Protecting More Than Animals

Goldberg, Alan M.; Thomas, Hartung

doi:10.1038/scientificamerican0106-84

Cited by 23 publications

(3 citation statements)

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“…It is obvious that the strategy presented here has to be validated in other substances but it does bring research a further step forward toward predicting toxic effects in vivo . The development of novel computational technologies and their application to the modeling of human and animal physiology signify that in silico tests can, in fact, reduce and, in specific cases, even replace experimental tests on animals (Goldberg and Hartung, 2006). …”

Section: Discussionmentioning

confidence: 99%

A Multi-Scale Modeling Framework for Individualized, Spatiotemporal Prediction of Drug Effects and Toxicological Risk

Ochoa¹,

Bucher²,

Pery³

et al. 2013

Front. Pharmacol.

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In this study, we focus on a novel multi-scale modeling approach for spatiotemporal prediction of the distribution of substances and resulting hepatotoxicity by combining cellular models, a 2D liver model, and whole body model. As a case study, we focused on predicting human hepatotoxicity upon treatment with acetaminophen based on in vitro toxicity data and potential inter-individual variability in gene expression and enzyme activities. By aggregating mechanistic, genome-based in silico cells to a novel 2D liver model and eventually to a whole body model, we predicted pharmacokinetic properties, metabolism, and the onset of hepatotoxicity in an in silico patient. Depending on the concentration of acetaminophen in the liver and the accumulation of toxic metabolites, cell integrity in the liver as a function of space and time as well as changes in the elimination rate of substances were estimated. We show that the variations in elimination rates also influence the distribution of acetaminophen and its metabolites in the whole body. Our results are in agreement with experimental results. What is more, the integrated model also predicted variations in drug toxicity depending on alterations of metabolic enzyme activities. Variations in enzyme activity, in turn, reflect genetic characteristics or diseases of individuals. In conclusion, this framework presents an important basis for efficiently integrating inter-individual variability data into models, paving the way for personalized or stratified predictions of drug toxicity and efficacy.

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Section: Discussionmentioning

confidence: 99%

A Multi-Scale Modeling Framework for Individualized, Spatiotemporal Prediction of Drug Effects and Toxicological Risk

Ochoa¹,

Bucher²,

Pery³

et al. 2013

Front. Pharmacol.

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“…In vitro tests are currently used in traditional toxicity testing and indicate the success of developing and using in vitro assays (Goldberg & Hartung, 2006). In vitro tests include the 3T3 neural red uptake phototoxicity assay (Spielman & Liebsch, 2001), cytotoxicity assays (O’Brien & Haskins, 2007), skin-corrosivity tests, and assays measuring vascular injury using human endothelial cells (Schleger et al, 2004).…”

Section: Tools and Technologiesmentioning

confidence: 99%

Toxicity Testing in the 21st Century: A Vision and a Strategy

Krewski

Acosta

Andersen

et al. 2010

Journal of Toxicology and Environmental Health, Part B

790

475

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With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

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“…Finally, inconsistent with the above-mentioned directives, the Registration, Evaluation and Authorization of Chemicals (REACH) legislation [18] will soon be implemented, resulting in an increase in the number of animal experiments to be carried out for risk assessment of nearly 30,000 chemicals already marketed in the EU. All in all, this has resulted in a huge stimulus to develop new in vitro techniques to replace animal testing for both the scientific and industrial community [19] .…”

Section: Current Animal Models and The Need For Animal Alternativesmentioning

confidence: 99%

In vitro Irritation Models and Immune Reactions

Gibbs

2009

Skin Pharmacol Physiol

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Irritant contact dermatitis is the result of an innate inflammatory response of the skin to direct injury. It is caused by a single, repeated or continued application of an irritant, with the source most often being a chemical. Therefore, European regulations require strict screening of all ingredients in consumer products. Until recently, identifying a potential irritant has completely relied on animal testing (for example, Draize test). Besides the ethical problems, both the 7th Amendment to the Cosmetics Directive and Registration, Evaluation and Authorization of Chemicals legislation have stimulated the development of alternative tests for the assessment of potential toxicological effects of substances. This review is aimed at describing current in vitro skin irritation models and the biomarkers used to assess the degree of irritancy of a potential irritant. Four models are described: keratinocyte and fibroblast cultures grown under submerged culture conditions, epidermal equivalents, skin equivalents and freshly isolated skin. Biomarkers such as IL-1α, IL-6, IL-8, PGE2, SKALP, HSP70 and kinases are described along with changes in metabolic activity (MTT assay) and cytosolic leakage (lactate dehydrogenase assay). Noticeable is the limited number of genomic and proteomic studies. Such studies have the potential to identify novel biomarkers and to elucidate the mechanism of irritant contact dermatitis.

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Protecting More Than Animals

Cited by 23 publications

References 0 publications

A Multi-Scale Modeling Framework for Individualized, Spatiotemporal Prediction of Drug Effects and Toxicological Risk

A Multi-Scale Modeling Framework for Individualized, Spatiotemporal Prediction of Drug Effects and Toxicological Risk

Toxicity Testing in the 21st Century: A Vision and a Strategy

In vitro Irritation Models and Immune Reactions

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