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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

Determination of skin:air partition coefficients for volatile chemicals: experimental method and applications.

The partition coefficient (PC) of a chemical in skin is an indicator of the capacity for a chemical in the skin and may reflect the rate at which a chemical penetrates the skin and enters into systemic circulation. In this study we present a simple method to measure the skin:air PC for volatile organic chemicals. Important considerations in the development of this method for a skin:air PC were the effect of size and shape of the skin sample, initial chemical concentration, and time to equilibrium in the skin. Clipped, whole-thickness skin was obtained from the dorsal surface of 8- to 16-week-old male F-344 rats. After removal of the hypodermis, skin was cut into strips and placed on the side of a glass vial. An organic chemical vapor was introduced into a sealed sample vial (initial concentration before equilibration was 203 ppm) and a corresponding reference vial, which were equilibrated at 32 degrees C. Headspace concentrations at equilibrium were used to determine a skin:air PC value. After developing the technique using dibromomethane, a skin:air PC value was determined for perchloroethylene, trichloroethylene, benzene, hexane, toluene, m-xylene, styrene, methyl chloroform, methylene chloride, carbon tetrachloride, halothane, and isoflurane. The skin:air PC values correlated with previously determined vapor permeability constants but correlated poorly with octanol/water PC values. This method provides a screening technique for predicting skin penetration of volatile chemicals.

Air↗
PubMed1994

Computer simulation of the lactational transfer of tetrachloroethylene in rats using a physiologically based model.

A physiologically based pharmacokinetic (PBPK) model describing transfer of inhaled tetrachloroethylene (PCE) into breast milk with the consequent exposure of the nursing pups was developed and validated in lactating rats. The PBPK model was based on partition coefficients (PCs), which were determined by the equilibration of tissues with known concentrations of PCE vapor. The blood/air and milk/blood PCs for the dam were 33.5 and 12.0, the liver/blood and fat/blood PCs for the dam were 1.9 and 42.4, and the slowly perfused tissues/blood and rapidly perfused tissues/blood PCs for the dam were 0.9 and 1.7, respectively. The blood/air PC for the pup was 24.3, and the solid tissues/blood PC for the pup was 4.5. Metabolic constants were determined by a gas uptake method. The pseudo-maximal velocity of PCE metabolism in the dam was low, 0.03 mg/kg/hr, and the apparent Michaelis-Menten constant was 0.3 mg/liter. The lactating Sprague-Dawley females were exposed to PCE vapor for 2 hr with concentrations ranging from 20 to 1000 ppm PCE. The dams were returned to the pups after exposure and the pups received PCE via breast milk while they nursed. PCE concentrations in the air, blood, milk, and tissues were determined by gas chromatography and compared to PBPK model predictions. Nursing resulted in a peak pup blood PCE concentration of 0.9 mg/liter and a peak pup solid tissue PCE concentration of 8 mg/kg. The PBPK lactation model adequately described the distribution of inhaled PCE in maternal blood and milk, as well as in the nursed pup's gastrointestinal tract, blood, and solid tissues. It is concluded that the predictions based on PBPK modeling for disposition of PCE in lactating rats and their pups were in good agreement with the experimental data.

Administration, Inhalation↗
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↗
PubMed1994

Adenosine A2 receptor modulation of erythropoietin secretion in hepatocellular carcinoma cells.

The present studies were undertaken using a cloned erythropoietin (Ep) producing hepatocellular carcinoma cell line (Hep3B) to attempt to correlate the receptor binding properties and biological activities of 5'-N-ethylcarboxamideadenosine (NECA), N6-cyclohexyladenosine (CHA) and N6-cyclopentyldenosine (CPA). Ep and cAMP levels in cultures of Hep3B cells in response to these adenosine analogues were measured by radioimmunoassay. Receptor binding affinities of the adenosine analogues were determined by measuring inhibition of binding of [3H] NECA to Hep3B cell membranes. Scatchard analysis of [3H]NECA to Hep3B cell membranes. Scatchard analysis of [3H]NECA binding to Hep3B cell membranes indicates a single class of binding sites with a dissociation constant of 431 nM and a binding capacity of 573 fmol/mg protein. The adenosine analogues tested produced a significant increase in Ep secretion and cAMP accumulation (ED50 for cAMP accumulation, NECA = 3.3 x 10(-7) M, CHA = 4.2 x 10(-6) M, CPA = 2.2 x 10(-6) M). In addition, NECA showed a higher binding affinity (Ki, 3.8 x 10(-7) M) for Hep3B cell membranes in comparison with CHA (Ki, 6.3 x 10(-6) M) and CPA (Ki, 3.9 x 10(-6) M). These results indicate that the rank order for potency for NECA, CHA and CPA in their binding to Hep3B cell membrane receptors correlates very well with their biological effects on Ep secretion and cAMP accumulation in Hep3B cells.

Adenosine↗
PubMed1994

Mechanistic insights aid the search for CFC substitutes: risk assessment of HCFC-123 as an example.

An international consensus on the need to reduce the use of chlorofluorocarbons (CFCs) and other ozone-depleting gases such as the halons led to the adoptions of the 1987 Montreal Protocol and Title VI of the 1990 Clean Air Act Amendments, "Protecting Stratospheric Ozone." These agreements included major provisions for reducing and eventually phasing out production and use of CFCs and halons as well as advancing the development of replacement chemicals. Because of the ubiquitous use and benefits of CFCs and halons, an expeditious search for safe replacements to meet the legislative deadlines is of critical importance. Toxicity testing and health risk assessment programs were established to evaluate the health and environmental impact of these replacement chemicals. Development and implementation of these programs as well as the structural-activity relationships significant for the development of the replacement chemicals are described below. A dose-response evaluation for the health risk assessment of the replacement chemical HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) is also presented to show an innovative use of physiologically based pharmacokinetic (PBPK) modeling. This is based on a parallelogram approach using data on the anesthetic gas halothane, a structural analog to HCFC-123. Halothane and HCFC-123 both form the same metabolite, trifluoroacetic acid (TFA), indicative of the same metabolic oxidative pathway attributed to hepatotoxicity. The parallelogram approach demonstrates the application of template model structures and shows how PBPK modeling, together with judicious experimental design, can be used to improve the accuracy of health risk assessment and to decrease the need for extensive laboratory animal testing.

Air Pollutants↗
PubMed1994

Lactational transfer of tetrachloroethylene in rats.

Tetrachloroethylene (PCE) is a commonly used organic solvent and a suspected human carcinogen, reportedly transferred to human breast milk following inhalation exposure. Transfer of PCE to milk may represent a threat to the nursing infant. A physiologically based pharmacokinetic (PBPK) model was developed to quantitatively assess the transfer of inhaled PCE into breast milk and the consequent exposure of the nursing infant. The model was validated in lactating rats. Lactating Sprague-Dawley female rats were exposed via inhalation to PCE at concentrations ranging from 20-1000 ppm, and then returned to their nursing, 10- to 11-day-old pups. Tetrachloroethylene concentrations in the air, blood, milk, and tissue were determined by gas chromatography and compared to model predictions. The model described the distribution of inhaled PCE in maternal blood and milk, as well as the nursed pup's gastrointestinal tract, blood, and tissue. Several computer simulations of PCE distribution kinetics in exhaled air, blood, and milk of exposed human subjects were run and compared with limited human data available from the literature. It is concluded that the PBPK model successfully described the concentration of PCE in both lactating rats and humans. Although predictions vs. observations were good, the model slightly underpredicted the peak whole pup PCE concentration and underpredicted systemic clearance of PCE from the pup.

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↗