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PubMed1986

Liver tumour promotion by chemicals: models and mechanisms.

Tumour promotion is defined as the process whereby a carcinogen initiated organ develops focal proliferations such as nodules, polyps or papillomas, one or more of which become precursors for subsequent steps in the carcinogenic process. The available models for a sequential analysis of carcinogenesis in liver have been examined within the framework of this operational definition with respect to the models themselves as well as the promoted hepatocytes. Using initiation-promotion protocols, several promoters which differ in the biological responses they elicit have been identified. The key issue in promotion pertains to the mechanisms involved in the focal proliferation of the initiated hepatocytes. The resistant hepatocyte model and perhaps the phenobarbital model suggest that focal proliferation of the initiated hepatocyte is induced by exerting a selective mitoinhibitory effect on the surrounding cells while permitting the initiated hepatocyte to respond to the proliferative stimulus, whether it is exogenous or endogenous. The promoter orotic acid, on the other hand, is a natural precursor of pyrimidine nucleotide biosynthesis and is neither an inducer nor an inhibitor of liver cell proliferation but it creates an imbalance in cellular nucleotide pools. Since nucleotides are intermediates in DNA synthesis as well as in the glycosylation of proteins and lipids including that of membranes, it has been postulated that the promotional effect of orotic acid is mediated through this imbalance affecting both DNA and membranes. There is some experimental evidence for this. The importance of this hypothesis is that it raises the possibility of achieving promotion in several organs by disturbing the normal nucleotide pool patterns. Indeed orotic acid has also been found to promote duodenal cancer. The finding that hepatic nodules, regardless of how they have been promoted, exhibit a common biochemical pattern with resistance to several agents has raised some important issues. For example, what is the basis for the resistant phenotype and how is it related to cancer development? Are all initiated hepatocytes identical? If not, do all promoters exert their effect on the same population of initiated hepatocytes? Is the heterogeneity of the initiated hepatocyte population generated by the carcinogen due to the induction of more than one critical lesion: a primary lesion responsible for initiation and secondary lesions in which different types of initiated cells are selected by different promoters?(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Division↗
PubMed1987

Chemical model of osteoarthritis--a pharmacological evaluation.

For pharmacological testing of drugs with antidegenerative potency we developed an animal model of biochemically induced osteoarthritis (OA) by blocking the glycolytic energy metabolism and synthetic processes in articular chondrocytes. After local injection of sodium iodoacetate osteoarthritic reactions will progress within 2-4 months. Using a standardized radiological, histological, and macroscopical grading we could demonstrate that corticosteroids and some NSAID exert negative effects on articular cartilage, while a few other NSAID showed no influence. Diclofenac had even a pronounced antidegenerative potency which was comparable to the antiosteoarthritic properties of two glycosaminoglycan derivatives investigated in the model of biochemically induced OA in the knee joint of hens and rats.

Adrenal Cortex Hormones↗
PubMed1998

Estimation of toxicity of chemical mixtures through modeling of chemical interactions.

The Agency for Toxic Substances and Disease Registry (ATSDR), in collaboration with the Dutch Organization for Applied Scientific Research (TNO) Nutrition and Food Research Institute, is conducting studies to evaluate the role of chemical interactions in the expression of toxicity from low-level exposure to combinations of chemicals. The goal of this collaborative effort is to use a weight-of-evidence (WOE) approach to estimate joint toxicity of some simple chemical mixtures and to compare the estimations with test results from animal toxicity studies. The WOE approach uses individual chemical dose-response assessments and algorithms that incorporate various assumptions regarding potential chemical interactions. Qualitative evaluations were prepared for binary combinations of chemicals for the effect of butyl hydroxyanisole on di(2-ethylhexyl)phthalate, the effect of stannous chloride on Cd chloride (CdCl2), and the effect of CdCl2 on loperamide. Analyses of these evaluations and their comparison with the conclusions of laboratory animal experiments indicate that the WOE approach can be used to estimate qualitatively the joint toxicity of such simple mixtures. To further test the utility of the WOE approach, qualitative and semiquantitative evaluations were prepared for two chemical mixtures--one with similarly acting halogenated aliphatics (trichloroethylene, tetrachloroethylene, hexachloro-1,3-butadiene[HCBD], and 1,1,2-trichloro-3,3,3-trifluoropropene [TCTFP]) and the other with dissimilarly acting nephrotoxic components (mercuric chloride, lysinolalanine, D-limonene, and HCBD). These two sets of data were used to estimate the overall toxicities of the mixtures using the WOE algorithm for the mixture. The comparison of the results of the estimated toxicity with experimentally determined toxicity of the mixture of similarly acting nephrotoxicants demonstrated that the WOE approach correctly adjusted for the observed interactions in experimental animal studies. However, this was not true for the mixture of dissimilarly acting nephrotoxicants. This could be attributed to the fact that WOE evaluations are based on dose additivity that postulates that all chemicals in a given mixture act in the same way--by the same mechanism--and differ only in their potencies. In these cases the WOE approach evaluations, based on consideration of common mechanisms for simple chemical mixtures, can lead to better estimates of joint toxicity of chemical mixtures than the default assumption of dose additivity. The results also show that the WOE evaluations should be target-organ specific because none of the models tested could approximate the observed responses in organs other than the target organs in the laboratory animal studies.

Algorithms↗
PubMed1988

Biophysical and catalytic properties of the phenobarbital p-hydroxylase--a cytochrome P-450 dependent mixed function oxidase.

1. A sensitive method to detect and quantify the products of phenobarbital (PB) hydroxylation by model chemical systems and by biological systems has been developed. 2. Chemical model systems hydroxylate PB in the p-position of the phenyl ring and form one or two additional oxidation products, while in vitro and in vivo (bile fistula rats) biological systems hydroxylate PB only in the p-position. 3. Phenobarbital hydroxylation rates in vitro are of the order of 0.007 nmol/nmol cytochrome P-450 per min. These values are decreased by pretreatment of the rats with inducing doses of phenobarbital. 4. Enzymes catalysing the p-hydroxylation reaction of phenobarbital are localized in the microsomes and have the biophysical and chemical properties that are usually associated with cytochrome P-450-dependent mixed function oxidases.

Animals↗
PubMed2002

Simulation of the mobility of metal-EDTA complexes in groundwater: the influence of contaminant metals.

Reactive transport simulations were conducted to model chemical reactions between metal-EDTA (ethylenediaminetetraacetic acid) complexes during transport in a mildly acidic quartz-sand aquifer. Simulations were compared with the results of small-scale tracer tests wherein nickel-, zinc-, and calcium-EDTA complexes and free EDTA were injected into three distinct chemical zones of a plume of sewage-contaminated groundwater. One zone had a large mass of adsorbed, sewage-derived zinc; one zone had a large mass of adsorbed manganese resulting from mildly reducing conditions created by the sewage plume; and one zone had significantly less adsorbed manganese and negligible zinc background. The chemical model assumed that the dissolution of iron(III) from metal-hydroxypolymer coatings on the aquifer sediments by the metal-EDTA complexes was kinetically restricted. All other reactions, including metal-EDTA complexation, zinc and manganese adsorption, and aluminum hydroxide dissolution were assumed to reach equilibrium on the time scale of transport; equilibrium constants were either taken from the literature or determined independently in the laboratory. A single iron(III) dissolution rate constant was used to fit the breakthrough curves observed in the zone with negligible zinc background. Simulation results agreed well with the experimental data in all three zones, which included temporal moments derived from breakthrough curves at different distances downgradient from the injections and spatial moments calculated from synoptic samplings conducted at different times. Results show that the tracer cloud was near equilibrium with respect to Fe in the sediment after 11 m of transport in the Zn-contaminated region but remained far from equilibrium in the other two zones. Sensitivity studies showed that the relative rate of iron(III) dissolution by the different metal-EDTA complexes was less important than the fact that these reactions are rate controlled. Results suggest that the published solubility for ferrihydrite reasonably approximates the Fe solubility of the hydroxypolymer coatings on the sediments. Aluminum may be somewhat more soluble than represented by the equilibrium constant for gibbsite, and its dissolution may be rate controlled when reacting with Ca-EDTA complexes.

Chelating Agents↗
PubMed1985

Clinical decision making in chemical dependence treatment: a programmatic model.

Chemical dependence treatment has traditionally been based on either an inpatient or outpatient model. With the current emphasis on cost effectiveness, these separate approaches are being intensively scrutinized. Recent studies suggest that not all chemically dependent patients can be treated with the same model and that patient characteristics other than chemical of abuse are significant factors in retention and outcome. A program model is presented which takes into consideration clinical decision making based on patient characteristics, intensity of care and treatment modalities.

Decision Making↗
PubMed2004

Efficient chemical kinetic modeling through neural network maps.

An approach to modeling nonlinear chemical kinetics using neural networks is introduced. It is found that neural networks based on a simple multivariate polynomial architecture are useful in approximating a wide variety of chemical kinetic systems. The accuracy and efficiency of these ridge polynomial networks (RPNs) are demonstrated by modeling the kinetics of H(2) bromination, formaldehyde oxidation, and H(2)+O(2) combustion. RPN kinetic modeling has a broad range of applications, including kinetic parameter inversion, simulation of reactor dynamics, and atmospheric modeling.

Algorithms↗
PubMed2001

Evaluation and comparison of multimedia mass balance models of chemical fate: application of EUSES and ChemCAN to 68 chemicals in Japan.

The European Union System for Evaluation of Substances (EUSES) and the ChemCAN chemical fate model are applied to describe the fate of 68 chemicals on two spatial scales in Japan. Emission information on the chemicals has been obtained from Japan's Pollutant Release and Transfer Registry and available monitoring data gathered from government reports. Environmental concentrations calculated by the two models for the four primary environmental media of air, water, soil and sediment agree within a factor of 3 for over 70% of the data, and within a factor of 10 for over 87% of the data. Reasons for certain large discrepancies are discussed. Concentrations calculated by the models are generally consistent with the lower range of concentrations that are observed in the environment. Agreement between modeled and observed concentrations is considerably improved by including an estimate of the advective input of chemicals in air from outside Japan. The agreement between the EUSES and ChemCAN models suggests that results of individual chemical assessments are not likely to be significantly affected by the choice of chemical fate model. Primary sources of discrepancy between modeled and observed concentrations are believed to be uncertainties in emission rates, degradation half-lives, and the lack of data on advective inflow of contaminants in air.

Biodegradation, Environmental↗
PubMed1998

Modeling NMR chemical shifts: a comparison of charge models for solid state effects on 15N chemical shift tensors.

This paper presents results from applying different point charge models to take into account intermolecular interactions to model the solid state effects on the 15N NMR chemical shifts tensors. The DFT approach with the BLYP gradient corrected exchange correlation functional has been used because it can include electron correlation effects at a reasonable cost and is able to reproduce 15N NMR chemical shifts with reasonable accuracy. The results obtained with the point charge models are compared with the experimental data and with results obtained using the cluster model, which includes explicitly neighboring molecular fragments. The results show that the point charge models can take into account solid state effects at a cost much lower than the cluster methods.

Magnetic Resonance Spectroscopy↗
PubMed1989

Treatment implications of chemical dependency models an integrative approach.

Five basic models of chemical dependency and their treatment implications are described. The moral model, although disdained by most treatment professionals, actually finds expression in over half the steps of Alcoholics Anonymous. The learning model, albeit the center of the controlled drinking controversy, is also utilized by most abstinence-oriented programs. The disease model, which enjoys current popularity, sometimes ignores the presence of coexisting disorders. The self-medication model, which tends to regard chemical dependency as a symptom, can draw needed attention to coexisting disorders. The social model emphasizes the importance of environmental and interpersonal influences in treatment, although the substance abuser may endorse it as a justification to adopt a victim's role. A sixth model, the dual diagnosis model, is presented as an example of how two of the basic models can be integrated both to expand the treatment focus and to increase treatment leverage. Whereas the five basic models are characterized by a singular, organizing treatment focus, the dual diagnosis model is viewed as an example of a multifocused, integrative model. It is concluded that effective therapy requires (a) flexibility in combining elements of different models in order to individualize treatment plans for substance abusers, and (b) careful assessment of both the therapist's and the substance abuser's beliefs about treatment models in order to insure a treatment match based on a healthy alliance.

Alcoholics Anonymous↗
PubMed2004

Free energy transduction in a chemical motor model.

Motor enzymes catalyse chemical reactions, like the hydrolysis of ATP, and in the process they also perform work. Recent studies indicate that motor enzymes perform work with specific biochemical steps in their catalysed reactions, challenging the classical view that work can only be performed within a biochemical state. To address these studies an alternative class of models, often referred to as chemical motor models, has emerged in which motors perform work with biochemical transitions. In this paper, I develop a novel, self-consistent framework for chemical motor models, which accommodates multiple pathways for free energy transfer, predicts rich behaviors from the simplest multi-motor systems, and provides important new insights into muscle and motor function.

Adenosine Triphosphate↗
PubMed2005

Quantitative identification of sources of dioxin-like polychlorinated biphenyls in sediments by a factor analysis model and a chemical mass balance model combined with Monte Carlo techniques.

The major sources of dioxin-like polychlorinated biphenyls (PCBs) in two sediment cores from Tokyo Bay and Lake Shinji (both in Japan) were identified and their source contributions estimated using two receptor models. The first was a nonnegative constrained factor analysis (FA) model, and the second was a nonnegative constrained chemical mass balance model combined with Monte Carlo techniques (CMB-MC) to take into account the variability and uncertainty in both PCB congener profiles of sources and environmental samples. According to the FA model, variations in the concentrations of dioxin-like PCBs in each sediment core were accounted for almost entirely by two factors, which were considered to correspond to Kanechlors (KCs; Japanese PCB products) and incineration. The CMB-MC model investigated the trends of the burdens from four types of KCs and incineration to the concentrations of dioxin-like PCBs in each sediment core. The results for both sediment cores obtained by both models indicated that the burden from KCs increased gradually beginning in the 1950s, peaked around 1970, and declined thereafter, whereas the burden from incineration increased gradually from the 1950s to the early 1990s. The estimated contribution from incineration to the toxic equivalent concentration of dioxin-like PCBs was comparable to that from KCs.

Dioxins↗