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PubMed2001

In vitro human tissue models in risk assessment: report of a consensus-building workshop.

Advances in the technology of human cell and tissue culture and the increasing availability of human tissue for laboratory studies have led to the increased use of in vitro human tissue models in toxicology and pharmacodynamics studies and in quantitative modeling of metabolism, pharmacokinetic behavior, and transport. In recognition of the potential importance of such models in toxicological risk assessment, the Society of Toxicology sponsored a workshop to evaluate the current status of human cell and tissue models and to develop consensus recommendations on the use of such models to improve the scientific basis of risk assessment. This report summarizes the evaluation by invited experts and workshop attendees of the current status of such models for prediction of human metabolism and identification of drug-drug interactions, prediction of human toxicities, and quantitative modeling of pharmacokinetic and pharmaco-toxicodynamic behavior. Consensus recommendations for the application and improvement of current models are presented.

Cell Culture Techniques↗
PubMed1976

A quantitative dermatophyte infection model in the guinea pig--a parallel to the quantitated human infection model.

A method is described for inducing quantitative dermatophyte infections in guinea pigs. This model is unique in that the epidermis in the infection site is not traumatized nor is it epilated. One hundred spore-inocula of Trichophyton mentagrophytes var. granulosum ATCC number 18748 induced infections in 85% of tested guinea pigs. The course of these infections in guinea pigs that had not had a previous infection (inexperienced) and those that had (experienced) paralleled that seen in experimental infections of human volunteers.

Animals↗
PubMed1986

Enhancement of pancreatic carcinogenesis by raw soy protein isolate: quantitative rat model and nutritional considerations.

Foods containing soybean products have been shown to modify the biochemical and physiological status of the pancreas of several species of experimental animals. Recently, these products have been implicated as a factor in the causation of pancreatic neoplasms. Extensive experimental studies into the possible mechanisms need to be undertaken. Experimental details of a rat/azaserine model for the study of pancreatic carcinogenesis are reviewed. Emphasis is given to the quantitative components of this model and the adaptation of this model to the two-stage (initiation-promotion) concept of carcinogenesis. Particular attention is devoted to considerations of the experimental diets. Application of these concepts to the study of the postinitiational effects of raw and heated soybean protein isolate with and without the addition of high levels of unsaturated fat were undertaken. The results indicate that raw soybean isolate enhanced the growth of azaserine-induced pancreatic foci; whereas, a high level of unsaturated fat had a minimal effect. The effects of the soybean isolate were abolished by heat treatments, but the effects of the unsaturated fat would not be expected to be abolished by similar treatment with heat.

Animals↗
PubMed1985

A timed intravenous pentylenetetrazol infusion seizure model for quantitating the anticonvulsant effect of valproic acid in the rat.

A convulsive seizure model that utilizes timed intravenous infusions of pentylenetetrazol (PTZ) was developed to quantitate the magnitude of anticonvulsant effect in individual rats. PTZ was infused through an indwelling jugular vein catheter, and the threshold dose of PTZ was calculated from the time needed to produce clonic convulsions, the body weight of the animal, and the rate of infusion of the convulsant. The threshold dose of PTZ was determined in all animals 48 hr before and 15 min after anticonvulsant treatment. From theoretical considerations, the magnitude of anticonvulsant effect was defined as the logarithm of the posttreatment to pretreatment PTZ threshold dose ratio (log DR). The PTZ threshold was found to be insensitive to the rate of PTZ infusion and the body weight of the animal. Furthermore, the PTZ pretest did not influence the results of the posttest in animals treated with saline, and the interanimal variability in the PTZ threshold was found to be low (coefficient of variation of 12.2%). The PTZ infusion model was tested in a preliminary dose-response study of the anticonvulsant valproic acid (VPA). The ED50 for VPA determined with PTZ infusion technique (76.1 +/- 9.0 mg/kg) was in good agreement with a previous study that used the classical subcutaneous PTZ test. Since anticonvulsant effect is measured in individual, as opposed to groups, of animals, the PTZ infusion procedure may offer distinct advantages in the study of the pharmacodynamics of anticonvulsant compounds.

Animals↗
PubMed2001

Improving quantitative flowering models through a better understanding of the phases of photoperiod sensitivity.

A quantitative understanding of the phases of sensitivity to photo-thermal environment is important if the accuracy of flowering models is to be improved and if the timing of long and short day treatments in protected cropping is to be optimized. A simple method of quantifying the duration of the phases of sensitivity to photoperiod is through the use of reciprocal transfer experiments where plants are transferred between long and short days at regular intervals throughout development. The advantages and disadvantages of different analytical approaches used to analyse such data sets are examined. Inconsistencies between the approaches are highlighted, as are differences in the way authors have interpreted data. The problem of confounding the effects of photoperiod and light integral is considered, as is the need to separate the number of inductive cycles needed for flower commitment from the length of the juvenile phase. The effects of photo-thermal environment on the duration of these phases of photoperiod sensitivity are discussed, together with topics requiring further development.

Magnoliopsida↗
PubMed2006

Management of microbiological safety of ready-to-eat meat products by mathematical modelling: Listeria monocytogenes as an example.

The recent Commission Regulation (EC) No 2073/2005 establishes microbiological criteria in foods. For the pathogen Listeria monocytogenes in the category ready-to-eat foods able to support its growth, other than those intended for infants and for special medical purposes, two different microbiological criteria are proposed: (i) L. monocytogenes levels should be <100 cfu/g throughout the shelf-life of the product, (ii) absence in 25 g of the product at the stage before the food has left the immediate control of the food business operator, who has produced it. The application of either the first or the second of these criteria depends on whether or not the manufacturer is able to demonstrate that the level of L. monocytogenes in the food product will not exceed 100 cfu/g throughout its shelf-life. This demonstration should be based on physico-chemical characteristics of the target product and consultation of scientific literature, and, when necessary, on quantitative models and/or challenge tests. Once the characteristics of the product as well as scientific literature show that the pathogen has potential to grow on a specific food commodity, it seems adequate to use quantitative models and/or perform challenge tests to study the extent to which L. monocytogenes could grow. In this study, we aim to illustrate with an example in cooked ham the application of quantitative models as a tool to manage the compliance with these criteria. Two approaches were considered: deterministic and probabilistic, in three different commercial brands (A, B, and C). The deterministic approach showed that the limit 100 cfu/g was exceeded largely at the end of the shelf-life of all three; however, when reducing the storage time, the level of L. monocytogenes remained below 100 cfu/g in B. The probabilistic approach demonstrated very low percentiles corresponding to 100 cfu/g; when reducing the storage time, percentiles for three products increased, especially in products B and C (from 4.92% to 75.90%, and from 0.90% to 73.90%, respectively). This study shows how different storage times influence the level of L. monocytogenes at the end of the shelf-life of cooked ham, and, depending on the level reached, the microbiological criterion applied should be different, as stated above. Beside this, the choice of either point-estimate or probabilistic approach should be determined by the competent sanitary authority, and, in case of selecting the second approach, a certain percentile for the level 100 cfu/g should be established.

Animals↗
PubMed1984

A Quantitative Simulation Model for H-Amino Acid Cotransport To Interpret the Effects of Amino Acids on Membrane Potential and Extracellular pH.

The H(+) cotransport of neutral and acidic amino acids induces transient depolarizations of oat coleoptile (Avena sativa L., var Victory) plasma membranes. The depolarizations, which are completed within 1 or 2 minutes, are followed by repolarizations that are nearly completed within another 2 or 3 minutes. Cysteine induced a two-phased alkalinization of the tissue free space during the electrical changes. The first phase was a rapid, linear increase in pH that coincided with the depolarization; the second phase was a slower, also linear, increase in pH that coincided with the repolarization. Reacidification did not occur until cysteine was withdrawn. Five other acidic, basic, and neutral amino acids also induced persistent alkalinization of the free space.The notable features of these measurements are that free-space pH was measured more directly than previously, that pH changes corresponded in time to the electrical potential changes, and that reacidification of the free space did not occur. The latter observation indicates that net H(+) efflux did not occur during repolarization and that the repolarizing current was carried by some other ion. We propose that repolarization could have depended upon depolarization-induced changes in passive K(+) fluxes combined with an enhanced H(+) extrusion that increased until it equaled, but did not exceed, the enhanced influx of H(+).In support of the feasibility of our hypothesis, we present a quantitative simulation model for cotransport. The simulation model also provides an interpretation of the unique electrical effects of histidine and the basic amino acids. In addition, the model focuses attention upon the difficulties of interpreting H(+)-anion cotransport.

Journal Article↗
PubMed1994

Conformational analysis, molecular modeling, and quantitative structure-activity relationship studies of agents for the inhibition of astrocytic chloride transport.

Molecular modeling studies were carried out on a series of 1-oxoisoindolines which are pharmacologically active as inhibitors of astrocytic chloride transport. Conformational analysis revealed that the halogen substituent exerted a pronounced steric directing effect on the acid side chain. The 4-substituted analogs apparently provided for the best spatial arrangement of pharamacophoric elements of the molecules. Conventional quantitative structure-activity relationship (QSAR) studies using lipophilic and dipole moment characteristics of the molecules as physical descriptor variables in the regression equation yielded a statistically significant model. Comparative molecular field analysis (CoMFA) was utilized as a three-dimensional QSAR technique to explore changes in the steric and electrostatic fields of the molecules that can account for differences in biological activity values. A highly predictive model was attained which supported the results from the qualitative and conventional quantitative structure-activity relationship analyses. These modeling techniques represent the evolutionary process by which structure-activity methods were employed to aid in the development of novel more potent inhibitors of astrocytic chloride transport.

Astrocytes↗
PubMed1998

A double circadian oscillator model for quantitative photoperiodic time measurement in insects and mites

From studies on photoperiodic time measurement in insects it is known that different night lengths at the same side of the critical night length can have different inductive strengths. This means that nights of different length, and either longer or shorter than the critical night length, can have qualitatively different values. Nevertheless, few photoperiodic-clock models have been developed that are based on quantitative night-length measurement. In this paper a model is proposed that consists of two independent, circadian mechanisms. Both mechanisms determine the length of a night and give it a quantitative value, which is either zero or positive. One of the mechanisms (LN system) generally gives a scotophase a positive value when it is "long" (i.e. lights-on occurs when the LN oscillator is in its descending phase), whereas the other (SN system) gives a scotophase a positive value when it is "short" (i.e. lights-on occurs when the SN oscillator is in its ascending phase). In this particular context, therefore, "long" and "short" do not necessarily mean longer or shorter than the critical night length. The reasons for two time-measuring systems instead of one are: first, in some insects only long nights are accumulated, not short nights, or vice versa. Second, long nights are less sensitive to temperature than short nights. Third, in some cases it seems that long and short nights are determined in a different manner. These observations indicate that long and short nights could be determined by separate mechanisms. Responses generated by the proposed model parallel those observed experimentally with the spider mite, Tetranchus urticae and the aphid, Megoura viciae. General properties of the model are discussed and compared with Zaslavski's quantitative clock model which shares some features. Copyright 1998 Academic Press Limited

Journal Article↗
PubMedDate not supplied

Profiles of cognitive decline in Alzheimer disease.

Most recent studies have used only two observations to estimate the rate of cognitive decline in patients with Alzheimer disease (AD); few have data taken from more than a 2-year period; and none report on autopsy-verified cases. Repeated observations over the complete course of the disease are necessary to quantitatively evaluate hypotheses such as the triphasic linear model of Brooks et al. (1993). The goal of this study is to compare the triphasic linear and quadratic models of decline in a group of 12 AD patients confirmed at autopsy with a group of age- and sex-matched normal control subjects. Both groups were taken from the University of Western Ontario Dementia Study, and the Extended Scale for Dementia was used as the outcome measure. The squared multiple correlation as a measure of goodness of fit suggested the superiority of the more parsimonious quadratic model over the triphasic linear model. Quantitative models more accurately reflect the profiles of change in AD and may prove more sensitive in measuring the effects of drugs on these patterns.

Aged↗
PubMed1998

[Application of BMD models in quantitative evaluation of carcinogenic risk].

The characteristics of the relationship between the exposure level and the incidence of harmful health effects is a general objective of assessing health risk related to chemical exposure. A real dose-response relationship, particularly for low doses, is usually unknown thus it can only be deduced on the basis of biological and statistical considerations. Low dose risk estimation requires extrapolation beyond the range of data observed. Nowadays, quantitative risk assessment encounters certain duality as linear models are mostly used in evaluation of environmental exposure, and nonlinear models are most frequently applied in occupational exposure. Bearing in mind that the assumption on the dose-response linear relationship is an apparent simplification built on our lack of knowledge of carcinogenic mechanisms, it seems that the proposal of the US Environmental Protection Agency (US EPA) to use benchmark dose methods (BMD) for exposure effects manifested by neoplasms, is the compromise between a conservative approach of the EPA towards risk modelling resulting from the limited knowledge of these mechanisms and lack of criteria for selection of nonlinear models. In the case of carcinogenic risk assessment, this solution involves the identification of so called 'cut off point' by applying relevant statistical models. The cut off point indicates the exposure level that contributes to the increase in risk by 10%, 5% or 1%. Another possibility is to use interspecies extrapolation methods for the cut of point modification, and then draw a line between the cut off point and the beginning of the system of co-ordinates. Since it is not feasible to apply a complete BMD methods for certain chemicals (e.g. bezo(a)pirene), not because of chemical properties, but due to insufficient experimental experience, it is proposed to use the method of sticking together a straight line and a curve in relation to a two-grade curve and not to its confidence limitation.

Carcinogens↗
PubMed1985

Development of an animal model for quantitatively evaluating effects of drugs on endometriosis.

The present study was conducted to induce endometriosis in an experimental animal model in which the condition and its response to pharmacologic agents could be quantified. Endometriosis was induced in New Zealand White rabbits by transplanting endometrial sections into various sites throughout the peritoneum. After 7 weeks, the mean implant weight increased in concomitant controls from 10.3 to 89.0 mg. In the next 8 weeks, endometrial implant weight increased to 163.6 mg. Daily subcutaneous administration of a luteinizing hormone-releasing hormone agonist, histrelin, or oral administration of danazol, reduced the ectopic implant weight within 8 weeks to 21.7 and 46.0 mg, respectively. In a group of animals that were bilaterally ovariectomized, implant weight decreased significantly in the same 8-week period to 22.4 mg. Furthermore, histologic analysis of the endometriomas showed that ovariectomy, histrelin, or danazol treatment reduced the number of endometrial glands and atrophied the stroma. We conclude that this animal model represents an excellent method for quantitative evaluation of potential therapeutic agents for endometriosis.

Animals↗
PubMed2002

Quantitative reactivity model for the hydration of carbon dioxide by biomimetic zinc complexes.

A quantitative structure-reactivity relationship has been derived from the results of B3LYP/6-311+G calculations on the hydration of carbon dioxide by a series of zinc complexes designed to mimic carbonic anhydrase. The reaction mechanism found is general for all complexes investigated. The reaction exhibits a low (4-6 kcal/mol) activation energy and is exothermic by about 8 kcal/mol. The calculations suggest an equilibrium between Lipscomb and Lindskog intermediates. The effectiveness of the catalysis is a function of the nucleophilicity of the zinc-bound hydroxide and the nucleofugicity of the zinc-bound bicarbonate. Hydrogen bridging of the bicarbonate to NH moieties in the ligands also plays an important role.

Bicarbonates↗
PubMed2004

Quantitative information management for the biochemical computation of cellular networks.

Understanding complex protein networks within cells requires the ability to develop quantitative models and to numerically compute the properties and behavior of the networks. To carry out such computational analysis, it is necessary to use modeling tools and information management systems (IMSs) where the quantitative data, associated to its biological context, can be stored, curated, and reliably retrieved. We have focused on the biochemical computation of cellular interactions and developed an IMS that stores both quantitative information on the cellular components and their interactions, and the basic reactions governing those interactions. This information can be used to construct pathways and eventually large-scale networks. This system, SigPath, is available on the Internet (http://www.sigpath.org). Key features of the approach include (i) the use of background information (for example, names of molecules, aliases, and accession codes) to ease data submission and link this quantitative database with other qualitative databases, (ii) a strategy to allow refinement of information over time by multiple users, (iii) the development of a data representation that stores both qualitative and quantitative information, and (iv) features to assist contributors and users in assembling custom quantitative models from the information stored in the IMS. Currently, models assembled in SigPath can be automatically exported to several computing environments, such as Kinetikit/Genesis, Virtual Cell, Jarnac/JDesigner, and JSim. We anticipate that, when appropriately populated, such a system will be useful for large-scale quantitative studies of cell-signaling networks and other cellular networks. SigPath is distributed under the GNU General Public License.

Animals↗
PubMed1999

The rat Subcutaneous Air Sac model: a quantitative assay of antiangiogenesis in induced vessels.

A new in vivo experimental model--the Subcutaneous Air Sac (SAS) model-has recently been presented to replace a previous in vivo rabbit cornea assay where neovascularisation was induced by chemical injury of the cornea or by implantation of tumour cells intracorneally, a methodology which is believed to cause severe pain to the animals. In the SAS model, an air sac is induced by injection of air subcutaneously on the back of the animal. After 10-14 days the air sac appears as an almost transparent avascular membrane in which induction of new vessels can be studied. We present recent developments of this technique: In the SAS-tumour technique, vascular endothelial growth factor-producing tumour cells are inoculated subcutaneously directly on the membrane, and the formation of new vessels is measured 8 days later. In the SAS-pellet technique, slow-release pellets containing angiogenic factors, basic fibroblast growth factor or vascular endothelial growth factor are implanted on the subcutaneous membrane by a simple operation. The formation of new vessels is measured 10 days later. The ability of the SAS-tumour- and SAS-pellet techniques to detect an antiangiogenic effect of a systemically administered compound was investigated using the fumagillin analogue TNP-470 (o-chloroacetyl-carbamoyl)-fumagillol) as a positive control given subcutaneously for 7 and 9 days, respectively. At a dose of 10 mg TNP-470/kg/day the angiogenesis was reduced by approximately 70% in the SAS-tumour technique and by 40-60% in the SAS-pellet technique. The animals were unaffected by the SAS methodology. The SAS-tumour and SAS-pellet models are considered complementary and make use of simple and almost similar techniques which facilitate the evaluation.

Air Sacs↗
PubMedDate not supplied

Commercial fibrin sealants are not equivalent in a rabbit liver-resection model which quantitatively evaluates hemostasis and formation of adhesions.

A rabbit partial liver resection model was used to determine the hemostatic effectiveness of a new fibrin sealant. Persistent bleeding, with a mean bleeding time of 372 s and blood loss of 18 ml, from a resected lobe of the liver was achieved after rabbits in the untreated control group had been infused continuously with unfractionated heparin over 20 min with 0.2 IU/ml at a rate of 1 ml/min. Spraying the resected surface with the new fibrin sealant, Quixil, reduced bleeding to < 1 ml and the post-resection bleeding times was 25 s. Bleeding time, blood loss and the volume of sealant used in the rabbit model were inversely correlated with the thrombin concentration in the sealant. In direct comparisons with Tissucol and Beriplast, Quixil was associated with the shortest bleeding times, the lowest volume of sealant used and the lowest score of abdominal adhesions.

Aerosols↗
PubMed1999

Regression diagnostics for the class A regressive model with quantitative phenotypes.

Regression diagnostic methods are developed and investigated under the Class A regressive model proposed by Bonney [(1984) Am J Med Genet 18:731-749]. We call a family whose phenotypic distribution does not conform to the same genetic model as the majority of the families an etiotic family. The exact case-deletion approach for identifying etiotic families, based on examining the changes in each model parameter estimate by excluding one family at a time, is very time-consuming. We proposed three alternative diagnostic methods: the empirical influence function (EIF), the one-step approximation, and the approximated one-step approach. These methods can be computed efficiently and were incorporated into the existing software package S.A.G.E. A thorough Monte-Carlo investigation of the performance of the diagnostic methods was conducted and generally supports the EIF approach as the recommended alternative. The phenotypic variance is the parameter whose associated regression diagnostic most frequently and correctly identified etiotic families in the models that were examined. An analysis of body mass index data from 402 individuals in 122 Muscatine, Iowa families is used to illustrate the methods. A Class A regressive model with a recessive major locus and equal mother-offspring and father-offspring correlations provided the best-fitting model. The proposed regression diagnostics identified up to 7.4% of the 122 families as etiotic. As a result of this investigation, case-deletion diagnostic assessment is now a practical component in the analysis of quantitative family data.

Adolescent↗
PubMed2005

Quantitative risk modelling for new pharmaceutical compounds.

The process of discovering and developing new drugs is long, costly and risk-laden. Faced with a wealth of newly discovered compounds, industrial scientists need to target resources carefully to discern the key attributes of a drug candidate and to make informed decisions. Here, we describe a quantitative approach to modelling the risk associated with drug development as a tool for scenario analysis concerning the probability of success of a compound as a potential pharmaceutical agent. We bring together the three strands of manufacture, clinical effectiveness and financial returns. This approach involves the application of a Bayesian Network. A simulation model is demonstrated with an implementation in MS Excel using the modelling engine Crystal Ball.

Algorithms↗