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Introduction

Thyroid cancer is the most common endocrine malignancy originating from follicular epithelial cells or parafollicular C cells, and an estimated over 43,720 new cases occurred in 2023 in the US (1). Throid cancer has become an increasingly important public health concern worldwide during the past few decades (2).

A number of modifiable risk factors for thyroid cancer have been identified; however, it is unclear which of these factors contribute to the increase in thyroid cancer incidence. The majority of the known or suspected risk factors include patient age, sex, radiation exposure, dietary nutrition, environmental pollutants, age/ethnicity and family history (3,4). Among these factors, exposure to ionizing radiation, notably during childhood (5), is the only conclusively established risk factor for thyroid cancer (6). The radiation-related risk declines with increasing age at exposure (7). The risk following adulthood exposure, notably occupational exposure, remains uncertain.

Occupational exposure to ionizing radiation is common in medical research. Accordingly, evidence of occupational exposure has been obtained primarily from population-based studies of medical radiation workers (8,9). They represent the largest group of workers with occupational radiation exposures and the majority of them are women. Furthermore, their number is growing rapidly worldwide as a result of the increased use of interventional radiotherapy (8). Therefore, the importance of investigating radiation exposure and sex-specific health effects has attracted considerable attention. Although medical radiation workers are routinely exposed to low doses due to their daily activities, their doses are monitored and data are being stored. However, these workers also include high-exposure subgroups, such as those performing fluoroscopically-guided procedures, and those with long-term, chronic low dose-rate exposures. Epidemiological studies have shown that medical radiation workers have an increased risk of developing certain types of cancer (9).

Current evidence on thyroid cancer risk following occupational radiation exposure is inconsistent (10), largely due to the lack of individual dose estimates and limited statistical power, resulting from the low range of doses and the relative rarity of the disease in the population. Therefore, it is necessary to combine similar studies, which may aid the identification of the mechanism of action of thyroid cancer development after radiation exposure, leading us to solve these controversial issues. To determine the association between occupational radiation exposure and the risk of thyroid cancer, and assess the potential sex-specific differences between the two, the available cohort studies were systematically reviewed and analyzed.

Materials and methods

Study guidelines and registration

A systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (11). The protocol of the present meta-analysis was registered in the International Prospective Register of Systematic Reviews platform (registration no. CRD42021289824).

Data sources and searches

The PubMed (https://pubmed.ncbi.nlm.nih.gov), China National Knowledge Infrastructure (https://www.cnki.net/), Embase (https://www.embase.com/), ChinaInfo (https://www.wanfangdata.com.cn/), Weipu (http://www.cqvip.com/) and Chinese Biomedical Literature (http://www.sinomed.ac.cn/) databases were searched for cohort studies published from database inception to January 1st, 2023. No language restrictions were made, and the search strategy combined the use of medical subject headings and key words. The search terms included the following items: ‘Thyroid neoplasms’, ‘thyroid carcinoma’, ‘thyroid cancer’, ‘thyroid adenoma’, ‘radiation exposure’, ‘radiation’ and ‘risk’. The search strategy was guided by an information specialist with >5 years of experience. The full search strategy of six databases is presented in Table SI. The reference lists of the included studies and other related meta-analyses were also examined to identify compliant studies.

Eligibility criteria

The studies were included on the basis of the following eligibility criteria: i) Cohort studies; ii) investigation of the association of occupational radiation with the risk of incident of all-cause thyroid cancer; iii) participants who were persistently exposed to medical radiation and clinically verified to be free of any cancer prior to study recruitment. Studies including radiation caused by nuclear leakage and personnel in the nuclear industry were not included.

The studies were excluded if they did not provide a relative-risk estimate with corresponding 95% confidence interval (CI). Furthermore, the following research studies were also excluded: Conference abstracts, study protocols, duplicate publications and studies without the outcomes of interest.

Study selection

A study selection database was established using Endnote X7.0 software (Thomson Reuters Corporation). Following the elimination of duplicates, the titles and abstracts were evaluated for preliminary screening. When the titles and abstracts could not be definitively excluded, the full text was downloaded and refiltered until all studies were confirmed. Study selection was performed by two authors (HQ and CH) who independently screened the literature based on the eligibility and exclusion criteria. Any disagreements were resolved by a third author (XS), who acted as an arbitrator.

Data extraction

Predesigned forms were used for extracting data on the first author, year of publication, country, study type, cancer cases, sample size, follow-up years, exposure doses and diagnosis of thyroid cancer. One researcher (HQ) extracted the aforementioned basic information, which complied with the guidelines on data extraction for systematic reviews and meta-analyses (12). An additional researcher (CH) assessed the extracted data, and in case of any dispute, referred to the original text and revised it.

Risk of bias assessment

The Newcastle-Ottawa Scale (NOS) (13), which is a scale for assessing the quality of observational studies, was used to assess the quality of the cohort studies. The rating ranged from 0 to 9 stars on this scale as follows: 4 Stars were used for the selection of participants and the measurement of exposure, 2 stars for comparability and 3 stars for assessment of outcomes and adequacy of follow-up; a higher number of stars indicated higher quality of included studies. The score ranges of 0–3, 4–6 and 7–9 were considered to indicate low, moderate and high quality, respectively.

Statistical analysis

The present meta-analysis was performed by computing odds ratios (ORs) with 95% CIs using a random-effects model, accounting for clinical heterogeneity. Heterogeneity across included studies was assessed by using the Q-test and I2 statistics. I2 was calculated from the degrees of freedom (df) and Cochran's heterogeneity Q statistic as 100% × (Q-df)/Q. A larger value of I2 indicates increased heterogeneity across the included studies. A sensitivity analysis was performed by excluding one study each time and performing re-runs to verify the robustness of the overall effects. The Begg's rank test and Egger's regression test was used to statistically assess the publication bias, as they were proposed for all types of outcomes. A subgroup analysis by sex was preformed to explore the differences in the risk of thyroid cancer caused by occupational radiation. All statistical analyses were performed using Stata statistical software version 17.0 (StataCorp LP).

Results

Literature search

A total of 3,296 records were identified in the initial search. Following adjustment of the duplicates, 2,145 entries remained, of which 1,312 were discarded due to not meeting the inclusion criteria following review of the titles and abstracts. The full text of the remaining 15 articles was examined in more detail. Following application of the inclusion criteria, six retrospective cohort studies were included in the present meta-analysis (7,14–18). The selection process is illustrated in Fig. 1.

Figure 1. Flowchart of the study selection process.

Study characteristics

The included studies were published between 2006 and 2021 and were from 4 countries. The number of participants per study ranged from 67,562 to 2,992,166 and the number of cancer events in each study ranged from 134 to 2,599 cases. The participant characteristics and the diagnostic criteria of thyroid cancer were heterogeneous; however, the follow-up time periods were available for all studies, which ranged from 12 to 36 years. The exposure doses to occupational radiation were available for almost all studies, even though the measurement standards were slightly different. The main characteristics of the included studies are shown in Table I.

Table I. Basic characteristics of the included studies.

Table I.

Basic characteristics of the included studies.

First author, year	Country	Study type	Cancer cases, n	Sample size, n	Follow-up, years	Exposure doses	Diagnosis of thyroid cancer	NOS score	(Refs.)
Lee et al, 2021	Korea	Cohort	986	93,920; Males, 53,582; Females, 40,338	22	7.2 mSv average	ICD-10	8	(18)
Lee et al, 2019	Korea	Cohort	827	93,092; Males, 53,276; Females, 39,819	20	10.4 mGy average	ICD-O-3	7	(17)
Kitahara et al, 2018	America	Cohort	467	89,897; Males, 20,416; Females, 69,481	21	Low-to-moderate dose range <0.5 Gy	Self-report or medical examination	7	(7)
Zielinski et al, 2009	Canada	Cohort	1,309	67,562; Males, 23,580; Females, 43,982	36	<0.20 mSv	Derived from the National Cancer Incidence Reporting System	7	(16)
Lope et al, 2006	Spain	Cohort	2,599	2,992,166; Males, 1,890,497; Females,1,101,669	28	>0.20 µT	ICD-7	7	(15)
Zabel et al, 2006	America	Cohort	134	73,080	12	X-ray procedures at least 50 times	Self-report	8	(14)

[i] ICD, international classification of diseases; NOS, Newcastle-Ottawa Scale.

Quality assessment

According to the NOS criteria, the mean score of the 6 cohort studies was 7.33. Among them, 4 cohort studies (7,15–17) scored 7 stars and 2 cohort studies (14,18) scored 8 stars, which indicated that the methodological quality of the cohort was high. The score of the included studies is shown in Table I.

Occupational radiation and risk of thyroid cancer

A total of five cohort studies explored the association between occupational radiation and the risk of thyroid cancer (7,14–16,18). The pooled analysis result is presented in Fig. 2 (OR=1.61; 95% CI: 1.27–2.04; I2=84.2%, P<0.001). Sensitivity analysis suggested that the large heterogeneity was caused by the study of Lee et al (18). Subsequent to exclusion of this study, the following results were obtained: P=0.554; OR=1.82; 95% CI: 1.62–2.06. The results of the sensitivity analysis are presented in Fig. S1.

Figure 2. Meta-analysis of occupational radiation and risk of thyroid cancer. OR, odds ratio; CI, confidence interval.

Subgroup analysis by sex

In the subgroup analysis, three studies (16–18) reported the risk of thyroid cancer in male patients exposed to occupational radiation and the pooled result was as follows: OR=1.74, 95% CI: 1.61–1.87, P=0.726. Furthermore, 4 studies (15–18) reported the risk of thyroid cancer in female patients during occupational radiation and pooled analysis yielded the following results: OR=1.30, 95% CI: 1.15–1.48, P=0.032. Male patients with a history of occupational radiation had a slightly higher risk of thyroid cancer than female patients. The effects of sex on occupational radiation and on the risk of developing thyroid cancer are shown in Fig. 3.

Figure 3. Occupational radiation and risk of thyroid cancer for different sexes. OR, odds ratio; CI, confidence interval.

Publication bias

The statistical result derived from the Egger's regression test was as follows: P=0.286; this indicated no evidence of significant publication bias in the outcome of occupational radiation and the risk of thyroid cancer (Fig. S2).

Discussion

The present systematic review and meta-analysis of cohort studies compiled current evidence on the association between occupational radiation exposure and the risk of thyroid cancer in 3,409,717 individuals from six population-based studies. To the best of our knowledge, this is the first study to explore the association between occupational exposure to ionizing radiation and thyroid cancer occurrence. The data indicated that occupational exposure to ionizing radiation is a potential risk indicator of thyroid cancer. Male patients with a history of occupational radiation exposure are more susceptible to thyroid cancer than female patients.

Occupational radiation exposure may be a potential predictor for thyroid cancer. Epidemiological studies of exposure to radiotherapy and fallout from atomic bombings during childhood indicated that radiation is a plausible risk factor for thyroid cancer (19). Richardson (20) demonstrated that exposure to ionizing radiation in adulthood also increased the risk of thyroid cancer within female atomic bomb survivors, although the risk seemed to be lower than that noted for those exposed to radiation in childhood. This is consistent with the results of a pooled analysis of five cohort and two case-control studies reported by Ron et al (21). The age difference noted in the risk of thyroid cancer was due to the higher radiosensitivity of the thyroid gland in children than in adults, as shown by Ron et al (22). However, the time window of exposure, notably the early adult years, and potential confounding or effect modification factors from medical radiation exposure remain unclear, which leads to inconsistent results. Previous studies have not found a correlation between occupational radiation exposure and the risk of thyroid cancer (23,24). Vimercati et al (24) conducted a cross-sectional study to investigate the prevalence of thyroid diseases in healthcare workers exposed to low-level ionizing radiation compared with a control group working at the University Hospital of Bari, Southern Italy; the study reported a lack of association between exposure to ionizing radiation and thyroid cancer. Fincham et al (23) performed a case-control study to explore the etiology of thyroid cancer in 1,272 patients with thyroid cancer identified via provincial cancer registries or hospital records in Canada and 2,666 controls randomly selected via various provincial administrative databases; these controls were frequency-matched to the expected age and sex distribution of the patients during 1986–1988. The data indicated that exposure to ionizing radiation did not affect the risk of thyroid cancer (23). These negative findings are likely due to the study design and limited sample size. The results of the present study were supported by the findings of a field survey of interventional medical workers in nationwide branches of the Korean Society of Interventional Radiology conducted by Lee et al (17) in 2019. The authors demonstrated that the highest lifetime attributable risk and lifetime fractional risk from occupational radiation exposure were observed for thyroid cancer. These findings indicated that occupational radiation exposure may be a potential predictor for thyroid cancer.

In addition, it was important to assess whether sex differences affected occupational radiation exposure and the risk of thyroid cancer. It was found that male patients with a history of occupational radiation experienced a slightly higher risk of thyroid cancer than female patients. By contrast, female patients have been described as being more sensitive to radiation-induced thyroid cancer than male patients (20,25). However, no references regarding sex-based differences were available that could explain this result. Additional studies are warranted to further confirm and assess the sex-based differences.

To the best of our knowledge, no previous meta-analysis of occupational radiation exposure and thyroid cancer risk has been published, and the present findings suggest that occupational exposure to ionizing radiation is a potential risk indicator of thyroid cancer. However, the current meta-analysis has certain limitations. For instance, it is difficult to make a detailed subgroup analysis of the occupation type (such as radiological technologists, radiologists, nurses and other physicians), dose-effect and time-effect relationship due to the limited data provided by the included studies; therefore, additional research is required for this type of analysis. Furthermore, the control population included in the studies may differ with regard to country, health status and demographic characteristics, which may result in confounding results.

In conclusion, the existing data included in the present meta-analysis provide evidence that occupational radiation is associated with an increased risk of thyroid cancer. Male patients with a history of occupational radiation exposure are more susceptible to thyroid cancer than female patients. The results also highlighted that population-based data on the association of occupational radiation with thyroid cancer risk remain limited and that further analysis into the underlying mechanism of the association is warranted. In addition, large, well-designed epidemiological and experimental studies are required to investigate the influence of occupational radiation on the occurrence of thyroid cancer.

Supplementary Material

Supporting Data

Supporting Data

Acknowledgements

Not applicable.

Funding

The present study was supported by the Science and Technology Project of Liaoning Province (grant no. 2020JH2/10300172) and the Shenyang Science and Technology Planning Project (grant no. 223213389).

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

HQ, CH, HX, XR, XS and YX contributed to the study conception and design. Material preparation, data collection and analysis were performed by HX and XR. The first draft of the manuscript was prepared by HQ and CH. XS and YX provided advice on the data analyses and critically revised the manuscript. HQ and XS confirm the authenticity of all the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References