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Article: Ten Years of Using Key Characteristics of Human Carcinogens to Organize and Evaluate Mechanistic Evidence in IARC Monographs on the Identification of Carcinogenic Hazards to Humans: Patterns and Associations.

Rusyn, Ivan / Wright, Fred A

bioRxiv : the preprint server for biology

2023

Abstract: Systematic review and evaluation of the mechanistic evidence only recently been instituted in cancer hazard identification step of decision-making. One example of organizing and evaluating mechanistic evidence is the Key Characteristics approach of the ... ...

Abstract	Systematic review and evaluation of the mechanistic evidence only recently been instituted in cancer hazard identification step of decision-making. One example of organizing and evaluating mechanistic evidence is the Key Characteristics approach of the International Agency for Research on Cancer (IARC) Monographs on the Identification of Carcinogenic Hazards to Humans. The Key Characteristics of Human Carcinogens were proposed almost 10 years ago and have been used in every IARC Monograph since 2015. We investigated the patterns and associations in the use of Key Characteristics by the independent expert Working Groups. We examined 19 Monographs (2015-2022) that evaluated 73 agents. We extracted information on the conclusions by each Working Group on the strength of evidence for agent-Key Characteristic combinations, data types that were available for decisions, and the role mechanistic data played in the final cancer hazard classification. We conducted both descriptive and association analyses within and across data types. We found that IARC Working Groups were cautious when evaluating mechanistic evidence: for only ∼13% of the agents was strong evidence assigned for any Key Characteristic. Genotoxicity and cell proliferation were most data-rich, while little evidence was available for DNA repair and immortalization Key Characteristics. Analysis of the associations among Key Characteristics revealed that only chemical's metabolic activation was significantly co-occurring with genotoxicity and cell proliferation/death. Evidence from exposed humans was limited, while mechanistic evidence from rodent studies
Language	English
Publishing date	2023-07-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.11.548354
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Article ; Online: Ten years of using key characteristics of human carcinogens to organize and evaluate mechanistic evidence in IARC Monographs on the identification of carcinogenic hazards to humans: Patterns and associations.

Rusyn, Ivan / Wright, Fred A

Toxicological sciences : an official journal of the Society of Toxicology

2023 Volume 198, Issue 1, Page(s) 141–154

Abstract: Systematic review and evaluation of mechanistic evidence using the Key Characteristics approach was proposed by the International Agency for Research on Cancer (IARC) in 2012 and used by the IARC Monographs Working Groups since 2015. Key Characteristics ... ...

Abstract	Systematic review and evaluation of mechanistic evidence using the Key Characteristics approach was proposed by the International Agency for Research on Cancer (IARC) in 2012 and used by the IARC Monographs Working Groups since 2015. Key Characteristics are 10 features of agents known to cause cancer in humans. From 2015 to 2022, a total of 19 Monographs (73 agents combined) used Key Characteristics for cancer hazard classification. We hypothesized that a retrospective analysis of applications of the Key Characteristics approach to cancer hazard classification using heterogenous mechanistic data on diverse agents would be informative for systematic reviews in decision-making. We extracted information on the conclusions, data types, and the role mechanistic data played in the cancer hazard classification from each Monograph. Statistical analyses identified patterns in the use of Key Characteristics, as well as trends and correlations among Key Characteristics, data types, and ultimate decisions. Despite gaps in data for many agents and Key Characteristics, several significant results emerged. Mechanistic data from in vivo animal, in vitro animal, and in vitro human studies were most impactful in concluding that an agent could cause cancer via a Key Characteristic. To exclude the involvement of a Key Characteristic, data from large-scale systematic in vitro testing programs such as ToxCast, were most informative. Overall, increased availability of systemized data streams, such as human in vitro data, would provide the basis for more confident and informed conclusions about both positive and negative associations and inform expert judgments on cancer hazard.
MeSH term(s)	Animals ; Humans ; Carcinogens/toxicity ; Retrospective Studies ; Systematic Reviews as Topic ; Carcinogenesis ; Neoplasms/chemically induced ; Neoplasms/epidemiology
Chemical Substances	Carcinogens
Language	English
Publishing date	2023-12-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfad134
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Article ; Online: Decision-Making with New Approach Methodologies: Time to Replace Default Uncertainty Factors with Data.

Rusyn, Ivan / Chiu, Weihsueh A

Toxicological sciences : an official journal of the Society of Toxicology

2022 Volume 189, Issue 1, Page(s) 148–149

MeSH term(s)	Decision Making ; Uncertainty
Language	English
Publishing date	2022-04-11
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfac033
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Article ; Online: Assessing proarrhythmic potential of environmental chemicals using a high throughput in vitro-in silico model with human induced pluripotent stem cell-derived cardiomyocytes.

Lin, Hsing-Chieh / Rusyn, Ivan / Chiu, Weihsueh A

ALTEX

2023 Volume 41, Issue 1, Page(s) 37–49

Abstract: QT prolongation and the potentially fatal arrhythmia Torsades de Pointes are common causes for withdrawing or restricting drugs; however, little is known about similar liabilities of environmental chemicals. Current in vitro-in silico models for testing ... ...

Abstract	QT prolongation and the potentially fatal arrhythmia Torsades de Pointes are common causes for withdrawing or restricting drugs; however, little is known about similar liabilities of environmental chemicals. Current in vitro-in silico models for testing proarrhythmic liabilities, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), provide an opportunity to address this data gap. These methods are still low- to medium-throughput and not suitable for testing the tens of thousands of chemicals in commerce. We hypothesized that combining high-throughput population- based in vitro testing in hiPSC-CMs with a fully in silico data analysis workflow can offer sensitive and specific predictions of proarrhythmic potential. We calibrated the model with a published hiPSC-CM dataset of drugs known to be positive or negative for proarrhythmia and tested its performance using internal cross-validation and external validation. Additionally, we used computational down-sampling to examine three study designs for hiPSC-CM data: one replicate of one donor, five replicates of one donor, and one replicate of a population of five donors. We found that the population of five donors had the best performance for predicting proarrhythmic potential. The resulting model was then applied to predict the proarrhythmic potential of environmental chemicals, additionally characterizing risk through margin of exposure (MOE) calculations. Out of over 900 environmental chemicals tested, over 150 were predicted to have proarrhythmic potential, but only seven chemicals had a MOE < 1. We conclude that a high-throughput in vitro-in silico approach using population-based hiPSC-CM testing provides a reasonable strategy to screen environmental chemicals for proarrhythmic potential.
MeSH term(s)	Humans ; Induced Pluripotent Stem Cells ; Myocytes, Cardiac ; Arrhythmias, Cardiac/chemically induced ; Torsades de Pointes/chemically induced ; Computer Simulation
Language	English
Publishing date	2023-10-19
Publishing country	Germany
Document type	Journal Article
ZDB-ID	165707-0
ISSN	1868-8551 ; 1018-4562 ; 0946-7785
ISSN (online)	1868-8551
ISSN	1018-4562 ; 0946-7785
DOI	10.14573/altex.2306231
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Article ; Online: Editorial overview of the special issue on application of tissue chips in toxicology.

Rusyn, Ivan / Roth, Adrian

Toxicology

2021 Volume 450, Page(s) 152687

MeSH term(s)	Animals ; Cell Culture Techniques/methods ; Cytotoxins/toxicity ; High-Throughput Screening Assays/methods ; Humans ; Induced Pluripotent Stem Cells/drug effects ; Induced Pluripotent Stem Cells/physiology ; Organ Culture Techniques/methods ; Toxicity Tests/methods
Chemical Substances	Cytotoxins
Language	English
Publishing date	2021-01-20
Publishing country	Ireland
Document type	Editorial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	184557-3
ISSN	1879-3185 ; 0300-483X
ISSN (online)	1879-3185
ISSN	0300-483X
DOI	10.1016/j.tox.2021.152687
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Article ; Online: Evaluating scientific confidence in the concordance of in vitro and in vivo protective points of departure.

Lu, En-Hsuan / Ford, Lucie C / Chen, Zunwei / Burnett, Sarah D / Rusyn, Ivan / Chiu, Weihsueh A

Regulatory toxicology and pharmacology : RTP

2024 Volume 148, Page(s) 105596

Abstract: To fulfil the promise of reducing reliance on mammalian in vivo laboratory animal studies, new approach methods (NAMs) need to provide a confident basis for regulatory decision-making. However, previous attempts to develop in vitro NAMs-based points of ... ...

Abstract	To fulfil the promise of reducing reliance on mammalian in vivo laboratory animal studies, new approach methods (NAMs) need to provide a confident basis for regulatory decision-making. However, previous attempts to develop in vitro NAMs-based points of departure (PODs) have yielded mixed results, with PODs from U.S. EPA's ToxCast, for instance, appearing more conservative (protective) but poorly correlated with traditional in vivo studies. Here, we aimed to address this discordance by reducing the heterogeneity of in vivo PODs, accounting for species differences, and enhancing the biological relevance of in vitro PODs. However, we only found improved in vitro-to-in vivo concordance when combining the use of Bayesian model averaging-based benchmark dose modeling for in vivo PODs, allometric scaling for interspecies adjustments, and human-relevant in vitro assays with multiple induced pluripotent stem cell-derived models. Moreover, the available sample size was only 15 chemicals, and the resulting level of concordance was only fair, with correlation coefficients <0.5 and prediction intervals spanning several orders of magnitude. Overall, while this study suggests several ways to enhance concordance and thereby increase scientific confidence in vitro NAMs-based PODs, it also highlights challenges in their predictive accuracy and precision for use in regulatory decision making.
MeSH term(s)	Animals ; Humans ; Bayes Theorem ; Risk Assessment/methods ; Mammals
Language	English
Publishing date	2024-03-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	604672-1
ISSN	1096-0295 ; 0273-2300
ISSN (online)	1096-0295
ISSN	0273-2300
DOI	10.1016/j.yrtph.2024.105596
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Article ; Online: Novel adult cortical neuron processing and screening method illustrates sex- and age-dependent effects of pharmaceutical compounds.

Sefiani, Arthur / Rusyn, Ivan / Geoffroy, Cédric G

Scientific reports

2022 Volume 12, Issue 1, Page(s) 13125

Abstract: Neurodegenerative diseases and neurotraumatic injuries are typically age-associated disorders that can reduce neuron survival, neurite outgrowth, and synaptic plasticity leading to loss of cognitive capacity, executive function, and motor control. In ... ...

Abstract	Neurodegenerative diseases and neurotraumatic injuries are typically age-associated disorders that can reduce neuron survival, neurite outgrowth, and synaptic plasticity leading to loss of cognitive capacity, executive function, and motor control. In pursuit of reducing the loss of said neurological functions, novel compounds are sought that promote neuron viability, neuritogenesis, and/or synaptic plasticity. Current high content in vitro screenings typically use cells that are iPSC-derived, embryonic, or originate from post-natal tissues; however, most patients suffering from neurodegenerative diseases and neurotrauma are of middle-age and older. The chasm in maturity between the neurons used in drug screens and those in a target population is a barrier for translational success of in vitro results. It has been historically challenging to culture adult neurons let alone conduct screenings; therefore, age-appropriate drug screenings have previously not been plausible. We have modified Miltenyi's protocol to increase neuronal yield, neuron purity, and neural viability at a reduced cost to expand our capacity to screen compounds directly in primary adult neurons. To our knowledge, we developed the first morphology-based screening system using adult cortical neurons and the first to incorporate age and sex as biological variables in a screen using adult cortical neurons. By using primary adult cortical neurons from mice that were 4 to 48 weeks old for screening pharmaceutical agents, we have demonstrated age- and sex-dependent effects on neuritogenesis and neuron survival in vitro. Utilizing age- and sex-appropriate in vitro models to find novel compounds increasing neuron survival and neurite outgrowth, made possible by our modified adult neuron processing method, will greatly increase the relevance of in vitro screening for finding neuroprotective compounds.
MeSH term(s)	Animals ; Cell Survival ; Cells, Cultured ; Mice ; Neurites ; Neuronal Outgrowth ; Neurons/physiology ; Pharmaceutical Preparations
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2022-07-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-17389-4
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Article ; Online: Model systems and organisms for addressing inter- and intra-species variability in risk assessment.

Rusyn, Ivan / Chiu, Weihsueh A / Wright, Fred A

Regulatory toxicology and pharmacology : RTP

2022 Volume 132, Page(s) 105197

Abstract: Addressing inter- and intra-species differences in potential hazardous effects of chemicals remains a long-standing challenge in human health risk assessment that is typically addressed heuristically through use of 10-fold default "uncertainty" or " ... ...

Abstract	Addressing inter- and intra-species differences in potential hazardous effects of chemicals remains a long-standing challenge in human health risk assessment that is typically addressed heuristically through use of 10-fold default "uncertainty" or "safety" factors. Although it has long been recognized that chemical-specific data would be preferable to replace the "defaults," only recently have there emerged experimental model systems and organisms with the potential to experimentally quantify the population variability in both toxicokinetics and toxicodynamics for specific chemicals. Progress is most evident in the use of population in vitro human cell-based models and population in vivo mouse models. Multiple case studies were published in the past 10-15 years that clearly demonstrate the utility of such models to derive data with direct application to quantifying variability at hazard identification, exposure-response assessment, and mechanistic understanding of toxicity steps of traditional risk assessments. Here, we review recent efforts to develop fit-for-purpose approaches utilizing these novel population-based in vitro and in vivo models in the context of risk assessment. We also describe key challenges and opportunities to broadening application of population-based experimental approaches. We conclude that population-based models are now beginning to realize their potential to address long-standing data gaps in inter- and intra-species variability.
MeSH term(s)	Animals ; Mice ; Models, Theoretical ; Risk Assessment ; Toxicokinetics ; Uncertainty
Language	English
Publishing date	2022-05-28
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	604672-1
ISSN	1096-0295 ; 0273-2300
ISSN (online)	1096-0295
ISSN	0273-2300
DOI	10.1016/j.yrtph.2022.105197
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Article ; Online: Cumulative Risk Meets Inter-Individual Variability: Probabilistic Concentration Addition of Complex Mixture Exposures in a Population-Based Human In Vitro Model.

Jang, Suji / Ford, Lucie C / Rusyn, Ivan / Chiu, Weihsueh A

Toxics

2022 Volume 10, Issue 10

Abstract: Although humans are continuously exposed to complex chemical mixtures in the environment, it has been extremely challenging to investigate the resulting cumulative risks and impacts. Recent studies proposed the use of “new approach methods,” in ... ...

Abstract	Although humans are continuously exposed to complex chemical mixtures in the environment, it has been extremely challenging to investigate the resulting cumulative risks and impacts. Recent studies proposed the use of “new approach methods,” in particular in vitro assays, for hazard and dose−response evaluation of mixtures. We previously found, using five human cell-based assays, that concentration addition (CA), the usual default approach to calculate cumulative risk, is mostly accurate to within an order of magnitude. Here, we extend these findings to further investigate how cell-based data can be used to quantify inter-individual variability in CA. Utilizing data from testing 42 Superfund priority chemicals separately and in 8 defined mixtures in a human cell-based population-wide in vitro model, we applied CA to predict effective concentrations for cytotoxicity for each individual, for “typical” (median) and “sensitive” (first percentile) members of the population, and for the median-to-sensitive individual ratio (defined as the toxicodynamic variability factor, TDVF). We quantified the accuracy of CA with the Loewe Additivity Index (LAI). We found that LAI varies more between different mixtures than between different individuals, and that predictions of the population median are generally more accurate than predictions for the “sensitive” individual or the TDVF. Moreover, LAI values were generally <1, indicating that the mixtures were more potent than predicted by CA. Together with our previous studies, we posit that new approach methods data from human cell-based in vitro assays, including multiple phenotypes in diverse cell types and studies in a population-wide model, can fill critical data gaps in cumulative risk assessment, but more sophisticated models of in vitro mixture additivity and bioavailability may be needed. In the meantime, because simple CA models may underestimate potency by an order of magnitude or more, either whole-mixture testing in vitro or, alternatively, more stringent benchmarks of cumulative risk indices (e.g., lower hazard index) may be needed to ensure public health protection.
Language	English
Publishing date	2022-09-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2733883-6
ISSN	2305-6304 ; 2305-6304
ISSN (online)	2305-6304
ISSN	2305-6304
DOI	10.3390/toxics10100549
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Article ; Online: A Model of Human Small Airway on a Chip for Studies of Subacute Effects of Inhalation Toxicants.

Sakolish, Courtney / Georgescu, Andrei / Huh, Dan Dongeun / Rusyn, Ivan

Toxicological sciences : an official journal of the Society of Toxicology

2022 Volume 187, Issue 2, Page(s) 267–278

Abstract: Testing for acute inhalation hazards is conducted in animals; however, a number of robust in vitro human cell-based alternatives have been developed and tested. These models range in complexity from cultures of cell lines or primary cells in air-liquid ... ...

Abstract	Testing for acute inhalation hazards is conducted in animals; however, a number of robust in vitro human cell-based alternatives have been developed and tested. These models range in complexity from cultures of cell lines or primary cells in air-liquid interface on Transwells, to more complex and physiologically relevant flow- and mechanical stimulation-enabled tissue chips. Although the former models are relatively straightforward to establish and can be tested in medium/high throughput, the latter require specialized equipment and lack in throughput. In this study, we developed a device that can be easily manufactured while allowing for the production of a differentiated lung tissue. This multilayered microfluidic device enables coculture of primary human small airway epithelial cells and lung microvascular endothelial cells under physiological conditions for up to 18 days and recreates the parenchymal-vascular interface in the distal lung. To explore the potential of this airway on a chip for applications in inhalation toxicology, we also devised a system that allows for direct gas/aerosol exposures of the engineered airway epithelium to noxious stimuli known to cause adverse respiratory effects, including dry flowing air, lipopolysaccharide, particulate matter, and iodomethane. This study generated quantitative, high-content data that were indicative of aberrant changes in biochemical (lactate dehydrogenase), barrier (dextran permeability), functional (ciliary beating), and molecular (imaging for various markers) phenotypes of the small airway epithelium due to inhalational exposures. This study is significant because it established an in vitro model of human small airway on a chip that can be used in medium/high-throughput studies of subacute effects of inhalation toxicants.
MeSH term(s)	Administration, Inhalation ; Aerosols ; Animals ; Endothelial Cells ; Humans ; Inhalation Exposure/adverse effects ; Inhalation Exposure/analysis ; Lab-On-A-Chip Devices
Chemical Substances	Aerosols
Language	English
Publishing date	2022-03-31
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfac036
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