Biomedical subjects

M L Gargas

Publications and source records attributed to M L Gargas.

At least 37 records · Page 2Linked to original sources

PubMed1995

Development of a mechanism-based dosimetry model for 2,4,4-trimethyl-2-pentanol-induced alpha 2u-globulin nephropathy in male Fischer 344 rats.

A mechanism-based dosimetry model was developed to describe 2,4,4-trimethyl-2-pentanol (TMP-2-OH) dosimetry and renal alpha 2u-globulin (alpha 2u) nephropathy in the male Fischer 344 rat. Experimental data were collected to estimate the chemical-specific parameters (metabolic constants, tissue solubility, and oral absorption rate) necessary to describe TMP-2-OH dosimetry in male rats. The concentrations of alpha 2u and TMP-2-OH were measured in male rats up to 64 hr after a single oral dose of TMP-2-OH (6, 60, or 600 mg/kg). The model predicted the time course behavior of TMP-2-OH and alpha 2u in the kidney, but overestimated their renal concentrations by two or threefold. Simulations of renal alpha 2u concentration were sensitive to changes in TMP-2-OH-alpha 2u-binding affinity and degradation rate of the TMP-2-OH-protein complex. In contrast, simulation of the concentration of TMP-2-OH in the kidney was most sensitive to the amount of protein present. Oral absorption of TMP-2-OH was dose dependent. The model predicted that alpha 2u and TMP-2-OH concentration in the kidney is sensitive to changes in the rate of TMP-2-OH absorbed after oral administration. This model permitted a more rigorous evaluation than has previously been possible of the combination of protein characteristics and chemical dosimetry required for the accumulation of alpha 2u in the kidney of male rats. The behavior of the model is consistent with the qualitative aspects of the alpha 2u hypothesis. However, further characterization of alpha 2u distribution and renal hydrolysis will be required in order to fully characterize the hypothesis at the quantitative level.

Administration, Oral↗

PubMed1995

A physiologically based dosimetry description of acrylonitrile and cyanoethylene oxide in the rat.

The cytochrome P450-mediated oxidation of acrylonitrile (ACN) to the mutagen 2-cyanoethylene oxide (CEO) is thought to be important for the carcinogenic effects of ACN in rats, while glutathione (GSH) conjugation of ACN and CEO is regarded as detoxication. A physiologically based dosimetry description for ACN and CEO in the male F-344 rat has been developed from in vitro data and studies of the iv pharmacokinetics of ACN and CEO. The dosimetry description includes tissue partition coefficients and in vitro estimates of the rates of reaction of ACN and CEO with hemoglobin and blood macromolecules and the reaction of CEO with tissue GSH. Metabolic parameters for ACN and CEO were estimated from iv pharmacokinetic studies. Rats were given bolus doses of 3.4, 47, 55, or 84 mg ACN/kg via the femoral vein and blood samples were collected at selected time points. ACN and CEO blood concentrations were determined by gas chromatography. The iv pharmacokinetics of CEO were also determined using 0.6 or 5.3 mg CEO/kg. ACN elimination from blood was described by saturable P450 epoxidation (Vmax of 6.5 mg/hr/kg and Km of 1.5 mg/liter) and first-order GSH conjugation (30 hr-1/kg). CEO elimination was described by first-order GSH conjugation (750 hr-1/kg). Calculation of hepatic clearance values shows first-pass hepatic extractions of 61 and 90% for ACN and CEO, respectively. The dosimetry description accurately simulated the dose-dependent urinary excretion of ACN metabolites derived from epoxidation to CEO and from direct GSH conjugation of ACN. The dose-dependent formation of hemoglobin adducts from ACN was also well simulated.

Acrylonitrile↗

PubMed1995

Pharmacokinetic modeling approaches for describing the uptake, systemic distribution, and disposition of inhaled chemicals.

A fundamental relationship in toxicology is that an external chemical exposure leading to an internal tissue dose can result in an adverse biological response. An understanding of these relationships in experimental animals is often used to extrapolate and predict the potential risk to humans following exposure to toxic chemicals. The exposure-dose-response relationships for volatile compounds inhaled by the lungs are complicated by the fact that many toxic effects caused by these chemicals have been identified in tissues and organ systems other than the lungs. Pharmacokinetic modeling approaches have been devised to quantitate the relationships between inhaled concentrations of volatile compounds and the resulting critical tissue doses in experimental animals. These animal models have also been extrapolated to predict chemical disposition in humans for estimation of human health risks. This communication reviews three pharmacokinetic descriptions, each representing different levels of complexity, that have been used to assess chemical disposition of inhaled, volatile chemicals. The mathematical structures, assumptions, data needs, and risk assessment capabilities of each modeling approach are described.

Administration, Inhalation↗

PubMed1994

Determination of tissue partition coefficients for volatile tissue-reactive chemicals: acrylonitrile and its metabolite 2-cyanoethylene oxide.

Partition coefficients (PCs) are chemical-specific parameters used in physiologically based pharmacokinetic models to describe chemical solubility in tissues. Tissue:air PCs for volatile chemicals can be estimated using vial equilibration techniques in which the chemical concentration in the vial headspace is measured by gas chromatography after equilibrium is reached between the chemical in tissue and air. However, equilibrium would not be expected with tissue-reactive chemicals such as acrylonitrile (ACN) or its epoxide metabolite 2-cyanoethylene oxide (CEO). Active uptake of ACN was observed in rat blood due to reaction with blood sulfhydryl groups, while CEO reacted with all tissues examined (rat blood, muscle, fat, liver, and brain). The active uptake processes were first order as evidenced by a linear decrease in the log of the vial headspace concentrations over time. Linear extrapolation of the log of the apparent PC to zero time, where the contribution of the active uptake process is zero, yielded an estimated PC of 487 for ACN in blood. Equilibrium was achieved with ACN after treatment of blood with diethyl maleate to modify blood sulfhydryl groups, with a PC of 512 +/- 29 (mean +/- SE, n = 14). These PC estimates were verified by direct measurement of ACN concentrations in both the air and the blood (stabilized by acidification). The directly measured ACN blood:air PC was 437 +/- 8 (n = 8), which compared well with the estimated values. Treatment of tissues with diethyl maleate or 2,4-dinitrofluorobenzene did not abolish the active uptake of CEO. However, pretreatment of tissues with CEO itself abolished subsequent CEO uptake. The CEO blood:air PC estimates obtained from zero time extrapolation of four CEO concentrations (1672 +/- 139) and from CEO pretreatment (1658 +/- 137, n = 8) were in good agreement. These data indicate that tissue:air PCs for volatile reactive chemicals can be estimated by extrapolation of a first-order uptake process to zero time or at equilibrium following chemical modification of reactive groups in tissues.

Acrylonitrile↗

PubMed1994

Pharmacokinetic modeling of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and in rabbit brain following single dose administration.

A physiologically based pharmacokinetic (PBPK) model has been developed to describe the kinetics of organic anions in the central nervous system using 2,4-dichlorophenoxyacetic acid (2,4-D) as a model compound. The model consists of brain, body, venous, and arterial compartments. The brain compartment is subdivided into brain plasma, brain tissue and cerebrospinal fluid (CSF). Brain uptake is membrane-limited via a blood-brain barrier with saturable clearance from the CSF into the venous blood by the choroid plexus. The body has both a central and a deep compartment with saturable renal clearance from the central compartment. The model was used to examine venous plasma time course curves with experimental data from rats given 2,4-D by i.v. (5 or 90 mg/kg) or by oral ingestion (10, 50, or 150 mg/kg). The model was then extended to examine studies in which rabbit plasma, brain, and CSF concentrations were measured at 2 h after i.p. injection (40 mg/kg). In the rat, elimination was saturable (Vmax2 = 3.45 mg/h; Km2 = 86 mg/l) and the deep-compartment transfer coefficients were K12 (0.013 l/h) and K21 (0.048 l/h) between body and deep tissue compartment. Both oral and i.v. data were well described with these values. Limited single time point brain data from rabbits were analyzed with a lumped brain model assuming the generic model for 2,4-D in rat applies to the rabbit. The model simulations were in good agreement with rabbit plasma, brain, and CSF concentrations at 2 h after i.p. injection.

2,4-Dichlorophenoxyacetic Acid↗

PubMed1994

In vivo metabolism of butadiene by mice and rats: a comparison of physiological model predictions and experimental data.

1,3-Butadiene (BD), a rodent carcinogen, is metabolized to mutagenic and potentially DNA-reactive epoxides, including butadiene monoepoxide (BMO) and butadiene diepoxide. A physiological model containing five tissue groups (liver, lung, fat, slowly perfused tissues and rapidly perfused tissues) and blood was developed to describe uptake and metabolism of inhaled BD and BMO. Maximal rates for hepatic and pulmonary metabolism of BD and hepatic metabolism of BMO incorporated into the model were extrapolated from in vitro data (Csanády et al., Carcinogenesis, 13, 1143-1153, 1992). Apparent enzyme affinities used in the model were identified to the values measured in vitro. Model stimulations for BD and BMO uptake were compared to results from experiments in which groups of male Sprague-Dawley rats and B6C3F1 mice were exposed to initial concentrations of 50-5000 p.p.m. BD in closed chamber experiments and published data on BMO uptake by rats and mice. Metabolic rate constants extrapolated from in vitro data stimulated both BMO and BD uptake from closed chambers. The Vmax for hepatic metabolism of BD extrapolated from in vitro studies was 62 mumol/kg/h for rats and 340 mumol/kg/h for mice, while the Vmax for pulmonary metabolism of BD was 1.0 and 22 for rats and mice, respectively. These results demonstrate the usefulness of data derived in vitro for predicting in vivo behavior. Model simulations were also conducted in which only hepatic metabolism of BD was incorporated. These simulations underestimated BD uptake for mice, but not rats. Inclusion of in vitro-derived rates of pulmonary metabolism of BD into the model improved the fit to the data for mice. Since mice, but not rats, develop lung tumors after exposure to BD, these results point to the need for further characterize the metabolic capacity and target cells in the lung for BD and its metabolites. Once characterized, these models can be extended to predict in vivo behavior of BD in humans.

Animals↗

PubMed1994

Urinary excretion of chromium following ingestion of chromite-ore processing residues in humans: implications for biomonitoring.

Biomonitoring programs for urinary chromium (Cr) typically attempt to evaluate occupational exposure via the inhalation route. This study investigated whether Cr can be detected in the urine of people following the ingestion of soils that contain relatively high concentrations of chromium in chromite ore processing residue (COPR). To evaluate the reasonableness of using urinary monitoring to assess environmental exposure, six volunteers ingested 400 mg of soil/day (low-dose group), two others ingested 2.0 g of soil/day (high-dose group) for 3 consecutive days, and one person ingested a placebo on each of 3 days. The soil and COPR mixture contained concentrations of total chromium (Cr) and hexavalent chromium [Cr(VI)] of 103 +/- 20 and 9.3 +/- 3.8 mg/kg, respectively. Therefore, the low-dose group ingested 41 micrograms Cr/day [including 3.7 micrograms Cr(VI)] and the high-dose group ingested 206 micrograms Cr/day [including 18.6 micrograms Cr(VI)] on each of 3 consecutive days. All urine samples were collected and analyzed individually for total Cr on the day prior to dosing, during the 3 days of dosing, and up to the first void 48 h after the last dose. No significant increases in urinary Cr excretion were found when background excretion data were compared with data following each of the 3 days of dosing or in daily mean urine concentrations of the high- vs the low-dose groups. It appears that Cr present in a soil and COPR mixture at Cr doses up to 200 micrograms/day is not sufficiently bioavailable for biomonitoring of urine to be informative.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

1,3-Butadiene: linking metabolism, dosimetry, and mutation induction.

There is increasing concern for the potential adverse health effects of human exposures to chemical mixtures. To better understand the complex interactions of chemicals within a mixture, it is essential to develop a research strategy which provides the basis for extrapolating data from single chemicals to their behavior within the chemical mixture. 1,3-Butadiene (BD) represents an interesting case study in which new data are emerging that are critical for understanding interspecies differences in carcinogenic/genotoxic response to BD. Knowledge regarding mechanisms of BD-induced carcinogenicity provides the basis for assessing the potential effects of mixtures containing BD. BD is a multisite carcinogen in B6C3F1 mice and Sprague-Dawley rats. Mice exhibit high sensitivity relative to the rat to BD-induced tumorigenesis. Since it is likely that BD requires metabolic activation to mutagenic reactive epoxides that ultimately play a role in carcinogenicity of the chemical, a quantitative understanding of the balance of activation and inactivation is essential for improving our understanding and assessment of human risk following exposure to BD and chemical mixtures containing BD. Transgenic mice exposed to 625 ppm BD for 6 hr/day for 5 days exhibited significant mutagenicity in the lung, a target organ for the carcinogenic effect of BD in mice. In vitro studies designed to assess interspecies differences in the activation of BD and inactivation of BD epoxides reveal that significant differences exist among mice, rats, and humans. In general, the overall activation/detoxication ratio for BD metabolism was approximately 10-fold higher in mice compared to rats or humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Kinetic analysis of furan biotransformation by F-344 rats in vivo and in vitro.

Furan is both hepatotoxic and hepatocarcinogenic in rats. The kinetics of furan biotransformation by male F-344 rats were studied in vivo and in vitro in order to understand target tissue dosimetry. A physiologically based pharmacokinetic (PBPK) model for furan in rats was developed from gas uptake studies using initial furan concentrations of 100, 500, 1050, and 3850 ppm. Tissue partition coefficients for furan were determined in vitro using vial equilibration techniques. Furan gas uptake kinetics in vivo were described by a single saturable process with a Vmax of 27.0 mumol/hr/250 g rat and a KM of 2.0 microM. Furan metabolism in vivo was inhibited by pyrazole. The furan PBPK model adequately simulated blood and liver furan concentrations following 4-hr inhalation exposures to 52, 107, and 208 ppm furan. The biotransformation of furan was studied in freshly isolated rat hepatocytes in vitro and compared to biotransformation in vivo. Furan biotransformation by isolated rat hepatocytes exhibited a KM of 0.4 microM and a Vmax of 0.018 mumol/hr/10(6) cells. Inhibition and induction studies indicated that cytochrome P450 was the catalyst of furan oxidation. Acetone pretreatment of the rats produced a five-fold increase in the rate of the hepatocyte oxidation of furan, suggesting an important role for cytochrome P450 2E1. The Vmax determined in hepatocytes in vitro extrapolated to 23.0 mumol/hr/250 g rat, assuming 128 x 10(6) hepatocytes/g liver. Incorporation of the in vitro hepatocyte kinetic parameters into the PBPK model for furan accurately simulated in vivo pharmacokinetics. These results suggest that freshly isolated hepatocytes are a valuable in vitro system for predicting chemical pharmacokinetics in vivo.

Animals↗

PubMed1993

Modeling receptor-mediated processes with dioxin: implications for pharmacokinetics and risk assessment.

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD), a widespread polychlorinated aromatic hydrocarbon, caused tumors in the liver and other sites when administered chronically to rats at doses as low as 0.01 microgram/kg/day. It functions in combination with a cellular protein, the Ah receptor, to alter gene regulation, and this resulting modulation of gene expression is believed to be obligatory for both dioxin toxicity and carcinogenicity. The U.S. EPA is reevaluating its dioxin risk assessment and, as part of this process, will be developing risk assessment approaches for chemicals, such as dioxin, whose toxicity is receptor-mediated. This paper describes a receptor-mediated physiologically based pharmacokinetic (PB-PK) model for the tissue distribution and enzyme-inducing properties of dioxin and discusses the potential role of these models in a biologically motivated risk assessment. In this model, ternary interactions among the Ah receptor, dioxin, and DNA binding sites lead to enhanced production of specific hepatic proteins. The model was used to examine the tissue disposition of dioxin and the induction of both a dioxin-binding protein (presumably, cytochrome P4501A2), and cytochrome P4501A1. Tumor promotion correlated more closely with predicted induction of P4501A1 than with induction of hepatic binding proteins. Although increased induction of these proteins is not expected to be causally related to tumor formation, these physiological dosimetry and gene-induction response models will be important for biologically motivated dioxin risk assessments in determining both target tissue dose of dioxin and gene products and in examining the relationship between these gene products and the cellular events more directly involved in tumor promotion.

Animals↗

PubMed1992

An in vitro gas equilibration method for determination of chemical partition coefficients in fish.

1. A gas equilibration method for the determination of in vitro chemical partition coefficients in mammals was adapted for use with fish. 2. In vitro blood: water and tissue: blood partition coefficients were determined for three chlorinated ethanes in rainbow trout (Oncorhynchus mykiss). 3. In vitro partition coefficients accurately predicted chemical concentrations in tissues of exposed trout.

Adipose Tissue↗

PubMed1991

Physiologically based pharmacokinetic modeling with trichloroethylene and its metabolite, trichloroacetic acid, in the rat and mouse.

The uptake and metabolism of trichloroethylene (TCE), and the stoichiometric yield and kinetic behavior of one of its major metabolites, trichloroacetic acid (TCA), were compared in Fischer 344 rats and B6C3F1 mice using a physiological model. Physiologically based pharmacokinetic (PB-PK) model parameters (metabolic rate constants and tissue partition coefficients) were determined in male and female B6C3F1 mice and were taken from the literature for the male and female Fischer 344 rats. The kinetic behavior of TCA was described by a classical one-compartment model linked to a PB-PK model for TCE. The TCE blood/air partition coefficients for male and female mice, determined by vial equilibration, were 13.4 and 14.3. The Vmaxe values for male and female mice, using gas uptake techniques, were 32.7 +/- .06 and 23.2 +/- 0.1 mg/kg/hr and the Km was 0.25 mg/liter. The PB-PK model for TCE adequately described the uptake and clearance of TCE in male and female rats exposed to a single, constant concentration of TCE vapor, but failed to describe the uptake and clearance of TCE in male and female mice exposed to a wide range TCE vapor concentrations. Computer-predicted blood concentrations of TCE were generally greater than observed blood concentrations of TCE. The stoichiometric yield of TCA in mice exposed to these TCE vapors was concentration dependent. The capacity for oxidation of TCE was much greater in B6C3F1 mice than in Fischer 344 rats, and as a result the systemic concentration of TCA was greater in these mice than rats. An increased body burden of TCA in B6C3F1 mice may be related to the formation of hepatocellular carcinomas in B6C3F1 mice exposed to TCE.

Administration, Inhalation↗

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↗

PubMed1991

PB-PK derived metabolic constants, hepatotoxicity, and lethality of BrCCl3 in rats pretreated with chlordecone, phenobarbital, or mirex.

Pharmacokinetic modeling has been very useful in examining the complex relationships between exposure concentration and target tissue dose. This study utilizes a physiologically based pharmacokinetic (PB-PK) modeling approach for assessing the metabolism of BrCCl3 and to investigate its relationship with hepatotoxicity and lethality. Male Sprague-Dawley rats maintained for 15 days on normal diet (control), or on diets containing either chlordecone (CD, 10 ppm), phenobarbital (PB, 225 ppm) or mirex (M, 10 ppm), were used in gas uptake studies to determine the kinetic constants of BrCCl3 metabolism. Four initial concentrations of BrCCl3 at approximately 30, 200, 700, and 3000 ppm were used for each group. The uptake data were analyzed by computer simulation using a PB-PK model containing relevant tissue solubilities and physiological parameters as well as an equation describing the behavior of BrCCl3 in the closed chamber atmosphere. Liver injury was assessed by serum enzyme elevations (alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase) and histopathological examination, at 24 hr after the exposure to BrCCl3. Another group of similarly pretreated rats was exposed to BrCCl3 and observed over a 14-day period for mortality. Dietary exposures resulted in increased Vmaxc value for BrCCl3 metabolism as compared to control (3.55 +/- 0.14 mg/hr/kg) for PB (8.52 +/- 0.28 mg/hr/kg) and M (5.06 +/- 0.19 mg/hr/kg) but not for CD (3.92 +/- 0.19 mg/hr/kg). Kfc, the first-order rate constant for BrCCl3 metabolism, was decreased after PB (12.9 +/- 0.5 hr-1/kg) and increased after M (17.6 +/- 0.5 hr-1/kg), but unchanged after CD (15.5 +/- 0.6 hr-1/kg) exposure as compared to control (15.0 +/- 0.3 hr-1/kg). The total amount of BrCCl3 metabolism at any initial concentration employed remained unchanged in all the pretreated groups as compared to control. However, the amount of BrCCl3 metabolized through saturable pathway only, at higher initial concentrations, was increased in the PB and M pretreated groups, but not in the CD pretreated group. It is concluded that the rates of metabolism of BrCCl3 were unchanged after CD pretreatment as compared to control, while PB and M pretreatment alter both the saturable and first-order rates. Serum enzymes were significantly increased in all the groups after exposure to BrCCl3 at 200 and 700 ppm concentrations. The increase was more pronounced in PB and M pretreated groups as compared to control and CD pretreated groups. Similarly, histopathological examination of liver showed alterations in the lobular architecture, the extent of alterations being dependent on the dose of BrCCl3 and the pretreatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗

PubMed1990

Estimating the risk of liver cancer associated with human exposures to chloroform using physiologically based pharmacokinetic modeling.

A physiologically based pharmacokinetic (PB-PK) model for CHCl3 has been used to prepare estimates of the probability that human populations exposed to low levels of CHCl3 will develop liver tumors similar to those seen in rodent bioassays. The PB-PK model for CHCl3 was based on a model reported earlier by Corley et al. (1990), but this model differed from that of Corley et al. in that it was also capable of describing a pharmacodynamic endpoint: induction of cytotoxicity in the liver of CHCl3-exposed animals produced by reactive metabolites of CHCl3. Pharmacodynamic descriptions in this model were derived from experimental measurements of cell replication ([3H]thymidine incorporation) as well as from quantitative histopathology in the liver of rats and mice. Two different approaches were used for hazard evaluation: (1) a "Safety Factor" approach based on no observed effect levels for liver tumors. and (2) calculation of lower confidence limits on risk-specific doses with the GLOBAL83 computer program. In each case, cytotoxicity produced by reactive CHCl3 metabolites was used as the measure of "dose" to the liver. The Safety Factor approach suggested that continuous exposure of human populations to concentrations of CHCl3 less than 2840 ppb in air or 13,900 ppb in water would not be likely to significantly increase the risk of developing liver tumors. The second approach suggested a "plausible upper 95% confidence limit" of 1 x 10(-5) for lifetime excess cancer risk for human populations continuously exposed to 2200 or 13,100 ppb CHCl3 in air or water, respectively.

Administration, Inhalation↗

PubMed1990

Development of a physiologically based pharmacokinetic model for chloroform.

A physiologically based pharmacokinetic model describing the disposition of chloroform in mice, rats, and humans was developed. This model was designed to facilitate extrapolations from high doses, such as those used in chronic rodent studies, to low doses that humans may be exposed to in the workplace or the environment. Kinetic constants for mice and rats were derived from in vivo experiments. Enzymatic studies conducted with samples of rodent and human tissues provided a rational basis for estimating human in vivo metabolic rate constants. Incorporation of physiological descriptions of the processes of absorption, distribution, metabolism, and excretion allowed extrapolation between different routes of exposure as well. The model was validated by comparing model predictions with experimental data gathered in mice, rats, and humans after inhalation, oral, or intraperitoneal administration of chloroform. Consistent with previous reports, the metabolic activation of chloroform to toxic intermediates was shown to occur most rapidly in the mouse, less rapidly in the rat, and most slowly in humans. Estimates of the "delivered dose" of chloroform metabolites to internal organs sensitive to chloroform toxicity were calculated. This model may be used to develop refined dose estimates for human populations exposed to low levels of chloroform in the environment.

Administration, Inhalation↗

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

Development of a physiologically based pharmacokinetic model for risk assessment with 1,4-dioxane.

A six compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the disposition of diethylene-1,4-dioxide (dioxane) and its principal metabolite beta-hydroxyethoxyacetic acid in rats, mice, and humans. The model was developed from experimentally measured partition coefficients (reported here for the first time) as well as pharmacokinetic data previously reported. The completed PB-PK model adequately described data from gavage and intravenous studies in rats, as well as inhalation studies in rats and humans. Substantial nonlinearities were observed in the kinetic behavior of dioxane under high exposure conditions (water concentrations greater than 0.1% dioxane and atmospheric concentrations greater than 300 ppm dioxane). The PB-PK model was subsequently used to prepare quantitative estimates of the "plausible upper bounds" on carcinogenic risk for human populations exposed to dioxane in air or water. Based on these quantitative estimates, it appears that human populations continuously exposed to 740-3700 ppb dioxane in air or 20,000-120,000 ppb dioxane in water would be unlikely to experience increased frequencies of tumors.

Animals↗