Thyroid cancer is a malignant tumor of the endocrine gland that arises from the follicular or parafollicular epithelium of the thyroid gland. As a result of an increased use of diagnostic imaging and surveillance, the incidence of thyroid cancer has been steadily increasing worldwide, with more than 62,000 new cases diagnosed each year ^[1][2][3][1,2,3]. The most frequent kind of thyroid cancer is differentiated thyroid carcinoma (DTC), which accounts for more than 95% of cases ^[4][5][4,5]. Thyroidectomy, lymph node dissection, and ¹³¹I therapy are the primary therapeutic options [6]. In clinical practice, ¹³¹iodine (¹³¹I), a γ/β radiation radionuclide with a half-life of 8 days, can accumulate in thyroid tissue. As shown in Figure 1, it is commonly used to ablate residual thyroid tissue after surgery (known as thyroid remnant ablation) to reduce the likelihood of local recurrence, treat metastatic disease, and clear hidden thyroid cancer cells ^[7][8][9][7,8,9]. Iodine-131 is also used as a means of addressing persistent disease as reflected by the thyroid globulin levels [10], with a typical dosage range of 1110 MBq (30 mCi) to 3700 MBq (100 mCi) [11].

However, there is evidence that ¹³¹I γ/β radiation interferes with the REDOX cell signaling pathways, causing an imbalance between cellular oxidants and antioxidants, resulting in systemic oxidative stress, cell and tissue damage, and an increase in the risk of genetic DNA damage and secondary cancer ^{[12][13][14][15]}[12,13,14,15]. Furthermore, it can cause side effects, including salivary gland dysfunction, gastrointestinal reactions, dry eye, pulmonary fibrosis, gonad damage, nasolacrimal duct obstruction, secondary cancer, permanent myelosuppression, and genetic effects ^[16][17][16,17]. To achieve optimal effectiveness and minimize discomfort in thyroid cancer patients, adjuvant medication combinations that reduce the adverse effects of ¹³¹I are required.

Antioxidants are chemicals that bind free radicals and drastically decrease or prevent substrate oxidation ^[18][19][18,19]. They limit free radical damage by blocking free radicals from damaging lipids, protein amino acids, polyunsaturated fatty acids, and the double bonds of DNA bases ^[20][21][22][20,21,22]. Notably, substances such as β-carotene and vitamin E have been proven to dramatically minimize the negative effects of ¹³¹I ^[23][24][23,24]. 

3. Oxidative Stress Dominates ¹³¹I Side Effects

RAI is the standard and effective treatment for DTC. The thyroid gland can accumulate iodine at up to 40 times the concentration of plasma under physiological conditions. This relies on the NIS located in the basolateral membrane of thyrocytes using the electrochemical gradient generated by the Na,K-ATPase as the driving forces that coordinate with the KCNQ1-KCNE2 K⁺ channels located in the basolateral membrane These promote the potassium efflux, thus facilitating iodine transport into the intracellular compartments, and thereby increasing the oxidative stress and cytotoxic efficacy from the radioactivity ^{[25][26][27][28]}[39,48,49,50]. Oxidative stress is the result of increased free radical production and/or a decreased antioxidant defense system physiological activity ^[29][30][51,52]. Each cell in a living organism maintains a reductive environment. The reducing environment is maintained by enzymes, which provide constant metabolic energy input to maintain the reducing state ^[31][32][53,54]. This disruption of the normal reduction oxidation (REDOX) state can be mediated by the generation of peroxide-reactive radicals (hydrogen peroxide (H₂O₂), superoxide (O₂⁻), singlet oxygen (1/2O₂), ROS, and the hydroxyl radical (^∙OH). The abnormal expression of these substances may result in the destruction of all the components of the cell, resulting in toxic effects ^[33][34][35][55,56,57]. Severe cases can lead to cell death (Figure 23A). The damage can involve multiple parts throughout the body (Figure 23B). Iodine-131 can increase the overexpression of NADPH oxidase (NOX)1 in thyroid tissue, resulting in numerous ROS [12]. At the same time, mitochondria are more vulnerable to damage when exposed to iodine radiation. This is due to ultrastructural changes resulting in a decreased antioxidant capacity ^[36][37][58,59]. In other words, the levels of enzymatic antioxidants, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and thioredoxin (Trx), as well as non-enzymatic antioxidants such as glutathione (GSH), ascorbic acid, and tocopherol, were reduced in response to ¹³¹I ^[38][39][60,61]. Herein, ferroptosis described a novel form of regulatory cell death that was induced by fatal lipid peroxidation ^[40][62], dependent on iron, which was subsequently induced by an oxidation-damaged phospholipid accumulation and associated with the glutathione-dependent antioxidant defense dysfunction mediated by GPX4 via various pathways. Radiation has been shown to induce ferroptosis ^[41][63]. Iodine-131 likely triggered the declines in the metabolism of the lipid peroxides catalyzed by the GPX4 and GSH levels intracellularly and lead to Fe²⁺ oxidizing lipids in a Fenton-like manner, which enhanced ferroptosis and was responsible for thyroid cancer cell death ^[42][64]. Comparatively, a GSH deficiency disrupts the REDOX homeostasis, causing ROS accumulation, which eventually results in cell death. The CAT and SOD enzymes play a key role in free radical management, and their reduced activity contributes to an increase in the accumulation of O²⁻ and H₂O₂ ^{[43][44][45][46][47][48][49]}[65,66,67,68,69,70,71]. Additionally, excessive ROS interact with specific cellular targets to trigger a cascade reaction involving polyunsaturated fatty acid free radicals (lipid peroxidation) on the cell membranes, resulting in an increase in the malondialdehyde (MDA) (marker of lipid peroxidation) levels and a decrease in the CAT, SOD, and GSH activity, resulting in an imbalance between oxidants and antioxidants. The excessive depletion of endogenous antioxidants leads to a decrease in the total antioxidant status (TAS), which ultimately contributes to oxidative stress ^[48][50][51][70,72,73]. As a result, RAI in the remaining thyroid tissue may result in significant apoptosis and mitotic cell death ^[52][74]. In contrast, although most radiation from RAI enters the thyroid gland, a small amount of ¹³¹I present in the blood and tissues is also capable of causing radiation in other parts of the body ^[53][75], such as lipid peroxidation in the kidney, salivary glands, and erythrocytes, resulting in structural and functional damage to the cells ^[22][53][22,75]. Specifically, reductions in salivary TAS, SOD, CAT, and uric acid molecules may have long-term cumulative effects on the oral cavity. A study found that ¹³¹I treatment decreased SOD activity by 40%. The gastrointestinal tract may be adversely affected as saliva is continuously swallowed after secretion [16]. Other studies have demonstrated that ¹³¹I ionizing radiation can indirectly promote or induce significant changes in the red blood cell oxidative and antioxidant status. In addition, it can alter the appearance of erythrocytes, as well as their characteristics, such as their lifespan, permeability, and microcirculation ^[52][74].

3. Antioxidants Reduce ¹³¹I Side Effects

In general, it can be observed that oxidative stress mediates the pathological process of almost all the ¹³¹I side effects. Herein, the antioxidants showed a robust effectiveness against their side effects. The antioxidants that have been proven to alleviate the side effects of ¹³¹I are shown in Figure 34 and the drug type, drug treatment, subject, dose, side effects, and drug efficacy are summarized in Table 12.

3.1. Natural Antioxidant

Natural antioxidants, sourced mostly from plants, counteract radiation by neutralizing the free radicals produced in the body when it is exposed to the radiation ^[70][71][98,99]. The mechanism of action generally involves scavenging free radicals and preventing them from damaging cells, tissues, and DNA. As a result, they are capable of shielding the organism cells from damage and aiding in the prevention of cancer and other health problems associated with exposure to radiation ^[72][100]. One of the advantages of natural antioxidants is that they are safer than synthetic antioxidants and have been utilized in conventional medicine for centuries. Furthermore, natural antioxidants are metabolized by the body into harmless compounds, most of which are excreted through normal metabolic processes and are more easily tolerated ^[73][74][101,102]. Vitamin C as ascorbic acid regulates the activity of the glutamate receptors, lowering the level of free radicals produced by the glutamate release, and has been proven to reduce the frequency of chromosomal aberrations by approximately 30%, significantly reduces the number of DNA breaks, and has a repairing effect on DNA ^[75][76][103,104].Vitamin C reacts directly with alkoxyl, hydroxyl, and lipid peroxyl radicals or neutralizes them and converts them into water, alcohols, and hydroperoxylated lipids, respectively. Importantly, studies have indicated that vitamin C has a radioprotective effect against oxidative stress, regardless of the timing of administration before and after RAI treatment ^[57][43]. Vitamin C in plasma leads to an increased resistance to lipid peroxidation and a decrease in DNA, lipid, and protein oxidation. In addition, vitamin C leads to the neutralization of free radicals of other antioxidants in the form of glutathione and vitamin E, as well as their regeneration. Approx. 2 days after RAI (5550 MBq), the MDA levels and CAT activity declined and the GSH levels decreased, while the daily administration of 1500 mg vitamin C starting two days before significantly reduced the MDA levels and not only prevented the reduction in GSH, but also significantly increased its levels after RAI treatment [22]. Additionally, vitamin E is the collective term for four tocopherols (α-, β-, γ-, and δ-tocopherols) and four tocotrienols (α-, β-, γ-, and δ-tocotrienols) found in food, and is a lipid-soluble antioxidant that protects polyunsaturated fatty acids in the membranes from oxidation, regulates the production of reactive oxygen species and reactive nitrogen species, and modulates the signal transduction ^[51][73]. The significant protective effect of vitamin E on the parotid and submandibular glands after ¹³¹I (23 mCi) treatment with DTC has been published ^[55][77][87,105], which was comparable to the results of Filiz Aydoğan et al. ^[78][106]. RAI (111 MBq/kg) resulted in a significant increase in the tissue TOS, TNF-α, IL-6 levels and a significant decrease in the IL-10 and TAS levels, while vitamin D (200 ng/kg/day) dramatically reversed all these parameters ^[56][88]. Meanwhile, sialogogues such as lemon candy, vitamin E, lemon juice, and lemon slices as well as parotic gland massages may all minimize injury to the salivary glands [10]. Parotid massages, aromatherapy, vitamin E, selenium, and bethanechol showed a significant reduction in the salivary gland dysfunction induced from the ¹³¹I treatment (2960–7890 MBq) ^[57][43]. Additionally, keratinocyte growth factor-1 (KGF-1) (100 μg/1 mL PBS) restored saliva homeostasis and reduced the ¹³¹I-induced (0.01 mCi/g) cell apoptosis in the mice ^[60][90]. A marker of lipid peroxidation, 8-Epi-PGF_2α, is the outcome of free radical-mediated arachidonic acid peroxidation, and the effect of high-activity treatment (2960 or 7400 MBq) is significantly higher and longer in length than that of low-activity treatment (185 or 740 MBq), with a dose-dependent oxidative damage in vivo ^[79][107]. In the research of Rosário et al., the 8-epi-PGF_2α concentrations were significantly higher in thyroid cancer patients 2 days before and 7 days after the ¹³¹I injection, and the increase (percentage) was significantly larger (mean 112.3% vs. 56.3% compared to the intervention group). Iodine-131 (3.7 GBq) after 2 days of plasma 8-epi-PGF_2α significantly increased, while the daily intake of 2000 mg of vitamin C, 1000 mg of vitamin E, and 400 µg of selenium for 21 days before RAI treatment significantly reduced 8-epi-PGF_2α and inhibited oxidative stress ^[54][86]. In terms of the protection against DNA damage, the use of curcumin and alginate as antioxidants reduced the number of DSBs caused by ¹³¹I. At the same time, the radiation protection effect of curcumin exceeded that of trehalose ^[59][84]. Melatonin and Se NPs (as radioprotective agents) reduced the ¹³¹I-induced DSBs levels in peripheral lymphocytes ^[60][90]. Vitamins E and C were capable of reducing the DSBs levels by 21.5% and 36.4%, respectively [23]. The positive results of the Barbados cherry fruit radiation protection may be due in part to its rich content of antioxidant compounds, including vitamins A, B1, B2 and C; carotenoids; anthocyanins; phenols; and flavonoids. The ¹³¹I (25 μCi) treatment of Wistar rats with an increased thyroid function and associated vitamins and sugars from the Barbados cherry fruit stimulated a significant increase in the mitotic index in the normal cells of the rat bone marrow. In particular, the Barbados cherry juice (5 mg) may act as an effective scavenger of the reactive oxygen species in acute radiation protection treatment, protecting the cells by neutralizing free radicals before and during treatment. Meanwhile, it may play a role in the healing process of ionizing radiation-induced damage after treatment. Barbados cherry sub-chronic treatment has higher radioprotective activity in terms of trapping free radicals or preventing their formation ^[61][91]. N-acetyl-L-cysteine has also been demonstrated to guard against an increase in ROS and eventual DNA damage in thyroid cells caused by ¹³¹I in vivo ^[62][92]. Before, during, and after ¹³¹I treatment, β-carotene exerts a significant anti-mutagenic/radioprotective activity, stimulates the DNA repair systems, and minimizes chromosomal aberrations and genetic material damage [12]. Apart from this, resveratrol had anticancer and antioxidant effects, protected the histopathological pattern of the lacrimal gland from damage, reduced inflammation in the histopathological assessment, and decreased the histocytokine levels, apoptosis, and DNA fragmentation on the lacrimal gland after RAI ^[63][93]. Iodine-131 caused an edema of the duodenum and ileum lamina propria, duodenal ulceration, gastric mucosal erosion, and gastric and colonic mucosal degeneration in the rats, whereas lycopene resulted in a statistically corresponding reduction in the inflammation present ^[64][94].

3.2. Synthetic Antioxidants

Synthetic antioxidants have advantages in radiation protection due to their greater potency, consistency, stability, and application flexibility. Despite the fact that natural substances have been used in traditional medicine for centuries, their variability, lack of specificity, and instability require modifications to their properties ^[80][81][108,109]. Accordingly, synthetic substances offer a reliable and effective way to protect against the harmful effects of radiation. Thus, further research and development is required to create more effective radiation protection, safer synthetic substances for human consumption, and to determine the safe limits for their applications ^[82][83][84][110,111,112]. However, it is important to note that synthetic antioxidants can frequently cause adverse health effects when used in high doses ^[85][113]. Iodine-131 (555–660 MBq) treatment with 200 mg/kg L-carnitine or amifostine for 10 days can provide radiation protection and reduce salivary gland injury ^[65][34]. Amifostine is an organic thiophosphate, which is dephosphorylated to the active metabolite WR-1065 in normal tissues. Once activated in the cells, WR-1065 acts as a free radical scavenger. Additionally, many studies have reported the radiation-proof effect on ¹³¹I treatment ^[86][87][35,114]. Iodine-131 causes transient unstable DNA damage composed of reactive oxygen-induced SSBs, and increased chromosome damage in hypothyroidism patients (mutations in enzymes deputed to DNA repair (DNA-1) or in the enzymes involved in the scavenging of free oxygen radicals (DNA-2)). The rhTSH administration reduced radiation exposure by 27% over 120 h and decreased the genomic instability by maintaining hyperthyroidism and normal renal clearance (Epi-GFR and creatinine values). It significantly induced a reduction in the reactive oxygen metabolites-derived compounds. The patients had less radiation-induced chromosome damage, even though several enzyme mutations were present [13]. Lin et al. prepared a drug delivery system with ¹³¹I-labeled caerin 1.1 peptide (F1) (200 μCi ¹³¹I and 8 μg caerin 1.1 peptide). The MTT results showed that 5 μg F1 had an inhibitory effect on the CAL-62 cells cultured in vitro. Interestingly, studies identified weight loss over time in the ¹³¹I treatment group in vivo, but not in the ¹³¹I-F1 or F1 groups. It is possible that ¹³¹I-F1 or F1 was confined to the tumor after injection, while ¹³¹I may have entered the microcirculation through the blood vessels within the tumor and then entered the internal circulation. In view of the fact that radiation entering the human body can cause acute injury, the occurrence of acute radiation sickness or syndrome characterized by weight loss suggests that ¹³¹I-F1 is safer with fewer side effects ^[67][96]. Additionally, synthetic drugs have been studied for the treatment of other side effects. Treatment with dexmedetomidine (3 μg/kg) significantly decreased the levels of MDA, advanced the oxidized protein products induced by RAI (2 MBq), significantly increased the levels of the total sulfur group and CAT, and reduced histopathological abnormalities, which could be applied as a post-¹³¹I liver protection regimen ^[68][97]. In the case of RAI, a high absorbed dose may be produced in the lung parenchyma, thus causing lung damage ^[88][115]. Montelukast (10 mg/kg/day) significantly reduced the degree of inflammation and pulmonary fibrosis in the Wistar rats treated with ¹³¹I (111 MBq/kg). The authors attributed this protective effect in part to the antioxidant effect of montelukast ^[69][45].

3.3. Antioxidant Deficiency

In summary, the application of the above antioxidants will hopefully play an important role in alleviating the side effects of ¹³¹I. It is important to highlight that even when the use of antioxidants has been shown to ameliorate the side effects of ¹³¹I therapy, there are also reports on the drawbacks of using them. Some antioxidants induce oxidative stress at high concentrations (e.g., β-carotene) [24]. Meanwhile, it has been reported that an excessive vitamin E intake can affect the absorption and function of other fat-soluble vitamins ^[89][116]. Furthermore, synthetic antioxidants have been reported to cause potential health hazards, including liver damage and cancer ^[90][91][92][117,118,119]. Therefore, further investigation is needed at a pre-clinical level to standardize the use of antioxidants as adjuvants for ¹³¹I treatment.