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Melvin E Andersen

Publications and source records attributed to Melvin E Andersen.

54 records · Page 3Linked to original sources
PubMed2003

Physiological modeling of inhalation kinetics of octamethylcyclotetrasiloxane in humans during rest and exercise.

In a recent pharmacokinetic study, six human volunteers were exposed by inhalation to 10 ppm (14)C-D(4) for 1 h during alternating periods of rest and exercise. Octamethylcyclotetrasiloxane (D(4)) concentrations were determined in exhaled breath and blood. Total metabolite concentrations were estimated in blood, while the amounts of individual metabolites were measured in urine. Here, we use these data to develop a physiologically based pharmacokinetic (PBPK) model for D(4) in humans. Consistent with PBPK modeling efforts for D(4) in the rat, a conventional inhalation PBPK model assuming flow-limited tissue uptake failed to adequately describe these data. A refined model with sequestered D(4) in blood, diffusion-limited tissue uptake, and an explicit pathway for D(4) metabolism to short-chain linear siloxanes successfully described all data. Hepatic extraction in these volunteers, calculated from model parameters, was 0.65 to 0.8, i.e., hepatic clearance was nearly flow-limited. The decreased retention of inhaled D(4) seen in humans during periods of exercise was explained by altered ventilation/perfusion characteristics during exercise and a rapid approach to steady-state conditions. The urinary time course excretion of metabolites was consistent with a metabolic scheme in which sequential hydrolysis of linear siloxanes followed oxidative demethylation and ring opening. The unusual properties of D(4) (high lipophilicity coupled with high hepatic and exhalation clearance) lead to rapid decreases in free D(4) in blood. The success of D(4) PBPK models with a similar physiological structure in both humans and rats increases confidence in the utility of the model for predicting human tissue concentrations of D(4) and metabolites during inhalation exposures.

Adjuvants, Immunologic↗
PubMed2002

Application of a physiologically based pharmacokinetic model for isopropanol in the derivation of a reference dose and reference concentration.

An interspecies physiologically based pharmacokinetic (PBPK) model describing isopropanol (IPA) and its major metabolite, acetone, was applied to perform route-to-route and cross-species dosimetry to derive reference dose (RfD) and reference concentration (RfC) values for IPA. Adult PBPK models for rats and humans were extended to simulate exposure to IPA during pregnancy and used to estimate internal dose metrics in the mother and fetus during development. Endpoints from chronic, developmental, and reproductive toxicity studies were considered for the derivation of RfDs and RfCs. Due to uncertainties in the mode of action of toxicity for IPA and acetone, the dose metric used for most responses was the total area under the blood concentration curve (AUC) for the combination of IPA and acetone. This combined dose metric provided a more conservative estimate than those based on AUCs for IPA or acetone. Peak blood concentration of IPA was the dose metric for neurobehavioral effects. The recommended RfD and RfC for IPA are 10 mg/kg/day and 40 ppm, respectively, based on decreased fetal body weights. All of the PBPK-derived RfD or RfC values for various endpoints were similar (within a factor of 3), regardless of route of exposure in the animal study.

2-Propanol↗
PubMed2002

Physiologically based pharmacokinetic (PBPK) models for nasal tissue dosimetry of organic esters: assessing the state-of-knowledge and risk assessment applications with methyl methacrylate and vinyl acetate.

Mathematical models have been developed to describe nasal epithelial tissue dosimetry with two compounds, vinyl acetate (VA) and methyl methacrylate (MMA), that cause toxicity in these tissues These models couple computational fluid dynamics (CFD) calculations that map airflow patterns within the nose with physiologically based pharmacokinetic (PBPK) models that integrate diffusion, metabolism, and tissue interactions of these compounds. Dose metrics estimated in these models for MMA and VA, respectively, were rates of MMA metabolism per volume of tissue and alterations in pH in target tissues associated with VA hydrolysis and metabolism. In this article, four scientists who have contributed significantly to development of these models describe the many similarities and relatively few differences between the MMA and VA models. Some differences arise naturally because of differences in target tissues, in the calculated measures of tissue dose, and in the modes of action for highly extracted vapors (VA) compared with poorly extracted vapors (MMA). A difference in the approach used to estimate metabolic parameters from human tissues provides insights into interindividual extrapolation and identifies opportunities for studies with human nasal tissues to enhance current risk assessments. In general, the differences in model structure for these two esters were essential for describing the biology of the observed responses and in accounting for the different measures of target tissue dose. This article is intended to serve as a guide for understanding issues of optimum model structure and optimal data sources for these nasal tissue dosimetry models. We also hope that it leads to greater international acceptance of these hybrid CFD/PBPK modeling approaches for improving risk assessment for many nasal toxicants. In general, these models predict either equivalent (VA) or lower (MMA) nasal tissue doses in humans compared with tissue doses at equivalent exposure concentrations in rats.

Air Movements↗
PubMed2002

Physiologically based pharmacokinetic modeling of styrene and styrene oxide respiratory-tract dosimetry in rodents and humans.

Styrene (ST) is widely used to manufacture resins, glass-reinforced plastics, and a number of commercially important polymers (Miller et al., 1994). Chronic ST inhalation studies in rodents have demonstrated unique species specificity in the resulting pulmonary toxicity and carcinogenicity. Increased incidences of pulmonary bronchioloalveolar tumors have been observed in mice, but not in rats. No other tumor type was increased significantly in either species. Clara cells lining the respiratory epithelium metabolize ST to styrene 7,8-oxide (SO), which is cytotoxic and weakly genotoxic. Rodent species show marked differences in the distribution and regional density of Clara cells within the respiratory tract, as well as in their capacity to produce and eliminate SO. A mode of action-based physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of ST and SO in blood, liver, and the respiratory-tract tissues, particularly in terminal bronchioles (target tisue), in order to conduct interspecies extrapolations and determine the extent to which there is a pharmacokinetic basis for the observed species specificity. This PBPK model has a multicompartment description of the respiratory tract and incorporates species-specific quantitative information on respiratory-tract physiology, cellular composition, and metabolic capacity. The model is validated against multiple data sets, including blood, liver, and whole lung tissue concentration of ST and SO following multiple routes of exposure. The trend in neoplastic incidences in mice correlated well with model-estimated SO concentration in the terminal bronchioles. The PBPK model predicts a 10-fold lower SO concentration in the terminal bronchioles in rats compared to mice, which is consistent with the observed species sensitivity to the development of respiratory-tract neoplasms. The model-based analysis suggests that humans would be expected to be 100-fold less sensitive to ST-inducted lung tumors than mice, based on pharmacokinetic differences. Pharmacodynamic factors are also expected to contribute to species sensitivity, potentially augmenting pharmacokinetics-based differences.

Animals↗
PubMed2002

Comparing respiratory-tract and hepatic exposure-dose relationships for metabolized inhaled vapors: a pharmacokinetic analysis.

Inhaled vapors that are metabolized locally in the respiratory-tract tissues and systemically in the liver and other organs have different dose-response relationships at the portal of entry compared to systemic target organs. For instance, inhaled chloroform and styrene cause cytotoxicity in the nasal cavity at concentrations much lower that those causing hepatic or renal toxicity. Here, we develop a physiologically based pharmacokinetic (PBPK) model that incorporates a multicompartment, unidirectional flow description of the respiratory tract within a whole-body model in order to estimate both respiratory tract and hepatic metabolism. We then use this model to study the difference in exposure-dose relationship between the respiratory-tract tissues and the liver. The integrated PBPK model confirms that for soluble vapors the exposure-dose curve for metabolism in respiratory-tract tissue will be shifted dramatically to lower concentrations compared to the exposure-dose relationship in systemic organs. This behavior is the result of direct air to tissue equilibration at the portal of entry while other systemic tissues only respond to concentrations in the blood. For cases where metabolism/metabolites of inhaled vapors produce local toxicity, portal of entry effects are expected at lower concentrations and, in general, will be the limiting response for setting reference concentrations (RfCs) for many compounds. The difference in dose-response relationships for metabolism in the respiratory tract versus systemic organs depends on blood/air and blood/tissue partition coefficients and on the degree of systemic extraction of the metabolized vapors.

Animals↗
PubMed2002

Dose-response modeling of cytochrome p450 induction in rats by octamethylcyclotetrasiloxane.

Inhalation of octamethylcyclotetrasiloxane (D4) induces CYP2B1/2 protein and causes liver enlargement. We have developed a pharmacodynamic (PD) extension to a physiologically based pharmacokinetic (PBPK) model to characterize these dose-response behaviors. The PD model simulates interactions of D4 with a putative receptor, leading to increased production of cytochrome P450 2B1/2. Induction was modeled with a Hill equation with dissociation constant, Kd, and Hill coefficient, N. Both a 1- and a 5-compartment liver model were evaluated. The PBPK model provided excellent simulations of tissue D4 and hepatic CYP2B1/2 protein concentrations following 6 h/day, 5-day inhalation exposures to 0, 1, 7, 30, 70, 150, 300, 500, 700, or 900 ppm D4. Either the 1- or 5-compartment liver model could accurately simulate increases in CYP2B1/2 protein in the liver. With a 1-compartment liver, Kd and N were 0.67 microM (free liver concentration) and 1.9, respectively. The 5-compartment model used higher N-values (approximately 4.0) and varied Kd between compartments. The fitted 5-compartment model parameters were Kd = 0.67 microM in the midzonal compartment with geometric differences in Kd between compartments of 2.9. On the basis of unbound (free) plasma concentrations, D4 appeared to be a higher potency inducer than phenobarbital (PB). Dose-response curves for increased liver weights had N/mS 1.0 and Kd/mS 3.4 microM, very different values from those for enzyme induction. Exposure concentration leading to a 0.1% increase in CYP2B1/2 protein predicted by the 1- and 5-compartment models were 2.1 ppm and 5.1 ppm, respectively. The 1- and 5-compartment liver models provided very similar fits to the whole liver induction data, excluding the lowest dose, but the 5-compartment liver model had the additional advantage of simultaneously describing the regional induction of CYP2B1/2.

Adjuvants, Immunologic↗
PubMed2002

In silico toxicology: simulating interaction thresholds for human exposure to mixtures of trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane.

In this study, we integrated our understanding of biochemistry, physiology, and metabolism of three commonly used organic solvents with computer simulation to present a new approach that we call "in silico" toxicology. Thus, we developed an interactive physiologically based pharmacokinetic (PBPK) model to predict the individual kinetics of trichloroethylene (TCE), perchloroethylene (PERC), and methylchloroform (MC) in humans exposed to differently constituted chemical mixtures of the three solvents. Model structure and parameterization originate from the literature. We calibrated the single-compound PBPK models using published data and described metabolic interactions within the chemical mixture using kinetic constants estimated in rats. The mixture model was used to explore the general pharmacokinetic profile of two common biomarkers of exposure, peak TCE blood levels and total amount of TCE metabolites generated, in rats and humans. Assuming that a 10% change in the biomarkers corresponds to a significant health effect, we calculated interaction thresholds for binary and ternary mixtures of TCE, PERC, and MC. Increases in the TCE blood levels led to higher availability of the parent compound for glutathione conjugation, a metabolic pathway associated with kidney toxicity/carcinogenicity. The simulated change in production rates of toxic conjugative metabolites exceeded 17% for a corresponding 10% increase in TCE blood concentration, indicating a nonlinear risk increase due to combined exposures to TCE. Evaluation of metabolic interactions and their thresholds illustrates a unique application of PBPK modeling in risk assessment of occupational exposures to chemical mixtures.

Biological Availability↗
PubMed2002

A consistent approach for the application of pharmacokinetic modeling in cancer and noncancer risk assessment.

Physiologically based pharmacokinetic modeling provides important capabilities for improving the reliability of the extrapolations across dose, species, and exposure route that are generally required in chemical risk assessment regardless of the toxic end point being considered. Recently, there has been an increasing focus on harmonization of the cancer and noncancer risk assessment approaches used by regulatory agencies. Although the specific details of applying pharmacokinetic modeling within these two paradigms may differ, it is possible to identify important elements common to both. These elements expand on a four-part framework for describing the development of toxicity: a) exposure, b) tissue dosimetry/pharmacokinetics, c) toxicity process/pharmacodynamics, and d) response. The middle two components constitute the mode of action. In particular, the approach described in this paper provides a common template for incorporating pharmacokinetic modeling to estimate tissue dosimetry into chemical risk assessment, whether for cancer or noncancer end points. Chemical risk assessments typically depend upon comparisons across species that often simplify to ratios reflecting the differences. In this paper we describe the uses of this ratio concept and discuss the advantages of a pharmacokinetic-based approach as compared to the use of default dosimetry.

Animals↗
PubMed2002

Application of biologically based computer modeling to simple or complex mixtures.

The complexity and the astronomic number of possible chemical mixtures preclude any systematic experimental assessment of toxicology of all potentially troublesome chemical mixtures. Thus, the use of computer modeling and mechanistic toxicology for the development of a predictive tool is a promising approach to deal with chemical mixtures. In the past 15 years or so, physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling has been applied to the toxicologic interactions of chemical mixtures. This approach is promising for relatively simple chemical mixtures; the most complicated chemical mixtures studied so far using this approach contained five or fewer component chemicals. In this presentation we provide some examples of the utility of PBPK/PD modeling for toxicologic interactions in chemical mixtures. The probability of developing predictive tools for simple mixtures using PBPK/PD modeling is high. Unfortunately, relatively few attempts have been made to develop paradigms to consider the risks posed by very complex chemical mixtures such as gasoline, diesel, tobacco smoke, etc. However, recent collaboration between scientists at Colorado State University and engineers at Rutgers University attempting to use reaction network modeling has created hope for the possible development of a modeling approach with the potential of predicting the outcome of toxicology of complex chemical mixtures. We discuss the applications of reaction network modeling in the context of petroleum refining and its potential for elucidating toxic interactions with mixtures.

Computer Simulation↗
PubMed2002

Molecular circuits, biological switches, and nonlinear dose-response relationships.

Signaling motifs (nuclear transcriptional receptors, kinase/phosphatase cascades, G-coupled protein receptors, etc.) have composite dose-response behaviors in relation to concentrations of protein receptors and endogenous signaling molecules. "Molecular circuits" include the biological components and their interactions that comprise the workings of these signaling motifs. Many of these molecular circuits have nonlinear dose-response behaviors for endogenous ligands and for exogenous toxicants, acting as switches with "all-or-none" responses over a narrow range of concentration. In turn, these biological switches regulate large-scale cellular processes, e.g., commitment to cell division, cell differentiation, and phenotypic alterations. Biologically based dose-response (BBDR) models accounting for these biological switches would improve risk assessment for many nonlinear processes in toxicology. These BBDR models must account for normal control of the signaling motifs and for perturbations by toxic compounds. We describe several of these biological switches, current tools available for constructing BBDR models of these processes, and the potential value of these models in risk assessment.

Cell Differentiation↗
PubMedDate not supplied

Dose-response modeling in reproductive toxicology in the systems biology era.

Systems biology approaches for modeling cellular signaling networks affected by chemical exposures should soon produce integrated methodologies capable of predicting dose-response relationships for developmental toxicants and for other toxic responses. This paper outlines an emerging strategy for systems biology approaches in dose-response modeling. Genome-wide functional screens, bioinformatic tools, and network mapping technologies together can provide directed graph representations of the cellular signaling networks. The graphical representations can be converted into mathematical models that permit predicting the shapes of dose-response curves for altered cell signaling by test compounds during development. Systems biology approaches require interdisciplinary teams with expertise in reproduction, cell biology, signal transduction, mathematical/biomedical modeling, and risk assessment. In addition to outlining a systems approach for dose-response research, this paper discusses initial stages of application of this strategy to examine inhibition of steroidogenesis in testes by phthalate esters.

Animals↗
PubMedDate not supplied

The use of quantitative histological and molecular data for risk assessment and biologically based model development.

In organs with diverse cell populations, it is not uncommon for one type of cell to respond while others are spared. Even in an organ with common cell types, such as hepatocytes within the liver, the population of cells may respond with different sensitivities for injury or for biochemical responses to toxicants. In the liver, many tumor promoters induce cytochrome P450 enzymes and other proteins in centrilobular cells at much lower doses than required to cause induction in periportal cells. In addition, these induction responses appear to occur at the level of individual cells--a 50% response of the liver for induction does not represent 50% induction in all cells. Instead, half of the cells are fully induced and half are unaffected. Cells "switch" from one phenotypic state to another. Over the past 10 years, several attempts have been made to model these cellular switches and to understand their relevance for hepatic tumor promotion and risk assessment. The data used for analyzing these switches include responses of the entire liver (total induction), responses of individual cells in the liver (regional induction), and cellular responses such as proliferation and apoptosis. This brief overview describes the development of biologically based, dose-response (BBDR) models for protein induction and tumor promotion in liver by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with emphasis on the role of specific types of histological and molecular data in providing insights about mechanisms for cellular switches and their implications for tumor promotion. As the biological basis of these switches become unraveled and incorporated into the models, these BBDR models should eventually serve to improve risk assessments with a variety of liver tumor promoters with receptor-based modes of action.

Animals↗
PubMedDate not supplied

Regional induction of CYP1A1 in rat liver following treatment with mixtures of PCB 126 and PCB 153.

Liver enzyme induction has been shown previously to be regional with clear borders between induced and uninduced regions in vivo, and cells either fully induced or not induced in vitro. The current study examined this phenomenon in vivo by evaluating enzyme induction after exposure to PCB 126 and PCB 153 in female Fisher 344 (F344) and male Sprague-Dawley (SD) rats. IHC revealed a regional induction of CYP1A1 after exposure to PCB 126, apparent in the centrilobular region at lower doses and progressing to panlobular with higher doses. PCB 153 exposure induced CYP2B1/2 in the centrilobular region, which spread to the midzonal region as the dose increased, but never became panlobular even at the highest dosage tested. In rats treated with PCB 126 in combination with high doses of PCB 153, induction of CYP1A1 occurred preferentially in the periportal region, a reversal from the pattern seen with PCB 126 alone. This CYP1A1 induction pattern reversal is a unique example of complex biological interactions between coplanar (PCB 126) and noncoplanar (PCB 153) halogenated aromatic hydrocarbons.

Animals↗
PubMedDate not supplied

Applying mode-of-action and pharmacokinetic considerations in contemporary cancer risk assessments: an example with trichloroethylene.

The guidelines for carcinogen risk assessment recently proposed by the U.S. Environmental Protection Agency (U.S. EPA) provide an increased opportunity for the consideration of pharmacokinetic and mechanistic data in the risk assessment process. However, the greater flexibility of the new guidelines can also make their actual implementation for a particular chemical highly problematic. To illuminate the process of performing a cancer risk assessment under the new guidelines, the rationale for a state-of-the-science risk assessment for trichloroethylene (TCE) is presented. For TCE, there is evidence of increased cell proliferation due to receptor interaction or cytotoxicity in every instance in which tumors are observed, and most tumors represent an increase in the incidence of a commonly observed, species-specific lesion. A physiologically based pharmacokinetic (PBPK) model was applied to estimate target tissue doses for the three principal animal tumors associated with TCE exposure: liver, lung, and kidney. The lowest points of departure (lower bound estimates of the exposure associated with 10% tumor incidence) for lifetime human exposure to TCE were obtained for mouse liver tumors, assuming a mode of action primarily involving the mitogenicity of the metabolite trichloroacetic acid (TCA). The associated linear unit risk estimates for mouse liver tumors are 1.5 x 10(-6) for lifetime exposure to 1 microg TCE per cubic meter in air and 0.4 x 10(-6) for lifetime exposure to 1 microg TCE per liter in drinking water. However, these risk estimates ignore the evidence that the human is likely to be much less responsive than the mouse to the carcinogenic effects of TCA in the liver and that the carcinogenic effects of TCE are unlikely to occur at low environmental exposures. Based on consideration of the most plausible carcinogenic modes of action of TCE, a margin-of-exposure (MOE) approach would appear to be more appropriate. Applying an MOE of 1000, environmental exposures below 66 microg TCE per cubic meter in air and 265 microg TCE per liter in drinking water are considered unlikely to present a carcinogenic hazard to human health.

Animals↗
PubMedDate not supplied

Toxicokinetics and physiologically based toxicokinetics in toxicology and risk assessment.

Toxicokinetics is the study of kinetics of absorption, distribution, metabolism, and excretion of a xenobiotic under the conditions of toxicity evaluation. Conventional toxicokinetics uses the hypothetical compartments, and the model is composed of rate equations that describe the time course of drug and chemical disposition. The utility of toxicokinetics in toxicity evaluation and interpretation of animal toxicology data is emerging as an important tool in product discovery and development. With implementation of the International Conference on Harmonization (ICH) guidelines on systemic exposure and dose selection, toxicokinetics have been integrated in routine toxicity evaluations. Although traditional compartmental/noncompartmental models are generally adequate for assessing systemic exposure, they are unable to the predict time course of drug disposition in target tissues and often fail to relate systemic drug levels to a biological response. Physiologically based toxicokinetic (PB-TK) models address this deficiency of traditional compartmental models. PB-TK models are the kinetic models of the uptake and disposition of chemicals based on rates of biochemical reactions, physiological and anatomical characteristics. These models, when developed appropriately, can predict target organ drug distribution in different species under variety of conditions. This minireview discusses the basic principles, and applications of traditional compartmental toxicokinetic and physiologically based toxicokinetics (PB-TK) models in drug development and risk assessment. Special emphasis will be placed on discussion related to interpretation of the ICH guidelines related to toxicokinetics and the utility of toxicokinetics data in dose selection for toxicity and carcinogenicity studies. The utility of PB-TK models in risk assessment of methylene chloride, vinyl chloride, retinoic acid, dioxin, and inhaled organic esters is discussed.

Animals↗
PubMedDate not supplied

Quantitative identification of atrazine and its chlorinated metabolites in plasma.

The objective of this study was to develop an analytical method to detect and quantitate the chlorotriazine herbicide atrazine (ATRA), and its chlorinated metabolites [desethylatrazine (DE-ATRA), desisopropylatrazine (DI-ATRA), and diaminochlorotriazine (DACT)] in plasma. Control plasma separated from whole rat blood was fortified with known concentrations of ATRA, DE-ATRA, DI-ATRA, and DACT. These compounds were extracted from the plasma using a liquid-liquid extraction technique, and the resulting extracts were derivatized with tetrabutyl ammonium hydroxide and methyl iodide to produce methylated derivatives of ATRA and its chlorinated metabolites. Derivatized samples and standards were analyzed using gas chromatography-mass spectrometry with selected ion monitoring. Recoveries of fortified plasma samples ranged from 84% to 97% and were validated to 100 ng/mL. This analytical method was subsequently verified in a small-scale animal study to determine time course concentrations of chlorotriazines in plasma following a single oral gavage dose of ATRA to female Sprague Dawley rats.

Animals↗