The endocrine system is one of the most important part of metabolism, and it plays a vital role for growth of humans (Mullur et al., 2014). However, when the endocrine is disordered, our bodies will suffer from many kinds of diseases consequently, even malignant tumors (Wright et al., 2021). As the largest endocrine gland, thyroid has multiple functions such as synthesizing thyroid hormones, regulating growth and development and metabolism in the body, and its lesions will inevitably cause serious damage to the body (Cabanillas et al., 2016). Thyroid cancer (TC) is the most common endocrine cancer nowadays, which causes a particularly serious burden. The latest cancer statistics of the World Health Organization (WHO) in 2020 had showed that new TC cases were more than 580 thousand worldwide, accounting for nearly 3.0% of the total cases of all cancers (Siegel et al., 2021). The age-standardized rate (ASR) of TC increased nearly by 20% from 1990 to 2013 (Lim et al., 2017); it is estimated that TC will become the fourth most common cancer in 2030. More seriously, TC incidence among females was higher than males, and the ratio of males to women was approximately 1:3 (Siegel et al., 2020; Sung et al., 2021). In 2016, the incidence of TC in China ranked eighth for all malignant tumors, and the ASR had risen from 2.89 in 2003 to 10.37 in 2015 (per 100,000); moreover, this number in females were higher (15.81). Therefore, TC has become one of main tumors endangering the health of Chinese (Wang et al., 2021).

According to the pathological classification, TC can generally be divided into several categories, in which papillary thyroid cancer (PTC) accounted for more than 80% of the total (Stojsavljević et al., 2021). Currently, the most widely known factors of TC were the exposure to ionizing radiation, and excessive or deficiency intake of iodine (Zimmermann and Boelaert, 2015). Besides, some countries like South Korea, has carried out many large-scale health examinations frequently, and these results revealed that some daily behaviors (e.g. smoking, alcohol, and dietary habits, etc.) were related to PTC risk (Kang et al., 2022; Kim et al., 2022). Additionally, other factors, such as reproductive factors for females, and abnormal levels of estrogen, which were used to explain the increasing risk (He et al., 2021b). Of course, the personal and family history of thyroid-related diseases was always the key issued in previous researches to explore the etiology of thyroid cancer (Banik et al., 2021). In addition, some people believed that the increasing incidence of TC is closely related to the development of medical diagnostic technology, which made it easier to detect TC with a diameter of <1 cm (Nabhan et al., 2021). However, a study from Shanghai, China pointed out that the incidence of PTC of 1.1–2.0 cm increased by 30%, and the tumor diameters >2.0 cm increased by 20% (Wang and Wang, 2015). Therefore, over-diagnosis cannot fully explain the high incidence. Therefore, we wanted to start with the actual level of metabolites in the human body, and tried to further explain the potential factors.

Nowadays, a large quantity of researches has confirmed that there is an inseparable relationship between metabolic disorders and cancers (Gyamfi et al., 2022). The various systems of our bodies are coupled with each other, so the disorder or disease of other systems may also affect the endocrine system. There could be a question existed: why is normal metabolism destroyed? We should admit that genetic mutations must exist; but it is not advisable to attribute so many cancer patients to their own genetic material (Abdul-Maksoud et al., 2022; Martínez-Camberos et al., 2022). Human beings live in nature and exchange materials from environment all the time. By this way, external substances can enter in our bodies through various ways. Therefore, it is urgent to pay attention to the effects of external environmental exposure on endocrine, especially thyroid function.

With the rapid development of population growth, industrialization, urbanization and agricultural modernization, the chances of Chinese people being exposed to external substances were also increasing (Wu et al., 2019). Trace elements are ubiquitous in the natural environment; humans are often exposed to them in many ways, such as ingesting food, drinking water, air inhalation, and skin contact (Cannas et al., 2020). In terms of human needs, these trace elements in the environment are generally divided into essential elements and non-essential elements. As an important component of body functions, the change of these elements is always subtle. Some of them are absorbed and utilized by related tissues; others are preserved in specific tissues for future use; the remaining part is excreted with urine and feces (Martinez-Finley et al., 2012; Potocki et al., 2012). But when there were significant changes in their levels, even beyond the threshold, it will cause compensatory negative effects in homeostasis. Undoubtedly, abnormal changes in the concentrations of these elements will inevitably lead to disorders in the endocrine system, also including thyroid gland, definitely.

As we all know, long-term exposure to non-essential metals may have adverse effects on the immune, neurological and endocrine systems, as well as increase the risk of liver and kidney dysfunction, cardiovascular diseases and malignant tumors (Bjorklund et al., 2018; Zhang et al., 2020; Zhou et al., 2021). Especially, heavy metals (including metalloid elements) can also cause severe damages to thyroid. For example, arsenic (As) and cadmium (Cd) had been confirmed as common carcinogens by the International Agency for Research on Cancer (IARC) (Stojsavljević et al., 2019b); coincidentally, mercury (Hg) and lead (Pb) were also be listed as possible carcinogens (Zhang et al., 2021). In particular, Cd can accumulate in follicular cells actively, and further cause thyroid tissue damages. The result from a previous study in Serbia showed TC patients who had higher Cd than healthy people. Besides, Cd can significantly decrease triiodothyronine (T3) and thyroxine (T4) secretion in rats (Stojsavljević et al., 2019a). Conversely, the higher level of selenium (Se) was be reported to have a protective effect on thyroid cells (Duntas, 2006). Interestingly, Se was seemed to protect serum T4 level which induced by Cd, indicated that Se has antagonistic effect with Cd. Zhang et al. had showed a significant dose-response effect for Hg exposure and PTC risk (Zhang et al., 2019). Other elements, such as copper (Cu) or iron (Fe), have also been reported to be positively associated with TC risk (Kosova et al., 2012).

However, the relationships between mixed-exposure of multiple elements and TC had not been determined. On the other hand, previous studies had failed to vividly reflect the mixed effects of different elements. Considering the severe situation of thyroid cancer in China, we designed a case-control study in Anhui Province, to explore the combined effects of multiple trace elements, and evaluated the fixed-exposure effects on TC risk, for explaining its etiology among Chinese people.