David M. Balshaw

Personalized exposure assessment : Promising approaches for human environmental health research

New technologies and methods for assessing human exposure to chemicals, dietary and lifestyle factors, infectious agents, and other stressors provide an opportunity to extend the range of human health investigations and advance our understanding of the relationship between environmental exposure and disease. An ad hoc Committee on Environmental Exposure Technology Development was convened to identify new technologies and methods for deriving personalized exposure measurements for application to environmental health studies. The committee identified a “toolbox” of methods for measuring external (environmental) and internal (biologic) exposure and assessing human behaviors that influence the likelihood of exposure to environmental agents. The methods use environmental sensors, geographic information systems, biologic sensors, toxicogenomics, and body burden (biologic) measurements. We discuss each of the methods in relation to current use in human health research; specific gaps in the development, validation, and application of the methods are highlighted. We also present a conceptual framework for moving these technologies into use and acceptance by the scientific community. The framework focuses on understanding complex human diseases using an integrated approach to exposure assessment to define particular exposure–disease relationships and the interaction of genetic and environmental factors in disease occurrence. Improved methods for exposure assessment will result in better means of monitoring and targeting intervention and prevention programs.

Mitochondria, energetics, epigenetics, and cellular responses to stress

Background: Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways not only through energetics and ATP production but also through metabolites generated in the tricarboxylic acid cycle, as well as mitochondria–nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation. Objectives: We investigated the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and we examined DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function. Methods: The National Institute of Environmental Health Sciences sponsored the Workshop on Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response on 25–26 March 2013. Here, we summarize key points and ideas emerging from this meeting. Discussion: A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways. Conclusions: Understanding mitochondria–cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors. Citation: Shaughnessy DT, McAllister K, Worth L, Haugen AC, Meyer JN, Domann FE, Van Houten B, Mostoslavsky R, Bultman SJ, Baccarelli AA, Begley TJ, Sobol RW, Hirschey MD, Ideker T, Santos JH, Copeland WC, Tice RR, Balshaw DM, Tyson FL. 2014. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect 122:1271–1278; http://dx.doi.org/10.1289/ehp.1408418

Gene-Environment Interplay in Common Complex Diseases: Forging an Integrative Model—Recommendations From an NIH Workshop

Although it is recognized that many common complex diseases are a result of multiple genetic and environmental risk factors, studies of gene‐environment interaction remain a challenge and have had limited success to date. Given the current state‐of‐the‐science, NIH sought input on ways to accelerate investigations of gene‐environment interplay in health and disease by inviting experts from a variety of disciplines to give advice about the future direction of gene‐environment interaction studies. Participants of the NIH Gene‐Environment Interplay Workshop agreed that there is a need for continued emphasis on studies of the interplay between genetic and environmental factors in disease and that studies need to be designed around a multifaceted approach to reflect differences in diseases, exposure attributes, and pertinent stages of human development. The participants indicated that both targeted and agnostic approaches have strengths and weaknesses for evaluating main effects of genetic and environmental factors and their interactions. The unique perspectives represented at the workshop allowed the exploration of diverse study designs and analytical strategies, and conveyed the need for an interdisciplinary approach including data sharing, and data harmonization to fully explore gene‐environment interactions. Further, participants also emphasized the continued need for high‐quality measures of environmental exposures and new genomic technologies in ongoing and new studies. Genet. Epidemiol. 35: 217‐225, 2011.  © 2011 Wiley‐Liss, Inc.

The Importance of the Biological Impact of Exposure to the Concept of the Exposome

Background: The term “exposome” was originally coined in 2005 and defined as the totality of exposures throughout the lifetime. The exposome provides an excellent scientific framework for studying human health and disease. Recently, it has been suggested that how exposures affect our biology and how our bodies respond to such exposures should be part of the exposome. Objectives: The authors describe the biological impact of the exposome and outline many of the targets and processes that can be assessed as part of a comprehensive analysis of the exposome. Discussion: The processes that occur downstream from the initial interactions with exogenous and endogenous compounds determine the biological impact of exposures. If the effects are not considered in the same context as the exposures, it will be difficult to determine cause and effect. The exposome and biology are interactive—changes in biology due to the environment change one’s vulnerability to subsequent exposures. Additionally, highly resilient individuals are able to withstand environmental exposures with minimal effects to their health. We expect that the vast majority of exposures are transient, and chemicals underlying exposures that occurred weeks, months, or years ago are long gone from the body. However, these past chemical exposures often leave molecular fingerprints that may be able to provide information on these past exposures. Conclusions: Through linking exposures to specific biological responses, exposome research could serve to improve understanding of the mechanistic connections between exposures and health to help mitigate adverse health outcomes across the lifespan. Citation: Dennis KK, Auerbach SS, Balshaw DM, Cui Y, Fallin MD, Smith MT, Spira A, Sumner S, Miller GW. 2016. The importance of the biological impact of exposure to the concept of the exposome. Environ Health Perspect 124:1504–1510; http://dx.doi.org/10.1289/EHP140

Biomonitoring in the Era of the Exposome.

Background: The term “exposome” was coined in 2005 to underscore the importance of the environment to human health and to bring research efforts in line with those on the human genome. The ability to characterize environmental exposures through biomonitoring is key to exposome research efforts. Objectives: Our objectives were to describe why traditional and nontraditional (exposomic) biomonitoring are both critical in studies aiming to capture the exposome and to make recommendations on how to transition exposure research toward exposomic approaches. We describe the biomonitoring needs of exposome research and approaches and recommendations that will help fill the gaps in the current science. Discussion: Traditional and exposomic biomonitoring approaches have key advantages and disadvantages for assessing exposure. Exposomic approaches differ from traditional biomonitoring methods in that they can include all exposures of potential health significance, whether from endogenous or exogenous sources. Issues of sample availability and quality, identification of unknown analytes, capture of nonpersistent chemicals, integration of methods, and statistical assessment of increasingly complex data sets remain challenges that must continue to be addressed. Conclusions: To understand the complexity of exposures faced throughout the lifespan, both traditional and nontraditional biomonitoring methods should be used. Through hybrid approaches and the integration of emerging techniques, biomonitoring strategies can be maximized in research to define the exposome. Citation: Dennis KK, Marder E, Balshaw DM, Cui Y, Lynes MA, Patti GJ, Rappaport SM, Shaughnessy DT, Vrijheid M, Barr DB. 2017. Biomonitoring in the era of the exposome. Environ Health Perspect 125:502–510; http://dx.doi.org/10.1289/EHP474

Informatics and Data Analytics to Support Exposome-Based Discovery for Public Health

The complexity of the human exposome-the totality of environmental exposures encountered from birth to death-motivates systematic, high-throughput approaches to discover new environmental determinants of disease. In this review, we describe the state of science in analyzing the human exposome and provide recommendations for the public health community to consider in dealing with analytic challenges of exposome-based biomedical research. We describe extant and novel analytic methods needed to associate the exposome with critical health outcomes and contextualize the data-centered challenges by drawing parallels to other research endeavors such as human genomics research. We discuss efforts for training scientists who can bridge public health, genomics, and biomedicine in informatics and statistics. If an exposome data ecosystem is brought to fruition, it will likely play a role as central as genomic science has had in molding the current and new generations of biomedical researchers, computational scientists, and public health research programs.

Toward Greater Implementation of the Exposome Research Paradigm within Environmental Epidemiology.

Investigating a single environmental exposure in isolation does not reflect the actual human exposure circumstance nor does it capture the multifactorial etiology of health and disease. The exposome, defined as the totality of environmental exposures from conception onward, may advance our understanding of environmental contributors to disease by more fully assessing the multitude of human exposures across the life course. Implementation into studies of human health has been limited, in part owing to theoretical and practical challenges including a lack of infrastructure to support comprehensive exposure assessment, difficulty in differentiating physiologic variation from environmentally induced changes, and the need for study designs and analytic methods that accommodate specific aspects of the exposome, such as high-dimensional exposure data and multiple windows of susceptibility. Recommendations for greater data sharing and coordination, methods development, and acknowledgment and minimization of multiple types of measurement error are offered to encourage researchers to embark on exposome research to promote the environmental health and well-being of all populations.

Assessing the Exposome with External Measures: Commentary on the State of the Science and Research Recommendations

The exposome comprises all environmental exposures that a person experiences from conception throughout the life course. Here we review the state of the science for assessing external exposures within the exposome. This article reviews (a) categories of exposures that can be assessed externally, (b) the current state of the science in external exposure assessment, (c) current tools available for external exposure assessment, and (d) priority research needs. We describe major scientific and technological advances that inform external assessment of the exposome, including geographic information systems; remote sensing; global positioning system and geolocation technologies; portable and personal sensing, including smartphone-based sensors and assessments; and self-reported questionnaire assessments, which increasingly rely on Internet-based platforms. We also discuss priority research needs related to methodological and technological improvement, data analysis and interpretation, data sharing, and other practical considerations, including improved assessment of exposure variability as well as exposure in multiple, critical life stages.

ONE Nano: NIEHS's Strategic Initiative on the Health and Safety Effects of Engineered Nanomaterials

Background: The past decade has seen tremendous expansion in the production and application of engineered nanomaterials (ENMs). The unique properties that make ENMs useful in the marketplace also make their interactions with biological systems difficult to anticipate and critically important to explore. Currently, little is known about the health effects of human exposure to these materials. Objectives: As part of its role in supporting the National Nanotechnology Initiative, the National Institute of Environmental Health Sciences (NIEHS) has developed an integrated, strategic research program—“ONE Nano”—to increase our fundamental understanding of how ENMs interact with living systems, to develop predictive models for quantifying ENM exposure and assessing ENM health impacts, and to guide the design of second-generation ENMs to minimize adverse health effects. Discussion: The NIEHS’s research investments in ENM health and safety include extramural grants and grantee consortia, intramural research activities, and toxicological studies being conducted by the National Toxicology Program (NTP). These efforts have enhanced collaboration within the nanotechnology research community and produced toxicological profiles for selected ENMs, as well as improved methods and protocols for conducting in vitro and in vivo studies to assess ENM health effects. Conclusion: By drawing upon the strengths of the NIEHS’s intramural, extramural, and NTP programs and establishing productive partnerships with other institutes and agencies across the federal government, the NIEHS’s strategic ONE Nano program is working toward new advances to improve our understanding of the health impacts of engineered nanomaterials and support the goals of the National Nanotechnology Initiative.

EXPOsOMICS: final policy workshop and stakeholder consultation

The final meeting of the EXPOsOMICS project “Final Policy Workshop and Stakeholder Consultation” took place 28–29 March 2017 to present the main results of the project and discuss their implications both for future research and for regulatory and policy activities. This paper summarizes presentations and discussions at the meeting related with the main results and advances in exposome research achieved through the EXPOsOMICS project; on other parallel research initiatives on the study of the exposome in Europe and in the United States and their complementarity to EXPOsOMICS; lessons learned from these early studies on the exposome and how they may shape the future of research on environmental exposure assessment; and finally the broader implications of exposome research for risk assessment and policy development on environmental exposures. The main results of EXPOsOMICS in relation to studies of the external exposome and internal exposome in relation to both air pollution and water contaminants were presented as well as new technologies for environmental health research (adductomics) and advances in statistical methods. Although exposome research strengthens the scientific basis for policy development, there is a need in terms of showing added value for public health to: improve communication of research results to non-scientific audiences; target research to the broader landscape of societal challenges; and draw applicable conclusions. Priorities for future work include the development and standardization of methodologies and technologies for assessing the external and internal exposome, improved data sharing and integration, and the demonstration of the added value of exposome science over conventional approaches in answering priority policy questions.