Article

Toxicology for the Twenty-First Century

Department of Environmental Health Sciences at the Johns Hopkins University Bloomberg School of Public Health, USA.
Nature (Impact Factor: 41.46). 08/2009; 460(7252):208-12. DOI: 10.1038/460208a
Source: PubMed

ABSTRACT

The testing of substances for adverse effects on humans and the
environment needs a radical overhaul if we are to meet the challenges of
ensuring health and safety.

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Available from: Thomas Hartung
    • "This, in turn, further emphasizes the need for a careful characterization of nanomaterials as well as standardized and validated procedures for toxicity testing, both in vitro and in vivo, to enable the comparison of results across different studies. However, to keep up with the rapid pace of development of new classes of nanomaterials of ever increasing sophistication, it is also clear that new approaches are needed in nanotoxicology; indeed, it may be argued that this is true for (regulatory) toxicology in general (Hartung, 2009). Understanding the potential health and environmental risks associated with exposure to chemicals and nanomaterials requires accurate and predictive risk assessment approaches. "
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    ABSTRACT: Engineered nanomaterials are being developed for a variety of technological applications. However, the increasing use of nanomaterials in society has led to concerns about their potential adverse effects on human health and the environment. During the first decade of nanotoxicological research, the realization has emerged that effective risk assessment of the multitudes of new nanomaterials would benefit from a comprehensive understanding of their toxicological mechanisms, which is difficult to achieve with traditional, low-throughput, single end-point oriented approaches. Therefore, systems biology approaches are being progressively applied within the nano(eco)toxicological sciences. This novel paradigm implies that the study of biological systems should be integrative resulting in quantitative and predictive models of nanomaterial behaviour in a biological system. To this end, global 'omics' approaches with which to assess changes in genes, proteins, metabolites, etc are deployed allowing for computational modelling of the biological effects of nanomaterials. Here, we highlight omics and systems biology studies in nanotoxicology, aiming towards the implementation of a systems nanotoxicology and mechanism-based risk assessment of nanomaterials.
    No preview · Article · Dec 2015 · Toxicology and Applied Pharmacology
    • "Understanding the impact of endocrine bioactive chemicals on human health and the environment is a high priority for U.S. and international agencies. The large number of untested chemicals in commerce (>80,000) necessitates the use of high-throughput screening (HTS) programs such as the U.S. Environmental Protection Agency (EPA) ToxCast initiative and the Tox21 U.S. federal partnership to quickly identify potential endocrine disruptors and help characterize any hazards they may pose (Dix et al. 2007; Judson et al. 2010; Kavlock et al. 2012; Tice et al. 2013; U.S.EPA 2011a, 2012)Further, there is growing societal pressure to avoid animal testing and develop alternative approaches that replace, reduce, or refine the use of animals in toxicity testing (Hartung 2009; ICCVAM, 2000 ). "
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    ABSTRACT: Background: Novel in vitro methods are being developed to identify chemicals that may interfere with estrogen receptor (ER) signaling, but results are difficult to put into biological context due to the reliance on reference chemicals established using results from other in vitro assays and the lack of high-quality in vivo reference data. The OECD-validated rodent uterotrophic bioassay is considered the "gold standard" for identifying potential ER agonists. Objectives: We performed a comprehensive literature review to identify and evaluate data from uterotrophic studies and to analyze study variability. Methods: We reviewed 670 articles with results from 2615 uterotrophic bioassays using 235 unique chemicals. Study descriptors, such as species/strain, route of administration, dosing regimen, lowest effect level, and test outcome, were captured in a database of uterotrophic results. Studies were assessed for adherence to six criteria based on uterotrophic regulatory test guidelines. Studies meeting all criteria (458 bioassays on 118 unique chemicals) were considered guideline-like (GL) and subsequently analyzed. Results: The immature rat model was used for 76% of the GL studies. Active outcomes were more prevalent across rat models (74% active) compared to mouse models (36% active). Of the 70 chemicals with at least two GL studies, 18 (26%) had discordant outcomes and were classified as both active and inactive. Many discordant results were attributable to differences in study design (e.g. injection vs. oral dosing). Conclusions: This uterotrophic database provides a valuable resource for understanding in vivo outcome variability and for evaluating performance of in vitro assays that measure estrogenic activity.
    No preview · Article · Oct 2015 · Environmental Health Perspectives
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    • "Traditional animal models used to evaluate hepatotoxicity are expensive and time consuming (Hartung 2009). In vitro assays are used as an alternative to better understand hepatotoxicity (Adler et al. 2011; Zhu et al. 2014a). "
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    ABSTRACT: Background: Hepatotoxicity accounts for a substantial number of drugs withdrawn from the market. Traditional animal models used to detect hepatotoxicity are expensive and time consuming. Alternative in vitro methods, especially cell-based High-Throughput Screening (HTS) studies, have provided the research community with a large amount of data from toxicity assays. Among the various assays used to screen potential toxicants is the Antioxidant Response Element beta lactamase reporter gene assay (ARE-bla), which identifies chemicals that have the potential to induce oxidative stress and was used to test > 10,000 compounds from the Tox21 program. Objective: The ARE-bla computational model and HTS data from a big data source (PubChem) was used to profile environmental and pharmaceutical compounds with hepatotoxic data. Methods: Quantitative Structure-Activity Relationship models were developed based on ARE-bla data. The models predicted the potential oxidative stress response for known liver toxicants when there was no ARE-bla data available. Liver toxicants were used as probe compounds to search PubChem Bioassay and generate a response profile, which contained thousands of bioassays (> 10 million data points). By ranking the In Vitro-In Vivo Correlations (IVIVC), the most relevant bioassay(s) related to hepatotoxicity were identified. Results: The liver toxicants profile contained the ARE-bla and relevant PubChem assays. Potential toxicophores for well-known toxicants were created by identifying chemical features that existed only in compounds with high IVIVC. Conclusion: Profiling the chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources.
    Full-text · Article · Sep 2015 · Environmental Health Perspectives
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