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 4 and the drug type, drug treatment, subject, dose, side effects, and drug efficacy are summarized in Table 2.

Natural antioxidants, sourced mostly from plants, counteract radiation by neutralizing the free radicals produced in the body when it is exposed to the radiation [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 [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 [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 [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 [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 [73]. The significant protective effect of vitamin E on the parotid and submandibular glands after ¹³¹I (23 mCi) treatment with DTC has been published [87,105], which was comparable to the results of Filiz Aydoğan et al. [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 [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) [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 [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 [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 [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 [84]. Melatonin and Se NPs (as radioprotective agents) reduced the ¹³¹I-induced DSBs levels in peripheral lymphocytes [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 [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 [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 [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 [94].

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 [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 [110,111,112]. However, it is important to note that synthetic antioxidants can frequently cause adverse health effects when used in high doses [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 [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 [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 [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 [97]. In the case of RAI, a high absorbed dose may be produced in the lung parenchyma, thus causing lung damage [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 [45].

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 [116]. Furthermore, synthetic antioxidants have been reported to cause potential health hazards, including liver damage and cancer [117,118,119]. Therefore, further investigation is needed at a pre-clinical level to standardize the use of antioxidants as adjuvants for ¹³¹I treatment.