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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Identification of the potential hazards of chemicals has traditionally relied on studies in laboratory animals where changes in clinical pathology and histopathology compared to untreated controls defined an adverse effect. In the past decades, increased consistency in the definition of adversity with chemically-induced effects in laboratory animals, as well as in the assessment of human relevance has been reached. More recently, a paradigm shift in toxicity testing has been proposed, mainly driven by concerns over animal welfare but also thanks to the development of new methods. Currently, in vitro approaches, toxicogenomic technologies and computational tools, are available to provide mechanistic insight in toxicological Mode of Action (MOA) of the adverse effects observed in laboratory animals. The vision described as Tox21c (Toxicity Testing in the 21st century) aims at predicting in vivo toxicity using a bottom-up-approach, starting with understanding of MOA based on in vitro data to ultimately predict adverse effects in humans. At present, a practical application of the Tox21c vision is still far away. While moving towards toxicity prediction based on in vitro data, a stepwise reduction of in vivo testing is foreseen by combining in vitro with in vivo tests. Furthermore, newly developed methods will also be increasingly applied, in conjunction with established methods in order to gain trust in these new methods. This confidence is based on a critical scientific prerequisite: the establishment of a causal link between data obtained with new technologies and adverse effects manifested in repeated-dose in vivo toxicity studies. It is proposed to apply the principles described in the WHO/IPCS framework of MOA to obtain this link. Finally, an international database of known MOAs obtained in laboratory animals using data-rich chemicals will facilitate regulatory acceptance and could further help in the validation of the toxicity pathway and adverse outcome pathway concepts.
    Critical Reviews in Toxicology 01/2015; 45(2):1-12. DOI:10.3109/10408444.2014.986054 · 6.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Biological monitoring of vanadium (V) and arsenic (As) for residents living near a big petrochemical complex has not been previously studied. This study aims to investigate distance-to-source trends in urinary levels and dispersion-estimated concentrations of V and As in areas surrounding a petrochemical complex in central Taiwan. Our study subjects were 1424 residents living in the townships up to ~40 km from the petrochemical complex, and categorized as near (Zone A), further (Zone B) and furthest (Zone C) from the complex. Urinary and ambient V and As levels were analyzed by inductively coupled plasma mass spectrometry. Two-stage dispersion model was used to estimate V and As concentrations at each study subject's address. Multiple linear regression models were used to study the effects of distance-to-source and estimated air concentrations of V and As on the urinary V and As levels of study subjects. Area-wide levels of both V and As showed a high-to-low trend in urinary levels (μg/g-creatinine) from Zone A (V with 2.86±2.30 and As with 104.6±147.9) to Zone C (V with 0.73±0.72 and As with 73.8±90.8). For study subjects, urinary V and As levels were decreased by 0.09 and 1.17 μg/g-creatinine, respectively, with 1 km away from the emission source of the petrochemical complex, and urinary V levels were significantly elevated by 0.38 μg/g-creatinine with a 1 ng/m(3) increase in estimated ambient V concentrations at their addresses. Our study concludes a distance-to-source gradient in V and As exposures exists for residents living near a petrochemical complex with oil refineries and coal-fired power plants and two-stage dispersion model can predict such a trend for V when inhalation is the major exposure route, but not for As that exposure may be from multiple sources and exposure routes.Journal of Exposure Science and Environmental Epidemiology advance online publication, 18 February 2015; doi:10.1038/jes.2015.2.
    Journal of Exposure Science and Environmental Epidemiology 02/2015; DOI:10.1038/jes.2015.2 · 3.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo responses from in vitro and in silico data, and to define the goals for the future. Presentations and discussions were held on priority concerns such as predicting and modeling of metabolism, cell growth and differentiation, effects on sensitive subpopulations, and integrating data into risk assessment. Emerging trends in technologies such as stem cell-derived human cells, 3D organotypic culture models, mathematical modeling of cellular processes and morphogenesis, adverse outcome pathway development, and high-content imaging of in vivo systems were discussed. Although advances in moving towards an in vitro/in silico based risk assessment paradigm were apparent, knowledge gaps in these areas and limitations of technologies were identified. Specific recommendations were made for future directions and research needs in the areas of hepatotoxicity, cancer prediction, developmental toxicity, and regulatory toxicology. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail:


Available from
Feb 9, 2015