Exposure-Based Context for Toxicology: Gauging Interest in New Specialty Section

 Submitted by John Wambaugh and Barbara Wetmore

“The dose makes the poison.” The adage that launched thousands of toxicology careers continues to ring as true today as when Paracelsus first uttered it over 500 years ago. Although many toxicologists typically focus on the poison or hazard part of the statement, anchoring any hazard assessment to the dose—or its antecedent, exposure— is vital not only to characterizing the hazard but also in understanding risk. As we all know, there are many ways to define and to characterize exposure.

We are witnessing a paradigm shift in exposure science comparable to the advent of the polymerase chain reaction (PCR) in biology and inexpensive computing in analytics [1–4]. The tools available to exposure scientists now include meaningful passive samplers that are as simple as wrist bands [5], computational models that can make coarse estimates for thousands of chemicals [6, 7], and non-targeted analytical chemistry that can identify thousands of previously untested chemicals in everything from a glass of drinking water to a handful of dust [8].

T.S. Eliot wrote, “I will show you fear in a handful of dust.”[9] We propose an Exposure Specialty Section (ESS) to replace fear with knowledge. The ESS will inform toxicologists and allow discussion of these new data and other exposure information. The ESS will help align toxicological needs relevant to the advances among exposomics, biomonitoring, non-targeted screening, high-throughput and fit-for-purpose models, and exposure pathways. By endorsing sessions and disseminating information, the ESS will work to promote the exposure science critical for risk decisions. 

When used together, toxicological data and exposure information allows prioritization and analysis of the potential risk posed by chemicals [10]. Traditionally, there has been little or no exposure data available for most chemicals to place possible chemical hazard within a relevant human exposure context [1, 11]. New and emerging computational exposure science tools are rapidly turning this on its end [3, 4], to the point that we now identify chemicals in everyday objects without having the appropriate toxicological information for these chemicals to establish context [12]. ESS will work to bring together experts from industry, academia, and government to discuss existing and emerging methods for characterizing chemical exposure. A key example has been the series of papers exemplified by Wetmore et al. [13] in which high-throughput screening data was placed into context using predictions from high-throughput exposure models. This allowed rapid identification of chemicals where potential human exposures might possibly, though by no means certainly, cause biological activity while separating out many other chemicals where the putative margin between exposure and activity greatly diminished the putative risk [13]. ESS will interact with the Risk Assessment Specialty Section to help better inform chemical priorities when exposure data are lacking.

A parallel and ongoing challenge lies in our understanding of the impact of exposure on a particular outcome due to the multi-faceted nature of the exposure landscape. Although many efforts have focused exclusively on the contribution of one chemical or stressor to an adverse effect, the modulation of these effects or resulting cellular responses are in many cases impacted by the overall environment or “exposome” of the cell or organism. Wild [14] suggested an exposome that “encompasses life-course environmental exposures (including lifestyle factors), from the prenatal period onwards.” Just as genome wide association studies (GWAS) can search for genes related to health effects, exposome wide association studies (EWAS) may allow new toxicological hypotheses for chemical-induced alterations [15]. It is becoming increasingly recognized that exposures to any stressor, chemical or otherwise, need to be considered within the broader context of diet, behavior, and other agents, endogenous and exogenous alike [16]. Miller and Jones recently proposed a refinement of the original definition of the exposome to capture these thoughts considering cumulative assessments of environmental influences and biological response across the life course [2]. With momentum growing to examine exposure through these varied lenses of exposomics and the more traditional tools, the timing is right to encourage a dialogue that addresses these challenges with emerging approaches and perspectives.

Advances in exposomics go hand in hand with advances in non-targeted analytical chemistry and suspect screening (i.e., untargeted analysis). As opposed to targeted analytical chemistry focused upon individual analytes, untargeted high resolution mass spectrometry now allows indicators of thousands of chemicals to be discovered in biological [17] and environmental media [8]. Identifying these chemicals can be fraught with difficulty, but the needed tools [18] and databases [19] are rapidly developing. A particularly relevant, novel methodology was suggested by Rager et al. [8] where, in addition to exposure considerations, data from high-throughput toxicity screening was used to prioritize among potential matches to mass features, i.e., those chemicals with greater potential to do harm should be considered first. By the nature of their methods, untargeted analysis help identify those mixtures that occur in people and the environment, and therefore the ESS will be able to support the Mixtures Specialty Section.

An area that is currently of keen interest to the exposure science community is consumer products (e.g., cosmetics, cleaning products, building materials, and food contact materials). The presence of chemicals in such “near field” sources has been shown to be a key driver of high exposure levels in Centers for Disease Control (CDC) National Health and Nutrition Survey (NHANES) exposure biomonitoring data [6]. Information on chemical constituents of products, while only one prerequisite for exposure, provides demonstrable heuristics for estimating human exposure [6]. New high-throughput measurement strategies that combine high-resolution mass spectrometry with chemo-informatics data could enable rapid forensic analysis of chemicals present in these products [12]. Government requirements for product testing and new industry initiatives are providing additional inventories of chemicals present in products due to either intentional inclusion or contamination. These new data sources, in concert with data-driven or mechanistic modeling approaches, can elucidate potential human exposures to thousands of commercial chemicals and reduce uncertainty in modeling approaches. The ESS will be able to directly support the Food Safety and Occupational and Public Health Specialty Sections.

Pharmaco/toxicokinetics (PK/TK) exist at the intersection of toxicology and exposure science. Some ideas from exposure science, such as reverse dosimetry to infer exposures from biomarkers [20], have already been adapted to toxicology for establishing risk priorities for chemicals in the environment [13]. Efforts to build rapid, “fit for purpose” models to describe PK/TK for hundreds of chemicals are starting to yield insights that can inform development of more traditional PK/TK models [21, 22]. Many ESS activities will be aligned with the priorities of the Biological Modeling Specialty Section.

Finally, the ESS will be a conduit for the toxicological community to inform the development of exposure pathways. Teeguarden et al. [4] argue for “the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences.” We already have seen profound evidence for the need for exposure pathway consideration: the biomarkers of chemical exposure resulting from “near field” (in the home) sources are significantly higher than those for chemicals with “far field” sources [6]. New models have been developed to predict from chemical structure the probable functional roles of chemicals in consumer products since that information is often unavailable [23, 24]. These new models have been combined with toxicity information to begin to suggest “green” substitutes—chemicals that may serve similar functions with lesser bioactivity [24].

The January 2017 report by the National Academies of Science (NAS), “Using 21st Century Science to Improve Risk-Related Evaluations", found that “chemicals that have predicted high concentrations in humans and environmental media can then be used to identify toxicity-data gaps and set priorities for toxicity-testing for risk-based applications.” The NAS report recommended that “Interpreting the monitoring data and appropriately applying exposure data in risk-based evaluations will require continued complementary development and evaluation of exposure assessment tools and information, such as fate and transport models, PBPK models, and data on chemical quantity and use, partitioning properties, reaction rates, and human behavior.” The ESS can help ensure that the Society of Toxicology (SOT) is well integrated in these efforts.

The mission of ESS will be shaped by the membership. As we currently envision it, we see that such a group will serve as a community to 1) facilitate the exchange of information and interactions across scientists participating in exposure research; 2) educate graduate students and postdoctoral fellows and scientists alike about this area to promote the development of the field; and to 3) disseminate and communicate these efforts to the broader SOT and toxicology community. We feel that such a community—that encourages collaboration and the exchange of ideas—will contribute significantly to key advances in the field of exposure research.

Over the course of our careers, we have recognized the value and need for the incorporation of varied disciplines to explore the adoption of new tools and thought processes to address the challenges facing us as 21st century toxicologists. We have mutually benefited and see great value in facilitating similar interactions and collaborations amongst other researchers. We see the establishment of an Exposure Specialty Section as providing a key venue to facilitate such interactions and to allow dissemination of further relevant advances in this multifaceted research area.

We approach you today to propose the establishment of an SOT Exposure Specialty Section. If you are interested in joining, please contact John Wambaugh or Barbara Wetmore. SOT requires a charter member list of 50 interested individuals for us to proceed. We hope you also see the need and value of such a section and will consider joining us.

Thank you.

John Wambaugh and Barbara Wetmore

References
1. Hubal, E.A.C., Biologically Relevant Exposure Science for 21st Century Toxicity Testing. Toxicological Sciences, 2009. 111(2): p. 226–232.

2. Miller, G.W. and D.P. Jones, The Nature of Nurture: Refining the Definition of the Exposome. Toxicological Sciences, 2013. 137(1): p. 1–2.

3. Egeghy, P.P., et al., Computational Exposure Science: An Emerging Discipline to Support 21st-Century Risk Assessment. Environmental Health Perspectives, 2016. 124(6): p. 697.

4. Teeguarden, J.G., et al., Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework. Environmental Science & Technology, 2016. 50(9): p. 4579-4586.

5. O’Connell, S.G., L.D. Kincl, and K.A. Anderson, Silicone Wristbands as Personal Passive Samplers. Environmental Science & Technology, 2014. 48(6): p. 3327–3335.

6. Wambaugh, J.F., et al., High-Throughput Heuristics for Prioritizing Human Exposure to Environmental Chemicals. Environmental Science and Technology, 2014. 48(21): p. 12760–7.

7. Isaacs, K.K., et al., SHEDS-HT: An Integrated Probabilistic Exposure Model for Prioritizing Exposures to Chemicals with Near-Field and Dietary Sources. Environmental Science & Technology, 2014. 48(21): p. 12750–12759.

8. Rager, J.E., et al., Linking High Resolution Mass Spectrometry Data with Exposure and Toxicity Forecasts to Advance High-Throughput Environmental Monitoring. Environment International, 2016. 88: p. 269–280.

9.  Eliot, T.S., The Waste Land. 2016: CreateSpace Independent Publishing Platform.

10. Thomas, R.S., et al., Incorporating New Technologies into Toxicity Testing and Risk Assessment: Moving from 21st Century Vision to a Data-Driven Framework. Toxicological Sciences, 2013. 136(1): p. 4–18.

11. Egeghy, P.P., et al., The Exposure Data Landscape for Manufactured Chemicals. Sci Total Environ, 2012. 414: p. 159–66.

12. Wambaugh, J., et al. Product Deformulation to Identify Exposure Pathways for ToxCast Chemicals. in Society of Toxicology Annual Meeting. 2016. New Orleans, LA.

13. Wetmore, B.A., et al., Incorporating High-Throughput Exposure Predictions With Dosimetry-Adjusted In Vitro Bioactivity to Inform Chemical Toxicity Testing. Toxicological Sciences, 2015. 148(1): p. 121–36.

14. Wild, C.P., Complementing the Genome with an “Exposome”: The Outstanding Challenge of Environmental Exposure Measurement in Molecular Epidemiology. Cancer Epidemiology Biomarkers & Prevention, 2005. 14(8): p. 1847–1850.

15.  Rappaport, S.M., et al., The Blood Exposome and Its Role in Discovering Causes of Disease. Environmental Health Perspectives (Online), 2014. 122(8): p. 769.

16.  Jones, D.P., Y. Park, and T.R. Ziegler, Nutritional Metabolomics: Progress in Addressing Complexity in Diet and Health. Annual Review of Nutrition, 2012. 32(1): p. 183–202.

17.  Jones, D.P., Sequencing the Exposome: a Call to Action. Toxicology Reports, 2016. 3: p. 29–45.

18. McEachran, A.D., J.R. Sobus, and A.J. Williams, Identifying Known Unknowns Using the US EPA’s CompTox Chemistry Dashboard. Analytical and Bioanalytical Chemistry, 2016: p. 1–7.

19. Dionisio, K.L., et al., Exploring Consumer Exposure Pathways and Patterns of Use for Chemicals in the Environment. Toxicology Reports, 2015. 2: p. 228–237.

20. Tan, Y.-M., et al., Use of a Physiologically Based Pharmacokinetic Model to Identify Exposures Consistent with Human Biomonitoring Data for Chloroform. Journal of Toxicology and Environmental Health, Part A, 2006. 69(18): p. 1727–1756.

21. Obach, R.S., F. Lombardo, and N.J. Waters, Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 670 Drug Compounds. Drug Metabolism and Disposition, 2008. 36(7): p. 1385–1405.

22. Wambaugh, J.F., et al., Toxicokinetic Triage for Environmental Chemicals. Toxicological Sciences, 2015. 147(1): p. 55–67.

23. Isaacs, K.K., et al., Characterization and Prediction of Chemical Functions and Weight Fractions in Consumer Products. Toxicology Reports, 2016. 3: p. 723–732.

24. Phillips, K.A., et al., High-Throughput Screening of Chemicals as Functional Substitutes Using Structure-based Classification Models Green Chemistry, 2017: p. in press.

 

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