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M E Andersen

Publications and source records attributed to M E Andersen.

At least 19 recordsLinked to original sources
PubMed1992

Biologically based modeling in toxicology research.

Biologically based modeling can be described as the process by which the specific mechanistic steps governing tissue disposition and toxic action of chemicals are expressed in quantitative terms by a set of equations leading to prediction of the outcome of specific toxicological experiments by computer simulation. These models are useful in risk assessment because their mechanistic biological basis permits the high-to-low dose, route to route and interspecies extrapolation of the tissue disposition and toxic action of chemicals. By far their greatest utility is not as "finished" risk assessment models, but as research tools that convey a quantitative expression of our hypotheses of tissue disposition and toxic action of a chemical. A structured modeling approach to toxicology problems helps identify the data gaps in the areas of chemical disposition and toxic action, thus prioritizing on-going research to obtain critical information required to conduct quantitative risk assessment. This paper examines progress in developing comprehensive biologically based models for cancer induction by non-genotoxic carcinogens that are cytotoxic in target tissues. The strategies for linking the models on dosimetry, cytotoxicity, and carcinogenicity are described in detail. The basic concepts and approaches discussed here can be applied to many other toxic chemicals and to toxicity endpoints other than cancer.

Animals↗
PubMed1992

A physiologically based pharmacokinetic and pharmacodynamic model to describe the oral dosing of rats with ethyl acrylate and its implications for risk assessment.

A physiologically based pharmacokinetic and pharmacodynamic model has been developed to describe the absorption, distribution, and metabolism of orally dosed ethyl acrylate. The model describes the metabolism of ethyl acrylate in 14 tissues based on in vitro metabolic studies conducted with tissue homogenates. The routes of metabolism included in the model are carboxylesterase-catalyzed ester hydrolysis, conjugation with glutathione, and binding to protein. To adequately describe the rate and extent of glutathione depletion following gavage dosing, the steady-state rate of glutathione synthesis in the organs of interest was included. In vivo validation of the model was conducted by comparing the predictions of the model to the results of a variety of gavage dosing experiments with ethyl acrylate, including (1) the time course of glutathione depletion in a variety of tissues up to 98 hr following dosing at three dose levels, (2) the rate and extent of radiolabeled carbon dioxide excretion, and (3) protein binding in the forestomach. The very rapid metabolism predicted by the model was consistent with the observation that ethyl acrylate was metabolized too rapidly in vivo to be detected by common analytical techniques for tissue metabolite analysis. The validation data indicated that the model provides a reasonable description of the pharmacokinetics and the pharmacodynamic response of specific rat tissues following gavage dosing of ethyl acrylate. A dose surrogate, or measure of delivered dose, for ethyl acrylate was calculated and correlated with the incidence and severity of contact site toxicity (edema, inflammation, ulceration, and hyperplasia). The model provides a quantitative tool for evaluating exposure scenarios for their potential to induce contact-site toxicity, and it provides a quantitative approach for understanding the lack of toxicity in tissues remote from the dosing site.

Acrylates↗
PubMed1992

A physiologically based pharmacokinetic model for nicotine disposition in the Sprague-Dawley rat.

A physiologically based pharmacokinetic (PBPK) model was developed to describe the disposition of nicotine in the Sprague-Dawley (SD) rat. Parameters for the model were either obtained from the literature (blood flows, organ volumes) or determined experimentally (partition coefficients). Nicotine metabolism was defined in the liver compartment by the first-order rate constants KNC and KNP which control the rate of nicotine metabolism to cotinine and "polar metabolites" (PM), respectively. These rate constants were estimated by optimizing the model fit to pharmacokinetic data obtained by administering an intraarterial (S)-[5-3H]nicotine bolus of 0.1 mg/kg to 6 rats. Model simulations that optimized for the appearance of cotinine in plasma estimated KNC and KNP to be 75.8 and 24.3 hr-1, respectively. Use of these constants in the model allowed us to accurately predict nicotine plasma kinetics and the fraction of the dose eliminated by renal (8.5%) and metabolic (91.5%) clearance. To validate the model's ability to predict tissue kinetics of nicotine, 21 male SD rats were administered 0.1 mg/kg (S)-[5-3H]nicotine intraarterially. At seven time points following treatment, 3 rats were euthanized and tissues were removed and analyzed for nicotine. Model-predicted nicotine tissue kinetics were in agreement with those determined experimentally in muscle, liver, skin, fat, and kidney. The brain, heart, and lung exhibited nonlinear nicotine elimination, suggesting that saturable nicotinic binding sites may be important in nicotine disposition in these organs. Inclusion of saturable receptor binding expressions in the mathematical description of these compartments resulted in better agreement with the experimental data. The Bmax and KD estimated by model simulations for these tissues were brain, 0.009 and 0.12; lung, 0.039 and 2.0; and heart, 0.039 nmol/tissue and 0.12 nM, respectively. This PBPK model can successfully describe the tissue and plasma kinetics of nicotine in the SD rat and will be a useful tool for pharmacologic studies in humans and experimental animals that require insight into the plasma or tissue concentration-effect relationship.

Animals↗
PubMed1992

Polychlorotrifluoroethylene (PCTFE) oligomer pharmacokinetics in Fischer 344 rats: development of a physiologically based model.

The hydraulic fluid oil polychlorotrifluoroethylene (PCTFE) is hepato- and nephrotoxic in the rat. Male Fischer 344 rats were exposed to PCTFE either for a single 6-hr exposure (0.5 or 0.25 mg/liter) or daily 5 days/week, 6 hr/day, for 13 weeks (0.5, 0.25, or 0.01 mg/liter). Blood, tissue, and urinary PCTFE concentrations measured postexposure were used to develop a physiologically based pharmacokinetic (PB-PK) model. The PCTFE hydraulic fluid used was a mixture of trimeric and tetrameric oligomers with minor amounts of other chain lengths. The PB-PK model was designed to describe the behavior, not of individual oligomers, but of total mass for the trimer and tetramer in each tissue. Partition coefficients were estimated using the model to optimize tissue/blood concentration ratios measured at the end of the 13-week exposure. First-order metabolic rate constants for both trimeric (2.0 hr-1) and tetrameric (1.0 hr-1) portions were estimated by optimization against urinary fluoride data assuming release of 0.77 mole fluoride per mole trimer and 0.844 mole fluoride per mole tetramer metabolized. To obtain accurate simulation of pharmacokinetic data it was necessary to hypothesize two fat compartments with diffusion-limited exchange of PCTFE oligomer with the blood. Relative concentrations of trimer and tetramer in venous blood, liver, and fat after a single 6-hr exposure were proportional to inhaled concentrations. Tetramer accumulated preferentially with multiple exposure. Components of PCTFE were metabolized to carboxylic acids with release of fluoride. Due to their persistence tetrameric oligomers appear to be more important than trimeric oligomers as causative agents of PCTFE hepato- and nephrotoxicity in the rat.

Administration, Inhalation↗
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↗
PubMed1991

Physiological modelling of organic compounds.

In pharmacokinetic modelling the body is represented as a set of compartments. The characteristics of these compartments are defined either by fitting predetermined mathematical equations to the data ('data-based compartments') or by defining compartments based on the actual biological structure of the animal ('physiologically based compartments'). Physiological models of chemical disposition are developed using these physiologically based compartments. These models then consist of sets of organs or types of tissue compartments whose characteristics are based as far as possible on the anatomy and physiology of the test species. Individual organs or types of tissue are defined with respect to their blood flow, volume, kinetic constants for metabolism, storage capacity for the compound involved, protein binding and other relevant characteristics. Linking these compartments together in a proper anatomical arrangement yields the physiological model for compound disposition. This paper provides an overview of the basics for constructing physiological models for organic compounds, focusing on the structure of individual compartments in these models and the data required for model development. Some past applications of physiological models are reviewed and speculation offered on future developments in this field.

Animals↗
PubMed1991

Biologically based pharmacodynamic models: tools for toxicological research and risk assessment.

The cancer model contains extensive biological detail, but is not fully validated. It is extremely useful for organizing what is known about malignant transformation, for linking measures of tissue dose with biological processes, and for proposing new experiments. It became very clear, as the cancer model was developed, that we lack an adequate understanding of the details of biochemical mechanisms of carcinogen action linking the target-tissue dose of carcinogen with effects on cell birth, death, and mutation rates as specified by the MVK model. This problem extends to noncarcinogenic toxicants such as methotrexate and the organophosphates. In these cases the biologically based descriptions of toxicity stop at the first interaction of the chemical with tissue. The linkage from the primary interaction to ultimate toxic effect is a "black box" that, at present, can only be described empirically rather than in biologically based terms. The models for dioxin and prednisolone do illustrate how biological events several steps removed from the initial tissue interaction of the toxicant can be described in quantitative, biologically based terms. As such they point the way for future development of more realistic descriptions in which the use of purely empirical linkages is reduced. Rigorous organization of current knowledge and specification of a logical sequence of new experiments encompass the major reasons for developing biologically based (structural) descriptions of any process. It bears emphasis that biologically based tissue response models, for cancer, for chloroform cytotoxicity, for functional impairment following organophosphate exposure, etc, are in reality quantitative formulations of an hypothesis or proposed mechanism incorporating the pharmacokinetics of the chemical and the linkage between target-tissue dose and toxic effect(s). The quantitative model allows us to see if the hypothesis is consistent with pertinent data and aids in designing experiments to define, refute, or bolster the general nature of the proposed linkages between tissue dose, tissue response and the whole organism's response to the chemical exposure. In this sense these biologically based models are quantitative descriptions of the current level of understanding of toxic effects in animals. We began this review article by looking at the literature on empirical tissue-response models to educate ourselves on the history of PD modeling. We rapidly found that the clear distinction between PK and PD models described in the literature blurs when one moves to biologically based modeling of tissue disposition and tissue response. Many articles on physiologically based pharmacokinetics turn out on close scrutiny to be as closely related to tissue response as they are to kinetics.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
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

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 physiological pharmacokinetic description of the tissue distribution and enzyme-inducing properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat.

A five-compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the tissue disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Sprague-Dawley rat. This description included blood, liver, fat, muscle/skin, and visceral tissue groups. On the basis of other literature, the liver compartment was modeled to include two TCDD-binding sites, corresponding to a cytosolic receptor and a microsomal binding protein. A pharmacodynamic description was developed in which microsomal enzyme induction, both of arylhydrocarbon hydroxylase activity and of the amount of the microsomal TCDD-binding protein, was linked to fractional occupancy of the cytosolic receptor. This description was then used to analyze previously published data on TCDD disposition. The dissociation constant of the cytosolic Ah receptor (KB1) in vivo was estimated to be 15 pM by fitting enzyme induction data from McConnell et al. (1984). The ratio of liver to fat concentration of TCDD (about 4:1) was found to be primarily determined by the dissociation constant of the microsomal binding protein (7 nM) and the basal and induced concentration of this protein in the liver (25 and 200 nmol/liver, respectively). With these parameter values, the tissue distribution of TCDD in fat and liver, the two primary sites of accumulation, was accurately described following either single or repeated dosing with TCDD in the rat. The pharmacokinetic behavior described by the model was extremely sensitive to binding affinities, and only moderately sensitive to binding capacities in the dose range studied. Induction of microsomal TCDD-binding proteins was necessary in order to account for the differences in disposition at low (0.01 microgram/kg) and high (1.0 microgram/kg) daily doses of TCDD. Since the tumorigenicity of TCDD in rats is believed to be correlated with the biological responses of the Ah-TCDD complex, the present physiological pharmacokinetic description, which contains information on receptor occupancy at various dose levels, provides a plausible mechanistic connection for devising pharmacodynamic models which predict the cancer risk of TCDD in the rat.

Animals↗
PubMed1990

Pharmacokinetics of [125I]-2-iodo-3,7,8-trichlorodibenzo-p-dioxin in mice: analysis with a physiological modeling approach.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of hepatic microsomal enzymes. The influence of an inducing dose of TCDD on tissue distribution and other pharmacokinetic behavior of a TCDD analog in the mice was examined by employing a high specific activity radioligand. [125I]-2-iodo-3,7,8-trichlorodibenzo-p-dioxin (ITCDD). Female C57BL/6J mice were pretreated with 0.1 mumol/kg of TCDD or the vehicle only, followed by 0.1 nmol ITCDD/kg 3 days later. The control animals had the highest concentration of ITCDD-derived radioactivity in the fat, but the TCDD-pretreated animals had the highest concentration in their livers. Whole-body elimination of ITCDD approximated first-order behavior, and induction by pretreatment with the inducing dose of TCDD almost doubled the rate of excretion (control mice, t1/2 = 14.2 days; pretreated mice, t1/2 = 8.0 days). All disposition results in naive and pretreated mice were satisfactorily described by a consistent physiologically based pharmacokinetic model (Leung et al., 1988a) in which induction increased the amount of microsomal ITCDD-binding protein from 1.75 to 20 nmol/liver and increased the rate constant for metabolism of free ITCDD from 1 to 3/hr/kg liver. The binding affinity of the microsomal ITCDD-binding protein was the same (20 nM) in both induced and noninduced mice. Model simulations indicated a time delay in the elimination of nonparent ITCDD metabolites from the body and a more rapid absorption of the parent ligand in the pretreated mice. Consistent with previous physiological modeling with TCDD in different mouse strains, the primary factor influencing the liver/fat concentration ratio appears to be the affinity and capacity of the microsomal TCDD-binding proteins, which are altered by induction. These dose-dependent pharmacokinetic differences with ITCDD are important considerations for TCDD risk assessment in which data from high dose rodent experiments are extrapolated to predict behavior at much lower environmental concentrations in exposed humans.

Adipose Tissue↗
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↗