Identification and Characterization of Adverse Effects in 21st Century Toxicology

Sanofi US, Bridgewater, New Jersey 08807, USA.
Toxicological Sciences (Impact Factor: 3.85). 01/2012; 126(2):291-7. DOI: 10.1093/toxsci/kfr350
Source: PubMed


The practice of toxicology is changing rapidly, as demonstrated by the response to the 2007 NRC report on "Toxicity Testing in the 21(st) Century." New assays are being developed to replace animal testing; yet the use of data from these assays in decision making is not clear. A Health and Environmental Sciences Institute committee held a May 2011 workshop to discuss approaches to identifying adverse effects in the context of the NRC report. Scientists from industry, government, academia, and NGOs discussed two case studies and explored how information from new, high data content assays developed for screening can be used to differentiate adverse effects from adaptive responses. The terms "adverse effect" and "adaptive response" were defined, as well as two new terms, the relevant pathways of toxicological concern (RPTCs) and relevant responses for regulation (RRRs). RPTCs are biochemical pathways associated with adverse events and need to be elucidated before they are used in regulatory decision making. RRRs are endpoints that are the basis for risk assessment and may or may not be at the level of pathways. Workshop participants discussed the criteria for determining whether, at the RPTC level, an effect is potentially adverse or potentially indicative of adaptability, and how the use of prototypical, data-rich compounds could lead to a greater understanding of RPTCs and their use as RRRs. Also discussed was the use of RPTCs in a weight-of-evidence approach to risk assessment. Inclusion of data at this level could decrease uncertainty in risk assessments but will require the use of detailed dosimetry and consideration of exposure context and the time and dose continuum to yield scientifically based decisions. The results of this project point to the need for an extensive effort to characterize RPTCs and their use in risk assessment to make the vision of the 2007 NRC report a reality.

Download full-text


Available from: Douglas C Wolf,
37 Reads
    • "An adaptive response is a homeostatic process that is activated by the system to survive in a new environment without impairment of function (Keller et al. 2012). We believe that our analysis of trajectories and tipping points brings us a step closer to realizing the vision of 21 st Century Toxicology by providing a framework to identify where " transition points occur between adaptive changes and adverse effects " (Keller et al. 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: High-content imaging (HCI) allows simultaneous measurement of multiple cellular phenotypic changes and is an important tool for evaluating the biological activity of chemicals. Objectives: Our goal was to analyze dynamic cellular changes using HCI to identify the "tipping point" at which the cells did not show recovery towards a normal phenotypic state. Methods: The effects of 967 chemicals were evaluated using HCI in HepG2 cells over a 72 h exposure period to concentrations ranging from 0.4 to 200 µM. The HCI endpoints included p53, c-Jun, phospho-Histone H2A.x, alpha tubulin, phospho-Histone H3, alpha tubulin, mitochondrial membrane potential, mitochondrial mass, cell cycle arrest, nuclear size and cell number. A computational model was developed to interpret HCI responses as cell-state trajectories. Results: Analysis of cell-state trajectories showed 336 chemicals produced tipping points, whereas HepG2 cells were resilient to the effects of 334 chemicals up to the highest concentration (200 µM) and duration (72 h) tested. Tipping points were identified as concentration-dependent transitions in system recovery and the corresponding critical concentrations were generally between 5 and 15 times (25th and 75th percentiles, respectively) lower than the concentration that produced any significant effect on HepG2 cells. The remaining 297 chemicals require more data before they can be placed in either of the former categories. Conclusions: These findings show the utility of HCI data for reconstructing cell state trajectories, and provide insight into adaptation and resilience of in vitro cellular systems based on tipping points. Cellular tipping points could be used to define a point of departure for risk-based prioritization of environmental chemicals.
    Environmental Health Perspectives 10/2015; DOI:10.1289/ehp.1409029 · 7.98 Impact Factor
  • Source
    • "One important task in the context of novel methods of characterizing effects of chemicals (see section "New challenges and novel approaches") will be to develop tools to define called pathways of toxicity or adverse outcome pathways (Burden et al. 2015). Furthermore, the development of criteria to distinguish between adaptive responses and adverse changes (Keller et al. 2012) will become extremely important . The background for the latter are changes observed in 'omics' studies where harmless influences, e.g. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The paper describes the importance of toxicology as a discipline, its past achievements, current scientific challenges, and future development. Toxicological expertise is instrumental in the reduction of human health risks arising from chemicals and drugs. Toxicological assessment is needed to evaluate evidence and arguments, whether or not there is a scientific base for concern. The immense success already achieved by toxicological work is exemplified by reduced pollution of air, soil, water, and safer working places. Predominantly predictive toxicological testing is derived from the findings to assess risks to humans and the environment. Assessment of the adversity of molecular effects (including epigenetic effects), the effects of mixtures, and integration of exposure and biokinetics into in vitro testing are emerging challenges for toxicology. Toxicology is a translational science with its base in fundamental science. Academic institutions play an essential part by providing scientific innovation and education of young scientists.
    Archives of Toxicology 08/2015; 89(10). DOI:10.1007/s00204-015-1577-7 · 5.98 Impact Factor
  • Source
    • "Toxicology and toxicity testing are in the midst of a transformation . A series of expert panels, workshops, and strategic reviews have proposed a transition from an apical endpoint-based evaluation of chemical and drug safety to a focus on identifying key molecular initiating events and pathway perturbations leading to adverse effects (Woodruff et al., 2008; Firestone et al., 2010; Berg et al., 2011; Silbergeld et al., 2011; Keller et al., 2012). The proposed transition is being driven by the need to reduce the cost and time associated with evaluating the safety of drugs and chemicals, to allow broader coverage of compounds , mixtures, endpoints and life-stages in the evaluation, and to provide a more robust basis for risk assessment through the identification and application of mechanistic data (National Research Council. "
    [Show abstract] [Hide abstract]
    ABSTRACT: New approaches to toxicity testing have incorporated high-throughput screening across a broad-range of in vitro assays to identify potential key events in response to chemical or drug treatment. To date, these approaches have primarily utilized repurposed drug discovery assays. In this study, we describe an approach that combines in vitro screening with genetic approaches for the experimental identification of genes and pathways involved in chemical or drug toxicity. Primary embryonic fibroblasts isolated from 32 genetically-characterized inbred mouse strains were treated in concentration-response format with 65 compounds, including pharmaceutical drugs, environmental chemicals, and compounds with known modes-of-action. Integrated cellular responses were measured at 24 and 72 h using high-content imaging and included cell loss, membrane permeability, mitochondrial function, and apoptosis. Genetic association analysis of cross-strain differences in the cellular responses resulted in a collection of candidate loci potentially underlying the variable strain response to each chemical. As a demonstration of the approach, one candidate gene involved in rotenone sensitivity, Cybb, was experimentally validated in vitro and in vivo. Pathway analysis on the combined list of candidate loci across all chemicals identified a number of over-connected nodes that may serve as core regulatory points in toxicity pathways.
    Frontiers in Genetics 08/2014; 5:272. DOI:10.3389/fgene.2014.00272
Show more