Biomedical subjects

M A Medinsky

Publications and source records attributed to M A Medinsky.

At least 73 records · Page 4Linked to original sources

PubMed1989

A physiologically based model of 1-nitropyrene metabolism after inhalation or ingestion.

The nitrogen-containing polycyclic aromatic hydrocarbon 1-nitropyrene (NP), a bacterial mutagen and mammalian carcinogen, is a ubiquitous environmental pollutant. A physiologically based toxicokinetic model was developed describing the disposition of NP after oral administration (ingestion) or after inhalation. The model incorporated the following compartments: blood, upper respiratory tract, lung, liver, kidney, gastrointestinal (GI) tract, and a general tissue compartment. First-order rate constants for absorption of NP from the GI tract (2 h-1), metabolism by the liver (30 h-1), excretion of metabolites in bile and urine (2 and 4 h-1, respectively), and covalent binding of NP metabolites to tissue macromolecules (0.05, 0.05, 0.1, and 0.001 h-1 for lung, liver, kidney, and general tissue compartment, respectively) determined from model simulations were used to describe absorption, biotransformation, and excretion of NP. Physiological parameters such as alveolar ventilation, cardiac output, blood flow to organs volume, and tissue/blood partition coefficients described movement of NP and metabolites among compartments. Model predictions for concentrations of NP and metabolites in tissues were compared to experimentally determined data obtained in rats after inhalation of NP. Model predictions for concentrations of NP metabolites covalently bound to tissue macromolecules agreed with experimentally determined data in rats. Levels of bound material in lung and liver were about one-tenth that found in kidney. Results indicated that NP movement among tissue compartments could be described to a large extent by blood flow and organ volume alone (e.g., tissue/blood partition coefficients = 1). The use of physiologically realistic parameters will enable scaling of the model developed using animal studies to predict disposition of NP in humans.

Administration, Inhalation↗

PubMed1989

Differences in the pathways for metabolism of benzene in rats and mice simulated by a physiological model.

Studies conducted by the National Toxicology Program on the chronic toxicity of benzene indicated that B6C3F1 mice were more sensitive to the carcinogenic effects of benzene than were F344 rats. A physiological model was developed to describe the uptake and metabolism of benzene in rats and mice. Our objective was to determine if differences in toxic effects could be explained by differences in pathways for benzene metabolism or by differences in total uptake of benzene. Compartments incorporated into the model included liver, fat, a poorly perfused tissue group, a richly perfused tissue group, an alveolar or lung compartment and blood. Metabolism of benzene was assumed to take place only in the liver and to proceed by four major competing pathways. These included formation of hydroquinone conjugates (HQC), formation of phenyl conjugates (PHC), ring-breakage and formation of muconic acid (MUC), and conjugation with glutathione with subsequent mercapturic acid (PMA) formation. Values for parameters such as alveolar ventilation, cardiac output, organ volumes, blood flow, partition coefficients, and metabolic rate constants were taken from the literature. Model simulations confirmed that during and after 6-hr inhalation exposures mice metabolized more benzene on a mumole per kilogram body weight basis than did rats. After oral exposure, rats metabolized more benzene than mice at doses above 50 mg/kg because of the more rapid absorption and exhalation of benzene by mice. Model simulations for PHC and PMA, generally considered to be detoxification metabolites, were similar in shape and dose-response to those for total metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1989

The effect of dose, dose rate, route of administration, and species on tissue and blood levels of benzene metabolites.

Studies were completed in F344/N rats and B6C3F1 mice to determine the effect of dose, dose rate, route of administration, and rodent species on formation of total and individual benzene metabolites. Oral doses of 50 mg/kg or higher saturated the capacity for benzene metabolism in both rats and mice, resulting in an increased proportion of the administered dose being exhaled as benzene. The saturating air concentration for benzene metabolism during 6-hr exposures was between 130 and 900 ppm. At the highest exposure concentration, rats exhaled approximately half of the internal dose retained at the end of the 6-hr exposure as benzene; mice exhaled only 15% as benzene. Mice were able to convert more of the inhaled benzene to metabolites than were rats. In addition, mice metabolized more of the benzene by pathways leading to the putative toxic metabolites, benzoquinone and muconaldehyde, than did rats. In both rats and mice, the effect of increasing dose, administered orally or by inhalation, was to increase the proportion of the total metabolites that were the products of detoxification pathways relative to the products of pathways leading to putative toxic metabolites. This indicates low-affinity, high-capacity pathways for detoxification and high-affinity, low-capacity pathways leading to putative toxic metabolites. If the results of rodent studies performed at high doses were used to assess the health risk at low-dose exposures to benzene, the toxicity of benzene would be underestimated.

Administration, Inhalation↗

PubMed1989

Azodicarbonamide: methods for the analysis in tissues of rats and inhalation disposition.

1. A method has been developed for measuring azodicarbonamide (ADA) and its metabolite biurea in tissues of rat. The method is based on the reaction of ADA with triphenylphosphine; the derivative so formed was isolated and quantified using reversed-phase h.p.l.c. Quantification was by u.v. detection with 14C-ADA as internal standard. Biurea was measured by oxidation to ADA, followed by treatment as described above. 2. When biurea was added to tissues at 100-400 micrograms, recoveries of 92-125% were observed. In contrast, recoveries of ADA added to tissues were generally much less than 100% and could not be reliably determined. The inability to quantify ADA added to tissues was ascribed to its rapid and facile reduction by tissue sulphydryl groups. 3. When rats were exposed to ADA aerosol concentrations of 200, 100, 50 and 0 mg/m3 for 13 weeks by inhalation, a non-linear dose-dependent accumulation of biurea was observed in lungs. No ADA was detected in lungs. Neither biurea nor ADA could be detected in kidneys.

Administration, Inhalation↗

PubMed1988

Disposition of inhaled 1-chloro-2-propanol in F344/N rats.

Propylene chlorohydrins, of which 1-chloro-2-propanol (1-CP) is a constituent, used as intermediates in the manufacture of propylene oxide and have been identified as potential air pollutants. The objective of these studies was to determine whether changes in the inhaled exposure concentration would affect the disposition of 1-CP in rats. In addition, experiments were conducted to identify the carbon atom of 1-CP that is metabolized to CO2. Rats were exposed nose-only to [14C]1-CP for 6 hr to 8.3 +/- 1.0 ppm (26.1 +/- 3.2 micrograms/liter air) or 77 +/- 4 ppm (245 +/- 13 micrograms/liter air) (mean +/- SE). There were two major routes of elimination of 14C, urinary and exhalation of CO2, which together accounted for about 80% of the total 14C in excreta and carcass. Half-times for elimination of 14C in urine as 14CO2 were between 3 and 7 hr with no effect of exposure concentration on the elimination half-times for either route. After the end of exposure, kidneys, livers, trachea, and nasal turbinates contained high concentrations of [14C]1-CP equivalents at both exposure concentrations (30-50 nmol 14C/g tissue for the 8 ppm exposure level and 200-350 nmol 14C/g tissue for the 80 ppm exposure level). Elimination of 14C from tissues was biphasic with about 50% of the material in a tissue being rapidly eliminated with a half-time of 1 to 3 hr and the remaining material slowly eliminated with a half-time of 40 to 80 hr. There was no effect of exposure concentration on elimination half-times in tissues. Major metabolites detected in urine and tissues (liver, kidney, and lung) were N-acetyl-S-(hydroxypropyl)cysteine and/or S-(2-hydroxypropyl)-cysteine. Little unmetabolized 1-CP (less than 1%) was detected in analyzed tissues or urine. We propose a metabolic scheme in which the major pathway for metabolism of 1-CP is to CO2 (which is exhaled) and to cysteine conjugates and mercapturic acids that are excreted in the urine. Both carbon-2 and carbon-3 are metabolized in part to CO2.

Administration, Inhalation↗

PubMed1988

The effect of molecular weight/lipophilicity on clearance of organic compounds from lungs.

The objective of this study was to test the hypothesis that lipophilicity (as measured by the octanol/water partition coefficient, P) and/or molecular weight are determining factors in the rate of clearance of organic compounds from the lung. Previous work in our laboratory has shown that organic-soluble compounds such as pyrene, benzo[a]pyrene, 1-nitropyrene, 2-aminoanthracene, phenanthridone, dibenzo[c,g]carbazole, 1,3-dichloropropene, and methyl bromide, all of which have a log P less than 6.1, clear the lung rapidly (t 1/2 less than 12 hr). In the present study, organic compounds (mainly anthraquinone dyes) having a wider range of log P's (1.95-8.65) were instilled into rat lungs and the percentage of the compound retained in the lungs at 24 hr was determined. A positive correlation between the log of the theoretical P and the percentage of the compound retained in lungs at 24 hr was found. The lipophilicity of the series of compounds studied was highly dependent on the molecular weight, so that there was also a positive correlation between the molecular weight of the compounds and the percentage of the compound retained in the lung at 24 hr. To help understand the relative importance of lipophilicity and molecular weight in determining lung retention, an additional compound with a high molecular weight but containing a polar functional group [1,5-di(2-sulfo-p-toluidino)anthraquinone] was studied. The results indicated that the lipophilicity was the more important factor in whether the material was retained in the lung. On the basis of the results of this study, organic-soluble compounds with molecular weights less than 300 Da can be expected to clear the lungs rapidly. Nonpolar, organic-soluble compounds with a molecular weight greater than 300 Da can be expected to clear the lungs more slowly.

Animals↗

PubMed1988

Uptake of vinylidene fluoride in rats simulated by a physiological model.

The purpose of this study was to develop a physiological model to simulate the uptake of vinylidene fluoride (VDF), an important plastics monomer, in laboratory animals. Male Fischer 344/N rats were exposed nose-only for 6 hr to concentrations of VDF ranging from 27 to 16,000 ppm. Tidal volume (mean, 1.51 ml/breath) and respiratory frequency (mean, 132 breaths/min) were not influenced by exposure concentration. Experimentally determined, steady-state blood levels of VDF, obtained by gas chromatography-head space analysis of samples from rats with indwelling jugular cannulas, increased linearly with increasing exposure concentration up to 16,000 ppm. VDF tissue/air partition coefficients were determined experimentally to be 0.07, 0.18, 0.8, 1.0, and 0.29 for water, blood, liver, fat, and muscle, respectively. These values and calculated constants for total body elimination of VDF, Km and Vmax were incorporated into the physiological model. Model predictions agreed with the experimentally determined data. Time to reach steady-state blood levels of VDF was less than 15 min for all concentrations. After cessation of exposure, blood levels of VDF decreased to 10% of steady-state levels by 1 hr. Simulation of the metabolism of VDF indicated that although blood levels of VDF increased linearly with increasing concentration the amount of VDF metabolized per 6-hr exposure period approached a maximum at about 2000 ppm VDF.

Animals↗

PubMed1988

Evaluation of a real-time aerosol monitor (RAM-S) for inhalation studies.

Measurement of the aerosol concentration in inhalation toxicology studies is generally done by gravimetric and/or chemical analysis of filter samples taken over a known period of time at a fixed sampling flow rate. The value obtained represents the time-averaged concentration in an exposure chamber. However, the filter method does not provide information as to the stability of aerosol concentration in "real-time" nor as to the time required for the aerosol concentration to reach the target value during the start-up of exposures. In order to accomplish evaluation of aerosol stability and chamber rise and fall times, a direct measurement device is required. An available real-time aerosol monitor (RAM-S, GCA Corp., Bedford, MA) is a photometer which collects scattered light from an aerosol cloud at a 70 +/- 25 degrees angle. The output signal is 0 to 10 volt with three ranges corresponding to maximum aerosol concentrations of 200, 20, and 2 mg/m3. The performance of the RAM-S was evaluated in inhalation studies involving nickel sulfate hexahydrate, nickel oxide, nickel subsulfide, and azodicarbonamide. Several RAM-S units were calibrated by obtaining both filter samples and voltage readings of a RAM-S simultaneously. Results indicated that the response of the RAM-S instruments was linear. However, the voltage output per given aerosol concentration was different for each compound used. Furthermore, there was interinstrument variability in the voltage response to aerosol concentration of a given compound. At concentrations higher than 100 mg/m3, modification of the flow system in the RAM-S was made to increase the sheath air around the optical system and also to dilute the aerosol concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1988

Lung, liver, and kidney as potential target organs after exposure to 1-nitropyrene, as determined by the time course of covalently bound material.

Previous studies in which rats were exposed to [14C]-1-nitropyrene by inhalation indicated that lung, liver, and kidney consistently accumulated the highest concentrations of 14C after exposure. The purpose of the study described here was to determine the extent to which this 14C was covalently bound to macromolecules. Male F344/N rats were exposed to 360 ng [14C]-1-nitropyrene/l air for 1 h resulting in an average of 2.2 micrograms 1-nitropyrene deposited per rat. An additional group of rats was given 4.2 micrograms [14C]-1-nitropyrene by gavage. Total 14C in 23 tissues was determined for up to 96 h after inhalation exposure and up to 30 d after gavage. Lung, liver, and kidney contained the highest concentrations of 14C. Samples of these tissues were exhaustively extracted to determine the amount of radioactivity covalently bound to macromolecules. Regardless of the route of administration, the kidneys had the highest concentrations of covalently bound 14C. At 96 h after exposure kidneys had overall mean concentrations of 2.7 pmol bound/g tissue.micrograms nitropyrene administered. The overall mean concentration in liver was 0.18 pmol bound/g.microgram and the overall mean concentration in lung was 0.06 pmol/g.microgram at 96 h after exposure. Covalently bound material persisted in kidneys for the duration of the study (30 d postexposure). The calculated half-time for removal of bound 14C from kidneys was 150 d. These data suggest that kidney should be considered as one of the organs at risk after exposure to nitropyrene by inhalation or ingestion.

Administration, Inhalation↗

PubMed1987

The fate of inhaled azodicarbonamide in rats.

Azodicarbonamide (ADA) is widely used as a blowing agent in the manufacture of expanded foam plastics, as an aging and bleaching agent in flour, and as a bread dough conditioner. Human exposures have been reported during manufacture as well as during use. Groups of male F344/N rats were administered ADA by gavage, by intratracheal instillation, and by inhalation exposure to determine the disposition and modes of excretion of ADA and its metabolites. At 72 hr following gavage, 30% of the administered ADA was absorbed whereas following intratracheal instillation, absorption was 90%. Comparison between groups of rats exposed by inhalation to ADA to achieve body burdens of 24 or 1230 micrograms showed no significant differences in modes or rates of excretion of [14C]ADA equivalents. ADA was readily converted to biurea under physiological conditions and biurea was the only 14C-labeled compound present in excreta. [14C]ADA equivalents were present in all examined tissues immediately after inhalation exposure, and clearance half-times on the order of 1 day were evident for all tissues investigated. Storage depots for [14C]ADA equivalents were not observed. The rate of buildup of [14C]ADA equivalents in blood was linearly related to the lung content as measured from rats withdrawn at selected times during a 6-hr inhalation exposure at an aerosol concentration of 25 micrograms ADA/liter. In a study extending 102 days after exposure, retention of [14C]ADA equivalents in tissues was described by a two-component negative exponential function. The results from this study indicate that upon inhalation, ADA is rapidly converted to biurea and that biurea is then eliminated rapidly from all tissues with the majority of the elimination via the urine.

Administration, Inhalation↗

PubMed1987

Lung clearance and disposition of 63Ni in F344/N rats after intratracheal instillation of nickel sulfate solutions.

Epidemiology studies have indicated increased incidences of respiratory tract and renal cancer in nickel refinery workers. Since the most likely route of exposure to nickel in the workplace is via the respiratory tract, the objectives of the experiments described here were to determine the retention pattern of Ni in the lungs, identify the target organs for Ni absorbed from the respiratory tract, and determine rates for excretion of Ni. Male and female F344 rats were given 17, 190, or 1800 nmoles Ni (as a nickel sulfate solution) in saline, containing trace amounts of 63Ni, by intratracheal instillation. Urine and feces were collected, and rats were necropsied at predetermined times up to 96 hr after instillation. At all times, lungs, trachea, larynx, kidney, and urinary bladder contained the highest concentrations of Ni as determined by liquid scintillation spectrometry. Urine was the major route for excretion of Ni, accounting for 50% of the dose after instillation of 17 or 190 nmoles Ni, and 80% of the dose after instillation of 1800 nmoles Ni. The half-time for urinary excretion of Ni increased from 4.6 hr at the highest dose to 23 hr at the lowest dose used. Fecal excretion accounted for 30% (17- and 190-nmole doses) or 13% (1800 nmoles) of the initial dose. Of the Ni remaining in the body at the end of 96 hr, over 50% was in the lungs. The long-term half-time for clearance of Ni from the lungs ranged from 21 hr at the highest dose to 36 hr at the lowest dose instilled. As the amount of instilled Ni decreased, the fraction of the instilled Ni associated with the long-term clearance component increased (from 24% at the highest dose to 40% at the lowest dose). Results suggest that, over the range of doses studied, both pulmonary clearance of Ni and routes for excretion of Ni were dependent on the instilled dose.

Animals↗

PubMed1987

Acute inhalation exposure of azodicarbonamide in the guinea pig.

Humans have been exposed to azodicarbonamide (ADA) by inhalation where bulk quantities of ADA are handled in the workplace. Responses of some workers have led to concern for the potential irritant and sensitizing properties of inhaled ADA. This study examined the effects of inhaling ADA on lung structure and function of guinea pigs during and after an acute exposure. Groups of 20 guinea pigs were exposed to each of 3 concentrations of ADA (19, 58, and 97 mg/m3), plus air as a control, for 1 hr. Pulmonary function was measured before exposure (baseline), during exposure, immediately after exposure and 24 hr after exposure. Dynamic compliance (Cdyn), total pulmonary resistance (RL), tidal volume (VT), respiratory frequency and minute volume were measured. In addition, gross necropsies and histological examinations of respiratory tract tissues were done either immediately following the exposure or 24 hr after exposure. There were no effects of ADA exposure on gross necropsy, histology, Cdyn, or RL. Some significant, concentration-related decreases in VT, respiratory frequency and minute volume were seen. The magnitudes of these changes were small: the largest change was seen in minute volume, amounting to a 24% decrease in the high concentration group. Inhalation exposure of guinea pigs to ADA at concentrations of up to 97 mg/m3 resulted in minor changes in pulmonary function without any changes in lung histology.

Air Pollutants↗

PubMed1986

Deposition, metabolism, and excretion of 1-[14C]nitropyrene and 1-[14C]nitropyrene coated on diesel exhaust particles as influenced by exposure concentration.

Nitrated polycyclic aromatic hydrocarbons (nitro-PAH) have been detected in the environment, originating from sources such as diesel exhaust emissions and coal combustion fly ash. 1-Nitropyrene (NP) is a predominant mutagenic and carcinogenic nitro-PAH found in diesel exhaust emissions. Since inhalation of NP is a likely route of exposure in humans, it is important to determine the biological fate of inhaled NP both in its pure form and associated with particles. The purpose of this study was to determine the disposition of NP aerosols inhaled by rats. The studies described in this paper were designed to determine the deposition of [14C]NP over a range of exposure concentrations, identify the pathways and half-times for excretion of absorbed NP, and determine the distribution of inhaled NP and metabolites in tissues. Male F344 rats were exposed nose only to various concentrations of NP and NP coated on diesel exhaust particles (50-1100 ng/liter). The results indicate that, over the range of concentrations tested, pathways for excretion of [14C]NP equivalents in urine and feces were independent of the exposure concentration of NP, whether in its pure form or associated with diesel exhaust particles. In all cases, fecal excretion was the major route of elimination of [14C]NP equivalents, with about 2 times more excreted by this route than by urine. The fractional deposition of [14C]NP in the respiratory tract did not appear to be dependent on exposure concentration. Half-times for elimination of 14C in urine and feces were about 15 to 20 hr. In all exposures, 14C was widely distributed in the tissues examined. Analysis of the tissues for NP and its metabolites indicated that within 1 hr after exposure, greater than 90% of the 14C was NP metabolites. Lungs of rats exposed to [14C]NP coated on diesel exhaust particles contained nearly 5 times more 14C than lungs from rats exposed to pure aerosols of [14C]NP (148 vs 29 pmol/g lung) within 1 hr after exposure. This difference was increased to 80-fold at 94 hr after exposure (80 vs 1 pmol/g lung). Long-term clearance half-times of 14C from various tissues were similar. The results demonstrate that particle association of NP significantly alters the biological fate of inhaled NP.

Aerosols↗

PubMed1986

Disposition and metabolism of 14C-solvent yellow and solvent green aerosols after inhalation.

Solvent yellow (2-(2'-quinolinyl)-1,3-indandione) and solvent green (1,4-di-p-toluidinoanthraquinone) are components of colored smoke munitions and may become airborne and be inhaled by workers during the manufacture of the munitions. Little is known about the disposition of either dye after inhalation. To obtain this information, we exposed male F344/N rats to 14C-solvent yellow aerosols (160 nmol solvent yellow/liter air) or a mixture of 14C-solvent yellow and unlabeled solvent green (340 nmol solvent yellow and 370 nmol solvent green/liter air) for 60 min. After either exposure, solvent yellow was rapidly cleared from the respiratory tract, with a t1/2 of 2-3 hr. Solvent green was retained in the lungs with a minimum estimated t1/2 for clearance of 22 days. Solvent green was not detected in other tissues during the 70-hr postexposure period. After either exposure, high-pressure liquid chromatography analysis of tissues extracts indicated that 40 to 75% of the 14C in liver and kidney consisted of solvent yellow metabolites. Greater than 90% of the 14C in the lungs was unmetabolized solvent yellow. The major pathway for excretion of solvent yellow and solvent yellow metabolites was the feces (74% of the initial body burden); the t1/2 for excretion was 14 hr. Urinary 14C accounted for 14% of the initial body burden and the t1/2 for excretion was 10 hr. Over 90% of the 14C excreted in the urine was solvent yellow metabolites. Very little solvent yellow (2%) was metabolized to 14CO2. By 72 hr after exposure, only 10% of the initial 14C deposited remained in the body.

Aerosols↗

PubMed1986

Disposition and metabolism of free and particle-associated nitropyrenes after inhalation.

The objective of this project was to determine the biological fate of 1-nitropyrene (NP) aerosols in rats. The results from these studies indicate that, over the range of aerosol concentrations tested, pathways for excretion of 14C-NP equivalents in urine and feces were independent of the exposure concentration of NP, either in its pure form or associated with diesel exhaust particles. In all cases, fecal excretion was the major route of elimination of 14C-NP equivalents, with about 2 times more excreted by this route than by urine. Fractional respiratory tract deposition of 14C-NP did not appear to be dependent on exposure concentration. In most cases, half-times for elimination of 14C in urine and feces were about 15 to 20 hours. In all exposures, 14C was widely distributed in the tissues examined. Analysis of the tissues for NP and metabolites indicated that within 1 hour after exposure greater than 90% of the 14C was associated with NP metabolites. Lungs of rats exposed to 14C-NP coated on diesel exhaust particles contained nearly 5 times more 14C than lungs from rats exposed to pure aerosols of 14C-NP (148 vs 29 pmole g lung) within 1 hour after exposure. This difference was increased to 80-fold at 94 hours after exposure (80 vs 1 pmole g lung). Long-term clearance half-times of 14C from various tissues were similar, with values of about 30 to 50 hours measured. Pre-exposure to diesel exhaust prior to exposure to NP may result in increased retention of a small fraction of the NP. Equilibrium organ concentrations predicted for tissues following continuous exposure to NP suggest that both low inhaled concentrations of NP and association of NP with insoluble diesel particles can result in an increased retention of NP in the lungs above what might be predicted using data obtained from animal studies using high concentrations of pure NP. The liver and kidneys are among the other organs predicted to contain the highest amounts of NP.

Administration, Inhalation↗

PubMed1986

Disposition and metabolism of [14C]dibenzo[c,g]carbazole aerosols in rats after inhalation.

Dibenzo[c,g]carbazole (DBC) is a nitrogen-containing polycyclic aromatic hydrocarbon that has been detected in tobacco tars, industrial oils, and diesel engine exhaust fumes. DBC is carcinogenic in respiratory tract tissue of hamsters and in lungs, kidneys, and livers of mice. The purpose of this research was to determine the respiratory tract deposition, distribution in tissues, metabolism, and excretion of DBC in rats after inhalation. Rats were exposed nose-only to 1.1 or 13 micrograms [14C]DBC/liter air for 60 min. Activity median aerodynamic diameters for the two concentrations of DBC ranged from 0.7 to 0.8 micron. Urine, feces, and selected tissues were collected for various times after exposure. The fractional deposition for the 1.1 and 13 micrograms/liter exposure concentrations was similar, 13 and 16%, respectively. The dominant route of excretion of 14C following exposure to either concentration of DBC was the feces, accounting for approximately 95% of the total 14C eliminated. Half-time for fecal excretion was 20 +/- 6 hr (means +/- SE). Gastrointestinal absorption of [14C]DBC was 43%. Radioactivity was widely distributed to all tissues examined, with the respiratory tract (lung, trachea, larynx, and nasal turbinates), upper gastrointestinal tract (stomach and small intestine), the liver, and the adrenals containing the highest concentrations of [14C]DBC equivalents within 1 hr after exposure. At both concentrations of DBC tested, clearance of 14C from tissues was rapid, with approximately 60 to 98% of the initial tissue burden being cleared with half-times ranging from 1 to 16 hr. The remaining 2 to 40% in the tissues was cleared with half-times that ranged from 1.5 to 14 days. Several metabolites were detected in the urine and feces, none of which appeared to be either glucuronide or sulfate conjugates. Small quantities of [14C]DBC were detected in the urine, although quantities were less than 1% of the initial respiratory tract burden of [14C]DBC. The results from this research indicate that DBC was rapidly absorbed from the lungs and translocated to many tissues. Prior to elimination, primarily in the feces, DBC was extensively metabolized. There appeared to be no effect of exposure concentration on the toxicokinetics of inhaled DBC.

Aerosols↗

PubMed1985

Biliary excretion and enterohepatic circulation of 1-nitropyrene metabolites in Fischer-344 rats.

1-Nitropyrene (1-NP), present in diesel engine emissions, is a potent mutagen to bacteria, such as those found in mammalian intestinal tract, which contain nitroreductase enzymes. The purposes of this study were to determine the importance of bile as a route of excretion of 1-NP metabolites and to determine if reabsorption of biliary metabolites required the presence of intestinal bacteria. The bile ducts of male Fischer-344 rats were cannulated, 0.3 or 1.2 mumoles [3H]1-NP was given i.v., and bile, urine, and feces were collected for 24 hr. Biliary excretion accounted for 70 (80%) or 170 (60%) nmoles of [3H]1-NP after the low and high dose, respectively, with half-times for excretion of 1.7 hr +/- 0.3 (+/- S.E.M.) and 3.4 hr +/- 1.6 (+/- S.E.M.). Excretion of [3H]1-NP equivalents in the urine was linearly related to dose, with 6 or 16 nmoles (8%) excreted in 24 hr. At the low dose, more radioactivity appeared in the urine in control rats compared to bile-duct cannulated rats, suggesting that reabsorption of 1-NP metabolites occurred. Pretreatment of rats with orally administered antibiotics prior to i.v. injection of 0.3 mumole [3H]1-NP decreased radioactivity excreted in urine compared to untreated controls, suggesting that intestinal microorganisms may alter the biliary metabolites of 1-NP to facilitate reabsorption. Pretreatment of rats with buthionine sulfoximine, a glutathione depletor, decreased the excretion of certain biliary metabolites, suggesting that they were mercapturic acids of 1-NP metabolites. In summary, the results of these studies indicate that bile was an important route of excretion of nitropyrene metabolites. A portion of the excreted metabolites was reabsorbed from the gut, and this reabsorption required the presence of gut microorganisms.

Animals↗

PubMed1985

Pulmonary retention of [14C]benzo[a]pyrene in rats as influenced by the amount instilled.

Studies on the pulmonary retention of benzo[a]pyrene after inhalation have shown that clearance is biphasic, with one component clearing with a half-time greater than 1 day and another with a half-time less than 1 day. In the work reported here we demonstrated that the amount of benzo[a]pyrene instilled in the lungs can affect the rate at which the benzo[a]pyrene is cleared into the blood. Fischer-344 rats were given 16, 90 or 6400 ng of [14C]benzo[a]-pyrene/rat by intratracheal instillation. Rats were sacrificed at various times up to 7 days after instillation. Individual lung lobes and trachea were removed, digested, and analyzed by liquid scintillation spectrometry. At 24 h after instillation the amount of 14C covalently bound to lung macromolecules was determined in some rats. Benzo[a]pyrene equivalents remaining in the lungs was expressed as a percentage of the instilled dose as a function of time. A two-component negative exponential function was fit to the data. With increasing dose (16-6400 ng/rat), an increasing percent (89-99.76%) was cleared with a half-time less than 1 day and a decreasing percent (11.3-0.24%) was cleared with a half-time greater than 1 day, suggesting that the mechanism by which the slower clearances occurred had been saturated at higher doses. At 24 h after instillation, from 1 to 2 pmol of [14C]benzo[a]-pyrene equivalents/lung were covalently bound to lung macromolecules. There was no difference in the amount of covalently bound 14C over the range of instillation doses used, suggesting that a small amount of benzo[a]-pyrene equivalents was bound in the lungs regardless of the amount instilled. These results suggested that linear extrapolation from high dose studies to environmental concentrations might underestimate lung burdens of benzo[a]pyrene.

Animals↗