Thyroid nodules (TNs) are highly prevalent worldwide with 4 to 7% by physical examinations and 30 to 67% by imaging studies (1). Although most nodules are benign, up to 20% have been found to be malignant on excision (2). Increased diagnosis of TNs may be partly due to the advancements in diagnostic technologies, especially high resolution ultrasonography, but the worldwide increase of TNs may be due to multiple factors (2), including a list of individual-level risk factors (3–5), such as sex, age, iodine intake, obesity, diabetes, dyslipidemia, and thyroid autoimmunity. Air pollution may play a significant role in the development of TNs.

Air pollutants, especially particulate matters in outdoor air pollution, are well-known human carcinogens and are increasingly associated with adverse effects on the thyroid, including disturbance of thyroid function (6–9). For example, one study with 433 pregnant women reported an inverse association between maternal exposure to PM_2.5 and the maternal free thyroxine (FT4) levels (6); airborne particulate matter (APM), has significantly affected thyroxine binding to transthyretin (TTR) and the reduction of thyroxine (T4) level (10). Understanding the association of air pollutants and the risk of TNs has particularly important public health implications for disease prevention. Existing studies have been focused on evaluating the associations between air pollutants and thyroid dysfunction, however, in a relatively limited sample (6–9). Moreover, most participants with TNs presented morphological changes but were rarely hypothyroid/thyrotoxic (11). To the best of our knowledge, no human studies have examined the associations between major air pollutants and TNs.

Therefore, this study aimed to investigate the associations between exposure to six major air pollutants (PM_2.5, PM₁₀, NO₂, SO₂, CO, and O₃) and the prevalent risk of thyroid nodules in a large health check-up population. This study has particularly important public health implications for TN prevention and air pollution control policies in all countries with serious air pollution issues and challenges.

As mentioned before, there has been no prior study that has extensively discussed the potential risk that outdoor air pollutants have on the increasing prevalence of TNs. This study found that each of the six major air pollutants (PM_2.5, PM₁₀, NO₂, SO₂, CO, and O₃) were statistically associated with an increased risk of TNs among about 4.9 million Chinese adults. These associations were significantly stronger in the participants, who were men, younger, and also having lower urine iodine level. Those associations were close to linear in all and subgroup analyses, indicating that air pollutants exposure was associated with an elevated TNs risk without minimum effective concentrations.

The association between major air pollutants and TNs was near linear without minimum effect concentrations. The linear results for PM_2.5 and PM₁₀ were indeed unsurprising because the minimum levels for both the two pollutants in this study exceeded the level (minimum 10 μg/m³ vs. 20 μg/m³) suggested by the WHO air quality guideline (18). However, it was unexpected for NO₂, SO₂, CO, O₃, and ORs to remain statistically significantly heightened when only participants with concentrations far below corresponding the WHO air quality guideline (<25 μg/m³ for NO₂, 10 μg/m³ for SO₂, 700 μg/m³ for CO, and 60 μg/m³ for O₃) were included. The current WHO annual mean limit value for NO₂, SO₂, CO, and O₃ were 40 μg/m³, 20 μg/m³, 4,000 μg/m³, 100 μg/m³, respectively. These findings suggest that significant adverse health effects occur at concentrations well below accepted limits, supporting the idea that significant health benefits can be achieved by moving towards that guideline, while also adding new evidence concerning the important human organ.

The significant associations between air pollutants exposure and TNs remained stable in this study, even after thoroughly adjusting well-known confounders adhering to previous studies (9, 21). Those findings were complementarily consistent with existing sets of evidence focused on the association between air pollutants and thyroid dysfunction (6–9). The potential mechanisms explaining the effect of outdoor air pollutants on TNs risk are still unclear. Several signaling pathways may be involved. First, the outdoor air pollutants exposure may cause oxidative stress in the body, which has been described as an endogenous factor contributing to the thyroid hyperplasia (22). Second, exposure to particulate matters shapes DNA methylation through the lifespan (23), which may also be a potential mechanism for TNs pathogenesis. In addition, other pathways such as systemic inflammation and insulin resistance might also be among potential mechanisms (24, 25).

Furthermore, it was found that the association of air pollutants was ameliorated with TSH adjustment. TSH has been proposed to promote growth in size of thyroid cells (26). In this study, the TSH levels were relatively lower in the TNs group, which might be due to its ability to maintain TSH levels at a lower normal range by autonomous hyperfunctioning (27). Thyroid antibodies might also contribute to the growth and progression of TN (28). In this study, most of the ORs turned to be nonsignificant in anti-TG(+) and anti-TPO(+) group except for CO and O₃. One possible reason was that the effects of anti-TG and anti-TPO on TNs progression were too high that the effect of air pollutants was masked. Another possible reason was that the anti-TG(+) and anti-TPO(+) patients have more sophisticated immune systems compared to the anti-TG(−) and anti-TPO(−) groups, which may have a stronger inflammatory response when their immune systems are triggered, and the moderate inflammation may play some role in defending air pollutant effect. Some studies also reported that high anti-TPO titers appear to protect against differentiated thyroid cancer in patients with Hashimoto’s thyroiditis (29).

Females have been reported to be more vulnerable to air pollution (PM₁₀, SO₂, NO₂, and O₃), and to have a higher air pollution-related mortality than males in a few studies (30). However, this study with a large sample size demonstrated that ORs for each pollutant with TNs were consistently lower in participants who were women and/or elderly, which contradicts the sex-specific effect of air pollutant on other outcomes including thyroid function indexes and mortality. Clear reasons for the sex-specific effects of air pollution are not well known. One explanation could be due to the fact that women and the elderly were already more likely to suffer from TNs (5), while the group with higher risk profiles is always apt to detect a relatively lower OR resulting from some loss of statistical power (20). Another reason is that the estrogen and progesterone might also contribute to the sex disparity (31), which needs further study to confirm. Another interesting discovery in this study was that lower urine iodine level has higher ORs for each pollutant. The relatively low risk profile in the group with appropriate urine iodine level should also be one reason. Besides, cigarette smoking could inhibit iodine transport, iodine organification, and increase iodide efflux, which may promote the occurrence of thyroid nodules (32). It is reasonable to postulate that the effect of air pollutant on iodine metabolism is ameliorated in the excess iodine region.

Air pollutants especially particulate matter in outdoor air pollution has become one of the biggest threats to the health of the Chinese people. Although appreciable reductions of the annual average concentrations for most of pollutants were observed from 2013 (33), the current concentrations for fine particulate, NO₂ and SO₂ were still higher than the WHO recommendations. The newly-found associations together with previous researches (6–9), have at least two implications. First, the new evidence was added for the adverse health effect of air pollution in the perspective of the important endocrine organ, with connecting major air pollutants with the highly prevalent disease. Second, it is safely assumed that plenty of TNs patients would unsurprisingly appear in next decades without expeditious and effective measures to control air pollutants. The findings provide evidence to implement effective air-quality improvement strategies and management plans, addressing an arduous task in managing the challenges of environmental pollution in China and other countries facing similar air pollution issues.

Nonetheless, the study has several limitations. First, assigning each participant the average concentration of air pollutants over the city in which he or she visited the health screening center was a rough estimate, but the corresponding variation is expected to be minimal. Second, whether TNs were benign or cancerous were not diagnosed by the general practice in health screening centers, which has hindered further exploration of the relationship between air pollutants and the different types of TNs (21). Lastly, causal inference was limited by the observational study design, although the reverse effect of TNs causing air pollutants changes is scarcely possible.

In conclusion, with an unprecedented large sample size and measures of multiple air pollutants across a wide geographic area, the findings of this study show that exposure to six air pollutants is significantly associated with an increased risk of thyroids nodules, even at concentration ranges well below the annual mean limit value suggested by the WHO. Further longitudinal studies are needed to confirm these findings, and to clarify potential mechanisms that might be responsible for the association between air pollutants exposure and TNs.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethical Committee of the Health Science Center of Peking University. The patients/participants provided their written informed consent to participate in this study.

Conception: SW, YFS, and YN. Design: SW, YFS, and YN. Administrative support: YN and LL. Provision of study material or patients: CJ. Collection and assembly of data: YZ, WQ, SW, and CJ. Data analysis and interpretation: YZ, KW, SW, YFS, YQS, PJ, YN, and LL. Manuscript writing: YZ, KW, SW, and YFS. All authors contributed to the article and approved the submitted version.

This work was funded by the National Natural Science Foundation of China (81922016, 91846303, and 81502884) and the National Key R&D program (2020YFC2003400). The funders had no role in the study design; collection, analysis, and interpretation of data; writing of the report; or decision to submit the article for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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