scholarly journals Generic solving of one-compartment toxicokinetic models

2021 ◽  
Author(s):  
Sandrine CHARLES ◽  
Aude Ratier ◽  
Christelle Lopes
Keyword(s):  
Experimental Data ◽  
Marketing Authorisation ◽  
Parent Compound ◽  
Parameter Estimates ◽  
Chemical Substances ◽  
Inference Algorithms ◽  
Living Organisms ◽  
Exposure Routes ◽  
Generic Set ◽  
Active Substances

This paper gives the full analytical solution of the generic set of ordinary differential equations that define one-compartment toxicokinetic models. These models describe uptake and elimination processes taking place within living organisms when exposed to chemical substances. The models solved in this paper consider living organisms as a unique compartment, into which a parent compound enters via several possible exposure routes and from which it is eliminated as well as its potential metabolites. Benefiting from generic solutions of one-compartment toxicokinetic models is particularly useful when fitting them to experimental data, facilitating the writing of the inference algorithms leading to parameter estimates. Additionally, these models are of crucial interest in environmental risk assessment for the calculation of bioaccumulation metrics as required by regulators in support of decision making when they evaluate dossiers for marketing authorisation of active substances.

scholarly journals A ready-to-use online tool to calculate the BCF of active substances: MOSAIC bioacc

2021 ◽  
Author(s):  
Aude Ratier ◽  
Christelle Lopes ◽  
Gauthier Multari ◽  
Marc Babut ◽  
Vanessa Mazerolles ◽  
...  
Keyword(s):  
Experimental Data ◽  
Plant Protection ◽  
Parent Compound ◽  
Plant Protection Products ◽  
Model Parameters ◽  
Individual Traits ◽  
Scientific Opinion ◽  
On Line ◽  
Toxicokinetic Model ◽  
Active Substances

Toxicokinetic/toxicodynamic (TKTD) models are used to describe and predict the toxicity and the effects of chemical substances on individual traits based on experimental data. The toxicokinetic (TK) part describes the relationship between the exposure medium and the organism, considering various processes such as ADME (accumulation, depuration, metabolization and excretion). Regulation laying down the data requirements for active substances for the placing of plant protection products on the market, a bioaccumulation study on fish is required for substances with a partition coefficient octanol / water greater than or equal to 3, following the OECD guideline 305. Such a TK test allows to define the bioconcentration factor (BCF), the biomagnification factor (BMF) or the bioaccumulation factor (BAF). These factors are decisive criteria for estimating the concentration of active substances present in food items of vertebrates and more particularly of piscivorous birds and mammals. In a recent study, a relevant inference framework (Bayesian inference) was proposed to estimate toxicokinetic model parameters accounting for their correlation, based on the experimental data from standard guidelines and leading to the calculation of BCF/BMF/BAF. Models underlying this framework can be directly integrated and used as TK parts of TKTD models. Achieved in agreement with EFSA's scientific opinion on good modeling practices, the objective of this project is to develop a ready-to-use on-line tool for easily estimating BCF/BMF/BAF in a regulatory framework, by taking into account bioaccumulation of a parent compound and its metabolites through biotransformation. We built a Shiny interface to make available the inference method and the BCF/BMF/BAF calculation from the MOSAIC platform, which may be used for research as well as by companies or regulatory agencies. This tool will be integrated more broadly into the development and widespread use of TKTD models within the risk assessment framework.

Neutral Lipids of Oats Fruit (Avena Sativa L.)

2020 ◽  
Vol 9 (4) ◽  
pp. 40-43
Author(s):  
N. K. Yuldasheva ◽  
S. D. Gusakova ◽  
D. Kh. Nurullaeva ◽  
N. T. Farmanova ◽  
R. P. Zakirova ◽  
...  
Keyword(s):  
Avena Sativa ◽  
Neutral Lipids ◽  
The Body ◽  
Biologically Active ◽  
Absorption Bands ◽  
Vital Functions ◽  
The Republic ◽  
Living Organisms ◽  
Main Components ◽  
Active Substances

Introduction. Lipids are a widespread group of biologically active substances in nature, making up the bulk of the organic substances of all living organisms. They accumulate in plants in seeds, as well as in fruits and perform a number of vital functions: they are the main components of cell membranes and the energy reserve for the body.Aim. Study of neutral lipids of sown oats (Avena sativa L.).Materials and methods. The objects of the study were fruits (grains) of oats of the sown variety "Tashkent 1," harvested in the Republic of Uzbekistan. Results and discussions. Neutral lipids of oat grains have been found to contain 13 fatty acids with a predominance of the sum of oleic, linolenic and linoleic acids. The total degree of unsaturation was almost 78%. Absorption bands characteristic of these substances were observed in the IR spectrum of MEGC.Conclusion. According to the results of the NL analysis, oat grains consisted of triacylglycerides and free LCDs, which were accompanied by hydrocarbons, phytosterols, triterpenoids and tocopherols.

GENOTOXIC ACTIVITY OF THE PESTICIDE MIXTURES

2020 ◽  
pp. 9-13 ◽  
Author(s):  
N. A. Ilyushina ◽  
Yu. A. Revazova
Keyword(s):  
Public Health ◽  
Combined Effect ◽  
Literature Information ◽  
Genotoxic Effects ◽  
Antagonistic Effects ◽  
Pesticide Mixtures ◽  
The World ◽  
Living Organisms ◽  
Genetic Structures ◽  
Active Substances

In order to overcome resistance to individual pesticides and improve their effectiveness, formulations containing two or more active substances are constantly being developed and put on the market over recent years. Mixtures of residual amounts of pesticides can be present in water and food and enter the human and animal bodies. However, the combined effect of pesticides on living organisms, including genetic structures in cells, has not been studied enough and it is not yet possible to predict the genotoxic effects of their mixtures based on available data. The purpose of this review was to collect and summarize literature information on the genotoxicity of pesticide combinations obtained at different objects. The results of studies conducted in different countries of the world are discussed, examples of detected synergistic, additive and antagonistic effects are given, indicating the need for testing the genotoxicity of preparative forms of pesticides containing several active substances, as well as mixtures of jointly used pesticides in order to ensure the safe use of pesticides for public health.

scholarly journals Reducing complexity and unidentifiability when modelling human atrial cells

2020 ◽  
Vol 378 (2173) ◽  
pp. 20190339 ◽  
Author(s):  
C. Houston ◽  
B. Marchand ◽  
L. Engelbert ◽  
C. D. Cantwell
Keyword(s):  
Experimental Data ◽  
Clinical Decision Making ◽  
Cell Model ◽  
Sodium Current ◽  
Clinical Decision ◽  
Complex Model ◽  
Parameter Estimates ◽  
Gating Kinetics ◽  
Complex Formulation ◽  
Approximate Bayesian

Mathematical models of a cellular action potential (AP) in cardiac modelling have become increasingly complex, particularly in gating kinetics, which control the opening and closing of individual ion channel currents. As cardiac models advance towards use in personalized medicine to inform clinical decision-making, it is critical to understand the uncertainty hidden in parameter estimates from their calibration to experimental data. This study applies approximate Bayesian computation to re-calibrate the gating kinetics of four ion channels in two existing human atrial cell models to their original datasets, providing a measure of uncertainty and indication of potential issues with selecting a single unique value given the available experimental data. Two approaches are investigated to reduce the uncertainty present: re-calibrating the models to a more complete dataset and using a less complex formulation with fewer parameters to constrain. The re-calibrated models are inserted back into the full cell model to study the overall effect on the AP. The use of more complete datasets does not eliminate uncertainty present in parameter estimates. The less complex model, particularly for the fast sodium current, gave a better fit to experimental data alongside lower parameter uncertainty and improved computational speed. This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.

scholarly journals The Alginate Immobilization of Metabolic Enzymes Platform Retrofits an Estrogen Receptor Transactivation Assay With Metabolic Competence

2020 ◽  
Vol 178 (2) ◽  
pp. 281-301
Author(s):  
Chad Deisenroth ◽  
Danica E DeGroot ◽  
Todd Zurlinden ◽  
Andrew Eicher ◽  
James McCord ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Biological Effects ◽  
Parent Compound ◽  
False Negative ◽  
Metabolic Enzymes ◽  
Vitro Assay ◽  
Transactivation Assay ◽  
Alginate Immobilization ◽  
Active Substances ◽  
Receptor Transactivation

Abstract The U.S. EPA Endocrine Disruptor Screening Program utilizes data across the ToxCast/Tox21 high-throughput screening (HTS) programs to evaluate the biological effects of potential endocrine active substances. A potential limitation to the use of in vitro assay data in regulatory decision-making is the lack of coverage for xenobiotic metabolic processes. Both hepatic- and peripheral-tissue metabolism can yield metabolites that exhibit greater activity than the parent compound (bioactivation) or are inactive (bioinactivation) for a given biological target. Interpretation of biological effect data for both putative endocrine active substances, as well as other chemicals, screened in HTS assays may benefit from the addition of xenobiotic metabolic capabilities to decrease the uncertainty in predicting potential hazards to human health. The objective of this study was to develop an approach to retrofit existing HTS assays with hepatic metabolism. The Alginate Immobilization of Metabolic Enzymes (AIME) platform encapsulates hepatic S9 fractions in alginate microspheres attached to 96-well peg lids. Functional characterization across a panel of reference substrates for phase I cytochrome P450 enzymes revealed substrate depletion with expected metabolite accumulation. Performance of the AIME method in the VM7Luc estrogen receptor transactivation assay was evaluated across 15 reference chemicals and 48 test chemicals that yield metabolites previously identified as estrogen receptor active or inactive. The results demonstrate the utility of applying the AIME method for identification of false-positive and false-negative target assay effects, reprioritization of hazard based on metabolism-dependent bioactivity, and enhanced in vivo concordance with the rodent uterotrophic bioassay. Integration of the AIME metabolism method may prove useful for future biochemical and cell-based HTS applications.

On the interpretation of age–prevalence curves for trypanosome infections of tsetse flies

Parasitology ◽  
1998 ◽  
Vol 116 (2) ◽  
pp. 149-156 ◽  
Author(s):  
M. E. J. WOOLHOUSE ◽  
J. W. HARGROVE
Keyword(s):  
Experimental Data ◽  
Glossina Pallidipes ◽  
Tsetse Fly ◽  
Tsetse Flies ◽  
Parameter Estimates ◽  
Published Data ◽  
Data Sets ◽  
Trypanosoma Vivax ◽  
Epidemiological Models ◽  
Maturation Period

Epidemiological models are used to analyse 8 published data sets reporting age–prevalence curves for trypanosome infections of the tsetse fly Glossina pallidipes. A model assuming a fixed maturation period and a rate of infection which is independent of fly age is adequate for Trypanosoma vivax-type infections, explaining 98% of observed variance in prevalence by site and age, allowing that the rate of infection may be site dependent. This model is not adequate for T. congolense-type infections and the fit can be improved by allowing (i) the rates of infection to decline with age (although non-teneral flies remain susceptible), (ii) a fraction of resistant flies, which may vary between sites, (iii) increased mortality of infected flies and (iv) variation in the maturation period. Models with these features can explain up to 97% of observed variance. Parameter estimates from published experimental data suggest that all may contribute in practice but that (i) and/or (ii) are likely to be the most important.

scholarly journals Brief communication: new perspectives on the calculation of bioaccumulation factors for active substances in living organisms

2020 ◽  
Author(s):  
Aude Ratier ◽  
Christelle Lopes ◽  
Gauthier Multari ◽  
Vanessa Mazerolles ◽  
Patrice Carpentier ◽  
...  
Keyword(s):  
Plant Protection ◽  
Plant Protection Products ◽  
Daily Work ◽  
Bioaccumulation Factors ◽  
On Line ◽  
Living Organisms ◽  
User Friendly ◽  
Data Requirements ◽  
Active Substances ◽  
Test Guideline

AbstractToday, there are no ready-to-use convenient tools in ecotoxicology to diagnose and predict the accumulation and effects of chemical substances on living organisms, accounting for exposure situations that are known to be complex (routes of exposure, metabolization processes, cocktail effects, etc.). Regarding plant protection products in marketing authorization applications, regulation No 283/2013 (EU) defines the data requirements for active substances with a bioaccumulation test on fish according to OECD Test guideline 305. This paper presents new perspectives on the estimation of the bioaccumulation factors via an innovative ready-to-use web tool providing these factors, associated with their uncertainty to facilitate the daily work of regulators, but also of any user, by benefiting of a freely available and user-friendly on-line interface avoiding to invest into underlying mathematical and statistical technicalities. This tool, MOSAICbioacc, is available at https://mosaic.univ-lyon1.fr/bioacc, and can be used by any environmental scientists, ecotoxicologists or managers when accumulation-depuration data are collected and need to be easily and quickly analysed.

scholarly journals Error sensitivity and optimization of steady-state kinetic parameters using multidimensional chemical kinetic analysis

2018 ◽  
Author(s):  
Joseph S. Eskew ◽  
Christopher G. Connell ◽  
Jared C. Cochran
Keyword(s):  
Experimental Data ◽  
Chemical Kinetic ◽  
Parameter Estimates ◽  
Data Sets ◽  
Raw Data ◽  
Test Error ◽  
Error Sensitivity ◽  
Steady State Kinetic ◽  
Time Domains ◽  
State Kinetic

AbstractEnzyme behavior has been described using the Michaelis-Menten mechanism. The analysis of extended time domains provides a means to extract the Michaelis-Menten constants through direct fitting of raw data. We have developed a scheme for determining Michaelis-Menten rate constants by appropriate fitting of multidimensional experimental data sets to the closed form of the Michaelis-Menten model. We considered how varying parameters in experimental data affect the accuracy of the remaining parameter estimates. We determine how to improve experimental design to achieve a given accuracy, relative to the amount of intrinsic or external error. We analyze this scheme on data sets built around 20 hypothetical and 2 natural enzymes (kinesin and apyrase) to test error sensitivity in different parameter regimes. Overall, we provide evidence that our data fitting regime will tolerate significant experimental error in the raw data and still converge on the four Michaelis-Menten constants.

scholarly journals Modeling Amantadine Treatment of Inuenza A Virus In Vitro

2021 ◽  
Author(s):  
Catherine A. A. Beauchemin ◽  
James J. McSharry ◽  
George L. Drusano ◽  
Jack T. Nguyen ◽  
Gregory T. Went ◽  
...  
Keyword(s):  
Experimental Data ◽  
Viral Infection ◽  
Mathematical Models ◽  
Influenza A ◽  
Mdck Cells ◽  
Rapid Development ◽  
Human Model ◽  
Parameter Estimates

We analyzed the dynamics of an influenza A/Albany/1/98 (H3N2) viral infection, using a set of mathematical models highlighting the differences between in vivo and in vitro infection. For example, we found that including virion loss due to cell entry was critical for the in vitro model but not for the in vivo model. Experiments were performed on influenza virus-infected MDCK cells in vitro inside a hollow-fiber (HF) system, which was used to continuously deliver the drug amantadine. The HF system captures the dynamics of an influenza infection, and is a controlled environment for producing experimental data which lend themselves well to mathematical modeling. The parameter estimates obtained from fitting our mathematical models to the HF experimental data are consistent with those obtained earlier for a primary infection in a human model. We found that influenza A/Albany/1/98 (H3N2) virions under normal experimental conditions at 37°C rapidly lose infectivity with a half-life of ~ 6.6 ± 0.2 h, and that the lifespan of productively infected MDCK cells is ~ 13 h. Finally, using our models we estimated that the maximum efficacy of amantadine in blocking viral infection is ~ 74%, and showed that this low maximum efficacy is likely due to the rapid development of drug resistance.

Understanding the Role of Surface Active Substances in Flotation Deinking Mills by Coupling Surfactant and Ink Balance With Process Simulation

TAPPI Journal ◽  
2010 ◽  
Vol 9 (2) ◽  
pp. 31-39
Author(s):  
Davide Beneventi ◽  
Elisa Zenob ◽  
Bruno Carréb ◽  
Jérémy Allixb ◽  
Patrice Nortiera ◽  
...  
Keyword(s):  
Experimental Data ◽  
Process Simulation ◽  
Raw Materials ◽  
Mass Balances ◽  
Second Stage ◽  
Functional Additives ◽  
Paper Sizing ◽  
Surface Active ◽  
Active Substances

Surfactants are largely present in papermaking/recycling processes. They are added intentionally or come with raw materials or process/functional additives. Once they have reached the process, they build-up in the circuits and, depending on their surface activity and concentration, they can have adverse effects on deinking and on the whole papermaking process, such as excessive frothing, depression of ink floatability, and paper sizing/retention difficulties. In this paper, the removal of apparent surface active chemicals (ASAASAASAC) is first evaluated in different flotation deinking mills through mass balances using surface tension measurements and a specific methodology. Mill data show that, in two-stage deinking lines, ASAASAASAC are slightly concentrated in the second stage, contributing to an increase in pulp frothing behavior, in flotation loss, and in some cases to a low ink removal efficiency. Trends observed in deinking mills are then interpreted using experimental data obtained at the laboratory scale in the presence of a model surfactant, and by process simulation. The effect of ASAASAASAC concentration on the efficiency of the flotation deinking process is explained in terms of their effect on particle and water transport sub processes, namely, flotation, entrainment, frothing, and drainage.

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