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H A el-Masri

Publications and source records attributed to H A el-Masri.

9 recordsLinked to original sources
PubMed1998

Enhanced regional expression of glutathione S-transferase P1-1 with colocalized AP-1 and CYP 1A2 induction in chlorobenzene-induced porphyria.

A distinct, nonfocal expression pattern was observed for glutathione S-transferase P1-1 (rGSTP1-1) in rats exposed to either hexachloro-(HCB) or pentachlorobenzene (PeCB). The nonfocal expression was localized to the centrilobular region with the most intense staining nearest the central vein. A Western blot analysis revealed a 5- and 15-fold induction of rGSTP1-1 with PeCB and HCB treatment on an equal molar basis, respectively. Evaluation of porphyrin fluorescence also revealed a centrilobular accumulation with average porphyrin measurements of 0.319, 0.590, and 0.206 micrograms/g tissue for PeCB, HCB, and corn-oil controls, respectively. Due to the role of Activator Protein-1 (AP-1) in rGSTP1-1 expression and CYP 1A2 in the pathogenesis of porphyria cutanea tarda, immunohistochemical localization of c-jun, c-fos, and CYP 1A2 was also performed. Increased expression and colocalization within the liver lobule was observed for c-jun, c-fos, CYP 1A2, rGSTP1-1, and areas of porphyrin accumulation. These observations are consistent with studies that have associated the induction of GST-P with jun- and fos-related gene products.

Animals↗
PubMed1997

Integrated approaches for the analysis of toxicologic interactions of chemical mixtures.

Although an overwhelmingly large portion of the resources in toxicologic research is devoted to single chemical studies, the toxicology of chemical mixtures, not single chemicals, is the real issue regarding health effects of environmental and/or occupational exposure to chemicals. The relative lack of activities in the area of toxicology of chemical mixtures does not suggest ignorance of the importance of the issue by the toxicology community. Instead, it is a reflection of the difficulty, complexity, and controversy surrounding this area of research. Until recently, much of the literature on the toxicology of chemical mixtures has been either very focused on certain specific interaction studies or slanted toward broad-based, relatively vague theoretical deliberation. The typical interaction study involved binary mixtures at relatively high dose levels with acute toxicities as endpoints. Although the theoretical papers have been valuable contributions, little is available on actual, practical experimental approaches toward a systematic solution of this immensely complex area of research. We present here a broad discussion on the important issues of the toxicology of chemical mixtures. First, we provide some background information with respect to the problem and significance of toxicology of chemical mixtures in relation to some of the real life issues. Second, we review and compare the existing experimental approaches relevant to toxicologic interactions of chemical mixtures. Third, we propose three integrated approaches that involve the combination of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with: (1) Monte Carlo simulation, (2) median effect principle (MEP), and (3) response surface methodology (RSM). These modeling approaches, coupled with very focused mechanistically based toxicology studies, could be the basis for solving the problems of toxicology and risk assessment of chemical mixtures.

Analysis of Variance↗
PubMed1996

Physiologically based pharmacodynamic modeling of an interaction threshold between trichloroethylene and 1,1-dichloroethylene in Fischer 344 rats.

Physiologically based pharmacokinetic modeling (PBPK) and gas uptake experiments have been used by researchers to demonstrate the competitive inhibition mechanism between trichloroethylene (TCE) and 1,1-dichloroethylene (DCE). Expanding on their work, we showed that this pharmacokinetic interaction was absent at levels of 100 ppm or less of either chemical in gas uptake systems. In this study, we further illustrate the presence of such an interaction threshold at the pharmacodynamic level by examining the interaction effect of either chemical on the other's ability to bind and deplete hepatic glutathione (GSH) in Fischer 344 rats. However, at this end point, the pharmacodynamic interaction is complicated by the ability of the liver to resynthesize GSH in response to its depletion. To quantitatively resolve the interaction effects on GSH content from the resynthesis effects, physiologically based pharmacodynamic (PBPD) modeling is applied. Initially, the PBPD model description of hepatic GSH kinetics was calibrated against previously published data and by gas uptake experiments conducted in our laboratory. Then, the model was used to determine the duration of the gas uptake exposure experiments by identifying the critical time point at which hepatic GSH is at a minimum in response to both chemicals. Subsequently, gas uptake experiments were designed following the PBPK/PD model predictions. In these model-directed experiments, DCE was the only chemical capable of significantly depleting hepatic GSH. The application of TCE to the rats at concentrations higher than 100 ppm obstructed the ability of DCE to deplete hepatic GSH. Since the metabolites of DCE bind to hepatic GSH, this obstruction signaled the presence of metabolic inhibition by TCE. However, TCE, at concentrations less than 100 ppm, was not effective in inhibiting DCE from significantly depleting hepatic GSH. The same observations were made when the ability of DCE to cause hepatic injury, as measured by aspartate aminotransferase serum activity, was assessed. Both conclusions validated the previous findings of the presence of the interaction threshold at the pharmacokinetic level.

Animals↗
PubMed1996

Exploration of an interaction threshold for the joint toxicity of trichloroethylene and 1,1-dichloroethylene: utilization of a PBPK model.

Physiologically based pharmacokinetic (PBPK) modeling and gas uptake experiments were utilized to verify the competitive inhibition mechanism of interaction between trichloroethylene (TCE) and 1,1-dichloroethylene (DCE) and to investigate the presence of an interaction threshold between the two chemicals. Initially, gas uptake experiments were conducted on Fischer 344 rats where the initial concentrations of both DCE and TCE were 2000:0, 0:2000, 2000:2000, 1000:0, 1000:1000, and 500:500 ppm, respectively. When the different modes of inhibition interactions (competitive, uncompetitive and noncompetitive) were employed in the PBPK model, the model description of the competitive inhibition provided the best description of the declining concentrations in the gas uptake chamber. Furthermore, to predict the range at which the interaction threshold would be found, the PBPK model included a mathematical description of the percentage of enzyme sites occupied by either chemical in the presence or the absence of the other. By comparing the percentage of occupied sites by one chemical, in the presence of the other, to those sites occupied in the absence of the latter, the PBPK model predicted a range of concentrations (100 ppm or less) of either chemical where the competitive inhibition interaction would not be observed. Consequently, gas uptake experiments were designed where the initial concentration was selected at 2000 ppm for one chemical while the other chemical was set at 100 in one experiment and 50 ppm in another. Under these conditions, the best stimulation to the concentration depletion curves in the gas uptake system of the chemical in the higher concentration was obtained when the PBPK model was run under the assumption of no-interaction. This substantiated the model predictions of the presence of observable interaction only at concentrations higher than 100 ppm.

Animals↗
PubMed1996

Physiologically based pharmacokinetic/pharmacodynamic modeling of the toxicologic interaction between carbon tetrachloride and Kepone.

Carbon tetrachloride (CCl4) lethality in Sprague-Dawley rats is greatly amplified by pretreatment of Kepone (decachlorooctahydro-1,3,2-metheno-2H-cyclobuta[cd] pentalen-2-one). The increase in lethality was attributed to the obstruction of liver regenerative processes. These processes are essential for restoring the liver to its full functional capacity following injury by CCl4. Based on the available mechanistic information on Kepone/CCl4 interaction, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was constructed where the following effects of Kepone on CCl4 toxicity are incorporated: (1) inhibition of mitosis; (2) reduction of repair mechanism of hepatocellular injury; (3) suppression of phagocytosis. The PBPK/PD model provided computer simulation consistent with previously published time-course results of hepatotoxicity (i.e., pyknotic, injured and mitotic cells) of CCl4 with or without Kepone. As a further verification of this model, the computer simulations were also consistent with exhalation kinetic data for rats injected with different intraperitoneal (i.p.) doses of CCl4 in our laboratory. Subsequently, the PBPK/PD model, coupled with Monte Carlo simulation, was used to predict lethalities of rats treated with CCl4 alone and CCl4 in combination with Kepone. The experimental lethality studies performed in our laboratories were as follows: Sprague-Dawley rats were given either control diet or diet containing 10 ppm Kepone for 15 days. On day 16, rats in the Kepone treated group were given i.p. doses of 0, 10, 50, and 100 microliters/kg CCl4 (n = 9) while control rats were exposed to 0, 100, 1000, 3000, and 6000 microliters/kg CCl4 (n = 9). Lethality was observed at the 1000 (1/9), 3000 (4/9), and 6000 (8/9) microliters/kg doses for the control group and at the 50 (4/9) and 100 (8/9) microliters/kg for the treated group. Based on Monte Carlo simulation, which was used to run electronically 1000 lethality experiments for each dosing situation, the LD50 estimates for CCl4 toxicity with and without Kepone pretreatment were 47 and 2890 microliters/kg, respectively. Monte Carlo simulation coupled with the PBPK/PD model produced lethality rates which were not significantly different from the observed mortality, with the exception of CCl4 at very high doses (e.g., 6000 microliters/kg, p = 0.014). Deviation at very high doses of the predicted mortality from the observed may be attributed to extrahepatic systemic toxicities of CCl4, or solvent effects on tissues at high concentrations, which were not presently included in the model. Our modeling and experimental results verified the earlier findings of Mehendale (1990) for the 67-fold amplification of CCl4 lethality in the presence of Kepone. However, much of this amplification of CCl4 lethality with Kepone pretreatment was probably due to pharmacokinetic factors, because when target tissue dose (i.e., model estimated amount of CCl4 metabolites) was used to evaluate lethality, this amplification was reduced to 4-fold.

Animals↗
PubMed1995

Physiologically based pharmacokinetic/pharmacodynamic modeling of chemical mixtures and possible applications in risk assessment.

Human exposure to chemicals, be it environmental or occupational, is rarely, if ever, limited to a single chemical. Therefore, it is essential that we consider multiple chemical effects and interactions in our risk assessment process. However, with the almost infinitely large number of chemical mixtures in the environment, systematic studies of the toxicology of these chemical mixtures with conventional methodologies and approaches are impossible because of the immense resources and unrealistically long durations required. Thus, the development of predictive and alternative toxicology method is imperative. In order to have a reasonable chance to deal with the complex issue of toxicology of chemical mixtures, we believe that the following concepts must be considered: (1) the exploitation of recent advances in computational technology; (2) the utilization of mathematical/statistical modeling; (3) coupling computer modeling with very focused, mechanistically based, and short-term toxicology studies. Our approach is, therefore, the utilization of physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) modeling, coupled with very focused, model-directed toxicology experiments as well as other statistical/mathematical modeling such as isobolographic analysis and response surface methodology. Tissue dosimetry at the pharmacokinetic and pharmacodynamic levels is achievable with simple and complex, but chemically defined, mixtures. Our long-term goal is to formulate innovative risk assessment methodologies for chemical mixtures. In this presentation, one of our specific research projects is described: PB-PK/PD modeling of toxicologic interactions between Kepone and carbon tetrachloride (CCl4) and the coupling of Monte Carlo simulation for the prediction of acute toxicity.

Animals↗
PubMed1995

The application of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling for exploring risk assessment approaches of chemical mixtures.

When dealing with health impacts of environmental or occupational exposure such as groundwater contamination from or remediation effort associated with hazardous waste sites, we are obviously not facing individual, single chemicals. Thus, we are immediately confronted with the following questions: (1) Is single chemical risk assessment approach applicable to the multiple chemicals in hazardous waste sites? (2) How do we handle risk assessment of chemical mixtures? Although there were pioneering and commendable efforts from the USEPA to formulate guidelines for risk assessment of chemical mixtures, these guidelines were principally based on additivity concept. As new scientific advances are made, improvement and refinement of risk assessment methodology will be anticipated. At Colorado State University (CSU), our research effort is devoted to the challenges and potential applications of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling in the risk assessment of chemical mixtures. With the ultimate goal of Predictive Toxicology, 3 specific research projects are described: (1) PBPK/PD modeling of toxicologic interactions between trichloroethylene (TCE) and 1,1-dichloroethylene (1,1-DCE) and the investigation and defining of an 'Interaction Threshold'; (2) PBPK/PD modeling of toxicologic interactions between Kepone and carbon tetrachloride (CCl4) and the coupling of Monte Carlo simulation for the prediction of acute toxicity; (3) PBPK modeling of the inhibition of pharmacokinetics and enzyme kinetics of TCE caused by low-level, repeated dosing of a chemical mixture of 7 groundwater contaminants. Since this paper is meant to be a commentary and the emphasis is on approaches for dealing with chemical mixtures, detailed presentation of data is avoided. These examples illustrate partially our ongoing research activities and the related ideas with respect to possible novel risk assessment applications to chemical mixtures.

Animals↗
PubMed1995

The use of physiologically-based pharmacokinetic/pharmacodynamic dosimetry models for chemical mixtures.

Human exposure to chemicals is rarely, if ever, limited to a single chemical. Therefore, it is essential that we consider multiple chemical effects and interactions in our risk assessment process. However, with the almost infinitely large number of chemical mixtures in the environment, systematic studies of the toxicology of these chemical mixtures with conventional methodologies and approaches are impossible because of the immense resources and unrealistically long durations required. Thus, the development of 'Predictive and Alternative Toxicology' is imperative. At Colorado State University (CSU), our research effort is entirely devoted to this challenge. In order to have a reasonable chance to deal with the complex issue of toxicology of chemical mixtures, we believe that the following concepts must be considered: (1) the utilization of computer, (2) the exploitation of mathematical/statistical methodologies; (3) developing very focused, mechanistically based, and short-term toxicology studies; (4) coupling computer/mathematical modeling with mechanistically-based toxicology. Our strategy therefore the utilization of physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling, coupled with very focused, model-directed toxicology experiments as well as other statistical/mathematical methodologies such as Monte Carlo simulation, isobolographic analysis, and response surface methodology. We believe that 'Predictive and Alternative Toxicology' in terms of tissue dosimetry at the pharmacokinetic and pharmacodynamic levels is achievable with simple and complex but chemically defined mixtures. In this presentation, we describe two ongoing research projects as an illustration of our 'Bottom-Up' and 'Top-Down' approaches for handling the chemical mixtures: (1) PBPK/PD modeling of toxicologic interactions between Kepone and carbon tetrachloride (CCl4) and the coupling of Monte Carlo simulation for the prediction of acute toxicity; (2) the conceptual development of PBPK/PD modeling for a more complex chemical mixture of seven groundwater contaminants from hazardous waste sites and the consideration of subfractionation of this chemical mixture.

Animals↗