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Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

This Request for Information (RFI) solicits voluntary information from all stakeholders in the radiation research community to provide input on how sex differences in radiation responses influence: 1) radiation-induced injuries in preclinical animal models, 2) efficacy of medical countermeasures (MCMs), and/or 3) evolution of biomarkers (for biodosimetry development). The goal of this RFI is to gain insight into the current research landscape on sex differences in radiation injury, and specifically to learn about the challenges and gaps in the field. The NIAID may use the information acquired via this RFI to develop future programs or initiatives to support research in the scientific areas mentioned above, to better understand sex differences after radiation exposure.

Background

The Radiation and Nuclear Countermeasures Program (RNCP) was established in 2004 under the Division of Allergy, Immunology, and Transplantation (DAIT), within NIAID/NIH to help prepare the United States to respond quickly and effectively to injuries caused by radiation exposure during a public health emergency. The mission of the RNCP is to accelerate the development of approaches to diagnose, mitigate, and treat injuries resulting from a radiological or nuclear incident through funding early through advanced, basic, and translational research. The Department of Health and Human Services (HHS) Public Health Emergency Medical Countermeasures Enterprise Implementation Plan for Chemical, Biological, Radiological and Nuclear (CBRN) Threats (HHS PHEMCE Implementation Plan) (https://www.govinfo.gov/content/pkg/FR-2007-04-23/pdf/07-1983.pdf) provides a blueprint for all U. S. Government CBRN diagnostic and MCM-related activities, and since 2004, NIAID has had the responsibility to develop and manage a comprehensive research and product development portfolio focused on medical therapies and diagnostics for radiation injuries. The program is guided by the NIH Strategic Plan and Research Agenda for Medical Countermeasures against Radiation and Nuclear Threats (https://www.niaid.nih.gov/sites/default/files/radnucstrategicplan.pdf), which was updated in 2012 (https://www.niaid.nih.gov/sites/default/files/radnucprogressreport.pdf).

To date, four drugs have been approved by the U.S. Food and Drug Administration (Neupogen®, Neulasta®, Leukine®, and Nplate®) [1] to treat hematopoietic acute radiation syndrome (ARS), with three of the approvals based on animal studies supported by NIAID, in close collaboration with Amgen Inc. The RNCP is now more focused on identifying MCMs to treat other acute and long-term radiation effects involving the gastrointestinal, pulmonary, cutaneous, renal, cardiovascular, and central nervous systems. However, a major challenge in identifying appropriate biomarkers of injury and developing effective MCMs is that radiation appears to elicit differential effects in males versus females.

The impact of sex differences in radiation-induced disease progression, severity, and sensitivity to treatments is well-documented. Of particular interest are sex-related, human health outcomes that have been identified after radiation exposure. For example, studies of atomic bomb survivors from Hiroshima and Nagasaki showed that cancer incident rates were higher in females compared to their male counterparts[2]; and after the Chernobyl accident, in Belarus and Ukraine, thyroid cancer affected women disproportionately compared to male counterparts [3]. Many other non-cancerous, sex-dependent health outcomes observed after the Chernobyl accident present at higher rates in females, including increased adult bronchial asthma, high blood pressure, and heart attacks [4]. Preclinical research shows that genomic damage occurs more frequently in male mice, demonstrated through increased micronuclei detection [5], and through higher p53-dependant apoptosis of human and mouse male germ cells [6] exposed to radiation. MCM studies also show sex differences, where post-irradiation survival increased after treatment in male, but not female animals [7, 8]. Understanding reasons for these sex differences in radiation studies is important to ensure MCMs and biodosimetry tools benefit all. Research to understand these sex-based differences in radiation responses and sensitivity could lead to the identification of novel drug targets, MCMs, and robust biomarker identification and biodosimetry tools.

Information Requested

All stakeholders in the radiation community, including academic groups, industry representatives, and government research staff are invited to respond. NIAID is seeking voluntary information to inform and facilitate understanding sex differences in radiation research. Topics include, but are not limited to:

• Identifying sex-linked sensitivity in radiation injury in human exposures and animal models in response to total and/or partial body irradiation.
• Dissecting mechanistic pathways leading to sex differences in radiation injury.
• Determining the influence of sex confounders (e.g., chromosomal, reproduction stage, excreted chemicals such as pheromones and hormones) or sex-linked organ specificity (heart, lung, etc.) on the development of radiation animal models and MCMs.
• Improving identification of robust biomarkers for diagnosis and/or radiation injury prediction models in acute or delayed effects of acute radiation exposure.
• Examining sex difference effects of MCMs that are administered 24 hours or later post-irradiation and are relevant to a radiological or nuclear incident.

Submitting a Response

Responses to this RFI must be submitted electronically to: Olivia.Molinar-Inglis@nih.gov

Responses must be received by May 4, 2022.

Responses should be limited to 2 pages and emailed as an attachment (Microsoft Word or PDF). Please do not include proprietary, classified, confidential, or sensitive information in your response. Submitted data and information will not be returned and will not be considered confidential.

Responses to this RFI are voluntary. This RFI is for planning purposes only and should not be construed as a solicitation or as an obligation on the part of the Federal Government, the National Institutes of Health, or NIAID. The NIH does not intend to make any awards in response to this RFI or to pay for either the preparation of information submitted or the Government’s use of such information.

Inquiries

Please direct all inquiries to:

Olivia Molinar-Inglis, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-7755
Email: Olivia.Molinar-Inglis@nih.gov

Citations:

1. DiCarlo, A.L., et al., Use of Growth Factors and Other Cytokines for Treatment of Injuries During a Radiation Public Health Emergency. Radiation Research, 2019. 192(1): p. 99-120, 22.
2. Brenner, A.V., et al., Comparison of All Solid Cancer Mortality and Incidence Dose-Response in the Life Span Study of Atomic Bomb Survivors, 1958-2009. Radiat Res, 2022.
3. Mahoney, M.C., et al., Thyroid cancer incidence trends in Belarus: examining the impact of Chernobyl. International Journal of Epidemiology, 2004. 33(5): p. 1025-1033.
4. Narendran, N., L. Luzhna, and O. Kovalchuk, Sex Difference of Radiation Response in Occupational and Accidental Exposure. Frontiers in Genetics, 2019. 10.
5. Stojković, R., et al., Age and sex differences in genome damage between prepubertal and adult mice after exposure to ionising radiation. Arh Hig Rada Toksikol, 2016. 67(4): p. 297-303.
6. Guerquin, M.-J., et al., Sex-specific differences in fetal germ cell apoptosis induced by ionizing radiation. Human Reproduction, 2008. 24(3): p. 670-678.
7. Velardi, E., et al., Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med, 2018. 24(2): p. 239-246.
8. Daniel, A.R., et al., Inhibiting Glycogen Synthase Kinase-3 Mitigates the Hematopoietic Acute Radiation Syndrome in a Sex- and Strain-dependent Manner in Mice. Health Phys, 2020. 119(3): p. 315-321.