Strategic Research Agenda for the Canadian Organization on Health Effects from Radiation Exposure (COHERE) – 2020

Introduction

Currently, radiation protection standards are derived primarily from the extrapolation of data from epidemiological studies using cohorts exposed to high doses of ionizing radiation. It has long been acknowledged that this approach may not accurately represent health risks due to uncertainties around responses at lower doses and dose rates (< 100 mGy; < 6 mGy/h). Internationally, there is renewed interest in reducing this uncertainty using new approaches to advance the understanding of molecular- and cellular-level responses and to identify sensitive, early and key molecular events that have the greatest likelihood of leading to an apical adverse outcome.

The Canadian Organization on Health Effects from Radiation Exposure (COHERE) is a partnership between radiation protection and research programs from Health Canada (HC) and the Canadian Nuclear Safety Commission (CNSC). These organizations agree that knowledge of the underlying mechanisms of biological responses to ionizing radiation strengthens their ability to exercise their mandates for risk assessment, risk communication and health protection. They are also optimistic that interdisciplinary research using today ’s tools and technologies can shed light on molecular- and cellular-level responses at doses/dose rates relevant to public and occupational exposure scenarios.

Through COHERE, the CNSC and HC envision creating a Canadian platform to coordinate federal low-dose radiation research, and to connect and collaborate with academic and industry programs, other research platforms and international coordinating bodies. COHERE is already linked with EURATOM ’s Multidisciplinary European Low Dose Initiative (MELODI) through the CNSC, which is a member. The new organization is also represented by both HC and CNSC at meetings of the High Level Group on the global coordination of low-dose radiation research that was recently initiated by the Organisation for Economic Co-operation and Development (OECD) Nuclear Energy Agency (NEA). Outputs from COHERE will contribute to the body of knowledge that supports the international system of radiation protection.

COHERE builds on the formal agreement between HC and CNSC to share information and to cooperate on studies or assessments relevant to the health effects of nuclear substances and nuclear energy and radiation emitting devices. Immediate goals include:

1. maintaining and enhancing expertise in dosimetry, radiobiology and epidemiology within the Government of Canada
2. better aligning HC and CNSC research priorities to focus and leverage resources
3. providing an informed and consistent message to the public and stakeholders on matters involving low dose/dose rate ionizing radiation

The COHERE strategic research agenda (SRA) supports the first two goals. This document identifies the research areas that the CNSC and HC have determined to be priorities for the next few years. It also describes several projects led by HC and/or CNSC research scientists that pre-date this SRA but which are now included under the COHERE umbrella.

Strategic research agenda (SRA)

The CNSC is the federal agency responsible for regulating the use of nuclear energy and materials to protect health, safety, security and the environment, as described in the Nuclear Safety and Control Act ^{Footnote 1}.HC is the federal department responsible for helping Canadians maintain and improve their health, which includes implementing the Radiation Emitting Devices Act ^{Footnote 2}, delivering the National Radon Program and providing guidance for managing exposures during nuclear emergencies and from naturally occurring radioactive materials.

The SRA, presented in table 1, aims to address the challenges and inconsistencies encountered by CNSC and HC staff when applying and updating current radiation protection regulations and recommendations, and when communicating with stakeholders. It also considers stakeholder input as received through public enquiries, expressions of public concern and requests from CNSC Commission members.

Priorities identified by the international community and other research platforms, including the International Commission on Radiological Protection (ICRP) and MELODI ^{Footnote 3 Footnote 4}, informed the themes and research lines. Priority areas narrow the scope of the agenda to focus on topics of primary concern in the Canadian landscape, as well as opportunities, tools and technologies that best leverage Canadian federal expertise. COHERE identified five key research themes as being best aligned with its priorities (table 1):

Table 1: Five research themes under the COHERE SRA

Sex- and gender-based analysis plus

There is a strong sex bias in radiation science and this contributes to important risk uncertainties. These biases are the result of the historical use of cohorts predominantly composed of men (occupational studies) and the omission of sex as contributing factor ^{Footnote 5}.

Sex and gender-based analysis (SGBA) is an analytical process used to determine how diverse groups of women, men, girls, boys and gender-diverse people may be impacted by federal initiatives.

Health Canada’s Sex and Gender Action Plan aims to systematically integrate sex and gender considerations into all of Health Canada's research, legislation, policies, regulations, programs and services ^{Footnote 6}.

In keeping with this action plan, COHERE will consider biological sex as a contributing factor when planning new projects.

Other factors should be considered, including age and genetics, in the course of project design where appropriate in order to reduce risk uncertainties.

Descriptions of priority areas

Cancer effects

Radon

Radon (radon‑222) is a naturally occurring radioactive gas that is generated from the decay of uranium-238. An estimated 16% of annual lung cancer deaths are attributable to residential radon exposure in Canada ^{Footnote 7 Footnote 8}. Accordingly, there is interest in research to investigate lung cancer risk from radon gas exposure in occupational and residential exposure scenarios. The intent is to improve mechanistic knowledge on chronic low-dose radon exposure, reduce uncertainty around the dosimetry of radon progeny and investigate the existence of a dose threshold for radon-induced lung cancer.

Priority research:

1. Conduct animal and in vitro-based studies to identify early key biological events related to phenotypic changes using a radon chamber.
2. Generate new mechanistic knowledge on the development of lung cancer from chronic low dose exposure to radon and radon progeny using human cohorts.
3. Address uncertainties around radon dosimetry based on indoor aerosol characteristics for radiobiological research.

Tritium

Tritium is used or produced by the nuclear energy industry, in tritium-processing facilities and for research. It is therefore reasonable that public and professional concerns have highlighted issues with handling, control and releases of tritium, tritium drinking-water limits, the fate of tritium in the environment and the health effects of tritium exposure ^{Footnote 9}. The CNSC commissioned additional research to address these concerns by increasing the scientific understanding of tritium. Questions of interest in tritium research include the mechanistic and biokinetic nature of tritiated water (HTO) and organically bound tritium (OBT) ingested and incorporated in different forms.

Priority research:

1. Development of an appropriate micro-dosimetric approach to better understand the distribution of dose from various organic forms of tritium within a cell and within tissues and organs. This includes an approach for assessing doses to germ cells, the embryo, the fetus and the infant.
2. In vitro studies researching the complexity of DNA damage induced by DNA synthesis precursors or tritium-labelled amino acids in chromatin binding proteins (e.g., histones), the triggering of DNA damage-signalling pathways and the activation of various cellular processes (e.g., repair, cell cycle arrest, apoptosis, differentiation, proliferation, senescence) in terms of toxicity and genomic instability.
3. Histopathological assessments of organs for the identification of cancer markers in animals exposed to HTO and different forms of OBT.

Uranium

Uranium is abundant in Canada. Uranium mining in Canada is considered part of the nuclear fuel cycle; therefore, the resulting occupational and public exposures are regulated by the CNSC. Uranium and uranium progeny are also released from rock and soil in their natural state, and this can lead to elevated levels in drinking water sources unaffected by mines. These exposures are managed in accordance with the Canadian Drinking Water Guidelines, for which Health Canada serves as a technical authority. Although the health risks of acute exposures to natural and depleted uranium are well known, there remains some uncertainty about the health effects from long‑term chronic exposure.

Priority research:

1. Studies to identify early key biological events related to phenotypic changes, and ultimately, adverse outcomes (such as nephrotoxicity), at levels of uranium and long-lived progeny that are relevant to public exposure from naturally-occurring sources.
2. Understanding the molecular mechanism of action of uranium as both a toxic heavy metal and an alpha emitting radionuclide using in vitro and in vivo animal models, including the identification of biomarkers.
3. Identifying risk of mortality and cancer incidence in uranium workers due to low cumulative occupational radon (and gamma).

Non-cancer effects

Cataracts

Several countries (including Canada) are currently planning to reduce the lens of the eye dose limit to the same value as the effective dose limit. The equivalent dose limit for the lens of an eye for a nuclear energy worker is currently 150 mSv in a one-year dosimetry period. In 2011, the ICRP recommended a reduced equivalent dose limit for the lens of an eye based on new scientific evidence which indicated that tissue reactions for the lens of an eye have dose thresholds that are or might be lower than previously considered ^{Footnote 10}. Following the recommendations of the ICRP and the IAEA GSR Part 3 ^{Footnote 11}, the CNSC amended the Radiation Protection Regulations:

• the equivalent dose limit for the lens of an eye for a nuclear energy worker has changed from 150 mSv to 50 mSv in a one-year dosimetry period; and
• a new equivalent dose limit has been added for the lens of an eye for a nuclear energy worker of 100 mSv in a five-year dosimetry period.

Priority research:

1. In vitro studies using low LET radiation to research the radiation-induced biological mechanisms of the lens of the eye opacities, including a basic understanding of the development of cataracts.

Globalized data sharing and consolidation

Decades of research have been conducted to understand the human health effects of ionizing radiation source exposures and have produced vast amounts of data. There is a need to identify the best approach to efficiently harness these large and diverse datasets for the purpose of identifying knowledge gaps that allow for directed research studies to better support human health risk assessment and management.

Priority research:

1. Developing the adverse outcome pathway framework to areas of relevance to radiation risk assessment.
2. Conducting systematic reviews of the fundamental biological mechanisms (e.g., bystander effect, hyper-radio sensitivity, increased radio resistance, adaptive response) and feeding the information into an adverse outcome pathway framework.
3. Applying existing modeling approaches used in chemical toxicity (e.g., benchmark dose modeling) to archived radiation datasets (mega mouse and beagle dog studies).

Capacity building

Emerging technologies and approaches that have shown promise in other disciplines will be explored for their sensitivity to detect radiation effects at low doses and dose rates of exposure from low and high linear energy transfer radiation exposures. These approaches may also provide new avenues for investigating non-targeted and targeted effects and individual susceptibility.

Priority research:

1. Testing and validating new technologies for their ability to support low-dose radiation risk assessment (e.g., lipidomics, optical spectroscopy, chromosome conformation capture). Use of organ-on-a-chip technology, microfluidics, 3D organoid systems.
2. Examining the latest research discoveries/breakthroughs in the area of phenotypic changes and dosimetry.

Epidemiological studies

Current radiation protection standards have been built by extrapolating data from high to low doses of exposures, primarily using atomic bomb survivors’ data, which is representative of acute and high doses. To better refine health risk estimates from chronic low-dose exposures, emerging mathematical approaches will need to be applied to existing or new epidemiological studies conducted at low doses and dose rates.

Priority research:

1. Investigating biomarkers from individuals exposed to sources of ionizing radiation, such as naturally occurring radioactive radon gas, to have a better mechanistic understanding of biological effects at low doses.
2. Testing various statistical approaches and biologically based models to identify cancer risk from low-dose/low dose-rate epidemiological studies.
3. Linking data from the National Dose Registry with national repositories of health information to identify associations between occupational exposures and health outcomes.

Communications strategy

To bring awareness to COHERE research initiatives, annual events will be jointly organized. Activities will include hosting workshops and webinars, developing website content, publishing research articles and meeting proceedings, participating in seminars and supporting the COHERE communications committee to promote program initiatives. The communications committee will develop a strategy.

Partnerships

COHERE comprises staff from the following Government of Canada organizations:

• HC’s Radiation Protection Bureau (RPB) and Clinical and Consumer Radiation Protection Bureau (CCRPB) 
• the CNSC’s Directorate of Environmental and Radiation Protection and Assessment (DERPA)

External collaborators

External partners from academia, and national and international collaborators include:

• Institute for Clinical Evaluative Sciences (ICES)
• CanPath - Canadian Partnership for Tomorrow's Health
• International Commission of Radiological Protection (ICRP)
• Electric Power Research Institute Radiation Program (EPRI)
• Canadian Nuclear Laboratories (CNL)
• University of Ottawa (Ottawa, Ontario)
• Carleton University (Ottawa, Ontario)
• University of California, San Francisco
• Georgetown University (Washington, DC)
• University of Saskatchewan (Saskatoon, Saskatchewan)
• University of Calgary (Calgary, Alberta)
• Atomic Energy Canada Limited (AECL)

Memberships

COHERE scientists are active members of the following organizations:

• Canadian Radiation Protection Association
• Multidisciplinary European Low Dose Initiative (MELODI)
• United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR)
• Organisation for Economic Cooperation and Development (OECD) Nuclear Energy Agency (NEA)
  • NEA High Level Group on low dose research
  • Committee on Radiation Protection and Public Health
• Radiation Research Society

Stakeholders

Our stakeholders include, but are not limited to:

• CANDU Owners Group (COG)

SRA review process

The COHERE SRA will be reviewed every three years or at a frequency determined by the participating organizations. The process will consider advances in the priority areas and remaining gaps as assessed through publications, conference proceedings and patents, as well as knowledge of the current state of science at the time. Areas of focus will revised, added or deleted primarily in response to stakeholder interests, the mandated priorities of the federal departments, available resources and important international developments of interest to the program.

References

• Nuclear Safety and Control Act (S.C. 1997, c. 9) (last amended 2017). Justice Canada.
• Radiation Emitting Devices Act (R.S.C., 1985, c. R-1) (last amended 2016). Justice Canada.
• Areas of Research to Support the System of Radiological Protection (2017). International Commission on Radiological Protection.
• MELODI Strategic Research Agenda (2019). Multidisciplinary European Low Dose Initiative.
• Langen, Britta. Age and sex bias in radiation research – and how to overcome it. The Journal of Nuclear Medicine. 60(4): 466. 2019.
• Sex- and Gender-based Analysis in Action at Health Canada. Health Canada.
• Chen J, Moir D, Whyte J. Canadian population risk of radon induced lung cancer: a re-assessment based on the recent cross-Canada radon survey. Radiat Prot Dosimetry. 2012 Nov; 152(1-3):9-13.
• Cross-Canada Survey of Radon Concentrations in Homes – Final Report. 2012 Cat.: H144-2/2012E. ISBN: 978-1-100-20115-3. Health Canada.
• Health effects, dosimetry and radiological protection of tritium – part of the Tritium Studies Project. INFO-0799. 2010. Canadian Nuclear Safety Commission.
• ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs–threshold doses for tissue reactions in a radiation protection context, ICRP Publ. 118, Ann. ICRP 41 (1–2) (2012). International Commission on Radiological Protection.
• Radiation protection and safety of radiation sources: international basic safety standards. General safety requirements, Part 3. International Atomic Energy Agency.

Ongoing projects

Radiation-induced thyroid cancer and non-malignant disease: A systematic review

Start: 2022

End: 2024

Project lead: Julie Burtt, Canadian Nuclear Safety Commission

COHERE contact: Julie Burtt (julie.burtt@cnsc-ccsn.gc.ca)

SRA themes: Cancer and non-cancer effects

A systematic review will be conducted to assess the current state of knowledge on radiation-induced thyroid diseases (cancer and non-cancer outcomes) in adult populations. Thyroid diseases are important potential outcomes when considering occupational settings and nuclear emergency situations. The review will offer insights on radiation-induced thyroid disease risk in adults, which is less well understood than in children.

Development of an adverse outcome pathway (AOP) relevant to health outcomes from space travel

Start: 2021

End: Ongoing

Project lead: Vinita Chauhan

COHERE contact: Vinita Chauhan (vinita.chauhan@hc-sc.gc.ca)

SRA themes: Cancer effects, non-cancer effects, globalized data sharing/consolidation

Long-duration space flight poses increased health risks to astronauts. This is primarily from exposure to a multitude of stressors that can significantly impact human physiology in the hostile space environment.

Microgravity, space radiation and altered atmospheric gas are some examples of stressors, with radiation being particularly detrimental, as it is difficult to shield from.

Solar particle radiation and, to a lesser extent, galactic cosmic rays are the most abundant sources of space radiation, which is made up primarily of heavy ions, high-energy protons and secondary particles.

These stressors may combine and interact to damage biomolecules, cells, tissues and organs, leading to short- and long-term effects that include impacts to various organ systems. The Canadian Space Agency (CSA), the National Aeronautics and Space Administration (NASA) and Health Canada recognize the value of having established adverse outcome pathways (AOPs) that are relevant to space travel to facilitate the risk assessment of potential health effects from exposures to this complex environment. Thus, this collaborative effort across these agencies will lead to the development of AOPs to cardiovascular effects, bone loss, ocular disorders, and cognitive/behaviour effects, which are most relevant to space travel.

AOP publications

International horizon-style exercise: Advancing the use of the adverse outcome pathway (AOP) framework in radiation protection

Start: 2021

End: 2022

Project lead: Julie Burtt, Canadian Nuclear Safety Commission

COHERE contact: Julie Burtt (julie.burtt@cnsc-ccsn.gc.ca)

SRA themes: Capacity building

This project examined the challenges of using the adverse outcome pathway (AOP) framework to support the radiation protection community by conducting an international horizon-style exercise (HSE). The HSE was initiated through the Radiation/Chemical AOP Joint Topical Group of the OECD Nuclear Energy Agency High-Level Group on Low-Dose Research, in conjunction with COHERE members. 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. The objective of the HSE was to facilitate the collection of ideas from a range of experts; 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 dose-rate exposures; and reduce uncertainties in estimating the risk of developing adverse health outcomes following such exposures.

Linkage of the National Dose Registry to mortality (1950–2018) and cancer incidence (1969–2018) outcomes – Update and data validation

Start: 2018

End: 2023

Project lead: Tim Prendergast, Health Canada

COHERE contact: Rachel Lane (rachel.lane@cnsc-ccsn.gc.ca)

SRA themes: Epidemiological studies, cancer effects, non-cancer effects

The National Dose Registry (NDR) contains dose records for about 1 million Canadian workers occupationally exposed to radiation. Occupational health and safety legislation establishes thresholds for radiation exposure, as well as workplace and personal protective measures, to minimize the hazards to individuals whose work includes exposure to radiation. Given that radiation-related health effects may take years to manifest, the principle aim of this study is to estimate the long-term health risks of occupational radiation exposure. The analytical database required to do this analysis requires linkage of the NDR (1942–2018) to Statistics Canada’s health outcome databases: the National Cancer Incidence Reporting System (1969–1991), Canadian Cancer Registry (1992–2019), Canadian Vital Statistics Death Database (1945–2018), and T1 Personal Master File (1981–2020). Probabilistic record linkage between the NDR and Statistics Canada’s Social Data Linkage Environment Derived Record Depository was completed in March 2019. Validation of the record linkage is underway.

The Canadian Fluoroscopy Cohort Study (CFCS): Lifespan mortality (1950–2017) and cancer incidence (1969–2017) follow-up

Start: 2014

End: 2027

Project lead: Dr. Lydia Zablotska, University of California San Francisco

COHERE contact: Rachel Lane (rachel.lane@cnsc-ccsn.gc.ca)

SRA themes: Epidemiological studies, cancer effects, non-cancer effects

The Canadian Fluoroscopy Cohort Study (CFCS) includes 63,715 patients from Canada exposed to X-ray fluoroscopies to the chest and abdomen during treatment for tuberculosis between 1930 and 1969. The cohort includes patients of all ages and both sexes, and about half of patients were exposed to at least 1 fluoroscopy that carried a substantial radiation exposure. The CFCS recently updated its mortality and incidence follow-up to 2017, with a proposed extension to the end of 2025. These updates will allow analysis of lifetime mortality and cancer risks. The study will address critical gaps in our knowledge of the long-term health risks of protracted X-ray radiation exposures such as from current-day computed tomography (CT) scans, an area of public health interest and concern. By directly comparing radiation risk estimates for cancer and non-cancer disease in a combined analysis of CFCS and Life Span Studies (LSS), we will be able to determine the appropriateness of current radiation safety standards based on the risk projections from the study of survivors of the atomic bombings in Japan.

Verification and correction of early Atomic Energy of Canada Limited (AECL) doses in the National Dose Registry (NDR) and updated mortality and cancer incidence analysis of Canadian nuclear energy workers

Start: 2018

End: 2027

Project co-leads: Rachel Lane, Canadian Nuclear Safety Commission / Tim Prendergast, Health Canada

COHERE contact: Rachel Lane (rachel.lane@cnsc-ccsn.gc.ca)

SRA themes: Epidemiological studies, cancer effects, non-cancer effects

Health Canada’s National Dose Registry (NDR) has been in operation since the mid-1970s and contains the occupational radiation dose records of all monitored workers in Canada from the 1940s to the present. Around 2004, the NDR participated in an international study that found that Canadian results were inexplicably different from other countries. It was later discovered that important historical dose records from Atomic Energy of Canada Limited (AECL) were missing that dated back to the 1940s and 1950s, when 2 incidents at AECL facilities led to significant worker exposures. It was suspected that the missing doses skewed the results, which significantly reduced the utility and credibility of the NDR dataset for epidemiological studies. The NDR team (including Health Canada, AECL and the CNSC) located those records. However, there is still a need to integrate them into the NDR database and verify that their inclusion will fix the problem. If it does, there is a further need for an epidemiological analysis of the radiation-related health risks (mortality, cancer incidence) to Canadian nuclear energy workers (NEWs), using the restored historical AECL dose data as well as dose data collected up to and including 2018. The overarching objectives of this project are to validate that the NDR database contains all the best available data for AECL workers, and then use the NDR dataset, linked to mortality (1950–2018) and cancer incidence (1969–2018), to characterize the dose-response relationship between occupational exposure to ionizing radiation and health outcomes among Canadian NEWs.

Development of automated biologically based methods for measuring human radiation exposure

Start: 2014

End: Ongoing

Project lead: Lindsay Beaton

COHERE contact: Lindsay Beaton (lindsay.beaton@hc-sc.gc.ca)

SRA themes: Capacity building

Biodosimetry is a determination of the dose of ionizing radiation that an individual may have received based on the evaluation of biological damage. Conventional biodosimetry methods include a number of cytogenetic assays, and while these methods are often used to assist with the evaluation of patients on a case-by-case basis, they are also critical tools for triage following a large-scale radiological/nuclear event. In the case of such an event, hundreds to thousands of people could require biodosimetry, and laboratories performing conventional biodosimetry would be quickly overwhelmed. The need for rapid population triage to sort casualties into broad dose groups (the worried well, those requiring medical surveillance and those requiring extensive medical intervention) and to assure the worried well post-event could be addressed through automated, high-throughput methods of processing, acquisition and analysis.

The objective of this project is to develop high-throughput methods for biodosimetry. Recently, imaging flow cytometry technology has been developed, which combines the statistical power of traditional flow cytometry with the sensitivity and specificity of microscopy. The technology is capable of automated sample acquisition and batch analysis. As a result, this technology is well suited for the adaptation of the assays into a fully automated imaging cytometry method (e.g., CBMN and γH2AX-ISX) for high-throughput screening.

Monte Carlo modelling of radiation interactions with biological systems

Start: 2019

End: 2027

Project lead: Lindsay Beaton

COHERE contact: Lindsay Beaton (lindsay.beaton@hc-sc.gc.ca)

SRA themes: Capacity building

Health Canada has been providing biodosimetry analysis for Canadian and European astronauts since 2007 through coordination with the Canadian Space Agency. Over this time, data has been accumulated for several astronauts who have completed long-duration missions to the International Space Station.

Currently, astronaut biodosimetry uses individualized, in vitro X-ray equivalent calibration curves. The goal of this project is to use radiation modelling tools to convert the X-ray equivalent dose estimates to a mixed-field, protracted exposure scenario. This would better reflect the unique radiation space environment and the biological response, as measured by biodosimetry assays. This work will be done in collaboration with Canadian Nuclear Laboratories.

Canadian Nuclear Uranium Worker Study (CANUWS)

Start: 2018/19

End: 2022/23

Contributors: Joint, including other collaborators

Project lead: Rachel Lane

COHERE contact: Rachel Lane (Rachel.lane@cnsc-ccsn.gc.ca)

SRA themes: Epidemiological studies, cancer effects

The Canadian Nuclear Uranium Worker Study is a large epidemiological study to assess the health effects of occupational radiation exposure among uranium workers (miners, millers, processors). A follow-up of over 80,000 Canadian uranium mine, mill and processing workers will look at their occupational radiation exposures (1932–2017), mortality (1950–2017) and cancer incidence (1969–2017) using data from the National Dose Registry, the Canadian Mortality Database and the Canadian Cancer Registry. The study will take approximately four years to conduct.

The main objective of the study is to assess the radon­–lung cancer relationship, considering confounding and effect modifying factors. Importantly, the study will assess the health effects of low cumulative exposures and exposure rates. This is possible due to long-term follow-up of workers’ low cumulative exposures and high quality measurements after radiation protection measures were put in place to significantly reduce occupational radiation exposures. This information is relevant to radiation protection for current and future uranium workers with low occupational radiation exposures. We can investigate many other research questions because of the large cohort size and long-term exposure, mortality and cancer incidence follow-up.

The study will improve the quality of Canadian information included in future international collaboration studies, such as the current Pooled Uranium Miners Analysis (PUMA) and the International Pooled Analysis of Uranium Workers (iPAUW). This work will further advance the international understanding of radiation risk and support the International Radiation Protection Framework, and more specifically, the International Commission on Radiological Protection ’s recommendations on radon.

International Pooled Analysis of Uranium Processing Workers (iPAUW)

Start: September 2019

End: 2022/2023

Contributors: Joint, including other collaborators

Project lead: Dr. Lydia Zablotska, University of California San Francisco

COHERE contact: Rachel Lane (Rachel.lane@cnsc-ccsn.gc.ca)

SRA themes: Epidemiological studies, cancer effects

Description: The iPAUW study is a large international pooled epidemiological study to assess the health effects of occupational radiation exposure among uranium processing workers (mill, refining, processing and fabrication). Researchers will harmonize the exposure information of about 100,000 uranium-processing workers from 16 different cohorts and a new set of organ doses from uranium bioassay, radon daughter progeny (RDP) and external ionizing radiation exposures to be calculated by applying a harmonized protocol. Researchers will describe the overall mortality of uranium-processing workers in comparison with the general population, by stage of uranium processing. They will also examine RDP and gamma-related risks of mortality and temporal effects modifiers for radiation-associated risks. Outcomes of interest will be cancers and non-cancer diseases of uranium-target organs, including lung and bronchi, liver, kidney, bone, brain and lympho-hematopoietic tissues. Larger statistical power of the analysis of pooled data will give the proposed collaborative study substantially greater ability to describe radon-, gamma- and long-lived radionuclide-associated risks for this unique group of workers many years after exposure. Researchers will also consider uncertainties in exposure estimates and their potential effect on radiation risk estimates.

This work will further advance the international understanding of radiation risk and support the International Radiation Protection Framework, and more specifically, the International Commission on Radiological Protection ’s recommendations on radon.

Publication: (Golden et al., 2021) see hyperlink below

Golden, A. P., Milder, C. M., Ellis, E. D., Anderson, J. L., Boice, J. D., Jr., Bertke, S. J., & Zablotska, L. B. (2021). Cohort profile: four early uranium processing facilities in the US and Canada. Int J Radiat Biol, 97(6), 833-847. https://doi.org/10.1080/09553002.2021.1917786

Analysis of Histological Subtypes of Incident Lung Cancer among Eldorado Uranium Workers

Start: June 3, 2019

End: Completed

Project lead: Dr. Lydia Zablotska, University of California San Francisco

COHERE contact: Rachel Lane (Rachel.lane@cnsc-ccsn.gc.ca)

SRA themes: Epidemiological studies, cancer effects

The study will assess the relationship between RDP exposure and subtypes of incident lung cancer, using advanced statistical analysis of a cohort of 17,660 Eldorado uranium workers from Canada first employed from 1932 to 1980 and followed for cancer incidence through the Canadian Incidence DataBase from 1969 to 1999.

This study will examine radiation-related risks for incident lung cancer, with special attention to three main histological subtypes (squamous cell, small cell and adenocarcinoma), separately and together for RDP internal exposures and gamma ray external exposures.

It will determine modifying effects of histological subtype, time since exposure, exposure rate and age at risk on the RDP exposure–lung cancer associations, together and separately by histological subtype.

Finally, it will investigate radiation-related risks of gamma-ray doses to determine whether they provide improved fit of the model with RDP exposures.

Publication: (Zablotska et al., 2022)

Zablotska, L. B., Lane, R. S. D., & Randhawa, K. (2022). Association between exposures to radon and gamma-ray radiation and histologic type of lung cancer in Eldorado uranium mining and milling workers from Canada. Cancer. https://doi.org/10.1002/cncr.34351

Occupational Exposure to Radon and the Risk of Lung Cancer: Updated Findings from the Newfoundland Fluorspar Miners ’ Cohort

Start: November 30, 2017

End: Completed

Contributors: Joint, including other collaborators

Project lead: Dr. Paul Villeneuve, Carleton University

COHERE contact: Rachel Lane (Rachel.lane@cnsc-ccsn.gc.ca)

SRA themes: Epidemiological studies, cancer effects

The Newfoundland cohort of fluorspar miners includes 2,121 miners employed in the mining of fluorspar from 1933 to 1978 in St. Lawrence, Newfoundland. Cause of death information was determined through linkage to the Canadian Mortality Database from 1950 to December 31, 2016. Each cohort member had cumulative exposures to radon progeny in working-level months by year. External cohort analyses generated standardized mortality ratios relative to mortality rates for males in the province of Newfoundland. We applied linear excess relative risk models to characterize variations in the radon–lung cancer risk across effect modifiers, including categories of duration of exposure, time since last exposure, cigarette smoking and age attained. We also evaluated associations between radon progeny and lung cancer across histological subtypes of lung cancer. Finally, we analyzed associations between radon progeny and cardiovascular disease mortality. Analyses of the updated cohort is ongoing.

Exploring the Adverse Outcome Pathway (AOP) Framework in Radiation Risk Assessment

Start: 2018

End: 2025

Project lead: Dr. Vinita Chauhan, Health Canada

COHERE contact: Vinita Chauhan (Vinita.Chauhan@canada.ca)

SRA Themes: Globalized data sharing, consolidation and interpretation

The adverse outcome pathway (AOP) framework is a means to consolidate existing mechanistic and epidemiological studies. It assembles knowledge across levels of biological organization by identifying key events that are causally linked to an adverse outcome of relevance to regulatory decision making. AOPs have shown promise in addressing knowledge gaps, informing test method development and supporting predictive toxicology for risk assessment in chemical toxicity. For this project, work is underway to advance the approach in the radiation field through the development of radiation-relevant AOPs related to space-flight health outcomes. International work is also progressing through the Radiation/Chemical AOP Joint Topical Group of the Nuclear Energy Agency High-Level Group on Low-Dose Research, which aims to make AOPs appealing to international and national radiation protection agencies and the community of regulators, policymakers and researchers.

Investigation of Biomarkers of Radiation Exposure in Radon Cohorts

Start:  2018

End: Ongoing

Project lead: Dr. Vinita Chauhan, Health Canada

COHERE contact: Vinita Chauhan (Vinita.Chauhan@canada.ca)

SRA theme: Cancer effects

This study will perform in vivo validation using blood samples from individuals chronically exposed to naturally-occurring radioactive radon gas. Technologies that include cytogenetics and the various “omics” will be used for biomarker identification. Radiobiological assessments of the selected individuals will be performed to confirm that the proposed biomarkers vary with radon exposure. The study will validate the potential for new and classic technologies to identify biomarkers of radon gas exposure in blood specimens and generate new mechanistic knowledge about chronic LDR exposures.

Exploring the Application of Genomics and Raman Spectroscopy in the Area of Risk Assessment

Start: 2018

End: Ongoing

Project lead: Dr. Vinita Chauhan, Health Canada

COHERE contact: Vinita Chauhan (Vinita.Chauhan@canada.ca)

SRA theme: Capacity building in risk assessment

This project will explore the feasibility of new technologies to identify biomarkers of radiation exposure following low levels of exposure to ionizing radiation (<0.5 Gy) in the most radiosensitive cell types, which are found in the blood and the eyes. The two main technologies that will be explored include genomics and Raman spectroscopy. The end goal of this work is to generate new mechanistic data to help strengthen our understanding of the shape of the dose–response relationship, which could be applied to risk identification.

Identify Transcriptional Points of Departure Using Benchmark Dose Modeling (BMD) for Various Tissues/Bio-fluids Exposed to Radiation

Start: 2018

End: Ongoing

Project lead: Dr. Vinita Chauhan, Health Canada

COHERE contact: Vinita Chauhan (Vinita.Chauhan@canada.ca)

SRA theme: Capacity building in risk assessment

Transcriptional datasets deposited in repositories will be identified and subjected to transcriptional BMD modeling The work will determine whether pathway activation is dependent on radiation quality, dose, dose rate and time, and whether these results are consistent across studies. This will identify mechanistic pathways and dose thresholds most relevant to low dose/dose-rate exposures, derive “omics” based relative biological effectiveness values for radiation qualities and dose rates and identify differences in cell/tissue sensitivity.

Health Effects of Chronic Exposure to Natural Uranium in Drinking Water

Start: 2019

End: Ongoing

Project lead: Dr. Baki Sadi, Health Canada

COHERE contact: Baki Sadi (Baki.Sadi@canada.ca)

SRA theme: Cancer effects

Previous studies have shown that concentrations of natural uranium in well water from some communities can be well above the levels recommended in Health Canada’s Drinking Water Guidelines. Health effects and underlying biological effects from the long-term consumption of uranium from such water are not well understood and require further investigation. To address this knowledge gap, an in vivo study on a rodent model is currently underway through a collaborative research project between Canadian Nuclear Laboratories and Health Canada’s Radiation Protection Bureau, approved under the Federal Nuclear Science and Technology (FNST) initiative. The FNST project will focus on the genotoxicity and kidney toxicity through subcellular uranium distribution and phenotypic assays. In order to gain further mechanistic understanding of the toxicological effects, a subset of these samples will be studied using “omics” technology approved under a Genomics Research and Development Initiative (GRDI) project. For the GRDI project, genomic and proteomic analysis of blood and kidney tissues samples will be conducted in collaboration with Health Canada’s Consumer and Clinical Radiation Protection Bureau.

A Better Understanding of Radon Dosimetry Through Indoor Aerosol Characterization and Computational Simulation

Start: 2019

End: Ongoing

Project lead: Dr. Baki Sadi, Health Canada

COHERE contact: Baki Sadi (Baki.Sadi@canada.ca)

SRA theme: Cancer effects

Radon is the second leading cause of lung cancer, after smoking. Although the guideline for radon exposure in homes is provided in concentration of radon gas, it is actually the short-lived radon progenies that deposit most of the energy to the lung, contributing to the annual effective dose. The majority of the radon progenies attach to particulate matter; deposition in the lung, therefore, depends on the particle concentration and relative size distribution. In this study, measurements will be taken of indoor aerosol characteristics relevant to radon dosimetry, such as radon progeny concentration, equilibrium factor, unattached fraction and radon progeny particle-size distribution. These characteristic parameters will be used in conjunction with a radon dosimetry computational simulation tool to calculate the annual effective dose. The knowledge generated from this project will give us a better understanding of the relative contribution of indoor particulate matter to annual effective dose from radon.

Development of an Adverse Outcome Pathway Relevant to Uranium-Induced Kidney Toxicity

Start: 2019

End: Ongoing

End: Ongoing

Project lead: Dr. Baki Sadi, Health Canada

COHERE contact: Baki Sadi (Baki.Sadi@canada.ca)

SRA themes: Globalized data sharing, consolidation and interpretation

Uranium is a naturally occurring radioactive element as well as a heavy metal. Biological and health effects of uranium have been attributed to both its radiological and chemical toxicity. While the majority of the published studies indicate uranium toxicity is primarily due to chemical damage to the kidney, other in vitro and in vivo experiments show genotoxic effects that could be attributed to both chemical and radiological toxicity. Due to potential occupational exposure in the uranium-based nuclear fuel cycle, environmental exposure from mining and other industrial activities and chronic exposure through drinking water, especially in communities served by underground well water, the adverse health effects of uranium is a concern to the risk assessors and regulators in both radiological and chemical communities. The objective of this project is to develop an adverse outcome pathway relevant to uranium-induced kidney toxicity for submission to the Extended Advisory Group on Molecular Screening and Toxicogenomics of the Organisation for Economic Co-operation and Development.

Systematic Review on How Biological Sex Modifies Ionizing Radiation-Induced Health Effects

Start: 2020

End: 2023

Project lead: Dr. Julie Leblanc, Canadian Nuclear Safety Commission

COHERE contact: Julie Leblanc (julie.leblanc@cnsc-ccsn.gc.ca)

SRA themes: Globalized data sharing, consolidation and interpretation

Through the ICRP Mentorship Program, a systematic review will be conducted to assess the current state of evidence on how biological sex can modify several radiation-induced health outcomes (cancer, cardiovascular/circulatory/cerebrovascular disease, cognitive effects and cataracts). Biological sex is one factor of many that governs individual responses to ionizing radiation, which are complex and not well understood. The review will inform the work conducted by ICRP Task Group 111.

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=207563