Request for Pre-Proposals for ADME/Toxicology on Erythritol

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The Institute for the Advancement of Food and Nutrition Sciences (IAFNS) is a non-profit, 501(c)(3) scientific organization that pools funding from industry collaborators and advances science through the in-kind and financial contributions from public and private sector participants.

The IAFNS Working Group on Erythritol is committed to proactively improving the science and evidence basis for decision making by all sectors. Regulators globally are seeking current information on the safety profile of erythritol and a deeper understanding of erythritol exposure (the how much erythritol is added to foods). Industry is seeking to fully understand various low and no calorie sweeteners. And, academic researchers, including those focused on nutrition are seeking additional hypotheses to test.

IAFNS adheres to rigorous procedures to maintain scientific integrity in all work we support. These requirements include adhering to the 9 Guiding Principles for Scientific Integrity and the Center for Open Science TOP Guidelines.

Background
Erythritol is an ingredient added to foods and beverages as a no calorie sweetener. Additionally, it can be added as a flavoring agent and/or a bulking agent. Erythritol is also produced endogenously in the human body and occurs naturally in some fruits, vegetables, and fermented foods.

A 2023 Nature Medicine paper (Witkowski, M., Nemet, I., Alamri, H. et al., 2023) reported an association between high erythritol blood levels and adverse cardiovascular events. The study also reported pilot data on 8 subjects showing a substantial dietary erythritol intake was associated with increased blood clotting.

References
Witkowski, M., Nemet, I., Alamri, H. et al. The artificial sweetener erythritol and cardiovascular event risk. Nat Med 29, 710–718 (2023).
https://doi.org/10.1038/s41591-023-02223-9.

Teysseire, F., Bordier, V., Budzinska, A., et al. Metabolic Effects and Safety Aspects of Acute D-allulose and Erythritol Administration in Healthy Subjects. Nutrients, 15(2), 458. (2023).
https://doi.org/10.3390/nu15020458.

Mazi, T. & Stanhope, K.L., Elevated Erythritol: A Marker of Metabolic Dysregulation or Contributor to the Pathogenesis of Cardiometabolic Disease? Nutrients, 15(18), 4011 (2023).
https://doi.org/10.3390/nu15184011.

Mazi, T. & Stanhope, K.L., Erythritol: An In-Depth Discussion of Its Potential to Be a Beneficial Dietary Component. Nutrients, 15(1):204 (2023). https://doi.org/10.3390/nu15010204.

Bordier, V., Teysseire, F., Senner, F., et al., Absorption and Metabolism of the Natural Sweeteners Erythritol and Xylitol in Humans: A Dose-Ranging Study. International journal of molecular sciences, 23(17), 9867 (2022). https://doi.org/10.3390/ijms23179867.

Wölnerhanssen, B. K., Meyer-Gerspach, A. C., Beglinger, C., & Islam, M. S., Metabolic effects of the natural sweeteners xylitol and erythritol: A comprehensive review. Critical reviews in food science and nutrition, 60(12), 1986–1998 (2020). https://doi.org/10.1080/10408398.2019.1623757.

Wang, Z., Zhu, C., Nambi, V., et al. Metabolomic Pattern Predicts Incident Coronary Heart Disease. ATVB, 1475 – 1482 (2019). https://doi.org/10.1161/ATVBAHA.118.312236.

Hootman, K., Trezzi, J.P., Kraemer, L. et al. Erythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults. PNAS, 114 (21) E4233-E4240 (2017).
https://doi.org/10.1073/pnas.1620079114.

Munro, I. C., Berndt, W. O., Borzelleca, J. F., et al. Erythritol: an interpretive summary of biochemical, metabolic, toxicological and clinical data. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 36(12), 1139–1174. (1998).
https://doi.org/10.1016/s0278-6915(98)00091-x.

Bernt, W. O., Borzelleca, J. F., Flamm, G., & Munro, I. C. Erythritol: a review of biological and toxicological studies. Regulatory toxicology and pharmacology : RTP, 24(2 Pt 2), S191–S197(1996).
https://doi.org/10.1006/rtph.1996.0098.

Objective and Proposal Content
The IAFNS Working Group on Erythritol is requesting pre-proposals for a project that explores through a literature review, the potential relationships between dietary erythritol and human health outcomes. The review should address the following:

  • The current state of the science regarding the absorption, distribution, metabolism, and excretion of erythritol – including the unknowns.
  • The current state of the science regarding the toxicological profile of erythritol – including the unknowns.
  • Review of potential cellular and biochemical mechanisms by which endogenous and dietary erythritol could impact the blood clotting cascade.
  • Information on the expected exposure levels from endogenous and dietary erythritol.

The resulting updated ‘state of the science’ summarizing the bioavailability, exposure, pharmacokinetics and toxicology of dietary erythritol would support decision making across the public and private sectors.

Pre-Proposal Preparation Instructions
The Working Group requests that applicants address each of the following components below in their proposal, which should be not more than 3 pages single-spaced:

  1. Overview. Briefly discuss the purpose of the literature review. Describe how the proposed review will add to existing knowledge.
  2. Approach. Outline what the proposed review is intended to accomplish (i.e. list project objectives or aims) and briefly describe the methodologies that will be used to capture the appropriate information. This may include the search strategy, and a discussion on the inclusion of regulatory filings (such as GRAS notifications) and/or dissertations.
  3. Timeline and Key Deliverables:
    1. Update to the Working Group on Erythritol (via webinar).
    2. Publication in a peer reviewed journal.
    3. Presentation at appropriate scientific forum.
    4. Timeline to completion: 6-9 months.
  4. Potential Conflicts of Interest. List any potential conflicts of interests for all investigators, co-investigators, collaborators. We suggest using the Conflict of Interest Guidelines as set forth by the American Society for Nutrition: https://nutrition.org/publications/guidelines-and-policies/conflict-of-interest/
  5. Principle Investigator CV is also required but is not included in the page limit

In addition, as you prepare your pre-proposal, please note the following points:

  • Attachments such as reprints of scientific papers and budgets are discouraged. This information will be required later if a full proposal is requested.
  • There is no restriction regarding either the citizenship of applicants or the country where the research will be conducted. However, all submitted documents must be in English.
  • Receipt of a research grant does not preclude the recipient from obtaining grant support in the same or similar area from other sources.
  • Under the terms of this grant program, the amount of institutional overhead or indirect costs that can be included in the project budget is limited to 10%.
  • Grants awarded under this program are typically approved for up to a one-year period. In exceptional cases, funding for an additional 6 months may be considered.

Page Limit: 3 pages, single spaced (not including PI’s CV)

Pre-Proposal Submission Deadline Extended to November 30, 2023

Submission Instructions: Proposals (and questions) can be submitted to Neal Saab, PhD Senior Scientific Program Manager, nsaab@iafns.org

Review Process:
A review committee composed of scientists from academia, government, and industry will evaluate the pre-proposals. It is anticipated that applicants will be notified of the status of their pre-proposals within a few weeks. At that time, successful pre-proposal applicants will be asked to submit full proposals for projects to begin in January 2024, if funded. Critiques of individual pre-proposals cannot be provided.