Update and Evaluation of a High-Throughput In Vitro Mass Balance Distribution Model: IV-MBM EQP v2.0

This study demonstrates the utility of an updated mass balance model for predicting the distribution of organic chemicals in in vitro test systems (IV-MBM EQP v2.0) and evaluates its performance with empirical data. The IV-MBM EQP v2.0 tool was parameterized and applied to four independent data sets with measured ratios of bulk medium or freely-dissolved to initial nominal concentrations (e.g., C24/C0 where C24 is the measured concentration after 24 h of exposure and C0 is the initial nominal concentration). Model performance varied depending on the data set, chemical properties (e.g., “volatiles” vs. “non-volatiles”, neutral vs. ionizable organics), and model assumptions but overall is deemed acceptable. For example, the r2 was greater than 0.8 and the mean absolute error (MAE) in the predictions was less than a factor of two for most neutral organics included. Model performance was not as good for the ionizable organic chemicals included but the r2 was still greater than 0.7 and the MAE less than a factor of three. The IV-MBM EQP v2.0 model was subsequently applied to several hundred chemicals on Canada’s Domestic Substances List (DSL) with nominal effects data (AC50s) reported for two in vitro assays. We report the frequency of chemicals with AC50s corresponding to predicted cell membrane concentrations in the baseline toxicity range (i.e., >20–60 mM) and tabulate the number of chemicals with “volatility issues” (majority of chemical in headspace) and “solubility issues” (freely-dissolved concentration greater than water solubility after distribution). In addition, the predicted “equivalent EQP blood concentrations” (i.e., blood concentration at equilibrium with predicted cellular concentration) were compared to the AC50s as a function of hydrophobicity (log octanol-water partition or distribution ratio). The predicted equivalent EQP blood concentrations exceed the AC50 by up to a factor of 100 depending on hydrophobicity and assay conditions. The implications of using AC50s as direct surrogates for human blood concentrations when estimating the oral equivalent doses using a toxicokinetic model (i.e., reverse dosimetry) are then briefly discussed.

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Calibration and evaluation of a high-resolution surface mass-balance model for Paakitsoq, West Greenland

Journal of Glaciology ◽

10.3189/2012jog12j034 ◽

2012 ◽

Vol 58 (212) ◽

pp. 1047-1062 ◽

Cited By ~ 14

Author(s):

Alison F. Banwell ◽

Ian C. Willis ◽

Neil S. Arnold ◽

Alexandra Messerli ◽

Cameron J. Rye ◽

...

Keyword(s):

Mass Balance ◽

Model Performance ◽

Greenland Ice Sheet ◽

Balance Model ◽

Threshold Temperature ◽

Mass Balance Model ◽

Surface Mass ◽

West Greenland ◽

Landsat 7 ◽

Normalized Difference Snow Index

AbstractModelling the hydrology of the Greenland ice sheet, including the filling and drainage of supraglacial lakes, requires melt inputs generated at high spatial and temporal resolution. Here we apply a high spatial (100 m) and temporal (1 hour) mass-balance model to a 450 km2 subset of the Paakitsoq region, West Greenland. The model is calibrated by adjusting the values for parameters of fresh snow density, threshold temperature for solid/liquid precipitation and elevation-dependent precipitation gradient to minimize the error between modelled output and surface height and albedo measurements from three Greenland Climate Network stations for the mass-balance years 2000/01 and 2004/05. Bestfit parameter values are consistent between the two years at 400 kg m-3, 2°C and +14% (100 m)-1, respectively. Model performance is evaluated, first, by comparing modelled snow and ice distribution with that derived from Landsat-7 ETM+ satellite imagery using normalized-difference snow index classification and supervised image thresholding; and second, by comparing modelled albedo with that retrieved from the MODIS sensor M0D10A1 product. Calculation of mass-balance components indicates that 6% of surface meltwater and rainwater refreezes in the snowpack and does not become runoff, such that refreezing accounts for 31% of the net accumulation.

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Comparison of mass balances for Vernagtferner, Oetzal Alps, as obtained from direct measurements and distributed modeling

Annals of Glaciology ◽

10.3189/172756409787769582 ◽

2009 ◽

Vol 50 (50) ◽

pp. 169-177 ◽

Cited By ~ 16

Author(s):

Frank Paul ◽

Heidi Escher-Vetter ◽

Horst Machguth

Keyword(s):

Mass Balance ◽

Satellite Image ◽

Global Radiation ◽

Model Performance ◽

Remote Sensing Data ◽

Balance Model ◽

Glacier Mass Balance ◽

Catchment Scale ◽

Equilibrium Line Altitude ◽

Direct Measurements

AbstractThe direct comparison of modeled glacier mass-balance distribution with field measurements could be problematic, as the methodology of determination and the processes considered at the point or catchment scale could differ strongly. Moreover, direct measurements cover only small parts of a glacier, and model performance is thus difficult to assess outside these regions. Remaining opportunities for model validation include comparison of snowlines, as derived from remote-sensing data, and maps of the mass-balance distribution, as interpreted by observers with local knowledge. This study compares such hand-drawn maps of the Vernagtferner (Oetzal Alps) mass balance with the modeled pattern as obtained from a distributed energy-/mass-balance model of intermediate complexity. The model is driven by measured daily values of temperature, global radiation and precipitation from a nearby climate station and grids of mean daily potential global radiation and climatologic annual precipitation sums. Compared with the direct measurements, the calculated mean mass balance and equilibrium-line altitude agreed very well in both balance years, although the spatial pattern of the mass-balance distribution displayed larger deviations in regions influenced by snowdrift or local topographic undulations. However, compared with the remaining snow as visible on a satellite image from 1999, the modeled snowline pattern for a larger sample of glaciers is in very good agreement.

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Evaluation of Cytotoxicity of the First Twenty MEIC Chemicals by Using Haemolysis of Human Erythrocytes as an Endpoint

Alternatives to Laboratory Animals ◽

10.1177/026119299202000208 ◽

1992 ◽

Vol 20 (2) ◽

pp. 226-229

Author(s):

Boris Isomaa ◽

Henrik Lilius ◽

Anne West

Keyword(s):

Maximum Degree ◽

Human Lymphocytes ◽

Rat Hepatocytes ◽

Haemolytic Activity ◽

In Vitro Test ◽

3T3 Cells ◽

Blood Concentrations ◽

Vitro Test ◽

Lethal Blood

The cytotoxicity of the first twenty chemicals on the MEIC list was evaluated by determining the haemolytic activity of the chemicals. All the tested chemicals, except malathion, were haemolytic. With digoxin and sodium fluoride, however, the maximum degree of haemolysis achieved remained less than 50%. The EC10 for the chemicals varied from 0.38mM (digoxin) to 4,830mM (ethylene glycol). Comparing our data for the first ten MEIC chemicals with data obtained with other in vitro test systems, they correlated well with data reported for human lymphocytes (r = 0.93), rat hepatocytes (r = 0.98) and 3T3 cells (r = 0.95). However, in comparison with these tests, the haemolysis assay was less sensitive. The EC10 for the first ten MEIC chemicals correlated rather well (r = 0.84) with human lethal blood concentrations, but the haemolysis assay underestimated the toxicity of most of the chemicals and particularly underestimated the toxicity of digoxin.

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Analysis of the Surface Mass Balance for Deglacial Climate Simulations

10.5194/tc-2020-173 ◽

2020 ◽

Author(s):

Marie-Luise Kapsch ◽

Uwe Mikolajewicz ◽

Florian Andreas Ziemen ◽

Christian B. Rodehacke ◽

Clemens Schannwell

Keyword(s):

Mass Balance ◽

Ice Sheet ◽

Greenland Ice Sheet ◽

Meridional Overturning Circulation ◽

Balance Model ◽

Surface Mass Balance ◽

Equilibrium Line Altitude ◽

Data Set ◽

Surface Mass ◽

Climate Conditions

Abstract. Most studies analyzing changes in the surface mass balance (SMB) of the Greenland ice sheet are limited to the last century, due to the availability of observations and the computational limitations of regional climate modeling. Using transient simulations with a comprehensive Earth System Model (ESM) we extend previous research and study changes in the SMB and equilibrium line altitude (ELA) for deglacial climate conditions. An energy balance model (EBM) is used to downscale atmospheric processes. It determines the SMB on higher spatial resolution and allows to resolve SMB variations due to topographic gradients not resolved by the ESM. An evaluation for historical climate conditions (1980–2010) shows that derived SMBs compare well with SMBs from regional modeling. Throughout the deglaciation changes in insolation dominate the Greenland SMB: 1) The increase in insolation and associated warming early in the deglaciation result in an ELA and SMB increase. The SMB increase is caused by compensating effects of melt and accumulation, as a warmer atmosphere precipitates more. After 13 ka before present (BP) melt begins to dominate and the SMB decreases. 2) The decline in insolation after 9 ka BP leads to an increasing SMB and decreasing ELA. Superimposed on these long-term changes are episodes of significant SMB/ELA decreases, related to slowdowns of the Atlantic Meridional Overturning Circulation (AMOC) that lead to cooling over most of the Northern Hemisphere. To study associated changes in the ice sheet geometry, the SMB data set is made available to the ice sheet modeling community.

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In-vitro anti-malarial activity of Chikadoma plant from the rainforest of Southern Nigeria

Journal of Drug Delivery and Therapeutics ◽

10.22270/jddt.v10i5.4322 ◽

2020 ◽

Vol 10 (5) ◽

pp. 251-254

Author(s):

CE Okolo ◽

LK Eban ◽

LU Amazu ◽

LC Chukwu ◽

SC Ohadoma ◽

...

Keyword(s):

Leaf Extract ◽

Culture Medium ◽

Antimalarial Activity ◽

Negative Control ◽

Probit Analysis ◽

Tropical Disease ◽

Malarial Parasite ◽

In Vitro Assays ◽

In Vitro Test

Background: Malaria remains a life-threatening tropical disease. Due to the development of resistance to the commonly available orthodox antimalarials which of course, poses a great challenge in malaria-controlling-program, alternative and complementary approach becomes imperative thereby making phytotherapy a research focus. Objectives: To investigate the effect of chikadoma plant using its methanol leaf extract against a plasmodium-mediated tropical disease, malaria. Materials and Methods: The culture samples of Plasmodium (P.) falciparum from 20 symptomatic adult outpatients were used in the antimalarial in-vitro test. For cultivation of P. falciparum, the culture medium employed was Roswell Park Memorial Institute (RPMI) 1640. Optical microscopy was used for parasite quantification in the performance of antiplasmodial in-vitro assays. The leaf extract of chikadoma dissolved in dimethylsulphoxide (DMSO) was the treatment, prepared into 7 different levels of concentration (3.125, 6.25, 12.5, 25, 50, 100, and 200 mg/mL) while culture medium with the malarial parasite alone served as negative control. Micromalarial culture preceded by culture synchronized with sorbitol 5%, were divided into “control” and “treated groups”, followed by incubation in CO2 candle jar at 370C for 72 h. The percentage of parasitemia was measured 8 h, showing the activity of the extract on P. falciparum stages of proliferation. Thin blood smear from the erythrocytes layer was made and stained with 10% Giemsa for 30 mins to estimate the parasitemia. The antimalarial activity of the extract was calculated using Probit analysis by counting the 50% growth inhibition (IC50). Results: The growth of P. falciparum was inhibited by the extract on mature schizont stage; and the IC50 of the extract after 40 h incubation was 3.0 mg/mL. Conclusion: The leaf extract of chikadoma significantly has antimalarial effect in-vitro against P. falciparum. Keywords: Chikadoma; Lupinus arboreus; antimalarial activity; tropical disease; Nigeria.

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Integrating Cell Morphology with Gene Expression and Chemical Structure to Aid Mitochondrial Toxicity Detection

10.1101/2022.01.07.475326 ◽

2022 ◽

Author(s):

Srijit Seal ◽

Jordi Carreras-Puigvert ◽

Maria-Anna Trapotsi ◽

Hongbin Yang ◽

Ola Spjuth ◽

...

Keyword(s):

Gene Expression ◽

Drug Discovery ◽

Chemical Structure ◽

Structural Information ◽

Chemical Space ◽

Model Performance ◽

In Vitro Assays ◽

Mitochondrial Toxicity ◽

Mitochondrial Membrane Depolarization

Mitochondrial toxicity is an important safety endpoint in drug discovery. Models based solely on chemical structure for predicting mitochondrial toxicity are currently limited in accuracy and applicability domain to the chemical space of the training compounds. In this work, we aimed to utilize both -omics and chemical data to push beyond the state-of-the-art. We combined Cell Painting and Gene Expression data with chemical structural information from Morgan fingerprints for 382 chemical perturbants tested in the Tox21 mitochondrial membrane depolarization assay. We observed that mitochondrial toxicants significantly differ from non-toxic compounds in morphological space and identified compound clusters having similar mechanisms of mitochondrial toxicity, thereby indicating that morphological space provides biological insights related to mechanisms of action of this endpoint. We further showed that models combining Cell Painting, Gene Expression features and Morgan fingerprints improved model performance on an external test set of 236 compounds by 60% (in terms of F1 score) and improved extrapolation to new chemical space. The performance of our combined models was comparable with dedicated in vitro assays for mitochondrial toxicity; and they were able to detect mitochondrial toxicity where Tox21 assays outcomes were inconclusive because of cytotoxicity. Our results suggest that combining chemical descriptors with different levels of biological readouts enhances the detection of mitochondrial toxicants, with practical implications for use in drug discovery.

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Distributed mass-balance modelling on two neighbouring glaciers in Ortles-Cevedale, Italy, from 2004 to 2009

Journal of Glaciology ◽

10.3189/2012jog11j111 ◽

2012 ◽

Vol 58 (209) ◽

pp. 467-486 ◽

Cited By ~ 20

Author(s):

Luca Carturan ◽

Federico Cazorzi ◽

Giancarlo Dalla Fontana

Keyword(s):

Mass Balance ◽

Meteorological Data ◽

Model Performance ◽

Temporal Distribution ◽

Balance Model ◽

Simple Method ◽

Temperature Index ◽

Multiplicative Algorithm ◽

Different Characteristics ◽

Simulation Errors

AbstractA 6 year application of an enhanced temperature-index mass-balance model to Careser and La Mare glaciers, Eastern Italian Alps, is presented. The two glaciers exhibit very different characteristics, and a comprehensive dataset of distributed mass-balance measurements was used to test the model performance. The model was run using meteorological data acquired outside the glaciers. The work was focused on two main aspects: (1) the development of a morphological redistribution procedure for snow, and (2) the comparison of three different melt algorithms proposed in the literature. The results show that the simple method proposed for snow redistribution can greatly improve simulation of winter balance, and further improvements would be achievable by collecting data on inaccessible and high-altitude areas. All three melt formulations displayed a good skill level and very similar results in modelling the mass-balance distribution over glacier areas, with slightly better results from a multiplicative algorithm in capturing the vertical balance gradient. The simulation errors are related to aspect and elevation, and tend to be spatially aggregated. Some assumptions concerning the spatial and temporal distribution of air temperature and incoming solar radiation, although reasonable and widely used in the literature, may be responsible for this aggregation. Hence, there is a need to further investigate the processes that regulate the distribution of melt energy, and that appear to control the current deglaciation phase in this area.

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The Prediction of Human Acute Systemic Toxicity by the EDIT/MEIC In Vitro Test Battery: The Importance of Protein Binding and of Partitioning into Lipids

Alternatives to Laboratory Animals ◽

10.1177/026119290303100306 ◽

2003 ◽

Vol 31 (3) ◽

pp. 245-256 ◽

Cited By ~ 1

Author(s):

Cecilia Clemedson ◽

Paul J. Dierickx ◽

Michael Sjöström

Keyword(s):

Protein Binding ◽

Mercuric Chloride ◽

Culture Medium ◽

Systemic Toxicity ◽

Test Battery ◽

In Vitro Test ◽

Blood Concentrations ◽

Uptake Inhibition ◽

Vitro Test

The aim of the two studies presented in this paper was to further improve the predictability of the original Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) in vitro test battery for acute systemic toxicity. In the first study, whether a protein-free cytotoxicity assay could improve the prediction of human acute systemic toxicity was investigated. The cytotoxicity of 39 MEIC reference chemicals was measured by the neutral red uptake inhibition test after 30 minutes in phosphate-buffered saline (PBS), with hepatoma-derived Fa32 cells. The results were compared with the corresponding values obtained in complete culture medium, including 10% fetal calf serum. Mercuric chloride and hexachlorophene were much more cytotoxic in PBS, as was the case, to a lesser extent, for seven other chemicals. Potassium cyanide and eight other chemicals were less cytotoxic in PBS than in complete culture medium, probably because of poor physiological conditions. The correlation between the cytotoxicity measured in PBS and human acute toxicity was rather low, but became of the same order as for other assays, when mercuric chloride and hexachlorophene were withdrawn from the comparison. In the second study, modelling of human lethal blood concentrations by using the results of the three cell line tests of the original MEIC test battery were complemented by logP (octanol–water partition coefficient) values. The introduction of logP into the modelling did not improve the correlations, but some improvement of both R2 and Q2 was obtained by expanding the logP values with logP2 values. The highest R2 (0.84) and Q2 (0.80) values were obtained for a model in which both experimental and calculated (ambiguous) logP values were used. When only experimental logP values were used, the corresponding values were 0.80 and 0.78. These two studies showed that including protein binding and the partition of chemicals in the MEIC in vitro test battery is important, in order to improve the predictability of the results obtained.

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Assimilating near-real-time mass balance stake readings into a model ensemble using a particle filter

The Cryosphere ◽

10.5194/tc-15-5017-2021 ◽

2021 ◽

Vol 15 (11) ◽

pp. 5017-5040

Author(s):

Johannes Marian Landmann ◽

Hans Rudolf Künsch ◽

Matthias Huss ◽

Christophe Ogier ◽

Markus Kalisch ◽

...

Keyword(s):

Energy Balance ◽

Particle Filter ◽

Mass Balance ◽

Real Time ◽

Model Performance ◽

Point Mass ◽

Solar Irradiation ◽

Balance Model ◽

Model Parameters ◽

Mass Balances

Abstract. Short-term glacier variations can be important for water supplies or hydropower production, and glaciers are important indicators of climate change. This is why the interest in near-real-time mass balance nowcasting is considerable. Here, we address this interest and provide an evaluation of continuous observations of point mass balance based on online cameras transmitting images every 20 min. The cameras were installed on three Swiss glaciers during summer 2019, provided 352 near-real-time point mass balances in total, and revealed melt rates of up to 0.12 m water equivalent per day (mw.e.d-1) and of more than 5 mw.e. in 81 d. By means of a particle filter, these observations are assimilated into an ensemble of three TI (temperature index) and one simplified energy-balance mass balance models. State augmentation with model parameters is used to assign temporally varying weights to individual models. We analyze model performance over the observation period and find that the probability for a given model to be preferred by our procedure is 39 % for an enhanced TI model, 24 % for a simple TI model, 23 %, for a simplified energy balance model, and 14 % for a model employing both air temperature and potential solar irradiation. When compared to reference forecasts produced with both mean model parameters and parameters tuned on single mass balance observations, the particle filter performs about equally well on the daily scale but outperforms predictions of cumulative mass balance by 95 %–96 %. A leave-one-out cross-validation on the individual glaciers shows that the particle filter is also able to reproduce point observations at locations not used for model calibration. Indeed, the predicted mass balances is always within 9 % of the observations. A comparison with glacier-wide annual mass balances involving additional measurements distributed over the entire glacier mostly shows very good agreement, with deviations of 0.02, 0.07, and 0.24 mw.e.

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Air temperature variability over three glaciers in the Ortles–Cevedale (Italian Alps): effects of glacier fragmentation, comparison of calculation methods, and impacts on mass balance modeling

The Cryosphere ◽

10.5194/tc-9-1129-2015 ◽

2015 ◽

Vol 9 (3) ◽

pp. 1129-1146 ◽

Cited By ~ 16

Author(s):

L. Carturan ◽

F. Cazorzi ◽

F. De Blasi ◽

G. Dalla Fontana

Keyword(s):

Mass Balance ◽

Air Temperature ◽

Temperature Variability ◽

Cooling Effect ◽

Balance Model ◽

Spatial And Temporal Variability ◽

Glacier Mass Balance ◽

Ambient Conditions ◽

Data Set ◽

Mass Balance Models

Abstract. Glacier mass balance models rely on accurate spatial calculation of input data, in particular air temperature. Lower temperatures (the so-called glacier cooling effect) and lower temperature variability (the so-called glacier damping effect) generally occur over glaciers compared to ambient conditions. These effects, which depend on the geometric characteristics of glaciers and display a high spatial and temporal variability, have been mostly investigated on medium to large glaciers so far, while observations on smaller ice bodies (< 0.5 km2) are scarce. Using a data set from eight on-glacier and four off-glacier weather stations, collected in the summers of 2010 and 2011, we analyzed the air temperature variability and wind regime over three different glaciers in the Ortles–Cevedale. The magnitude of the cooling effect and the occurrence of katabatic boundary layer (KBL) processes showed remarkable differences among the three ice bodies, suggesting the likely existence of important reinforcing mechanisms during glacier decay and fragmentation. The methods proposed by Greuell and Böhm (1998) and Shea and Moore (2010) for calculating on-glacier temperature from off-glacier data did not fully reproduce our observations. Among them, the more physically based procedure of Greuell and Böhm (1998) provided the best overall results where the KBL prevails, but it was not effective elsewhere (i.e., on smaller ice bodies and close to the glacier margins). The accuracy of air temperature estimations strongly impacted the results from a mass balance model which was applied to the three investigated glaciers. Most importantly, even small temperature deviations caused distortions in parameter calibration, thus compromising the model generalizability.

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