The NIEHS Superfund Research Program (SRP) hosted a Risk e-Learning webinar series focused on understanding the health effects of exposures when there is a lag between exposure and the onset of the disease.

Session I - Linking Exposures to Diseases with Long Latency Periods
May 11, 2020 • 1:00 – 3:00 p.m. EDT
To view the archive, visit EPA's CLU-IN Training & Events webpage.

The first session provided an introduction to exposures and latent disease risk, including information about windows of susceptibility and later-life health outcomes, and set the stage for the other sessions.

Speakers:

• Bill Suk, Ph.D., National Institute of Environmental Health Sciences
• Rebecca Fry, Ph.D., University of North Carolina SRP Center
• Heather Stapleton, Ph.D.,  Duke University SRP Center
• Seth Kullman, Ph.D., North Carolina State University and Duke University SRP Center
• Brian Berridge, D.V.M., Ph.D., National Toxicology Program
• Moderator: Danielle Carlin, Ph.D., National Institute of Environmental Health Sciences

SRP Director William Suk, Ph.D., M.P.H., provided an overview of the series and briefly discussed the importance of linking exposures to diseases with long latency periods.

Rebecca Fry, Ph.D., of the University of North Carolina at Chapel Hill SRP Center, provided an overview of arsenic and its latent life health impacts. Inorganic arsenic continues to poison the drinking water of millions of individuals around the globe. Exposure to arsenic early in life is associated with later life health effects in both human populations and rodent models. Increasing evidence suggests that these later life health effects may be tied to changes to the epigenome.

Heather Stapleton, Ph.D., of the Duke University SRP Center, and Seth Kullman, Ph.D., a co-investigator on Stapleton’s Duke SRP project as well as a North Carolina State University SRP Center researcher, discussed how flame retardants and environmentally relevant mixtures induce adipogenesis, and the long-term impacts on metabolic disorders. People are chronically exposed to mixtures of contaminants in the indoor environment, and many of these contaminants are known to impact endocrine function. Their research groups have been exploring the mechanisms by which flame retardants and mixtures containing flame retardants isolated from house dust effect adipogenesis and osteogenesis. They seek to understand whether these compounds and mixtures of these compounds can potentially impact human health outcomes. This talk will discuss research on the adipogenic and osteogenic activity from commercial mixtures such as Firemaster 550, individual chemicals, and house dust extracts, and their associations with select phenotypic and metabolic endpoints measured in a small fish models of human disease, cell cultures, and human cohorts.

Brian Berridge, D.V.M., Ph.D., scientific director of the NIEHS Division of the National Toxicology Program (NTP), discussed the assessment of latent hazards at NTP. It is generally accepted that early life and chronic low-level exposures to some environmental agents can cause or contribute to later life health effects. Modeling these contributions is challenging and the focus of a number of traditional approaches to environmental toxicology testing. The DNTP is actively building capabilities to expand our ability to understand the long-term health effects of environmental exposures

Session II - Identifying Hallmarks and Key Characteristics
May 28, 2020 • 2:00 – 4:00 p.m. EDT
To view the archive, visit EPA's CLU-IN Training & Events webpage.

In the second session, presenters discussed new methods to better understand potential disease risk by identifying key characteristics or hallmarks of chemicals and disease. This research may provide insight into identifying chemicals that may lead to disease earlier on in the disease progression and help explore how aging itself can be a risk factor for disease.

Speakers:

• Martyn Smith, Ph.D., University of California, Berkeley SRP Center
• Michele La Merrill, Ph.D., University of California, Davis
• Ron Kohanski, Ph.D., National Institute on Aging
• Moderator: Heather Henry, Ph.D., National Institute of Environmental Health Sciences

Martyn Smith, Ph.D., director of the University of California, Berkeley SRP Center, described the key characteristics approach to helping identify chemicals that cause cancer and other adverse outcomes. In evaluating whether a chemical can cause cancer or another adverse outcome, three lines of evidence are typically considered: epidemiology, animal bioassays, and mechanistic evidence. The key characteristics (KC) form the basis of a uniform approach for searching, organizing, and evaluating mechanistic evidence to support hazard identification without the need for a deductive hypothesis. KCs are the established properties of the chemicals and have been developed for carcinogens, endocrine disruptors, reproductive and neuro-toxicants, and are becoming increasingly used by authoritative bodies and regulatory agencies.

Michelle La Merrill, Ph.D., associate professor at the University of California, Davis, focused on using the key characteristics of endocrine disruptors to organize mechanistic support of the developmental basis of endocrine disruption. Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing health risks, such as for cancer, reproductive impairment, cognitive deficits, and obesity. Inspired by work to improve hazard identification of carcinogens using KCs, they have developed 10 KCs of EDCs based on our knowledge of hormone actions and EDC effects. This presentation revealed how these 10 KCs can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs that contribute to developmental vulnerability to adult disease, and use DDT and bisphenol A as examples to illustrate this approach.

Ron Kohanski, Ph.D., deputy director of the Division of Aging Biology at the National Institute on Aging, focused on aging as a risk factor for disease. Geroscience is a recently evolved field of research on the intersection between the biology of aging and the biology of disease. The geroscience hypothesis states that “slowing the rate of aging will delay the onset and decrease the severity of chronic diseases and comorbidities that primarily impact older people.” This does not mean that old age per se is a risk factor, any more than claiming that childhood is a risk factor for diseases that primarily afflict children. However, in the latter case the underlying causes may be the stage of development does not yet confer resilience against pathogens, for example. In the former case, the underlying causes may be loss of that resilience (acquired over a lifetime) from the failure of underlying molecular networks that maintain the body and adapt to environmental changes. This talk presented a viewpoint that aging can be treated as a risk factor, attempting to show that both the magnitude and duration of changes that are the process of aging can be altered in ways that are either beneficial or detrimental to health.

Session III - Arsenic as a Case Study
June 8, 2020 • 1:00 – 3:00 p.m. EDT
To view the archive, visit EPA's CLU-IN Training & Events webpage.

In the third session, presenters described studies linking early-life arsenic exposure and later-life disease risk. The focus on arsenic as a case study provided insights into linking other exposures to latent disease risk and identifying windows of susceptibility.

Speakers:

• Yu Chen, Ph.D., New York University, Columbia University SRP Center
• Maria Argos, Ph.D., University of Chicago, Columbia University SRP Center
• Fenna Sille, Ph.D., Johns Hopkins University
• Erik Tokar, Ph.D., National Institute of Environmental Health Sciences
• Moderator: Brittany Trottier, National Institute of Environmental Health Sciences

Yu Chen, Ph.D., and Maria Argos, Ph.D., co-investigators of a project with the Columbia University SRP Center, presented research from the Health Effects of Arsenic Longitudinal Study (HEALS) and ancillary studies linking early-life arsenic exposure and disease risk across the life course. For nearly two decades, HEALS has provided individual-level epidemiologic data evaluating risks from chronic arsenic exposure through drinking water in rural Bangladesh with clinical and molecular endpoints.

Fenna Sille, Ph.D., assistant professor at the Johns Hopkins University Bloomberg School of Public Health, discussed her research focused on early-life exposures to arsenic and immune system changes. As an alumna of the University of California, Berkeley SRP Center, she also discussed studies assessing the long-term effects of a unique early-life arsenic exposure situation in Northern Chile. She presented data from in vitro and in vivo models as well as from the Chilean population study.

Erik Tokar, Ph.D., leader of the NIEHS National Toxicology Program Stem Cell Toxicology Group, discussed the association between early-life arsenic exposure and cancer in adulthood. His presentation focused on cancer formation in adulthood following in utero and "whole life" exposure to arsenic. He covered in vivo and in vitro models and discussed the effects of arsenic on stem cell recruitment and the microenvironment during transformation and cancer stem cell formation.

Session IV - Moving Forward
June 16, 2020 • 1:00 – 3:00 p.m. EDT
To view the archive, visit EPA's CLU-IN Training & Events webpage.

In the fourth and final session, presenters discussed emerging toxicology and modeling methods, as well as needs, to better link exposure to latent disease risk.

Speakers:

• Stephen Ferguson, Ph.D., National Institute of Environmental Health Sciences
• Manish Arora, Ph.D., Icahn School of Medicine at Mount Sinai
• Stefano Monti, Ph.D., Boston University
• Moderator: Michelle Heacock, Ph.D., National Institute of Environmental Health Sciences

Stephen Ferguson, Ph.D., a scientist in the National Toxicology Program (NTP) Division of the NIEHS, described emerging toxicological approach methods (TAMs), which seek to enhance our understanding of human responses to xenobiotic exposures and their translation to human health outcomes. He discussed progress at NTP towards enhancing the physiological relevance of Tox21 research through qualification of 3D liver screening models paired with informative assay systems (e.g., high throughput transcriptomics) in response to reference human therapeutics and environmental chemicals.

Manish Arora, Ph.D., professor at the Icahn School of Medicine at Mount Sinai, described his work focused on environmental biodynamics, which focuses on the interplay between the environment and the body. He also discussed rethinking the role of time in environmental health research and shared his work on neurological disorders at different life stages.

Stefano Monti, Ph.D., associate professor at Boston University, was scheduled to present but was not able to due to a bicycle accident. His presentation was recorded at a later date and added to the archive of the webinar. Monti provided an overview of the experimental and computational approaches he and his team have developed and applied to model environmental chemicals and to predict their long-term adverse effects from short-term omics assays. In particular, he presented vignettes from two studies, the first aimed at predicting chemical carcinogenicity and genotoxicity, and the second aimed at defining a molecular taxonomy of metabolism-disrupting chemicals. The focus was on the experimental design and the computational approaches adopted, as well as on some of the challenges and lessons learned.