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Biomedical subjects

M E Andersen

Publications and source records attributed to M E Andersen.

162 records · Page 9Linked to original sources
PubMed1977

Oral toxicity of 1,1-dichloroethylene in the rat: effects of sex, age, and fasting.

Mortality curves for groups of fasted male rats treated with single, oral doses of 1,1-dichloroethylene (1,1-DCE, vinylidene chloride) were not monotonically increasing sigmoids, but were complex with maxima or extended plateaus in the region of dose between 100 and 700 mg of 1,1-DCE/kg. The exact shape was a function of the size (age) of the rat used. When groups of rats of various sizes were dosed with 50 mg/kg, mortality and hepatotoxicity were greatest for those groups whose average weight was between 100 and 150 g. Smaller and larger male rats were less susceptible to 1,1-DCE intoxication. The toxicity of 1,1-DCE was less severe in female rats and there was no significant effect of rat size on 1,1-DCE toxicity in females. In rats of both sexes the dose dependence of the hepatotoxic response was complex, possessing a threshold level, a region of precipitous increase, and a plateau, where larger doses were ineffective in increasing hepatotoxicity. The threshold in male rats of 100-150 g occurred near 50 mg/kg, and for females it was closer to 100 mg/kg. Considered in their entirety these data suggest that 1,1-DCE is metabolized to a toxic intermediate via some saturable pathway. Based on the effects of pretreatment with microsomal enzyme inhibitors and activators on 1,1-DCE toxicity in rats of various sizes, it appears that there are at least two microsomal reactions involved in 1,1-DCE metabolism.

Administration, Oral↗
PubMed1976

Sulfolane-induced convulsions in rodents.

In rodents oral or parenteral administration of sulfolane (tetrahydrothiophene-1,1-dioxide) produced hyperactivity, followed by clonic-tonic convulsions. The analeptic effects of sulfolane were nearly additive with those of Metrazol. When injected simultaneously with pentobarbital, sulfolane decreased pentobarbital sleeping time in mice. But sulfolane increased sleeping time when the barbiturate was administered 1 hr after sulfolane.

Administration, Oral↗
PubMedDate not supplied

Development of a physiologically based pharmacokinetic model for 2,4-dichlorophenoxyacetic acid dosimetry in discrete areas of the rabbit brain.

A basic PBPK model for the dosimetry of organic acids in discrete areas of the brain was constructed using 2,4-D as a model compound. The PBPK model describes distribution of 2,4-D throughout the body and within discrete areas of the brain. The brain compartments in the model were the hypothalamus, caudate nucleus, hippocampus, forebrain, brainstem, and cerebellum. The remainder of the model consisted of two-body compartments and venous and arterial blood compartments. In the model, chemical uptake by the brain was membrane-limited by the blood-brain barrier (BBB) with saturable clearance from the cerebrospinal fluid (CSF) into the venous blood by the choroid plexus. The body has both a central and a deep compartment with saturable clearance from the central compartment. The model was used to examine the brain and CSF concentrations of 2,4-D as a function of plasma 2,4-D, as well as plasma time-course behavior using experimental data from rabbits given 2,4-D 40 or 100 mg/kg, IP or Na-2,4-D 40 mg/kg, i.v. administration. Model parameters were adjusted to fit the observed 2,4-D concentrations in blood and brain regions over a 2-h time frame. PBPK models could be a useful tool for evaluating the safety of this class of organic acids.

2,4-Dichlorophenoxyacetic Acid↗
PubMedDate not supplied

Prediction of in vivo kinetic constants for metabolism of inhaled vapors from kinetic constants measured in vitro.

Benzene and toluene are metabolized by microsomal preparations in a closed metabolism flask. The Km values for benzene and toluene were 8.0 and 10.3 microM; the Vmax values were 17.2 and 20.8 nmol/g liver/min, respectively. By the use of a toxicokinetic model which acknowledges the potential for perfusion limitations on in vivo metabolism, the in vivo Km values (in terms of atmospheric concentration) for benzene and toluene were calculated based on the constants determined in vitro. The predicted in vivo constants were 0.20 and 0.21 mg/L, respectively. In vivo Km values experimentally determined by gas uptake techniques in the same strain of animal were 0.13 and 0.59 mg/L for benzene and toluene, respectively. For benzene predicted values and observed values for Km gave good correlation. The values for toluene did not correlate quite as well. The Vmax values predicted by direct conversion of the values obtained in vitro were 3.3 and 4.7 mg/kg/hr for benzene and toluene, respectively, and agreed well with the respective values observed in vivo of 2.2 and 4.6 mg/kg/hr. The model appeared capable of accurately predicting in vivo Km values from in vitro constants. Vmax values were predicted directly from in vitro constants.

Animals↗
PubMedDate not supplied

A physiologically based description of ethylene oxide dosimetry in the rat.

A physiologically based pharmacokinetic (PB-PK) model providing a quantitative description of ethylene oxide (ETO) dosimetry in the rat was developed by integrating information on physiology, tissue solubility of ETO, and rate constants for ETO metabolism and binding. The PB-PK model consisted of nine compartments; liver, lung, testis, brain, fat, venous blood, arterial blood, richly perfused and poorly perfused tissues. The tissue: air partition coefficients of ETO, determined by vial equilibration, were similar among the various tissues (range 44-83). The rate constants for glutathione (GSH) conjugation, hydrolysis, and hemoglobin (Hb)- and DNA-binding were estimated from published data and by conducting in vivo inhalation exposure studies. The model adequately predicted the concentrations of Hb and DNA adducts, hepatic and extrahepatic GSH, and urinary N-acetyl-S-(2-hydroxyethyl)-cysteine following inhalation exposures of 1.2 to 1,200 ppm and intravenous administration of 1 to 100 mg/kg of ETO in male Fischer-344 and Sprague-Dawley rats. There was no evidence of nonlinearity in the overall elimination of ETO in the dose range examined. However, nonlinearities in the components of this first order elimination process (namely GSH conjugation, hydrolysis, exhalation) were found to occur at high exposure concentrations. Characterization of the individual metabolic pathways that affect the tissue dosimetry of ETO is important for interspecies extrapolation and risk assessment for this chemical.

Animals↗
PubMedDate not supplied

Physiologically-based pharmacokinetic modeling and bioactivation of xenobiotics.

This paper describes the development and implementation of physiologically-based pharmacokinetic (PB-Pk) models to examine the disposition of xenobiotics and their bioactivation. In a PB-Pk model, the structure of the model is based, to as great extent as practicable, on the actual physiological and biochemical structure of the animal system being described. This paper provides an overview of the PB-Pk modeling approach using a series of models as examples. PB-Pk models for styrene and the dihalomethanes are discussed in relation to their ability to predict the kinetics of uptake, distribution, metabolism (bioactivation), and elimination in both rodents and humans. Three models are discussed which demonstrate the process of describing increasing complexity in bioactivation with reference to saturation of metabolism (methylene chloride), suicide enzyme inactivation (trans-1,2-dichloroethylene), and glutathione depletion (allyl chloride). Experimental studies to quantify these particular examples of non-linear kinetics were conducted by closed chamber gas uptake techniques. All of these behaviors can be quantitatively expressed within the framework of a PB-Pk model.

Animals↗
PubMedDate not supplied

Enhancement of 1,1-dichloroethylene toxicity by pretreatment of fasted male rats with 2,3-epoxypropan-1-ol.

The efficacy of pretreatment with various low molecular weight epoxides in increasing the toxicity of orally administered 1,1-dichloroethylene (1,1-DCE) has been determined in fasted male rats. Rats were dosed ip with either 2,3-epoxypropan-1-ol (EP), 1,1,1-trichloropropane-2,3-oxide (TCPO), styrene oxide (SO), cyclohexene oxide (CHO), butadiene monoxide (BMO) or the sulfhydryl reagent, diethylmaleate (DEM) 1 hr before intubation with 1,1-DCE. Increases in plasma aspartate transaminase (AsT) 24 hr after 1,1-DCE intubation were used as a measure of toxicity. In rats pretreated with 278 mg of EP/kg the acute LD50 of 1,1-DCE was reduced by a factor of 5 (to less than 40 mg/kg) and doses of 1,1-DCE as low as 12.5 mg/kg increased AsT levels. While 25 mg of 1,1-DCE/kg did not increase plasma AsT activities in naive rats, this dose did increase AsT levels in rats pretreated with 30 mg of EP/kg. The severity of 1,1-DCE toxicity in EP pretreated rats was greater in large, mature rats than in small, immature rats. On a molar basis the abilities of these various epoxides and DEM to exacerbate 1,1-DCE toxicity were related as follows: EP greater than SO greater than TCPO greater than CHO greater than DEM greater than BMO. These epoxides appeared to increase the toxicity of 1,1-DCE by interfering with the metabolism of a toxic product of the microsomal oxidation of 1,1-DCE.

1-Propanol↗
PubMedDate not supplied

Pharmacokinetic data needs to support risk assessments for inhaled and ingested manganese.

Manganese (Mn)-deficiency or Mn-excess can lead to adverse biological consequences. Central nervous system tissues, rich in dopaminergic neurons, are the targets whether the Mn gains entrance by inhalation, oral ingestion, or intravenous administration. Risk assessments with Mn need to ensure that brain concentrations in the globus pallidus and striatum stay within the range of normal. This paper first provides a critical review of the biological factors that determine the disposition of Mn in tissues within the body. Secondly, it outlines specific data needs for developing a physiologically based pharmacokinetic (PBPK) model for Mn to assist in conducting risk assessments for inhaled and ingested Mn. Uptake of dietary Mn appears to be controlled by several dose-dependent processes: biliary excretion, intestinal absorption, and intestinal elimination. Mn absorbed in the divalent form from the gut via the portal blood is complexed with plasma proteins that are efficiently removed by the liver. Absorption of Mn via inhalation, intratracheal instillation or intravenous infusions bypasses the control processes in the gastrointestinal tract. After absorption into the blood system by these alternate routes, Mn is apparently oxidized by ceruloplasmin and the trivalent Mn binds to the iron carrying protein, transferrin. Brain uptake of Mn occurs via transferrin receptors located in various brain regions. Transferrin-bound trivalent Mn is not as readily removed by the liver, as are protein complexes with divalent Mn. Thus, Mn delivered by these other dose routes would be available for uptake into tissues for a longer period of time than the orally administered Mn, leading to quantitative differences in tissue uptake for different dose routes. Several important data gaps impede organizing these various physiological factors into a multi-dose route PK model for Mn. They include knowledge of (1) oxidation rates of Mn in blood, (2) uptake rates of protein-bound forms of Mn by the liver, (3) neuronal transfer rates within the CNS, and (4) quantitative analyses of the control processes that regulate uptake of ingested Mn by the intestines and liver. These data gaps are the main obstacles to developing a risk assessment strategy for Mn that considers contributions of both inhalation and ingestion of this essential nutrient in determining brain Mn concentrations.

Administration, Oral↗
PubMedDate not supplied

The comparative toxicity of operational Air Force hydraulic fluids.

The subchronic (26 day) oral toxicities of two AF hydraulic fluids (MIL-H-5606 [H5], MIL-H-83282 [H8]), a commercial phosphate ester (PE), and two candidate hydraulic fluids (low temperature version of MIL-H-83282 [LT] and chlorotrifluorethylene oligomers [polyCTFE]) were compared in male F-344 rats. Oral dosing was used in order to quickly compare these fluids to PolyCTFE, the only fluid at the time to have been tested in a 90-day inhalation study. Rats were initially dosed with 1.0 g/kg/day of each fluid. H8 increased alkaline phosphatase (ALKP) while LT produced an anemia and leukocytosis. Exposure to H5 fluid resulted in lymphocytopenia and persistent diuresis. Due to their greater toxicity, resulting in lethality in the first dosing study, only 0.5 g/kg/day of PE and PolyCTFE were administered in the second study. Exposure to PE (0.5 g/kg) resulted in an anemia and decreases in BW (day 10 until day 25), spleen/BW ratio, blood urea nitrogen (BUN), and creatinine (CREAT). PolyCREAT (0.5 g/kg) decreased BW (day 11 to the end of the study) and testicular weight. PolyCTFE (0.5 g/kg) increased relative spleen weights, various clinical chemistry parameters, and triggered a reversible diuresis. PolyCTFE (0.5 g/kg), PE (0.5 g/kg), and H5 produced an increase in absolute and relative liver weights compared to control livers. Peroxisomal beta oxidation, an indicator of peroxisomal proliferation, was significantly increased above control levels in the livers of all rats except the PE (0.5 g/kg) group, where the increase was not significant. Hydrocarbon nephropathy, indicated by increased levels of hyaline droplets in kidney tubules, was severe in H5, mild in H8, LT, and PolyCTFE (0.5 g/kg), and minimal in PE (0.5 g/kg). The MIL-H-83282 fluids (H8 and LT) were the least toxic hydraulic fluids. PolyCTFE and PE were the most toxic, with H5 intermediate.

Administration, Oral↗