Biomedical subjects

M E Andersen

Publications and source records attributed to M E Andersen.

At least 127 records · Page 7Linked to original sources

PubMed1988

The effects of perfluorodecanoic acid on hepatic stearoyl-coenzyme A desaturase and mixed function oxidase activities in rats.

Perfluorodecanoic acid (PFDA) causes a dioxin-like toxic syndrome and alters the hepatic oleate/stearate ratio in rats. The acute toxic effects of a single ip dose (50 mg/kg) of PFDA on hepatic stearoyl-CoA desaturase and mixed function oxidases were studied in male Fischer-344 rats, 14 days after dosing. PFDA causes a marked decrease in food intake in rats, resulting in severe body weight loss with delayed lethality (2-3 weeks after dosing). To distinguish the effects of hypophagia from those caused by PFDA, pair-fed control rats were used in addition to ad libitum-fed controls. Stearoyl-CoA desaturase activity, responsible for the conversion of stearoyl-CoA to oleoyl-CoA, was absent in both PFDA-dosed rats and their pair-fed controls at Day 14. Electron transfer through the desaturase system was significantly reduced in PFDA-treated rats only, and in these rats there was a significant reduction in microsomal cytochrome b5, an important component of this electron transfer system. Pentobarbital sleeping times were significantly prolonged in both the PFDA-dosed and pair-fed rats, as compared with the ad libitum-fed controls. This effect was more pronounced in PFDA-dosed rats. Waking plasma pentobarbital concentration was similar in all treatment groups. Hepatic microsomal cytochrome P-450 content was unaffected. Aminopyrine N-demethylase activity was greatly reduced in PFDA-dosed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Toxicokinetics: an analytical tool for assessing chemical hazards to man.

The Toxic Hazards Division has pioneered the development of toxicokinetic analysis for the study of the toxicity of various chemicals of importance to the U.S. Air Force. Toxicokinetic analysis permits calculation of tissue exposure based on biochemical, physiological, and physical chemical properties of the animal-chemical system. This paper describes the application of toxicokinetic analysis in the study and control of chemical hazards. Physiological models for both carbon tetrachloride and methylene chloride are discussed in relation to their ability to predict human kinetics and their use in estimating the risk of these chemicals to exposed humans. The emerging use of the toxicokinetic approach to analyze the mechanistic basis of chemical carcinogenesis is also discussed.

Aerospace Medicine↗

PubMed1988

Physiological model for tissue glutathione depletion and increased resynthesis after ethylene dichloride exposure.

Ethylene dichloride (EDC) is metabolized by two competing pathways both of which consume glutathione (GSH). EDC undergoes oxidation to form chloroacetaldehyde (CAA) which is detoxified by GSH and also reacts directly with GSH to form 2-(s-chloroethyl)-GSH. A physiological pharmacokinetic model developed for EDC was extended to describe tissue GSH turnover and its depletion after EDC exposures. This GSH model was necessary to keep track of GSH concentrations with time, as EDC metabolism is affected by GSH status. Reactions of GSH with EDC and GSH with CAA were defined as second-order. Steady-state GSH formation was modeled as zero-order and GSH loss as first-order. GSH rebound effects after its depletion were controlled by a GSH synthetase reaction, which allowed time- and GSH concentration-dependent feedback for increased GSH resynthesis. The model was developed for liver GSH in the rat and was extrapolated to include the lung. Allometric scaling was used to extrapolate the model to other animal species. Experimental observations in the rat and mouse were consistent with model predictions.

Animals↗

PubMed1987

Quantitative evaluation of the metabolic interactions between trichloroethylene and 1,1-dichloroethylene in vivo using gas uptake methods.

Gas uptake simulation methods were used to determine kinetic constants for trichloroethylene (TCE) and 1,1-dichloroethylene (1,1-DCE) metabolism in vivo in male Fischer 344 rats. Both are metabolized by single, saturable, oxidative pathways with high-affinity substrate binding. The allometrically scaled maximum velocities (Vmaxc) for TCE and 1,1-DCE were, respectively, 11 and 7.5 mg/hr (i.e., 84 and 77 mumol/hr). Gas uptake studies were also conducted with three mixed atmosphere exposures with the following initial concentrations in parts per million: 500 (1,1-DCE):2000 (TCE); 500 (1,1-DCE):500 (TCE); and 2000 (1,1-DCE):500 (TCE). Mixture uptake curves were described by a system of equations in which a full physiologically based pharmacokinetic (PB-PK) model was provided for each chemical and each was regarded as an inhibitor of the other's metabolism. A generic model was developed to accommodate multiple mechanisms of inhibitory interactions, i.e., competitive, noncompetitive, or uncompetitive. An excellent correspondence was obtained between predicted and observed behavior when the inhibition was assumed to be purely competitive with binding constants for TCE and 1,1-DCE set to 0.25 and 0.10 mg/liter, respectively; i.e., in vivo 1,1-DCE is a slightly better substrate for microsomal oxidation than is TCE. The PB-PK model which was successful in describing the mixture data was used to predict conditions under which 1,1-DCE hepatotoxicity would be expected in coexposure to constant concentration atmospheres of these two chloroethylenes. These predictions were compared with data on the increases in plasma liver enzymes resulting from exposures to either 1,1-DCE alone or to 1,1-DCE in combination with TCE.

Animals↗

PubMed1987

Physiologically based pharmacokinetics and the risk assessment process for methylene chloride.

Methylene chloride (dichloromethane, DCM) is metabolized by two pathways: one dependent on oxidation by mixed function oxidases (MFO) and the other dependent on glutathione S-transferases (GST). A physiologically based pharmacokinetic (PB-PK) model based on knowledge of these pathways was used to describe the metabolism of DCM in four mammalian species (mouse, rat, hamster, and humans). Kinetic constants for the model were derived from in vivo experiments or the literature. The model was constructed to distinguish contributions from the two pathways of metabolism in lung and liver tissue, and to permit extrapolation from rodents to humans. Model validation was conducted by comparing predicted blood concentration time-course data in rats, mice, and humans with experimental data from these species. The tumor incidence in two chronic studies of DCM toxicity in mice was correlated with various measures of target tissue dose calculated with the PB-PK model. Tumor incidence correlated well with tissue AUC (area under the concentration/time curve) and amount of DCM metabolized by the GST pathway. However, tumor incidence did not correlate with the amount of DCM metabolized by the MFO pathway. Because of its low chemical reactivity, DCM is unlikely to be directly involved in carcinogenesis. Consequently, metabolism of DCM by GST appears to be important in carcinogenesis. The PB-PK model was used to estimate target doses of presumed toxic chemical species in humans exposed to DCM by inhalation or by drinking water. Target tissue doses in humans exposed to low concentrations of DCM are 140- to 170-fold lower (inhalation) or 50- to 210-fold lower (drinking water) than would be expected from the linear extrapolation and body surface area factors which have been used in conventional risk assessment methods (D. V. Singh, H. L. Spitzer, and P. D. White (1985). Addendum to the Health Assessment Document for Dichloromethane (Methylene Chloride). EPA/600/8-82/004F). The PB-BK analysis thus suggests that conventional risk analyses greatly overestimate the risk in humans exposed to low concentrations of DCM. PB-PK considerations provide a scientific basis for risk assessment, improve experimental design in chronic studies, and structure collection of quantitative metabolic constants required for risk assessment.

Animals↗

PubMed1987

Adjusting exposure limits for long and short exposure periods using a physiological pharmacokinetic model.

The rationale for adjusting occupational exposure limits for unusual work schedules is to assure, as much as possible, that persons on these schedules are placed at no greater risk of injury or discomfort than persons who work a standard 8 hr/day, 40 hr/week. For most systemic toxicants, the risk index upon which the adjustments are made will be either peak blood concentration or integrated tissue dose, depending on what chemical's presumed mechanism of toxicity. Over the past ten years, at least four different models have been proposed for adjusting exposure limits for unusually short and long work schedules. This paper advocates use of a physiologically-based pharmacokinetic (PB-PK) model for determining adjustment factors for unusual exposure schedules, an approach that should be more accurate than those proposed previously. The PB-PK model requires data on the blood:air and tissue:blood partition coefficients, the rate of metabolism of the chemical, organ volumes, organ blood flows and ventilation rates in humans. Laboratory data on two industrially important chemicals--styrene and methylene chloride--were used to illustrate the PB-PK approach. At inhaled concentrations near their respective 8-hr Threshold Limit Value-Time-weighted averages (TLV-TWAs), both of these chemicals are primarily eliminated from the body by metabolism. For these two chemicals, the appropriate risk indexing parameters are integrated tissue dose or total amount of parent chemical metabolized. Since methylene chloride is metabolized to carbon monoxide, the maximum blood carboxyhemoglobin concentrations also might be useful as an index of risk for this chemical.(ABSTRACT TRUNCATED AT 250 WORDS)

Air Pollutants, Occupational↗

PubMed1987

Research strategy in industrial toxicology.

While much of industrial toxicology is observational in character, pursuit of specific research is needed to facilitate the overall evaluation of potential toxicity for man. Two such areas are the application of physiologic pharmacokinetic models to inter-species extrapolation of toxic effects and an understanding of the role of cellular oncogenes in the process of spontaneous tumor formation in animals. A physiologic pharmacokinetic model was developed for methylene chloride (MeCl2) which describes the fate of MeCl2 and its metabolic products in numerous species including the mouse, rat, hamster and man. This model has been used to predict specific tissue concentrations of critical metabolic reaction products in target tissues between animals and man. If it is assumed that toxicity is related to target tissue concentrations such methodology provides a means of relating interspecies toxicity to absorbed dose. This methodology precludes the necessity of using arbitrary factors in relating animal toxicity data to man. A particular controversial issue in animal toxicology is the significance of the enhancement of animal tumors in tissues which already have a high spontaneous incidence. Without a better understanding of the basic process of spontaneous tumor formation it remains difficult to interpret results from chemical treatment. In particular spontaneous liver tumors in the B6C3F1 mouse have been shown to contain an activated cellular oncogene identified as H-RAS. The activated cellular oncogene is present in tumor tissue only and not in surrounding normal liver tissue. Of particular significance is the high frequency of activation in these mouse liver tumors (82%) compared to a 10-20% incidence of oncogenes present in a variety of human tumors. This suggests the ultra sensitivity of this mouse strain to liver tumor induction. Additional studies in progress are designed to determine whether genotoxic and nongenotoxic hepatocarcinogens show differences in oncogene activation.

Animals↗

PubMed1987

Pathological and hepatic ultrastructural effects of a single dose of perfluoro-n-decanoic acid in the rat, hamster, mouse, and guinea pig.

In rats, the liver is the primary target organ of perfluoro-n-decanoic acid (PFDA) toxicity. Therefore, the effects of PFDA on hepatic ultrastructure were studied in rats. Pathological changes induced by PFDA in hamsters, mice, and guinea pigs were also examined. PFDA caused a severe reduction in body weight in all four species studied. A reduction in food intake was observed in rats and hamsters. However, hamsters continued to consume food at a reduced level, while rats stopped eating for a 5- to 6-day period about 6 days after dosing. The PFDA-induced pathological changes in the hamsters, mice, and guinea pigs resembled those seen in rats to varying degrees. As in the rat, PFDA caused a marked liver enlargement in mice and hamsters and a moderate swelling in guinea pigs. This hepatomegaly was ascribed primarily to individual cell swelling. Thymic atrophy was noted in PFDA-treated hamsters, mice, and guinea pigs. Seminiferous tubular degeneration observed in hamsters and guinea pigs, but not in mice, was not as severe as in the rat, where in some cases frank necrosis has been seen. Ultrastructural changes in the livers of all PFDA-treated animals, regardless of species, included disruption of the rough endoplasmic reticulum, rounding and swelling of the mitochondria with related structural alterations, and mild to extensive proliferation of peroxisomes. This peroxisome proliferative response was greatest in mice and almost absent in guinea pigs. Accumulation of lipid droplets in liver cells due to PFDA treatment was more pronounced in hamsters and guinea pigs than in rats and mice. PFDA-induced hepatomegaly with a concomitant increase in peroxisomes in several rodent species may be associated with an impairment of normal lipid metabolism in the liver by PFDA.

Animals↗

PubMed1986

Toxic effects of nonadecafluoro-n-decanoic acid in rats.

Nonadecafluoro-n-decanoic acid (ND-FDA) has a single dose ip LD50 of 41 mg/kg and causes anorexia and a wasting syndrome. NDFDA also appears to affect lipid metabolism although the metabolic fate and mechanism of action are not known. Control rats were pair fed with rats given 50 mg/kg. Body weights and food consumption were measured daily; body and organ weights, tissue histopathology, and hematological and clinical chemistry parameters were determined at 4, 8, 12, 16, and 30 days postdosing. Liver samples were obtained for determining cholesterol, cholesterol esters, phospholipids, total lipids, fatty acid ratios, and NDFDA. The rats became anorectic within 4 days and did not resume feeding for 10-12 days, losing about 40% of their body weight. There was a decrease in serum protein; total liver protein decreased and there was an increase in measured fatty acids except for stearic. Liver to body weight ratios of dosed rats were twice those of control rats since absolute liver weights in dosed rats remained constant during the weight loss period. The most striking histopathological change was seen in the liver with a uniform persistent cellular swelling at all times. Separation of the lipids by thin layer chromatography indicated that NDFDA was present in the most polar fraction. There also were fatty changes in the proximal tubular epithelium of the kidneys.

Animals↗

PubMed1986

A physiological pharmacokinetic model for dermal absorption of vapors in the rat.

Absorption of chemical vapors through the skin is a passive process that is not easily quantitated, but may be important in the assessment of health hazards in some occupational circumstances. Physiological modeling is a quantitative technique which may provide insight into the system being modeled and can be used for interspecies extrapolation. We developed a physiological model for the penetration of organic vapors through skin in vivo which allows the prediction of blood concentrations, after dermal vapor exposures in the rat, when chemical distribution coefficients, physiological and metabolic parameters, and skin permeability constants are known. We used the model in two distinct ways. First, permeability constants for dibromomethane (DBM), bromochloromethane (BCM), and methylene chloride (DCM) were calculated by using a physiologically based pharmacokinetic model for dihalomethanes to relate blood concentrations during dermal vapor exposures to the total amount of chemical which was absorbed through the skin. Second, a skin compartment was added to the model which had input based on the permeability-area-concentration product. This predictive model adequately described blood concentrations after DBM, BCM, and DCM dermal vapor exposures over a wide range of concentrations. This model could easily be modified for use with other organic vapors, and could be used to extrapolate to human vapor exposure conditions by substituting human physiological parameters for the animal values, providing permeability constants are known or can be determined.

Animals↗

PubMed1986

Metabolism of inhaled dihalomethanes in vivo: differentiation of kinetic constants for two independent pathways.

Dihalomethanes are metabolized by two major pathways: an oxidative, cytochrome P-450-mediated pathway that has been previously thought to yield only CO, and a glutathione (GSH)-dependent one that yields CO2. Both give 2 mol of halide ion. We studied the kinetic properties of the two pathways in vivo by exposing male rats to various inhaled concentrations of CH2Cl2,CH2F2, CH2FCl, CH2BrCl, and CH2Br2 and determining end-exposure carboxyhemoglobin (HbCO) and plasma bromide (where appropriate). Closed atmosphere gas uptake studies were employed for CH2F2, CH2FCl, CH2Cl2, and CH2BrCl metabolism. A physiologically based kinetic model was used to determine kinetic constants based on gas uptake or plasma bromide data and these constants were used to predict HbCO concentrations. Oxidation was high affinity, low capacity. The maximum metabolic rates for this pathway with CH2Br2, CH2BrCl, and CH2Cl2 were, respectively, 72, 54, and 47 mumol metabolized/kg/hr. CH2FCl did not undergo significant oxidative metabolism and appears more like CH3C1 than a dihalomethane in its metabolic reactivity. The GSH pathway was low affinity, but high capacity and could be described as a single first-order process at all accessible exposure concentrations. The rate constant for this first-order GSH-dependent pathway was related as CH2BrCl greater than CH2Cl2 congruent to CH2FCl greater than CH2Br2 greater than CH2F2. Presumably bromide is a preferred leaving group but steric hindrance in the initial reaction with GSH is important with CH2Br2. We also studied the effects of pyrazole (which inhibits microsomal oxidation) and 2,3-epoxypropanol (which depletes GSH) on dihalomethane metabolism. Pyrazole abolished CO production from CH2Br2, CH2BrCl, and CH2Cl2. GSH depletion did not change the yield of halide ion from the high-affinity pathway; it did increase the steady-state HbCO concentrations with CH2Cl2 and CH2ClBr, but not with CH2Br2. The putative formyl chloride (FC) intermediate from CH2Cl2 or CH2BrCl appears to have a longer life than the formyl bromide from CH2Br2 and a significant portion of the FC (congruent to 20-30%) may react with other cellular nucleophiles instead of spontaneously decomposing to CO. This portion of the oxidative pathway probably yields CO2.

1-Propanol↗

PubMed1986

A physiologically based simulation approach for determining metabolic constants from gas uptake data.

In vivo metabolic constants were determined in male Fischer rats for five chemicals: 1,1-dichloroethylene (1,1-DCE), diethyl ether (DE), bromochloromethane (BCM), methyl chloroform (MC), and carbon tetrachloride (CCl4). A closed recirculated exposure system was used to collect a series of uptake curves for each chemical at a range of initial concentrations. The shapes of these curves were a function of the tissue partition coefficients and the kinetic characteristics of the metabolism of these chemicals. Tissue:air partition coefficients were experimentally determined for each chemical and incorporated into a physiological kinetic model which was then used to simulate the uptake process. An optimal fit of the family of uptake curves for each chemical was obtained by adjusting the biochemical constants for metabolism of the chemical. Metabolism of both 1,1-DCE and CCl4 was represented by a single saturable process while MC required only a first-order pathway. BCM and DE exhibited a combination of both a saturable and a first-order process. Pyrazole, which blocks oxidative microsomal metabolism, inhibited the saturable pathways of 1,1-DCE, BCM, DE, and CCl4 metabolism and abolished the first-order pathway for MC. The maximum velocity of metabolism for the saturable pathway with 1,1-DCE, BCM, DE, and CCl4 for a 225-g rat was 27.2, 19.9, 26.1, and 0.92 mol/hr, respectively. The simulation approach for analyzing gas uptake data distinguishes between single and multiple metabolic pathways and provides kinetic constants that can be used in predictive toxicokinetic models for describing constant concentration inhalation exposure as well as exposures by other routes of administration.

Animals↗

PubMed1985

Dermal absorption of dihalomethane vapors.

The dermal absorption of dibromomethane (DBM) and bromochloromethane (BCM) vapors was studied in rats placed in a specially designed chamber incorporating individual respiratory protection to avoid pulmonary uptake. Exposures (DBM: 500 to 10,000 ppm; BCM: 2500 to 40,000 ppm) lasted 4 hr during which time five blood samples were drawn from jugular cannulae for analysis of the parent dihalomethane by gas chromatography. Estimates of the amounts of chemicals stored in tissues and exhaled were based on concentrations in the blood and tissue partition coefficients, tissue volumes, and ventilation rate. Total metabolism was estimated from the amount of bromide released during the 4-hr exposure. The total amount of vapor absorbed through the skin was calculated from the estimates of the amount of parent chemical in blood and tissues, and the amounts exhaled and metabolized. The dermal flux for each concentration (DBM: 0.004 to 0.078 mg/cm2/hr; BCM: 0.011 to 0.164 mg/cm2/hr) was calculated by dividing the amount absorbed by exposed surface area and duration of exposure. Flux was divided by exposure concentration to calculate a permeability constant. With each dihalomethane the permeability constants (DBM: congruent to 1.12 cm/hr; BCM: congruent to 0.79 cm/hr) were essentially independent of exposure concentration. This study shows that a whole-body dermal vapor exposure in rodents is technically possible, and quantitation of penetration can be accomplished using calculations based on achieved blood concentrations and some measure of metabolism.

Animals↗

PubMed1985

Potentiation of 2,5-hexanedione neurotoxicity by methyl ethyl ketone.

Chronic oral administration of a combination of 2.2 mmol methyl ethyl ketone (MEK) and 2.2 mmol 2,5-hexanedione (2,5-HD)/kg/day, 5 days/week resulted in more rapid onset of motor deficits than did chronic dosing with 2.2 mmol 2,5-HD/kg/day alone. In kinetic studies blood time courses of 2,5-HD were determined in rats in the presence and absence of MEK. Concomitant administration of MEK reduced blood 2,5-HD clearance and increased the area under the curve (AUC) for the blood 2,5-HD. In companion experiments with 2,5-[1,6-14C]HD as a tracer, neural and nonneural tissues were examined 72 hr following the last treatment at Weeks 1, 2, and 3 of chronic administration of 2,5-HD alone or in combination with an equimolar dose of MEK. Rats treated with 2,5-[14C]HD alone or in combination with MEK demonstrated no difference in total or trichloroacetic acid-precipitable radioactivity in blood, in liver homogenates, or in neurofilament-enriched fractions from sciatic nerve and spinal cord. The data support a suggestion that the potentiation of hexacarbon neurotoxicity by MEK is the result of the persistence of the neurotoxic metabolite in the blood and not the enhanced metabolism of parent hexacarbon to 2,5-HD.

Administration, Oral↗

PubMed1985

Risk assessment extrapolations and physiological modeling.

The process of assessing the risk associated with human exposure to environmental chemicals inevitably relies on a number of assumptions, estimates and rationalizations. One of the more challenging aspects of risk assessment involves the need to extrapolate beyond the range of conditions used in experimental animal studies to predict anticipated human risks. The most obvious extrapolation required is that from the tested animal species to humans; but others are also generally required, including extrapolating from high dose to low dose, from one route of exposure to another and from one exposure timeframe to another. Several avenues are available for attempting these extrapolations, ranging from the assumption of strict correspondence of dose to the use of statistical correlations. One promising alternative for conducting more scientifically sound extrapolations is that of using physiologically based pharmacokinetic models that contain sufficient biological detail to allow pharmacokinetic behavior to be predicted for widely different exposure scenarios. In recent years, successful physiological models have been developed for a variety of volatile and nonvolatile chemicals, and their ability to perform the extrapolations needed in risk assessment has been demonstrated. Techniques for determining the necessary biochemical parameters are readily available, and the computational requirements are now within the scope of even a personal computer. In addition to providing a sound framework for extrapolation, the predictive power of a physiologically based pharmacokinetic model makes it a useful tool for more reliable dose selection before beginning large-scale studies, as well as for the retrospective analysis of experimental results.

Animals↗

PubMed1984

A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans.

A physiologically based pharmacokinetic model which describes the behavior of inhaled styrene in rats accurately predicts the behavior of inhaled styrene in humans. The model consists of a series of mass-balance differential equations which quantify the time course of styrene concentration within four tissue groups representing (1) highly perfused organs, (2) moderately perfused tissues such as muscle, (3) slowly perfused fat tissue, and (4) organs with high capacity to metabolize styrene (principally liver). The pulmonary compartment of the model incorporates uptake of styrene controlled by ventilation and perfusion rates and the blood:air partition coefficient. The metabolizing tissue group incorporates saturable Michaelis-Menten metabolism controlled by the biochemical constants Vmax and Km. With a single set of physiological and biochemical constants, the model adequately simulates styrene concentrations in blood and fat of rats exposed to 80, 200, 600, or 1200 ppm styrene (data from previously published studies). The simulated behavior of styrene is particularly sensitive to changes in the constants describing the fat tissue group, and to the maximum metabolic rate described by Vmax. The constants used to simulate the fate of styrene in rats were scaled up to represent humans. Simulated styrene concentrations in blood and exhaled air of humans are in good agreement with previously published data. Model simulations show that styrene metabolism is saturated at inhaled concentrations above approximately 200 ppm in mice, rats, and humans. At inhaled concentrations below 200 ppm, the ratio of styrene concentration in blood to inhaled air is controlled by perfusion limited metabolism. At inhaled concentrations above 200 ppm, this ratio is controlled by the blood:air partition coefficient and is not linearly related to the ratio attained at lower (nonsaturating) exposure concentrations. These results show that physiologically based pharmacokinetic models provide a rational basis with which (1) to explain the relationship between blood concentration and air concentration of an inhaled chemical, and (2) to extrapolate this relationship from experimental animals to humans.

Administration, Oral↗

PubMed1984

Inhalation pharmacokinetics: evaluating systemic extraction, total in vivo metabolism, and the time course of enzyme induction for inhaled styrene in rats based on arterial blood:inhaled air concentration ratios.

A method is described for evaluating systemic extraction of soluble vapors during inhalation exposures. The physiological basis of the method is the inability to achieve complete equilibrium of vapor between arterial blood and inhaled air whenever there is substantial extraction of the soluble vapor during a single pass through the systemic circulation. The technique was applied to estimate styrene extraction ratios at the end of 6-hr exposures in male rats exposed to various concentrations of inhaled styrene. From extraction ratios and several physiological constants, metabolic constants were evaluated for styrene metabolism in vivo. In naive rats, the maximum velocity of metabolism was 10.0 mg/kg/hr, and Km was of the order of 0.2 mg/liter. Pretreatment with pyrazole (320 mg/kg, 1/2 hr before exposure) essentially abolished in vivo styrene metabolism, while pretreatment with phenobarbital (80 mg/kg/day for the 4 days before styrene exposure) increased Vmax about sixfold. Prior exposure to styrene (1000 ppm for 6 hr/day on each of 4 days before experimentation) increased Vmax by a factor of 2. Significant induction of styrene metabolism in vivo was observed in 24-hr continuous exposure to 400, 600, or 1200 ppm. A curve fitting routine was employed with a physiological model of styrene inhalation kinetics to estimate the dynamics of the induction process in the 24-hr exposures. At 400 ppm, induction began after a lag of 15.5 hr, had a half-life of 3.5 hr, and reached 2.7 times the Vmax in naive rats. At 600 ppm, it began after 10.6 hr, proceeded with a half-life of 2.2 hr, and increased Vmax by 3.4 times. At 1200 ppm, induction began earlier, 4.6 hr, and reached a greater value, 4.4 times Vmax, but had a half-life similar to that at 600 ppm. No induction occurred in 48-hr exposure to 200 ppm. Induction complicates kinetic modeling of continuous inhalation with soluble, well-metabolized vapors because it is time and concentration dependent. These methods should prove useful for studying the in vivo metabolism of other soluble, well-metabolized vapors and for examining the time course of induction of the metabolizing enzymes for these chemicals.

Air↗

PubMed1983

The acute toxicity of perfluorooctanoic and perfluorodecanoic acids in male rats and effects on tissue fatty acids.

The acute toxicities of single ip injections of perfluorooctanoic (PFOA) and perfluorodecanoic (NDFDA) acids were evaluated in male Fischer rats. The LD50/30 day for PFOA was 189 (208-175) mg/kg and for NDFDA was 41 (47-34) mg/kg. All rats treated with lethal doses of PFOA died within the first 5 days; with NDFDA there was delayed lethality, with deaths in the second and third weeks after dosing. Four groups of rats were used for a more detailed study of toxicity and for analysis of fatty acids from liver, testes, and whole blood. One group received a single dose of 100 mg PFOA/kg; a second, a single dose of 2 ml of propylene glycol-water (1:1)/kg (vehicle control); a third, a single dose of 50 mg NDFDA/kg; the fourth was given 2 ml vehicle/kg and pair-fed with the NDFDA group. The first three groups were fed ad libitum. Rats from each group were killed at 2, 4, 8, and 16 days after dosing for fatty acid analysis. Rats dosed with NDFDA lost half their body weight in 16 days and ate virtually no food from Day 7 to Day 14 after dosing. Weight loss was less rapid in pair-fed controls. With PFOA there were transient decreases in food intake and body weight which were reversed by Day 7. Liver weights of PFOA rats were slightly greater than those from vehicle controls. With NDFDA, liver weights were much greater than those from pair-fed controls. In the livers of PFOA rats there were transient increases in oleic and palmitic acids and a decrease in stearic and docosahexaenoic acids. These changes were maximum by Day 2 and nearly resolved by Day 8. With NDFDA, similar changes were observed and arachidonic acid was also greatly decreased. These changes were quantitatively much larger and more persistent. NDFDA has unusually high toxic potency for a perfluorinated hydrocarbon, and some of the toxic effects caused by this acid are remarkably similar to those seen with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The acute toxicity of NDFDA may be due to an ability to interfere with fatty acid metabolism, and studies of its toxicity may be valuable in helping to understand mechanisms of action of TCDD.

Animals↗