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, Oct 13, 2015
34 Reads
  • 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
  • Source
    • "Recently, there has been an increased focus in systems toxicology on systems-oriented methodologies that emphasize the understanding on the biological impact of chemical exposures with increased mechanistic granularity [1,2]. In particular, a recent report by the US National Research Council Committee on Toxicity Testing and Assessment of Environmental Agents advocates for a shift away from toxicological assessment at the level of apical endpoints towards the understanding of the effects of an exposure on toxicity pathways [3]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background In the past years, significant progress has been made to develop and use experimental settings for extensive data collection on tobacco smoke exposure and tobacco smoke exposure-associated diseases. Due to the growing number of such data, there is a need for domain-specific standard ontologies to facilitate the integration of tobacco exposure data. Results The CSEO (version 1.0) is composed of 20091 concepts. The ontology in its current form is able to capture a wide range of cigarette smoke exposure concepts within the knowledge domain of exposure science with a reasonable sensitivity and specificity. Moreover, it showed a promising performance when used to answer domain expert questions. The CSEO complies with standard upper-level ontologies and is freely accessible to the scientific community through a dedicated wiki at Conclusions The CSEO has potential to become a widely used standard within the academic and industrial community. Mainly because of the emerging need of systems toxicology to controlled vocabularies and also the lack of suitable ontologies for this domain, the CSEO prepares the ground for integrative systems-based research in the exposure science.
    Journal of Biomedical Semantics 07/2014; 5(1):31. DOI:10.1186/2041-1480-5-31 · 2.26 Impact Factor
  • Source
    • "European legislation (e.g., Directive 2012/69/EU) and the US National Research Council (NRC) vision and strategy for toxicity testing in the 21st century (Tox21) [37] are currently driving toxicity testing from animal-based testing towards in vitro testing using human cell-based tests addressing pathways of toxicological concern (e.g., sensitization and allergy development [38,39]). While relevant pathways of toxicological concern have not yet been accurately described for sensitization and allergy triggered by food proteins, progress has been made in the understanding of skin sensitization to chemicals and respiratory sensitization to both chemicals and proteins [40,41]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Experimental in silico, in vitro, and rodent models for screening and predicting protein sensitizing potential are discussed, including whether there is evidence of new sensitizations and allergies since the introduction of genetically modified crops in 1996, the importance of linear versus conformational epitopes, and protein families that become allergens. Some common challenges for predicting protein sensitization are addressed: (a) exposure routes; (b) frequency and dose of exposure; (c) dose-response relationships; (d) role of digestion, food processing, and the food matrix; (e) role of infection; (f) role of the gut microbiota; (g) influence of the structure and physicochemical properties of the protein; and (h) the genetic background and physiology of consumers. The consensus view is that sensitization screening models are not yet validated to definitively predict the de novo sensitizing potential of a novel protein. However, they would be extremely useful in the discovery and research phases of understanding the mechanisms of food allergy development, and may prove fruitful to provide information regarding potential allergenicity risk assessment of future products on a case by case basis. These data and findings were presented at a 2012 international symposium in Prague organized by the Protein Allergenicity Technical Committee of the International Life Sciences Institute's Health and Environmental Sciences Institute.
    04/2014; 4(1):13. DOI:10.1186/2045-7022-4-13
Show more