Radiation exposure during space voyage is expected to increase health risks including cancer in astronauts after return to earth. During space flight, astronauts ...
The British Journal of Radiology, 78 (2005), 485–492 DOI: 10.1259/bjr/87552880
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2005 The British Institute of Radiology
Review article
Rationale for using multiple antioxidants in protecting humans against low doses of ionizing radiation K N PRASAD, PhD Center for Vitamins and Cancer Research, Department of Radiology, School of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA
Abstract. Health risks of low doses of ionizing radiation (10 cGy or less) may not be accurately estimated in humans by epidemiological study or mathematical modelling because of several inherent confounding factors including environmental, dietary and biological variables that cannot be accounted for in any radioepidemiological study. In addition, the expression of radiation-induced damage in humans not only depends upon total dose, dose rate, linear energy transfer (LET), and fractionation and protraction of total doses, but also on repair mechanisms, bystander effects, and exposure to chemical carcinogens, tumour promoters and other toxins. It also depends upon the levels of anti-carcinogenic and anti-tumour promoting agents. Low doses of ionizing radiation should not be considered insignificant with regard to increasing the incidence of somatic mutations (neoplastic and non-neoplastic diseases) and heritable mutations in humans owing to its interaction with other toxins that can enhance damage produced by irradiation. It is very prudent to continue to support the well-established radiobiological concept that no radiation dose can be considered completely safe, and that all efforts must be made to reduce both the radiation dose and biological damage, no matter how small that damage might be, without sacrificing the benefits of radiation. Based on the results of many scientific experiments, formulations containing multiple antioxidants for biological protection against radiation damage in humans can be developed, and this strategy together with the existing physical concept of radiation protection, should further reduce potential risks of low doses of ionizing radiation in humans.
Ionizing radiation is a potent mutagen and carcinogen; however, it is also used in the diagnosis and treatment of human diseases. Diagnostic doses of radiation are generally 10 cGy or less. In the USA, background radiation at sea level is about 1 mSv year21 and consists of cosmic radiation and radiation emitted from radioactive substances present in the ground or commercial sources. In addition to standard hospital-based diagnostic radiation equipment (X-ray machine, CT scan, positron emission tomography (PET), nuclear medicine procedures), new ionizing radiation-based Diagnostic Centres for heart scan, virtual colonoscopy and whole-body scan are opening at a rapid rate throughout the world, especially in the USA. Individuals at younger ages are exposed to very low doses of radiation for the early diagnosis of diseases that may help to develop effective prevention and treatment strategies. However, low doses of ionizing radiation may also increase the level of genetic defects in present and future generations if no strategy for biological protection against such damage is developed and implemented. Radiation exposure during space voyage is expected to increase health risks including cancer in astronauts after return to earth. During space flight, astronauts are primarily exposed to high atomic number and highenergy particle radiation (HZE particles). Therefore, the success of long space voyages depends upon how well our astronauts are protected against radiation damage. Frequent flyers (public), flight attendants and fight crews on commercial jets, and Air Force personnel flying at very Received 30 July 2004 and accepted 18 January 2005.
The British Journal of Radiology, June 2005
high altitudes are also exposed to low doses of ionizing radiation. Recently, a new threat of exploding so called ‘‘dirty bombs’’ that may emit radiation doses varying from a few cGy to a couple of Gy (may or may not produce acute lethality) has added to the urgency for developing a strategy for biological protection against radiation damage. At present there is no effective strategy to reduce the potential risk of low doses of radiation in humans. Although some of these issues have been discussed in our recent reviews [1, 2], they did not focus on the development of scientifically rational nutritional formulations that are safe and could be effective in reducing the risk of radiation damage in humans. This review briefly discusses the potential health risks of low doses of ionizing radiation and provides scientific data in support of developing nutritional formulations containing multiple antioxidants that are known to be safe and that could provide biological protection against radiation damage in humans.
Hypotheses for potential health risks of low doses of radiation in humans Radiobiologists have been debating the health risks from low doses of ionizing radiation in humans for decades. This is supported by the fact that six biological effects of ionizing radiation (BEIR) reports have extensively analysed in vitro, animal and human studies on somatic and heritable mutations, and the incidence of cancers and birth defects following radiation exposure. Heritable mutations are of particular concern, especially 485
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among women, because the number of oocytes may be fixed at birth, and mutations, if not repaired, are cumulative and can increase health risks of future generations. At present, two opposing hypotheses on the potential risks of low dose radiation in humans are being debated. We support the hypothesis that there is no dose of ionizing radiation that can be considered completely safe, and that the use of radiation must always be determined on the basis of risk vs benefit [1, 2]. Another hypothesis suggests that the health risks of diagnostic doses less than 10 cGy are not measurable and may even be non-existent [3, 4]. This hypothesis ignores the effect of interaction between ionizing radiation and other carcinogens, mutagens and tumour promoters that may enhance the risk of radiation-induced cancer. Health risks include not only neoplastic diseases, but also somatic mutations that may contribute to other illnesses (including birth defects and ocular maladies) and heritable mutations that may increase the risk of diseases in future generations.
Proposed mechanisms of radiation-induced human cancer In mammals including humans, normal cellular turnover includes proliferation, differentiation and death of cells. This process is interfered with when carcinogenic changes occur. Cancer cells can arise from any dividing cells or cells that have potential to divide owing to accumulation of multiple genetic abnormalities (over-expression of genes, deletion of genes or gene mutations), some of which must occur in critical genes that regulate proliferation and differentiation. The processes may undergo three distinct processes, initiation, immortalization (pre-maligant change) and transformation (expression of malignant phenotype). Radiation-induced human cancers have long latent periods; 10 years for leukaemia and over 30 years for solid tumours [5], and may undergo similar carcinogenic processes. During the initiation phase, radiationinduced mutations (due to gene mutations and/or chromosomal damage) are detected within 24 h of radiation exposure, but these changes can be considered initiating events and may not be directly responsible for malignant transformation, because such cells continue to divide and proliferate like unirradiated normal cells. However, radiation-induced mutations cause genetic instability in irradiated cells making these cells more sensitive to mutagenic changes. Such cells may continue to proliferate and differentiate like non-irradiated cells while accumulating additional mutations for a long time without immortalization or transformation. Immortalization of irradiated cells, the first step in carcinogenesis, occurs only when the expression of genes regulating differentiation is altered. Immortalized cells can continue to proliferate until the expression of some key cellular genes, oncogenes or anti-oncogenes is altered by exposure to mutagens, carcinogens and/or tumour promoters. These cells then become malignant [6, 7].
Radiation dose–response models to estimate human cancer risk Two dose–response models are used to estimate cancer risk in humans. The first model proposes that 486
cancer risk following exposure to low doses of radiation (10 cGy or less) may be best estimated by a linear nothreshold relationship, since any dose has the potential to induce cancer [8–10]. The second model suggests that there is a threshold dose below which radiation may not induce cancer in humans [3, 4, 11]. Both models have relied on mathematical modelling and human radioepidemiological studies. Mathematical modelling may assume certain constant physical factors such as body weight [11] that may not reflect the inherent biological variations associated with radiation-induced carcinogenesis. The biological variables include differences in radiosensitivity with respect to age, organs, body mass, and differences in the efficacy of repair mechanisms. The second model also utilizes data that support hormesis [4]. ‘‘Radiation hormesis’’ is the name given to the putative stimulatory/adaptive effects of low level ionizing radiation generally in the range of 1–50 cGy of lowlinear energy transfer (LET) radiation [12–15]. It should be noted that adaptive responses are commonly observed with tissue injuries irrespective of the source of the insult. For example, hyperthermia and acute trauma also induce adaptive responses. Unlike other injurious agents such as heat and trauma, ionizing radiation is a potent mutagen and carcinogen, and radiation-induced adaptive responses do not reflect the mutagenic changes that might occur after exposure. Therefore, adaptive responses based on certain biological criteria following exposure to low doses of radiation cannot be considered beneficial to humans. On the contrary, they simply reflect that cells have been exposed to injurious agents and that attempts are being made to repair some of the damage. Numerous radio-epidemiological studies are available in the literature [5, 8, 16–21] and if selectively used, can support either hypothesis. Radio-epidemiological studies have so many confounding factors that it is not possible to quantify purely radiation-induced cancer risk in humans. These confounding factors include environment, diet and lifestyle-related factors that contain mutagens, carcinogens and tumour promoters as well as cancer protective substances, and cellular repair systems that may vary from one individual to another owing to variation in age, environment, and diet and lifestylerelated factors. Other confounding factors include: (a) interaction of radiation with other physical (UV light), chemical and biological mutagens and carcinogens in a synergistic manner; (b) variation in sensitivity of bystander cells to subsequent radiation exposure that depends on whether they have been pre- or post-irradiated; and (c) variation in adaptive response that depends on radiation doses and protective substances (antioxidants). Thus, humans are simultaneously exposed to varieties of mutagens, carcinogens, and tumour promoters as well as to cancer protective agents, in addition to ionizing radiation. Therefore, low dose radiation-induced cancer in humans depends upon several variables, most of which are not possible to correct for in any epidemiological study. This may explain why radio-epidemiological studies in humans have produced inconsistent results. Nevertheless, these studies are important in establishing an association between radiation doses and health risks in humans. The British Journal of Radiology, June 2005
Review article: Antioxidants and radiation protection in humans
Radiation-induced delayed cell death, genomic instability and the bystander effect In recent years, radiation-injuries have been observed in cells away from those that are irradiated. These include radiation-induced genomic instability, bystander effects, clastogenic factors produced in plasma from irradiated individuals that can cause chromosomal damage when cultured with non-irradiated cells, and transgenerational effects of parental irradiation that can manifest in the progeny [22, 23]. Bystander cells damaged by previous radiation doses may show increased sensitivity to subsequent damage [24]. It is likely that these processes may be important factors in determining the long-term response of populations to ‘‘sub-lethal’’ doses of ionizing radiation [25–29]. These data further complicate the interpretation of any radiation dose–response model for estimating human health risks. Using microbeam technology, it was found that below 200 mGy, the survival potential was dominated by the bystander effect and at higher doses, the direct effect of radiation on cell killing becomes dominant [30, 31]. Below 200 mGy, the response after irradiation of a single cell was not significantly different from the response when all cells were irradiated. This observation is particularly significant, because at low doses certain repair mechanisms are not activated [32]. These results further support the suggestion that no dose of radiation can be insignificant or totally safe.
Effect of interaction of radiation with other carcinogens and cancer protective agents Radiation-induced cancer in humans depends upon several factors. They include interaction with several chemical carcinogens and tumour promoters, anti-carcinogenic and anti-tumour-promoting agents. The efficacy of repair mechanisms also influences the risk of cancer. Some examples of these are given below. X-irradiation enhances chemical carcinogen-induced transformation in normal mammalian cells by about nine-fold [33] and UV-induced transformation by about 12-fold [34]. X-irradiation also enhances the level of ozone-induced [35] and viral-induced [36] transformation in cell culture. Radiation doses that alone do not transform normal fibroblasts, do so when combined with a tumour promoter [37]. Ionizing radiation in combination with tobacco smoking increases the risk of lung cancer by about 50% [5]. A low dose of radiation (2 cGy) does not produce detectable levels of mutations as measured by chromosomal damage; however, in the presence of caffeine (which inhibits repair of DNA damage), mutations become detectable [38]. Low doses of radiation (2 cGy and 5 cGy) can act as a mitogen [39], and even lower doses (about 1 mGy) do not activate double-strand DNA break repair mechanisms [32]. This lack of repair can lead to accumulation of mutations. It has been reported that c-radiation at a dose as little as 1.5 cGy [40], and space radiation doses of 5 cGy or less enhanced the levels of oxidative stress in human cell lines and rats in vivo [41]. At the same time, dietary and endogenously made antioxidants are known to protect tissue against radiation damage [16, 42–44]. Thus, it is nearly impossible to estimate quantitatively the health risks of low doses of radiation alone in the human The British Journal of Radiology, June 2005
population by any dose–response models owing to the above confounding factors. However, the health risks of low doses of radiation cannot be ignored.
Epidemiological studies on cancer risk in children of women exposed to low doses of radiation before and after conception In recent debates, issues of radiation damage to children of women who have been exposed to diagnostic doses of radiation before and after conception have been ignored. Since the number of oocytes may be fixed at birth, radiation damage to oocytes, one of the most radiosensitive cells, may be cumulative, and therefore, may be very crucial for inducing heritable genetic damage. Although radio-epidemiological studies are not considered very reliable, they have addressed these issues in women. Stewart and Kneale [20] have reported that an increase in cancer risk is directly proportional to the number of X-ray films or fetus doses received. It was estimated that 1 cGy delivered to the fetus shortly before birth would cause an increase of 300–800 deaths per million before the age of 10 years due to cancer. A significant increase [19] in malignancy has been found even after 2.0–2.5 mGy to human fetuses (relative incidence of cancer51.25). One of the most surprising results published showed an increased cancer risk by a factor of 1.6–2.0 among the children of women who received diagnostic doses of radiation before conception [45]. Another study [21] reported that diagnostic doses (0.5–7 cGy) to the gonads before conception induced aneuploidy in 10 children (8 mongoloid and 2 trisomy) among 975 exposed women in comparison with 1 aneuploidy case among unexposed women. Gonadal exposure of 5 cGy increased eye defects [46], and of 3 cGy increased the mutation rate by 1% [18]. These epidemiological studies have the same confounding problems in quantifying radiation-induced health risks as discussed with the adults.
Determination of intermediate health risk factors and non-neoplastic diseases in children exposed to low doses of radiation The incidence of non-neoplastic diseases and intermediate health risks measured by certain specific biochemical markers were studied in children living in radiationcontaminated areas near the Chernobyl nuclear accident site. The incidence of thyroid gland enlargement and vision disorders, mostly dry eye syndrome, was closely related to the levels of contamination [47]. Increased levels of oxidized conjugated dienes, products of lipid peroxidation, were found among these children. In another report, increased levels of spontaneous chemiluminescence, an indicator of enhanced oxygen radical activity, in leukocytes of children living in contaminated areas were observed [48]. The accuracy of these intermediate markers for predicting health risks remains unknown.
Concept of maximum permissible dose (MPD) Because of the growing use of nuclear energy in the world, especially in developing countries for civilian and military purposes, and the potential for increased risk of 487
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somatic and heritable mutations owing to increased usage of ionizing radiation, the concept of maximum permissible dose (MPD) was developed for the two major population groups (radiation workers and general population) in order provide a certain degree of safety against radiation damage. The annual MPD value for stochastic-effects (where the probability of the biological effect is proportional to the dose: linear no-threshold effect) for the general population is about 50 times less (1 mSv) than that recommended for radiation workers (50 mSv) [49]. Although the value of MPD for radiation workers for the above effect has remained fairly constant during the last several decades, this value for the population was reduced by a factor of 5 in 1993 [50, 51]. This is due to the emergence of new data on low doses of radiation on somatic and heritable mutations in mammals and in mammalian cells in culture [5, 32, 38, 52], the synergistic effect of the interaction of radiation with other chemical [33, 35] and biological [36] carcinogens and tumour promoters [37] on cancer incidence and mutations, and epidemiological studies in humans [16]. The MPD value is never considered a safe radiation dose, although some may presume it to be the case.
Evolution of radiation protection strategy in humans Efforts to protect normal tissue were started soon after the discovery of X-rays by Dr Roentgen in 1895. However, the observation by Dr Muller of Columbia University in 1927, that radiation causes gene mutations in Drosophila melanogaster (common fruit fly) provided new impetus to reduce radiation exposure. The initial concept of radiation protection involved three physical principles: (a) shielding (usually by lead) of unexposed areas, especially radiosensitive organs such as bone marrow, gonads and thyroid; (b) increased distance between the radiation source and radiation workers or patients; and (c) reduction of exposure time. Each of these factors has been very useful, but they have limitations. For example, during fluoroscopy, it may not be possible to protect the gastrointestinal tract (one of the most radiosensitive organs) against radiation damage by lead shielding. Increasing the distance between the radiation source and recipients may not be practical for many radiation workers, patients, civilian or military personnel. Reducing exposure time may also not be pertinent to all populations, except those that are involved in taking care of patients who have received c-emitting radioisotopes for medical purposes or who are responsible for radioactive decontamination as a result of accidents or attack. To address the growing concerns of radiation-induced somatic and heritable mutations, the concept of as low as reasonably achievable (ALARA) with respect to dose was recommended by national and international radiation protection agencies for radiation workers [53]. Radiation protection based on physical factors has been successful in reducing the level of unnecessary medical exposure to patients and to radiation workers. The development of a novel strategy for biological protection may improve the efficacy of current efforts in reducing the risk of radiation injuries in humans. 488
Search for biological radiation protection Identification of radioprotective agents In order to protect normal tissues from potential radiation damage, it would be important to identify biological or chemical agents which, when given before radiation exposure, could protect all normal tissues. The search for non-toxic radioprotective agents that can protect normal tissue against radiation damage began soon after World War II. Extensive radiobiological research yielded numerous agents which, when given before radiation exposure, protected animals (primarily rodents) against radiation injury [16, 42]. Most widely studied (SH)-compounds like cysteamine, cystamine and aminoethylisothiourea dihydrobromide (AET) and a cysteamine analogue, amifostine, were toxic to humans [16, 42, 54–59].
Potassium iodide as a radioprotective agent The increased use of radioactive iodine (131I) in research, diagnosis and treatment of thyroid diseases, and the release of 131I during nuclear explosion made it imperative that all radiation workers working with 131I take potassium iodide pills. Since iodine selectively accumulates in the thyroid gland, and the thyroid is considered a very radiosensitive organ, it was thought that the intake of potassium iodide would saturate the thyroid gland with iodine, and thus would prevent the accumulation of radioactive iodine in the thyroid. Thus potassium iodide remains a valuable strategy for protecting the thyroid gland against damage produced by radioactive iodine. However, this agent does not protect any other radiosensitive organ against c-radiation that is produced by radioactive iodine. In addition, potassium iodide does not protect against damage produced by other radioactive isotopes or other radiation sources such as X-irradiation or c-irradiation. Therefore, additional non-toxic agents must be identified to protect humans against radiation damage produced by sources other than radioactive iodine.
Multiple antioxidants as radioprotective agents Although earlier identified radioprotective SH-compounds were found to be toxic in humans, glutathioneelevating agents such as N-acetylcysteine (NAC) and alipoic acid, that are non-toxic (within certain concentration ranges) to humans, protect normal tissues against radiation damage [48, 60]. In addition to glutathioneelevating agents, dietary antioxidants such as vitamins E, C and b-carotene are also of radioprotective value [57, 60– 82], but very little attention has been given to these agents with respect to their use in protecting normal tissue against radiation damage in humans. Based on published data on antioxidants and radiation protection, it is possible to develop a non-toxic, cost-effective mixture of antioxidants (dietary and glutathione-elevating agents) that can provide biological protection against radiation damage in humans. Indeed, such formulations, referred to as Bio-Shield, (patent pending) are available commercially (Premier Micronutrient Corporation, Nashville, TN). In vitro animal and human studies that support the rationale of The British Journal of Radiology, June 2005
Review article: Antioxidants and radiation protection in humans
using multiple antioxidants in reducing the risk of radiation damage in humans are described below.
In vitro studies supporting the scientific rationale for using antioxidants for radiation protection in humans It has been reported that mitotic cells, which are most sensitive to radiation, have the lowest levels of SHcompounds, whereas S-phase cells, which are the most resistant to radiation, have the highest levels of these compounds [83]. The role of SH-compounds in radiation protection was further substantiated by the fact that an elevation of the intracellular levels of these compounds in mitotic cells makes them radioresistant to the same level as S-phase cells [83]. It has been shown that vitamin E and selenium reduced radiation-induced transformation in cell culture; the combination was more effective than the individual agents [61, 62]. Natural b-carotene protected against radiation-induced neoplastic transformation in cell culture [63]. Vitamins E and C reduced radiation-induced mutations and chromosomal damage in mammalian cells [64–71], and radiation-induced lethality [69–72].
In vivo (animal) studies supporting the scientific rationale for using antioxidants for radiation protection in humans Alpha-lipoic acid, a glutathione-elevating agent, increases the LD50 in mice with a dose reduction factor (DRF) of 1.26 [84]. Vitamin E, Vitamin C and b-carotene protected rodents against the acute effects of irradiation [70–79]. Vitamin A and b-carotene protected normal tissue during radiation therapy of cancer in an animal model [78]. A combination of vitamin A, C and E protected against radiation-induced myelosuppression during radiation therapy of cancer in an animal model [79]. It has been reported that L-selenomethionine and several different types of antioxidants (vitamin C, vitamin E, glutathione, n-acetylcysteine (NAC), lipoic acid and co-enzyme Q10 and soy bean-derived Bowman-Birk inhibitor) protected human cells in culture and rats in vivo against oxidative stress produced by photons, protons and 1 GeV iron ions [41].
Human studies supporting the scientific rationale for using antioxidants for radiation protection Vitamin A and NAC may be effective against radiationinduced carcinogenesis [60]. Alpha-lipoic acid treatment for 28 days lowered lipid peroxidation among children chronically exposed to low doses of radiation in the area contaminated by the Chernobyl nuclear accident [48]. In another study, b-carotene reduced cellular damage in the above population of children [47]. A combination of vitamin E and a-lipoic acid was more effective than the individual agents [48]. b-carotene also protected against radiation-induced mucositis during radiation therapy of cancer of the head and neck [80]. A combination of dietary antioxidants was more effective in protecting normal tissue during radiation therapy than the individual agents [81, 82]. The British Journal of Radiology, June 2005
Table 1. Estimated doses of ionizing radiation delivered once during various diagnostic procedures Procedure type
Effective dose (mSv)
Chest or dental X-ray Electron-beam CT (cardiac) Electron-beam CT coronary angiography Catheter coronary angiography Electron-beam CT whole body CT (head) CT (abdomen) Barium enema Upper GI examination IV urogram Lumbar spine Mammogram Passenger from Athens to New York Occupational annual dose limit General public annual dose limit Background annual dose at sea level
0.01 1.0–1.3 1.5–2.0 2.1–2.5 5.2 2.0 10.0 7.0 3.0 2.5 1.3 7.0 0.06 50.0 1.0 1.0
Occupational and general public dose limit refers to chronic exposure and does not include background radiation. GI, gastrointestinal; IV, intravenous.
When and how to use multiple antioxidants for radiation protection in humans Commonly used doses in diagnostic procedures are listed in Tables 1 and 2. It is suggested that patients receiving diagnostic radiation doses take orally an appropriately prepared multiple antioxidants pill once 30 min to 60 min before radiation procedure. Radiation workers are advised to keep the body level of antioxidants high at all times by taking the appropriate multiple vitamins with antioxidants, B-vitamins and appropriate minerals, but no iron, copper or manganese. They may take a booster dose antioxidant pill 30 min to 60 min before exposure to higher radiation doses is anticipated. Frequent-flyers may also follow the same dose and dose schedule as radiation workers. The proposed strategy of increasing antioxidant levels in the body can also be implemented in populations living in regions with high background radiation that show increased levels of intermediate risk markers such as increased chromosomal damage or evidence of increased oxidative damage such as lipid peroxidation. Such a strategy may reduce the levels of intermediate risk markers, and thereby, protect against long-term adverse health consequences of radiation exposure among this population. The proposed antioxidant strategy, in addition to potassium iodide, should be adopted in the event of nuclear accident or explosion of a ‘‘dirty bomb’’. The efficacy of antioxidant strategy for biological radiation protection in humans against low Table 2. Estimated doses of radiation from radioactive nuclides administered once during nuclear medicine procedures Procedure type
Effective dose (mSv)
18
4.8 0.60 4.0 0.60
F-Flurodeoxyglucose, 10 mCi Tcm-MAA lung scan, 5 mCi 99 Tcm-HDP bone scan, 20 mCi 201 Tl Thallium scan, 3 mCi 99
MAA, macroaggregated albumin; HDP, hydroxyethylene diphosphonate.
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doses of radiation has not been tested; however, all proposed antioxidant ingredients have exhibited radiation protection in humans and/or in laboratory experiments. Direct experiments with radioprotective antioxidant formulations cannot be performed in humans for obvious ethical reasons. However, implementation of the proposed recommendation may allow prospective studies among radiation workers to determine its efficacy in reducing health risks of low doses of radiation in present and future generations.
Toxicity of antioxidants Dietary antioxidants (vitamins C and E, b-carotene and selenium) and glutathione-elevating agents (NAC and alipoic acid) have been consumed by humans for decades, and within certain dose ranges, no toxicity of these nutrients has been reported. However, higher doses of these nutrients can produce some toxicity. For example, doses of 10 g or more of vitamin C as ascorbic acid can cause upset stomach in some individuals, and may increase the risk of kidney stones after long-term consumption among those who are susceptible to develop this complication. Vitamin E at doses 2000 IU or more after prolonged consumption may induce clotting defects in some individuals. b-carotene at doses of 60 mg or more can induce bronzing of the skin that is reversible after discontinuing its intake. Vitamin A at doses 10 000 IU or more can cause birth defects in pregnant women. Higher doses of vitamin A can cause liver and skin toxicity. NAC at a daily dose of 800 mg can increase the excretion of zinc in the urine. The references for the above studies have been provided in a review [85]. In summary, following the physical principles of radiation protection and the guidelines of ALARA combined with the biological protection provided by multiple antioxidants, may further reduce the health risks of low doses of radiation no matter how small that risk might be.
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