National Toxicology Program

NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)

By Catherine Sprankle

NICEATM Scientist Honored for Advancing Use of In Vitro to In Vivo Extrapolation

NICEATM scientist Xiaoqing Chang (Inotiv, contractor supporting NICEATM) is first author on two 2022 publications describing applications of in vitro to in vivo extrapolation (IVIVE) that were honored by the publishing journals.

• “IVIVE: facilitating the use of in vitro toxicity data in risk assessment and decision making” was included by the journal Toxics on its list of “Annual Recommended Reviews in 2022.” The complete list of reviews, with links to the papers, is available at mdpi.com.
• “Quantitative in vitro to in vivo extrapolation for developmental toxicity potency of valproic acid analogues” received the 2023 James G. Wilson Publication Award from the Society of Birth Defects Research and Prevention. The award recognizes the best paper accepted or published in the journal Birth Defects Research during the prior year. Chang will receive her award at the Society’s 63rd Annual Meeting in Charleston, South Carolina this summer. The paper is available at https://doi.org/10.1002/bdr2.2019.

EPA Seeks Comment by March 20 on Use of NAMs for Endocrine Disruptor Screening

In a January 19 Federal Register notice, the U.S. Environmental Protection Agency (EPA) announced availability of a draft white paper, “Availability of New Approach Methodologies (NAMs) in the Endocrine Disruptor Screening Program (EDSP).” The white paper states that certain NAMs have been validated and may now be accepted by the EPA as alternatives for certain Tier 1 assays used within the EDSP. Other NAMs may be useful for prioritization purposes and for use as other scientifically relevant information, where appropriate, in weight-of-evidence evaluations. EPA is accepting comment on the draft white paper through March 20.

The EDSP was established by the Federal, Food, Drug and Cosmetic Act, which required EPA to develop a screening program to determine whether certain substances may have effects in humans similar to effects produced by naturally occurring estrogens or other endocrine effects. The purpose of Tier 1 EDSP screening is to identify chemicals that have potential biological activity in the estrogen, androgen, or thyroid hormone pathways. Recent EPA research efforts have focused on the development and evaluation of high-throughput in vitro assays and in silico methods as NAMs, including databases and computational models, for use as alternatives to the current suite of assays in the EDSP Tier 1 battery, to accelerate the pace of screening, add efficiencies, decrease costs, and reduce animal testing.

NICEATM and ICCVAM Activities at SOT 2023

An NTP webpage is available listing activities of NICEATM and Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) at the upcoming Annual Meeting of the Society of Toxicology (SOT) on March 19-23. The page includes downloadable files of selected abstracts.

NICEATM and ICCVAM will have a strong presence at SOT.

• ICCVAM representative Cecilia Tan (EPA) is chairing and presenting in a continuing education course on “A Training on the OECD Guidance for Characterizing, Validating, and Reporting Physiologically Based Kinetic Models.”
• NICEATM scientist Helena Hogberg is co-chairing and presenting in a continuing education course on “In Vitro to In Vivo Extrapolation Strategy and Guidance across Organ System Toxicities.”
• A March 21 exhibitor-hosted session sponsored by the National Institute of Environmental Health Sciences will focus on “ICCVAM Progress on Advancing Alternatives: Five Years into the Strategic Roadmap.”
• NICEATM staff are chairing, co-chairing, or presenting at eight oral presentation sessions and 12 poster sessions.
• ICCVAM committee members are chairing, co-chairing, or presenting at nine oral presentation sessions and 24 poster sessions.
• ICCVAM committee members are presenting at a March 23 satellite meeting on “21^st Century Toxicology: Sneak Preview of Ongoing Relevant Activities.” This event is organized by the Johns Hopkins University Center for Alternatives to Animal Testing and Humane Society International/Animal-free Safety Assessment Collaboration. It is free and open to both SOT attendees and remote viewers.

Funding Available to Support Development of MPS

Several recent announcements offer funding to support development of microphysiological systems (MPS), or organs-on-chips. These systems provide in vitro models of properties that define organ or tissue function and can enable biologically relevant investigation of toxicity.

• Three institutes of the National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA) are offering funding to establish research centers that will accelerate the translational use of MPS in drug development through regulatory acceptance and adoption for industrial use. U.S.-based nonprofit and for-profit institutions are encouraged to apply for funding; foreign institutions are not eligible. Applications are due by March 28.
• NIH and FDA are also offering Small Business Innovation Research and Small Business Technology Transfer grants to support development of neuromuscular junction tissue chips to replace the mouse lethality assay for testing potency of botulinum toxin. Applications are due August 21. Only U.S. small businesses are eligible for this funding.
• The National Institute of Diabetes and Digestive and Kidney Diseases has established the (Re)Building a Kidney Consortium to apply new technologies to understand and treat kidney diseases. Strategies of interest include development of in vitro cultures and organoids. The Consortium is offering grants of up to $100,000 that may be applied to direct and indirect costs of relevant activities. Researchers affiliated with U.S. and foreign non-profit and for-profit organizations are encouraged to apply. Applications are due April 3.

Slides and Video Available from Fall and Winter Meetings

Materials are now available from three past meetings about NICEATM activities.

• Slides, video, and minutes are available from the September 2022 meeting of the Scientific Advisory Committee on Alternative Toxicological Methods (SACATM). SACATM advises ICCVAM, NICEATM, and the Director of NIEHS and NTP on the statutorily mandated duties of ICCVAM and NICEATM activities. The 2023 SACATM meeting is planned for September 21-22 at NIEHS in Research Triangle Park, NC.
• Slides and video are available for an October 2022 NICEATM symposium webinar on “Using New Approach Methodologies to Address Variability and Susceptibility Across Populations.”
• Slides and video are also available from a January 30 webinar on “Emerging Approaches for Anchoring Biological Relevance of New Approach Methodologies.” This webinar, which was viewed by about 400 people, was the latest in the Communities of Practice webinar series presented by NICEATM on behalf of ICCVAM.

For information about other upcoming NICEATM and ICCVAM events, visit the NICEATM 3Rs Meetings, Workshops & Webinars page. The annual ICCVAM Public Forum will be May 18-19 at the National Institutes of Health in Bethesda, MD. Materials and a link to register will be posted on the meeting information webpage when available.

Recent NICEATM Publications

• NICEATM Director Nicole Kleinstreuer is an author of a report of a 2021 symposium that explored the use of new approach methodologies for regulatory decision making for tobacco products. The symposium illustrated common ground and interest in science-based engagement across the scientific community and stakeholders in support of tobacco regulatory science.
  Lee et al. 2022. Advancing new approach methodologies (NAMs) for tobacco harm reduction: synopsis from the 2021 CORESTA SSPT–NAMs symposium. Toxics. https://doi.org/10.3390/toxics10120760.
• A paper by NICEATM Director Nicole Kleinstreuer and collaborators presents an analysis of data from the mouse local lymph node assay (LLNA), a standard animal test to identify skin sensitizers. A comparison of LLNA and human data indicates that the LLNA has a high false-positive rate for lipophilic chemicals, suggesting that validation of non-animal tests for skin sensitization intended for use with lipophilic chemicals should not be based solely upon LLNA data.
  Natsch et al. 2023. Reduced specificity for the local lymph node assay for lipophilic chemicals: Implications for the validation of new approach methods for skin sensitization. Reg Toxicol Pharmacol. https://doi.org/10.1016/j.yrtph.2023.105333.
• A paper in Applied In Vitro Toxicology describes the use of non-animal defined approaches to characterize skin sensitization potential of isothiazolinones. These substances are widely used as antimicrobial preservatives in cosmetics and consumer and industrial products. The study by NICEATM scientists and collaborators indicated that defined approaches show promise to support hazard and potency classification and quantitative risk assessment for isothiazolinones.
  Strickland et al. 2022. Application of defined approaches to assess skin sensitization potency of isothiazolinone compounds. Appl In Vitro Toxicol. https://doi.org/10.1089/aivt.2022.0014.