Biomedical subjects

H J Clewell

Publications and source records attributed to H J Clewell.

At least 19 recordsLinked to original sources

PubMed1991

Physiologically based pharmacokinetic modeling with dichloromethane, its metabolite, carbon monoxide, and blood carboxyhemoglobin in rats and humans.

Dichloromethane (methylene chloride, DCM) and other dihalomethanes are metabolized to carbon monoxide (CO) which reversibly binds hemoglobin and is eliminated by exhalation. We have developed a physiologically based pharmacokinetic (PB-PK) model which describes the kinetics of CO, carboxyhemoglobin (HbCO), and parent dihalomethane, and have applied this model to examine the inhalation kinetics of CO and of DCM in rats and humans. The portion of the model describing CO and HbCO kinetics was adapted from the Coburn-Forster-Kane equation, after modification to include production of CO by DCM oxidation. DCM kinetics and metabolism were described by a generic PB-PK model for volatile chemicals (RAMSEY AND ANDERSEN, Toxicol. Appl. Pharmacol. 73, 159-175, 1984). Physiological and biochemical constants for CO were first estimated by exposing rats to 200 ppm CO for 2 hr and examining the time course of HbCO after cessation of CO exposure. These CO inhalation studies provided estimates of CO diffusing capacity under free breathing and for the Haldane coefficient, the relative equilibrium distribution ratio for hemoglobin between CO and O2. The CO model was then coupled to a PB-PK model for DCM to predict HbCO time course behavior during and after DCM exposures in rats. By coupling the models it was possible to estimate the yield of CO from oxidation of DCM. In rats only about 0.7 mol of CO are produced from 1 mol of DCM during oxidation. The combined model adequately represented HbCO and DCM behavior following 4-hr exposures to 200 or 1000 ppm DCM, and HbCO behavior following 1/2-hr exposure to 5160 ppm DCM or 5000 ppm bromochloromethane. The rat PB-PK model was scaled to predict DCM, HbCO, and CO kinetics in humans exposed either to DCM or to CO. Three human data sets from the literature were examined: (1) inhalation of CO at 50, 100, 250, and 500 ppm; (2) seven 1/2-hr inhalation exposures to 50, 100, 250, and 500 ppm DCM; and (3) 2-hr inhalation exposures to 986 ppm DCM. An additional data set from human volunteers exposed to 100 or 350 ppm DCM for 6 hr is reported here for the first time. Endogenous CO production rates and the initial amount of CO in the blood compartment were varied in each study as necessary to give the baseline HbCO value, which varied from less than 0.5% to greater than 2% HbCO. The combined PB-PK model gave a good representation of the observed behavior in all four human studies.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗

PubMed1990

Physiologically based pharmacokinetic modeling of the lactating rat and nursing pup: a multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid.

A physiologically based pharmacokinetic (PB-PK) model was developed to describe trichloroethylene (TCE) kinetics in the lactating rat and nursing pup. The lactating dam was exposed to TCE either by inhalation or by ingestion in drinking water. The nursing pup's exposure to TCE was by ingestion of maternal milk containing TCE. The kinetics of trichloroacetic acid (TCA), a metabolite of TCE, were described in the lactating dam and developing pup by a hybrid one-compartment model. The lactating dam's exposure to TCA was from metabolism of TCE to TCA. The pup's exposure to TCA was from metabolism of TCE ingested in suckled milk and from direct ingestion of TCA in maternal milk. For the PB-PK model, partition coefficients (PCs) were determined by vial equilibration, and metabolic constants for TCE oxidation, by gas uptake methods. The blood/air and the fat/blood PCs for the dam were 13.1 and 34.2, and for the pup, 10.6 and 42.3, respectively. The milk/blood PC for the dam was 7.1. In lactating rats and rat pups (19-21 days old) the maximum velocities of oxidative metabolism were 9.26 +/- 0.073 and 12.94 +/- 0.107 mg/kg/hr. The plasma elimination rate constant (K = 0.063 +/- 0.004 hr-1) and apparent volume of distribution (Vd = 0.568 liter/kg) for TCA in the lactating dam were estimated from both intravenous dosing studies and an inhalation study with TCE. For the pup, K (0.014 +/- hr-1) and Vd (0.511 liter/kg) were estimated from a single 4-hr inhalation exposure with TCE. The dose-rate-dependent stoichiometric yield of TCA from oxidative metabolism of TCE in the lactating rat is 0.17 for a low-concentration inhalation exposure (27 ppm TCE) and 0.27 for an exposure above metabolic saturation (about 600 ppm TCE). For the pup, the stoichiometric yield of TCA is 0.12. With changing physiological values during lactation for compartmental volumes, blood flows, and milk yields obtained from the published literature and kinetic parameters and PCs determined by experimentation, a PB-PK model was constructed to predict maternal and pup concentrations of TCE and TCA. To test the fidelity of the PB-PK lactation model, a multiday inhalation exposure study was conducted from Days 3 to 14 of lactation and a drinking water study, from Days 3 to 21 of lactation. The inhalation exposure was 4 hr/day, 5 days/week, at 610 ppm. The TCE concentration in the drinking water was 333 micrograms/ml. Prediction compared favorably with limited data obtained at restricted time points during the period of lactation.

Animals↗

PubMed1990

Physiologically based pharmacokinetic and pharmacodynamic model for the inhibition of acetylcholinesterase by diisopropylfluorophosphate.

Organophosphate (OP) exposure can be lethal at high doses while lower doses may impair performance of critical tasks. The ability to predict such effects for realistic exposure scenarios would expedite OP risk assessment. To this end, a physiologically based model for diisopropylfluorophosphate (DFP) pharmacokinetics and acetylcholinesterase (AChE) inhibition was developed in mammals. DFP tissue:blood partition coefficients, rates of DFP hydrolysis by esterases, and DFP-esterase bimolecular inhibition rate constants were determined in rat tissue homogenates. Other model parameters were scaled for rats and mice using standard allometric relationships. These DFP-specific parameter values were used with the model to simulate expected in vivo pharmacokinetic data from mice and rats. Literature data were used for model validation. DFP concentrations in mouse plasma and brain were successfully simulated after a single iv injection (B.R. Martin, 1985, Toxicol. Appl. Pharmacol. 77, 275-284). AChE inhibition and AChE resynthesis data from this study were also simulated. Effects of repeated, subcutaneous DFP dosing on AChE activity in rat plasma and brain (H. Michalek, A. Meneguz, and G.M. Bisso, 1982, Arch. Toxicol., Suppl. 5, 116-119; M.E. Traina and L.A. Serpietri, 1984, Biochem. Pharmacol. 33, 645-653) were also simulated well, but the return of brain AChE activity to basal levels after cessation of repeated dosing was not as well described. The initial model structure returned brain AChE activity to the original level, while in the laboratory studies brain AChE never returned to basal levels, even at 35 days after the last dose. These data suggest modulation of AChE synthesis with prolonged DFP exposure. This study demonstrated the possibility of using a model based on mammalian physiology and biochemistry to simulate in vivo data on DFP pharmacokinetics and AChE inhibition. Scaling of the model between rats and mice was also successful. The approach holds promise for predictive simulation of organophosphate-mediated AChE inhibition in humans.

Animals↗

PubMed1990

A physiologically based toxicokinetic model for the uptake and disposition of waterborne organic chemicals in fish.

A physiologically based toxicokinetic model was developed to predict the uptake and disposition of waterborne organic chemicals in fish. The model consists of a set of mass-balance differential equations which describe the time course of chemical concentration within each of five tissue compartments: liver, kidney, fat, and richly perfused and poorly perfused tissue. Model compartmentalization and blood perfusion relationships were designed to reflect the physiology of fishes. Chemical uptake and elimination at the gills were modeled as countercurrent exchange processes, limited by the chemical capacity of blood and water flows. The model was evaluated by exposing rainbow trout (Oncorhynchus mykiss) to pentachloroethane (PCE) in water in fish respirometer-metabolism chambers. Exposure to 1500, 150, or 15 micrograms PCE/liter for 48 hr resulted in corresponding changes in the magnitude of blood concentrations without any change in uptake kinetics. The extraction efficiency for the chemical from water decreased throughout each exposure, declining from 65 to 20% in 48 hr. Extraction efficiency was close to 0% in fish exposed to PCE to near steady state (264 hr), suggesting that very little PCE was eliminated by metabolism or other extrabranchial routes. Parameterized for trout with physiological information from the literature and chemical partitioning estimates obtained in vitro, the model accurately predicted the accumulation of PCE in blood and tissues, and its extraction from inspired water. These results demonstrate the potential utility of this model for use in aquatic toxicology and environmental risk assessment.

Animals↗

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↗

PubMed1989

Physiologically based pharmacokinetic modeling of the pregnant rat: a multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid.

A physiologically based pharmacokinetic (PB-PK) model was developed to describe trichloroethylene (TCE) kinetics in the pregnant rat exposed to TCE by inhalation, by bolus gavage, or by oral ingestion in drinking water. The kinetics of trichloroacetic acid (TCA), an oxidative metabolite of TCE, were described by a classical one-compartment pharmacokinetic model. Among the required model parameters for TCE, partition coefficients (PCs) and kinetic constants for oxidation were determined by vial equilibration and gas uptake methods, respectively. The fat:blood PC was 33.9; the blood:air PC was 13.2; and the fetal tissue:fetal blood PC was 0.51. TCE was readily metabolized with high substrate affinity. In naive and pregnant female rats the maximum velocities of oxidative metabolism were 10.98 +/- 0.155 and 9.18 +/- 0.078 mg/kg/hr, while the estimated Michaelis constant for the two groups of rats was very low, 0.25 mg/liter. The first-order rate constant for oral absorption of TCE from water was 5.4 +/- 0.42/hr-1 in naive rats. With TCA, the volume of distribution (0.618 liter/kg) and the plasma elimination rate constant (0.045 +/- 0.0024/hour) were estimated both from intravenous dosing studies with TCA and from an inhalation study with TCE. By comparison of the two routes of administration, the stoichiometric yield of TCA from TCE was estimated to be 0.12 in pregnant rats. To develop a data base for testing the fidelity of the PB-PK model, inhalation and bolus gavage exposures were conducted from Day 3 to Day 21 of pregnancy and a drinking water exposure from Day 3 to Day 22 of pregnancy. Inhalation exposures with TCE vapor were 4 hr/day at 618 ppm. The TCE concentration in drinking water was 350 micrograms/ml and the gavaged rats received single daily doses of 2.3 mg TCE/kg. Time varying physiological parameters for compartment volumes and blood flows during pregnancy were obtained from the published literature. Using the kinetic parameters determined by experimentation, TCE concentrations in maternal and fetal blood and TCA concentrations in maternal and fetal plasma were predicted from the PB-PK model by computer simulation and compared favorably with limited data obtained at restricted time points during pregnancy for all three routes of exposure. On the basis of the PB-PK model, fetal exposure to TCE, as area-under-the-curve, ranged from 67 to 76% of maternal exposure. For TCA the fetal exposure was 63 to 64% of the maternal exposure. The fetus is clearly at risk both to parent TCE and its TCA metabolite.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗

PubMed1989

Improving toxicology testing protocols using computer simulations.

Computer simulation can be used to integrate existing toxicity information within a biologically realistic framework. Simulation models calculate relevant measures of target tissue dose based on physiological, biochemical and physicochemical properties and readily support the dose, route, species and interchemical extrapolations necessary for human risk assessment. Because these models require very specific information, much of which can be obtained in vitro, they are much less dependent on extensive animal experiments than conventional risk assessment methods. With continuing development, simulation modeling will become an invaluable tool for improving experimental designs, for interpreting animal toxicity tests, and for estimating the importance of the animal toxicity observations for people.

Administration, Inhalation↗

PubMed1989

Biologically motivated models for chemical risk assessment.

Assessing the risk associated with human exposure to environmental chemicals depends to a large extent on the ability to extrapolate from a particular range of exposure conditions in the test animal species to a very different range of exposure conditions in the human. One of the more promising tools for accomplishing this extrapolation is the biologically motivated pharmacokinetic/pharmacodynamic model. In a biologically motivated model, the structure is based on the physiological and biochemical structure of the animal system being described. This paper provides an overview of the biologically motivated modeling approach. Examples of models for styrene and methylene chloride are discussed in relation to their ability to predict human kinetics for these chemicals and their use in estimating the risk of chemicals to exposed humans. Finally, the use of a biologically motivated model to analyze the mechanistic basis of chemical carcinogenesis is discussed.

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

Pharmacokinetics, biochemical mechanism and mutation accumulation: a comprehensive model of chemical carcinogenesis.

Chemical carcinogenesis is a process beginning with carcinogen absorption and ending with development of a malignant tumor. Individual elements of this process have been studied intensively but no comprehensive model has been developed. This report describes a comprehensive model which incorporates carcinogen pharmacokinetics, biochemical mechanism of action, and the resultant mutation of normal cells to malignancy. Model parameters correspond to specific physiological and biochemical structures and processes. The model was encoded in a simulation language and used to examined biochemical and cellular effects of exposure to an initiator and a promoter. With laboratory validation, the model should be useful for interpretation and design of studies on carcinogenic mechanisms and for risk assessment.

Carcinogens↗

PubMed1988

Toxicokinetics: an analytical tool for assessing chemical hazards to man.

The Toxic Hazards Division has pioneered the development of toxicokinetic analysis for the study of the toxicity of various chemicals of importance to the U.S. Air Force. Toxicokinetic analysis permits calculation of tissue exposure based on biochemical, physiological, and physical chemical properties of the animal-chemical system. This paper describes the application of toxicokinetic analysis in the study and control of chemical hazards. Physiological models for both carbon tetrachloride and methylene chloride are discussed in relation to their ability to predict human kinetics and their use in estimating the risk of these chemicals to exposed humans. The emerging use of the toxicokinetic approach to analyze the mechanistic basis of chemical carcinogenesis is also discussed.

Aerospace Medicine↗

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↗

PubMed1987

Adjusting exposure limits for long and short exposure periods using a physiological pharmacokinetic model.

The rationale for adjusting occupational exposure limits for unusual work schedules is to assure, as much as possible, that persons on these schedules are placed at no greater risk of injury or discomfort than persons who work a standard 8 hr/day, 40 hr/week. For most systemic toxicants, the risk index upon which the adjustments are made will be either peak blood concentration or integrated tissue dose, depending on what chemical's presumed mechanism of toxicity. Over the past ten years, at least four different models have been proposed for adjusting exposure limits for unusually short and long work schedules. This paper advocates use of a physiologically-based pharmacokinetic (PB-PK) model for determining adjustment factors for unusual exposure schedules, an approach that should be more accurate than those proposed previously. The PB-PK model requires data on the blood:air and tissue:blood partition coefficients, the rate of metabolism of the chemical, organ volumes, organ blood flows and ventilation rates in humans. Laboratory data on two industrially important chemicals--styrene and methylene chloride--were used to illustrate the PB-PK approach. At inhaled concentrations near their respective 8-hr Threshold Limit Value-Time-weighted averages (TLV-TWAs), both of these chemicals are primarily eliminated from the body by metabolism. For these two chemicals, the appropriate risk indexing parameters are integrated tissue dose or total amount of parent chemical metabolized. Since methylene chloride is metabolized to carbon monoxide, the maximum blood carboxyhemoglobin concentrations also might be useful as an index of risk for this chemical.(ABSTRACT TRUNCATED AT 250 WORDS)

Air Pollutants, Occupational↗

PubMed1986

A physiological pharmacokinetic model for dermal absorption of vapors in the rat.

Absorption of chemical vapors through the skin is a passive process that is not easily quantitated, but may be important in the assessment of health hazards in some occupational circumstances. Physiological modeling is a quantitative technique which may provide insight into the system being modeled and can be used for interspecies extrapolation. We developed a physiological model for the penetration of organic vapors through skin in vivo which allows the prediction of blood concentrations, after dermal vapor exposures in the rat, when chemical distribution coefficients, physiological and metabolic parameters, and skin permeability constants are known. We used the model in two distinct ways. First, permeability constants for dibromomethane (DBM), bromochloromethane (BCM), and methylene chloride (DCM) were calculated by using a physiologically based pharmacokinetic model for dihalomethanes to relate blood concentrations during dermal vapor exposures to the total amount of chemical which was absorbed through the skin. Second, a skin compartment was added to the model which had input based on the permeability-area-concentration product. This predictive model adequately described blood concentrations after DBM, BCM, and DCM dermal vapor exposures over a wide range of concentrations. This model could easily be modified for use with other organic vapors, and could be used to extrapolate to human vapor exposure conditions by substituting human physiological parameters for the animal values, providing permeability constants are known or can be determined.

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↗

PubMed1985

Dermal absorption of dihalomethane vapors.

The dermal absorption of dibromomethane (DBM) and bromochloromethane (BCM) vapors was studied in rats placed in a specially designed chamber incorporating individual respiratory protection to avoid pulmonary uptake. Exposures (DBM: 500 to 10,000 ppm; BCM: 2500 to 40,000 ppm) lasted 4 hr during which time five blood samples were drawn from jugular cannulae for analysis of the parent dihalomethane by gas chromatography. Estimates of the amounts of chemicals stored in tissues and exhaled were based on concentrations in the blood and tissue partition coefficients, tissue volumes, and ventilation rate. Total metabolism was estimated from the amount of bromide released during the 4-hr exposure. The total amount of vapor absorbed through the skin was calculated from the estimates of the amount of parent chemical in blood and tissues, and the amounts exhaled and metabolized. The dermal flux for each concentration (DBM: 0.004 to 0.078 mg/cm2/hr; BCM: 0.011 to 0.164 mg/cm2/hr) was calculated by dividing the amount absorbed by exposed surface area and duration of exposure. Flux was divided by exposure concentration to calculate a permeability constant. With each dihalomethane the permeability constants (DBM: congruent to 1.12 cm/hr; BCM: congruent to 0.79 cm/hr) were essentially independent of exposure concentration. This study shows that a whole-body dermal vapor exposure in rodents is technically possible, and quantitation of penetration can be accomplished using calculations based on achieved blood concentrations and some measure of metabolism.

Animals↗