Considerations for application of benchmark dose modeling in radiation research: workshop highlights.

BACKGROUND: Exposure to different forms of ionizing radiation occurs in diverse occupational, medical, and environmental settings. Improving the accuracy of the estimated health risks associated with exposure is therefore, essential for protecting the public, particularly as it relates to chronic low dose exposures. A key aspect to understanding health risks is precise and accurate modeling of the dose-response relationship. Toward this vision, benchmark dose (BMD) modeling may be a suitable approach for consideration in the radiation field. BMD modeling is already extensively used for chemical hazard assessments and is considered statistically preferable to identifying low and no observed adverse effects levels. BMD modeling involves fitting mathematical models to dose-response data for a relevant biological endpoint and identifying a point of departure (the BMD, or its lower bound). Recent examples in chemical toxicology show that when applied to molecular endpoints (e.g. genotoxic and transcriptional endpoints), BMDs correlate to points of departure for more apical endpoints such as phenotypic changes (e.g. adverse effects) of interest to regulatory decisions. This use of BMD modeling may be valuable to explore in the radiation field, specifically in combination with adverse outcome pathways, and may facilitate better interpretation of relevant in vivo and in vitro dose-response data. To advance this application, a workshop was organized on June 3rd, 2022, in Ottawa, Ontario that brought together BMD experts in chemical toxicology and the radiation scientific community of researchers, regulators, and policy-makers. The workshop's objective was to introduce radiation scientists to BMD modeling and its practical application using case examples from the chemical toxicity field and demonstrate the BMDExpress software using a radiation dataset. Discussions focused on the BMD approach, the importance of experimental design, regulatory applications, its use in supporting the development of adverse outcome pathways, and specific radiation-relevant examples. CONCLUSIONS: Although further deliberations are needed to advance the use of BMD modeling in the radiation field, these initial discussions and partnerships highlight some key steps to guide future undertakings related to new experimental work.

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

PURPOSE: The Adverse Outcome Pathway (AOP) framework, a systematic tool that can link available mechanistic data with phenotypic outcomes of relevance to regulatory decision-making, is being explored in areas related to radiation risk assessment. To examine the challenges including the use of AOPs to support the radiation protection community, an international horizon-style exercise was initiated through the Organisation for Economic Co-operation and Development Nuclear Energy Agency High-Level Group on Low Dose Research Radiation/Chemical AOP Joint Topical Group. The objective of the HSE was to facilitate the collection of ideas from a range of experts, to short-list a set of priority research questions that could, if answered, improve the description of the radiation dose-response relationship for low dose/dose-rate exposures, as well as reduce uncertainties in estimating the risk of developing adverse health outcomes following such exposures. MATERIALS AND METHODS: The HSE was guided by an international steering committee of radiation risk experts. In the first phase, research questions were solicited on areas that can be supported by the AOP framework, or challenges on the use of AOPs in radiation risk assessment. In the second phase, questions received were refined and sorted by the SC using a best-worst scaling method. During a virtual 3-day workshop, the list of questions was further narrowed. In the third phase, an international survey of the broader radiation protection community led to an orderly ranking of the top questions. RESULTS: Of the 271 questions solicited, 254 were accepted and categorized into 9 themes. These were further refined to the top 25 prioritized questions. Among these, the higher ranked questions will be considered as 'important' to drive future initiatives in the low dose radiation protection community. These included questions on the ability of AOPs to delineate responses across different levels of biological organization, and how AOPs could be applied to address research questions on radiation quality, doses or dose-rates, exposure time patterns and deliveries, and uncertainties in low dose/dose-rate effects. A better understanding of these concepts is required to support the use of the AOP framework in radiation risk assessment. CONCLUSION: Through dissemination of these results and considerations on next steps, the JTG will address select priority questions to advance the development and use of AOPs in the radiation protection community. The major themes observed will be discussed in the context of their relevance to areas of research that support the system of radiation protection.

Association between exposures to radon and γ-ray radiation and histologic type of lung cancer in Eldorado uranium mining and milling workers from Canada.

BACKGROUND: The authors assessed the association between radon decay products (RDP) exposure and histologic types of incident lung cancer in a cohort of 16,752 (91.6% male) Eldorado uranium workers who were first employed from 1932 to 1980 and were followed through 1969-1999. METHODS: Substantially revised identifying information and RDP exposures were obtained on workers from the Port Radium and Beaverlodge uranium mines and from the Port Hope radium and uranium refinery and processing facility in Canada. Poisson regression was conducted using the National Research Council's Biological Effects of Ionizing Radiation (BEIR) VI-type models to estimate the risks of lung cancer by histologic type from RDP exposures and γ-ray doses. RESULTS: Lung cancer incidence was significantly higher in workers compared with the general Canadian male population. Radiation risks of lung cancer for all histologic types (n = 594; 34% squamous cell, 16% small cell, 17% adenocarcinoma) increased with increasing RDP exposure, with no indication of curvature in the dose response (excess relative risk per 100 working level months = 0.61; 95% confidence interval, 0.39-0.91). Radiation risks did not differ by histologic type (p = .144). The best-fitting BEIR VI-type model included adjustments for the significant modifying effects of time since exposure, exposure rate, and attained age. The addition of γ-ray doses to the model with RDP exposures improved the model fit, but the risk estimates remained unchanged. CONCLUSIONS: The first analysis of radiation risks of lung cancer histologic types in the Eldorado cohort supported the use of BEIR VI-type models to predict the future risk of histologic types of lung cancer from past and current RDP exposures. LAY SUMMARY: Lung cancer survival depends strongly on the cell type of lung cancer. The best survival rates are for patients who have the adenocarcinoma type. This study included 16,752 Eldorado uranium workers who were exposed to radon and γ-ray radiation during 1932-1980, were alive in 1969, and were followed for the development of new lung cancer during 1969-1999. One third of all lung cancers were of the squamous cell type, whereas the adenocarcinoma and small cell types accounted for less than 20% each. Radiation risks of lung cancer among men increased significantly with increasing radon exposure for all cell types, with the highest risks estimated for small cell and squamous cell lung cancers.

COHERE - strengthening cooperation within the Canadian government on radiation research.

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.

The Global Spine Care Initiative: public health and prevention interventions for common spine disorders in low- and middle-income communities.

PURPOSE: The purpose of this study was to develop recommendations for prevention interventions for spinal disorders that could be delivered globally, but especially in underserved areas and in low- and middle-income countries. METHODS: We extracted risk factors, associations, and comorbidities of common spinal disorders (e.g., back and neck pain, spinal trauma, infection, developmental disorders) from a scoping review of meta-analyses and systematic reviews of clinical trials, cohort studies, case control studies, and cross-sectional studies. Categories were informed by the Global Spine Care Initiative (GSCI) classification system using the biopsychosocial model. Risk factors were clustered and mapped visually. Potential prevention interventions for individuals and communities were identified. RESULTS: Forty-one risk factors, 51 associations, and 39 comorbidities were extracted; some were associated with more than one disorder. Interventions were at primary, secondary, tertiary, and quaternary prevention levels. Public health-related actions included screening for osteopenia, avoiding exposure to certain substances associated with spinal disorders, insuring adequate dietary intake for vitamins and minerals, smoking cessation, weight management, injury prevention, adequate physical activity, and avoiding harmful clinical practices (e.g., over-medicalization). CONCLUSION: Prevention principles and health promotion strategies were identified that were incorporated in the GSCI care pathway. Interventions should encourage healthy behaviors of individuals and promote public health interventions that are most likely to optimize physical and psychosocial health targeting the unique characteristics of each community. Prevention interventions that are implemented in medically underserved areas should be based upon best evidence, resource availability, and selected through group decision-making processes by individuals and the community. These slides can be retrieved under Electronic Supplementary Material.

A scoping review of biopsychosocial risk factors and co-morbidities for common spinal disorders.

OBJECTIVE: The purpose of this review was to identify risk factors, prognostic factors, and comorbidities associated with common spinal disorders. METHODS: A scoping review of the literature of common spinal disorders was performed through September 2016. To identify search terms, we developed 3 terminology groups for case definitions: 1) spinal pain of unknown origin, 2) spinal syndromes, and 3) spinal pathology. We used a comprehensive strategy to search PubMed for meta-analyses and systematic reviews of case-control studies, cohort studies, and randomized controlled trials for risk and prognostic factors and cross-sectional studies describing associations and comorbidities. RESULTS: Of 3,453 candidate papers, 145 met study criteria and were included in this review. Risk factors were reported for group 1: non-specific low back pain (smoking, overweight/obesity, negative recovery expectations), non-specific neck pain (high job demands, monotonous work); group 2: degenerative spinal disease (workers' compensation claim, degenerative scoliosis), and group 3: spinal tuberculosis (age, imprisonment, previous history of tuberculosis), spinal cord injury (age, accidental injury), vertebral fracture from osteoporosis (type 1 diabetes, certain medications, smoking), and neural tube defects (folic acid deficit, anti-convulsant medications, chlorine, influenza, maternal obesity). A range of comorbidities was identified for spinal disorders. CONCLUSION: Many associated factors for common spinal disorders identified in this study are modifiable. The most common spinal disorders are co-morbid with general health conditions, but there is a lack of clarity in the literature differentiating which conditions are merely comorbid versus ones that are risk factors. Modifiable risk factors present opportunities for policy, research, and public health prevention efforts on both the individual patient and community levels. Further research into prevention interventions for spinal disorders is needed to address this gap in the literature.

The Global Spine Care Initiative: a summary of guidelines on invasive interventions for the management of persistent and disabling spinal pain in low- and middle-income communities.

PURPOSE: The purpose of this study was to synthesize recommendations on the use of common elective surgical and interventional procedures for individuals with persistent and disabling non-radicular/axial with or without myelopathy, radicular back pain, cervical myelopathy, symptomatic spinal stenosis, and fractures due to osteoporosis. This review was to inform a clinical care pathway on the patient presentations where surgical interventions could reasonably be considered. METHODS: We synthesized recommendations from six evidence-based clinical practice guidelines and one appropriate use criteria guidance for the surgical and interventional management of persistent and disabling spine pain. RESULTS: Lower priority surgery/conditions include fusion for lumbar/non-radicular neck pain and higher priority surgery/conditions include discectomy/decompressive surgery for cervical or lumbar radiculopathy, cervical myelopathy, and lumbar spinal stenosis. Epidural steroid injections are less expensive than most surgeries with fewer harms; however, benefits are small and short lived. Vertebroplasty should be considered over kyphoplasty as an option for patients with severe pain and disability due to osteoporotic vertebral compression fracture. CONCLUSION: Elective surgery and interventional procedures could be limited in medically underserved areas and low- and middle-income countries due to a lack of resources and surgeons and thus surgical and interventional procedures should be prioritized within these settings. There are non-invasive alternatives that produce similar outcomes and are a recommended option where surgical procedures are not available. These slides can be retrieved under Electronic Supplementary Material.

The Global Spine Care Initiative: a consensus process to develop and validate a stratification scheme for surgical care of spinal disorders as a guide for improved resource utilization in low- and middle-income communities.

PURPOSE: The purpose of this study was to develop a stratification scheme for surgical spinal care to serve as a framework for referrals and distribution of patients with spinal disorders. METHODS: We used a modified Delphi process. A literature search identified experts for the consensus panel and the panel was expanded by inviting spine surgeons known to be global opinion leaders. After creating a seed document of five hierarchical levels of surgical care, a four-step modified Delphi process (question validation, collection of factors, evaluation of factors, re-evaluation of factors) was performed. RESULTS: Of 78 invited experts, 19 participated in round 1, and of the 19, 14 participated in 2, and 12 in 3 and 4. Consensus was fairly heterogeneous for levels of care 2-4 (moderate resources). Only simple assessment methods based on the clinical skills of the medical personnel were considered feasible and safe in low-resource settings. Diagnosis, staging, and treatment were deemed feasible and safe in a specialized spine center. Accurate diagnostic workup was deemed feasible and safe for lower levels of care complexity (from level 3 upwards) compared to non-invasive procedures (level 4) and the full range of invasive procedures (level 5). CONCLUSION: This study introduces a five-level stratification scheme for the surgical care of spinal disorders. This stratification may provide input into the Global Spine Care Initiative care pathway that will be applied in medically underserved areas and low- and middle-income countries. These slides can be retrieved under Electronic Supplementary Material.

The Effectiveness of Multimodal Care for the Management of Soft Tissue Injuries of the Shoulder: A Systematic Review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration.

OBJECTIVE: The purpose of this systematic review was to evaluate the effectiveness of multimodal care for the management of soft tissue injuries of the shoulder. METHODS: We conducted a systematic review and searched MEDLINE, EMBASE, CINAHL, PsycINFO, and the Cochrane Central Register of Controlled Trials from 1990 to 2015. Two independent reviewers critically appraised studies using the Scottish Intercollegiate Guidelines Network criteria. We used best evidence synthesis to synthesize evidence from studies with low risk of bias. RESULTS: We screened 5885 articles, and 19 were eligible for critical appraisal. Ten randomized controlled trials had low risk of bias. For persistent subacromial impingement syndrome, multimodal care leads to similar outcomes as sham therapy, radial extracorporeal shock-wave therapy, or surgery. For subacromial impingement syndrome, multimodal care may be associated with small and nonclinically important improvement in pain and function compared with corticosteroid injections. For rotator cuff tendinitis, dietary-based multimodal care may be more effective than conventional multimodal care (exercise, soft tissue and manual therapy, and placebo tablets). For nonspecific shoulder pain, multimodal care may be more effective than wait list or usual care by a general practitioner, but it leads to similar outcomes as exercise or corticosteroid injections. CONCLUSIONS: The current evidence suggests that combining multiple interventions into 1 program of care does not lead to superior outcomes for patients with subacromial impingement syndrome or nonspecific shoulder pain. One randomized controlled trial suggested that dietary-based multimodal care (dietary advice, acupuncture, and enzyme tablets) may provide better outcomes over conventional multimodal care. However, these results need to be replicated.

The effectiveness of passive physical modalities for the management of soft tissue injuries and neuropathies of the wrist and hand: a systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) collaboration.

OBJECTIVE: The purpose of this systematic review was to determine the effectiveness of passive physical modalities compared to other interventions, placebo/sham interventions, or no intervention in improving self-rated recovery, functional recovery, clinical outcomes and/or administrative outcomes (eg, time of disability benefits) in adults and/or children with soft tissue injuries and neuropathies of the wrist and hand. METHODS: We systematically searched MEDLINE, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trials, accessed through Ovid Technologies, Inc, and CINAHL Plus with Full Text, accessed through EBSCO host, from 1990 to 2015. Our search strategies combined controlled vocabulary relevant to each database (eg, MeSH for MEDLINE) and text words relevant to our research question and the inclusion criteria. Randomized controlled trials, cohort studies, and case-control studies were eligible. Random pairs of independent reviewers screened studies for relevance and critically appraised relevant studies using the Scottish Intercollegiate Guidelines Network criteria. Studies with low risk of bias were synthesized following best evidence synthesis principles. RESULTS: We screened 6618 articles and critically appraised 11 studies. Of those, 7 had low risk of bias: 5 addressed carpal tunnel syndrome (CTS) and 2 addressed de Quervain disease. We found evidence that various types of night splints lead to similar outcomes for the management of CTS. The evidence suggests that a night wrist splint is less effective than surgery in the short term but not in the long term. Furthermore, a night wrist splint and needle electroacupuncture lead to similar outcomes immediately postintervention. Finally, low-level laser therapy and placebo low-level laser therapy lead to similar outcomes. The evidence suggests that kinesio tape or a thumb spica cast offers short-term benefit for the management of de Quervain disease. Our search did not identify any low risk of bias studies examining the effectiveness of passive physical modalities for the management of other soft tissue injuries or neuropathies of the wrist and hand. CONCLUSIONS: Different night orthoses provided similar outcomes for CTS. Night orthoses offer similar outcomes to electroacupuncture but are less effective than surgery in the short term. This review suggests that kinesio tape or a thumb spica cast may offer short-term benefit for the management of de Quervain disease.

Is exercise effective for the management of subacromial impingement syndrome and other soft tissue injuries of the shoulder? A systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration.

BACKGROUND: Exercise is a key component of rehabilitation for soft tissue injuries of the shoulder; however its effectiveness remains unclear. OBJECTIVE: Determine the effectiveness of exercise for shoulder pain. METHODS: We searched seven databases from 1990 to 2015 for randomized controlled trials (RCTs), cohort and case control studies comparing exercise to other interventions for shoulder pain. We critically appraised eligible studies using the Scottish Intercollegiate Guidelines Network (SIGN) criteria. We synthesized findings from scientifically admissible studies using best-evidence synthesis methodology. RESULTS: We retrieved 4853 articles. Eleven RCTs were appraised and five had a low risk of bias. Four studies addressed subacromial impingement syndrome. One study addressed nonspecific shoulder pain. For variable duration subacromial impingement syndrome: 1) supervised strengthening leads to greater short-term improvement in pain and disability over wait listing; and 2) supervised and home-based strengthening and stretching leads to greater short-term improvement in pain and disability compared to no treatment. For persistent subacromial impingement syndrome: 1) supervised and home-based strengthening leads to similar outcomes as surgery; and 2) home-based heavy load eccentric training does not add benefits to home-based rotator cuff strengthening and physiotherapy. For variable duration low-grade nonspecific shoulder pain, supervised strengthening and stretching leads to similar short-term outcomes as corticosteroid injections or multimodal care. CONCLUSION: The evidence suggests that supervised and home-based progressive shoulder strengthening and stretching are effective for the management of subacromial impingement syndrome. For low-grade nonspecific shoulder pain, supervised strengthening and stretching are equally effective to corticosteroid injections or multimodal care. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42013003928.