Article

The Vision of Toxicity Testing in the 21st Century: Moving from Discussion to Action

The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicological Sciences (Impact Factor: 4.48). 09/2010; 117(1):17-24. DOI: 10.1093/toxsci/kfq188
Source: PubMed

ABSTRACT Over the past year, a series on commentaries have appeared in the Toxicological Sciences Forum Series related to the 2007 National Research Council (NRC) publication, Toxicity Testing in the 21st Century: A Vision and A Strategy. The first article in the series provided an overview of the vision and was accompanied by an editorial by the three editors
of Toxicological Sciences. During the past year, eight invited commentaries from the academic, industrial, and regulatory sectors have provided diverse
perspectives on the vision, noted challenges to its implementation, and highlighted aspects of toxicity testing that were
not addressed in the original NRC report. Here, we offer a summary of the main points raised by the commentators in tabular
form, identify a number of common themes, and finish the series by providing our perspective on several key issues in charting
the path forward to move from discussion to action.

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Available from: Melvin Andersen, Feb 09, 2015
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    • "In the future , toxicity testing is likely to rely increasingly on in vitro test results for conducting risk and safety assessments ( Andersen and Krewski 2010 ; NRC 2007 ) . Interpretation of these tests will rely on understanding of toxicity pathways and the expected shapes of dose response curves arising for pathway perturbation by toxic chemicals ( Rossini and Hartung 2012 ) . "
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    ABSTRACT: Background: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations. Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data. Methods: Here we have examined dose–response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures. Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays. Citation: Zhang Q, Bhattacharya S, Conolly RB, Clewell HJ III, Kaminski NE, Andersen ME. 2014. Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses. Environ Health Perspect 122:1261–1270; http://dx.doi.org/10.1289/ehp.1408244
    Environmental Health Perspectives 08/2014; 122(12). DOI:10.1289/ehp.1408244 · 7.98 Impact Factor
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    • "Regarding the extrapolation to the in vivo situation, PBPK modeling proves to be a powerful tool; however, it cannot be widely applied, at least in the short term, because a lot of compound specific data on ADME are needed. Therefore, while it should be applied if available, and developed in specific cases that need a better hazard characterization, it is envisaged that in a not so distant future this approach will become easier and quicker (Andersen and Krewski, 2010; Judson et al., 2011; Meek et al., 2013; Tan et al., 2011; Wetmore et al., 2012a). It is certainly recognized that exposure considerations may drive the request for CRA or may indicate that there is no need to conduct a CRA, at least for certain compounds (EPA, 2006). "
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    ABSTRACT: The most relevant issues in cumulative risk assessment (CRA) are the identification of cumulative assessment groups and the hypothesis of dose-additivity, at relevant human exposures. In vitro methods can provide meaningful data to help solving those issues. Integration of in vitro studies, selected in vivo studies, and PBPK modeling for teratogenic conazoles confirmed that in vitro studies may give results in a cheaper and faster fashion. In particular, in vitro studies with explanted rat embryos provided support for dose-additivity for conazoles causing cranio-facial malformations. Although this could not be immediately quantitatively transferred to the in vivo situation, they provided indication on how to conduct targeted in vivo studies. In addition, by means of PBPK modeling, it was possible to estimate the dose in humans associated with a defined teratogenic risk and also to conclude that for cumulative risk assessment only exposures occurring within a short period of time (a day or less) need to be cumulated. Although PBPK modeling cannot be widely applied, at least in the short term, it should be considered if available. It is recommended to incorporate in vitro testing and PBPK modeling, whenever available and feasible in the process of risk assessment, particularly of CRA.
    Food and Chemical Toxicology 07/2014; 79. DOI:10.1016/j.fct.2014.07.006 · 2.90 Impact Factor
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    • "This is in line with a ‘proposed shift from primarily in vivo animal experimentation to in vitro assays and computational modeling for toxicity assessment,’ as suggested by the lead scientists of US national research agencies (Collins et al. 2008). It also follows the ‘vision for a new toxicology of the twenty-first century’ as promoted by the National Research Council (Andersen and Krewski 2010; NRC 2007). A key assumption for this vision is that it will be possible to define pathways of toxicity, i.e., a drug mode of action (MoA), linking molecular initiating events to a final adverse outcome. "
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    ABSTRACT: The superordinate principles governing the transcriptome response of differentiating cells exposed to drugs are still unclear. Often, it is assumed that toxicogenomics data reflect the immediate mode of action (MoA) of drugs. Alternatively, transcriptome changes could describe altered differentiation states as indirect consequence of drug exposure. We used here the developmental toxicants valproate and trichostatin A to address this question. Neurally differentiating human embryonic stem cells were treated for 6 days. Histone acetylation (primary MoA) increased quickly and returned to baseline after 48 h. Histone H3 lysine methylation at the promoter of the neurodevelopmental regulators PAX6 or OTX2 was increasingly altered over time. Methylation changes remained persistent and correlated with neurodevelopmental defects and with effects on PAX6 gene expression, also when the drug was washed out after 3–4 days. We hypothesized that drug exposures altering only acetylation would lead to reversible transcriptome changes (indicating MoA), and challenges that altered methylation would lead to irreversible developmental disturbances. Data from pulse-chase experiments corroborated this assumption. Short drug treatment triggered reversible transcriptome changes; longer exposure disrupted neurodevelopment. The disturbed differentiation was reflected by an altered transcriptome pattern, and the observed changes were similar when the drug was washed out during the last 48 h. We conclude that transcriptome data after prolonged chemical stress of differentiating cells mainly reflect the altered developmental stage of the model system and not the drug MoA. We suggest that brief exposures, followed by immediate analysis, are more suitable for information on immediate drug responses and the toxicity MoA. Electronic supplementary material The online version of this article (doi:10.1007/s00204-014-1279-6) contains supplementary material, which is available to authorized users.
    Archive für Toxikologie 06/2014; 88(7). DOI:10.1007/s00204-014-1279-6 · 5.08 Impact Factor
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