FutureTox II: In vitro Data and In Silico Models for Predictive Toxicology

Knudsen, Thomas B.; Keller, Douglas A.; Sander, Miriam; Carney, Edward W.; Doerrer, Nancy G.; Eaton, David L.; Fitzpatrick, Suzanne; Hastings, Kenneth L.; Mendrick, Donna L.; Tice, Raymond R.; Watkins, Paul B.; Whelan, Maurice

doi:10.1093/toxsci/kfu234

Cited by 117 publications

(74 citation statements)

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“…Therefore, the testing of neurotoxicity on the basis of human cells is an emerging research field in safety sciences. The generation of the relevant target cell populations from human pluripotent stem cells has aroused great hopes in biomedical research and the safety sciences [4][5][6] that model systems will be established to identify neurotoxicity hazards and to devise countermeasures.…”

Section: Introductionmentioning

confidence: 99%

Stem Cell-Derived Immature Human Dorsal Root Ganglia Neurons to Identify Peripheral Neurotoxicants

Hoelting

Klima

Karreman

et al. 2016

Stem Cells Translational Medicine

116

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Safety sciences and the identification of chemical hazards have been seen as one of the most immediate practical applications of human pluripotent stem cell technology. Protocols for the generation of many desirable human cell types have been developed, but optimization of neuronal models for toxicological use has been astonishingly slow, and the wide, clinically important field of peripheral neurotoxicity is still largely unexplored. A two-step protocol to generate large lots of identical peripheral human neuronal precursors was characterized and adapted to the measurement of peripheral neurotoxicity. High content imaging allowed an unbiased assessment of cell morphology and viability. The computational quantification of neurite growth as a functional parameter highly sensitive to disturbances by toxicants was used as an endpoint reflecting specific neurotoxicity. The differentiation of cells toward dorsal root ganglia neurons was tracked in relation to a large background data set based on gene expression microarrays. On this basis, a peripheral neurotoxicity (PeriTox) test was developed as a first toxicological assay that harnesses the potential of human pluripotent stem cells to generate cell types/tissues that are not otherwise available for the prediction of human systemic organ toxicity. Testing of more than 30 chemicals showed that human neurotoxicants and neurite growth enhancers were correctly identified. Various classes of chemotherapeutic agents causing human peripheral neuropathies were identified, and they were missed when tested on human central neurons. The PeriTox test we established shows the potential of human stem cells for clinically relevant safety testing of drugs in use and of new emerging candidates. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:476-487 SIGNIFICANCEThe generation of human cells from pluripotent stem cells has aroused great hopes in biomedical research and safety sciences. Neurotoxicity testing is a particularly important application for stem cell-derived somatic cells, as human neurons are hardly available otherwise. Also, peripheral neurotoxicity has become of major concern in drug development for chemotherapy. The first neurotoxicity test method was established based on human pluripotent stem cell-derived peripheral neurons. The strategies exemplified in the present study of reproducible cell generation, cell function-based test system establishment, and assay validation provide the basis for a drug safety assessment on cells not available otherwise.

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Section: Introductionmentioning

confidence: 99%

Stem Cell-Derived Immature Human Dorsal Root Ganglia Neurons to Identify Peripheral Neurotoxicants

Hoelting

Klima

Karreman

et al. 2016

Stem Cells Translational Medicine

116

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“…Phase I of ToxCast tested predominantly food-use pesticides that already had a wealth of animal toxicity data from regulatory guideline studies. The results were used to create computational models to predict endpoints such as developmental and reproductive toxicity (Martin et al, 2011;Kleinstreuer et al, 2011;Knudsen, 2012). Phase II and Phase III vastly expanded the chemical libraries to cover many untested compounds, providing the opportunity to validate the predictive signatures and prioritize environmental chemicals for potential hazards (http:// epa.gov/ncct/toxcast/data.html).…”

Section: Introductionmentioning

confidence: 99%

Integrated testing strategies (ITS) for safety assessment

Rovida

2015

ALTEX

147

128

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SummaryIntegrated testing strategies (ITS), as opposed to a single definitive test or fixed batteries of tests, are expected to efficiently combine different information sources in a quantifiable fashion to satisfy an information need, in this case for regulatory safety assessments. With increasing awareness of the limitations of each individual tool and the development of highly targeted tests and predictions, the need for combining pieces of evidence increases. The discussions that took place during this workshop, which brought together a group of experts coming from different related areas, illustrate the current state of the art of ITS, as well as promising developments and identifiable challenges. The case of skin sensitization was taken as an example to understand how possible ITS can be constructed, optimized and validated. This will require embracing and developing new concepts such as adverse outcome pathways (AOP), advanced statistical learning algorithms and machine learning, mechanistic validation and "Good ITS Practices".Keywords: in vitro methods, testing strategy, Tox21c, skin sensitization, computational toxicology this is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is appropriately cited. *A report of t 4 -the transatlantic think tank for toxicology, a collaboration of the toxicologically oriented chairs in Baltimore, Konstanz and Utrecht sponsored by the Doerenkamp-Zbinden Foundation; participants do not represent their institutions and do not necessarily endorse all recommendations made.

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“…This is due in large part to traditional methods of ecotoxicological risk assessment that are time consuming and expensive. Accordingly, high-throughput screening (HTS) methods have been a promising approach for rapid risk assessment of new compounds, including nanomaterials (Nel et al, 2013;Knudsen et al, 2015). These approaches attempt to predict and explain responses of whole organisms and ecological systems by measuring responses at lower levels of biological organization, typically using in vitro assays to identify high-risk compounds and prioritize in vivo tests (Judson et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Photosynthetic efficiency predicts toxic effects of metal nanomaterials in phytoplankton

et al. 2017

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a b s t r a c tHigh Throughput Screening (HTS) using in vitro assessments at the subcellular level has great promise for screening new chemicals and emerging contaminants to identify high-risk candidates, but their linkage to ecological impacts has seldom been evaluated. We tested whether a battery of subcellular HTS tests could be used to accurately predict population-level effects of engineered metal nanoparticles (ENPs) on marine phytoplankton, important primary producers that support oceanic food webs. To overcome wellknown difficulties of estimating ecologically meaningful toxicity parameters, we used novel Dynamic Energy Budget and Toxicodynamic (DEBtox) modeling techniques to evaluate impacts of ENPs on population growth rates. Our results show that population growth was negatively impacted by all four ENPs tested, but the HTS tests assessing many cell/physiological functions lacked predictive power at the population level. However, declining photosynthetic efficiency, a traditional physiological endpoint for photoautotrophs, was a good predictor of population level effects in phytoplankton. DEBtox techniques provided robust estimates of EC 10 for population growth rates in exponentially growing batch cultures of phytoplankton, and should be widely useful for ecotoxicological testing. Adoption of HTS approaches for ecotoxicological assessment should carefully evaluate the predictive power of specific assays to minimize the risk that effects at higher levels of biological organization may go undetected.

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FutureTox II: In vitro Data and In Silico Models for Predictive Toxicology

Cited by 117 publications

References 50 publications

Stem Cell-Derived Immature Human Dorsal Root Ganglia Neurons to Identify Peripheral Neurotoxicants

Stem Cell-Derived Immature Human Dorsal Root Ganglia Neurons to Identify Peripheral Neurotoxicants

Integrated testing strategies (ITS) for safety assessment

Photosynthetic efficiency predicts toxic effects of metal nanomaterials in phytoplankton

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