Abstract
Background:
The global incidence of thyroid cancer has increased over the past several decades. While this increase is partially due to increased detection, environmental pollutants have also emerged as a possible contributing factor. Our goal was to perform a systematic review to assess the relationship between environmental air pollution and thyroid cancer.
Methods:
Systematic literature search was performed using PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus databases for original articles published prior to March 2024, investigating outdoor air pollution and thyroid cancer/nodules (PROSPERO CRD42024517624). Inclusion criteria included quantitative reporting of pollutant levels and effect size. Specific pollutants included ozone (O3), particulate matter less than 2.5 (PM2.5) or 10 microns in diameter (PM10), sulfur dioxide (SO2), nitric oxides (NOx), carbon monoxide (CO), and polyaromatic hydrocarbons (PAHs). Study design, sample size, pollution assessment method, covariates, and strength/direction of associations between pollutants and thyroid cancer/nodule detection were extracted, and descriptive synthesis was utilized to summarize pertinent findings. Risk of bias was assessed using the National Heart, Lung, and Blood Institute quality assessment tool.
Results:
Of 1294 identified studies, 11 met inclusion criteria. Over 6 million patients from diverse regions were represented across studies. Pollutants studied included O3 in 5 studies; PM2.5, PM10, SO2, and NOx in 3 studies; unspecified PM and CO in 2 studies; and PAHs in 1 study. Primary outcome was thyroid cancer diagnosis among 9 studies and thyroid nodule detection in 2. All studies examining NOx and O3 reported increased risks ranging from 1.03 to 1.5-fold and 1.1 to 1.3-fold, respectively. Both studies assessing PM2.5 reported 1.18 to 1.23-fold increased odds of thyroid cancer diagnosis, and the magnitude of association increased with increasing duration or concentration of PM2.5 Inconsistent results were observed for levels of CO, PM10, and SO2.
Conclusion:
While an emerging body of literature suggests a potential association between air pollution and thyroid cancer, the quality of evidence is limited by study design constraints, variability in exposure assessment, and inconsistent adjustment for potential confounding factors. The heterogeneity in study designs and methodologies present challenges in interpreting results, underscoring the need for standardized approaches in future research.
Introduction
Over the past several decades, there has been a steady rise in the global incidence of thyroid cancer. 1 As of 2020, worldwide age-standardized incidence rates for thyroid cancer were 10.1 per 100,000 women and 3.1 per 100,000 men, with papillary thyroid cancer (PTC) as the predominant histology. 2 –4 Some attribute the rise in thyroid cancer to increased detection, improved imaging, and enhanced access to health care, citing overdiagnosis. 5,6 However, between 1974 and 2013, PTC incidence rose for all tumor sizes and stages, and incidence-based mortality increased 1.1% per year, consistent with a true increase in thyroid cancer occurrence. 7 Due to geographic variations in this increased incidence, the focus shifted to evaluating the impact of environmental risk factors on thyroid cancer occurrence. Air pollution has emerged as one such risk factor due to the growing body of research linking it to carcinogenesis. However, the association between exposure to components of air pollution and thyroid cancer or nodules is unclear.
Outdoor environmental air pollution consists of sulfur dioxide (SO2), nitric oxides (NOx), carbon monoxide (CO), ozone (O3), and particulate matter (PM) that is further classified into PM10 and PM2.5 based on the aerodynamic diameter of PM. 8 Polyaromatic hydrocarbons (PAHs) are combustion byproducts that can bind to PM, enhancing its toxicity. Because of the association between air pollution and cardiopulmonary sequelae, specifically lung cancer, the International Agency for Research on Cancer Working Group classified air pollution as carcinogenic in 2013. 9 –12 Recently, long-term air pollution has been associated with increased incidence of other extrapulmonary malignancies including liver, breast, prostate, and ovarian cancer. 13 –15 Previous studies have attempted to assess a link between environmental air pollutants and thyroid cancer or nodules. 16 –19 However, variations in geography, pollutant measurement, choice of specific component of air pollution, and small sample sizes have led to uncertainty in this association. Therefore, our goal was to conduct a systematic review to critically evaluate and synthesize existing research on the association between each component of air pollution and thyroid cancer and nodules.
Methods
Data source and search
The protocol for the systematic review was registered with PROSPERO (http://www.crd.york.ac.uk/PROSPERO, CRD42024517624). Study methods were based on the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines and checklist and the Cochrane Handbook for Systematic Reviews. 20 PubMed, Cochrane Library, EMBASE, Web of Science, and SCOPUS were searched by a qualified data informationist (S.M.S.) to identify relevant studies. The search was completed on August 15, 2022, and updated on March 8, 2024. The search strategy for each database included control vocabulary and related keywords/synonym, and no restrictions were placed on date of publication (Appendix 1). Search terms including “environmental pollution,” “air pollution,” “particulate matter,” “ultrafine particle,” and “smog” were combined with “thyroid cancer,” “thyroid neoplasm,” “thyroid nodule,” “thyroid adenoma,” and “thyroid carcinoma.” No additional records were obtained from outside sources. Studies were managed in Covidence (Veritas Health Innovation, Melbourne, Australia), and articles were reviewed for inclusion based on title/abstract by two independent reviewers (V.V. and L.K.). Any disputes between reviewers were resolved by a third independent reviewer (M.R. or A.M.).
Study selection
After studies from the different sources and databases were merged and duplicates removed, two reviewers (V.V. and L.V.Y.) independently screened the abstracts. Studies were screened in two stages: (1) title and abstract and (2) full text. On retrieval of candidate abstracts, each full text publication was reviewed in its entirety by two independent reviewers and judged for inclusion for data extraction. Original research articles in English with human subjects examining the association between any specific component air pollution and diagnosis of thyroid cancer or thyroid nodules in adults (aged ≥18) were considered. Studies were included if there was a quantifiable measure of at least one of the six Environmental Protection Agency’s (EPA) criteria air pollutants (O3, PM2.5, PM10, CO, Lead, SO2, or NOx) or a measure of PAHs for the primary exposure assessment method, and the primary outcome assessed was the diagnosis of either thyroid cancer or nodules. Thus, it was necessary for the studies to present a measure of effect size or strength of association through statistical analysis. No restrictions were placed on the year of publication or geographical region. Studies were excluded if they utilized a categorical distinction for air pollutant exposure (e.g., urban vs. rural dwelling), used biomarkers as a surrogate of air pollution, or focused on the relationship between air pollution and thyroid cancer mortality.
Data extraction and quality assessment
Data extraction was performed by three independent reviewers (V.V., L.V.Y., and R.S.) with disagreements reviewed by the senior authors (M.R. and A.M.). Data collected included study period, patient population characteristics (size, age, sex, and geographic region), pollutants assessed, exposure metric and source of pollution data, study methods to evaluate association, method of outcome ascertainment and the specific outcome (nodules vs. cancer), and conclusions. After study design, sample size, methods of pollution or exposure assessment, covariates, and magnitude and direction of associations between pollutants and thyroid cancer/nodule detection were extracted, descriptive synthesis was utilized to summarize pertinent findings. Risk of bias was assessed by two independent reviewers with the NIH National Heart, Lung, and Blood Institute (NHLBI) quality assessment tools for cross-sectional and case–control studies. 21
Results
Study characteristics
The literature search identified 1294 studies (Fig. 1). After removal of 395 duplicates, 899 studies were screened for inclusion by title and abstract. After full-text review of 43 articles, 11 studies met criteria for final data extraction and analysis (Table 1, Supplementary Table S1). Of the included studies, two were retrospective cohort studies, five were ecological, two were cross-sectional, and two were case–control. Together, the selected studies included more than 6 million participants from geographically diverse regions. Six studies examined data from Asia (China [n = 3], South Korea [n = 1], Saudi Arabia [n = 1], and Iran [n = 1]), South America (Brazil), North America (United States [n = 2]), the European Union, and one worldwide study. Exposure to environmental air pollution was determined through the use of air quality monitoring systems, satellite data, and geographic estimations across the included studies. Of the included studies, the EPA criteria pollutants studied were PM2.5 in 3 studies, PM10 in 3 studies, SO2 in 3 studies, NOx in 3 studies, O3 in 5 studies, CO in 2 studies, and PAHs in 1 study. No included studies evaluated Pb exposure. The primary outcome was thyroid cancer diagnosis among 9 studies and thyroid nodule detection in 2. Across 9 cancer studies, only 1 study limited analysis by thyroid cancer subtype (PTC). 18
PRISMA diagram. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta‐Analyses.
Characteristics of 11 Included Studies Listed by Publication Year and Reported Direction of Association vwith Each Environmental Pollutant Studied
(+) = positive association; (−) = negative association; 0 = no association.
AQS, Air Quality System, satellite/meteorological; BMI, body mass index; CO, carbon monoxide; CTPR, China’s National Urban Air Quality Real Time Publishing Platform; EEA, European Environmental Agency; EPA, Environmental Protection Agency; GBD, Global Burden of Disease; NOx, nitric oxides; O3, ozone; PAH, polyaromatic hydrocarbons; PM, particulate matter; PMx, unspecified particulate matter size; SO2, sulfur dioxide; SPSEC, São Paulo State Environmental Company.
In general, the diagnosis of thyroid cancer was made by either including patients only in a cancer registry or utilizing diagnostic codes. Similarly, a diagnosis of nodules was ascertained in the studies by using diagnostic codes.
Ozone
Three studies examined the association between O3 exposure and diagnosis of thyroid cancer, and two studies examined detection of thyroid nodules. 25 –27,29,30 All five studies found significant associations between increased levels of O3 exposure and incidence of either thyroid cancer or thyroid nodules (Table 2).
Quantified Association Between Environmental Pollutant and Outcome by Study and Pollutant Type
Cubic splines model. Results were presented as a range of odds ratios as a function of annual mean O3 levels. All odds ratios above an O3 level of 0.036 were significant and ranged from 1.1 to 1.5 for corresponding O3 levels of approximately 0.036–0.05.
Increasing odds of thyroid cancer diagnosis with increasing duration of PM2.5 exposure.
Increasing odds of thyroid cancer diagnosis with increasing concentration of PM2.5 exposure.
aOR, adjusted odds ratio; CI, confidence interval; OLS, ordinary least square; PM, particulate matter; O3, ozone; RR, relative risk.
Dehghani et al. investigated the annual percent change (APC) and average APC between exposure to ambient air pollution and the incidence of thyroid cancer in Iranian adults. 26 Air pollution levels and thyroid cancer incidence were extracted from the Global Burden of Disease (GBD) 2019 dataset. Annual pollutant levels within the GBD 2019 study were determined using data from approximately 200 environmental air monitoring stations across Iran. These stations measured ambient O3 and PM concentrations over a 19-year period from 2000 to 2019, allowing for the calculation of average annual concentrations of these pollutants. Unadjusted analyses showed correlation between ambient O3 pollution and incidence of thyroid cancer in women (r = 0.94, p ≤ 0.001).
A 2023 ecological study by Maleki et al. examined the association between O3 levels and age-standardized incidence rates of thyroid cancer for 204 countries (1990–2019). 27 Pollutant levels from country-specific air monitoring stations and national thyroid cancer incidence data were obtained from the International Agency for Research on Cancer (IARC), Global Cancer Observatory database, and the GBD using a combination of International Classification of Diseases’ (ICD) diagnosis codes, health insurance claims data, and country-specific disease registries from 1990 to 2019. After controlling for sex, a sociodemographic index, and temperature, models indicated that a one unit increase (micrograms per cubic meter) in O3 levels was associated with a 1.03-fold [confidence interval or CI: 1.01–1.06] increased relative risk of age-stratified thyroid cancer incidence.
Park et al. performed a case–control study utilizing O3pollution data obtained from the South Korean Ministry of Environment. 25 Mean pollutant levels over a moving average of three years prior to the date of thyroid cancer diagnosis were linked to individual exposure estimates using the residential province of participants. Thyroid cancer data were retrieved from the Korean National Health Insurance Service—Health Screening Cohort data from 2002 to 2015 for participants with an ICD-10 code for malignant neoplasm of the thyroid gland and treatment claim codes for thyroidectomy. After adjusting for cholesterol, blood pressure, blood glucose, obesity, smoking status, alcohol, and Charlson Comorbidity Index, higher average 3-year exposure to O3 was associated with a 1.17-fold increased risk of thyroid cancer (adjusted odds ratio [aOR] = 1.17 [CI: 1.07–1.28]).
Both studies investigating incidence of thyroid nodules were conducted retrospectively in China and utilized environmental monitoring station data from China’s National Urban Air Quality Real Time Publishing Platform to determine exposure estimates. 29,30 Zhang et al. ascertained average city-level O3 exposure over a 3-year period (2015–2017) in which 1.8 million adults were diagnosed with thyroid nodules via screening ultrasound. 29 After adjusting for age, sex, plasma glucose, body mass index (BMI), lipids, GDP, education level, smoking status, and urine iodine, each increase of 10 μg/m3 of O3 was associated with a 1.15-fold [CI: 1.149–1.154] increased risk of thyroid nodule detection. Similarly, He et al. evaluated the association between 1- and 2-year average annual O3 exposure and the detection of thyroid nodules among 191,000 adults via ultrasound. 30 Participants’ residential addresses were used to determine city-level O3 exposure levels in the Hunan province of China. Adults with higher average O3 exposure levels had a greater likelihood of thyroid nodule diagnosis compared with adults with lower O3 exposure levels when annual mean O3 levels exceeded 0.036 ppm (p < 0.001), with estimates ranging from 1.1- to 1.5-fold increased risk of nodule detection.
Particulate matter
Seven studies examined the relationship between PM exposure (PM2.5 or PM10) and thyroid cancer or nodules. 18,22,25 –29 Five studies reported a positive association between PM and thyroid pathology (Table 2).
Particulate matter (PM2.5)
Karzai et al. conducted a case–control study in the United States (2013–2016) including 1990 patients with PTC and 3980 age- and sex-matched controls. 18 PM2.5 exposure data were based on patients’ residential zip codes, using a validated deep learning neural network model, which incorporated meteorological, satellite, and EPA Air Quality System data. PTC diagnosis was extracted from electronic medical records. After adjusting for demographics, BMI, smoking, alcohol use, hypertension, diabetes, Chronic Obstructive Pulmonary Disease, and asthma, authors noted an 18% increase in the odds of developing PTC after a 5 μg/m3 increase in 24-month PM2.5 exposure (aOR = 1.18 [CI: 1.00–1.40]) and a 23% increase after 36 months (aOR = 1.23 [CI: 1.05–1.44]), highlighting a dose- and time-dependent relationship.
Craver and colleagues examined the association between PM2.5 and cancer risk in the United States (2017–2022). 28 Air pollution data were ascertained from the EPA Air Quality System, including data from thousands of environmental air monitoring stations across the United States, and were linked to 3-digit zip codes to assess exposure estimates. Thyroid cancer diagnosis data were derived from participant electronic health records in the All of Us Research Program, a cohort of over 1 million participants. Logistic regression models, adjusted for sex, race/ethnicity, age, smoking status, education, and BMI, with PM2.5 exposure stratified into quartiles did not indicate any association between PM2.5 and thyroid cancer diagnosis even in the highest mean PM2.5 level areas (aOR = 0.89 [CI: 0.78–1.01]). However, an adjusted general additive model found a significant nonlinear increase in the odds of thyroid cancer diagnosis increased with rising PM2.5 levels suggesting a dose–response relationship.
Lastly, the 2015–2017 cross-sectional study in China (Zhang et al.) identified significant associations per increase of 10 μg/m3 for PM2.5 (OR = 1.06 [CI: 1.061–1.064]) and odds of thyroid nodule detection. 29 Stronger correlations were noted in men, younger individuals, and those with iodine deficiency.
Particulate matter (PM10)
Yanagi and colleagues performed an ecological study focused on annual PM10 levels from the São Paulo State Environmental Company from 1988 to 1997. 22 Using data from the São Paulo Cancer Registry, they noted an unadjusted positive correlation in thyroid cancer incidence from 1997 to 2005 in Brazil (r > 0.6, p < 0.05). In contrast, Park et al., in their case–control study, reported an inverse association between PM10 exposure and thyroid cancer incidence (aOR = 0.64 [CI: 0.60–0.69] p < 0.001) in South Korea among 4632 patients with thyroid cancer using 18,528 matched controls. 25 Lastly, Zhang et al. cross-sectionally examined PM10 exposure and thyroid nodule detection in China, reporting increased odds of thyroid nodules per 10 μg/m3 for PM10 (aOR = 1.04 [CI: 1.03–1.04]). 29
Ambient PM (size not specified)
Dehghani et al. reported a positive correlation between geographically estimated ambient PM and thyroid cancer incidence in Iranian women (p ≤ 0.001, r = 0.84), although PM was not divided by particle size. 26 The global study by Maleki et al additionally examined the association between ambient PM levels and thyroid cancer diagnosis across 204 countries from 1990 to 2019. 27 After controlling for sex, sociodemographic index, and temperature, results indicated that a unit increase (micrograms per cubic meter) in ambient PM was associated with a 28% (relative risk = 1.28 [CI: 1.19–1.37]) increased relative risk of age-stratified thyroid cancer incidence.
Nitric oxides
Two studies examined the effects of nitrogen dioxide (NO2) on thyroid cancer and one on thyroid nodules. 23,25,29 All three studies noted a significant positive correlation between NO2 levels and thyroid pathology.
In Saudi Arabia, Al-Ahmadi et al. examined satellite data, using spatial analysis to determine NO2 exposure levels from 2003 to 2010. 23 Thyroid cancer incidence data were obtained from the Saudi Arabian Cancer Registry. Authors reported ordinary least square (OLS) analysis, indicating that thyroid cancer was positively correlated with NO2 at the regional level (OLS 0.41, p < 0.05) but not at the governorate or city levels.
In their case–control study, after adjusting for comorbidities, smoking status, alcohol use, and various meteorological covariates (Table 1), Park et al. reported a 1.33-fold (aOR = 1.33 [CI: 1.24–1.43]) increased risk of thyroid cancer with NO2 exposure in South Korea. 25 Lastly, the cross-sectional Zhang et al. study in China demonstrated a 1.1-fold (aOR = 1.10 [CI: 1.09–1.10]) increased risk of thyroid nodules per increase of 10 μg/m3 of NO2. 29
Sulfur dioxide
Two studies examined the relationship between SO2 and thyroid cancer and one study on thyroid nodules. 19,25,29 Of these three, only two studies observed a significant relationship between SO2 and thyroid pathology (Table 2).
Cong et al. investigated the association between outdoor air pollution from waste gas emission (total waste gas, industrial waste gas, SO2, and soot) and cancer incidences in Shanghai, China from 1983 to 2010.
19
Pollutant exposure levels were determined from annual waste gas emission data reported by the Shanghai Environmental Protection Bureau from 1985 to 2010. ICD codes from the Shanghai Cancer Registry were used to collect thyroid cancer incidence data. After adjusting for sex, number of doctors per 10,000 population, education, and socioeconomic status, regression models revealed a significant correlation between waste gas emissions and thyroid cancer incidence in both males and females (
Carbon monoxide
One study examined the relationship between CO and thyroid cancer, and one study examined thyroid nodules (Table 2). In their case–control study in South Korea, Park et al. reported an inverse relationship between CO exposure and adjusted odds of thyroid cancer (aOR = 0.42 [CI: 0.27–0.64]) (Table 1). 25 In contrast, Zhang et al.’s cross-sectional analysis of CO levels in China indicated increased odds of thyroid nodule detection (aOR = 1.50 [CI: 1.49–1.52]). 29
Polyaromatic hydrocarbons
Giannoula et al. investigated the relationship between benzo(k)fluoranthene (a type of PAH) and age-standardized thyroid cancer incidence data for the 27 countries that compose the European Union (Table 2). 24 Mean pollutant concentrations in each country over a 30-year period at three time points 1992, 2002, and 2012 were obtained from the European Environment Agency. Thyroid cancer incidence data were obtained from IARC in each country in 2012. Authors identified a positive correlation between environmental concentration of benzo(k)fluoranthene in 2012 and the incidence of thyroid cancer (r 2 = 0.2142, p = 0.042).
Risk of bias
For observational cohort and cross-sectional studies, NHLBI quality assessment scores indicated that 4 studies had a “Good” quality rating, 3 studies had a “Fair” quality rating, and 2 studies had a “Poor” quality rating (Table 3). Meanwhile, for case–control studies, both studies were rated as “Good.” Overall, 6 studies showed a low risk of bias, and 5 studies showed a moderate-to-high risk of bias.
NIH National Heart, Lung and Blood Institute Study Quality Assessment Tool
Cross-sectional and observational:
Q1. Was the research question or objective in this article clearly stated?
Q2. Was the study population clearly specified and defined?
Q3. Was the participation rate of eligible persons at least 50%?
Q4. Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants?
Q5. Was a sample size justification, power description, or variance and effect estimates provided?
Q6. For the analyses in this article, were the exposure(s) of interest measured prior to the outcome(s) being measured?
Q7. Was the time frame sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed?
Q8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)?
Q9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?
Q10. Was the exposure(s) assessed more than once over time?
Q11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?
Q12. Were the outcome assessors blinded to the exposure status of participants?
Q13. Was loss to follow-up after baseline 20% or less?
Q14. Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)?
Case–control:
Q1. Was the research question or objective in this article clearly stated and appropriate?
Q2. Was the study population clearly specified and defined?
Q3. Did the authors include a sample size justification?
Q4. Were controls selected or recruited from the same or similar population that gave rise to the cases (including the same time frame)?
Q5. Were the definitions, inclusion and exclusion criteria, algorithms, or processes used to identify or select cases and controls valid, reliable, and implemented consistently across all study participants?
Q6. Were the cases clearly defined and differentiated from controls?
Q7. If less than 100% of eligible cases and/or controls were selected for the study, were the cases and/or controls randomly selected from those eligible?
Q8. Was there use of concurrent controls?
Q9. Were the investigators able to confirm that the exposure/risk occurred prior to the development of the condition or event that defined a participant as a case?
Q10. Were the measures of exposure/risk clearly defined, valid, reliable, and implemented consistently (including the same time period) across all study participants?
Q11. Were the assessors of exposure/risk blinded to the case or control status of participants?
Q12. Were key potential confounding variables measured and adjusted statistically in the analyses? If matching was used, did the investigators account for matching during study analysis?
NA, not applicable.
Discussion
To our knowledge, this is the first and largest systematic review to assess the association between individual components of environmental air pollution and thyroid cancer or nodules. All 5 studies assessing O3, all 3 studies assessing NOx, and all 4 studies examining PM2.5 consistently demonstrated positive associations with diagnosis of thyroid cancer and nodules. Importantly, the strength of these associations varied, with studies examining O3 and NOx reporting increased risks ranging from 1.03 to 1.5-fold and 1.1 to 1.3-fold, respectively. For PM2.5, studies noted dose-dependent risk increases, ranging from 1.18 to 1.23-fold for thyroid cancer diagnosis. While all studies noted a positive effect of PM2.5 on thyroid cancer risk, Craver and colleagues noted a significant effect only with a nonlinear analysis, suggesting additional consideration of alternate modeling in this complex relationship. 28
Inconsistencies between studies existed for PM10, SO2, and CO. Park et al. deviated from the majority by observing a lack of association between thyroid cancer and SO2 and a negative association between PM10 and CO exposure and thyroid cancer. 25 Several potential reasons may explain the observed discrepancies. First, methods used to assess pollution varied widely across studies, including different national air quality monitoring systems and satellite data, which could lead to inconsistent exposure measurements. Second, covariate adjustments differed significantly between studies, with some adjusting for a wide range of demographic and health-related factors while others did not adjust for any, affecting the comparability of the estimated effects. Third, regional differences in pollutant composition, due to industrial emissions or traffic patterns, may contribute to observed inconsistencies. For example, PM10 is a complex mixture, and its composition may vary significantly depending on the local environment, potentially affecting its carcinogenic potential. 31 Finally, population susceptibility may also play a role; genetic, lifestyle, or environmental factors could influence individual responses to pollutant exposure, leading to varying health outcomes.
Although the precise biological mechanism by which air pollution may lead to thyroid malignancy has not yet been identified, several hypotheses have been suggested. PM is known to be mutagenic, causing genomic instability, epigenetic modification, oxidative stress, and inflammation. 32,33 Chronic exposure to NO2 and O3 has also been associated with irreversible cellular damage and reactive oxygen species production, altering signaling pathways implicated in carcinogenesis. 34 Additionally, environmental air pollutants, particularly PAHs, may disproportionately impact endocrine organs by acting as “endocrine disruptors.” 35 Specifically, PM2.5 has been shown to interfere with hormone synthesis, metabolism, and transport in animal studies. 36 Indeed, PM2.5 has been associated with circulating thyroxine and thyrotropin (TSH) levels, as well as insulin resistance and even infertility. 37 –39 TSH has been suggested to modulate thyroid cell mass, offering a plausible mechanism for the observed relationship with thyroid nodules. 40 Additionally, while benign thyroid tumors account for most nodular thyroid disease, there is evidence that some benign thyroid nodules have malignant potential. 41 Prior studies identifying associations between air pollution and disparate forms of thyroid dysfunction, including autoimmune and congenital conditions, further support biological plausibility for the selective impact of air pollution on thyroid pathophysiology. 42,43 More directly, several recent studies have reported an association between air pollution and non-lung cancers, including ovarian, breast, and liver cancer. 13,44 –46
Several limitations inherent to this systematic review must be acknowledged. The heterogeneity of included studies, both in terms of methodologies and populations, may have impacted the consistency of the findings. For exposure assessment, significant variation existed in methods used to quantify pollutant exposure, ranging from different national air quality monitoring systems to satellite data. In terms of outcomes, few studies specified a specific subtype of thyroid cancer. Study design varied widely, with some studies concurrently examined pollutant levels and thyroid outcomes while others assessed exposures prior to thyroid outcomes. The wide range of reported associations, from odds ratios to correlation and regression coefficients, for various pollutants limited comparability and synthesis of estimated effects, precluding meta-analysis. Importantly, the potential confounding effect of increased availability of medical imaging and ultrasounds in areas with higher pollution levels could not be controlled in this review. In regions with greater pollution, there may be a higher likelihood of detecting thyroid abnormalities due to more frequent use of diagnostic tools, which may influence the observed associations between environmental pollution and thyroid cancer/nodules. Lastly, the quality assessment scores indicated a moderate risk of bias, and this review relied on the quality and completeness of the reported data in the included studies, which varied significantly.
Despite these limitations, this study benefits from being the first to systematically review evidence of the association between air pollutants and thyroid cancer diagnosis. Each of the included studies quantitatively assessed the association between pollutant exposure and the detection of thyroid nodules or cancer, suggesting that there may be a consistent pattern warranting further investigation. As the global incidence of thyroid cancer increases, such investigation into environmental air pollution is an integral avenue of public health policy. Future studies should aim to standardize pollutant measurement methods to ensure consistent exposure assessment across different regions and populations. This includes using a standardized approach for satellite-based monitoring and incorporation of local environmental data. Additionally, when examining an outcome of thyroid cancer, future studies should also specify the type of thyroid cancer and even examine molecular markers associated with those cancer. Exploring associations for dose-response, critical susceptible time window or duration of exposure, or even concentration of exposure may elucidate the thresholds at which pollutants may exert harmful effects on thyroid tissue. Thyroid cancer features such as tumor size, nodal status, and mutation status should also be incorporated. Research into potential genetic and epigenetic modifiers of susceptibility is crucial, as individual genetic predispositions or epigenetic changes may influence the degree of risk associated with air pollution exposure. Large-scale, longitudinal studies that integrate these factors will be essential to fully understand the complex interactions between environmental pollutants and thyroid cancer risk, ultimately guiding effective public health interventions and policy development.
Conclusions
While the emerging body of literature suggests a potential association between air pollution and thyroid cancer, the quality of evidence is limited due to study design constraints, variability in exposure assessment, and potential confounding factors. The heterogeneity in study designs and methodologies present challenges in interpreting results, underscoring the need for standardized approaches in future research.
Footnotes
Authors’ Contributions
Conceptualization and design were done by V.V., M.R., and A.M. Methodology was developed by M.R. and A.M. V.V., L.V.Y., R.S., M.R., and A.M. contributed to study screening and data extraction. S.M.S. performed the systematic search across databases. Quality assessment was performed by V.V. and R.S. V.V., L.V.Y., M.R., and A.M. drafted the article. N.C.D. and M.M.-D. revised the article. L.J.M., S.B., and L.F.M.-W. contributed to the analysis and interpretation of data. All authors gave final approval of the version to be published.
Author Disclosure Statement
The authors declare no conflict of interest.
Funding Information
The following funding have been received for this study: R01AI143731 (M.R.), R01AG076834 (A.M.), and American Cancer Society (RSG-21–079-01-CPSH) (N.C.D.).
Supplementary Material
Supplementary Table S1