular stomach and mucosal erosions or ulcers were observed in both portions of the stomach after repeated oral exposure to EtAc. The absence of systemic toxicity plus the dependency of gastric lesions on the gavage route of administration suggest that the EtAc-induced gastric lesions may be a consequence of localized hemodynamic changes, specifically those characteristic of a classical immediate inflammatory response to an injurious agent at the site of administration.

Acrylates↗
PubMed1985

Ethyl acrylate-induced gastric toxicity. II. Structure-toxicity relationships and mechanism.

Earlier studies conducted in this laboratory demonstrated that gavage administration of ethyl acrylate caused pronounced gastric toxicity in rats given single or repeated doses. The current studies were undertaken to investigate the structural, metabolic, and physical basis of this chemically induced gastric toxicity. Gavage administration of equimolar doses (2 mmol/kg) of methyl or ethyl acrylate in corn oil resulted in profound gastric toxicity in male F344 rats, while acrylic acid and n-butyl acrylate were without effect. Furthermore, gavage administration of equimolar doses of methyl propionate or ethyl propionate (saturated analogues of methyl acrylate and ethyl acrylate, respectively) as well as methacrylic acid esters were without gastric toxicity. These results indicate that structural requirements for acrylate esters to cause gastric lesions include an intact ester moiety, a double bond, and no substitution at carbon number 2. Additional studies indicate that gastric toxicity may be attributed to the intact ester molecule or to metabolite(s) other than products of carboxylesterase-mediated hydrolysis (acrylic acid and alcohol) and that gastric toxicity is dependent upon both acrylate ester concentration in dose vehicle and the lipophilicity of the dose vehicle (corn oil vs water).

Acrylates↗
PubMed1985

Identification of the major metabolite of 4,4'-thio-bis-(6-t-butyl-m-cresol).

Metabolism of 4,4'-thio-bis-(2-t-butyl-5-methylphenol)(TBBC) in rats resulted in the formation of a glucuronide conjugate of TBBC. This conjugate was identified by a combination of high-performance liquid chromatography (HPLC) and mass spectrometry and a tandem mass spectrometric method employing a fast particle ionization technique. A comparison of mass spectral data from the in-vivo metabolite of TBBC and an enzymically synthesized glucuronide conjugate of TBBC showed the metabolite to be the monoglucuronide.

Animals↗
PubMed1985

Benzyl acetate carcinogenicity, metabolism, and disposition in Fischer 344 rats and B6C3F1 mice.

Carcinogenesis studies of benzyl acetate (a fragrance and flavoring agent) were conducted in F344 rats and B6C3F1 mice. The chemical was given in corn oil by gavage once daily, 5 days/week for 103 weeks, to groups of 50 animals of each sex and species. For rats the doses were 0, 250, and 500 mg/kg body weight and for mice the doses were 0, 500, and 1000 mg/kg. Mean body weights of control and dosed rats and mice were not affected adversely by benzyl acetate. The survival of control and low dose female mice was lower than that of the high dose group. A genital tract infection may have contributed to the reduced survival. No other significant difference in survival was observed for dosed rats or mice. Benzyl acetate was absorbed from the gastrointestinal tract of rats and mice, with approximately 90% of the administered dose recovered as various metabolites in the urine within 24 h. The primary metabolite was hippuric acid, with minor amounts of a mercapturic acid, and one or more unidentified metabolites. This capacity for absorption, metabolism, and disposition was unaffected by the amount or number of doses administered. Under the conditions of these studies, benzyl acetate administration was associated with an increased incidence of acinar cell adenoma of the exocrine pancreas in male F344/N rats. No evidence of carcinogenicity was found for female F344/N rats. For male and female B6C3F1 mice there was evidence of carcinogenicity, in that benzyl acetate caused an increased incidence of hepatocellular neoplasms (particularly adenomas) and squamous cell neoplasms of the forestomach.

Absorption↗
PubMed1985

2,6-Dichloro-p-phenylenediamine: comparative disposition in male and female rats and mice.

2,6-Dichloro-p-phenylenediamine (DPA) was recently reported to induce hepatocellular adenomas and carcinomas in male and female B6C3F1 mice but not in F344 rats. The present investigation of comparative disposition in both sexes of each species was designed to detect species-related variations in DPA disposition that might explain variations in toxicity. Mouse tissues retained higher concentrations of radioactivity at the early time points (15 min and 2 h) than the corresponding rat tissues but were readily cleared at later time points. Elimination of DPA-derived radioactivity by each species was primarily in urine (56-63% of an intravenous dose of 600 mumol/kg body weight) and secondarily in feces (23-31%). Metabolites were qualitatively similar, but varied quantitatively with species. Rats excreted three major and eight minor metabolites in urine, while mice excreted one major and nine minor metabolites. The major metabolite present in mouse urine (61-78% of radioactivity) was approximately two-fold higher than the corresponding major metabolite in rat urine. Efforts to detect covalent binding of DPA and/or metabolites with hepatic DNA indicated no detectable binding in either species. The present study indicates that quantitative variations in disposition and metabolism exist between the two species but does not identify a likely source of species variation in susceptibility to DPA toxicity.

Animals↗
PubMed1985

p-Phenylenediamine dihydrochloride: comparative disposition in male and female rats and mice.

The absorption, distribution, metabolism, and excretion of p-phenylenediamine (PDA) was studied in both sexes of F344 rats and B6C3F1 mice. Absorption of PDA from the gastrointestinal tract was nearly complete in both species, and tissue distribution and excretion were not affected by the route of administration or dose in the range studied. The highest PDA-derived radioactivity was present in muscle, skin, and liver in both species at all time points examined. Both sexes of either species cleared radioactivity from all tissues rapidly, so that in 24 h only 10-15% of the total dose administered was still present in the animal body. Clearance of PDA-derived radioactivity was primarily through urine (68-86%) and secondarily through feces (10-19%). Over 95% of the radioactivity excreted in urine of both species was in the form of metabolites. The major metabolites in male and female rat urine were qualitatively and quantitatively similar, while major quantitative differences were observed between urinary metabolites of male and female mice. Variability in urinary metabolites was observed between the two species. Supplementary experiments have shown that PDA and/or metabolites do not bind covalently to hepatic DNA. However, PDA-derived radioactivity was found to bind with hepatic protein of both sexes of each species.

Animals↗
PubMed1985

Comparative chronic toxicities and carcinogenic potentials of 2-ethylhexyl-containing compounds in rats and mice.

Four compounds containing a 2-ethylhexyl moiety [di(2-ethylhexyl)phthalate (DEHP), di(2-ethylhexyl)adipate (DEHA), tris(2-ethylhexyl)phosphate (TEHP), and 2-ethylhexyl sulfate (EHS)] were tested for carcinogenic and other chronic and subchronic toxic effects in 90-day and 2-year studies in male and female Fischer 344 rats and B6C3F1 mice. The low generalized toxic potencies of the test chemicals allowed relatively high doses of all of these compounds to be administered. Despite differences in chemical structure, all four chemicals were related to increased occurrences of hepatocellular neoplasms, principally carcinomas, in female mice. DEHA and DEHP also induced hepatocellular neoplasms in male mice, while DEHP caused hepatocellular neoplasms in both male and female rats. No other neoplasms were considered to be unequivocally related to compound administration in these studies. There was a positive correlation between the magnitude of the hepatocarcinogenic response in female mice and the probability of a hepatocarcinogenic response in male mice and in male and female rats, suggesting quantitative differences in the carcinogenic potentials of these agents. These results suggest that compounds containing a 2-ethylhexyl moiety (and 2-ethylhexanol, by implication) may possess some carcinogenic potential, especially for the rodent liver. No other organ-specific toxic effects common to two or more test chemicals were observed in these studies.

Adipates↗
PubMed1984

Allyl isothiocyanate: comparative disposition in rats and mice.

Allyl isothiocyanate (AITC), the major component of volatile oil of mustard, was recently reported to induce transitional-cell papillomas in the urinary bladder of male Fischer 344 rats, but not in the bladders of female rats or B6C3F1 mice. The present investigation of comparative disposition in both sexes of each species was designed to detect sex or species differences in disposition which might explain susceptibility to AITC toxicity. AITC was readily cleared from all rat and mouse tissues so that within 24 hr after administration less than 5% of the total dose was retained in tissues. The highest concentration of AITC-derived radioactivity was observed in male rat bladder. Clearance of AITC-derived radioactivity by each species was primarily in urine (70 to 80%) and in exhaled air (13 to 15%) with lesser amounts in feces (3 to 5%). Rats excreted one major and four minor metabolites in urine. The major metabolite from rat urine was identified by NMR spectroscopy to be the mercapturic acid N-acetyl-S-(N-allylthiocarbamoyl)-L-cysteine. Mice excreted in urine the same major metabolite identified in rat urine as well as three other major and two minor metabolites. Sex-related variations were observed in the relative amounts of these metabolites. Both species excreted a single metabolite in feces. Metabolism of AITC by male and female rats was similar, but female rats excreted over twice the urine volume of male rats. Results of the present study indicate that excretion of a more concentrated solution of AITC metabolite(s) in urine may account for the toxic effects of AITC on the bladder of male rats.

Absorption↗
PubMed1984

Halogenated biphenyl transport by blood components.

Halogenated biphenyl transport by components of rat blood was studied under both in vivo and in vitro conditions. Fractionation of plasma components by gel filtration, ultracentrifugation, and chromatography on a column of fine glass beads indicate that halogenated biphenyls are associated with each major class of plasma proteins but are most concentrated in the lipoproteins. A significant portion of the total halogenated biphenyl in whole blood is also associated with the cellular component. Halogenated biphenyls are readily exchanged between plasma and the cellular component and between lipoproteins and other classes of plasma proteins. Partition of a series of halogenated biphenyls between lipoproteins and other plasma proteins indicated that the relative affinity of a biphenyl for each fraction was proportional to the lipid solubility of the biphenyl involved. Halogenated biphenyls in blood are not thought to be bound to specific sites on blood proteins but rather they are believed to be associated with hydrophobic sites on plasma proteins or the cellular component of blood. The rapid transfer of these compounds to tissues is thought to be by partition to similar sites on cellular proteins.

Animals↗
PubMed1984

Disposition and metabolism of p-nitroaniline in the male F-344 rat.

The disposition of p-[14C]nitroaniline (PNA) was studied in male F-344 rats following oral and/or intravenous (iv) administration. The gastrointestinal absorption of PNA was near complete and was not affected by dose in the range studied (2-100 mumol/kg). Following either oral or iv administration, PNA was rapidly distributed throughout the tissues and showed no marked affinity for any particular tissue. The clearance of [14C]PNA-derived radioactivity from various tissues was rapid and followed a two-component decay curve. The whole body half-life of PNA was approximately 1 hr. Within 3 days clearance of PNA-derived radioactivity from the body was almost complete. [14C]PNA was rapidly cleared by metabolism to nine metabolites which were excreted primarily in the urine and to a lesser extent in feces. Most (56%) of the urinary radioactivity was in the form of sulfate conjugates of two metabolites of PNA; the excretion of unmetabolized PNA was minimal (less than 3%). Biliary excretion of [14C]PNA was significant, however, much of this PNA-derived radioactivity underwent enterohepatic circulation and was subsequently excreted in urine. The results of this study indicate that, if metabolism is a detoxification process, the rapid metabolism and excretion of this compound minimize the likelihood of significant toxicity from repeated exposure to PNA beyond that predicted by data from acute or short-term exposures.

Aniline Compounds↗
PubMed1984

Absorption, distribution, metabolism, and excretion of 1,3-diphenylguanidine in the male F344 rat.

1,3-diphenylguanidine (DPG), a rubber accelerator, was readily absorbed from the gastrointestinal tract of the male Fischer rat and rapidly distributed throughout the body tissues. Absorption and disposition of DPG were not significantly affected by the route of administration or by the dose in the dose range studied, 1.5 to 150 mumol/kg. Most of the dose of DPG was excreted in the urine and feces at approximately equal amounts within 24 hr after oral or iv administration. Greater than 99% of the DPG dose was cleared into the urine and feces within 3 days after administration. Approximately 30% of the DPG-derived radioactivity excreted in urine was the parent compound, DPG, while the remainder was present in the form of two major and one minor metabolite. Close to 95% of the radioactivity excreted in bile was in the form of a single major metabolite. Administration of multiple doses resulted in a proportional increase of DPG-derived radioactivity in the liver as the number of doses increased. DPG-derived radioactivity did not increase in other tissues following multiple doses.

Administration, Oral↗
PubMed1984

Pharmacokinetics of PCBs.

The pharmacokinetics of PCBs are complicated by numerous factors, not the least of which is the existence of up to 209 different chlorinated biphenyls. Whereas all PCB congeners are highly lipophilic and most are readily absorbed and rapidly distributed to all tissues, PCBs are cleared from tissues at very different rates, and the same congeners may be cleared at different rates by different species. With the exception of special situations in which PCBs may be passively eliminated in lipid sinks, e.g. milk or eggs, clearance is minimal prior to metabolism to more polar compounds. Rates of PBC metabolism vary greatly with species and with the degree and positions of chlorination. Mammals metabolize these compounds most rapidly, but even among mammalian species rates of metabolism vary greatly. In all species studied, the more readily metabolized chlorinated biphenyls have adjacent unsubstituted carbon atoms in the 3-4 positions. Congeners that do not have adjacent unsubstituted carbon atoms may be metabolized very slowly and are therefore cleared very slowly. These PCBs not readily cleared concentrate in adipose tissue. A physiologic pharmacokinetic model best illustrates how the concentrations of PCBs in all tissues approach equilibrium with the blood and with one another. Thus, the model illustrates how a depot of PCBs in any tissue, e.g. adipose tissue, will result in exposure of all tissues in proportion to the respective tissue/blood ratios and the body burden. The disposition of a number of PCBs in the rate has been accurately described by a physiologic model, and the model has been extrapolated to predict the disposition of these same PCBs in the mouse (58). Therefore, the physiologic pharmacokinetic model is believed to offer the best opportunity to extrapolate data obtained with laboratory animals to predict the disposition of PCBs in other species, including man. Most of the parameters of a model of PCB disposition in man are available or could be estimated. The major limitation to the construction of such a model is the absence of accurate estimates of metabolic clearance of individual PCBs by man. Accurate estimates of metabolic clearance depend on development of suitable in vitro methods to accurately predict clearance in vivo.

Animals↗
PubMed1983

Metabolism and disposition of the flame retardant tris(2,3-dibromopropyl)phosphate in the rat.

The metabolism and disposition of the flame retardant, tris(2,3-dibromopropyl)phosphate (Tris-BP), were studied after po and iv administration of the 14C-labeled compound to the male rat. Tris-BP was readily absorbed from the gastrointestinal tract and rapidly distributed throughout the body. The distribution and excretion of Tris-BP derived radioactivity were similar after either po or iv administration. The only effects of route of administration on tissue distribution were slightly higher concentrations in liver after po administration and in lung after iv administration. The initial elimination of Tris-BP derived radioactivity in urine, feces, and as CO2 accounted for approximately 50% of the dose in 24 hr. An analysis of Tris-BP derived radioactivity remaining in the tissues one day after administration indicated that most of the radioactivity in all tissues was in the form of various metabolites rather than the parent compound. The terminal clearance of Tris-BP derived radioactivity from most of the tissues studied was best described by a single component exponential decay with a half-life of approximately 2.5 days. Clearance from liver and kidney was somewhat slower having a half-life of approximately 3.8 days. Approximately 33% of the radioactivity excreted in urine and approximately 50% of the radioactivity excreted in bile were identified by cochromatography with synthesized standards on high performance liquid chromatography (HPLC). Six metabolites and a trace of the parent compound were identified in urine and bile by this method. The six metabolites products of dealkylation and dehydrobromination of the parent compound. The metabolites of Tris-BP isolated from urine and bile were also formed in vitro by NADPH-dependent microsomal enzymes from rat liver. The soluble enzymes from liver metabolized Tris-BP to at least three unidentified polar metabolites.

Animals↗
PubMed1983

Physiological model for the pharmacokinetics of 2,3,7,8-tetrachlorodibenzofuran in several species.

A flow-limited physiological model was developed to describe the time course of 2,3,7,8-tetrachlorodibenzofuran (TCDF) in the blood and tissues of rats, mice, and monkeys. The liver showed the greatest tendency to concentrate the material with tissue-to-blood distribution coefficients ranging from 30 in the monkey to 130 in the mouse. TCDF was also concentrated in the fat with tissue-to-blood distribution coefficients between 25 and 40 in all species. TCDF was eliminated by metabolism followed by excretion primarily to the feces. Urinary excretion was a minor route of elimination in all species. Metabolism was modeled as a linear process occurring in the liver. Intrinsic metabolic clearances ranged from 0.45 ml/min/kg in the monkey to 2.8 ml/min/kg in one species of mice. Fecal excretion of TCDF-derived radioactivity can be simulated with a series of well-mixed compartments which receive input of metabolites in the bile.

Animals↗
PubMed1982

Pharmacokinetics, interactions with macromolecules and species differences in metabolism of DEHP.

The recent long-term carcinogenesis bioassay of di(2-ethylhexyl) phthalate (DEHP) in rats and mice reported by the National Toxicology Program was the first such bioassay to implicate DEHP as a hepatocarcinogen. At the levels of DEHP fed (up to 1.2% of the diet for two years), the livers of the rats would have been exposed to unhydrolyzed diester; this would not have been the case at lower dosages. Extrapolation to lower dosages is therefore questionable. We do not have sufficient pharmacokinetic data in mice to evaluate the dose relationships as yet. Rodents differ conspicuously from primates in their manner of metabolizing DEHP, both in terms of the demand made on the oxidation potential of the liver and in the chemical properties of the major metabolites. The relevance of these differences must be determined before rodent species can be considered models for the effects of DEHP in humans. Radioactivity from carbonyl-labeled DEHP did not associate with purified protein, RNA or DNA from rat liver in vivo. Label from 2-ethyl-(1-14C)-hexyl-labeled DEHP or mono(2-ethylhexyl) phthalate (MEHP) did appear to associate strongly with purified DNA, but label from free 14C-labeled 2-ethylhexanol did not. The apparent binding from DEHP and MEHP was not exchangeable, but was not proven to be covalent. This phenomenon needs additional study.

Absorption↗
PubMed1981

Enteric transport of chlordecone (Kepone) in the rat.

Disposition of chlordecone (Kepone) in the rat is quantitated. Particular attention is devoted to the role of the intestinal tract in excretion, as well as absorption, of the parent form of the halogenated pesticide. A detailed physiological pharmacokinetic model for the GI tract is presented in which the organs are segmented into a series of well-mixed compartments representing stomach, small intestine, cecum, and large intestine. The model is applied to the early time behavior of data from the following two types of studies in the rat: (1) the movement of a nonabsorbable tracer along the GI tract, and (2) the enteric transport of parent chlordecone. Model parameter values for the gut wall permeability-area products for parent chlordecone determined for the rat are used to estimate the corresponding values for man based on scale-up considerations. The enhancement of excretion rates through use of orally administered adsorbents is discussed.

Animals↗