The 2018 ICCVAM Strategic Roadmap identified stakeholder engagement as critically important to advancing development and use of alternative methods. The articles below and others throughout this document describe collaborations to advance alternatives within agencies, among agencies, and between agencies and stakeholders.

Activities of the Tri-Services Toxicology Consortium

The mission of the Tri-Services Toxicology Consortium is to communicate, coordinate, and optimize toxicology needs throughout DoD by providing a central point of contact to DoD toxicology resources. The Consortium currently includes over 200 individuals from 11 organizations within DoD, seven of which have laboratories. Given the shared missions, individuals from the Veterans Administration and Department of Homeland Security are also invited to participate.

The Consortium convened four meetings during 2020 and 2021. These meetings began with brief presentations of new work including efforts in toxicity of novel compounds in various in vitro and in vivo systems, improving in silico predictions of molecular targets, characterization of toxicity using evidence integration techniques, advances in PBPK modeling and development, use of NAMs in phased approaches to toxicity data collection and hazard assessment, and new developments in understanding the mechanism for toxicity for chemicals of military interest. Significant recent efforts included:

  • Substance-specific technical reviews and publications concerning chromium, lead, trichloroethylene, and selected PFAS.
  • Identification of toxicity and biomarkers of exposure to diesel exhaust using a circulated human multi-tissue organoid platform.
  • Investigations into biomarkers of pulmonary toxicants.
  • Evaluation of fluorine-free aqueous-film forming foam formulations.
  • Use of in silico methods, including QSAR models, to predict skin sensitization, to address mixtures, and to derive metabolic parameters from in vitro data.
  • Continued DoD technical representation on relevant government and scientific committees.
Botanical Safety Consortium

In 2019, FDA, NIEHS, and the non-profit Health and Environmental Sciences Institute signed a memorandum of understanding establishing the Botanical Safety Consortium. The Consortium includes over 20 participants from industry, academia, and government to promote scientific advances in evaluating the safety of botanical ingredients and mixtures in dietary supplements. This group will look at novel ways to use cutting-edge toxicology tools, including alternatives to animal testing, to promote the goals of safety and effectiveness.

The Botanical Safety Consortium held virtual annual meetings in 2020 and 2021. The 2020 meeting provided a forum to articulate the needs for a scientific approach to assessing botanicals safety and refine the goals of the Consortium. Presenters at the 2021 meeting described a project to characterize cardiotoxicity of botanicals and provided overviews of applications of in silico modeling and NAMs to predict toxicity of botanicals.

FDA Alternative Methods Working Group

In 2019, FDA chartered an Alternative Methods Working Group with representatives from all of FDA. The goals of this working group are to:

  • Strengthen FDA’s long commitment to promoting the development and use of new technologies and to reduce animal testing.
  • Discuss new alternative in vitro/in silico/in vivo methods across FDA.
  • Interact with federal government partners and other global stakeholders to facilitate discussion and development of draft performance criteria for such assays.

During 2020 and 2021, the working group coordinated an internal webinar series on alternative methods that provided test method developers the opportunity to present their new methods to FDA scientists.

The 2021 FDA report, Advancing Regulatory Science at FDA: Focus Areas of Regulatory Science, outlined areas needing continued targeted investment in regulatory science research to foster the development of innovative products, provide data and methods to inform regulatory decision-making, and improve guidance to sponsors. One of those priority areas was “Advancing Novel Technologies to Improve Predictivity of Non-clinical Studies and Replace, Reduce, and Refine Reliance on Animal Testing.”

MPSCoRe Working Group

In January 2021, NICEATM, the National Institute of Allergy and Infectious Diseases, the U.S. Army Combat Capabilities Development Command Chemical Biological Center, and NCATS established the MPS for COVID Research (MPSCoRe) Working Group in collaboration with NC3Rs. The MPSCoRe Working Group coordinates the use of MPS to reduce animal use in studies of COVID-19 and future emerging infectious diseases. Members include researchers, MPS model developers, therapeutic/vaccine manufacturers, and international regulators. A July 2021 feature article in Drug Discovery Today (Kleinstreuer and Holmes 2021) reviews MPCSCoRe Working Group activities in the context of the broader effort to apply MPS to the development of therapies for COVID-19.

Activities of the MPSCoRe Working Group have included:

  • An organizational meeting in January 2021.
  • A workshop in April 2021 that featured presentations on the themes of testing therapeutics and understanding disease mechanisms.
  • A tutorial in May 2021 on how to use the University of Pittsburgh Microphysiological Systems Database to find and share data on COVID-19 projects.
  • A series of four webinars from June-September 2021 in which working group members described applications of MPS technologies to understanding the mechanisms of COVID-19 disease and assessing the safety and efficacy of potential novel therapeutics.
  • A meeting with representatives of the World Health Organization in December 2021 to discuss research needs relevant to the biology and treatment of the Omicron SARS-CoV-2 variant and the potential for MPS to provide human-relevant platforms for rapidly addressing those needs.
The Tox21 Compound Library: Collaborative Chemistry Advancing Toxicology

Since 2009, the Tox21 project has screened about 8,500 chemicals in more than 70 high-throughput assays, generating upward of 100 million data points, with all data publicly available. Underpinning this public effort is the largest compound library ever constructed specifically for improving understanding of the chemical basis of toxicity across research and regulatory domains. The different programmatic objectives of the Tox21 partners led to three distinct, overlapping compound libraries that, when combined, not only covered a diversity of chemical structures, use categories, and properties but also incorporated many types of compound replicates. A 2021 publication (Richard et al. 2021) describes the history of development of the Tox21 "10K" chemical library and data workflows implemented to ensure quality chemical annotations and allow for various reproducibility assessments. The paper presents cheminformatics profiles that demonstrate how the three partner libraries complement one another to expand the reach of each individual library, as reflected in coverage of regulatory lists, predicted toxicity endpoints, and physicochemical properties.

National Academies Panel on Variability and Relevance of Mammalian Toxicity Tests

ICCVAM members from NIEHS and NIST are serving on a committee convened by the National Academies of Sciences, Engineering, and Medicine for the consensus study, “Variability and Relevance of Current Laboratory Mammalian Toxicity Tests and Expectations for New Approach Methods (NAMs) for use in Human Health Risk Assessment.” This study was undertaken by the National Academies in response to a request from EPA. It will review the variability and relevance of existing mammalian toxicity tests, specifically in the context of human health risk assessment. The review will support the establishment of data-driven and science-based expectations for NAMs based on the variability and relevance of the traditional toxicity testing models.

The committee was established in 2021 and has held two public meetings. The first of these on September 23 included discussions with EPA staff regarding the statement of task, reasons for the committee’s study, and description of the types of committee recommendations that would be most useful, as well as a brief public comment period. A workshop on December 9 featured expert presentations addressing several questions relevant to the study:

  • How are traditional toxicity studies used in informing chemical safety decisions?
  • What do we know about the variability and concordance of traditional mammalian toxicity studies?
  • What are the needs and expectations of different stakeholders?

Proceedings from this workshop will be published in 2022. The committee will hold additional public meetings in 2022 and expects to issue a report with recommendations late in the year.

Environmental Health Language Collaborative

NIEHS and EPA are fostering a community-driven initiative, the Environmental Health Language Collaborative, to advance integrative environmental health research by developing and promoting adoption of a harmonized language. This initiative will facilitate answering large-scale complex research questions that require integration of multiple disparate data sources by developing language standards for describing data and biomedical knowledge. Several webinar events were held during 2021 to help set the stage, begin discussions, and draft plans for how to make progress on the Collaborative’s goals. The Collaborative welcomes diverse representation of expertise, needs, and scientific interests to make this a successful and sustainable community, and those interested are invited to join its email distribution list.

FDA Partnership to Apply Lung Chips to Safety Evaluation of COVID-19 Vaccines and Therapies

In October 2020, FDA entered into a Cooperative Research and Development Agreement with Emulate, Inc. to enable multiple studies using Emulate’s Organ-Chips across FDA offices in priority research areas. Organ-Chips are in vitro systems that recreate the natural physiology of specific human tissues and organs. Some projects will evaluate COVID-19 vaccines or investigate human immune response against SARS-CoV-2, the virus that causes COVID-19. Under the agreement, FDA will use a range of Organ-Chips to study the safety, efficacy, and mechanisms of action of drugs regulated by the FDA. This new agreement follows the successful completion of the first Emulate Cooperative Research and Development Agreement with the FDA initiated in 2017 that focused on toxicity studies using Emulate's Liver-Chip.

U.S. Department of Veterans Affairs Office of Research and Development Joins ICCVAM as New Member Agency

In October 2020, the U.S. Department of Veterans Affairs Office of Research and Development (VA ORD) joined ICCVAM to become the 17th ICCVAM member agency. Joining ICCVAM will help VA ORD to coordinate efforts with other federal agencies in replacing, reducing, and refining animal use. It is part of an overall agency plan to reduce animal use while improving predictions of human health hazard.

Activities of the In Silico Carcinogenicity Protocol Workgroup

Scientists within the FDA Center for Devices and Radiological Health, FDA Center for Drug Evaluation and Research, and NIEHS participate in an international interdisciplinary consortium to develop publicly available in silico protocols to support the hazard assessment of major toxicological endpoints. Within that consortium, the In Silico Carcinogenicity Protocol Workgroup has focused on developing an in silico protocol for the hazard assessment of carcinogens based on the 10 key characteristics of carcinogens (Smith et al. 2016). The workgroup has published an assessment (Tice et al. 2021) of how current in silico methods address each of the key characteristics and where additional methods or data resources need to be developed. The workgroup is currently developing case studies on four chemicals to determine whether data available for current in silico approaches would be sufficient to generate predictions of in vivo bioassay outcomes. In a related activity, members of the workgroup are compiling a review of receptor-mediated carcinogenesis that will examine the degree to which interaction with nuclear receptors is a key driver of chemically induced carcinogenesis, as opposed to a downstream effect.

Activities of the Carcinogenesis Health Effects Innovation Program

Approximately one in three people will be diagnosed with cancer at some point in their lifetime. Despite tremendous progress in screening and treatment methods, cancer is still the second most common cause of death in the United States and the leading health concern of the American public.

The Carcinogenicity Health Effects Innovation Program (CarciHEI) is a program within the NIEHS Division of NTP. The CarciHEI is developing innovative approaches to quickly and efficiently assess the cancer risk posed by environmental exposures to help identify and mitigate the factors contributing to these increases. The program’s goal is to identify early molecular biomarkers of preneoplasia and neoplasia and develop in vitro screening assays that can predict a cancer hazard.

The CarciHEI is collaborating with the Murtha Cancer Center at Walter Reed National Military Medical Center and the DoD Serum Repository to identify cohorts of service members diagnosed with cancer believed to be related to environmental exposures. Through an interagency agreement with the DOE Pacific Northwest National Laboratory, the CarciHEI will conduct proteomic analysis of serum samples collected every 2 years from these service members with the hope of identifying biomarkers of preneoplastic and early neoplastic events that contribute to the subsequent development of cancer.