@article{manning_schlosser_tran_2010, title={A Multicompartment Liver-based Pharmacokinetic Model for Benzene and its Metabolites in Mice}, volume={72}, ISSN={["0092-8240"]}, DOI={10.1007/s11538-009-9459-x}, abstractNote={Benzene is a highly flammable, colorless liquid. Ubiquitous exposures result from its presence in gasoline vapors, cigarette smoke, and industrial processes. After uptake into the body, benzene undergoes a series of metabolic transformations to multiple metabolites that exert toxic effects on the bone marrow. We developed a physiologically based pharmacokinetic model for the uptake and elimination of benzene in mice to relate the concentration of inhaled and orally administered benzene to the tissue doses of benzene and its key metabolites. This model takes into account the zonal distribution of enzymes and metabolism in the liver rather than treating the liver as one homogeneous compartment, and considers metabolism in tissues other than the liver. Analysis was done to examine the existence and uniqueness of solutions of the system. We then formulated an inverse problem to obtain estimates for the unknown parameters; data from multiple laboratories and experiments were used. Despite the sources of variability, the model simulations matched the data reasonably well in most cases. Our study shows that the multicompartment metabolism model does improve predictions over the previous model (Cole et al. in J. Toxicol. Environ. Health, 439-465, 2001) and that in vitro metabolic constants can be successfully extrapolated to predict in vivo data for benzene metabolism and dosimetry.}, number={3}, journal={BULLETIN OF MATHEMATICAL BIOLOGY}, author={Manning, Cammey C. and Schlosser, Paul M. and Tran, Hien T.}, year={2010}, month={Apr}, pages={507–540} }
 @article{yokley_tran_schlosser_2008, title={Sensory irritation response in rats: Modeling, analysis and validation}, volume={70}, ISSN={["0092-8240"]}, DOI={10.1007/s11538-007-9268-z}, abstractNote={Inhaled gases can cause respiratory depression by irritating (stimulating) nerves in the nasal cavity. Respiratory depression, in turn, decreases the rate of delivery of those gases to the stimulated nerves, potentially leading to a complex feedback response. In order to better understand how the nervous system responds to such chemicals, a mathematical model is created to describe how the presence of irritants affects respiration in the rat. The ordinary differential equation model describes the dosimetry of these reactive gases in the respiratory tract, with particular focus on the physiology of the upper respiratory tract, and on the neurological control of respiration rate due to signaling from the irritant-responsive nerves in the nasal cavity. The ventilation equation is altered to account for an apparent change in dynamics between the initial ventilation decrease and the recovery to steady state as seen in formaldehyde exposure data. Further, the model is evaluated and improved through optimization of particular parameters to describe formaldehyde-induced respiratory response data and through sensitivity analysis. The model predicts the formaldehyde data well, and hence the model is thought to be a reasonable description of the physiological system of sensory irritation. The model is also expected to translate well to other irritants.}, number={2}, journal={BULLETIN OF MATHEMATICAL BIOLOGY}, author={Yokley, Karen A. and Tran, Hien and Schlosser, Paul M.}, year={2008}, month={Feb}, pages={555–588} }
 @article{zagera_schlosser_tran_2007, title={A delayed nonlinear PBPK model for genistein dosimetry in rats}, volume={69}, ISSN={["1522-9602"]}, DOI={10.1007/s11538-006-9068-x}, abstractNote={Genistein is an endocrine-active compound (EAC) found in soy products. It has been linked to beneficial effects such as mammary tumor growth suppression and adverse endocrine-related effects such as reduced birth weight in rats and humans. In its conjugated form, genistein is excreted in the bile, which is a significant factor in its pharmacokinetics. Experimental data suggest that genistein induces a concentration-dependent suppression of biliary excretion. In this article, we describe a physiologically based pharmacokinetic (PBPK) model that focuses on biliary excretion with the goal of accurately simulating the observed suppression. The mathematical model is a system of nonlinear differential equations with state-dependent delay to describe biliary excretion. The model was analyzed to examine local existence and uniqueness of a solution to the equations. Furthermore, unknown parameters were estimated, and the mathematical model was compared against published experimental data.}, number={1}, journal={BULLETIN OF MATHEMATICAL BIOLOGY}, author={Zagera, Michael G. and Schlosser, Paul M. and Tran, Hien T.}, year={2007}, month={Jan}, pages={93–117} }
 @article{schlosser_borghoff_coldham_david_ghosh_2006, title={Physiologically-based pharmacokinetic modeling of genistein in rats, part I: Model development}, volume={26}, ISSN={["1539-6924"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-33645288581&partnerID=MN8TOARS}, DOI={10.1111/j.1539-6924.2006.00743.x}, abstractNote={Genistein is a phytoestrogen—a plant‐derived compound that binds to and activates the estrogen receptor—occurring at high levels in soy beans and food products, leading to widespread human exposure. The numerous scientific publications available describing genistein's dosimetry, mechanisms of action, and identified or putative health effects in both experimental animals and humans make it ideal for examination as an example of endocrine‐active compound (EAC). We developed a physiologically‐based pharmacokinetic (PBPK) model to quantify the internal, target‐tissue dosimetry of genistein in adult rats. Complexities of the model include enterohepatic circulation, binding of both genistein and its conjugates to plasma proteins, and the multiple compartments used to describe transport through the bile duct and gastrointestinal tract. Other aspects of the model are simple perfusion‐limited transport to the tissue groups and first‐order rates of metabolism, uptake, and excretion. We describe here the model structure and initial calibration of the model by fitting to a large data set for Wistar rats. The model structure can be readily extrapolated to describe genistein dosimetry in humans or modified to describe the dosimetry of other phytoestrogens and phenolic EACs. The model does a fair job of capturing the pharmacokinetics. Although it does not describe the interindividual variability and we have not identified a single set of parameters that provide a good fit to the data for both oral and intravenous exposures, we believe it provides a good initial attempt at PBPK modeling for genistein, which can serve as a template for other phytoestrogens and in the design of future experiments and research that can be used to fill data gaps and better estimate model parameters.}, number={2}, journal={RISK ANALYSIS}, author={Schlosser, PM and Borghoff, SJ and Coldham, NG and David, JA and Ghosh, SK}, year={2006}, month={Apr}, pages={483–500} }
 @article{clark_schlosser_selgrade_2003, title={Multiple stable periodic solutions in a model for hormonal control of the menstrual cycle}, volume={65}, ISSN={["0092-8240"]}, DOI={10.1006/bulum.2002.0326}, number={1}, journal={BULLETIN OF MATHEMATICAL BIOLOGY}, author={Clark, LH and Schlosser, PM and Selgrade, JF}, year={2003}, month={Jan}, pages={157–173} }
 @misc{lovern_cole_schlosser_2001, title={A review of quantitative studies of benzene metabolism}, volume={31}, ISSN={["1547-6898"]}, DOI={10.1080/20014091111703}, abstractNote={Benzene is a ubiquitous, highly flammable, colorless liquid that is a known hematotoxin, myelotoxin, and human leukemogen. Benzene-induced toxicity in animals is clearly mediated by its metabolism. The mechanisms of acute hemato- and myelotoxicity in humans are almost certainly the same as in animals, and there is compelling evidence that metabolism is requisite for the induction of leukemia in humans. A very large number of experimental investigations of benzene metabolism have been conducted with animals, both in vivo and in vitro. There have also been many investigations of benzene metabolism in humans and with human tissues, Although the blood or tissue concentrations of benzene metabolites in humans resulting from benzene exposure have never been measured. Further, a number of mathematical models of benzene metabolism and dosimetry have been developed. In this article, we consider results from both experimental and mathematical modeling research, with particular emphasis on the last decade, and discuss the factors that are likely to be most influential in the metabolism of benzene.}, number={3}, journal={CRITICAL REVIEWS IN TOXICOLOGY}, author={Lovern, MR and Cole, CE and Schlosser, PM}, year={2001}, pages={285–311} }
 @article{cole_tran_schlosser_2001, title={Physiologically based pharmacokinetic modeling of benzene metabolism in mice through extrapolation from in vitro to in vivo}, volume={62}, ISSN={["1528-7394"]}, DOI={10.1080/00984100150501178}, abstractNote={Benzene (C6H6) is a highly flammable, colorless liquid. Ubiquitous exposures result from its presence in gasoline vapors, cigarette smoke, and industrial processes. Benzene increases the incidence of leukemia in humans when they are exposed to high doses for extended periods; however, leukemia risks in humans at low exposures are uncertain. The exposure-dose-response relationship of benzene in humans is expected to be nonlinear because benzene undergoes a series of metabolic transformations, detoxifying and activating, in the liver, resulting in multiple metabolites that exert toxic effects on the bone marrow. We developed a physiologically based pharmacokinetic model for the uptake and elimination of benzene in mice to relate the concentration of inhaled and orally administered benzene to the tissue doses of benzene and its key metabolites, benzene oxide, phenol, and hydroquinone. As many parameter values as possible were taken from the literature; in particular, metabolic parameters obtained from in vitro studies with mouse liver were used since comparable parameters are also available for humans. Parameters estimated by fitting the model to published data were first-order rate constants for pathways lacking in vitro data and the concentrations of microsomal and cytosolic protein, which effectively alter overall enzyme activity. The model was constrained by using the in vitro metabolic parameters (maximum velocities, first-order rate constants, and saturation parameters), and data from multiple laboratories and experiments were used. Despite these constraints and sources of variability, the model simulations matched the data reasonably well in most cases, showing that in vitro metabolic constants can be successfully extrapolated to predict in vivo data for benzene metabolism and dosimetry. Therefore in vitro metabolic constants for humans can subsequently be extrapolated to predict the dosimetry of benzene and its metabolites in humans. This will allow us to better estimate the risks of adverse effects from low-level benzene exposures.}, number={6}, journal={JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A}, author={Cole, CE and Tran, HT and Schlosser, PM}, year={2001}, month={Mar}, pages={439–465} }
 @article{schlosser_selgrade_2000, title={A model of gonadotropin regulation during the menstrual cycle in women: Qualitative features}, volume={108}, ISSN={["0091-6765"]}, DOI={10.2307/3454321}, journal={ENVIRONMENTAL HEALTH PERSPECTIVES}, author={Schlosser, PM and Selgrade, JF}, year={2000}, month={Oct}, pages={873–881} }
 @article{smethie_schlosser_bonisch_hopkins_2000, title={Renewal and circulation of intermediate waters in the Canadian Basin observed on the SCICEX 96 cruise}, volume={105}, ISSN={["2169-9291"]}, DOI={10.1029/1999jc900233}, abstractNote={During the summer of 1996 the nuclear submarine USS Pogy occupied a line of stations extending through the middle of the Canadian Basin between about 88°N, 44°W (Lomonosov Ridge) and about 78°N, 144°W (center of the Canada Basin). CTD/Niskin bottle casts extending to 1600 m were carried out at eight stations, providing the first high‐quality temperature, salinity, CFC, tritium, and 3He data obtained from this region, although XCTD data had previously been collected in this region. These data, along with data from stations at the basin boundary to the south and west, reveal the presence of well‐ventilated intermediate water beneath the halocline in the center of the Canada Basin, indicating renewal times of the order of 1–2 decades. The least ventilated intermediate water was observed at the northern end of the Canada Basin along the southern flank of the Alpha Ridge. Intermediate water is derived from the Atlantic Ocean and enters the Arctic Ocean through Fram Strait and the Barents Sea. It flows around the Arctic basins in boundary currents and splits in the eastern Amundsen Basin with one branch crossing the Lomonosov Ridge and flowing along the East Siberian continental slope and the other flowing along the Eurasian flank of the Lomonosov Ridge. From the 1996 Scientific Ice Expedition (SCICEX 96) observations we conclude that the branch that flows along the East Siberian continental slope transports this water to the Chukchi Rise, where it apparently enters the central Canada Basin with some flow continuing along the boundary to the southern Canada Basin. The Fram Strait Branch Water mixes extensively with waters from the Canadian Basin during its transit along the East Siberian continental slope, being diluted by a factor of about 5 by the time it reaches the central Canada Basin. The Barents Sea Branch Water does not undergo such extensive mixing and is diluted by a factor of only about 2 when it reaches the central Canada Basin.}, number={C1}, journal={JOURNAL OF GEOPHYSICAL RESEARCH-OCEANS}, author={Smethie, WM and Schlosser, P and Bonisch, G and Hopkins, TS}, year={2000}, month={Jan}, pages={1105–1121} }
 @article{lovern_maris_schlosser_1999, title={Use of a mathematical model of rodent in vitro benzene metabolism to predict human in vitro metabolism data}, volume={20}, ISSN={["0143-3334"]}, DOI={10.1093/carcin/20.8.1511}, abstractNote={Benzene, a ubiquitous environmental pollutant, is known to cause leukemia and aplastic anemia in humans and hematotoxicity and myelotoxicity in rodents. Toxicity is thought to be exerted through oxidative metabolites formed in the liver, primarily via pathways mediated by cytochrome P450 2E1 (CYP2E1). Phenol, hydroquinone and trans-trans-muconaldehyde have all been hypothesized to be involved in benzene-induced toxicity. Recent reports indicate that benzene oxide is produced in vitro and in vivo and may be sufficiently stable to reach the bone marrow. Our goal was to improve existing mathematical models of microsomal benzene metabolism by including time course data for benzene oxide, by obtaining better parameter estimates and by determining if enzymes other than CYP2E1 are involved. Microsomes from male B6C3F1 mice and F344 rats were incubated with [(14)C]benzene (14 microM), [(14)C]phenol (303 microM) and [(14)C]hydroquinone (8 microM). Benzene and phenol were also incubated with mouse microsomes in the presence of trans-dichloroethylene, a CYP2E1 inhibitor, and benzene was incubated with trichloropropene oxide, an epoxide hydrolase inhibitor. These experiments did not indicate significant contributions of enzymes other than CYP2E1. Mathematical model parameters were fitted to rodent data and the model was validated by predicting human data. Model simulations predicted the qualitative behavior of three human time course data sets and explained up to 81% of the total variation in data from incubations of benzene for 16 min with microsomes from nine human individuals. While model predictions did deviate systematically from the data for benzene oxide and trihydroxybenzene, overall model performance in predicting the human data was good. The model should be useful in quantifying human risk due to benzene exposure and explicitly accounts for interindividual variation in CYP2E1 activity.}, number={8}, journal={CARCINOGENESIS}, author={Lovern, MR and Maris, ME and Schlosser, PM}, year={1999}, month={Aug}, pages={1511–1520} }
 @article{schlosser_godo_fornes_hubal_1998, title={Application of a photographic method for determining mass transfer to flow around a submerged parallelepiped}, volume={41}, ISSN={["0017-9310"]}, DOI={10.1016/S0017-9310(98)00013-1}, abstractNote={A previously described method for quantifying uptake of dilute photographic developer solutions (Dasgupta et al., Int J Heat Mass Transfer 1995;38:2029-37) [1] was applied to the floor of a recirculating flow tank near a submerged parallelepiped. The method was calibrated for a new combination of film and developer. Unlike [1], we found it preferable to include an autocatalytic term in the rate equation for silver development to adequately describe the kinetics of development. A map of mass transfer resistance between the bulk fluid and the flow tank floor was generated for future comparison to CFD predictions.}, number={19}, journal={INTERNATIONAL JOURNAL OF HEAT AND MASS TRANSFER}, author={Schlosser, PM and Godo, MN and Fornes, TD and Hubal, EC}, year={1998}, month={Oct}, pages={2991–3004} }
 @article{lovern_turner_meyer_kedderis_bechtold_schlosser_1997, title={Identification of benzene oxide as a product of benzene metabolism by mouse, rat, and human liver microsomes}, volume={18}, ISSN={["0143-3334"]}, DOI={10.1093/carcin/18.9.1695}, abstractNote={Benzene is a ubiquitous environmental pollutant that is known to cause hematotoxicity and leukemia in humans. The initial oxidative metabolite of benzene has long been suspected to be benzene oxide (3,5-cyclohexadiene-1,2-oxide). During in vitro experiments designed to characterize the oxidative metabolism of [14C]benzene, a metabolite was detected by HPLC-radioactivity analysis that did not elute with other known oxidative metabolites. The purpose of our investigation was to prove the hypothesis that this metabolite was benzene oxide. Benzene (1 mM) was incubated with liver microsomes from human donors, male B6C3F1 mice, or male Fischer-344 rats, NADH (1 mM), and NADPH (1 mM) in 0.1 M sodium phosphate buffer (pH 7.4) and then extracted with methylene chloride. Gas chromatography-mass spectrometry analysis of incubation extracts for mice, rats, and humans detected a metabolite whose elution time and mass spectrum matched that of synthetic benzene oxide. The elution time of the benzene oxide peak was approximately 4.1 min, while phenol eluted at approximately 8 min. Benzene oxide also coeluted with the HPLC peak of the previously unidentified metabolite. Based on the 14C activity of this peak, the concentration of benzene oxide was determined to be approximately 18 microM, or 7% of total benzene metabolites, after 18 min of incubation of mouse microsomes with 1 mM benzene. The metabolite was not observed in incubations using heat-inactivated microsomes. This is the first demonstration that benzene oxide is a product of hepatic benzene metabolism in vitro. The level of benzene oxide detected suggests that benzene oxide is sufficiently stable to reach significant levels in the blood of mice, rats, and humans and may be translocated to the bone marrow. Therefore benzene oxide should not be excluded as a possible metabolite involved in benzene-induced leukemogenesis.}, number={9}, journal={CARCINOGENESIS}, author={Lovern, MR and Turner, MJ and Meyer, M and Kedderis, GL and Bechtold, WE and Schlosser, PM}, year={1997}, month={Sep}, pages={1695–1700} }