Biomedical subjects

M E Andersen

Publications and source records attributed to M E Andersen.

At least 109 records · Page 6Linked to original sources

PubMed1990

In vivo metabolic interactions of benzene and toluene.

The metabolic interactions of benzene and toluene co-exposure were investigated in male Fischer rats. A closed recirculated exposure system was used to obtain inhalation uptake curves for individual chemicals as well as for a mixture of the two compounds. Pharmacokinetic parameters for benzene and toluene individually were determined in previous experimental studies. These values were incorporated into a physiologically based pharmacokinetic model which simulated the inhalation uptake process for both chemicals simultaneously. An optimal fit to the uptake curves for simultaneous exposure was obtained by adjusting the metabolic interaction terms for each chemical. Mutual suppression of metabolism was apparent. Toluene more effectively inhibited benzene metabolism than the reverse. This simulation approach for analyzing gas uptake data provided a method to determine the metabolic interactions occurring upon inhalation exposure to two different chemicals. Such analyses will prove useful in improving predictive toxicokinetic models.

Animals↗

PubMed1989

Determining kinetic constants of chlorinated ethane metabolism in the rat from rates of exhalation.

The kinetic constants of chemical metabolism are used to develop physiologically based pharmacokinetic (PB-PK) models which predict the time course distribution of volatile chemicals in mammalian systems. Gas uptake techniques have proved useful in determining kinetic constants for a variety of volatile compounds including the following chloroethanes: ethyl chloride, 1,1-dichloroethane, 1,2-dichloroethane, and 1,1,1-trichloroethane. Unfortunately, low vapor pressure materials and those exhibiting increasing blood and tissue solubilities could not be examined by gas uptake methods. An alternative gas phase method was developed in which rats were first exposed by constant concentration inhalation for 6 hr and then placed in 2.5-liter exhaled breath chambers with fresh air flow and chamber effluent was serially analyzed for test chemical. The resulting elimination behavior was extremely sensitive to metabolism, and kinetic constants for chemical metabolism were estimated by simulation with a PB-PK model containing equations that accurately described the experimental conditions. Optimized maximum metabolic rates (Vmax) were determined for 1,1,2-trichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane, and hexachloroethane with resulting values of 7.69, 6.39, 12.9, 9.71, and 1.97 mg/kg/hr, respectively. With several of these test chemicals the PB-PK modeling identified fur adsorption of chemical as significantly contributing to the exhalation chamber concentration time course after whole body exposure.

Animals↗

PubMed1989

Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues.

Partition coefficients are required for developing physiologically based pharmacokinetic models used to assess the uptake, distribution, tabolism, and elimination of volatile chemicals in mammals. A gas-phase vial equilibration technique is presented for determining the liquid:air and tissue:air partition coefficients for low-molecular-weight volatile chemicals. This technique was developed from two previously described medium:air methods, relied solely on measurement of chemical concentration in the gas phase, and, compared to earlier work, extends the range of chemicals and tissues examined. Partition coefficients were determined with 0.9% saline, olive oil, and blood, liver, muscle, and fat tissues from rats for 55 compounds. Human blood:air coefficients were determined for 36 compounds and several blood:air values were also determined in the mouse and for one compound in the hamster. An approach is described for predicting the tissue solubilities of untested compounds based on oil:air and saline:air coefficients using regression analyses. A similar approach is used to model fat:air coefficients in terms of oil:air values and to model human blood: air coefficients in terms of rat blood:air coefficients.

Adipose Tissue↗

PubMed1989

Tissue dosimetry, physiologically-based pharmacokinetic modeling, and cancer risk assessment.

Chemical risk assessment is a complex process that requires integration of various biological data from test species, ultimately producing a prediction of the expected outcome of anticipated human exposure. There are two aspects of this process in which pharmacokinetic (PK) modeling can play an important role: in dosimetry, the process of estimating target tissue dose in the test species, and in extrapolation, the process of generalizing beyond the test species to predict human target tissue dose for various ambient exposure conditions. Mechanistic information on the cancer process is crucial in selecting the appropriate measure of target tissue dose: i.e., is it tissue exposure to parent chemical, tissue exposure to stable or reactive metabolite(s), occupancy of critical cellular receptors by parent or metabolite, or some measure of cytotoxicity with concomitant reparative hyperplasia? (This is not intended, by the way, to be an exhaustive list of the potential measures of tissue dose associated with cancer induction). With a presumed carcinogenic mechanism and its appropriate measure of tissue dose in mind, a pharmacokinetic model can then be developed to quantitate this measure of target tissue dose for various exposure conditions. Physiologically based pharmacokinetic (PB-PK) modeling is the preferred modeling strategy since it is more readily amenable to the interspecies extrapolation necessary to calculate human tissue dose. This essay focuses on the issues of what constitutes an appropriate measure of tissue dose and of how PB-PK models can be developed to estimate tissue dose for chemicals which cause cancer by differing mechanisms. It outlines preliminary attempts to include information on cytotoxicity into a quantitative risk assessment process. Quantitative, extrapolable cytotoxicity models are necessary to conduct biologically valid risk assessments for those chemicals whose primary effect is overt cellular toxicity instead of direct chemical interaction with cellular DNA. Rational, comprehensive risk assessments will only be possible with the advent of descriptions which combine information on both pharmacokinetics and pharmacodynamics into a single integrated model.

Animals↗

PubMed1989

Physiologically based pharmacokinetic modeling of the pregnant rat: a multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid.

A physiologically based pharmacokinetic (PB-PK) model was developed to describe trichloroethylene (TCE) kinetics in the pregnant rat exposed to TCE by inhalation, by bolus gavage, or by oral ingestion in drinking water. The kinetics of trichloroacetic acid (TCA), an oxidative metabolite of TCE, were described by a classical one-compartment pharmacokinetic model. Among the required model parameters for TCE, partition coefficients (PCs) and kinetic constants for oxidation were determined by vial equilibration and gas uptake methods, respectively. The fat:blood PC was 33.9; the blood:air PC was 13.2; and the fetal tissue:fetal blood PC was 0.51. TCE was readily metabolized with high substrate affinity. In naive and pregnant female rats the maximum velocities of oxidative metabolism were 10.98 +/- 0.155 and 9.18 +/- 0.078 mg/kg/hr, while the estimated Michaelis constant for the two groups of rats was very low, 0.25 mg/liter. The first-order rate constant for oral absorption of TCE from water was 5.4 +/- 0.42/hr-1 in naive rats. With TCA, the volume of distribution (0.618 liter/kg) and the plasma elimination rate constant (0.045 +/- 0.0024/hour) were estimated both from intravenous dosing studies with TCA and from an inhalation study with TCE. By comparison of the two routes of administration, the stoichiometric yield of TCA from TCE was estimated to be 0.12 in pregnant rats. To develop a data base for testing the fidelity of the PB-PK model, inhalation and bolus gavage exposures were conducted from Day 3 to Day 21 of pregnancy and a drinking water exposure from Day 3 to Day 22 of pregnancy. Inhalation exposures with TCE vapor were 4 hr/day at 618 ppm. The TCE concentration in drinking water was 350 micrograms/ml and the gavaged rats received single daily doses of 2.3 mg TCE/kg. Time varying physiological parameters for compartment volumes and blood flows during pregnancy were obtained from the published literature. Using the kinetic parameters determined by experimentation, TCE concentrations in maternal and fetal blood and TCA concentrations in maternal and fetal plasma were predicted from the PB-PK model by computer simulation and compared favorably with limited data obtained at restricted time points during pregnancy for all three routes of exposure. On the basis of the PB-PK model, fetal exposure to TCE, as area-under-the-curve, ranged from 67 to 76% of maternal exposure. For TCA the fetal exposure was 63 to 64% of the maternal exposure. The fetus is clearly at risk both to parent TCE and its TCA metabolite.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗

PubMed1989

Improving toxicology testing protocols using computer simulations.

Computer simulation can be used to integrate existing toxicity information within a biologically realistic framework. Simulation models calculate relevant measures of target tissue dose based on physiological, biochemical and physicochemical properties and readily support the dose, route, species and interchemical extrapolations necessary for human risk assessment. Because these models require very specific information, much of which can be obtained in vitro, they are much less dependent on extensive animal experiments than conventional risk assessment methods. With continuing development, simulation modeling will become an invaluable tool for improving experimental designs, for interpreting animal toxicity tests, and for estimating the importance of the animal toxicity observations for people.

Administration, Inhalation↗

PubMed1989

Biologically motivated models for chemical risk assessment.

Assessing the risk associated with human exposure to environmental chemicals depends to a large extent on the ability to extrapolate from a particular range of exposure conditions in the test animal species to a very different range of exposure conditions in the human. One of the more promising tools for accomplishing this extrapolation is the biologically motivated pharmacokinetic/pharmacodynamic model. In a biologically motivated model, the structure is based on the physiological and biochemical structure of the animal system being described. This paper provides an overview of the biologically motivated modeling approach. Examples of models for styrene and methylene chloride are discussed in relation to their ability to predict human kinetics for these chemicals and their use in estimating the risk of chemicals to exposed humans. Finally, the use of a biologically motivated model to analyze the mechanistic basis of chemical carcinogenesis is discussed.

Animals↗

PubMed1988

Physiologically based pharmacokinetic model for vinylidene chloride.

Vinylidene chloride (VDC), a potent hepatotoxin and suspected carcinogen, is metabolized by mixed-function oxidases into a reactive metabolite(s) which is responsible for its toxicity. The metabolite is detoxified by glutathione (GSH), and liver GSH status is an important factor in the expression of VDC toxicity. A physiologically based pharmacokinetic (PB-PK) model has been developed for VDC in the rat based on oxidative metabolism of VDC and subsequent GSH detoxification of metabolite. The model offers insight into the complex interrelationship between the processes of absorption, metabolism, and GSH conjugation, and simulates the manner in which these factors operate in regulating VDC toxicity. The PB-PK model successfully predicts blood, tissue, and exhaled air concentrations of VDC, and liver GSH levels as a function of dose and route of administration. The model also explains the complex dose-response mortality curves seen with VDC. Because of the low blood:air partition coefficient of VDC and its saturable metabolism, the amount of VDC dose that is metabolized is sensitive to the rate of absorption. After an intravenous bolus dose, most of the administered VDC is exhaled unchanged within a few minutes. Blood VDC half-life is not representative of metabolism rates but to reequilibration of VDC from fat. Rats with greater fat content, therefore, display longer VDC blood half-lives. Simulations are shown to demonstrate the strength of PB-PK modeling techniques in understanding the kinetic behavior of VDC in the rat under a variety of experimental conditions.

Adipose Tissue↗

PubMed1988

Pharmacokinetics of tetrachloroethylene.

A physiological pharmacokinetic model is developed to describe the pharmacokinetics of tetrachloroethylene (PCE) in mice, rats, and humans. The body is divided into four tissue compartments (vessel-rich, muscle, slowly perfused fat, and liver) connected by the arterial and venous blood flow pathways. The physiological parameters of the model are blood flow rates, cardiac output, tissue volumes, ventilation rate, and tissue/air and blood/air partition coefficients. Metabolism is assumed to occur only in the liver compartment and is described by a combination of a linear metabolic component and a Michaelis-Menten component. The metabolic parameters for PCE were determined by fitting model predictions to species-specific empirical data. Comparison of model results with independent empirical data on inhalation and gavage exposures in mice, rats, and humans demonstrates that the physiological pharmacokinetic model can be used to determine the time course of PCE in these species. We show that human metabolic parameters can be predicted by scaling rat metabolic parameters as a function of body weight, whereas scaling of the metabolic parameters of mice overestimates human metabolism.

Animals↗

PubMed1988

Perfluoro-n-decanoic acid: induction of peroxisomal beta-oxidation by a fatty acid with dioxin-like toxicity.

Perfluoro-n-decanoic acid (PFDA) produces toxic effects in rodents similar to those caused by 2,3,7,8-tetrachloro-dibenzo-p-dioxin. A single, intraperitoneal dose (50 mg/kg) of PFDA to Sprague-Dawley rats caused disruption of the endoplasmic reticulum, mitochondrial swelling and increases in intracellular lipid droplets in hepatocytes similar to effects reported previously in dioxin toxicity. PFDA treatment led to large decreases in the activity of plasma membrane alkaline phosphodiesterase and mitochondrial cytochrome c oxidase without affecting lysosomal N-acetyl-beta-glucosaminidase, endoplasmic reticulum NADPH-cytochrome c reductase or peroxisomal catalase activities. PFDA treatment led to moderate peroxisome proliferation and to very large (20-40-fold) increases in the activity of fatty acyl-CoA oxidase, the rate-limiting enzyme in the peroxisomal system of fatty acid beta-oxidation.

Animals↗

PubMed1988

A physiologically based pharmacokinetic model for inhaled carbon tetrachloride.

D.J. Paustenbach et al. (1986, Fundam. Appl. Toxicol. 6, 484-497) have described the pharmacokinetics of inhaled, radiolabeled carbon tetrachloride (14CCl4) in male Sprague-Dawley rats exposed for 8 or 11.5 hr/day for 1- or 2-week periods. These studies provided time-course information for exhaled 14CCl4, the exhaled 14CO2 metabolite, and 14C radioactivity eliminated in the feces and urine. A physiologically based pharmacokinetic (PB-PK) model which incorporated partition characteristics of CCl4 (blood:air and tissue:blood partition coefficients), anatomical and physiological parameters of the test species (body weight, organ weights, ventilation rates, blood flows, etc.), and biochemical constants (Vmax and Km) for CCl4 metabolism was developed to describe these results. The PB-PK model accurately predicted the behavior of CCl4 and its metabolites, both the exhaled CCl4 and 14CO2 and the elimination of radioactivity in urine and feces. The metabolism of CCl4, determined by gas uptake studies, was adequately described by a single saturable pathway. Metabolites were partitioned in the model to three compartments; the amounts to be excreted in the breath (as 14CO2), urine, and feces. Of total CCl4 metabolism, 6.5, 9.5, and 84.0% were formed via the degradative pathways leading to CO2, urinary, and fecal metabolites, respectively. The simplest kinetic explanation of the metabolite time course is that 4% of the initially metabolized CCl4 is directly converted to CO2 (probably via a chloroform intermediate) and the remainder of metabolized CCl4 binds to biological substrates. These adducts appear to be slowly degraded with an average half-life of 24 hr. The breakdown products subsequently appear in the feces and urine (the rate constant for elimination by these two routes is similar) and a small portion is converted all the way to CO2. The PB-PK model successfully described the elimination by all four routes for all four exposure scenarios using a single set of parameters. Vmax and Km were, respectively, 0.65 mg/kg/hr and 0.25 mg/liter. There was no evidence for loss of Vmax with repeated exposure, as would be expected if there was enzyme destruction at these concentrations of CCl4. The model was scaled-up to predict the expected behavior of parent CCl4 in monkeys and humans and the resulting simulations compared very favorably with data collected by McCollister et al. (1951) and Stewart et al. (1961). On the basis of this model and the published data on the rat at 100 ppm about 60% of the inhaled CCl4 is metabolized and the resulting blood levels are already in excess of saturation for the metabolizing enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1988

An inhalation distribution model for the lactating mother and nursing child.

A rule-of-thumb methodology is presented to assist in assessing risk to a nursing child due to the mother's occupational inhalation exposure. The method represents an example of the use of physiologically based pharmacokinetic modeling using state-of-the-art computational techniques. A computer model is developed to describe distribution of non-metabolized, inhaled contaminants into a mother/child system as a function of the contaminant's blood:air and octanol:water partition coefficients. Risk is assessed in terms of the area under the blood concentration vs. time curve of the exposure chemical. Since low partition values yield low risk for the nursing child and high values yield high risk, the model is exercised over a range of intermediate values (blood:air = [2,25]; octanol:water = [100, 1500]). Results are thus applicable to chemicals for which the mother's dose is a strong factor in estimating the child's risk. The most notable observation is that, for the range of partition values used, this model never predicts a risk for the child greater than 25% of that of the mother. An equation is provided (based on model results) that expresses the child's risk as a fraction of the mother's risk.

Adult↗

PubMed1988

Incorporation of in vitro enzyme data into the physiologically-based pharmacokinetic (PB-PK) model for methylene chloride: implications for risk assessment.

Physiologically-based pharmacokinetic (PB-PK) models provide a mechanism for reducing the uncertainty inherent in extrapolating the results of animal toxicity tests to man. This paper discusses a technique for incorporating data from in vitro studies of xenobiotic metabolism into in vivo PB-PK models. Methylene chloride is used as an example, and carcinogenic risk estimates incorporating PB-PK principles are presented.

Animals↗

PubMed1988

Pharmacokinetics, biochemical mechanism and mutation accumulation: a comprehensive model of chemical carcinogenesis.

Chemical carcinogenesis is a process beginning with carcinogen absorption and ending with development of a malignant tumor. Individual elements of this process have been studied intensively but no comprehensive model has been developed. This report describes a comprehensive model which incorporates carcinogen pharmacokinetics, biochemical mechanism of action, and the resultant mutation of normal cells to malignancy. Model parameters correspond to specific physiological and biochemical structures and processes. The model was encoded in a simulation language and used to examined biochemical and cellular effects of exposure to an initiator and a promoter. With laboratory validation, the model should be useful for interpretation and design of studies on carcinogenic mechanisms and for risk assessment.

Carcinogens↗

PubMed1988

Modeling the tissue solubilities and metabolic rate constant (Vmax) of halogenated methanes, ethanes, and ethylenes.

Experimental solvent:air and tissue:air partition coefficients for 25 halogenated methanes, ethanes, and ethylenes in saline solution; olive oil; and rat blood, muscle, liver, and fat tissues have been examined using theoretical molecular modeling techniques. The metabolic rate constant, Vmax, was also investigated by these techniques for 19 chlorinated compounds in this group. Two graph theoretical approaches (the distance method of Wiener and the connectivity index method of Randic, Kier, and Hall) and an approach utilizing ad hoc molecular descriptors were employed. Satisfactory regression models for solubility were obtained with both the Randic-Kier-Hall approach and the ad hoc descriptors approach. Fluorine substituents decrease tissue solubilities, whereas both clorine and bromine substituents increase tissue solubilities, with the relative influence being Cl less than Br. Tissue solubilities can also be represented conveniently in terms of contributions from oil and saline solubilities, a procedure reinforced by factor analysis of the data. Equations derived by these methods adequately estimated the solubilities for eight additional compounds. No approach could successfully model Vmax for all 19 compounds, but a subset of 16 compounds was modeled using the connectivity indices. The equation is limited in its use but indicated future modeling directions for Vmax.

Adipose Tissue↗

PubMed1988

A physiologically based pharmacokinetic model for 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J and DBA/2J mice.

A five-compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the time course of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the tissues of both C57BL/6J and DBA/2J mice. The PB-PK model included binding in blood and two hepatic binding sites, one in the cytosol and the other in the microsomes. First-order metabolism occurred in the liver. Model simulations were compared to literature results for the disposition of a single intraperitoneal dose of 10 micrograms/kg of [3H]TCDD, reported by Gasiewicz et al. [Drug Metab. Dispos. 11 (1983) 397-403]. In contrast to previous speculation, the greater accumulation of TCDD in the liver of the C57BL/6J mouse, as compared to the DBA/2J mouse, was not attributable to the higher fat content in the DBA/2J mouse. Instead, the disposition of TCDD in these mice was more dependent on the affinity of the microsomal binding proteins than on fat content. The microsomal dissociation constant in the C57BL/6J mouse estimated by the PB-PK model was about one-third its value in the DBA/2J mouse (20 versus 75 nM), i.e. there is more avid microsomal binding in the liver of the C57BL/6J mouse. In the concentration range covered in these time-course studies, the cytosolic receptor, with its low capacity and very high affinity binding characteristics, does not play a major role in determining the overall tissue distribution pattern. The concentration and affinity of the microsomal binding protein in the liver appear to be primarily responsible for explaining the differences in the liver/fat concentration ratios between various strains and species of laboratory animals.

Adipose Tissue↗

PubMed1988

Calcium oxalate in sarcoid granulomas. With particular reference to the small ovoid body and a note on the finding of dolomite.

The nature, prevalence, and specificity of birefringent calcific particles in granulomas of sarcoidosis have been examined, including histochemical reactions, single particle, and microchemical analyses. Particular attention was paid to small ovoid forms of which most were calcium oxalate monohydrate. Larger crystals, those within giant cells, and the birefringent component of a Schaumann complex were also calcium oxalate. Small ovoids appeared to originate in macrophages and to be precursors of other forms; they were found in 86% of lymph nodes and 73% of surgical lung specimens. They were not specific for sarcoidosis. Organisms could not be certainly identified in them. Their origin is discussed in relation to activated macrophages, calcium, and oxalate metabolism, and the role of calcium oxalate in granulomas is considered. Four particles from two cases were dolomite and two were a calcium-sulphur compound. The biologic origin of dolomite is reviewed.

Birefringence↗

PubMed1988

Bacterial vaginosis: a double-blind randomized trial of the effect of treatment of the sexual partner.

In a double-blind randomized controlled trial we assessed the effect of metronidazole treatment of the male partner on the recurrence rate of bacterial vaginosis. Women who fulfilled the diagnostic criteria for bacterial vaginosis were treated with metronidazole given in single doses of 2 g on days 1 and 3. The sexual partners were randomized to receive either the same dosage of metronidazole or a placebo. A total of 107 pairs completed the study. One week after the start of treatment 89% of the women considered themselves improved or cured and 93% no longer had the diagnostic criteria for bacterial vaginosis. At assessment 5 weeks after the treatment, 75% reported that they were cured or improved and the diagnostic criteria were not present in 73%. Treatment of the male partner did not affect subjective symptoms, clinical signs and isolation rates of Gardnerella vaginalis at 1 and 5 weeks after treatment.

Adolescent↗