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


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,
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    • "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.
    Environmental Health Perspectives 10/2015; DOI:10.1289/ehp.1510183 · 7.98 Impact Factor
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    • "In this way, REACH is expected to play a major role in driving the scientific validation and regulatory acceptance of alternative testing methods (Hartung, 2009, 2010). Many components of the WHO/IPCS IRA Framework (2001) can already be found in the REACH RA approach (Vermeire, 2009). "
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    ABSTRACT: The vision of a sustainable and safe use of chemicals to protect human health, preserve the environment and main- tain the ecosystem requires innovative and more holistic approaches to risk assessment (RA) in order to better in- form decision making. Integrated risk assessment (IRA) has been proposed as a solution to current scientific, societal and policy needs. It is defined as the mutual exploitation of environmental risk assessment (ERA) for human health risk assessment (HHRA) and vice versa in order to coherently and more efficiently characterize an overall risk to humans and the environment for better informing the risk analysis process. Extrapolating between species which are relevant for HHRA and ERA requires a detailed understanding of pathways of toxicity/modes of action (MoA) for the various toxicological endpoints. Significant scientific advances, changes in chemical legislation, and increas- ing environmental consciousness have created a favourable scientific and regulatory environment to develop and promote the concept and vision of IRA. An initial proof of concept is needed to foster the incorporation of IRA approaches into different chemical sectorial regulations and demonstrate their reliability for regulatory purposes. More familiarity and confidence with IRA will ultimately contribute to an overall reduction in in vivo toxicity testing requirements. However, significant progress will only be made if long-term support for MoA-related research is secured. In the short term, further exchange and harmonization of RA terminology, models and methodologies across chemical categories and regulatory agencies will support these efforts. Since societal values, public perceptions and cultural factors are of increasing importance for the acceptance of risk analysis and successful implementation of risk mitigation measures, the integration of socio-economic analysis and socio-behavioural considerations into the risk analysis process may help to produce a more effective risk evaluation and consideration of the risks and benefits associated with the use of chemicals.
    Science of The Total Environment 04/2015; · 4.10 Impact Factor
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    • "sub-chronic, reproductive toxicity). However, as previously mentioned, these guidelines are very resource intensive in terms of animals, time and overall cost (Rovida and Hartung 2009; Tsuji and Crofton 2012) and have been used only for a very limited number of pesticides and industrial chemicals. This highlights the pressing need for alternative methodologies that can more rapidly and cost-effectively screen large numbers of chemicals for their potential to cause DNT or investigate mechanisms to provide information on human relevance (Crofton et al. 2012). "
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    ABSTRACT: A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.
    Archive für Toxikologie 01/2015; 89(2). DOI:10.1007/s00204-015-1464-2 · 5.98 Impact Factor
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