[ Back to EurekAlert! ] Public release date: 9-Sep-2013
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Contact: Michael Bernstein
317-262-5907 (Indianapolis Press Center, Sept. 6-11)

Michael Woods
317-262-5907 (Indianapolis Press Center, Sept. 6-11)

American Chemical Society

21st century vision toxicity testing and risk assessment for agrochemicals

INDIANAPOLIS, Sept. 9, 2013 — How will emerging 21st century toxicity testing technologies impact agricultural products? How do they fit in the life cycle of discovery, regulatory registration and product defense or product stewardship? What's the outlook for improved, science-informed hazard prediction and risk assessment?

Those and other topics are on the agenda here today at a symposium during the 246th National Meeting & Exposition of the American Chemical Society (ACS), the world's largest scientific society. Entitled "21st Century Vision for Testing and Risk Assessment: Implications for Agrochemicals," the symposium includes presentations on new approaches for evaluating the human health and environmental effects of pesticides and other substances needed to sustain agricultural production.

The presentations are among almost 7,000 scheduled for the meeting, being held in the Indiana Convention Center and downtown hotels.

Abstracts in the symposium appear below.


A press conference on this topic will be held Monday, Sept. 9, at 1:30 p.m. in the ACS Press Center, Room 211, in the Indiana Convention Center. Reporters can attend in person or access live audio and video of the event and ask questions at http://www.ustream.tv/channel/acslive.

The American Chemical Society is a nonprofit organization chartered by the U.S. Congress. With more than 163,000 members, ACS is the world's largest scientific society and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.

To automatically receive news releases from the American Chemical Society, contact newsroom@acs.org.

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HESI's RISK21 roadmap: A transparent risk assessment methodology

Timothy Pastoor1, tim.pastoor@syngenta.com, Michelle Embry2, Alan Boobis3. (1) Product Safety, Syngenta, Greensboro, NC 27408, United States, (2) ILSI Health and Environmental Sciences Institute, Washington, DC 20005, United States, (3) Imperial College London, London, United Kingdom

For decades, human health risk assessment has depended primarily on animal testing to predict adverse effects in humans, but that paradigm has come under question because of calls for more accurate information, less use of animals, and more efficient use of resources. Moreover, the disproportionate use of hazard information has overshadowed the important role of exposure science in determining the definition of reasonable measures for human safety. In addition, major risk assessments may lack transparency, thereby hindering a clear understanding of the conclusions and hamper communication of key safety messages. To help answer these challenges, the HESI-managed RISK21 project was initiated to develop a scientific, transparent, and efficient approach to the evolving world of human health risk assessment. RISK21 involved over 120 participants from 12 countries, 15 government institutions, 20 universities, 2 non-governmental organizations, and 12 corporations. RISK21 developed a tiered approach that is problem formulation-based, makes maximum use of prior knowledge, and is led by exposure science to produce a highly transparent and flexible visualization of and approach to assessing human safety and risk. The general principles underlying the RISK21 approach as well as an overview of the RISK21 roadmap will be presented.

Approaches for establishing scientific confidence in 21st century methods for toxicity evaluations

Richard A Becker1, rick_becker@americanchemistry.com, Grace Patlewicz2, J. Craig Rowlands3. (1) American Chemistry Council, Washington, DC 20002, United States, (2) DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, DE 19711, United States, (3) The Dow Chemical Company, Midland, MI 48674, United States

Advances in high-throughput and high-content (HT/HC) methods such as those used in the fields of toxicogenomics, bioinformatics, and computational toxicology have the potential to improve both the efficiency and effectiveness of toxicity evaluations and risk assessments. However, prior to use, scientific confidence in these methods should be formally established. Traditional validation approaches that define relevance, reliability, sensitivity, and specificity, such as those in use by ICCVAM, may not be readily applicable. HT/HC methods are not exact replacements for in vivotesting, and although run individually, these assays are likely to be integrated together for decision making. Many of these assays rely on robotics, which may be unique in each laboratory setting. Building on the frameworks developed in the 2010 Institute of Medicine Report on Biomarkers and the OECD 2007 Report on (Q)SAR Validation, we present constructs that can be adapted to address the validation challenges of HT/HC methods. These constructs are both flexible and transparent, though require explicit specification of context and purpose of use such that scientific confidence (validation) can be defined to meet different regulatory applications. Transparency in the prediction model algorithms is a necessity to establish scientific confidence. Prediction models, filters, decision points, validation/performance data sets, and assay results should be publicly available and subjected to independent scientific peer review. We discuss some of the shortcomings of recently published models and recommend improvements, including how anchoring the assays and their prediction models to Adverse Outcome Pathways (AOPs) could facilitate the interpretation of results and support scientifically defensible fit-for-purpose applications.

Incorporating new technologies into toxicity testing and chemical risk assessment: Moving from 21st century vision to a data-driven framework

Russell S Thomas, rthomas@thehamner.org, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, United States

A series of studies has been performed that together may provide a data-driven framework to address the large number of chemicals with limited toxicity information. The framework integrates new experimental technologies such as high-throughput in vitro screening and in vivo transcriptomics with computational modeling and bioinformatic analyses to identify both the relative selectivity at which chemicals interact with biological targets and the concentration at which these interactions perturb signaling pathways. The results are used to calculate a point-of-departure and are compared with human exposure estimates to yield a margin-of-exposure. The margin-of-exposure determines progression of the chemicals between tiers. Based on data collected, a significant percentage of chemicals could be eliminated from further testing using only in vitro assays or short-term in vivo transcriptomic studies in the early tiers. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating advances in technology to increase efficiency.

In vitro screening data within Tox 21: How to use it?

Jason P Bailey1, jpbailey@dow.com, Jyotigna Mehta2. (1) Department of Human Health Assessment, Dow AgroSciences LLC, Indianapolis, IN 46062, United States, (2) Department of Human Health Assessment, Dow AgroSciences LLC, Milton Park, Abingdon, Oxon OX14 4RN, United Kingdom

In 2007, the seminal National Academy of Sciences report, Toxicity Testing in the 21st Century (TT21C), was published. It strongly advocated for utilizing in vitro and omics tools to make predictions for in vivo outcomes and guide more-targeted animal testing. In vitro assays and in silico tools provide a natural fit into the early stage of a testing program and an opportunity to begin implementation of the concepts of TT21C. Most of these assays and tools capitalize on the rapid growth of knowledge in the modes of action (MoA) for in vivo toxicities, as well as the technological advances in modern molecular and cellular biology. Evaluation of discrete molecular endpoints, such as receptor binding, nuclear receptor transactivation, and gene expression modulation provide insight into potential in vivo toxicities and a basis for understanding adverse effects, the MoA, and the potential human relevance. For registrants, these targeted molecular assays can aid in identification of a chemical with the most desirable attributes without the use of resource-intensive early animal screening studies. In vitro screening data can then be used to prioritize more complex and definitive testing, which includes more complex in vitro assays and/or definitive animal studies. Integrated animal testing strategies reduce animal use even further and maximize information gathered from those animal studies. This tiered approach of in vitro screening information triggering more definitive decision-making assays provides a bridge between traditional in vivo testing and a complete in vitro strategy. Furthermore, it allows for confidence to be built in in vitro screening assay results and gathering of useful toxicological information for product evaluation while reducing initial early stage animal-based screening studies.

Cumulative risk assessment for human health: Asking the right questions

Keith Solomon1, ksolomon@uoguelph.ca, Martin Wilks2, Angelo Moretto3, Alan Boobis4, Richard Philips5, Tim Pastoor6, Michelle Embry7. (1) Centre for Toxicology, SES, University of Guelph, Guelph, ON N1G 2W1, Canada, (2) Swiss Centre for Applied Human Toxicology, University of Basel, Basel, Switzerland, (3) Department of Occupational and Environmental Health, University of Milan, Milan, Italy, (4) Imperial College London, London, United Kingdom, (5) ExxonMobil Biomedical Sciences, Inc, Annandale, NJ, United States, (6) Syngenta Crop Protection, Greensboro, NC, United States, (7) Health and Environmental Sciences Institute, ILSI, Washington, DC, United States

When the current risk assessment–risk management paradigm as applied to humans was first elucidated in 1983, it did not explicitly include a problem formulation phase. The concept of problem formulation was first introduced in the context of ecotoxicological risk assessment (ERA) for the pragmatic reason to constrain and focus ERAs to the key questions. Subsequently, problem formulation has been introduced into human health risk assessment and is particularly pertinent in the context of cumulative risk assessment (CRA). In its broadest sense, CRA encompasses the combined risks from exposure via all relevant routes to all stressors, including biological, chemical, physical, and psychosocial. As part of the RISK21 program at HESI, we have proposed a framework for CRA that includes a problem formulation step. This framework is based on the tiered framework recommended for cumulative risk assessment of chemicals by WHO. Relative timing of exposures to multiple stressors is a major determinant of risks of adverse responses to cumulative exposures. In addition to contemporaneous, consecutive, or separate, exposures might also be important, depending on the kinetics of the chemicals, the duration of the response, any latency, and rate of recovery. Conceptual models for exposures in CRA need to include consideration and eventual quantification of non-chemical stressors such as physical environment, state of health and nutrition, and psychosocial status. At the highest tier, conceptual models for responses need to include measures of the interactions between stressors and the toxicodynamics and toxicokinetics that determine the cumulative response. This presentation will illustrate how conceptual models for exposures and responses can be developed, how data from new approaches to assessing responses can be used, and how testable risk hypotheses can be elaborated.

Evolution of the Endocrine Disruptor Screening Program (EDSP) in the 21st century

Mary Manibusan, manibusan.mary@epa.gov, Office of Science Coordination and Policy, US Environmental Protection Agency, Washington, DC, United States

Under the 1996 FFDCA and Safe Drinking Water Act, US EPA is required to screen all pesticide chemicals and those drinking water contaminants to which a substantial population is exposed for the potential to interact with the endocrine system. The combination of both pesticide and drinking water chemicals amounts to a universe of over 10,000 chemicals. The Agency must therefore prioritize which chemicals are listed for screening and testing in multiple biologically complex and resource intensive assays. In January 2013, the Agency brought a strategic prioritization scheme that combines physico-chemical properties, Structure Activity Relationship (SAR) and High ThroughPut (HTP) assays before the FIFRA Science Advisory Panel (SAP) for input on fit-for-purpose and regulatory application. The SAP provided key comments on the expansion of the SAR training set to cover a larger chemical universe and the approach to interpreting the HTP data to inform the SAR model. The SAP also provided recommendations on various aspects of the HTP data including transparency of how the data were generated, processed, and analyzed. These key recommendations will guide how the EDSP will evolve in the use of advanced robotics for rapid screening of the EDSP universe of chemicals.

Adverse outcome pathways for neurotoxicity: An example using pyrethroid insecticides

Timothy J Shafer, shafer.tim@epa.gov, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC 27711, United States

The National Academy of Science report on Toxicity Testing in the 21st Century advocated the use of adverse outcome pathways (AOPs) as a critical aspect of predictive toxicity testing. AOPs catalog the evidence in the peer reviewed literature to describe the interaction of a chemical with a molecular target in the cell and the subsequent alterations in cellular, tissue, and organism function that describe toxicity following exposure to that chemical. For neurotoxicity, one of the best examples of an established AOP is for pyrethroid insecticides. These compounds bind to voltage-gated sodium channels in the membranes of neurons, prolonging the time that these channels remain open. Numerous studies have documented the relationship between prolonged sodium channel kinetics and altered membrane excitability due to excess entry of sodium. The changes in membrane excitability have been documented both in vitro as well as in vivo and contribute to the behavioral changes associated with pyrethroid neurotoxicity. This talk will outline the concept of AOPs and use pyrethroid neurotoxicity as an example of how to establish an AOP for a neurotoxicant. It will also use the AOP approach to discuss the role of other potential molecular targets in pyrethroid neurotoxicity to compare and to contrast the levels of evidence for different AOPs for pyrethroids. (This abstract does not represent Agency policy.)

New technologies for exposure assessment

John Wambaugh, wambaugh.john@epa.gov, National Center for Computational Toxicology, US Environmental Protection Agency, Research Triangle Park, NC 27711, United States

Prioritization of chemicals requires reliable methods for screening on both hazard and exposure potential. High-throughput, typically in vitro, biological activity assays allow the ToxCast and Tox21 projects to investigate thousands of untested chemicals and compare the biological activity of chemicals with known in vivo toxicity to those with little or no in vivo data. Further, in vitro assays can characterize key aspects of pharmacokinetics and allow in vitro-in vivoextrapolation to predict the human uptake (mg/kg/day) that might be sufficient to cause bioactivity in vivo. Without similar capability to make quantitative, albeit uncertain, forecasts of exposure, the putative risk due to an arbitrary chemical cannot be rapidly evaluated. Using physico-chemical properties and provisional chemical use categories, most of the ∼10,000 Tox21 chemicals have been evaluated with respect to key routes of exposure. A mapping of chemicals to products and products to uses has categorized chemicals with respect to potential uses within the home. A Bayesian methodology was used to infer ranges of exposures consistent with biomarkers measured in urine samples and reported by the National Health and Nutrition Examination Survey (NHANES) in 2012. For each demographic group reported by NHANES we considered permutations of linear regression models, including as few as one and as many as all physico-chemical and use factors. Significantly associated factors provide heuristics for predicting exposures consistent with the NHANES data. For the Tox21 list, including hundreds of ToxCast pesticides, these simple heuristics alone were sufficient to make exposure predictions. These exposure predictions were then directly compared to the doses predicted to cause bioactivity for ~250 ToxCast chemicals. For chemicals with no other source of information, this approach allows prediction of a confidence interval within which the average human exposure due to near field sources is likely. (This abstract does not necessarily reflect US EPA policy.)

US EPA Office of Pesticide Program's 21st century vision and strategy for communication

Jennifer L McLain, mclain.jennifer@epa.gov, Vicki L Dellarco. Office of Pesticide Programs, US Environmental Protection Agency, Washington, DC, United States

US EPA Office of Pesticide Programs (OPP) is committed to protecting human health and the environment through the application of the latest scientific tools in assessing and managing pesticide risks. Traditional pesticide assessment approaches involve extensive studies that are often complex, expensive, use many animals, and are time consuming to conduct and to evaluate. OPP's vision for advancing integrated approaches to testing and assessment (IATA) combines existing knowledge of hazard and exposure and predictive tools in a weight-of-evidence approach to predict better potential risks for specific exposure scenarios and focus testing on likely risks of concern. OPP's efforts in this area are coordinated with those across US EPA (e.g., OPPT, ORD), other federal agencies (e.g., FDA), the stakeholder community, and internationally through several venues (OECD, WHO, NAFTA, EFSA, etc). OPP established a workgroup under our Federal Advisory Committee the Pesticide Program Dialogue Committee on 21st Century Strategies which is made up of a diverse range of stakeholders (e.g., environmental and public health interest groups, worker protection groups, pesticide manufacturers and trade associations, state agencies, animal welfare groups, academics) to provide us with advice on communication and transition issues. In the future, pesticide assessment will employ increasingly sophisticated scientific tools and continue to protect human health and the environment. OPP's application of IATA is intended to minimize animal testing while evaluating more chemicals across a broader range of potential effects in a shorter time frame thereby enhancing the quality and efficiency of risk assessment and risk management decisions. An early and ongoing dialogue with stakeholders is critical to ensure this change will be successful. Stakeholders need to have an understanding of the new technologies and feel comfortable that society will benefit, i.e., trust that the approach is as good as or better than status quo.

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