Exploring Advances in Predictive Toxicology to Reduce Adverse Children’s Health Outcomes

By Thomas Knudsen posted 08-23-2018 01:25 PM


Communique 2018 Issue 3 Masthead

Stakeholders working together from governmental and regulatory agencies, research institutes, academia, and the chemical and pharmaceutical industry are addressing the complex challenges facing toxicologists in the 21st century. Henry Ford, business tycoon and founder of the Ford Motor Company, is famously quoted as saying, “Coming together is a beginning; keeping together is progress; and working together is success.” The expanding scope and complexity of problems facing toxicologists in the 21st century have caused professionals across broad sectors to meet, network, learn, and exchange ideas. The SOT FutureTox series of Contemporary Concepts in Toxicology (CCT) meetings address the challenges facing the use of 21st-century toxicity testing technologies and tools to improve science-informed hazard prediction and risk assessment. This need was identified in two heavily cited reports by the National Research Council (NRC): Toxicity Testing in the Twenty-First Century: A Vision and a Strategy in 2007 and Science and Decisions: Advancing Risk Assessment in 2009.

Newborn in hospital holding woman's handOn November 14–16 2018, basic, clinical, and regulatory scientists will gather for FutureTox IV Progress to Maturity: Predictive Toxicology for Healthy Children, which will be an interactive forum to discuss the latest science and technology available to help make decisions about the effects of chemicals on adverse birth outcomes (e.g., preterm labor, malformations, low birth weight) and chronic conditions manifested postnatally (e.g., neurodevelopmental impairment, breast cancer, cardiovascular disease, fertility). The meeting will discuss the prevalence of adverse children’s health outcomes in the United States and the growing need for research to understand the impact of environmental factors on human development and for actionable solutions to evaluate chemical toxicity, drug efficacy, and safety assessment impacting children’s health.

FutureTox IV logo

All regulatory agencies and stakeholders need information on developmental and reproductive toxicology (DART) to make decisions about chemicals to better protect children’s health. With the passing of the 2016 Frank R. Lautenberg Chemical Safety for the 21st Century Act which highlights children and pregnant women as susceptible life stages/populations, there is renewed impetus for implementing new assays and technologies to address the safety of thousands of chemicals, including for evaluating risks to susceptible populations. This requires confidence in the high-throughput screening (HTS) testing paradigm, as well as effective communication of the emerging science and technology to stakeholders.

Quote about the need for new toxicology assaysDuring FutureTox IV, experts will highlight progress on in vitro profiling platforms and in silico modeling approaches for DART testing. The meeting also will include workshops on tools, data, and models; information sessions on testing batteries for developmental neurotoxicity, endocrine disruption, and nontargeted biomonitoring (pregnancy exposome); and breakout groups to discuss future strategies and regulatory gaps. Poster Sessions will offer an opportunity for participants to meet, network, learn, and exchange ideas with experts and trainees.  

The Defense Advanced Research Projects Agency (DARPA), US Food and Drug Administration (US FDA), National Institutes of Health (NIH), US Environmental Protection Agency (US EPA), and other federal agencies in the United States and Europe are investing in the development and implementation of alternative testing strategies, such as organ-on-chip and microphysiological system constructs, to support human disease models. Participants at FutureTox IV will discuss these and other newer in vitro platforms for high-dimensional testing, data integration into adverse outcome pathways (AOP)-based constructs, and virtual (computer-based) modeling of cell and tissue biology in support of regulatory decision making for DART testing.

FutureTox III logoThe upcoming meeting is the fourth in a series of SOT CCT meetings focused on exploring issues related to toxicology research in the 21st century. In 2016, FutureTox III: Bridges for Translation focused on how best to harness the new paradigm, science, and data for use in human risk assessment and regulatory decision making. A tenor of growing optimism and confidence that the vision laid out in the 2007 NRC report was attainable had been clearly articulated in two case presentations: 1) the US EPA Endocrine Disruptor Screening Program (EDSP) “Pivot” used ToxCast/Tox21 HTS data for rapid assessment of estrogenicity in a model which performed equal to or better than conventional EDSP Tier 1 bioassays and 2) the US FDA commitment to a radical departure from the status quo by utilizing the Comprehensive In Vitro Pro-Arrhythmia Assay (CiPA) for evaluating adverse cardiac events with in vitro data from engineered human cells and stem cell-derived cardiomyocytes together with in silico reconstruction of human cardiac action potential. Participants at FutureTox III also discussed the integration of hazard-based AOPs with the relatively new idea of systems exposure (exposome) in view of ratchetting these advancements toward high-throughput risk assessment. In 2000, writer Malcolm Gladwell described a “tipping point” as the moment when an idea, trend, or social behavior crosses a threshold, tips, and spreads like wildfire. Stakeholders working together have enabled toxicology to pass a critical tipping point en route to successful life stage-specific and organ-specific assessments.

FutureTox II logoIn 2014, FutureTox II: In Vitro Data and In Silico Models for Predictive Toxicology focused on priority concerns, such as predicting and modeling metabolism, cell growth and differentiation, effects on susceptible subpopulations, and integrating data into risk assessment. Recognizing significant progress toward predictive toxicology goals outlined by the NRC 2007 report, the organizers challenged participants with the important question of “how in vitro data and in silico models can be used to understand and predict in vivo toxicity.” While reducing the complexity of test systems to simpler cell assays and small model organisms enables more efficient testing strategies, in doing so, the reductionism loses the systems-level character which makes a human toxicological response complex in the first place, thereby neglecting factors that contribute to “false negative” predictions, such as drug metabolism, poly-pharmacology, vulnerable life stages, gender differences, genetic diversity, and cross-species extrapolation. Participants discussed newer in vitro platforms for high-dimensional testing on small model organisms, human stem cells, engineered microtissues and microphysiological systems; data integration into AOP-based constructs and virtual (computer-based) modeling of cell and tissue biology; and managing expectations in both the regulatory and regulated scientific communities.

FutureTox logoThe FutureTox series launched in 2012 with FutureTox: Building the Road for 21st-Century Toxicology and Risk Assessment Practices. Leaders joined forces to review and discuss the state of the science, better define the problems and challenges, and outline key goals to advancing newer technologies into practice. The conference organizers challenged participants with three questions: 1) How can predictive toxicology be integrated into existing safety assessment practices?; 2) What is the best use of human and environmental exposure, toxicity, and dosimetry data in the context of risk assessment?; and 3) How can emerging science impact and reshape current risk assessment practice? A nexus was an expanding data collection from in vitro profiling of thousands of pharma compounds and environmental chemicals through public HTS efforts in the Tox21 consortium. Data-driven models and tiered-testing strategies would aim to translate point of departure, mode of action, and AOP into real-world human exposure scenarios for hazard prediction. Participants discussed the challenges and limitations in building predictive models of whole organism hazard outcomes from in vitro data, such as metabolic capacity, ADME/pharmacokinetics, complexity of multicellular dynamics, life-stage considerations, and reductionism in the biological complexity and diversity of test systems in general.

Please join us in Arlington, Virginia, at the Westin Crystal City, November 14-16, 2018, for FutureTox IV. Registration and housing are currently available for this exciting CCT meeting.