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Your Environment. Your Health.

Key Characteristics Inform Risk Assessment

NIEHS-funded University of California, Berkeley Superfund Research Program Center (UC Berkeley SRP Center) researchers and collaborators developed a new approach to help risk assessors predict the toxicity of chemicals based on shared characteristics. The approach allows for identification of the events, or key characteristics, that are shared by chemicals with similar toxic effects.

Called the key characteristics approach, the method helps risk assessors more easily identify, organize, and summarize the potential health risks of many different chemicals. By defining specific molecular changes that lead to toxicity, the approach also helps decision makers prioritize resources for studying potentially chemicals more closely.

The infrastructure and decades of risk assessment expertise provided by UC Berkeley SRP Center researchers served as the springboard for development of the key characteristics approach, which was led by Center Director Martyn Smith, Ph.D. Their expertise, combined with the Center’s experience engaging communities affected by hazardous exposures and know-how in communicating with stakeholders, played a critical role in forming a multidisciplinary team for the key characteristics approach.

This team included experts from 35 academic and research organizations, five U.S. government agencies, two intergovernmental agencies, three SRP Centers, and three pharmaceutical companies. This diverse collaboration provided perspectives and insight from a range of stakeholders throughout the process, ensuring the team developed a useful and practical tool for risk assessors.

Timeline of Key Characteristics development

The Problem

Using existing analytical methods and approaches, it would be time consuming and expensive to test the many thousands of chemicals in use for potentially harmful effects in humans. For example, studying the health effects resulting from exposure to chemicals in human populations can take years or decades, particularly for diseases that take a long time to manifest, like cancer.

Mechanistic studies and initiatives like the Toxicology in the 21st Century program (Tox21) generate large amounts of data that can help researchers better understand how chemicals affect human health. Tox21, a collaboration among NIEHS, the National Toxicology Program (NTP), the National Center for Advancing Translational Sciences, the National Center for Computational Toxicology, the U.S. Food and Drug Administration, and the U.S. Environmental Protection Agency (EPA), uses robotics and high-throughput screening to rapidly assess the potential of more than 10,000 chemical substances to harm human health. 

However, scientists and decision makers have been challenged by the question of how best to systematically review and evaluate the machine-scale data generated by mechanistic studies to best understand potential implications for human health.

Finding Solutions

Key Characteristics of Carcinogens as a Building Block

  • Ten key characteristics of carcinogens identified
  • Established utility of approach for decision making
Key Characteristics of Human Carcinogens
Key characteristics of human carcinogens.
(Photo courtesy of Guyton et al., Chem Res Toxicol, 2019)

The key characteristics approach addresses the need for a systematic method for evaluating mechanistic data to help risk assessors make decisions about chemical, physical, and biological agents that may cause cancer, collectively called carcinogens.

In 2012, the International Agency for Research on Cancer (IARC) convened two workshops in Lyon, France for experts to discuss and identify the mechanisms by which known carcinogens cause cancer.

Experts reviewed the existing literature on chemicals known to cause cancer to define the early mechanistic changes in cells and organs caused by these chemicals.

As a result of these meetings, Smith and colleagues then defined ten key characteristics shared by cancer-causing chemicals and demonstrated how they could be used to organize data on mechanisms and to inform decision-making.

Next, in collaboration with Ivan Rusyn, Ph.D., and Weihsueh Chiu, Ph.D., of the Texas A&M University SRP Center, they systematically evaluated the strengths and limitations of the approach by reviewing the available mechanistic research on 34 chemicals with different IARC cancer classifications. The researchers demonstrated strong evidence of key characteristics for many of the agents classified as carcinogenic or probably carcinogenic to humans and identified gaps in evidence for further evaluation.

Expanding to New Health Hazards

In 2019, Smith, right, organized a session on the key characteristics at Collegium Ramazzini Days in Capri, Italy. Smith, chaired the session which included talks by, from left to right, Kathryn Guyton, Ph.D., Michele La Merrill, Ph.D., and former NIEHS and National Toxicology Program Director Linda Birnbaum, Ph.D.

In 2019, Smith, right, organized a session on the key characteristics at Collegium Ramazzini Days in Capri, Italy. Smith, chaired the session which included talks by, from left to right, Kathryn Guyton, Ph.D., Michele La Merrill, Ph.D., and former NIEHS and National Toxicology Program Director Linda Birnbaum, Ph.D.
(Photo courtesy of UC Berkeley SRP Center)

  • Working groups consider other health hazards
  • Key characteristics of reproductive toxicants identified
  • Key characteristics of endocrine disrupting chemicals defined

Building on the successes of the key characteristics approach for carcinogens, the team began developing key characteristics for chemicals that cause other types of harm to human health. Expanding the key characteristics approach was also a recommendation of a National Academies of Sciences, Engineering, and Medicine committee on risk assessment in the 21st century.

Smith and Lauren Zeise Ph.D., head of the Office of Environmental Health Hazard Assessment in the California Environmental Protection Agency (CalEPA), brought together a team of international researchers to carry out this effort.

Working group members identified eight key characteristics of male reproductive toxicants.

Working group members identified eight key characteristics of male reproductive toxicants.
(Photo courtesy of Arzuaga et al., 2019)

The collaborators convened two separate working groups to discuss the early changes in reproductive organs and cells that may represent key characteristics of chemicals that are potentially toxic to male and female reproduction. These changes include direct impacts on the ability of reproductive cells to create embryos and longer-term impacts on embryo viability or development. One of the eight key characteristics identified for male reproductive toxicants included altering the development, function, or death of sperm cells. For female reproductive toxicants, the group identified 10 key characteristics, including altering signaling or production of reproductive hormones.

Another group of experts, led by Michelle La Merrill, Ph.D., of the University of California, Davis, and Thomas Zoeller, Ph.D., of the University of Massachusetts, Amherst, evaluated mechanistic data and developed 10 key characteristics of endocrine disrupting chemicals, which mimic or interfere with hormone actions in the body. For example, two of the key characteristics defined by the group include interacting with or activating hormone receptors and altering the production of hormones. They also identified assays that could be used to assess these characteristics and identified gaps where additional validated tests are needed.

Key Characteristics Informs Decision Making

  • IARC Cancer Evaluations
  • NTP Report on Carcinogens
  • Environmental Protection Agency

IARC has successfully used this approach since 2015 to evaluate more than 50 different chemicals, and other agencies worldwide are beginning to apply it.

For example, the key characteristics approach was used in evaluations of antimony trioxide and six haloacetic acids by the NTP’s Report on Carcinogens. This was the first time that key characteristics were used to support a recommendation to list chemicals in the Report on Carcinogens.

According to Smith, the approach is being used by EPA’s Integrated Risk Information System program and by CalEPA to inform decision making.

Similarly, the pharmaceutical industry is interested in key characteristics as an approach that could reduce animal testing and improve predictive toxicology. Consulting groups have also used the approach to evaluate the mechanistic data on the carcinogenicity of sucralose, aspartame, and per- and polyfluoroalkyl substances.

Moving Forward

Instead of a narrow focus on specific pathways, the key characteristics approach has been a useful way to organize toxicity data that considers broad mechanistic evidence. This makes it adaptable to considering a wide range of health effects caused by harmful toxins.  

In collaboration with scientists from CalEPA and IARC, the UC Berkeley SRP Center Research Translation Core, led by Cliona McHale Ph.D., launched a website and Twitter account with resources for regulators and others interested in applying the key characteristics approach.

Research Translation and Community Engagement

In an archived May 2020 Superfund Research Program webinar, you can hear Smith and La Merrill describe the key characteristics approach to identify carcinogens and endocrine disrupting compounds. They also explain how key characteristics can be used to identify, organize, and utilize mechanistic data when evaluating chemicals that harm human health.

Now, additional working groups are focusing on identifying key characteristics of chemicals that harm other parts of the body. For example, led by Pamela Lein, Ph.D., of UC Davis, and Thomas Hartung, M.D., of Johns Hopkins University, they are refining and preparing to publish on key characteristics of chemicals that harm the brain and neurodevelopment. Rusyn is leading a working committee to define the key characteristics of liver toxicants, and Chiu is helping define key characteristics of cardiovascular toxicants in another working group.  

Moving forward, the working groups plan to expand their work to include key characteristics of chemicals that harm the immune system, metabolism, and more. Ultimately, they want to identify key characteristics of harmful chemicals more broadly, regardless of the specific body system that is targeted, and speed up provision of scientific information for decision makers.

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