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Biomedical subjects

M A Medinsky

Publications and source records attributed to M A Medinsky.

At least 91 records · Page 5Linked to original sources
PubMed1985

Disposition and metabolism of 2,3-[14C]dichloropropene in rats after inhalation.

2,3-Dichloropropene (2,3-DCP) is a constituent of some commercially available preplant soil fumigants for the control of plant parasitic nematodes. Human exposure potential exists during manufacture of the chemicals or during bulk handling activities. The purpose of this investigation was to determine the disposition and metabolism of 2,3-[14C]DCP in rats after inhalation. Male Fischer-344 rats were exposed nose-only to a vapor concentration of 250 nmol 2,3-[14C]DCP/liter air (7.5 ppm; 25 degrees C, 620 Torr) for 6 hr. Blood samples were taken during exposure, and urine, feces, expired air, and tissues were collected for up to 65 hr after exposure. Urinary excretion was the major route of elimination of 14C (55% of estimated absorbed 2,3-DCP). Half-time for elimination of 14C in urine was 9.8 +/- 0.05 hr (means +/- SE). Half-time for elimination of 14C feces (17% of absorbed 2,3-DCP) was 12.9 +/- 0.14 hr (means +/- SE). Approximately 1 and 3% of the estimated absorbed 2,3-[14C]DCP were exhaled as either 2,3-[14C]DCP or 14CO2, respectively. Concentrations of 14C in blood increased during 240 min of exposure, after which no further increases in blood concentration of 14C were seen. 14C was widely distributed in tissues analyzed after a 6-hr exposure of rats to 2,3-[14C]DCP. Urinary bladder (150 nmol/g), nasal turbinates (125 nmol/g), kidneys (84 nmol/g), small intestine (61 nmol/g), and liver (35 nmol/g) were tissues with the highest concentrations of 14C immediately after exposure. Over 90% of the 14C in tissues analyzed was 2,3-DCP metabolites. Half-times for elimination of 14C from tissues examined ranged from 3 to 11 hr. The data from this study indicate that after inhalation 2,3-DCP is metabolized in tissues and readily excreted.

Allyl Compounds↗
PubMed1985

Projected uptake and toxicity of selenium compounds from the environment.

Industrial workers and members of the general public may be exposed to selenium by inhalation of selenium in the workplace or atmosphere or by ingestion of selenium in food. A model has been developed to evaluate the potential uptake of selenium in body tissues by these two exposure routes. Rates were estimated for transport of selenium between five compartments including lung, gastrointestinal tract, blood, liver and other tissues. Results of model simulations were compared to published tissue distribution information obtained from single inhalation exposures of rats and dogs to radiolabeled selenium compounds at concentrations from 20 mg/m3 to 20 micrograms/m3 with initial body burdens of selenium ranging from 28 to 0.09 micrograms Se/kg body wt. The model was then modified to predict equilibrium organ concentrations of selenium in people after continual exposure to selenium in the air or in the diet. Daily intake levels of 100 micrograms/day and a fractional absorption value of 0.8 were used. With an air concentration of 1 ng Se/m3, model predictions indicated that most of the total body selenium in people is likely to come from their diet because selenium in the urban atmosphere contributes a very small part of the total body selenium. However, continual inhalation of selenium at the threshold limit value (TLV; 200 micrograms/m3) could contribute significantly to the total body burden of selenium. Levels of selenium predicted in lung, liver, and blood after inhalation of selenium at the TLV were 22,000, 1200, and 440 ng Se/g tissue. Predicted lung concentrations were near those that produced toxic effects in animals after ingestion of Se.

Absorption↗
PubMed1985

Uptake and excretion of [14C]methyl bromide as influenced by exposure concentration.

Methyl bromide is a widely used soil fumigant and poses potential inhalation hazard to workers. Uptake of methyl bromide and pathways for excretion of 14C were investigated in male Fischer-344 rats after nose-only inhalation of 50, 300, 5700, or 10,400 nmol (1.6 to 310 ppm) of [14C]methyl bromide/liter of air for 6 hr. Fractional uptake of methyl bromide decreased at the highest concentrations, 5700 and 10400 nmol/liter, with 37 and 27% of the inhaled methyl bromide absorbed, respectively, compared to 48% at the lower levels. This resulted in the same total amount of methyl bromide being absorbed at the two higher exposure concentrations (650 mumol/kg body wt). Total methyl bromide adsorbed was 9 or 40 mumol/kg body wt after exposure to 50 or 300 nmol/liter, respectively. Elimination of 14C was linearly related to the amount of methyl bromide absorbed as determined from urine, feces, expired CO2, and parent compound collected for 66 hr after the end of exposure. Exhaled 14CO2 was the dominant route of excretion, with from 1.2 to 110 mumol (50% of amount absorbed) exhaled, and was described by a two-component negative exponential function; 85% was exhaled with a t 1/2 of 4 hr, and the remaining 15% was exhaled with a t 1/2 of 17 hr. The rate of exhalation of 14CO2 was not affected by the amount of [14C]methyl bromide absorbed. From 0.4 to 54 mumol was excreted in urine (20% of amount absorbed). The half-time for excretion of 14C in urine was approximately 10 hr, and the rate of excretion was not dependent on the amount of [14C]methyl bromide absorbed. Little 14C was exhaled as methyl bromide (less than 4% of the dose) or excreted in feces (less than 2%). At the end of 66 hr, 25% of the 14C absorbed remained in the rats. Liver, kidneys, adrenals, lungs, thymus, and turbinates (maxilloturbinates, ethmoturbinates, and nasal epithelial membrane) contained the highest concentrations of 14C. Results indicated that uptake of inhaled methyl bromide could be saturated. Any [14C]methyl bromide equivalents absorbed, however, would be excreted by concentration-independent mechanisms.

Air Pollutants, Occupational↗
PubMed1985

Disposition of [14C]methyl bromide in rats after inhalation.

Methyl bromide is used as a disinfectant to fumigate soil and a wide range of stored food commodities in warehouses and mills. Human exposure occurs during the manufacture and use of the chemical. The purpose of this investigation was to determine the disposition and metabolism of [14C]methyl bromide in rats after inhalation. Male Fischer-344 rats were exposed nose only to a vapor concentration of 337 nmol [14C]methyl bromide/liter air (9.0 ppm, 25 degrees C, 620 torr) for 6 hr. Urine, feces, expired air, and tissues were collected for up to 65 hr after exposure. Elimination of 14C as 14CO2 was the major route of excretion with about 47% (3900 nmol/rat) of the total [14C]methyl bromide absorbed excreted by this route. CO2 excretion exhibited a biphasic elimination pattern with 85% of the 14CO2 being excreted with a half-time of 3.9 +/- 0.1 hr (means +/- SE) and 15% excreted with a half-time of 11.4 +/- 0.2 hr. Half-times for elimination of 14C in urine and feces were 9.6 +/- 0.1 and 16.1 +/- 0.1 hr, respectively. By 65 hr after exposure, about 75% of the initial radioactivity had been excreted with 25% remaining in the body. Radioactivity was widely distributed in tissues immediately following exposure with lung (250 nmol equivalents/g), adrenal (240 nmol equivalents/g), kidney (180 nmol equivalents/g), liver (130 nmol equivalents/g), and nasal turbinates (110 nmol equivalents/g) containing the highest concentrations of 14C. Radioactivity in livers immediately after exposure accounted for about 17% of the absorbed methyl bromide. Radioactivity in all other tissues examined accounted for about 10% of the absorbed methyl bromide. Elimination half-times of 14C from tissues were on the order of 1.5 to 8 hr. In all tissues examined, over 90% of the 14C in the tissues was methyl bromide metabolites. The data from this study indicate that after inhalation methyl bromide is rapidly metabolized in tissues and readily excreted.

Animals↗
PubMed1985

Effect of vapor concentration on the disposition of inhaled 2,3-dichloropropene in Fischer-344 rats.

2,3-Dichloropropene (DCP) is an intermediate used in the manufacture of carbamate herbicides and there is potential for human exposure during the manufacturing process. DCP is a known mutagen in bacteria systems and some structural analogs of DCP are carcinogenic. Since little is known about the disposition of DCP in animals after inhalation, studies were conducted in male Fischer-344 rats to determine the effect of vapor concentration on absorption and excretion. Uptake and elimination of 14C was studied in rats after nose-only inhalation of 17, 240, or 1650 nmol of [14C]DCP vapor/liter of air (0.4, 6, or 40 ppm, respectively, at 760 mm and 25 degrees C) for 6 hr. The percentage of inhaled DCP absorbed averaged 38% and was not statistically different at any vapor concentration, although minute volume was lower during exposure to 1650 nmol/liter. Urine, feces, and expired air were collected from rats for 65 hr after exposure. Rats were sacrificed and tissues, carcass, excreta, and expired air were analyzed for 14C. Routes of 14C excretion were independent of vapor concentration, with 50% of the 14C excreted in urine, 13% in feces, approximately 7% as CO2, and less than 1% as DCP in expired air. Rates of 14C excretion were also independent of vapor concentration, with the half-times averaging 9.9 hr (urine), 13.6 hr (feces), and 0.9 hr (14CO2). Sixty hours after inhalation, 29% of the initial body burden of 14C remained in the carcass. Most was associated with the pelt, but some 14C was found in all tissues. Respiratory tract, GI tract, liver, and kidney were tissues with the highest 14C contents. The results indicate that DCP metabolism and excretion rates are relatively constant throughout the vapor concentration range studied. This suggests that results from more detailed pharmacokinetic studies (and possibly toxicity studies) at one DCP concentration may be extrapolated to other concentrations within this range.

Absorption↗
PubMed1984

Metabolism of 1-[14C]nitropyrene in isolated perfused rat livers.

1-Nitropyrene (1-NP), a constituent of diesel exhaust, is carcinogenic to rats and is a bacterial and mammalian mutagen. Biliary and fecal excretion of 1-NP metabolites are the major routes of excretion in rats, suggesting that hepatic metabolism plays a dominant role in determining the biological fate of 1-NP. The purpose of this investigation was to quantitate 1-[14C]NP metabolites formed in isolated perfused rat livers and excreted in bile from rats. Perfused rat livers displayed a capacity for oxidation, reduction, acetylation, and conjugation of 1-NP (or its metabolites). Reduction of 1-NP followed by N-acetylation was the major metabolic pathway observed in the perfused livers. Acetylaminopyrene (AAP) was the major metabolite detected, with total quantities (150 nmol) accounting for about 60% of the total 1-[14C]NP dose (258 nmol) added to the perfusate. Considerably smaller quantities of aminopyrene and hydroxynitropyrenes were also detected. Livers perfused with 1-[14C]NP excreted about 36 nmol equivalents of 1-[14C]NP (12% of the total 1-NP dose) in bile after 60 min. Some of the biliary metabolites were tentatively identified as metabolites of the mercapturic acid pathway. The spectrum of biliary metabolites was qualitatively identical to that seen in bile from intact rats. Quantities of 14C covalently bound to hepatic macromolecules from perfused livers were 0.4 nmol 1-NP eq/g liver. The data from this study indicate that the liver may be an important site for metabolism of 1-NP.

Animals↗
PubMed1984

Disposition of [14C]methyl bromide in Fischer-344 rats after oral or intraperitoneal administration.

Methyl bromide is used as a disinfectant to fumigate soil. The intent of our study was to determine the disposition of methyl bromide following a single acute administration. Male Fischer-344 rats were given 250 mumol of [14C] methyl bromide/kg body wt by either oral or i.p. administration. Urine, feces and expired air were collected and at the end of 72 h the rats were sacrificed and tissues analyzed to determine 14C excretion and tissue distribution. After i.p. administration of methyl bromide, the dominant route of excretion was exhalation of 14CO2, with 46% of the dose exhaled as 14CO2. In contrast, urinary excretion of 14C was the major route of elimination (43% of the dose) when methyl bromide was given orally. Very little of the 14C appeared in the feces (less than 3% of the dose) regardless of route of administration. In rats with bile duct cannulations, 46% of an oral dose appeared in the bile over a 24-h period. Collection of bile significantly decreased the exhalation of 14CO2 and 14C excreted in urine compared to controls. At 72 h after oral or i.p. administration, 14-17% of the 14C remained in the rats, with liver and kidney being the major organs of retention. Results indicate that route of administration can affect the pathways for excretion. In addition, excretion of 14C in bile, coupled with the low levels of radioactivity found in the feces, indicates that reabsorption of biliary metabolites from the gut plays a significant role in the disposition of [14C] methyl bromide.

Administration, Oral↗
PubMed1984

Disposition of [14C]2,3-dichloropropene in Fischer-344 rats after oral or intraperitoneal administration.

2,3-Dichloropropene (2,3-DCP), a component of commercial fumigants and nematocides, was mixed with [14C]2,3-DCP and given to rats by peroral (p.o.) or intraperitoneal (i.p.) administration. Urine, feces, and expired air were collected over 72 h. Excretion of radioactivity in urine predominated over other routes, with 66% to 75% of the dose excreted in 72 h. Feces contained from 13% to 21% of dose. 8% of the dose was exhaled as 14CO2. At the end of 72 h, only 2% to 3% of the dose remained in the carcass with the highest concentrations of 14C in liver, kidney, testes, and lung. Approx. 91% of the p.o. dose was absorbed from the gastrointestinal (GI) tract.

Administration, Oral↗
PubMed1984

Dog pulmonary macrophage metabolism of free and particle-associated [14C]benzo[a]pyrene.

Pulmonary macrophages (PM) are involved in the clearance of inhaled particulate matter from the lung. PM also are capable of metabolizing xenobiotics such as benzo[a]pyrene (BaP). The objective of this investigation was to measure the ability of PM isolated from dogs to metabolize BaP coated onto diesel exhaust particles and to compare this metabolism with that of BaP in solution. PM were isolated from male beagle dogs and incubated with 1 microM [14C]BaP (solution or diesel particle coated) for select times up to 48 h. After incubation of PM with [14C]BaP, both the cells and the media were individually analyzed for [14C]BaP metabolites by high-performance liquid chromatography. Total quantities of [14C]BaP metabolites in both the media (125 pmol/10(6) cells) and cells (45 pmol/10(6) cells) increased with incubation time for up to 48 h. BaP-9,10-diol and BaP-7,8-diol were the major metabolites in organic extracts from the culture media, whereas BaP-7,8-diol and BaP-4,5-diol were the major metabolites in extracts of cells. Small quantities of BaP phenols and BaP quinones were detected in both the cells and media. Total quantities of BaP metabolites (20-30 pmol/10(6) cells) were not significantly different when PM were incubated for 24 h with either [14C]BaP in solution or [14C]BaP coated on diesel particles. The data suggest that particles retained in lungs are capable of being acted upon by PM metabolizing enzymes and that the ensuing metabolism may play an important role in the metabolic fate of organic material inhaled on particulate matter.

Animals↗
PubMed1984

A double isotope method for characterizing hygroscopic selenious acid aerosols used in inhalation exposures.

Methods of generating and characterizing selenious acid aerosols for use in deposition and toxicity studies are described. Selenious acid aerosols were nebulized and heat treated at varied temperatures. Because selenious acid is hygroscopic, a solution containing 3H2O and 75Se was nebulized to determine the water content in selenium aerosols after generation. The stable aerosol was a hydrate of selenious acid, H2SeO3 X 1/2 H2O, at New Mexico ambient relative humidity (ca. 20%). The mass median aerodynamic diameter of the collected droplets was 0.6 micron with a geometric standard deviation of 1.3.

Aerosols↗
PubMed1983

Absorption, distribution, and retention of inhaled selenious acid and selenium metal aerosols in beagle dogs.

We studied the distribution and retention of inhaled selenious acid and selenium metal aerosols which were similar in size and chemical form to selenium aerosols that may be produced during fossil fuel combustion. Beagle dogs were given 10 to 61 micrograms Se/kg of body weight by inhalation. Aerosols generated for the inhalation exposures were also collected and instilled into the upper respiratory tracts or stomachs of additional dogs to measure systemic absorption at these sites. Selenium-75, incorporated into the aerosols, was used to determine the Se content in the whole animal, excreta, and individual tissues as a function of time. Virtually all of the inhaled selenious acid aerosol was rapidly absorbed into the blood from the lungs, gastrointestinal tract, and the nasal membranes. Selenium metal aerosols were less rapidly absorbed. Selenium that was absorbed into the blood was translocated to the liver, kidney, spleen, and heart. Selenium-75 in these organs had a biological half-life of 30 to 40 days. Approximately 50% of the deposited Se was eliminated with a biological T1/2 of 1.2 days. Urine was the major route of excretion, accounting for 70 to 80% of the excreted Se. The long-term component of the whole-body retention function for both inhaled aerosols had a half-life of about 34 days and accounted for about 20% of the initial Se dose. The data suggested that although absorption of selenious acid into blood following inhalation was more rapid than absorption of selenium metal, once absorbed the disposition of both compounds was similar.

Aerosols↗
PubMed1983

Biliary excretion and enterohepatic circulation of 2,4-dinitrotoluene metabolites in Fischer-344 rats.

Technical grade dinitrotoluene (DNT) is hepatocarcinogenic when fed to rats. DNT is oxidatively metabolized by hepatic enzymes and reductively metabolized by rat intestinal microflora in vitro. The objectives of the present studies were to determine the importance of bile as a route of excretion for DNT metabolites and to investigate the role of enterohepatic circulation in the metabolism of DNT. The common bile ducts of male and female F-344 rats were cannulated with an uninterrupted cannula at the hepatic and ileal ends. After 24 hr, male rats were given a po dose of 35, 63, or 100 mg 2,4-[14C]DNT/kg; female rats received 35 mg 2,4-[14C]DNT/kg. Immediately prior to dosing, the cannula was snipped and bile was allowed to collect in a glass reservoir, surgically implanted in the peritoneal cavity, which could be sampled externally. In males, excretion of 14C in bile was linearly related to dose. From 9.2 to 29.2 mumol eq of [14C]DNT (approximately 25% of the dose) appeared in bile within 24 hr. Females dosed with 35 mg/kg excreted only 18% of the dose in the bile. Over 90% of the radioactivity in the bile was the glucuronide conjugate of 2,4-dinitrobenzyl alcohol (DNBAlc-G). In comparison to control rats, in which bile flow to the small intestine was uninterrupted, collection of bile decreased the amount of 14C excreted in urine. In both males and females most of the 2,4-DNT dose excreted in the urine was in the form of the oxidized metabolites DNBAlc-G and 2,4-dinitrobenzoic acid. These results indicate that bile is an important route of excretion for 2,4-DNT metabolites and that metabolites excreted in the bile can be reabsorbed from the gut.

Animals↗
PubMed1981

Sex-dependent metabolism and biliary excretion of [2,4-14C] dinitrotoluene in isolated perfused rat livers.

The incidence of hepatocellular carcinoma is higher in male rats fed 35 mg of dinitrotoluene (DNT) per kg than in female rats fed the same dose. Sex differences in DNT disposition and/or metabolism may account for this difference. This study characterized the metabolism and biliary excretion of 2,4-DNT in male and female isolated perfused rat livers. Livers from both sexes displayed a capacity for oxidation, reduction, acetylation and conjugation of 2,4-DNT (or its metabolites). Oxidation of 2,4-DNT to 2,4-dinitrobenzyl alcohol followed by glucuronidation to 2,4-dinitrobenzyl alcohol glucuronide (DNBalcG) was the major route of 2,4-DNT metabolism in both sexes. Formation of DNBalcG accounted for 10 to 30% of the total initial 2,4-DNT concentration in perfusates. After perfusion with 20 microM 2,4-DNT, male livers excreted larger quantities of DNBalcG in the bile (392 nmol) than female livers (172 nmol); at the same 2,4-DNT concentration, perfusates from female livers contained over 3 times as much DNBalcG as male perfusates. These data suggested that female livers transported DNBalcG into the bile at slower rates than male livers. The transport of DNBalcG into the bile of male, but not female, livers appeared to be saturated after perfusion with 20 micro M 2,4-DNT. No sex differences in the hepatic macromolecular covalent binding were observed after perfusion of livers with either 20 or 70 micro M 2,4-DNT. These data suggest that the major difference in the in vitro metabolism of 2,4-DNT between male and female rats is the larger quantities of DNBalcG excreted in the bile of male rats than female rats.

Animals↗
PubMedDate not supplied

Toxicity of selenium compounds to alveolar macrophages.

Selenium compounds released into urban atmospheres as a result of fossil fuel combustion may pose an inhalation hazard to people. Two chemical forms of selenium produced during coal combustion and present in combustion effluent are selenious acid. H2SeO3, and elemental selenium, Se. In an attempt to determine the toxicity of selenium compounds relative to other trace elements, the cytotoxicity of H2SeO3 and Se to rabbit alveolar macrophages in vitro was investigated. Macrophages were obtained by lung lavage and exposed in tissue culture after 20 h. Neither selenious acid nor elemental selenium caused cell lysis at concentrations which decreased total cell viability. Selenious acid was an order of magnitude more toxic then elemental selenium. Elemental selenium was similar in toxicity to environmental contaminants such as CdCl2 and V2O5. These in vitro cytotoxicity data can be used to predict the risk posed to people inhaling selenium compounds at levels found in urban atmospheres.

Animals↗
PubMedDate not supplied

Systemic absorption of selenious acid and elemental selenium aerosols in rats.

Absorption of Se from the nasal passages, lungs, gastrointestinal tract, and skin was studied in Fischer-344 rats. Radiolabeled selenious acid and elemental Se particles were administered by inhalation, gavage, nasal instillation, and iv injection. Selenious acid was always absorbed into the general circulation more rapidly and to a greater extent than elemental Se. By 4 h after inhalation of selenious acid and elemental Se aerosols, 94% of the selenious acid and 57% of the elemental Se deposited in lungs was absorbed into blood. Of the selenious acid instilled into nasal passages, 18% was absorbed into blood; 16% of the elemental Se was absorbed. Gastrointestinal absorption was 87% for selenious acid and 50% for elemental Se. Selenious acid solutions were also painted onto the pelts of rats. From 10 to 30% of the selenious acid was absorbed through the skin. Following inhalation or injection of either Se compound, most of the Se was excreted in the urine. Significantly more Se appeared in feces of animals receiving elemental Se by gavage than animals receiving selenious acid. Results indicate that if people were to absorb inhaled Se from the upper respiratory tract in a manner similar to that of rats, one-third more selenious acid would be absorbed into the general circulation than elemental Se. All Se deposited in the lungs would be absorbed into blood. However, selenious acid would be absorbed more rapidly than elemental Se.

Absorption↗
PubMedDate not supplied

A comparison of ethanolamine and potassium hydroxide as quantitative trapping agents for radiolabeled CO2 in metabolism studies.

The efficiency of ethanolamine and potassium hydroxide (KOH) as trapping agents for CO2 was determined using a flow of 500 mL/min through CO2 absorption towers containing trapping solutions. Radiolabeled 14CO2 was produced by acidification of suspensions containing Ba14CO3. Both 100% ethanolamine and 5M ethanolamine in 2-methoxyethanol were evaluated. With 200 mL of either solution, trapping efficiency of 14CO2 decreased when only 5% or less of the amount of ethanolamine available had reacted (22 mmoles of CO2 trapped). In contrast, use of 200 mL of 1M or 5M KOH was effective in retaining 88 mmoles of CO2. This is equivalent to the amount of CO2 produced by a rat over an 8-hr period. In summary, with flow rates commonly used in in vivo metabolism studies, the trapping efficiency of ethanolamine was far less than the theoretical efficiency. In these types of studies KOH would be a more suitable trapping agent or, if used, ethanolamine solutions must be changed frequently.

Carbon Dioxide↗