Biomedical subjects

M L Gargas

Publications and source records attributed to M L Gargas.

At least 55 records · Page 3Linked to original sources

PubMed1990

Dermal absorption of organic chemical vapors in rats and humans.

Quantitation of chemical vapor penetration through skin is necessary for assessment of health hazards involved in some occupational environments. Information on penetration of vapors through human skin is minimal because human exposures are not sanctioned. We have investigated the whole-body dermal penetration of styrene, xylene, toluene, perchloroethylene, benzene, halothane, hexane, and isoflurane in rats and compared the permeability constants with available human studies on vapor penetration. Rats with closely clipped fur were exposed to organic chemical vapors (3000 to 60,000 ppm) while breathing fresh air through a latex mask. Blood concentrations taken during the 4-hr exposures were determined by sampling through indwelling jugular cannulas. A physiologically based pharmacokinetic model was used to predict permeability constants consistent with the experimental blood concentrations. Permeability constants (cm/hr) were estimated by a least-square optimization and ranged from 1.75 cm/hr for styrene to 0.03 cm/hr for isoflurane. Rat permeability constants were uniformly two to four times greater when compared to the human constants which were calculated from the literature. These results indicate that organic vapor permeability constants in rats are a conservative estimate of organic vapor permeability constants in humans and that the consistent differences in permeability constants between these two species may be due to physiological differences in the skin.

Animals↗

PubMed1990

In vivo metabolic interactions of benzene and toluene.

The metabolic interactions of benzene and toluene co-exposure were investigated in male Fischer rats. A closed recirculated exposure system was used to obtain inhalation uptake curves for individual chemicals as well as for a mixture of the two compounds. Pharmacokinetic parameters for benzene and toluene individually were determined in previous experimental studies. These values were incorporated into a physiologically based pharmacokinetic model which simulated the inhalation uptake process for both chemicals simultaneously. An optimal fit to the uptake curves for simultaneous exposure was obtained by adjusting the metabolic interaction terms for each chemical. Mutual suppression of metabolism was apparent. Toluene more effectively inhibited benzene metabolism than the reverse. This simulation approach for analyzing gas uptake data provided a method to determine the metabolic interactions occurring upon inhalation exposure to two different chemicals. Such analyses will prove useful in improving predictive toxicokinetic models.

Animals↗

PubMed1989

Determining kinetic constants of chlorinated ethane metabolism in the rat from rates of exhalation.

The kinetic constants of chemical metabolism are used to develop physiologically based pharmacokinetic (PB-PK) models which predict the time course distribution of volatile chemicals in mammalian systems. Gas uptake techniques have proved useful in determining kinetic constants for a variety of volatile compounds including the following chloroethanes: ethyl chloride, 1,1-dichloroethane, 1,2-dichloroethane, and 1,1,1-trichloroethane. Unfortunately, low vapor pressure materials and those exhibiting increasing blood and tissue solubilities could not be examined by gas uptake methods. An alternative gas phase method was developed in which rats were first exposed by constant concentration inhalation for 6 hr and then placed in 2.5-liter exhaled breath chambers with fresh air flow and chamber effluent was serially analyzed for test chemical. The resulting elimination behavior was extremely sensitive to metabolism, and kinetic constants for chemical metabolism were estimated by simulation with a PB-PK model containing equations that accurately described the experimental conditions. Optimized maximum metabolic rates (Vmax) were determined for 1,1,2-trichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane, and hexachloroethane with resulting values of 7.69, 6.39, 12.9, 9.71, and 1.97 mg/kg/hr, respectively. With several of these test chemicals the PB-PK modeling identified fur adsorption of chemical as significantly contributing to the exhalation chamber concentration time course after whole body exposure.

Animals↗

PubMed1989

Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues.

Partition coefficients are required for developing physiologically based pharmacokinetic models used to assess the uptake, distribution, tabolism, and elimination of volatile chemicals in mammals. A gas-phase vial equilibration technique is presented for determining the liquid:air and tissue:air partition coefficients for low-molecular-weight volatile chemicals. This technique was developed from two previously described medium:air methods, relied solely on measurement of chemical concentration in the gas phase, and, compared to earlier work, extends the range of chemicals and tissues examined. Partition coefficients were determined with 0.9% saline, olive oil, and blood, liver, muscle, and fat tissues from rats for 55 compounds. Human blood:air coefficients were determined for 36 compounds and several blood:air values were also determined in the mouse and for one compound in the hamster. An approach is described for predicting the tissue solubilities of untested compounds based on oil:air and saline:air coefficients using regression analyses. A similar approach is used to model fat:air coefficients in terms of oil:air values and to model human blood: air coefficients in terms of rat blood:air coefficients.

Adipose Tissue↗

PubMed1988

Pharmacokinetics of tetrachloroethylene.

A physiological pharmacokinetic model is developed to describe the pharmacokinetics of tetrachloroethylene (PCE) in mice, rats, and humans. The body is divided into four tissue compartments (vessel-rich, muscle, slowly perfused fat, and liver) connected by the arterial and venous blood flow pathways. The physiological parameters of the model are blood flow rates, cardiac output, tissue volumes, ventilation rate, and tissue/air and blood/air partition coefficients. Metabolism is assumed to occur only in the liver compartment and is described by a combination of a linear metabolic component and a Michaelis-Menten component. The metabolic parameters for PCE were determined by fitting model predictions to species-specific empirical data. Comparison of model results with independent empirical data on inhalation and gavage exposures in mice, rats, and humans demonstrates that the physiological pharmacokinetic model can be used to determine the time course of PCE in these species. We show that human metabolic parameters can be predicted by scaling rat metabolic parameters as a function of body weight, whereas scaling of the metabolic parameters of mice overestimates human metabolism.

Animals↗

PubMed1988

A physiologically based pharmacokinetic model for inhaled carbon tetrachloride.

D.J. Paustenbach et al. (1986, Fundam. Appl. Toxicol. 6, 484-497) have described the pharmacokinetics of inhaled, radiolabeled carbon tetrachloride (14CCl4) in male Sprague-Dawley rats exposed for 8 or 11.5 hr/day for 1- or 2-week periods. These studies provided time-course information for exhaled 14CCl4, the exhaled 14CO2 metabolite, and 14C radioactivity eliminated in the feces and urine. A physiologically based pharmacokinetic (PB-PK) model which incorporated partition characteristics of CCl4 (blood:air and tissue:blood partition coefficients), anatomical and physiological parameters of the test species (body weight, organ weights, ventilation rates, blood flows, etc.), and biochemical constants (Vmax and Km) for CCl4 metabolism was developed to describe these results. The PB-PK model accurately predicted the behavior of CCl4 and its metabolites, both the exhaled CCl4 and 14CO2 and the elimination of radioactivity in urine and feces. The metabolism of CCl4, determined by gas uptake studies, was adequately described by a single saturable pathway. Metabolites were partitioned in the model to three compartments; the amounts to be excreted in the breath (as 14CO2), urine, and feces. Of total CCl4 metabolism, 6.5, 9.5, and 84.0% were formed via the degradative pathways leading to CO2, urinary, and fecal metabolites, respectively. The simplest kinetic explanation of the metabolite time course is that 4% of the initially metabolized CCl4 is directly converted to CO2 (probably via a chloroform intermediate) and the remainder of metabolized CCl4 binds to biological substrates. These adducts appear to be slowly degraded with an average half-life of 24 hr. The breakdown products subsequently appear in the feces and urine (the rate constant for elimination by these two routes is similar) and a small portion is converted all the way to CO2. The PB-PK model successfully described the elimination by all four routes for all four exposure scenarios using a single set of parameters. Vmax and Km were, respectively, 0.65 mg/kg/hr and 0.25 mg/liter. There was no evidence for loss of Vmax with repeated exposure, as would be expected if there was enzyme destruction at these concentrations of CCl4. The model was scaled-up to predict the expected behavior of parent CCl4 in monkeys and humans and the resulting simulations compared very favorably with data collected by McCollister et al. (1951) and Stewart et al. (1961). On the basis of this model and the published data on the rat at 100 ppm about 60% of the inhaled CCl4 is metabolized and the resulting blood levels are already in excess of saturation for the metabolizing enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1988

Modeling the tissue solubilities and metabolic rate constant (Vmax) of halogenated methanes, ethanes, and ethylenes.

Experimental solvent:air and tissue:air partition coefficients for 25 halogenated methanes, ethanes, and ethylenes in saline solution; olive oil; and rat blood, muscle, liver, and fat tissues have been examined using theoretical molecular modeling techniques. The metabolic rate constant, Vmax, was also investigated by these techniques for 19 chlorinated compounds in this group. Two graph theoretical approaches (the distance method of Wiener and the connectivity index method of Randic, Kier, and Hall) and an approach utilizing ad hoc molecular descriptors were employed. Satisfactory regression models for solubility were obtained with both the Randic-Kier-Hall approach and the ad hoc descriptors approach. Fluorine substituents decrease tissue solubilities, whereas both clorine and bromine substituents increase tissue solubilities, with the relative influence being Cl less than Br. Tissue solubilities can also be represented conveniently in terms of contributions from oil and saline solubilities, a procedure reinforced by factor analysis of the data. Equations derived by these methods adequately estimated the solubilities for eight additional compounds. No approach could successfully model Vmax for all 19 compounds, but a subset of 16 compounds was modeled using the connectivity indices. The equation is limited in its use but indicated future modeling directions for Vmax.

Adipose Tissue↗

PubMed1987

Quantitative evaluation of the metabolic interactions between trichloroethylene and 1,1-dichloroethylene in vivo using gas uptake methods.

Gas uptake simulation methods were used to determine kinetic constants for trichloroethylene (TCE) and 1,1-dichloroethylene (1,1-DCE) metabolism in vivo in male Fischer 344 rats. Both are metabolized by single, saturable, oxidative pathways with high-affinity substrate binding. The allometrically scaled maximum velocities (Vmaxc) for TCE and 1,1-DCE were, respectively, 11 and 7.5 mg/hr (i.e., 84 and 77 mumol/hr). Gas uptake studies were also conducted with three mixed atmosphere exposures with the following initial concentrations in parts per million: 500 (1,1-DCE):2000 (TCE); 500 (1,1-DCE):500 (TCE); and 2000 (1,1-DCE):500 (TCE). Mixture uptake curves were described by a system of equations in which a full physiologically based pharmacokinetic (PB-PK) model was provided for each chemical and each was regarded as an inhibitor of the other's metabolism. A generic model was developed to accommodate multiple mechanisms of inhibitory interactions, i.e., competitive, noncompetitive, or uncompetitive. An excellent correspondence was obtained between predicted and observed behavior when the inhibition was assumed to be purely competitive with binding constants for TCE and 1,1-DCE set to 0.25 and 0.10 mg/liter, respectively; i.e., in vivo 1,1-DCE is a slightly better substrate for microsomal oxidation than is TCE. The PB-PK model which was successful in describing the mixture data was used to predict conditions under which 1,1-DCE hepatotoxicity would be expected in coexposure to constant concentration atmospheres of these two chloroethylenes. These predictions were compared with data on the increases in plasma liver enzymes resulting from exposures to either 1,1-DCE alone or to 1,1-DCE in combination with TCE.

Animals↗

PubMed1987

Physiologically based pharmacokinetics and the risk assessment process for methylene chloride.

Methylene chloride (dichloromethane, DCM) is metabolized by two pathways: one dependent on oxidation by mixed function oxidases (MFO) and the other dependent on glutathione S-transferases (GST). A physiologically based pharmacokinetic (PB-PK) model based on knowledge of these pathways was used to describe the metabolism of DCM in four mammalian species (mouse, rat, hamster, and humans). Kinetic constants for the model were derived from in vivo experiments or the literature. The model was constructed to distinguish contributions from the two pathways of metabolism in lung and liver tissue, and to permit extrapolation from rodents to humans. Model validation was conducted by comparing predicted blood concentration time-course data in rats, mice, and humans with experimental data from these species. The tumor incidence in two chronic studies of DCM toxicity in mice was correlated with various measures of target tissue dose calculated with the PB-PK model. Tumor incidence correlated well with tissue AUC (area under the concentration/time curve) and amount of DCM metabolized by the GST pathway. However, tumor incidence did not correlate with the amount of DCM metabolized by the MFO pathway. Because of its low chemical reactivity, DCM is unlikely to be directly involved in carcinogenesis. Consequently, metabolism of DCM by GST appears to be important in carcinogenesis. The PB-PK model was used to estimate target doses of presumed toxic chemical species in humans exposed to DCM by inhalation or by drinking water. Target tissue doses in humans exposed to low concentrations of DCM are 140- to 170-fold lower (inhalation) or 50- to 210-fold lower (drinking water) than would be expected from the linear extrapolation and body surface area factors which have been used in conventional risk assessment methods (D. V. Singh, H. L. Spitzer, and P. D. White (1985). Addendum to the Health Assessment Document for Dichloromethane (Methylene Chloride). EPA/600/8-82/004F). The PB-BK analysis thus suggests that conventional risk analyses greatly overestimate the risk in humans exposed to low concentrations of DCM. PB-PK considerations provide a scientific basis for risk assessment, improve experimental design in chronic studies, and structure collection of quantitative metabolic constants required for risk assessment.

Animals↗

PubMed1986

Metabolism of inhaled dihalomethanes in vivo: differentiation of kinetic constants for two independent pathways.

Dihalomethanes are metabolized by two major pathways: an oxidative, cytochrome P-450-mediated pathway that has been previously thought to yield only CO, and a glutathione (GSH)-dependent one that yields CO2. Both give 2 mol of halide ion. We studied the kinetic properties of the two pathways in vivo by exposing male rats to various inhaled concentrations of CH2Cl2,CH2F2, CH2FCl, CH2BrCl, and CH2Br2 and determining end-exposure carboxyhemoglobin (HbCO) and plasma bromide (where appropriate). Closed atmosphere gas uptake studies were employed for CH2F2, CH2FCl, CH2Cl2, and CH2BrCl metabolism. A physiologically based kinetic model was used to determine kinetic constants based on gas uptake or plasma bromide data and these constants were used to predict HbCO concentrations. Oxidation was high affinity, low capacity. The maximum metabolic rates for this pathway with CH2Br2, CH2BrCl, and CH2Cl2 were, respectively, 72, 54, and 47 mumol metabolized/kg/hr. CH2FCl did not undergo significant oxidative metabolism and appears more like CH3C1 than a dihalomethane in its metabolic reactivity. The GSH pathway was low affinity, but high capacity and could be described as a single first-order process at all accessible exposure concentrations. The rate constant for this first-order GSH-dependent pathway was related as CH2BrCl greater than CH2Cl2 congruent to CH2FCl greater than CH2Br2 greater than CH2F2. Presumably bromide is a preferred leaving group but steric hindrance in the initial reaction with GSH is important with CH2Br2. We also studied the effects of pyrazole (which inhibits microsomal oxidation) and 2,3-epoxypropanol (which depletes GSH) on dihalomethane metabolism. Pyrazole abolished CO production from CH2Br2, CH2BrCl, and CH2Cl2. GSH depletion did not change the yield of halide ion from the high-affinity pathway; it did increase the steady-state HbCO concentrations with CH2Cl2 and CH2ClBr, but not with CH2Br2. The putative formyl chloride (FC) intermediate from CH2Cl2 or CH2BrCl appears to have a longer life than the formyl bromide from CH2Br2 and a significant portion of the FC (congruent to 20-30%) may react with other cellular nucleophiles instead of spontaneously decomposing to CO. This portion of the oxidative pathway probably yields CO2.

1-Propanol↗

PubMed1986

A physiologically based simulation approach for determining metabolic constants from gas uptake data.

In vivo metabolic constants were determined in male Fischer rats for five chemicals: 1,1-dichloroethylene (1,1-DCE), diethyl ether (DE), bromochloromethane (BCM), methyl chloroform (MC), and carbon tetrachloride (CCl4). A closed recirculated exposure system was used to collect a series of uptake curves for each chemical at a range of initial concentrations. The shapes of these curves were a function of the tissue partition coefficients and the kinetic characteristics of the metabolism of these chemicals. Tissue:air partition coefficients were experimentally determined for each chemical and incorporated into a physiological kinetic model which was then used to simulate the uptake process. An optimal fit of the family of uptake curves for each chemical was obtained by adjusting the biochemical constants for metabolism of the chemical. Metabolism of both 1,1-DCE and CCl4 was represented by a single saturable process while MC required only a first-order pathway. BCM and DE exhibited a combination of both a saturable and a first-order process. Pyrazole, which blocks oxidative microsomal metabolism, inhibited the saturable pathways of 1,1-DCE, BCM, DE, and CCl4 metabolism and abolished the first-order pathway for MC. The maximum velocity of metabolism for the saturable pathway with 1,1-DCE, BCM, DE, and CCl4 for a 225-g rat was 27.2, 19.9, 26.1, and 0.92 mol/hr, respectively. The simulation approach for analyzing gas uptake data distinguishes between single and multiple metabolic pathways and provides kinetic constants that can be used in predictive toxicokinetic models for describing constant concentration inhalation exposure as well as exposures by other routes of administration.

Animals↗

PubMed1984

Inhalation pharmacokinetics: evaluating systemic extraction, total in vivo metabolism, and the time course of enzyme induction for inhaled styrene in rats based on arterial blood:inhaled air concentration ratios.

A method is described for evaluating systemic extraction of soluble vapors during inhalation exposures. The physiological basis of the method is the inability to achieve complete equilibrium of vapor between arterial blood and inhaled air whenever there is substantial extraction of the soluble vapor during a single pass through the systemic circulation. The technique was applied to estimate styrene extraction ratios at the end of 6-hr exposures in male rats exposed to various concentrations of inhaled styrene. From extraction ratios and several physiological constants, metabolic constants were evaluated for styrene metabolism in vivo. In naive rats, the maximum velocity of metabolism was 10.0 mg/kg/hr, and Km was of the order of 0.2 mg/liter. Pretreatment with pyrazole (320 mg/kg, 1/2 hr before exposure) essentially abolished in vivo styrene metabolism, while pretreatment with phenobarbital (80 mg/kg/day for the 4 days before styrene exposure) increased Vmax about sixfold. Prior exposure to styrene (1000 ppm for 6 hr/day on each of 4 days before experimentation) increased Vmax by a factor of 2. Significant induction of styrene metabolism in vivo was observed in 24-hr continuous exposure to 400, 600, or 1200 ppm. A curve fitting routine was employed with a physiological model of styrene inhalation kinetics to estimate the dynamics of the induction process in the 24-hr exposures. At 400 ppm, induction began after a lag of 15.5 hr, had a half-life of 3.5 hr, and reached 2.7 times the Vmax in naive rats. At 600 ppm, it began after 10.6 hr, proceeded with a half-life of 2.2 hr, and increased Vmax by 3.4 times. At 1200 ppm, induction began earlier, 4.6 hr, and reached a greater value, 4.4 times Vmax, but had a half-life similar to that at 600 ppm. No induction occurred in 48-hr exposure to 200 ppm. Induction complicates kinetic modeling of continuous inhalation with soluble, well-metabolized vapors because it is time and concentration dependent. These methods should prove useful for studying the in vivo metabolism of other soluble, well-metabolized vapors and for examining the time course of induction of the metabolizing enzymes for these chemicals.

Air↗

PubMed1982