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H J Clewell

Publications and source records attributed to H J Clewell.

At least 37 records · Page 2Linked to original sources
PubMed1995

The application of physiologically based pharmacokinetic modeling in human health risk assessment of hazardous substances.

Physiologically based pharmacokinetic (PBPK) modeling is an important tool for improving the accuracy of human health risk assessments for hazardous substances in the environment. The proper use of PBPK modeling can reduce uncertainties that currently exist in risk assessment procedures by providing more scientifically credible extrapolations across species and routes of exposure, and from high experimental doses to potential environmental exposures. Current applications of PBPK models range from relatively straightforward uses for the extrapolation of chemical kinetics across species, route, and duration of exposure to much more demanding chemical risk assessment applications requiring a description of complex pharmacodynamic phenomena such as mitogenicity and hyperplasia secondary to cytotoxicity. PBPK modeling helps to identify the factors that are most important in determining the health risks associated with exposure to a chemical, and provides a means for estimating the impact of those factors both on the average risk to a population and on the specific risk to an individual. The chief challenge in the application of PBPK modeling in human health risk assessment lies in the need to generate chemical-specific data to support the development and validation of the models. Extensive use of rapidly developing in vitro and structure-activity relationship techniques is needed to provide the data required for the large number of hazardous chemicals currently contaminating the environment.

Animals↗
PubMed1995

An improved approximation to the exact solution of the two-stage clonal growth model of cancer.

Multistage clonal growth models are of interest for cancer risk assessment because they can explicitly incorporate data on cell replication. Both approximate and exact formulations of the two stage growth model have been described. The exact solution considers the conditional probability of tumors arising in previously tumor-free animals; the approximate solution estimates total probability of tumor formation. The exact solution is much more computationally intensive when time-dependent cell growth parameters are included. The approximate solution deviates from the exact solution at high incidences and probabilities of tumor. This report describes a computationally tractable, 'improved approximation' to the exact solution. Our improved approximation includes a correction term to adjust the unconditional expectation of intermediate cells based on the time history of formation of intermediate cells by mutation of normal cells (recruitment) or by cell division in the intermediate cell population (expansion). The improved approximation provided a much better match to the exact solution than the approximate solution for a wide range of parameter values. The correction term also appears to provide insight into the biological factors that contribute to the variance of the expectation for the number of intermediate cells over time.

Algorithms↗
PubMed1994

Kinetics of water vapor sorption in porcine stratum corneum.

The kinetics of water vapor absorption-desorption was studied in the porcine stratum corneum (sc) at 25 degrees C. Dry sc samples were exposed to several relative humidities followed by exposure to dry air, and the change in weight was monitored over time by use of a thermal gravimetric analysis technique. Diffusion coefficients were estimated by simulation and data fit optimization to modifications of the non-steady-state solution of Fick's law. Very good fits of experimental data to theoretical equations were obtained. The stratum corneum-water absorption isotherm was characterized by a linear increase from the origin, extending to about 55% relative humidity (10% water gain), followed by an upward curve where water gain increased further by increasing relative humidity. Water absorption and water desorption in the porcine sc were asymmetrical processes, desorption being the slower one. Water diffusivity for the absorption process was related to sc water content in two phases. In the first (water gain < 9%) diffusion coefficients increased as water concentration increased. In the second (water gain > 9%) diffusion coefficients were independent of water concentration, equal to 1.17 x 10(-10) cm2/s. Water diffusivity in the desorption phase was shown to decrease linearly as sc water content decreased. Analysis of the absorption isotherm and of the derived diffusion coefficients suggested at least two forms of water associated with the sc. The first, termed "firmly bound water" and characterized by low diffusion coefficients, was most apparent with dry sc and with a sc water gain of up to 10%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Gas uptake studies of deuterium isotope effects on dichloromethane metabolism in female B6C3F1 mice in vivo.

In common with a diverse group of low-molecular-weight volatile substrates, dichloromethane (DCM; methylene chloride) is a high-affinity, low-capacity substrate for oxidation by several cytochrome P450 isoenzymes in vivo. DCM oxidation, catalyzed primarily by the 2E1 and 2B1 cytochrome P450 isoforms, yields carbon monoxide (CO) and carbon dioxide. We have studied the characteristics of DCM oxidation in vivo by examining the metabolism of DCM and of both deuterated forms ([2H2]-DCM and [2H]DCM) in female B6C3F1 mice with gas uptake methods. Gas uptake and CO production curves were analyzed by physiologically based pharmacokinetic (PBPK) modeling techniques, permitting differentiation of isotope effects on specific metabolic parameters from those associated with blood flow or diffusion limitations in vivo. A marked isotope effect was observed on the moles of CO produced per mole of DCM oxidized (0.76 +/- 0.06, 0.33 +/- 0.006, and 0.31 +/- 0.07, with DCM, [2H]DCM, and [2H2]DCM, respectively). Based on these ratios, the calculated kH/kD ratio for the rate constant of disproportionation of the putative formyl chloride intermediate was about 7, indicating a significant role of C-H bond breaking in this reaction. Deuterium substitution altered the apparent Km for metabolism; there was 14-fold increase in the apparent Km between DCM and [2H2]DCM (6.5 +/- 0.69 to 97 +/- 3.5 microM) with little effect on Km with [2H]DCM (14.4 +/- 0.015 microM). Vmax was not greatly affected by deuteration (151 +/- 1.2, 116 +/- 0.82, and 149 +/- 2.3 mumol/hr/kg with DCM, [2H]DCM, and [2H2]DCM, respectively). Two kinetic mechanisms are discussed, both of which are consistent with these observations. One, a conventional cytochrome P450 mechanism has a rate-limiting product-release step after the isotopically sensitive step; a second, more like a peroxidase mechanism, has a flux-limiting oxygen activation step followed by a second-order reaction between an activated oxygen-enzyme complex and DCM. Regardless of the correct mechanism, the in vivo kinetic constants for oxidation of DCM are complex and represent more than simple rate-limiting bond-breaking (Vmax) and enzyme-substrate binding (Km). Current PBPK models for metabolism of these volatiles may have to be restructured to account for this unusual kinetic mechanism.

Administration, Inhalation↗
PubMed1994

Incorporation of pharmacokinetics in noncancer risk assessment: example with chloropentafluorobenzene.

Noncancer risk assessment traditionally relies on applied dose measures, such as concentration in inhaled air or in drinking water, to characterize no-effect levels or low-effect levels in animal experiments. Safety factors are then incorporated to address the uncertainties associated with extrapolating across species, dose levels, and routes of exposure, as well as to account for the potential impact of variability of human response. A risk assessment for chloropentafluorobenzene (CPFB) was performed in which a physiologically based pharmacokinetic model was employed to calculate an internal measure of effective tissue dose appropriate to each toxic endpoint. The model accurately describes the kinetics of CPFB in both rodents and primates. The model calculations of internal dose at the no-effect and low-effect levels in animals were compared with those calculated for potential human exposure scenarios. These calculations were then used in place of default interspecies and route-to-route safety factors to determine safe human exposure conditions. Estimates of the impact of model parameter uncertainty, as estimated by a Monte Carlo technique, also were incorporated into the assessment. The approach used for CPFB is recommended as a general methodology for noncancer risk assessment whenever the necessary pharmacokinetic data can be obtained.

Animals↗
PubMed1994

Sensitivity of physiologically based pharmacokinetic models to variation in model parameters: methylene chloride.

The parameters in a physiologically based pharmacokinetic (PBPK) model of methylene chloride were varied systematically, and the resulting variation in a number of model outputs was determined as a function of time for mice and humans at several exposure concentrations. The importance of the various parameters in the model was highly dependent on the conditions (concentration, species) for which the simulation was performed and the model output (dose surrogate) being considered. Model structure also had a significant impact on the results. For sensitivity analysis, particular attention must be paid to conservation equations to ensure that the variational calculations do not alter mass balance, introducing extraneous effects into the model. All of the normalized sensitivity coefficients calculated in this study ranged between -1.12 and 1, and most were much less than 1 in absolute value, indicating that individual input errors are not greatly amplified in the outputs. In addition to ranking parameters in terms of their impact on model predictions, time-dependent sensitivity analysis can also be used as an aid in the design of experiments to estimate parameters by predicting the experimental conditions and sampling points which will maximize parameter identifiability.

Animals↗
PubMed1994

Physiologically based pharmacokinetic model for the inhibition of acetylcholinesterase by organophosphate esters.

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 greatly improve OP risk assessment. To this end, a physiologically based model for diisopropylfluorophosphate (DFP) pharmacokinetics and acetylcholinesterase (AChE) inhibition was developed. 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 pharmacokinetic data from mice and rats. Literature data were used for model validation. DFP concentrations in mouse plasma and brain, as well as AChE inhibition and AChE resynthesis data, were successfully simulated for a single iv injection. Effects of repeated, subcutaneous DFP dosing on AChE activity in rat plasma and brain were also well simulated except for an apparent decrease in basal AChE activity in the brain which persisted 35 days after the last dose. The psychologically based pharmacokinetic (PBPK) model parameter values specific for DFP in humans, for example, tissue/blood partition coefficients, enzymatic and nonenzymatic DFP hydrolysis rates, and bimolecular inhibition rate constants for target enzymes were scaled from rodent data or obtained from the literature. Good agreement was obtained between model predictions and human exposure data on the inhibition of red blood cell AChE and plasma butyrylcholinesterase after an intramuscular injection of 33 micrograms/kg DFP and at 24 hr after acute doses of DFP (10-54 micrograms/kg), as well as for repeated DFP exposures.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1994

Physiologically based pharmacokinetic analyses of simple mixtures.

Exposure to multiple chemicals may cause significant alterations of tissue dose of the toxic moiety of one or more of the individual chemicals. The change in target tissue dose of a chemical present in simple mixtures can be predicted when the determinants of disposition of each chemical, and the mechanism of toxicokinetic interaction between chemicals are understood at a quantitative level. Determinants of disposition include physiological (e.g., breathing rates, cardiac output, tissue volumes, blood flow rates), biochemical (e.g., kinetic constants for metabolism and protein binding), and physicochemical factors (e.g., blood air and tissue blood partition coefficients). Mechanisms of toxicokinetic interactions refer to the manner in which coexposure alters these determinants of disposition as compared to exposure to the individual chemicals. Interactions between chemicals can be described quantitatively with physiologically based pharmacokinetic (PBPK) models, which integrate these mechanic determinants and permit prediction of alterations in tissue dose for various exposure situations by computer simulation. PBPK modeling studies of binary chemical interactions conducted so far indicate that inhibitory rather than potentiating metabolic interactions are more likely to be observed during multiple chemical exposures. As PBPK models of representative binary, tertiary and quaternary mixtures are developed, it will become increasingly possible to draw reliable conclusions about the risk associated with human exposure to chemical mixtures.

Animals↗
PubMed1993

Coupling of computer modeling with in vitro methodologies to reduce animal usage in toxicity testing.

The use of in vitro data to support the development of physiologically based pharmacokinetic (PBPK) models and to reduce the requirement for in vivo testing is demonstrated by three examples. In the first example, polychlorotrifluoroethylene, in vitro studies comparing metabolism and tissue response in rodents and primates made it possible to obtain definitive data for a human risk assessment without resorting to additional in vivo studies with primates. In the second example, a PBPK model for organophosphate esters was developed in which the parameters defining metabolism, tissue partitioning, and enzyme inhibition were all characterized by in vitro studies, and the rest of the model parameters were established from the literature. The resulting model was able to provide a coherent description of enzyme inhibition following both acute and chronic exposures in mice, rats, and humans. In the final example, the carcinogenic risk assessment for methylene chloride was refined by the incorporation of in vitro data on human metabolism into a PBPK model.

Animal Testing Alternatives↗
PubMed1993

Variability of physiologically based pharmacokinetic (PBPK) model parameters and their effects on PBPK model predictions in a risk assessment for perchloroethylene (PCE).

When used in the risk assessment process, the output from physiologically based pharmacokinetic (PBPK) models has usually been considered as an exact estimate of dose, ignoring uncertainties in the parameter values used in the model and their impact on model predictions. We have collected experimental data on the variability of key parameters in a PBPK model for tetrachloroethylene (PCE) and have used Monte Carlo analysis to estimate the resulting variability in the model predictions. Blood/air and tissue/blood partition coefficients and the interanimal variability of these data were determined for tetrachloroethylene (PCE). The mean values and variability for these and other published model parameters were incorporated into a PBPK model for PCE and a Monte Carlo analysis (n = 600) was performed to determine the effect on model predicted dose surrogates for a PCE risk assessment. For a typical dose surrogate, area under the blood time curve for metabolite in the liver (AUCLM), the coefficient of variation was 25% and the mean value for AUCLM was within a factor of two of the maximum and minimum values generated in the 600 simulations. These calculations demonstrate that parameter uncertainty is not a significant potential source of variability in the use of PBPK models in risk assessment. However, we did not in this study consider uncertainties as to metabolic pathways, mechanism of carcinogenicity, or appropriateness of dose surrogates.

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↗
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↗