# Radiation adverse outcome pathways (AOPs) are on the horizon: advancing radiation protection through an international Horizon-Style exercise

Julie J Burtt, Julie Leblanc, Kristi Randhawa, Addie Ivanova, Murray A Rudd, Ruth Wilkins, Edouard I Azzam, Markus Hecker, Nele Horemans, Hildegarde Vandenhove, et al.

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## ► To cite this version:

Julie J Burtt, Julie Leblanc, Kristi Randhawa, Addie Ivanova, Murray A Rudd, et al. Radiation adverse outcome pathways (AOPs) are on the horizon: advancing radiation protection through an international Horizon-Style exercise. International Journal of Radiation Biology, 2022, 98 (12), pp.1763-1776. 10.1080/09553002.2022.2121439. irsn-04021225

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Submitted on 9 Mar 2023

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# Radiation adverse outcome pathways (AOPs) are on the horizon: advancing radiation protection through an international Horizon-Style exercise

Julie J. Burtt, Julie Leblanc, Kristi Randhawa, Addie Ivanova, Murray A. Rudd, Ruth Wilkins, Edouard I. Azzam, Markus Hecker, Nele Horemans, Hildegarde Vandenhove, Christelle Adam-Guillermin, Olivier Armant, Dmitry Klokov, Karine Audouze, Jan Christian Kaiser, Simone Moertl, Katalin Lumniczky, Ignacia B. Tanaka III, Yutaka Yamada, Nobuyuki Hamada, Isaf Al-Nabulsi, R. Julian Preston, Simon Bouffler, Kimberly Applegate, Donald Cool, Danielle Beaton, Knut Erik Tollefsen, Jacqueline Garnier-Laplace, Dominique Laurier & Vinita Chauhan

**To cite this article:** Julie J. Burtt, Julie Leblanc, Kristi Randhawa, Addie Ivanova, Murray A. Rudd, Ruth Wilkins, Edouard I. Azzam, Markus Hecker, Nele Horemans, Hildegarde Vandenhove, Christelle Adam-Guillermin, Olivier Armant, Dmitry Klokov, Karine Audouze, Jan Christian Kaiser, Simone Moertl, Katalin Lumniczky, Ignacia B. Tanaka III, Yutaka Yamada, Nobuyuki Hamada, Isaf Al-Nabulsi, R. Julian Preston, Simon Bouffler, Kimberly Applegate, Donald Cool, Danielle Beaton, Knut Erik Tollefsen, Jacqueline Garnier-Laplace, Dominique Laurier & Vinita Chauhan (2022) Radiation adverse outcome pathways (AOPs) are on the horizon: advancing radiation protection through an international Horizon-Style exercise, *International Journal of Radiation Biology*, 98:12, 1763-1776, DOI: 10.1080/09553002.2022.2121439

**To link to this article:** https://doi.org/10.1080/09553002.2022.2121439

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ORIGINAL ARTICLE

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# Radiation adverse outcome pathways (AOPs) are on the horizon: advancing radiation protection through an international Horizon-Style exercise

Julie J. Burttª ID, Julie Leblancª ID, Kristi Randhawaª ID, Addie Ivanovaª ID, Murray A. Ruddb ID,
Ruth Wilkinsc ID, Edouard I. Azzamd ID, Markus Heckere ID, Nele Horemansf ID, Hildegarde Vandenhoveg ID,
Christelle Adam-Guillerminh ID, Olivier Armanth ID, Dmitry Klokovh,i ID, Karine Audouzej ID, Jan Christian Kaiserk ID,
Simone Moertl ID, Katalin Lumniczkym ID, Ignacia B. Tanaka III ID, Yutaka Yamadao ID, Nobuyuki Hamadap ID,
Isaf Al-Nabulsiq ID, R. Julian Prestonr ID, Simon Boufflerst ID, Kimberly Applegatet ID, Donald Coolu ID, Danielle
Beatond ID, Knut Erik Tollefsenv,w,x ID, Jacqueline Garnier-Laplaceh,y ID, Dominique Laurierh ID, and Vinita
Chauhanc ID

ªDirectorate of Environmental and Radiation Protection and Assessment, Canadian Nuclear Safety Commission, Ottawa, Canada;

ᵇIndependent Consulting Economist, Dartmouth, Canada; ᶜConsumer and Clinical Radiation Protection Bureau, Ottawa, Canada; ᵈIsotopes, Radiobiology and Environment Directorate, Canadian Nuclear Laboratories, Chalk River, Canada; ᵉSchool of Environment and Sustainability, University of Saskatchewan, Saskatoon, Canada; ᶠBiosphere Impact Studies, Belgian Nuclear Research Center (SCK CEN), Mol, Belgium;

gEnvironment, Health and Safety, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium; hHealth and Environment Division, Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France; iDepartment of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada; kUniversité Paris Cité, T3S, Inserm UMRS 1124, Paris, France; lDeutsches Forschungszentrum fur Gesundheit und Umwelt (GMBH), Helmholtz Zentrum Munchen, Neuherberg, Germany; mNational Public Health Centre, Unit of Radiation Medicine, Budapest, Hungary; nDepartment of Radiobiology, Institute for Environmental Sciences, Aomori, Japan; oDepartment of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum Science and Technology, Chiba, Japan; pBiology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry (CRIEPI), Tokyo, Japan; qUS Department of Energy, Office of Domestic and International Health Studies, Office of Health and Safety, Office of Environment, Health Safety and Security, Washington, DC, USA; rOffice of Air and Radiation, Radiation Protection Division, US Environmental Protection Agency, Research Triangle Park, NC, USA; sUK Health Security Agency, Chilton, Didcot, UK; tDepartment of Radiology, University of Kentucky College of Medicine, Lexington, KY, USA; uICRP Main Commission, Belmont, NC, USA; vSection for Ecotoxicology and Risk Assessment, Norwegian Institute for Water Research (NIVA), Oslo, Norway; wFaculty of Environmental Sciences and Natural Resource Management, Norwegian University of Life Sciences (NMBU), Ås, Norway; xCentre for Environmental Radioactivity, Norwegian University of Life Sciences (NMBU), Ås, Norway; yOn secondment from IRSN to the Committee on Radiological Protection and Public Health's secretariat, Paris, France

ABSTRACT

**Purpose:** The Adverse Outcome Pathway (AOP) framework, a systematic tool that can link available mechanistic data with phenotypic outcomes of relevance to regulatory decision-making, is being explored in areas related to radiation risk assessment. To examine the challenges including the use of AOPs to support the radiation protection community, an international horizon-style exercise was initiated through the Organisation for Economic Co-operation and Development Nuclear Energy Agency High-Level Group on Low Dose Research Radiation/Chemical AOP Joint Topical Group. The objective of the HSE was to facilitate the collection of ideas from a range of experts, to short-list a set of priority research questions that could, if answered, improve the description of the radiation dose-response relationship for low dose/dose-rate exposures, as well as reduce uncertainties in estimating the risk of developing adverse health outcomes following such exposures.

**Materials and methods:** The HSE was guided by an international steering committee of radiation risk experts. In the first phase, research questions were solicited on areas that can be supported by the AOP framework, or challenges on the use of AOPs in radiation risk assessment. In the second phase, questions received were refined and sorted by the SC using a best-worst scaling method. During a virtual 3-day workshop, the list of questions was further narrowed. In the third phase, an international survey of the broader radiation protection community led to an orderly ranking of the top questions.

**Results:** Of the 271 questions solicited, 254 were accepted and categorized into 9 themes. These were further refined to the top 25 prioritized questions. Among these, the higher ranked questions will be considered as 'important' to drive future initiatives in the low dose radiation protection community. These included questions on the ability of AOPs to delineate responses across different levels of biological organization, and how AOPs could be applied to address research questions on radiation quality, doses or dose-rates, exposure time patterns and deliveries, and

ARTICLE HISTORY

Received 15 July 2022
Revised 23 August 2022
Accepted 31 August 2022

KEYWORDS

Adverse outcome pathway;
regulatory application;
survey; low dose radiation;
radiation protection;
risk assessment

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uncertainties in low dose/dose-rate effects. A better understanding of these concepts is required to support the use of the AOP framework in radiation risk assessment.

**Conclusion:** Through dissemination of these results and considerations on next steps, the JTG will address select priority questions to advance the development and use of AOPs in the radiation protection community. The major themes observed will be discussed in the context of their relevance to areas of research that support the system of radiation protection.

# 1. Introduction

The Adverse Outcome Pathway (AOP) framework has been demonstrated to be an effective means to consolidate and structure multiple lines of evidence, spanning many levels of biological organization. The AOP framework facilitates access to and understanding of complex data for risk assessors and decision-makers involved in setting guidelines for the protection of human health and the environment. Briefly, an AOP is a collaborative tool. It begins with a molecular initiating event (MIE) and is followed by key events (KEs) to a hypothetical toxicity pathway that ends in an adverse outcome (AO) (including cancer and non-cancer outcomes) linked via key event relationships (KERs) (Figure 1) (OECD 2016, 2021). The KERs are empirically supported through evidence using the modified Bradford Hill (B-H) criteria and best represented through the development of AOP networks.

AOPs were initially conceived by experts in the chemical toxicology field (Ankley et al. 2010) and then adopted by the Organisation for Economic Co-operation and Development (OECD) Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST). Currently the framework has over 460 deposited AOPs at different stages of development and this number is continually growing to meet the needs of risk assessors. More recent discussions on formalizing the OECD AOP Development Programme within EAGMST is a testament of the framework's success.

This success has instigated dialog on the value of using the AOP framework to compile the decades of mechanistic data generated in the radiation field and linking it to health outcomes documented in epidemiological studies (NCRP 2020). Case examples of AOPs have been initiated (Chauhan, Hamada et al. 2021; Chauhan, Sherman et al. 2021; Azimzadeh et al. 2022; Jaylet et al. 2022; Klokov et al. 2022; Tollefsen et al. 2022), including a vision of how AOPs could broadly support the radiation field (Chauhan, Leblanc et al. 2021; Chauhan, Stricklin et al. 2021; Chauhan, Villeneuve et al. 2021; Chauhan, Wilkins et al. 2021). There is agreement that the AOP approach could help reduce uncertainties in health and environmental risks from low

dose and low dose-rate exposures, which are most relevant to the public. However, there is also hesitation on how the approach can effectively achieve this, considering its simplistic representation of disease progression.

In June 2021, the OECD Nuclear Energy Agency (NEA) High-Level Group on Low Dose Research (HLG-LDR) formed the Radiation and Chemical (Rad/Chem) AOP Joint Topical Group (JTG) to investigate how the successes of the AOP framework in chemical toxicology could be further explored for structuring knowledge and data from radiation research, guiding radiation risk assessment and regulation.

As described by Chauhan, Beaton et al. (2022), concrete tasks were documented to achieve the vision and mission of the Rad/Chem AOP JTG. A horizon-style exercise (HSE) was the first element of the workplan. Horizon scanning is a method for systematically searching for and identifying emerging trends, opportunities, and limitations that might impact the future direction of a defined subject (Sutherland et al. 2011). In this case, the HSE was conducted to gauge the level of awareness, interest, and hesitation or even barriers in implementing the AOP framework in radiation research and regulation. The HSE described here followed the methodology of a similar horizon scan previously completed in the chemical toxicology field (LaLone et al. 2017). However, the goal of the horizon scan by LaLone et al. (2017) was to clarify to AOP developers the basic knowledge on structure and terminology. It also led to recognizing a need for training sessions and workshops to address common misperceptions on AOPs. Several follow-on activities have helped to address these challenges, evolve the framework, and further engage the chemical toxicity community leading to an evident rise in AOP development (Hecker and LaLone 2019). Horizon scans facilitate expanding the input from few contributors to collecting thoughts and ideas from a broad range of international experts (Sutherland and Woodroof 2009; Sutherland et al. 2011).

The overall objective of this HSE was to short-list a set of priority research questions that could, if answered, improve the description of the radiation dose-response relationship for low dose and low dose-rate exposures as well as reduce uncertainties in estimating the risk of developing adverse health outcomes following such exposures.

<figure><img src="image_21.png" /><figcaption>**Figure 1.** A hypothetical adverse outcome pathway (AOP), beginning with a molecular initiating event (MIE), followed by measurable and essential key events (KEs) connected by key event relationships (KERs), leading to an adverse outcome (AO) of interest to regulatory decision-making.</figcaption></figure>
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Here, we describe the process and methodology used, present the results from the survey, and discuss how the findings can guide the future programme of work of the Rad/Chem AOP JTG. The outcomes and identified future research needs will also provide valuable awareness, insights, and engagement opportunities to the broader radiation protection community (which includes researchers, regulators, and policymakers) dealing with human health and ecological risk assessment from radiation exposure.

## 2. Materials and methods

### 2.1. Phase I: Solicitation of candidate research questions

The HSE comprised three main phases (Figure 2). Phase I of the HSE involved first establishing a steering committee (SC) with membership from industry, academia and government consisting of experts and researchers in various scientific fields related to radiation protection research, regulation, and practices (authors of this paper). The role of the SC was to guide and promote the different phases of the HSE, play an active role in sorting, ranking, and refining the questions; and to increase the international impact of the exercise.

To ensure broad participation in the solicitation of candidate research questions and future phases of the HSE, SC members advertised the HSE through the second half of 2021 and into 2022 at numerous events, including Radiation Research Society (RADRES) webinar (RADRES 2021), International Commission on Radiological Protection (ICRP) Digital Workshop (ICRP 2021), International Society of Radiation Epidemiology and Dosimetry (ISoRED) webinar (ISoRED 2021), International Dose Effect Alliance (IDEA) Virtual Workshop (EPRI 2021), the 5th European Radiation Protection Week (ERPW) (EURAMED 2021), and the 6th European Congress on Radiation Protection (IRPA 2022).

To promote additional participation, SC members reached out to their professional networks and encouraged submission of radiation related AOP questions through a dedicated website created for this purpose. The call for questions was further circulated within the broader community of radiation protection professionals via social media posts and select email distribution lists. Both individuals and organizations were encouraged to submit candidate research questions. There were no requirements to self-identify, though the website did give the opportunity for those submitting to provide general information on their professional backgrounds. For individuals, this included years of experience in radiation-related work, primary domain of work, work sector, country of residence, familiarity with AOPs, number of publications in the general field of radiation research, number of publications in the specific field of

AOP research, and engagement in professional organizations. For institutional submissions, background questions included only type of organization and country in which the organization is based.

Submissions could be either 'a research question of interest that can be supported by the AOP framework' or 'a question that may be a challenge or limitation for the AOP framework to support'. Following criteria outlined by Sutherland et al. (2011), the candidate research questions should:

* address 'important' knowledge gaps (e.g. significant improvement of understanding of biological effects of radiation exposure, or reduction of uncertainties in risk estimates, with positive impact of the robustness of the system of radiation protection);

* provide a factual answer that does not depend on value judgment;

* cover a spatial and temporal scale that can realistically be addressed by expert groups; and

* not be answerable by 'yes', 'no', or 'it depends'.

### 2.2. Phase II: Refining candidate research questions

Following an initial review of 271 questions, the SC accepted 254 for the inclusion in the next phase of the survey development. In addition to the criteria outlined by Sutherland et al. (2011) as listed in section 2.1, duplicate questions were merged. In the first stage of the refinement process, SC members independently sorted collected questions using a best-worst scaling (BWS) ranking methodology (completed in October 2021) as described in Rudd et al. (2014) and used in sustainable environmental quality research (Fairbrother et al. 2019; Van den Brink et al. 2018). In each ranking task, SC members were repeatedly shown subsets of 4 questions drawn from the full list of 254 relevant questions. This preliminary work helped streamline the deliberations during the second stage, a 3-day virtual workshop held in December 2021. The workshop was limited to SC members only and attended by 28 of the 30 members. It also ensured that the virtual workshop breakout groups could quickly scan 'important' (higher ranked) and 'unimportant' (lower ranked) questions, focusing their time on questions which needed more deliberation.

The workshop consisted of an opening plenary, 9 breakout groups (3 parallel sessions), and a final plenary. Participants could rephrase or combine candidate questions or propose new questions to address issues not directly covered by submitted candidate questions. During the final plenary, the group discussed and agreed on the 'top 25'

<figure><img src="image_23.png" /><figcaption>Figure 2. Phases of the horizon-style exercise (HSE).</figcaption></figure>
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candidate questions. Some post-workshop discussions were required to finalize the top 25 candidate question list.

## 2.3. Phase III: International survey

### 2.3.1. International survey approach

An internet-based survey sent to the broader radiation protection community was used to rank the top 25 priority questions using the BWS approach, as described in section 2.2. The representatives of the SC did not take part in the survey to avoid bringing bias into the replies. After the survey's purpose and measures to ensure confidentiality were outlined, respondents were requested to complete 15 BWS ranking tasks. In each ranking task, respondents were repeatedly shown subsets of 4 questions drawn from the top 25 questions and were asked to select which questions were of relatively greater and of lesser importance. In addition to the ranking choices, respondents were also asked to indicate if they viewed all, some or none of the options shown as 'important'. This option allowed for calibrating the responses, enabling the SC to determine if the research questions that scored low in the overall rank were still 'important'. Ranks for each item were calculated for each respondent in real time, allowing for follow-up open-end responses as to why respondents chose specific questions as top choices and whether they would like to propose any replacement questions for the items that they ranked lowest. Finally, because this was an international survey, the BWS approach eliminated anchoring effects (Furnham and Boo 2011) that can be caused in rating-based survey techniques, allowing for non-biased mixing of international respondents' answers.

### 2.3.2. International survey instrument

The survey was designed using Sawtooth Software's Lighthouse Studio 9.12.1 (Sawtooth Software 2009), a

professional marketing and research software platform with dedicated and secure hosting services. The international survey was non-interventional, querying respondents only about professional opinions, and did not collect any personal information that would identify respondents or their institutions. It was designed similar to other previous surveys (e.g. Fairbrother et al. 2019; Rudd et al. 2014; Van den Brink et al. 2018), and all confidentiality protection measures were of similar standards. Respondents were assigned randomly to one of 300 versions of the BWS design, each of which consisted of 15 individual ranking tasks. Figure 3 shows an example of a BWS ranking task exercise.

### 2.3.3. International survey delivery

The HSE used a simple distribution method involving a combination of emails to appropriate scientific organizations and one-on-one contact (i.e. SC members encouraging their networks to distribute the survey among relevant contacts). While this method was not an ideal approach, because it precludes (1) use of an individually oriented 'tailored design' protocol (Dillman et al. 2009), and (2) calculation of survey response rates, for the relatively small radiation protection community, it was the only viable option to ensure as many opinions as possible were received and recorded.

### 2.3.4. Data analysis

The overall rankings of the top 25 questions were calculated using counts derived from Lighthouse Studio (Sawtooth Software 2009). For each respondent completing the ranking tasks, a fit score (root likelihood x 1000) was calculated, a measure of how consistent participants were in making choices across their ranking tasks. When 4 items are shown in each ranking task, random responses would imply a fit score of 250 (any random set of responses should be able to predict respondents' answers correctly with 25% likelihood, giving a fit score of 250). With a small sample (n up to 150), any fit

## Topic A - AOP components

Considering only the four questions below for now, which do you consider of greater and lesser relative importance?

(Ranking comparison 14 of 24)

<table><thead><tr><td>Relatively least important</td><td>Relatively most important</td><td>Candidate question submission</td></tr></thead><tbody><tr><td>◯</td><td>◯</td><td>Can AOP determine the threshold dose for radiation effects and, if so, is the threshold dose determined for each KE, or is it determined only for AO?</td></tr><tr><td>◯</td><td>◯</td><td>Which adverse endpoints are of largest importance within the field of radiation protection?</td></tr><tr><td>◯</td><td>◯</td><td>Can an adverse event be predicted by an upstream key event?</td></tr><tr><td>◯</td><td>◯</td><td>Is it possible to incorporate the available knowledge on radiation-induced chronic inflammation, immunosenescence, and acceleration of organismal senescence at individual levels into the KE of "inflammation and tissue remodeling"?</td></tr></tbody></table>

Click the 'Next' button to continue...

<caption>Figure 3. Example of a best-worst scaling (BWS) ranking task exercise for AOP questions.</caption>
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score < 300 suggests that a respondent answered ranking tasks randomly and their answers could be deleted.

# 3. Results

## 3.1. Phase I: Candidate research question solicitation

A website for candidate research question solicitation was constructed in June 2021 and remained open until early September 2021. A total of 271 candidate questions were submitted by 88 individuals and 13 organizations across over 20 countries (Figure 4(A)). Respondents generally had a high level of professional experience and were from sectors including government (31), academia (32), industry (12), international agencies (5), other (9), as well as some unspecified (13). An overview of the experience, domain, sector, number of publications, and overall familiarity with AOPs of the question solicitation respondents is captured in Figure 4(B).

## 3.2. Phase II: Refining candidate research questions (i.e. question sorting into themes)

Of the 271 candidate research questions received, 254 were deemed relevant, and sorted by the SC into 9 general themes (Figure 5):

* Themes 1–3 all related to mechanisms of radiation injury, discussed in plenary (99 questions)

* Theme 4: AOP components, discussed in breakout session (37 questions)

* Theme 5: Regulatory significance, discussed in breakout session (24 questions)

* Theme 6: Radiation vs chemicals, discussed in breakout session (22 questions)

* Theme 7: AOP challenges, discussed in breakout session (26 questions)

* Theme 8: Tools, approaches, integration, discussed in breakout session (27 questions)

* Theme 9: Data or weight of evidence, discussed in breakout session (19 questions)

During the breakout groups, participants were tasked with identifying 3 or 4 priority research questions in each theme. This was an effective way of reducing the 254 candidate questions to the 25 priority questions (Figure 6) considered of significance in guiding low dose radiation protection research and regulation.

## 3.3. Phase III: International survey

### 3.3.1. International survey sample

The top 25 questions identified in phase II were used in the international survey, where respondents were asked to comparatively rank their importance. A total of 173 individuals visited the survey website (17 January to 23 February 2022), 98 of whom completed and submitted the full survey. Of the 75 incomplete surveys, 19 completed the ranking exercise but dropped out later in the survey. Given the low number of completed surveys, the ranking responses provided by the 19 who completed only the ranking exercise were included. One respondent was deleted due to random answers in the ranking tasks (root likelihood score of 0.270).

### 3.3.2. International survey ranking results

Upon completion of the ranking section of the survey, every respondent was shown the AOP research questions that they, as an individual, had ranked as top 5 and bottom 5 priorities. Respondents were then asked how accurate they felt the ranking results reflected their true priorities.

Among the 97 survey respondents who fully completed the survey, answers to the accuracy query were:

* 31 excellent ('the list of higher and lower-ranked questions closely reflected my true priorities');

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<figure><img src="image_27.png" /><figcaption>**Figure 4.** (A) Demographic representation of the 101 participants in Phase I of the project, question solicitation, and (B) Overview of the experience, domain, sector, number of publications, and overall familiarity with AOPs of the question solicitation respondents. N.B. some respondents opted not to provide this information.</figcaption></figure>
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<figure><img src="image_29.png" /><figcaption>Figure 5. (A) Categories of questions received in Phase II of the HSE and (B) Emerging mechanistic themes from the solicitation process.</figcaption></figure>

Mechanistic Themes

* Epigenetic effects

* Immune responses

* Omic responses

* DNA damage/repair

* Multigenerational effects

* Positive effects

* Individual sensitivity

* Quantitative assessments
(dose/dose-rate/temporal
changes/radiation quality)

* 61 good ('the list reflected most of my priorities with only some minor discrepancies');

* 5 adequate ('the list reflected some of my priorities but there were also obvious discrepancies between this list and my true priorities'); and

* 0 poor ('the list did not at all reflect my true priorities').

A rank-order of the top 25 questions is provided in Supplemental Table 1. The proportion of times that a question was chosen as a top 3 and bottom 3 is provided in addition to the simple counts for which a priority research question was chosen as a top 3 or bottom 3 question. Differences in score values in Supplemental Table 1 indicate conflicts in ranking priority to some degree. For example, the 23rd ranked question, 'How can AOPs support enhancing the understanding of possible multigenerational and transgenerational radiation effects?' despite being ranked in the bottom 3 twenty-four times, still had 10 respondents rate it as being within their 3 most 'important' questions. Higher ranked questions, although lacking discernable separation from others, included questions on the ability of AOPs to delineate different levels of biological organization, and how AOPs could be applied to address regulatory and research questions on radiation quality, doses or dose-rates, exposure time patterns and deliveries, and uncertainties related to low dose and low dose-rate effects.

**4. Discussion**

To date, the HSE has met its objectives to short-list a set of priority research questions that could, if answered, improve the description of the radiation dose-response relationship for low dose and low dose-rate exposures as well as reduce uncertainties in estimating the risk of developing adverse

health effects following such exposures. The validity of the HSE was highly dependent on the successful collection of diverse views and opinions from a broad and representative stakeholder group throughout the entire length of the exercise. The HSE has engaged the broader international radiation community of researchers, regulators and policymakers, instigated discussions on AOPs and has helped prioritize key questions to guide future work. The process of the HSE has both strengths and limitations as described below.

**4.1. Strengths**

The greatest strength of the HSE was in the diverse experience of the SC members, which included regulators, epidemiologists, dosimetrists, radiation biologists, chemical toxicologists, among other disciplines. The SC was established through an international call for experts through the NEA Committee on Radiological Protection and Public Health (CRPPH). The composition of the CRPPH (as of July 2022) is approximately 140 delegates from 29 countries, with several strategic partners, including China and invited experts from relevant international organizations and regional associations with expertise in radiation protection research. This wealth in experiences and opinions was pivotal in driving the discussions and identifying the finalized list of questions. Additionally, SC members were instrumental in promoting and increasing awareness of the exercise and supporting the refinement of the questions to accurately represent the current deficiencies and needs. The HSE benefited from the experience of previous key question exercises in other fields. As a result of including experts with previous experience in horizon scans to the SC (Rudd 2014; Fleishman et al. 2011; Rudd and Fleishman 2014; Boxall et al. 2012; Rudd et al. 2014), the HSE collected additional information compared to
Twenty-five key questions to guide future areas of work

* How can AOPs add value to the current radiation risk assessment methods?

* Which adverse outcomes (AOs) should be prioritized in the radiation field for reducing uncertainties related to low dose and low dose-rate effects?

* What are the relevant molecular initiating event(s) (MIEs) that need to be considered for radiation AOPs and why?

* How can AOP networks accurately represent the interconnectivity in macromolecular and multi-organ responses leading to adverse outcome(s) (AO)?

* How can the complexity of biological damage correlated to time-effects, dose-ranges and dose rates of exposure be effectively captured in an AOP?

* How can the latency between radiation exposure and adverse outcome (AO) development be delineated when constructing an AOP?

* How can the AOP framework accurately reflect the effects of radiation of different qualities (e.g., alpha, beta, gamma, neutron)?

* For complex systemic biological processes (e.g., immune, endocrine responses, metabolic memory), what are the essential key events (KEs)?

* How can the AOP framework accurately reflect the effects of radiation with different exposure time patterns (e.g., acute, fractionated, and chronic radiation exposures) and deliveries (e.g., internal, external, partial, or whole body)?

* How can the AOP framework accommodate confounding variables/modulators (e.g., dietary status, smoking, life stage/age, sex, and individual genetic and epigenetic variation) of adverse outcomes (AOs)?

* How can the AOP framework accommodate different radiation-induced phenomena (e.g., bystander effects, genomic instability, adaptive responses)?

* How can AOPs support enhancing the understanding of possible multigenerational and transgenerational radiation effects?

* How can all relevant data from different levels of biological organization (e.g., molecular, cellular, tissue, individual, population) be optimally integrated in AOP?

* Which approaches are suitable for quantitative AOP development and how can these be pragmatically used?

* What criteria and/or approaches should be used to identify the most relevant studies to support weight of evidence considerations in AOP development?

* How can the AOP framework be applied to delineate or decipher causation to an adverse outcome (AO) from exposure to multiple stressors?

* How can AOPs be used to decipher or discern the toxicity of a stressor that has both chemical and radiological properties (e.g., for radioactive elements such as uranium, diagnostic and therapeutic radiopharmaceuticals)?

* How can AOPs support engagement and communication dialogs with stakeholders (including members of the public) for informed and sustainable decision-making?

* What processes (e.g., self-organization, workshops, training) and tools (e.g., AOP handbook, templates, common review tools) need to be considered for collaborative development of AOPs?

* What proof of concept examples and/or endorsement processes can enhance interest and willingness of funding agencies to adopt AOPs as an asset to a research proposal?

* How can AOPs be integrated with other approaches and/or techniques (e.g., modeling biologically based pathways, benchmark dose modeling) to support the formulation of dose-response models that alleviate uncertainty in quantitative risk estimates?

* How can the AOP framework support strategies in prevention/mitigation of human health outcomes and/or field monitoring (e.g., biodosimetry) for accidental or intentional exposures where there are uncertainties about exposure dose, dose rate and radiation quality?

* How can the AOP approach be used to understand key factors of radiosensitivity to support individual (human) and species (biota) radiation risk assessment?

* How can the scientific and regulatory communities, including scientific journals, support capturing relevant data to be used for AOP development and reporting AOPs in a feasible format for dissemination and implementation into research and the regulatory framework?

* How could AOPs help identify research gaps compared to already existing methods (e.g., systematic reviews, expert panels, international reports)?

Questions that align with EAGMST initiatives:

* How can AOPs be integrated with other approaches and/or techniques (e.g., modeling biologically based pathways, benchmark dose modeling) to support the formulation of dose-response models that alleviate uncertainty in quantitative risk estimates?

* Which approaches are suitable for quantitative AOP development and how can these be pragmatically used?

* What criteria and/or approaches should be used to identify the most relevant studies to support weight of evidence considerations in AOP development?

<figure><img src="image_30.png" /></figure>
<figure><img src="image_31.png" /></figure>

**Unique areas to the radiation field**

Dose/dose-rate effects

Adaptive/protective responses

Molecular initiating events

Transgenerational effects

**Common areas to the chemical field**

Omics data interpolation

Quantitative assessments

Systematic weight of evidence gathering

Biomarkers/tools to support risk
assessment strategies

<caption>**Figure 7.** Suggestions on areas to focus efforts and future initiatives.</caption>

previous publications. For example, detailed information was
collected on the respondents' rationale for choosing specific
research questions as their highest and lowest choices and
any foreseen constraints to answering those questions (dis-
cussed below in the 'specific comments and other considera-
tions' subsection). This additional information will help
inform the next steps of the Rad/Chem AOP JTG work plan.
Further, the paucity of new proposed questions confirm that
the initial two phases of the exercise successfully identified
and ranked the relevant candidate questions. Further, nearly
70% of respondents were familiar or somewhat familiar with
AOPs, ensuring strong candidate question submissions.

**4.2. Limitations**

From a methodological perspective, the main challenge in
conducting this HSE was the relatively small population of
experts from which to solicit candidate questions and recruit
international survey respondents. This limitation led to
some modifications in candidate question solicitation for the
final survey (i.e. very active solicitation efforts by SC mem-
bers within their own networks). Snowball sampling by ask-
ing contacted individuals to further spread survey invites by
email or social media is often used for research surveys for
which the sample frame is hard to identify or difficult to
contact, even if biases arise (Lopez et al. 2019). In this exer-
cise, the number of available experts who contributed to sur-
vey submissions was, however, limited, and the network ties
between those potentially relevant respondents were very
tight, resulting in possible clustering of specific questions.
Thus, the use of snowballing and personal outreach was
more relevant compared to surveys with many participants
where snowball sampling can be promoted within epistemic
communities, encouraging high response rates and poten-
tially biasing results. Some of the more relevant international
scientific organizations and associations to this exercise
included the ICRP, the United Nations Scientific Committee
on the Effects of Atomic Radiation (UNSCEAR), the NEA,
and the International Radiation Protection Association
(IRPA). The small sample size had another impact on the

results: the ranking of any individual AOP research question
was not distinctly discernable from the questions around it.
The data obtained allowed for a general distinction to be
made between groups of questions, but not for a compre-
hensive ranking of the questions in order of perceived
importance. Nonetheless, despite these few limitations, the
exercise did allow for the extraction of meaningful data to
support justification of future initiatives.

**4.3. Specific comments and other considerations**

The international survey permitted respondents to provide
additional comments explaining their rationale for the rank-
ing, note any anticipated constraints, and add any open-
ended comments or replacement questions. This information
was valuable for understanding the various perspectives and
misperceptions on the scope of AOPs. The large volume of
comments is summarized below, with applicable interests to
the radiation and chemical fields outlined in Figure 7.

Several respondents expressed that the value of AOPs
must be apparent to justify the effort of their development
in terms of defining clear criteria and purpose. AOPs offer
an excellent means to organize information from large num-
bers of epidemiological studies and biological experiments.
The systematic approach to gathering the most relevant
studies and data for inclusion with clear criteria is funda-
mental to the success of AOPs. Tangible examples of how
AOPs can support radiation risk assessment are needed.
Fundamentally, the value of AOPs can best be demonstrated
if current aspects in the system of radiation protection can
be improved to enhance protection of people and the
environment.

It is feasible for the AOP framework to address latency
effects related to temporal kinetics induced by various types
of radiation, dose ranges, and dose-rates. AOP networks
could be a means to facilitate this understanding through
the integration of common modes of action across different
hazards and exposure scenarios. Furthermore, the stressor-
response and response relationship along the AOP con-
tinuum will have utility for building quantitative AOPs
<figure><img src="image_32.png" /></figure>

(Moe et al. 2021; Song et al. 2020; Perkins et al. 2019). This will allow the framework to be used for risk assessment and create a bridge between radiobiological and epidemiological data. Additionally, quantitative AOPs will need to accurately account for the pattern of energy deposition, micro-environmental and susceptibility effects (e.g. age at exposure, sex), DNA damage repair systems, the role of direct (e.g. DNA damage directly mediated by radiation) and indirect (e.g. DNA damage mediated by radiation-induced ROS formation) damage related to progression of adverse outcome or disease (Tanabe, Beaton et al. 2022; Tanabe, O'Brien et al. 2022). Other aspects that need to be considered are factors that may modulate radiosensitivity and the role of AOPs in multiple stressor assessment (Beyer et al. 2014; Salbu et al. 2019), immune surveillance, persistence of inflammatory responses, and confounding factors (e.g. co-exposures) among others. However, these aspects are not unique to AOPs and are also considerations in the current approaches used in radiation protection.

Several comments emphasized that AOPs must consider the possibility of MIEs other than energy deposition resulting in DNA damage. These comments recognize the importance of defining and characterizing the initial molecular events related to the interaction of different types of radiation with a biomolecule. Although concrete suggestions on the prioritization of AOs (including cancer and non-cancer outcomes) were not identified by survey respondents, it was suggested that data-rich fields and critical gaps could be an area to focus AOP development. It was also suggested that particular focus could be given to the immune response and its role within tumorigenesis as well as a consideration for it to be a potential AO. Additionally, the emerging themes from the question solicitation phase of the HSE suggest a focus area could also be in new approach methods or technologies in the field of omic responses and AOP development (Azimzadeh et al. 2022; Yu et al. 2022). Given the complex nature of radiation effects, the use of artificial intelligence could be employed to delineate the multitude of biological changes, produced by radiation. Several comments were raised at the prospect of the AOP framework to include beneficial outcomes in addition to AOs.

For regulatory purposes, it is critical for stakeholders to benefit from the AOP framework approach. Otherwise, although relevant to basic knowledge of stress responses, the effort will remain an academic pursuit with limited real-world applicability. Much remains to be done to socialize the AOP framework and demonstrate viability of its use in decision-making to government agencies and other stakeholders, particularly where epidemiological studies lack statistical significance. An effective communication strategy will be critical to identify target audiences and appropriate messages for broader use of the tool (Chauhan, Hamada et al. 2022).

## 4.4. Key constraints of AOPs

In addition to providing specific comments on each of the top priority questions, survey respondents were also able to provide comments on key constraints they felt might impact

AOP development. Three key constraints were repeatedly raised by survey respondents, touching on resources (i.e. availability of experts and funding), multi-disciplinary collaborative teams, and limitations of the AOP framework itself (e.g. discussion on radiation stressors, agreement on nomenclature). Significant resources will be required to educate and train future AOP developers, engage with funders and other stakeholders, allow for confirmation of data reproducibility, as well as reduce difficulties in sharing financial and biological resources across different institutions. AOPs are designed as collaborative projects where knowledge across multiple fields is required, and so a central agency such as the OECD NEA is well positioned to facilitate the level of international collaboration required for future AOP development. It would be beneficial for these collaborative relationships to include communications and social science experts who can help advise on how to best distill the large amount of data and information to achieve a greater understanding of the risks associated with different radiation exposures (Chauhan, Hamada et al. 2022). Any constraint of individual AOPs to address different exposure patterns or tackle multiple stressors (Salbu et al. 2019) could be dealt with by building AOP networks (Moe et al. 2021; Song et al. 2020). However, in-depth knowledge and understanding of available data on the importance of exposure time patterns and deliveries must be systematically organized to identify gaps. Identifying these key constraints and considering them when developing AOPs will help minimize their impact.

## 4.5. Recommended activities

The HSE outcomes have identified clear hesitations on the use of AOPs. Addressing these challenges may advance application in the radiation field and alleviate some misperceptions on the scope of AOPs. This exercise and previous discussions from workshops on the topic (e.g. those described in section 2.1), highlighted that delineating dose and dose-rate effects could be explored in the context of AOP construction. It is well known that radiation parameters may influence KEs and associated biological processes to ensuing health effects. Another aspect that was considered a priority by the international radiation community was defining causal associations of KEs with protective and adaptive responses. Additionally, further discussions are needed on defining the early initiating events relevant to multiple exposures and radiation types. The initial case AOP of lung cancer uses deposition of energy (Chauhan, Sherman et al. 2021) to DNA damage; however, could other MIEs accurately reflect the first physical interaction of radiation exposure within the body? Multigenerational and transgenerational effects may also need considerations given the recent interest on this topic for international governing bodies. Additionally, efforts should also focus on new technologies, quantitative assessments, systematic weight of evidence gathering and biomarkers as indicators for development of tools and strategies (Kozbenko et al. 2022). A number of these latter topical areas align well with initiatives underway through EAGMST.
<figure><img src="image_33.png" /></figure>

To effectively address these questions, practical examples will be needed, including consideration of adaptions to the current OECD AOP Development Programme. It may also be useful to deliberate on whether these types of questions are beyond scope and possibly deter from the broad vision of AOPs as a platform to understand complex data, by simplifying the biology of disease.

Overall, the HSE has derived valuable data that can form the basis of further discussions through joint forums with the chemical community, similar to initiatives undertaken recently through EAGMST (Tanabe, Beaton et al. 2022). Priority questions that align well with EAGMST, such as development of quantitative AOPs and omic-informed AOPs, could also be priority focus areas to advance the use of AOPs in the radiation field (Figure 7).

## 5. Conclusions

Based on the large volume of data collected during this HSE, there is valuable information to shape the future programme of work of the JTG. This work has helped expand awareness of and highlight the potential application of the AOP framework to the field of radiation, while identifying challenges to be addressed. Moving forward, further discussions are needed on which research questions to prioritize and address first, using active solicitation of advice from the broader radiation protection community. Prioritization could be based on alignment of work undertaken by the broader radiation protection community, including EAGMST, particularly in new approach methodologies (e.g. omics), and assessments of qualitative AOPs. Synergies across these groups could also help to prioritize the AOs of interest and mechanisms to disease states that are critical to capture in an AOP. International coordination and collaborative partnerships and capacity/resource availability may also drive which initiatives move forward. Immediate next steps include potential forums to discuss some of the frequent challenges and concerns related to the MIE and dose/ dose-rate effects and applicability to support risk assessment. Ongoing efforts by the JTG, particularly in the context of advancing four AOP case studies (Chauhan, Hamada et al. 2021; Azimzadeh et al. 2022; Tollefsen et al. 2022; Klokov et al. 2022; Jaylet et al. 2022) can serve as a starting point to initiate discussions of challenges, including promotion of the work at international conferences, and hosting dedicated webinars. Through continued conversation and discussions, the broader HLG-LDR are confident that the list of priority research questions identified in this HSE could, if answered, improve the qualitative and quantitative description of the dose-response relationship for low dose and low dose-rate exposures as well as reduce uncertainties of radiation risk estimates.

## Acknowledgments

The authors wish to acknowledge the assistance of Annick Laporte (CNSC) and Veronica Grybas (Health Canada) with developing graphics and the Research and Support team at the CNSC. The authors also

thank CNSC and Health Canada staff for their valuable insights in reviewing this manuscript.

## Disclosure statement

No potential conflict of interest was reported by the author(s).

## Funding

The HSE was partially funded through the Canadian Organization on Health Effects from Radiation Exposure (COHERE), through project number R719.2 with the contract number 3000725863 provided by the Canadian Nuclear Safety Commission. The work of KET is partially funded by grants from the Research Council of Norway (RCN) through its Center of Excellence (CoE) funding scheme [Project No. 223268] and NIVAs Computational Toxicology Program, NCTP (www.niva.no/nctp, RCN Project no. 160016).

## Notes on contributors

Julie J. Burtt is a radiation biologist with the Canadian Nuclear Safety Commission. Her research focuses on the potential health effects of exposure to low doses of ionizing radiation. She has experience as an advisor for Canada to the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) as well as a technical expert for the UNSCEAR Secretariat. She also serves as vice-chair of the National Energy Agency's Expert Group on Non-radiological Public Health Aspects of Radiation Emergency Planning and Response. Julie is also a member of Committee 4 for the International Commission on Radiological Protection.

Julie Leblanc Ph.D., is a radiation biologist with the Canadian Nuclear Safety Commission. Her research focuses on the potential health effects of exposure to low doses of ionizing radiation. She is a Canadian Delegate on the High-Level Group on Low Dose Research and International Commission on Radiological Protection mentee and member of Task Group 111.

Kristi Randhawa is a Radiation and Health Sciences Officer (epidemiology) with the Canadian Nuclear Safety Commission. Her research involves studying the health effects of ionizing radiation exposure, particularly exposure to low doses of radiation or radiation delivered at low dose-rates. She works as a coordinator and advisor for various research projects and working groups including for the International Society of Radiation Epidemiology and Dosimetry (ISoRED).

Addie Ivanova is a Radiation and Health Sciences Officer with the Canadian Nuclear Safety Commission (CNSC). Her research focuses on health effects of ionizing radiation at low doses and the implications for radiation protection. She represents the CNSC on Theme 1 (Health) of Canada's Federal Nuclear Science and Technology Committee and the CANDU Owner's Group (COG) Strategic Research and Development Low Dose Program.

Murray Rudd Ph.D., is an economics and policy research consultant. He held prior academic appointments at World Maritime University (Sweden), Emory University (USA), the University of York (UK), and Memorial University (Canada). Dr. Rudd is an applied economist and policy researcher by training. Over recent years, much of his work has focused on assessing emerging research priorities for environmental science and on the ocean science-policy interface. He left academia in 2019 and has since been working as independent consultant in environmental economics and science horizon scanning.

Ruth C. Wilkins Ph.D., is a Research Scientist at the Consumer and Clinical Radiation Protection Bureau of Health Canada and the Chief of the Ionizing Radiation Health Sciences Division. She graduated with a Ph.D. in Medical Physics from Carleton University and has been employed at Health Canada for the past 25 years. She is an Adjunct Professor and lecturer in Radiobiology in the Department of Physics at
<figure><img src="image_34.png" /></figure>

Carleton University and the alternative representative of Canada to the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR).

**Edouard Azzam** is a Radiation Biologist at Canadian Nuclear Laboratories. He is also Professor Emeritus at Rutgers New Jersey Medical School and member of the US National Council on Radiation Protection and Measurements. His research over the past three decades has focused on the role of intercellular communication and oxidative metabolism in expression of adaptive responses and bystander effects induced by low doses/low fluences of ionizing radiation from environmental, occupational, or medical sources.

**Markus Hecker** is a Professor and Canada Research Chair in Predictive Aquatic Toxicology, with 24 years of experience in conducting research in ecotoxicology and chemical hazard assessment. He is considered a global expert in environmental risk assessment, ecotoxicogenomics, hazard characterization of contaminants in native fishes and amphibians, and development of alternatives to live animal testing. Dr. Hecker is a member of the College of the Royal Society of Canada, and a visiting/guest professor at Xiamen University, China. He is the co-Editor-in-Chief of Aquatic Toxicology and has been a member of the board of directors of the Society of Toxicology and Chemistry (North America) for the past three years. Dr. Hecker served as an advisor/expert to several national and international organizations including Environment and Climate Change Canada, Health Canada, the U.S. Environmental Protection Agency, the European Food Security Agency and the Organization for Economic Cooperation and Development. He has authored or coauthored over 190 peer-reviewed papers, review articles, editorials and book chapters over his career.

**Nele Horemans** Ph.D., Leads the research group Biosphere Impact Studies at the Belgian Nuclear Research Center (SCK CEN). Additionally, she is guest docent at the Center of Environmental sciences at Hasselt University (Belgium) for courses on 'ecotoxicology & environmental radioecology' and 'experimental design'. Within the radioecology platform ALLIANCE she leads the working group on transgenerational effects and species sensitivity to radiation. Her main research topic of interest is on the effects induced by ionizing radiation in plants from the molecular to the population level. This includes both lab and field-based studies. She is author of more than 90 peer reviewed papers and has an H-index of 30 (Web of Science).

**Hildegarde Vandenhove** Ph.D., is the Director of the Institute for the Environment, Health, and Safety (EHS) at the Belgium Research Center.

**Christelle Adam-Guillermin** Ph.D., is a research scientist in radioecotoxicology at the French Institute for Radiological Protection and Nuclear Safety (IRSN). In 2012, she became head of the radionuclide ecotoxicology laboratory (LECO/IRSN) until 2019, when she moved to the dosimetry division to lead radiobiology research programs at the MIRCOM microbeam. Her research focuses on the biological effects of low ionizing radiation (IR) doses and charged particles of different LET, especially on DNA (nuclear and mitochondrial) and epigenetic factors, and on characterization of biomarkers of radiation effects applicable to reprotoxicity and neurodegeneration. She has been involved in several collaborative international research projects including the EC funded ERICA (FP6, 2004–2007) and COMET project (FP7, 2013-2017). She has led the ALLIANCE's working group on IR transgenerational effects and radiosensitivity from 2015 to 2019 and is now member of the expert group on the development of radioprotection for non-human biota (ICRP Committee 1, IAEA/MODARIA group, OECD/NEA RAD/CHEM AOP working group of High-Level Group on Low-Dose Research, Article 31 Group of Experts of the European Commission).

**Olivier Armant** Ph.D., is a senior scientist at the French Institute of Radioprotection and Nuclear Safety (IRSN). His studies focus on the molecular mechanisms deregulated upon exposure to low dose of radiations during embryonic development and post-accidental effects on wild-life in Chernobyl and Fukushima. He is a member of the High-

Level Group on Low-Dose Research (HLG-LDR) Rad/Chem Joint Topical Group.

**Dmitry Klokov** is a Ph.D., in radiobiology, head of the Laboratory of Experimental Radiotoxicology and Radiobiology at the Institute of Radioprotection and Nuclear Safety in France. He also holds an Adjunct Professor position at the Department of Biochemistry, Microbiology and Immunology of the University of Ottawa. For 12 years, Dmitry Klokov has led a low-dose radiobiology program at the Canadian Nuclear Laboratories. His research interests include various domains within the filed of low-dose radiation effects, with an overarching goal to understand mechanisms of early genotoxic and molecular responses and how they may contribute to long-term health outcomes, such as cancer, cardiovascular and neurological pathologies and multigenerational effects. Dmitry Klokov has published 50+ papers, several book chapters, gave multiple invited talks. He has also been involved in various international initiatives in low-dose radiobiological research and cooperation, including those coordinated by UNSCEAR, NEA, MELODI, DOE, and others.

**Karine Audouze (KA)**, professor at the Université Paris Cité, is leading the Systems Toxicology group at INSERM. Her group has developed artificial intelligence-based tools to help the development of AOPs such as AOP-helpFinder (http://aop-helpfinder.u-paris-sciences.fr/). KA is member of the OECD advisory EAGMST working group, and of the AOP-KB and Rad/Chem AOP subgroups. KA is the coordinator of the H2020 OBERON project (https://oberon-4eu.com/) and is involved in various other ongoing EU projects such as Horizon Europe PARC and the H2020 RadoNorm.

**Jan Christian Kaiser** leads the working group 'Integrative Modeling' in the Institute of Radiation Medicine at the Helmholtz-Zentrum München, German Research Center for Environmental Health, in Munich, Germany. He holds a doctoral and masters' degree in statistical physics. His research involves integration of molecular biology and radiation epidemiology in biologically-based risk models.

**Simone Moertl** Ph.D., PD, is head of the section of Radiation Biology at the Federal Office for Radiation Protection (BfS) and an Adjunct Professor (Docent) of Radiation Biology at Technical University Munich. Until September 2019 she led the group of Clinical Radiobiology at the Institute of Radiation Biology, Helmholtz Zentrum München. Her research focuses on the cellular radiation response of tumors and normal tissues with the aim to understand the mechanisms of individual radiation sensitivity. She is particularly interested in the vesicle-mediated transfer (e.g. by exosomes) of RNAs between cells. She is a member of the HLG-LDR Rad/Chem AOP Joint Topical Group.

**Katalin Lumniczky** MD, Ph.D., is the head of the Unit of Radiation Medicine, Department of Radiobiology and Radiohygiene, National Public Health Center Budapest, Hungary. She is a radiation biologist with a more than 20 years experience in the field.

**Ignacia B. Tanaka III** DVM, Ph.D., is a Senior Researcher with the Pathology Group, Radiobiology Department at the Institute for Environmental Sciences (IES) at Rokkasho Village, Aomori, Japan. She received her Ph.D. (Doctor of Veterinary Science) from Hokkaido University (Graduate School of Veterinary Medicine), Japan. She is also holds an MS in Agriculture (Ruminant Nutrition, Obihiro University, Japan) and is a veterinarian (DVM, University of the Philippines, Philippines). Current interests are veterinary pathology and radiation biology [in utero, transgeneration and late effects (e.g. life span, neoplasia and non-neoplastic disease) of chronic low dose-rate radiation exposure in mice].

**Yutaka Yamada** DVM, Ph.D., is a research scientist of the Department of Radiation Effects Research, National Institute of Radiological Sciences, QST, Japan. His main field is radiation biology and radiotoxicology, and he has been focused on radiation-induced pulmonary carcinogenesis.
<figure><img src="image_35.png" /></figure>

**Nobuyuki Hamada** RT, Ph.D., is a Senior Research Scientist at CRIEPI and a Visiting Professor at Hiroshima University Research Institute for Radiation Biology and Medicine. He serves on ICRP Task Groups 102, 111 and 119, NCRP PAC 1, OECD/NEA/CRPPH/HLG-LDR/Rad/Chem AOP Joint Topical Group, IRPA Task Group on Tissue Reactions, and Consultation Committee on AOP development for space flight health outcomes (Canadian project).

**Isaf Al-Nabulsi** serves as the DOE Japan Program Manager since 2012. She also serves as the DOE Program Manager for the agency's participation in the Study of One Million U.S. Radiation Workers and Veterans. She previously served as an Acting Director, Office of Domestic and International Health Studies within the Office of Health and Safety, Office of Environment, health, Safety and Security, and was responsible for managing and coordinating day-to-day activities associated with the domestic and international health studies, including enduring that office activities comply with departmental regulations and law. Dr. Al-Nabulsi also served as Senior Technical Advisor, from 2012–2020, to Director, Office of Health and Safety and provided advice on a wide range of topics related to the office’s mission. Prior to joining DOE, she worked at the National Council on Radiation Protection and Measurements and the National Research Council/National Academy of Sciences. She has more than thirty years of scientific research and technical program management experience. Her research interest includes understanding health effects of low dose radiation exposures. She is a member of the Radiation Research Society, Health Physics Society, American Association for Cancer Research, and the National Energy Agency Organization for Economic Co-operation and Development High-Level Group on Low-Dose Research as well as the National Energy Agency Rad/Chem AOP Joint Topical Group.

**R. Julian Preston** Ph.D., has a Special Government Employee (Expert, Radiation Effects) appointment at the U.S. Environmental Protection Agency (EPA). He previously served as the Associate Director for Health (2007–2012) and the Director of the Environmental Carcinogenesis Division at EPA. Dr. Preston's research and current activities have focused on how knowledge of the mechanisms of induction of radiation-induced adverse health effects can be used in cancer risk assessments. He has served in various capacities with NCRP, ICRP (including Chair, Committee 1, and Radiation Effects) and UNSCEAR (Representative and Head of Delegation). Dr Preston was the 2002 Lauriston S. Taylor Lecturer awarded by the NCRP and is a Fellow of the UK's Royal Society for Radiation Protection. Dr. Preston has published over 250 peer reviewed papers. He has served on National Academies' committees including in 2021 as Vice Chair of the committee 'Space Radiation and Astronaut Health: Managing and Communicating Cancer Risks'. He also serves on an OECD/NEA committee addressing the use of Adverse Outcome Pathways in cancer risk assessment at low doses and dose-rates. He received his B.A. and M.A. from Peterhouse, Cambridge University, England, in genetics and his Ph.D. from Reading University, England, in radiation genetics.

**Simon Bouffler** is the deputy director of the Radiation Protection Science at the UK Health Security Agency. He was trained as a biologist, receiving a BSc and Ph.D. from the University of Southampton. Simon is a member of the main commission of ICRP and the UK representative to UNSCEAR.

**Kimberly Applegate (USA)** is the chair of Committee 3 of the ICRP, focusing on radiation protection in medicine and a member of the National Council for Radiation Protection and Measurements (NCRP). Dr. Applegate is a retired professor of radiology and pediatrics from the University of Kentucky in Lexington. Dr. Applegate's policy and research work, including 200 publications, has contributed to an improved understanding of the structure, process, and outcomes of how imaging, especially pediatrics, is practiced, including the volume and variation of imaging practice, toward its improvement and standardization. She has worked collaboratively around the world across medical specialties and geographic boundaries to improve access to best practices. From its start in 2007 to the present, she has worked on the Steering Committee for the Image Gently Campaign to improve children's care worldwide. Kimberly has received several awards that

include the 2019 AAPM's Honorary Membership and the American Association for Women in Radiology's Marie Skłodoska Curie Award for her unique roles in leadership and outstanding contributions to the advancement of women in the Radiology professions. She and her husband, George Parker, MD, have three grown sons, David, and twins Andrew and Eric.

**Donald Cool** is the Vice-Chair of the Main Commission of the International Commission on Radiological Protection. He was the Technical Executive for Radiation Safety with the Electric Power Research Institute (EPRI) until December 2021, and prior to EPRI spent nearly 33 years with U.S. Nuclear Regulatory Commission, where he served in various Senior Executive and Senior Advisor positions. Dr. Cool received his Master's and Doctorate degrees in Radiation Biology from the University of Rochester, School of Medicine and Dentistry. He is a Council Member of the U.S. National Council on Radiation Protection and Measurements and the Co-Chair of NCRP Council Committee 1 which produced NCRP Report 180, Management of Exposure to Ionizing Radiation: Radiation Protection Guidance for the United States. He has served on numerous panels and expert groups of the International Atomic Energy Agency and Nuclear Energy Agency. He is a Fellow of the Health Physics Society.

**Danielle Beaton** Ph.D., is a Research Scientist at Canadian Nuclear Laboratories. Her current research focuses on the effects of low dose radiation on biological systems. She is on the NEA HLG-LDR committee and assists the co-chairs of the HLG-LDR Rad/Chem AOP Joint Topical Group.

**Knut Erik Tollefsen** Ph.D., is a Chief Scientist at the Norwegian Institute for Water Research (NIVA), an Adjunct professor at the Norwegian University of Life Sciences (NMBU) and is a principal investigator and research area co-lead in the Center for Environmental Radioactivity (CERAD CoE). He is also the Norwegian delegate of the HLG-LDR and OECD EAGMST, co-chairs the HLG-LDR Rad/Chem AOP Joint Topical Group, co-ordinates NIVA's Computational Toxicology Program, NCTP (www.niva.no/nctp) and is a registered OECD AOP coach.

**Jacqueline Garnier-Laplace** Ph.D., a Senior Radiation Protection Specialist, is Deputy Head of the Division of Radiological Protection and Human Aspects of Nuclear Safety at the OECD Nuclear Energy Agency. She is the Scientific Secretary of the Committee on Radiological Protection and Public Health, and of the NEA HLG-LDR. Previously, she headed Radiation Protection research at France's IRSN. She served as scientific secretary of ICRP Committee 1 from 2017 to 2021 and is currently serving on Committee 4 with the same function.

**Dominique Laurier** Ph.D., is a Senior Epidemiologist and deputy director of health at the Health and Environment Division of the French Institute for Radiation Protection and Nuclear Safety (IRSN). He is Chair of Committee 1 of the International Commission on Radiological Protection (ICRP), French representative to UNSCEAR, and Chair of the NEA HLG-LDR.

**Vinita Chauhan** Ph.D., is a Senior Research Scientist at the Consumer and Clinical Radiation Protection Bureau of Health Canada. She is a Canadian delegate of the High-Level Group on Low Dose Research (HLG-LDR) and Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST) of the OECD. She co-chairs the OECD/NEA/HLG-LDR Rad/Chem AOP Joint Topical Group and is the co-founder of the Canadian Organization of Health Effects from Radiation Exposure (COHERE) initiative. [ORCID: 0000-0002-4498-0915]

ORCID

Julie J. Burtt http://orcid.org/0000-0002-0795-7142

<figure><img src="image_36.png" /></figure>

Julie Leblanc http://orcid.org/0000-0001-8946-6656

<figure><img src="image_37.png" /></figure>

Kristi Randhawa http://orcid.org/0000-0001-6563-7203

<figure><img src="image_38.png" /></figure>

Addie Ivanova http://orcid.org/0000-0002-9555-1985

<figure><img src="image_39.png" /></figure>

Murray A. Rudd http://orcid.org/0000-0001-9533-5070

<figure><img src="image_40.png" /></figure>
<figure><img src="image_41.png" /></figure>

Ruth Wilkins ID http://orcid.org/0000-0002-9621-477X

Edouard I. Azzam ID http://orcid.org/0000-0002-8968-1142

Markus Hecker ID http://orcid.org/0000-0002-7237-6192

Nele Horemans ID http://orcid.org/0000-0002-6241-0342

Hildegarde Vandenhove ID http://orcid.org/0000-0001-8958-0061

Christelle Adam-Guillermin ID http://orcid.org/0000-0002-8833-0762

Olivier Armant ID http://orcid.org/0000-0001-7101-9209

Dmitry Klokov ID http://orcid.org/0000-0003-1629-1431

Karine Audouze ID http://orcid.org/0000-0001-7525-4089

Jan Christian Kaiser ID http://orcid.org/0000-0003-0359-2251

Simone Moertl ID http://orcid.org/0000-0003-0644-0878

Katalin Lumniczky ID http://orcid.org/0000-0001-8661-1854

Ignacia B. Tanaka ID http://orcid.org/0000-0002-9526-0184

Yutaka Yamada ID http://orcid.org/0000-0002-2371-8723

Nobuyuki Hamada ID http://orcid.org/0000-0003-2518-6131

Isaf Al-Nabulsi ID http://orcid.org/0000-0002-6234-3071

R. Julian Preston ID http://orcid.org/0000-0001-5454-0588

Simon Bouffler ID http://orcid.org/0000-0003-1883-919X

Kimberly Applegate ID http://orcid.org/0000-0001-7716-1636

Donald Cool ID http://orcid.org/0000-0003-4105-0242

Danielle Beaton ID http://orcid.org/0000-0002-5764-5139

Knut Erik Tollefsen ID http://orcid.org/0000-0002-7534-0937

Jacqueline Garnier-Laplace ID http://orcid.org/0000-0002-3486-147X

Dominique Laurier ID http://orcid.org/0000-0003-1432-4738

Vinita Chauhan ID http://orcid.org/0000-0002-4498-0915

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