ICCVAM 2024 Public Forum Highlights
By Loza Taye | June 13th, 2024
The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) is a U.S. government committee established by law to promote the development, validation, and regulatory acceptance of new, revised, and alternative test methods that reduce, refine, or replace the use of animals in research and testing. ICCVAM operates as a permanent committee of the National Institute of Environmental Health Sciences (NIEHS) under the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM).
ICCVAM holds at least one public forum every calendar year. The purpose of the ICCVAM public forum is to facilitate transparency and collaboration in the development and adoption of alternative testing methods. It is a platform for stakeholders, including scientists, industry representatives, regulatory agencies, and the public, to exchange information, provide feedback, and discuss advancements. The forum allows stakeholders to hear updates from ICCVAM about their activities and future plans. ICCVAM encourages engagement and cooperation among diverse groups to support scientifically valid alternative testing methods.
This year's ICCVAM public forum was held at the NIH Natcher Center in Bethesda, MD, on May 20-21, 2024. The meeting highlights are summarized below.
Day 1 Highlights
EPA: NAMs Work Plan
The forum began with Alison Harrill from the U.S. Environmental Protection Agency (EPA) offering valuable insights into the EPA's NAMs Work Plan Implementation. The discussion primarily focused on integrating new approach methodologies into the EPA's regulatory frameworks, advancing more humane and efficient testing methods. Five goals were outlined in EPA’s work plan. Dr. Harrill reported that two goals have been achieved and are being developed further: developing NAMs to address critical information gaps and training and development for stakeholders. Three additional goals are still in progress, with plans to complete them by the end of the year. These goals encompass establishing baselines and metrics for assessing progress, building scientific confidence, demonstrating application, and evaluating regulatory flexibility to accommodate NAMs. Dr. Harrill underscored the necessity for NAMs, highlighting the lengthy time and resources required for chemical tests using animal studies for health assessment. She referenced former EPA administrator Eckardt Beck's query on "how much risk can we accept," prompting participants to weigh the risks of implementing NAMs against traditional methods in terms of time and cost savings.
Relevant to the Johns Hopkins Toxicology Policy Team's recent Capitol Hill briefing, an audience member inquired about the EPA's decision to eliminate the timelines for ending animal tests by 2035. However, Dr. Harrill refrained from commenting on policy matters. Nevertheless, she emphasized the EPA's strong commitment to modernizing approaches and reassured the audience that significant efforts are underway to achieve this goal.
FDA: Center for Food Safety and Applied Nutrition
During her presentation, Suzanne Fitzpatrick, from the FDA's Center for Food Safety and Applied Nutrition (CFAN) highlighted the Center’s initiatives in NAMs. She emphasized the FDA's commitment to advancing alternative food safety and nutrition methods, ensuring these innovations meet rigorous safety standards. Fitzpatrick noted the necessity of NAMs for swift results, pointing out that the FDA faces potential lawsuits if harm occurs during the post-approval program. She stated people don't want to hear "it takes a few years for animal studies" when products harm their loved ones. She discussed the FDA's burden to demonstrate safety, acknowledging the merit of animal studies but noting that the FDA cannot afford to wait for their completion.
Dr. Fitzpatrick detailed the work of the CFSAN NAMs working group, which focuses on in silico methods and conducts gap analyses to guide NAMs development for stakeholders. She mentioned the imminent release of this analysis. Additionally, she highlighted ongoing research aimed at developing programs to test bio-relevance. She also discussed the implementation of training programs where junior scientists are placed on senior projects, allowing them to gain significant experience working on projects they wouldn't otherwise have the opportunity to work on.
Among the ongoing projects, Fitzpatrick mentioned a collaboration with our Hopkins colleagues at CAAT, who are developing miniature brains to study metal mixtures. Overall, Dr. Fitzpatrick emphasized that NAMs are essential for the FDA's post-market approval process and was optimistic regarding their implementation in the future.
FDA: Center for Devices and Radiological Health
Echo Rufer, from the FDA's Center for Devices and Radiological Health (CDRH), presented CDRH’s ongoing research concerning NAMs. This research is pivotal for ensuring the safety and effectiveness of medical devices without resorting to animal testing. Rufer detailed her team's endeavors to diminish the dependence on animal tests for assessing medical device biocompatibility by exploring alternative methods. She noted that while in vitro methods hold significance, other computational approaches could yield actionable insights even before emerging vitro methods are fully validated. Additionally, she mentioned plans to develop a framework for "legacy" devices currently on the market, aiming to ensure reasonable safety standards when transitioning to alternatives. Dr. Rufer also addressed the limitations of current testing methodologies, which often involve soaking a device in a solution and then injecting that solution into an animal. She pointed out that this approach tests the device extract rather than the device itself and expressed the team's aspiration to develop NAMs to enhance this process.
NIEHS: PROMETHEUS Project
Warren Casey, a former executive director of ICCVAM, began his talk by expressing his satisfaction with the increasing acceptance of alternatives and ICCVAM over the past decade. He commended the forum for providing agencies with a platform to share insights. He emphasized the necessity for toxicology to shift from animal models to human models, noting the scarcity of human data in the field and the need for improvement. Dr. Casey elaborated on PROMETHEUS, a project that leverages federal resources to investigate how environmental exposures impact veterans and first responders. He stressed the significant investment in this endeavor from the Department of Defense (DoD) and beyond, highlighting its prioritization and the advantages of utilizing military data which is meticulously kept. Dr. Casey underscored the golden opportunity presented by this wealth of military data to develop human-relevant models that can enhance practices in toxicology research.
NIEHS: Division of Translational Toxicology
Will Gwinn, from the NIEHS Division of Translational Toxicology (DTT), offered an update on the Occupational and Inhalation Exposures (OIE) Program's work regarding Air-Liquid Interface Models. He emphasized the program's goal to enhance capabilities for predicting adverse health effects through proof-of-concept studies and adverse outcome pathways, where toxicity endpoints are utilized to correlate key events following toxin exposure. Dr. Gwinn also discussed a proposed inter-laboratory reproducibility study with NICEATM to improve understanding of these processes. Finally, he mentioned an upcoming release on June 7th of a DTT RFI summary report, advising forum participants to watch out for it.
NIST
Elijah Petersen, Darwin Reyes, and Mandy Esch from the National Institute of Standards and Technology (NIST) presented NIST's initiatives in NAMs. Their work is pivotal for developing accurate and reliable human health assessments while minimizing the necessity for animal testing. They outlined the efforts of working groups to standardize and research organ-on-a-chip technologies, focusing on the heart, kidney, and liver. Additionally, they explored the potential of MPS in addressing secondary drug toxicity, a challenging issue often leading to drug failures during clinical trials or post-approval. They emphasized the importance of developing standards for data quality parameters, including devices, tissues, and operational procedures (such as medium change frequency). Finally, they noted that the industry appears particularly interested in research concerning the liver, heart, kidney, and brain.
OECD Updates
Charles Kovatch, an EPA employee assigned to OECD, discussed the approval of nine items in the test guidelines and the addition of 18 new projects to the OECD work plan, with four of the 18 approved projects being NAM-related, which Dr. Kovatch considered positive. He highlighted the disparity between U.S. and EU-focused projects, noting that while five U.S. projects are centered on health effects, the E.U. is directing attention toward pollinator sensitivities. He mentioned a forthcoming workshop report in June 2024 for forum participants to watch out for. This report stems from a December 2023 workshop that followed a January 2023 call to mobilize resources to demonstrate the reproducibility and reliability of methods developed in single labs.
Day 2 Highlights
Public Statements and Discussions
The second day began with summaries of written public statements, followed by oral presentations from various stakeholders. Our policy team submitted an oral and written statement, which can be found here.
NIH: Advisory Committee to the Director
Anna Mazzucco provided an overview of the advisory committee to the director NAM working group recommendations, which were accepted by director Monica Bertagnolli earlier this year. Dr. Mazzucco emphasized the importance of integration, particularly involving combinatorial NAMs, and walked through the recommendations accepted by Dr. Bertagnolli. Audience members raised questions about the availability of funding data she presented, which does not appear publicly accessible. An internal plan for formal implementation was also mentioned, although no formal plan is currently available to the public. Dr. Mazzucco stated that the formal plan is still under discussion while timelines and metrics are being developed.
NIH: Complement-ARIE Program
Margaret Ochocinska presented the NIH's Complement-ARIE Program, which aims to supplement animal research with alternative methods. This program is part of a broader effort to incorporate NAMs into mainstream research practices, and a stakeholder summary is available online. Dr. Ochocinska discussed a landscape analysis that will be published later this year, emphasizing the program's goal to integrate and offer solutions in ways that were not previously feasible. She also mentioned broader scope centers featuring numerous projects highlighting priority areas. During the presentation, an audience member asked how much people discussed new techniques and Dr. Ochocinska responded by highlighting the high risk and high reward mentality of investigators.
Foundation for the NIH
Dana Connors discussed activities related to NAMs and human health translation in his role at the Foundation for the NIH, an organization that collaborates with both public and private sectors. He highlighted their Accelerating Medicine Partnership and the Biomarkers Consortium, which consists of shorter projects to deliver quicker validation results. Dr. Connors expressed hope in leveraging existing consortiums for the Complement-ARIE vision, emphasizing the importance of public-private partnerships (PPP) in advancing NAMs. They are reviewing proposals for the NIH and anticipate a network meeting in the next few months. Connors encouraged anyone interested in participating in the validation network for the 2025-2029 implementation phase to reach out. He noted significant interest from major pharmaceutical companies in establishing such a program, as they are actively pursuing NAMs but require external validation, which they cannot accomplish quickly enough on their own.
Botanical Safety Consortium
Cynthia Rider discussed the Botanical Safety Consortium's efforts to evaluate NAMs for use with complex mixtures, which is crucial for assessing the safety of botanical products containing multiple chemical constituents. The Botanical Safety Consortium employs public-private partnerships (PPP) to assess complex mixtures. She emphasized that while Tox21 primarily focuses on single chemicals, there are ongoing efforts to expand its scope to include mixtures. Dr. Rider highlighted the challenge of distinguishing between active and adverse effects. This led them to focus on highly toxic botanicals, compare expected outcomes with actual assay results, and develop reference data.
NIEHS: Division of Translational Toxicology
Erik Tokar discussed the Division of Translational Toxicology's (DTT) novel tools and approaches, encompassing 69 projects in their portfolio. These projects primarily focus on bioassays, biosystems, and novel applications in toxicology. Dr. Tokar highlighted several exemplary models for early life development within the portfolio. Although he was a new member of the team and unable to discuss the prioritization strategy of these methods, he emphasized the positive strides being taken to develop comprehensive tools for toxicity assessment.
USDA AWIC
Jessie Carder from the USDA Animal Welfare Information Center provided an update on AWIC’s available resources. These include a bibliography on NAMs in EcoTox, curated by professional librarians, and searchable databases regularly updated with new literature. Ms. Carder also discussed ALTBIB hedges, which will soon be available, along with tools that can be accessed to enhance literature search strategies. ALTBIB is a search tool that provides citations from publications related to alternatives in biomedical research. Search hedges are a comprehensive list of search terms to receive journal articles for systematic reviews. AWIC hopes the soon-to-be-released ALTBIB hedges will be a valuable tool for researchers to strengthen their search strategies.
I had the opportunity to attend a workshop hosted by Ms. Carder and her AWIC colleagues, and I will share my key takeaways in a future blog post, which will be available here.
Department of Defense's Research
Rebecca Clewell and Valerie Adams from the U.S. Department of Defense presented their research on using NAMs for hazard assessment. Their work aligns with the military's commitment to adopting safer and more ethical testing practices. Dr. Clewell focuses on product development and testing for the Air Force, emphasizing predictive risk capability building rather than basic research. They aim to aggregate exposure limit information for any chemical to facilitate quick decision-making. They are exploring multitask machine learning models to enhance the generalizability of Quantitative Structure-Activity Relationship (QSAR) models and collaborating with our colleagues at Hopkins' Applied Physics Laboratory (APL) to forecast emerging threats.
Dr. Adams is collaborating with service members and first responders at both federal and state levels to characterize hazards. Studying the military population offers insights that can benefit the general public, exemplified by their ongoing comparative analysis of per- and poly-fluoroalkyl substances (PFAS) in blood samples. Like Dr. Casey's update on PROMETHEUS, they are optimistic that the meticulous data collected on military personnel can improve the future of toxicology based on human, rather than animal, data.
NICEATM and ICCVAM Updates
Nicole Kleinstreuer provided updates from NICEATM, while Emily Reinke discussed recent developments within ICCVAM workgroups. These updates highlighted ongoing efforts to validate and promote NAMs across various sectors. Dr. Kleinstreuer was pleased to report that NCATS requested official membership in ICCVAM, indicating the growing number of agencies within ICCVAM. She also discussed ICCVAM's efforts to democratize informatics and utilize open-access tools to assist non-expert users. Additionally, she mentioned the ongoing work to automate manually curated Integrated Chemical Environment (ICE) data, which includes in vivo and in vitro test data, in silico toxicity predictions, reference chemical lists and more. Dr. Kleinstreuer also discussed the opportunity to beta-test the new Skin Allergy Risk Assessment (SARA) computational model. Finally, she highlighted the strong DNT program and collaboration with international consortia.
Dr. Reinke provided a quick overview of several workgroups, including the acute toxicity test, consideration of alternative methods, ecotoxicity test, and in vitro to in vivo extrapolation, validation, and PFAS working groups. These groups are continuing to publish reports throughout the year. After fulfilling its goals, the In Vitro to In Vivo Extrapolation working group has officially transitioned into an expert group, with several published papers available online. ICCVAM appears pleased with the current progress and optimistic for the future.
Concluding thoughts
The 2024 ICCVAM Public Forum highlighted progress and future directions in alternative testing methods and how that work is proceeding in federal agencies and some partners. The presentations and discussions underscored a shared commitment to reducing animal testing while improving regulatory science and maintaining rigorous safety standards. As these new methodologies develop and gain acceptance, they promise to transform toxicology and public health practice, making safety assessments more accurate, efficient, and relevant to human health and the environment and provide new insights that can improve public health protection while using far fewer animals.
The views expressed do not necessarily reflect the official policy or position of Johns Hopkins University or Johns Hopkins Bloomberg School of Public Health.
