By Cal Baier-Anderson, Melanie Biggs, and Laurie Roszell
On May 14, 2012, the National Capital Area SOT Regional Chapter held its Spring Symposium on "Systems Toxicology" at Lister Hill Auditorium on the NIH campus in Bethesda, Maryland. To better understand how exposure to xenobiotics can lead to adverse outcomes, systems toxicology incorporates multiple levels of toxicological information, biological organization, and technological platforms. This framework is expected to lead to better predictive methods.The invited speakers provided an overview of systems toxicology from origin to the potential for application in risk assessment.
The symposium was keynoted by Dr. Bruce Fowler, ICF International, who provided an historical overview of systems toxicology, beginning with its origins in cell and molecular biology. Technological advances, such as electron microscopy and electrophoretic techniques, allowed scientists to develop models linking subcellular events to larger system-wide processes. As our understanding of the complex relationships between organelles, cells, tissues, organs, and systems increased, so did our capacity to describe toxicological mechanisms. The duel biological and technological revolutions led to the generation of massive amounts of data, which requires computational techniques for analysis. Computational toxicology can work hand-in-hand with systems biology to conduct rapid screening to predict potential adverse outcomes. Dr. Fowler stressed that asking the right questions and understanding the limitations of the tools you use are critical for informing risk management decisions.
Donna Mendrick, Director, Division of Systems Biology, US Food and Drug Administration (US FDA), described how serious adverse effects from pharmaceuticals is rising faster than the number of drugs and prescriptions. Little is known about drug-drug interactions for the majority of pharmaceuticals in use, and this may be one of the reasons behind the rise in adverse effects. There are limitations to current test systems, such as animal testing under-predicting human effects and missing individual patient susceptibilities.This has prompted the search for new biomarkers to increase predictive capabilities. While biomarkers, such as blood pressure and serum glucose, have been standard practice for many decades, new biomarkers derived from ‘omic technologies can expand our ability to predict potential adverse effects. Among the challenges is finding useful biomarkers that are sufficiently specific. US FDA relies on a consortium to identify and test potential biomarkers that might be useful in predicting outcomes in heterogeneous populations.
Jennifer Sekowski, US Army Edgewood Chemical Biological Center (ECBC), presented the ECBC’s program for using ‘omics and computational toxicology to improve the characterization of chemical threats. Such threats not only encompass chemical warfare material but also pesticides, drugs, and industrial chemicals. The program will use the systems biology of host responses to understand risks to humans. Collaboration with academic research labs will allow the group to access and integrate different levels of biological organization. One approach will use the stamina biomarker in human pluripotent stem cells (WA09) to examine the effects of methyl parathion on early reproductive endpoints.
Integrating information from cells to tissues to behavior is the focus of Marion Ehrich’s research. Dr. Ehrich, Virginia Tech, described her interest in understanding how chemicals modulate behavior, noting that this is very difficult to model in vitro. Since many molecular effects are non-specific, potential markers must be screened for relevance and specificity. Dr. Ehrich described different types of assays that can provide insight into perturbation of the nervous system.There are, for example, in vitro systems that mimic the blood brain barrier, which can be used to test if compounds can pass through it. Also, target esterases can serve as useful indicators of neurotransmitter system perturbation. Ultimately, cross-disciplinary research teams are needed to implement systems toxicology approaches, and this has been an important goal at Virginia Tech.
Kevin Crofton’s research focuses on the relationship between thyroid perturbation and altered neurodevelopment. Dr. Crofton, US Environmental Protection Agency (US EPA), began by describing thyroid biology, including the role of the hypothalamus, pituitary, and liver. The linkage between thyroid hormone deficiency and impaired neurodevelopment is very well known, and impacts of certain xenobiotics on this system, such as propylthiouracil (PTU), perchlorate, and PBCs, have been characterized. Research questions focus on better characterization of adverse outcome pathways. To characterize these pathways, the molecular initiating event that leads to cellular effects that first manifest at the individual level needs to be determined. These effects can then have population effects. For example, the molecular-initiating effect of perchlorate is inhibition of iodine uptake, which results in thyroid hormone synthesis suppression. In pregnant women this can result in altered nervous system development, and at the population level, this can lead to a negative shift in population IQ. Community impacts can include a loss of productivity and increase in healthcare costs, with additional impacts at the family and social level. At each “node” in the pathway, there are mechanisms to return to homeostasis, and the processes are quantifiable. By studying the nodes as a system, we gain predictive power. Dr. Crofton emphasized that different pathways may be operative in different species, illustrating this concept with triclosan. Triclosan is a biocide that induces proteins CAR and PXR. In rodents, PXR is induced, whereas in humans, CAR is induced. This makes it possible to begin to define the triclosan adverse outcome pathways that are differentially operative in rodents and humans.
With tens of thousands of chemicals in commerce, can computational and systems toxicology facilitate risk management? This is the question addressed by Lynne Haber of Toxicology Excellence for Risk Assessment (TERA). Systems toxicology provides a framework to use high-throughput and computational data to move towards faster, predictive, and science-based decision making. Risk characterization incorporates hazard, dose-response, and exposure, and systems toxicology can play an important role in each of these areas. For example, hazard characterization can be informed by identification of adverse outcome pathways, including molecular initiating events, but also variability and susceptibility. Dose-response can be understood if biomarkers are well characterized with dose extrapolation. Computational methods can facilitate the understanding of cumulative and aggregate exposures. Dr. Haber reminded the audience of the importance of phenotypic anchoring for the interpretation of ‘omics data and that biological systems can be incredibly complex. For example, developmental toxicity is very complicated and requires communication between tissues. Progress is clearly being made with a number of multi-institutional efforts. Moving forward, validation of assays for probing system effects will require a multi-stakeholder dialog to bridge uncertainty.
The symposium ended with a panel discussion that allowed speakers and the audience to engage in discussion. Symposium presentations are available on the NCAC-SOT website.