COHERE – strengthening cooperation within the Canadian government on radiation research

Abstract

Purpose

Canadian Organization on Health Effects from Radiation Exposure (COHERE) is a government initiative to better understand biological and human health risks from ionizing radiation exposures relevant to occupational and environmental settings (<100 mGy, <6 mGy/h). It is currently a partnership between two federal agencies, Health Canada (HC) and the Canadian Nuclear Safety Commission (CNSC). COHERE’s vision is to contribute knowledge to reduce scientific uncertainties from low dose and dose-rate exposures. COHERE will advance our understanding by bridging the knowledge gap between human health risks and linkages to molecular- and cellular-level responses to radiation. Research focuses on identifying sensitive, early, and key molecular events of relevance to risk assessment.

Conclusions

The initiative will address questions of relevance to better apprize Canadians, including radiation workers and members of the public and Indigenous peoples, on health risks from low dose radiation exposure and inform radiation protection frameworks at a national and international level. Furthermore, it will support global efforts to conduct collaborative undertakings and better coordinate research. Here, we describe a historical overview of the research conducted, the strategic research agenda that outlines the scientific framework, stakeholders, opportunities to harmonize internationally, and how research outcomes will better inform communication of risk to Canadians.

Keywords:

• Low dose research
• radiation
• research program
• health effects
• ionizing radiation
• biomarkers

Introduction

Background

The current radiation protection framework is practical and built to ensure the health and safety of workers, the members of the public and Indigenous peoples, and the environment. While the framework is prudent and conservative, there continues to be a need for low-dose radiation research (LDRR) to fill existing knowledge gaps. New knowledge can help address: (1) large statistical uncertainties in dose-response at low doses (<100 mGy), (2) lack of consensus amid an ongoing debate among scientific communities regarding the biological and health effects at a low dose, and (3) continued public concern and fear of radiation.

The Nuclear Energy Agency (NEA) has been seeking inputs from member states on the possibility of global coordination and collaboration of low dose radiation research to more effectively address the relevant questions (i.e. cost and research efficiency) to operate and manage such a program (National Academies of Sciences, Engineering, and Medicine et al. 2019). This will support a multidisciplinary approach to LDRR, allowing for harmonization that can contribute new knowledge to international radiation protection bodies (Repussard 2019). This initiative began following NEA’s recognition of the continued need for an LDRR program for government funding as well as the ongoing efforts to effectively collaborate and coordinate research. Part of the discussions involved tasks geared toward developing a harmonized risk communication strategy for more efficient and targeted risk communication.

Two agencies of the Government of Canada [Health Canada (HC) and the Canadian Nuclear Safety Commission (CNSC)] are members of the NEA initiative and play an important role in conducting LDRR. Both agencies strive to communicate their research findings and inform Canadians of the risks from radiation. The factors impacting effective risk communication are complex, and most agree that risk communication and radiation education need improvement in a society where information (and misinformation) is so readily accessible (Weiss and Yonekura 2019). To this end, there is a concrete effort toward the integration of social sciences and humanities in radiation protection (Perko et al. 2019).

Given that HC and CNSC are invested in improving research coordination and how research information is communicated, the establishment of a Canadian Organization on the Health Effects from Radiation Exposure (COHERE) program will be valuable. In this paper, a historical perspective of the research conducted by the Government of Canada is provided as well as an overview of COHERE and possibilities for expansion to the national level.

Historical perspective

The Canadian radiation protection framework is modeled on the international framework which to date are informed by human health risks from radiation exposure derived using large databases of cancer and non-cancer health outcomes from atomic bomb survivors, nuclear accidents, and occupational and medical exposure scenarios. Accumulating scientific knowledge emerging over the last decades clearly indicates that these models may not be accurate at the low doses and more research is needed to reduce this uncertainty. Globally, conversations around this topic have led to identifying priority areas for research, efforts to better coordinate projects (to prevent unnecessary duplication of work), and improved ways to inform stakeholders about risks. Canada is a leader in low dose research (Radiation Research Special Issue: Snolab 2017; Health Physics Special Issue: Canadian Radiation Protection and Research 2019). Alone and in collaboration, HC and CNSC have contributed significantly to the Canadian landscape of LDRR in areas that include dosimetry, radiobiology, and epidemiology, demonstrating the value of a more formalized approach to cooperation and coordination between the two government institutions.

Health Canada LDRR

Health Canada is responsible for helping Canadians maintain and improve their health. It also acts on requests from other federal departments and agencies on occupational and public health matters related to radiation safety. Two Bureaus within HC focus on radiation health effects: The Radiation Protection Bureau (RPB) and the Consumer and Clinical Radiation Protection Bureau (CCRPB). Together, these Bureaus evaluate, monitor, and assist in the management of risk associated with radiation exposure from devices, occupational, and public environments. In addition, they undertake research into the biological effects of radiation exposure to develop technical advice for responsible authorities. Some HC scientists have recently focused their research efforts on developing experimental studies to reduce uncertainties at low doses. This includes radiation effects related to chronic and acute exposures, low and high doses, and varied dose rates. The outcomes of this research contribute to the Addressing Air Pollution Horizontal Initiative (AAPHI), the Radiation Emitting Device Act, as well as the work of international scientific committees, such as the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). HC developed the relevant studies, as described below, jointly with partners across academia and industry.

Adverse outcome pathway integration into radiation risk assessment

The adverse outcome pathway (AOP) framework is a means to consolidate existing mechanistic and epidemiological studies. It assembles knowledge across levels of biological organization to formulate key events linked to adverse outcomes of relevance to regulatory decision-making (Ankley et al. 2010). A formalized AOP development program was launched by the Organization for Economic Co-operation and Development (OECD) in 2012. It has shown promise in informing on knowledge gaps, test method development, and predictive toxicology for risk assessment in chemical toxicity. This approach is gaining traction within the wider radiation research community and HC scientists have been instrumental in these efforts. This has included knowledge transfer through organizing international and national workshops (Chauhan, Said, et al. 2019) and illustrating the approach with a case example of lung cancer-relevant to stressors, such as radon gas (Chauhan, Sherman, et al. 2021). The work has highlighted that, despite decades of mechanistic research in the radiation field, high-quality empirical evidence data to support causal linkages to adverse outcomes remains limited. Likewise, considerable uncertainties/inconsistencies in the literature are prevalent, predominantly because of the lack of coordinated research across institutions (Chauhan, Stricklin, et al. 2021; Chauhan, Villeneuve, et al. 2021). Continued work in this area will demonstrate the value of the approach to broadly support many areas in the radiation field including a better understanding of low dose/low dose-rate effects.

Genomics and benchmark dose modeling

Genomics enables an analysis of molecular effects at earlier time points than most conventional tests that rely on observations of disease or overt health effects. Tracking genomic changes over time following exposure to an agent can provide insight into the underlying molecular changes to the development of pathology. In the context of radiation, genomics has been moving forward for decades in several high-profile areas, resulting in a large amount of data but with no significant translation to human health risk assessment. Recent developments in high-throughput benchmark dose modeling in chemical toxicity have shown promise in using transcriptional data to identify critical mechanistic pathways and associated safe dose thresholds for various chemical exposure scenarios (Yang et al. 2007; Thomas et al. 2013). HC has applied these approaches to genomic studies relevant to radiation exposures and shown the approach to be valuable in identifying pathway and gene-based point-of-departures, that can be used to compare radiation qualities, dose-rates and model systems (Chauhan et al. 2016; Qutob et al. 2018; Chauhan, Rowan-Carroll, et al. 2019; Chauhan, Adam, et al. 2021). More recently, HC secured funding through the Genomics Research and Development Initiative (https://grdi.canada.ca/en) for a five-year project aimed at reducing knowledge gaps and uncertainty in risk associated with low-dose radiation exposures, using transcriptional data and benchmark dose modeling. Three projects are underway. The first is reviewing existing genomic studies and applying benchmark dose modeling to identify the dose needed to begin observing changes in pathways and gene responses under a variety of exposure scenarios. In the second sub-project, human blood will be exposed to ionizing radiation under physiological conditions (i.e. optimal pH and temperature) at a broad dose range using varied dose rates and at levels that will allow for effective modeling of data in the low-dose range. Such ex vivo blood irradiated studies are cost-effective and as informative as in vivo studies. The third sub-project will identify doses that trigger gene/protein markers in animal models that have been exposed to very low doses of radiation from uranium.

Lens of the eye

The deterministic nature of cataract formation from radiation exposure is of interest. The eye lens is one of the most radiosensitive tissues in the human body (ICRP, 2007). Post-radiation exposure, the lens of the eye can undergo subtle changes, which can take many years to manifest as visible cataracts. HC has led a series of studies that have contributed to the advancement of knowledge on mechanisms of radiation-induced cataracts. State-of-art genomic, proteomic, and targeted metabolic technology in conjunction with Raman spectroscopy have provided data on pathways that are critical drivers in radiation-induced cataracts. The approaches have identified biological pathways most important to radiation-induced macro-molecular level effects. Together, this information alongside published literature has been valuable for guiding further studies in occupational exposures with a long-term vision of being developed into early prognostic predictors of eye disease (Allen et al. 2018; Bahia et al. 2018; Chauhan, Rowan-Carroll, et al. 2019).

Cytogenetics

As the lead national laboratory for biological dosimetry, HC researchers have focused on the use of cytogenetics and DNA damage and repair to measure biological damage to radiation doses down to 100 mGy. Dicentrics measured by the dicentric chromosome assay (DCA), translocations measured by fluorescence in situ hybridization (FISH), micronuclei in binucleated cells, and DNA double-strand break induction as measured by γH2AX foci formation, all provide mechanistic information that feeds into the radiation response pathways (Andrievski and Wilkins 2009; McNamee et al. 2009; Flegal et al. 2012; Beaton-Green et al. 2016). Based on this work, HC scientists have contributed greatly to the development of standards for these methods (ISO 17099 2014; ISO 19238 2014; ISO 20046 2019) and a guidance document for the initial phase assessment of individual doses after acute exposure to ionizing radiation (ICRU 2019). Research is also being conducted on developing imaging flow cytometry-based methods for the measurement of radiation damage that might have applications in the low dose region (Rodrigues et al. 2016; Beaton-Green et al. 2017; Wilkins et al. 2017). Furthermore, the DCA, FISH, genomics (Chauhan et al. 2014) and γH2AX assays have been used to examine the radiation sensitivity of patients exposed to external beam radiotherapy for prostate cancer (Beaton et al. 2013; Beaton et al. 2013; Beaton et al. 2013).

Raman spectroscopy

Raman spectroscopy (RS) is a label-free technique that allows for the real-time acquisition of spectral data on vibrational changes of biologics in the specimen being analyzed (Baker et al. 2016). It measures the inelastic scattering of low-intensity, non-destructive laser light by a sample, providing information on its content. In the case of a biological sample, this would include nucleic acids, proteins, lipids, and fatty acids, etc. This process can require minimal sample preparation and is non-damaging to the specimen of interest (Bonifacio et al. 2015; Jahn et al. 2017). Sensitive portable Raman spectrometers are also available that contain a high-power excitation laser, low-fluorescence optics, and advanced software for in-field use and these systems have been shown to be useful for analyzing body fluids (e.g. blood, saliva, and urine) (Yan and Vo-Dinh 2007; Bonifacio et al. 2015). Published RS studies are extensive; studies have shown this technology to be successful in quantifying analytes in blood, such as C-reactive-protein, glucose, albumin, urea, cholesterol, and lactate despite their low concentrations (Berger et al. 1999; Qu et al. 1999; Bergholt and Hassing 2009). It has also been shown to be capable of detecting different blood types, metabolite concentration, and pH (Wu et al. 2010; Atkins et al. 2015, 2016) and to help understand the structure of heme and hemoglobin oxygenation in the blood (Strekas and Spiro 1972; Brunner and Sussner 1973; Brunner 1974; Spiro and Strekas 1974; Wood et al. 2005; Rusciano et al. 2008; Huang et al. 2011; Premasiri et al. 2012). HC researchers in collaboration with Carleton University and the University of Montreal are leading the design of studies directed to support a non-invasive, label-free, real-time molecular detection of biomolecules (e.g. lipids, proteins, and RNA) in cells, latent fingermarks, and blood using optical spectroscopic approaches. This innovative work has shown promise in identifying spectral molecular-level features indicative of radiation exposure at the single-cell level (Allen et al. 2018; Hansson et al. 2019).

Dosimetry and biological effects from exposure to uranium and radon

HC has a long history of studying the effects of environmental radiation on Canadians (Tracy et al. 1983; Letourneau 1985; Tracy et al. 1997; Thomas et al. 2001; Macdonald et al. 2007; Chen et al. 2009). In the late 1990s, Health Canada researchers conducted studies on the biological effects of chronic exposure to uranium in drinking water in a group of Canadians using private drinking water wells. The results indicated the loss of proximal tubular function of the kidney (Zamora et al. 1998; Zamora et al. 2009). More recently, HC, in collaboration with CNSC and the Canadian Nuclear Laboratories (CNL), has led the development of an AOP for kidney toxicity relevant to uranium exposure. To supplement the knowledge gap identified through this AOP development and to acquire a better understanding of the health effects of chronic exposure to uranium in drinking water, HC has launched a collaborative research project with CNL by undertaking an animal experiment on a rodent model.

Extensive efforts to characterize residential radon in Canada and the associated risk led to the establishment of Canada’s National Radon Program (McCullough et al. 1981; Levesque et al. 1997; Ayotte et al. 1998; Chen 2005a, 2005b; Tracy et al. 2006; Chen and Moir 2010; Chen 2019). More recently, HC has extended the scope of its radon calibration chamber from quality control for radon metrology to an exposure facility, to support studies of radon progeny concentration and indoor aerosol characteristics, thereby improving radon dosimetry. Development of an in-house computational modeling tool for radon dosimetry is also underway to help assess the contribution of indoor aerosol characteristics on the radiation dose to the lung from radon exposure. HC researchers, in collaboration with CNL, are also supporting the commissioning of a radon inhalation chamber for animal experiments (on rodent models) to investigate biomarkers of exposure for dose assessment and biomarkers of effects for risk assessment. HC researchers will use the radon chamber to conduct animal experiments to obtain mechanistic insights into lung carcinogenesis from co-exposure of radon and chemicals present in mainstream cigarette smoke. In addition, work is progressing in the area of identifying biomarkers of radiation exposure in radon cohorts. This pilot study will leverage the Canadian Partnership for Tomorrow’s Health Project (CanPath) that brings together data from over 330,000 Canadians linked to their health information (Awadalla et al. 2013; Sweeney et al. 2017; Dummer et al. 2018). The investigation will use ‘omic’ based technologies and classic cytogenetic techniques to identify biomarkers in the blood of individuals living in high radon areas.

Canadian Nuclear Safety Commission LDRR

As the Canadian nuclear regulator, the CNSC has been involved in LDRR for many years. Research drivers include the mandate (protect human health and the environment as well as disseminate objective scientific information), regulatory questions or changes (e.g. proposed changes to the lens of an eye dose limit), requests from the CNSC members (e.g. tritium toxicity project) and the broader international scientific community [e.g. International Commission on Radiological Protection (ICRP), UNSCEAR]. The CNSC recognizes the importance of research conducted both internally and externally to ensure that it remains a trusted nuclear regulator. A summary of projects supported under CNSC’s Research and Support Program is on the CNSC’s website (Canadian Nuclear Safety Commission 2020d).

Occupational exposures

Historically, much of the work has been epidemiology-based with significant contributions to the study of the health of nuclear energy workers, including uranium miners.

Canada has several cohorts of workers exposed to occupational radon with long-term follow-up of mortality and cancer incidence. These studies assess the radon-lung cancer risk relationship as well as other relationships:

• Eldorado cohort (Port Radium uranium mine, Beaverlodge uranium mine, and the Port Hope Radium and Uranium Refining and Conversion Facility),

• Ontario uranium miners (Elliott Lake, Bancroft, and Agnew areas),

• Newfoundland Fluorspar miners.

Findings from these three cohorts (Villeneuve et al. 2007; Lane et al. 2010; Navaranjan et al. 2016) have contributed significantly to the international understanding of the health effects of occupational radon exposure (National Research Council 1999; United Nations 2009). The Eldorado and Ontario cohorts are currently part of the Pooled Uranium Miners Analysis (PUMA) (Rage et al. 2020) and the International Pooled Analysis of Uranium Workers (iPAUW). Currently, CNSC is leading a Canadian Uranium Workers Study (CANUWS) of ∼80,000 uranium workers (i.e. Eldorado and Ontario cohorts of uranium miners, Northern Saskatchewan uranium mine and mill workers, and Ontario uranium processing and fabrication workers) with long-term mortality and cancer incidence follow-up to 2017.

Studies of Canadian nuclear energy workers include studies of the historic Atomic Energy of Canada Limited workers (Gribbin et al. 1993), and all workers occupationally exposed to radiation, whose dose records are in HC’s National Dose Registry (NDR) (Ashmore et al. 1998; Sont et al. 2001; Zablotska et al. 2004; Zablotska et al. 2014). These studies are included in international pooled analyses (Cardis et al. 1995; Cardis et al. 2005; Cardis et al. 2007) and have contributed to international scientific consensus documents (United Nations 2008). Currently, HC and CNSC are collaborating to address data issues identified among pre-1965 Atomic Energy of Canada Limited (AECL) workers (Ashmore et al. 2010; Zablotska et al. 2014) and to create an updated linkage of the NDR to mortality and cancer incidence databases at Statistics Canada. These linkages will provide long-term mortality and cancer incidence follow-up of workers to 2017 and many opportunities for future research and collaboration.

Public exposures

The CNSC and HC have conducted many studies of environmental radiation exposures and the health of people who live near nuclear facilities. A series of studies assessed the health of the community due to historic waste disposal practices of the radium and uranium refining and processing industry in Port Hope, Ontario before modern regulation and oversight (Burtt et al. 2011; Chen et al. 2013). Similarly, a study assessed environmental radiation exposures and cancer incidence around Ontario nuclear power plants (Lane et al. 2013). The CNSC also conducted a series of studies on the health effects of tritium in the environment (Thompson 2011; Bundy 2012). Most recently, in response to the Fukushima accident, the CNSC investigated the consequences of a hypothetical large-scale nuclear power plant accident (Burtt et al. 2020).

Radiobiology and the radiation protection framework

The CNSC has recently increased its expertise and capacity in radiobiology. The CNSC, in collaboration with the ICRP, is conducting a systematic review on how sex differences modify ionizing-radiation-induced health effects. It is also building capacity in the development of AOPs. In addition to the work conducted under the auspices of the Research and Support Program, staff regularly contribute to radiation science through publishing and also providing technical support to the Commission on the topic of radiation health sciences (Burtt et al. 2016; Leblanc and Burtt 2019).

As part of a larger project requested by the Commission to improve the regulation of tritium releases in Canada, the CNSC has and continues to conduct research on tritium environmental behavior and health effects, in collaboration with several national and international partners. Specifically, the report on the Health Effects, Dosimetry and Radiological Protection of Tritium reviewed the scientific literature to assess the health risk from exposures to tritium, assessed Canadian and international dosimetry practices for tritium intakes, and reviewed the current approaches for limiting exposure to tritium (Canadian Nuclear Safety Commission 2010; Bundy 2012).

Outreach, education, and trust

This research informs not only the radiation protection framework but also the communications to stakeholders. CNSC contributes to informing the members of the public, Indigenous peoples, and other stakeholders by regularly participating in outreach (schools, community events, open houses, etc.) and by creating communication products (information documents, various educational resources, content for social media, etc.) (Canadian Nuclear Safety Commission 2020c). CNSC staff engage with academia, where they supervise graduate student research and provide guest lectures. These activities build capacity and trust, a CNSC strategic priority, and trust-building is further strengthened by valuing stakeholder input and feedback. One example of many is when staff engages with stakeholders outside the context of Commission hearings or meetings through the Independent Environmental Monitoring Program. Stakeholder input is considered for the development of the sampling plan, but also for assessing other communication needs (i.e. concerns needed to be addressed). CNSC also acknowledges the importance of including stakeholders in research working groups to share knowledge and experiences, engagement, and communication. Lastly, CNSC staff are working with their federal partners to document a roadmap that will outline the tools necessary to address the perceived risks of members of the public and Indigenous peoples as they broadly relate to the nuclear industry.

History of federal collaboration

HC and the CNSC have a memorandum of understanding (MOU) which provides a formal framework to coordinate aspects of assessing and managing health risks to Canadians exposed to nuclear substances and radiation-emitting devices. With the CNSC’s regulatory authority, under the Nuclear Safety and Control Act (NSCA), and HC’s responsibilities under the AAPHI and the Radiation Emitting Device Act, they recognize the importance of comprehensive and consistent oversight of radiation safety. Furthermore, both HC and CNSC have federal nuclear emergency preparedness and response responsibilities. The MOU clearly outlines activities for consultation and cooperation to minimize duplication and use government resources effectively.

The CNSC and HC are building upon experience in research and radiation education and communication to ensure a more collaborative and coordinated approach to federal research and proper and effective dissemination of findings. To that end, HC and CNSC contribute to the Federal Nuclear Science & Technology (FNS&T) work plan, managed by the Atomic Energy Canada Limited (AECL) (2020). The objective of this initiative is to perform nuclear-related S&T research to support core federal roles and responsibilities while maintaining the necessary capabilities and expertise at CNL. The CNSC and HC, along with other interested federal departments and agencies, actively participate in FNS&T activities that determine the nature and prioritization of projects. This helps enable collaborations between CNL and COHERE partners and channels research resources toward projects that meet some of the radiobiology needs of both the CNSC and HC (McNamee et al. 2009; Flegal et al. 2012; Gueguen et al. 2018; Chauhan, Said, et al. 2019). Current CNL radiobiology research, including but not limited to activities conducted under FNS&T, is described in a recent review by Wang et al. 2019.

Canadian organization on health effects from radiation exposure (COHERE)

COHERE and its vision

Inspired by the NEA initiative for global coordination and collaboration, the Radiation Protection Bureau and the Consumer and Clinical Radiation Protection Bureau of HC, and the Directorate of Environmental and Radiation Protection and Assessment of the CNSC, agreed to improve collaboration and coordination of LDRR by establishing a joint LDRR program: Canadian Organization on Health Effects from Radiation Exposure (COHERE). This organization acts as a tool that strengthens the activities under the HC-CNSC MOU, but with a focus on LDRR. Its vision is to lead, contribute, and coordinate Government of Canada low dose research in high priority areas of relevance to Canada and provide insights into priority questions using tools, such as the AOP approach to help guide questions, most notably:

1. What are the adverse outcome pathways of regulatory interest?

2. Which early molecular events translate to health outcomes?

3. Can biologically based models and approaches be valuable in assessing health risk to the population?

4. Can in silico-derived data produce valuable models to predict relevant radiogenic effects and inform decision-making?

5. Is an ‘all hazards’ approach to risk assessment feasible in radiation protection practices?

COHERE will build the knowledge base to strengthen the weight of evidence to help address potential health risks from radiation exposure while supporting the respective mandates of HC and the CNSC (Figure 1(A)). Currently, the structural framework is comprised only of representatives from CNSC and HC to better align the research priorities of these two agencies. Champions for the program provide oversight to a scientific committee, which is responsible for establishing a strategic research agenda and work plan for conducting, presenting, and publishing high-quality research. A communication committee contributes to a communication plan, designs and produces promotional products (e.g. newsletters and pamphlets), and a website presence. Program coordinators interface with the Champions and the scientific and communication committees to ensure all activities under COHERE are delivered (Figure 1(B)).

Figure 1. The objective (A) and structural framework of COHERE (B).

The research from COHERE will contribute to the body of knowledge reviewed by UNSCEAR and ICRP to support assessments of the hazards posed by ionizing radiation exposure and inform the international system of radiation protection. This includes directed questions related to population and biological effects at acute and protracted doses <100 mGy. These doses are similar to those emitted from medical diagnostic procedures, occupational and environmental sources, and naturally occurring radioactive materials. The COHERE Workplan will integrate systematic literature surveillance and AOP development with experiments in areas of knowledge gaps using in vitro and animal studies at all levels of biological organization. The data generated will be linked using modeling approaches relevant to humans (Figure 2). Projects under the umbrella of this organization will focus on the following:

Figure 2. COHERE Research framework includes five main themes and contributes to Canadian guidance on radiation protection standards.

1. Understanding cancer risks from exposure to ionizing radiation at low doses and dose rates,

2. Understanding non-cancer risks from exposure to ionizing radiation at low doses and dose rates,

3. Leveraging globalized data-sharing initiatives to consolidate already-existing knowledge and identify knowledge gaps,

4. Validating emerging technologies and modernized approaches to support risk assessment,

5. Linking low dose radiation exposure data to cancer incidence and mortality effects.

Consistent with the aims of the international community, COHERE will also focus on risk communication. A communication strategy will guide the promotion of the program, the production of tools for the dissemination of information, and help with encapsulation of these tools in how the CNSC and HC regularly interact with the members of the public, Indigenous peoples, and other stakeholders.

Priority research areas

COHERE is aiming to align priority areas to that of the NEA’s initiative for the global coordination of low dose radiation research, the international [e.g. Multidisciplinary Effects of Low Dose Initiative (MELODI) and the ICRP] as well as the national priorities.

To facilitate this, COHERE has developed a strategic research agenda (SRA) to capture research priorities to address in the long term. This SRA will serve as a framework upon which COHERE can build collaborative relationships and develop a more coordinated approach both nationally and internationally. COHERE’s SRA has identified five key research themes that best align with COHERE’s priorities (Table 1):

Table 1. The five research themes under the COHERE SRA.

Themes	[1] Cancer effects	[2] Non-cancer effects	[3] Globalized data sharing and consolidation	[4] Capacity building	[5] Epidemiological studies
Research-lines	Conduct mechanistic based studies to examine dose-response relationships and links to adverse outcomes		Develop expertise in the area of data management and interpretation	Test new technologies/approaches for identifying low dose- response effects	Link occupational data to cancer/mortality data
Priority Area	Lung cancer (radon), kidney cancer (uranium), organ-level cancers (tritium)	Cataracts (high and low linear energy transfer), kidney toxicity (uranium)	Adverse outcome pathway, systematic reviews, benchmark dose modeling	Optical spectroscopy, 3 D organoid models, stem cell regeneration, phenotypic assays, dosimetry, ‘omics’ technology	International pooled studies, uranium workers; nuclear energy workers
Benefits	Mechanistic understanding in the area of low dose radiation exposures
	Better communication of risk to Canadians including radiation workers and members of the public and Indigenous peoples
	Harmonization with efforts internationally
	Contributing to Canadian guidance on radiation protection standards

Theme area 1 cancer effects

Three radionuclides: radon, tritium, and uranium are of particular interest in Canada due to the nature of the nuclear industry. While external exposures are also of interest, internal exposures to radon, tritium, and uranium are at the forefront of concern for Canadians including radiation workers and members of the public and Indigenous peoples.

Radon (Rn-222) is a naturally occurring radioactive gas and is the second leading cause of lung cancer after smoking (International Agency for Research on Cancer 2012). It is estimated that 16% of annual lung cancer deaths are attributable to residential radon exposure in Canada. Accordingly, the investigation of lung cancer risk from radon gas exposure in occupational and residential exposure scenarios is of interest. The work in this area will improve mechanistic knowledge on chronic low dose radon exposure, to reduce the uncertainty around the dose-modeling of radon progeny.

Tritium exposure can pose a health risk if ingested through drinking water or food, or if inhaled or absorbed through the skin in large quantities. Issues raised in Canada include handling, control, and releases of tritium, tritium drinking water limits, tritium’s fate in the environment, and the health effects of tritium exposure (Canadian Nuclear Safety Commission 2010; Bundy 2012). The CNSC conducted research to address these concerns and increased our scientific understanding of tritium. Tritium research questions of interest include the mechanistic and biokinetic nature of HTO (tritiated water) and OBT (organically bound tritium) ingested and incorporated in different forms.

Uranium is widespread in nature; Canadians primarily receive uranium exposure through drinking water and food. Natural events, such as forest fires can release uranium into the environment as with its release from rock and soil through natural processes. Artificial sources of uranium, largely stemming from the nuclear energy industry, also contribute to the release of uranium to the environment and contribute to the occupational exposures of workers. Although the health effects of acute (and very high) exposures to natural and depleted uranium exposures including nephrotoxicity are well-known, the health risks from long-term chronic consumption of uranium are less understood and deserve further investigation.

Theme area 2 non-cancer effects

In 2011, the International Commission of Radiation Protection (ICRP) recommended a reduction to the equivalent dose limit for the lens of an eye, based on new scientific evidence (International Commission on Radiological Protection 2012; International Atomic Energy Agency 2014). The evidence indicated that tissue reactions for the lens of an eye have dose thresholds that are or might be, lower than previously considered. In response to the scientific evidence published to date, several countries are considering or implementing a reduction to the worker dose limit for the lens of an eye. In Canada, effective 1 January 2021, the equivalent dose limit to the lens of an eye for a nuclear energy worker (NEW) will be decreased from the current limit of 150 mSv to 50 mSv in a one-year dosimetry period. Stakeholders have concerns about the scientific evidence behind the recommendations. Many questions remain about the mechanism of cataract development. For these reasons, research on the development of cataracts is a priority for COHERE. Other non-cancer endpoints are currently being explored under the subsequent research theme using the adverse outcome pathway approach.

Theme area 3 globalized data sharing and consolidation

Decades of research to understand the human health effects from exposure to sources of ionizing radiation have produced vast amounts of data. There is a need to determine the best approach to harness these large and diverse datasets, identify knowledge gaps, and develop directed research studies that can better support human health risk assessment and management (Schofield et al. 2019; Zander et al. 2019). Systematic methodologies can identify research gaps and feed data into the development of Adverse Outcome Pathways in areas relevant to radiation risk assessment. These reviews will also provide a framework to consolidate the data. COHERE will explore these methodologies as a means to vet and filter data and bridge the gap between radiobiological studies with epidemiology, a long-held goal of the radiation protection community (Ruhm et al. 2017). Adverse outcome pathways that are of interest include both cancer (lung cancer) and non-cancer (cardiovascular, cognitive, cataracts, and bone loss) outcomes.

Theme area 4 capacity building

COHERE will explore emerging technologies and approaches that have shown promise in other disciplines for their sensitivity to detect radiation effects at low doses and dose rates of exposure. These approaches may also provide new avenues for the investigation of non-targeted and targeted biological effects and individual susceptibility. Examples include:

1. chromosome conformation technologies, approaches that take into account the spatial organization of DNA when analyzing gene-gene interaction,

2. phenotypic assays, that can quantify disease phenotype changes in cells (to better understand the underlying biology with the aim to identify biomarkers), and

3. benchmark dose modeling to quantitatively analyze and interpret dose-response data.

Theme area 5 epidemiological studies

New studies on various populations, such as medical, occupational, and environmental exposures support the atomic bomb findings that as radiation dose increases, so too does radiation-induced cancer risk. Additional linkage of epidemiological cohorts of people with chronic low dose occupational exposures to cancer incidence and mortality outcomes, pooling of cohorts, and their analyses, will better refine health risk estimates at low doses and low dose rates. COHERE will also investigate emerging mathematical approaches related to confounders in the context of epidemiological studies

Discussion and conclusions

Radiobiological studies can strengthen epidemiological data by providing insight into biological mechanisms that can help reduce uncertainties. Much research is needed to help understand how early biological events in the body may translate to observed health effects and disease. COHERE will help integrate mechanistic and population-based data to support radiation protection. It will primarily work toward the development of sensitive technologies (i.e. genomics and optical spectroscopy techniques) to detect subtle changes in the cellular environment following radiation exposure. It will also exploit tools and methodologies that inform chemical toxicology to help refine risk estimates and link them to phenotypic changes (i.e. AOPs and benchmark dose modeling; Figure 1). In addition, modeling approaches will help interpret and extrapolate the in vitro measures to epidemiological studies. Better understanding in this area will provide a more biologically meaningful basis for reliable health risk estimation that is essential for a robust system of radiation protection. Collaborative undertakings between the two federal agencies will facilitate better use of resources, expertise and enable effective responses to inquiries and concerns from Canadians. In the long term, this will strengthen the weight of evidence needed for policy development and improvement of regulation and decision-making to help modernize radiation protection practices.

Stakeholder engagement and coordination

COHERE will engage stakeholders and research partners within and outside Canada. The work will be of interest to, and support ongoing efforts of UNSCEAR, ICRP, NEA, and the European MELODI/ALLIANCE consortium.

Before a national radiation protection community can become involved with global coordination and collaboration, we need domestic coordination. MELODI, which developed an SRA to help guide LDRR in Europe, is an international community that has demonstrated effective coordination of LDRR (Salomaa et al. 2017) and has provided guidance for the formation of COHERE. Their SRA facilitates the development of research projects, but more importantly collaboration. Similarly, COHERE’s SRA is not limited to the federal government and the FNS&T workplan; it can serve as a basis for collaborative work with other government departments, academic researchers, and industry partners, creating a strong foundation for future national coordination. A step toward global coordination is the harmonization of federal government LDRR in Canada followed by potential national coordination, with stakeholder partners conducting independent and/or collaborative research. Currently, national coordination of LDRR in Canada does not exist, but some initiatives have strengthened this vision (e.g. FNS&T) (Atomic Energy Canada Limited 2020). Coordinating on a domestic level will strengthen the Canadian low dose research community and, indirectly, the broader radiation research community. A well-coordinated research network will demonstrate Canadian leadership and will allow for more effective collaboration and partnerships internationally. Knowledge of Canadian research and expertise is essential to the Government departments who contract research and represent Canada on an international stage (e.g. NEA CRPPH, UNSCEAR, etc.). It will also facilitate the inclusion of all Canadian research/researchers/infrastructure in international coordination efforts, such as NEA HLG LDR initiatives.

Next steps

Dialogue has begun between COHERE and external organizations involved in LDRR. The goal is to put forward an approach to involve the broader Canadian LDRR community and to assess its interest in national coordination and a potential framework. One benefit of national coordination will be the effective compilation of the broader Canadian LDRR as input into the global coordination efforts. Optimizing resources will increase research output and reduce unnecessary duplication of effort with development in the area of technology and mechanistic translational research. Further, COHERE is committed to improving the understanding of low-dose radiation health effects.

Conclusions

The Canadian Nuclear Safety Commission and Health Canada have a long history of conducting scientific research to support their mandates. COHERE is a first step toward coordinating LDRR activities between these organizations and will facilitate the integration of Government of Canada research into global collaborations. It also has the potential to serve as a foundational input into national LDRR coordination in Canada.

The COHERE work plan will be reviewed annually and focuses on joint activities to advance COHERE goals and the SRA. The current work plan includes:

• Identifying and conducting joint projects to address research deficiencies in the area of LDRR without duplicating efforts nationally and internationally

• Collaboration and activities with stakeholders to promote COHERE goals

• Engaging with national and international community initiatives through working groups, conferences, meetings, etc.

• Professional development and training in building complementary skillsets in different disciplines

• Identifying, applying, and promoting emerging tools and techniques to inform and enhance radiation risk estimation, such as the Adverse Outcome Pathway (Figure 2)

The progress of COHERE can be followed through ResearchGate (Canadian Nuclear Safety Commission 2020a) and the COHERE webpage on the CNSC website (Canadian Nuclear Safety Commission 2020b). Promotion and outreach will also be an ongoing activity, including communication and presentation at national and international forums (i.e. conferences, workshops, meetings, etc.).

Acknowledgments

The authors would like to acknowledge Katya Feder and Sami Qutob for editorial comments; and Annick Laporte for figure design.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Notes on contributors

Vinita Chauhan

Dr. Vinita Chauhan is a Research Scientist at the Consumer and Clinical Radiation Protection Bureau of Health Canada. She is a Canadian Delegate on the High-Level Group on Low Dose Research (HLG-LDR) and Extended Advisory Group on Molecular Screening and Toxicogenomics of the Organisation for Economic Cooperation and Development and has recently been appointed as the co-chair of the newly formed RAD/CHEM AOP joint topical group through the HLG-LDR committee.

Julie Leblanc

Dr. Julie Leblanc 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.

Baki Sadi

Dr. Baki Sadi is a Research Scientist at the Radiation Protection Bureau.

Julie Burtt

Julie 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 with the UNSCEAR Secretariat. She also serves as a Canadian representative on the National Energy Agency’s Expert Group on Non-radiological Public Health Aspects of Radiation Emergency Planning and Response.

Kiza Sauvé

Kiza Sauvé is the Director of the Health Sciences and Environmental Compliance Division at the Canadian Nuclear Safety Commission (CNSC). With a wide range of expertise including in wastes and decommissioning, and environmental and radiation protection and assessment, she provides leadership and oversight to her team. She is a member of the Leading Group of Women in Nuclear (WiN) Canada, Eastern Ontario Chapter.

Rachel Lane

Dr. Rachel Lane is a Radiation and Health Sciences Specialist (epidemiology) with the Canadian Nuclear Safety Commission and an adjunct professor at Carleton University. Her research focuses on the health effects of occupational and environmental radiation exposure. Dr. Lane has been an advisor for Canada to the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) since 2006.

Kristi Randhawa

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).

Ruth Wilkins

Dr. Ruth Wilkins is the Division Chief of the Ionizing Health Sciences Division at Health Canada. She is an alternate representative of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR).

Debora Quayle

Debora Quayle is section head of the Radiation Health Assessment Division at Health Canada. She is a member of the Canadian Delegation on the OECD Nuclear Energy Agency Committee of Radiological Protection and Public Health.