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Biomedical subjects

J W Fisher

Publications and source records attributed to J W Fisher.

At least 19 recordsLinked to original sources
PubMed1995

A computer program linking physiologically based pharmacokinetic model with cancer risk assessment for breast-fed infants.

The risk assessment process predicts the chances of adverse health effects that the toxicant possibly can do to the target organism under expected conditions of exposure. Regulators chose among several mathematical approaches to estimate the risk, but in each case it is necessary to link the dosemetrics of the toxicant with its predicted health effect. In this paper, a computer program is described that allowed us to link a physiologically based pharmacokinetic (PBPK) model for tetrachloroethylene (PCE) in the lactating mother with the estimate of extra cancer risk for breast-fed infants, according to the U.S. Environmental Protection Agency (EPA) methodology. When inhaled by a lactating woman, PCE may partition into breast milk and may be transferred to the breast-fed infant. We have developed and validated experimentally a PBPK model for lactational transfer of PCE in rats, including a quantitative description of a milk compartment and the nursing pup. Subsequently, the model has been scaled to describe human physiology, and was validated with literature data for human cases of PCE exposure. Finally, we linked the dosage predictions of the PBPK model with equations used by EPA to estimate the cancer risk from PCE. The model predictions are in good agreement with both the measured values and those reported in the literature for exposure to PCE. This comparison confirms the usefulness of PBPK modeling in risk assessments.

Air Pollutants↗
PubMed1995

A trichloroethylene risk assessment using a Monte Carlo analysis of parameter uncertainty in conjunction with physiologically-based pharmacokinetic modeling.

A Monte Carlo simulation is incorporated into a risk assessment for trichloroethylene (TCE) using physiologically-based pharmacokinetic (PBPK) modeling coupled with the linearized multistage model to derive human carcinogenic risk extrapolations. The Monte Carlo technique incorporates physiological parameter variability to produce a statistically derived range of risk estimates which quantifies specific uncertainties associated with PBPK risk assessment approaches. Both inhalation and ingestion exposure routes are addressed. Simulated exposure scenarios were consistent with those used by the Environmental Protection Agency (EPA) in their TCE risk assessment. Mean values of physiological parameters were gathered from the literature for both mice (carcinogenic bioassay subjects) and for humans. Realistic physiological value distributions were assumed using existing data on variability. Mouse cancer bioassay data were correlated to total TCE metabolized and area-under-the-curve (blood concentration) trichloroacetic acid (TCA) as determined by a mouse PBPK model. These internal dose metrics were used in a linearized multistage model analysis to determine dose metric values corresponding to 10(-6) lifetime excess cancer risk. Using a human PBPK model, these metabolized doses were then extrapolated to equivalent human exposures (inhalation and ingestion). The Monte Carlo iterations with varying mouse and human physiological parameters produced a range of human exposure concentrations producing a 10(-6) risk.

Administration, Inhalation↗
PubMed1995

Nitric oxide enhancement of erythropoietin production in the isolated perfused rat kidney.

We have previously reported that nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cGMP) may be involved in the regulation of erythropoietin (Epo) production in response to hypoxia both in vivo and in vitro (20). In the present studies, we have used the isolated perfused rat kidney to assess the role of NO in oxygen sensing and Epo production. When arterial PO2 was reduced from 100 mmHg (normoxemic) to 30 mmHg (hypoxemic) in the perfusate of this system, perfusate levels of Epo were significantly increased. This hypoxia-induced increase in Epo production was significantly decreased by the addition of NG-nitro-L-arginine methyl ester (L-NAME; 1 mM) to the perfusates. Hypoxemic perfusion also produced a significant increase, and L-NAME significantly inhibited this increase, in intracellular cGMP levels in the kidney when compared with normoxemic perfused kidneys. Quantitative reverse transcription-polymerase chain reaction also revealed that hypoxemic perfusion produced significant increases in Epo mRNA levels in the kidney, which was blocked by L-NAME. Our findings further support an important role for the NO/cGMP system in hypoxic regulation of Epo production.

Animals↗
PubMed1995

Enhancement of erythropoietin production by selective adenosine A2 receptor agonists in response to hypoxia.

The purpose of this study was to characterize the effects of two new adenosine A2 agonists, 2-(p-(2-carboxyethyl)phenethyl amino)-5'-N-ethylcarboxamidoadenosine (CGS-21680) and N6-(2(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)-adenosine (DPMA), on erythropoietin (EPO) production in vivo and in vitro. Intravenous injections of CGS-21680 (100 to 500 nmol/kg mouse/day) and DPMA (50 to 500 nmol/kg mouse/day) for 4 days produced significant increases in serum levels of EPO in exhypoxic polycythemic mice. CGS-21680 (10(-7) to 10(-6) mol/L) and DPMA (10(-8) to 10(-5) mol/L) also produced significant increases in medium levels of EPO in a cloned EPO-producing Hep3B hepatocellular carcinoma cell line after 18 hours of incubation in 1% O2. Both compounds also increased cellular cAMP levels significantly in a dose-dependent manner after 1 hour of incubation. A2 receptor binding assays with tritiated CGS-21680 revealed a single type of adenosine receptor binding site on Hep3B cell membranes with a dissociation constant of 132.9 nmol/L and a binding capacity of 270.6 fmol/mg protein. The Ki competition binding values versus tritiated CGS-21680 were 217 nmol/L for CGS-21680 and 86.8 nmol/L for DPMA. These results indicate that adenosine A2 receptor activation amplifies EPO production in response to hypoxia, both in vivo and in vitro.

Adenosine↗
PubMed1994

Dose-dependent metabolism of 2,2-dichloro-1,1,1-trifluoroethane: a physiologically based pharmacokinetic model in the male Fischer 344 rat.

2,2-Dichloro-1,1,1-trifluorethane (HCFC-123) is used industrially as a refrigerant, as a foam blowing agent, and as a solvent. It is also being considered as a replacement for halons and chlorinated fluorocarbons which have been banned by the Montreal Protocol because they deplete atmospheric ozone. Male Fischer 344 rats were exposed to 1.0, 0.1, and 0.01% HCFC-123 by inhalation. Parent compound was measured in blood, fat, and exhaled breath and trifluoroacetic acid (TFA) was measured in blood and urine. A physiologically based pharmacokinetic (PBPK) model was developed which included a gut compartment and a variable size fat compartment in addition to the standard flow-limited compartments. Compartment volumes and flows were chosen from the literature, partition coefficients were measured in the laboratory, and metabolic parameters were optimized from experimental data using model simulations. Laboratory experiments showed that the TFA blood concentration during the 1.0% exposure was more than 50% less than the TFA blood concentration during the 0.1% exposure. After cessation of the 4-hr exposure, TFA blood concentrations from the 1.0% exposure rebounded and peaked between 12 and 26 hr after the exposure at about the same concentration as the 0.1% peak. This rebound phenomenon suggested that it was not killing of the metabolic enzymes but substrate inhibition that made the TFA blood concentrations lower than expected. Substrate inhibition by halothane, a structural analog of HCFC-123, has been described in the literature. Only by including a term for substrate inhibition in the PBPK model could pharmacokinetic data for TFA in blood be simulated adequately. This combination of laboratory experimentation and PBPK modeling can be applied to relate the levels of parent and metabolite to toxic effects with some hope of elucidating the toxic species. This work is the first step toward developing models that can be used to predict the toxicokinetics of HCFC-123 in humans throughout various potential use scenarios.

Adipose Tissue↗
PubMed1992

The role of hypoxia in renal production of erythropoietin.

Hypoxia is the fundamental stimulus for erythropoietin (EP) production. It is clear that hypoxia increases erythropoietin messenger RNA in a renal cell, which leads to the production of increased amounts of erythropoietin in the kidney. Hypoxia also increases external messenger substances that amplify the effects of hypoxia and increases erythropoietin messenger RNA to further accelerate erythropoietin production. Some of these messenger substances are adenosine, eicosanoids, oxygen-derived metabolites, and beta-2 adrenergic agonists that are postulated to act through the activation of cell membrane receptors and are coupled to an increase in a G stimulatory protein which activates adenylate cyclase. This leads to increased production of cyclic adenosine monophosphate (AMP) for the production of key phosphoproteins that are involved in the biosynthesis/secretion of erythropoietin. This paper considers the physicochemical properties of human erythropoietin, pharmacologic agents that increase and decrease erythropoietin production/secretion, serum erythropoietin levels in normal human subjects and in patients with several types of anemia, and a model for the role of adenosine and other external messenger substances in erythropoietin biosynthesis/secretion.

Adenosine↗
PubMed1992

Characterization of erythropoietin production in a hepatocellular carcinoma cell line.

This study reports the effects of cyclic adenosine 3'-5' monophosphate (cAMP) and hypoxia on erythropoietin biosynthesis in an erythropoietin-producing hepatocellular carcinoma cell line (Hep3B). Erythropoietin levels in the medium and cell extracts of low-density Hep3B cells after 20-hour incubation under hypoxic conditions (1% O2) were 25.33 +/- 1.50 mU/ml/10(7) cells and 3.60 +/- 0.50 mU/10(7) cells, respectively. These levels were significantly higher than in the respective normoxic controls (medium, 2.51 +/- 0.31 mU/ml/10(7) cells; cell extracts, undetectable [less than 0.31 mU/10(7) cells]). Cobalt also produced a significant increase in medium and cell erythropoietin levels. However, hypoxia and cobalt alone failed to produce an increase in cAMP accumulation in the cell cultures. Erythropoietin levels in the medium and cell extracts from cells exposed to 8-bromo cAMP (1 x 10(-4) mol/L) and forskolin (4 x 10(-6) mol/L) in a hypoxic atmosphere were significantly (p less than 0.05) higher than in the respective hypoxic controls. In addition, forskolin produced a significant (p less than 0.05) increase in cAMP accumulation (180 +/- 11.5 pmol/10(6) cells) under hypoxic conditions compared with the hypoxic controls (cAMP, 2.27 +/- 0.33 pmol/10(6) cells). These results suggest that cAMP elevation is not required in vitro in Hep3B cells for the increase in medium and cell levels of erythropoietin after hypoxia, but may be involved indirectly in erythropoietin biosynthesis, secretion, or both in vivo through some synergistic action with hypoxia.

8-Bromo Cyclic Adenosine Monophosphate↗
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

Polyamines in the anemia of end-stage renal disease.

The improvement in the anemia in patients with end-stage renal disease (ESRD) on continuous ambulatory peritoneal dialysis (CAPD) suggests that dialyzable substances present in the sera of uremic patients either inhibit erythropoiesis directly or inactivate erythropoietin (EPO). In the present study predialysis sera from patients with ESRD inhibited erythroid colony (CFU-E) (N = 10) formation to a significantly (P less than 0.01) greater degree than granulocyte-macrophage (CFU-GM) (N = 7) colony formation in mouse bone marrow (MBM) cultures. The polyamines spermine (SP) (18 to 560 nm/ml) and spermidine (SD) (4 to 648 nm/ml) exerted a more significant (P less than 0.05) inhibition of CFU-E (N greater than or equal to 5) than that of CFU-GM (N greater than or equal to 5) growth. Concentrations of 0.80, 1.0, and 1.5 nm/ml of putrescine (PU) were 92%, 85%, and 77% of erythroid colony (CFU-E) controls (N = 4) and 104%, 130%, and 127% of CFU-GM controls (N = 4). Putrescine (PU) at 1.5 nm/ml also produced a significant (P less than 0.05) inhibition of CFU-E, whereas CFU-GM were stimulated by PU. These data suggest that predialysis sera from uremic patients, as well as SP, SD, and PU, are selectively more inhibitory to CFU-E than CFU-GM growth. The immunoreactivity of EPO was not significantly changed when it was coincubated with SP, SD and PU and measured by radioimmunoassay. PU was found to inhibit noncompetitively the bioactivity of EPO in a CFU-E assay. These data support the hypothesis that polyamines may be important uremic toxins in the anemia of ESRD.

Anemia↗
PubMed1991

Increased erythropoietin secretion in human hepatoma cells by N6-cyclohexyladenosine.

The present studies were undertaken to assess the direct effects of N6-cyclohexyladenosine (CHA), a stable adenosine analogue, on erythropoietin (Ep) secretion in hepatocellular carcinoma cells (Hep 3B). Ep levels in the medium of low density Hep 3B cells treated with CHA in concentrations of 10(-5) and 5 x 10(-5) M for 20 h under hypoxic conditions (1% O2) were significantly higher than that of hypoxic controls. In addition, CHA at the same concentrations produced significant increases in adenosine 3',5'-cyclic monophosphate (cAMP) levels in Hep 3B cells after 1-h incubation under hypoxic conditions when compared with hypoxic controls. Dibutyryl cAMP (10(-5), 10(-4) M) also caused significant increases in Ep secretion when compared with control hypoxic cells. On the other hand, 8-phenyltheophylline, an adenosine receptor antagonist, significantly inhibited the stimulatory effects of CHA on both Ep secretion and cAMP accumulation in the Hep 3B cell cultures in response to hypoxia. These data suggest that Ep secretion may be regulated by adenosine receptor-coupled activation of adenylyl cyclase and the generation of cAMP.

Adenosine↗
PubMed1991

Von Hippel-Lindau disease and erythrocytosis: radioimmunoassay of erythropoietin in cyst fluid from a brainstem hemangioblastoma.

A 59-year-old woman with von Hippel-Lindau disease developed erythrocytosis and a recurrent intracranial hemangioblastoma. Radioimmunoassay showed an elevated level of erythropoietin in her serum. Cyst fluid from the tumor also contained erythropoietin, concentrated a thousandfold relative to the serum level. Production of erythropoietin by hemangioblastomas may explain the erythrocytosis present in some patients with von Hippel-Lindau disease.

Brain Neoplasms↗
PubMed1990

Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation.

BACKGROUND: Erythrocytosis occurs in 10 to 15 percent of renal-transplant recipients, and there is in vitro evidence that the production of erythropoietin is modulated by adenosine. METHODS: We prospectively evaluated the effects of theophylline, a nonselective adenosine antagonist, in eight patients with erythrocytosis after renal transplantation and in five normal controls. RESULTS: After an eight-week course of theophylline treatment, the mean (+/- SEM) serum erythropoietin levels were significantly reduced in both the renal-transplant recipients (from 60 +/- 14 units per liter at base line to 9 +/- 7 units after treatment; P less than 0.05) and the normal subjects (from 6.9 +/- 0.8 units per liter at base line to 4.7 +/- 0.5 units per liter after treatment; P less than 0.05). Similarly, the hematocrits were reduced in both the transplant recipients (from 0.58 +/- 0.04 at base line to 0.46 +/- 0.03 after treatment; P less than 0.05) and the normal subjects (from 0.43 +/- 0.01 at base line to 0.39 +/- 0.01; P less than 0.05). In the renal-transplant recipients, red-cell mass was also reduced after eight weeks of theophylline (from 3197 +/- 82 ml at base line to 2273 +/- 69 ml after treatment; P less than 0.05). The previous requirement of weekly phlebotomy was eliminated in all recipients. Plasma and urinary cyclic AMP levels were not increased. These effects were reproducible when the subjects were rechallenged with theophylline after a recovery period. CONCLUSIONS: Theophylline attenuates the production of erythropoietin in both normal subjects and patients with erythrocytosis after renal transplantation and may be useful in the treatment of the latter condition.

Adult↗
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

Development of a new radioimmunoassay for erythropoietin using recombinant erythropoietin.

The development of a 24 hour radioimmunoassay for erythropoietin (EPO) using EPO derived from recombinant DNA as both immunogen and ligand is described in the present paper. Mixed breed rabbits immunized with 10 micrograms/kg of EPO derived from a stably transfected cell line (Elanex Pharmaceuticals Inc., Bothel, Washington, USA, through McDonnell Douglas Corp., St. Louis, Missouri, USA; "MD") produced antibodies to EPO with high titer (up to 1:896,000 final dilution in the tube), high affinity (8.4 x 10(11) liter/M), and good specificity. Purified EPO from the above source or from AmGen Biologicals (Thousand Oaks, California, USA; "AG") were successfully radioiodinated with the chloramine-T method and used as ligand in the radioimmunoassay. Standard dose-response curves prepared with EPO from both commercial sources were not significantly different and showed a sensitivity of 0.75 to 0.96 mU/tube. The dose-response curves in both systems also showed parallelism with serially diluted serum from a patient with aplastic anemia. Within-assay and between-assay precision were determined by assaying multiple replicates of a serum pool. Recovery of exogenous EPO added to a serum pool averaged 97% for both systems. The range of normal human serum EPO was determined by assaying the sera of 153 hematologically-normal adult subjects and was found to be 1.1 to 27.3 mU/ml for MD EPO and 0.5 to 16.7 mU/ml for AG EPO. Sera from several patients with hematologic abnormalities were also assayed, including those of 36 patients with anemia of end-stage renal disease (mean +/- SEM, 29.5 +/- 4.0 mU/ml; P less than 0.01). In conclusion, this new, more rapid and sensitive radioimmunoassay system can be used to measure EPO levels in sera from normal human subjects and patients with several types of anemia, and should also be very useful in therapeutic drug monitoring of patients receiving EPO from various commercial sources.

Anemia↗
PubMed1990

Increased secretion of erythropoietin in human renal carcinoma cells in response to atrial natriuretic factor.

The present studies were undertaken to assess the effects of atrial natriuretic factor (ANF) on erythropoietin (Ep) secretion in Ep-producing renal carcinoma (RC) cells using a sensitive radioimmunoassay for Ep. Human ANF produced a significant dose-related increase in Ep secretion at concentrations of 10(-7) and 10(-6) M when compared with vehicle controls. ANF (greater than or equal to 10(-9) M) also significantly increased the intracellular guanosine 3',5'-cyclic monophosphate (cGMP) concentration after 5-min incubation with the RC cells. Scatchard analysis of the human 125I-labeled ANF binding data indicated that the RC cells contain a single class of binding sites with a dissociation constant (Kd) of 93 +/- 1 pM and a binding capacity of 2,190 +/- 750 sites/cell. Incubation of the RC cells with 8-bromo-cGMP in concentrations of 10(-7)-10(-5) M also produced a significant dose-related enhancement of Ep secretion. These findings suggest that the increase in Ep secretion in response to ANF can be attributed, at least in part, to activation of guanylate cyclase, which is coupled to specific ANF receptors on the RC cell.

Atrial Natriuretic Factor↗
PubMed1989

Measurement of erythropoietin in anephric children. A report of the Southwest Pediatric Nephrology Study Group.

Serum erythropoietin (Ep) levels were measured using a highly sensitive radioimmunoassay in 69 children undergoing chronic dialysis; 31 were anephric, whereas 38 were non-nephrectomized (nephric). Twenty-nine normal children were studied as controls. Serum Ep levels in the anephric group were much higher than anticipated (mean 19.7 +/- 1.8 mU/ml), albeit significantly lower than those measured in normal children (mean 26.2 +/- 2.4 mU/ml, P less than 0.05), or in nephric children on dialysis (33.0 +/- 2.9 mU/ml, P less than 0.001). Anephric children on peritoneal dialysis (PD) had significantly (P less than 0.05) higher serum levels of Ep (22.7 +/- 2.4 mU/ml, n = 19) than anephric children on hemodialysis (HD) (15.1 +/- 2.3 mU/ml, n = 12). There was no significant difference between Ep levels in anephric patients dialyzed for less than or equal to 1 year (19.6 +/- 2.0 mU/ml, n = 20) compared with anephric patients dialyzed for more than 1 year (20.0 +/- 3.9 mU/ml, n = 11). Although serum Ep levels showed a tendency to increase with time after nephrectomy, the mean values for less than 3 months (14.7 +/- 1.9), 3 months-12 months (21.0 +/- 2.7), and greater than 12 months (21.6 +/- 6.0) were not significantly different from each other. This demonstration of relatively normal levels of serum Ep in anephric children suggests that extrarenal sites of Ep production are able to exert a significant response to severe anemia in patients who are devoid of renal parenchyma.

Adolescent↗
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↗