MICRONUTRIENT FORMULATIONS FOR ENVIRONMENTAL EXPOSURE APPLICATIONS

Abstract

A radioactive protection micronutrient formulation system is provided and the system comprises: a formulation consisting essentially of antioxidants, the antioxidants are selected from the group consisting essentially of vitamin C, vitamin E, N-acetyl cysteine, natural mixed carotenoids, and alpha-lipoic acid, vitamin A (palmitate), vitamin D-3 (cholecalciferol), thiamine mononitrate, riboflavin, niacinamide ascorbate, d-calcium pantothenate, pyridoxine hydrochloride, cyanocobalamin, folic acid, D-Biotin, selenium (1-seleno-methionine), chromium picolinate, zinc glycinate, calcium citrate and magnesium citrate and mixtures thereof; and plus a booster formulation selected from a group consisting essentially of vitamin C, d-alpha tocopheryl acid succinate, alpha tocopherol, N-acetyl cysteine, natural mixed carotenoids and alpha lipoic acid, the formulation is designed to reduce the risk in humans exposed to doses of ionizing radiation of becoming subjected to at least one condition selected from the group consisting essentially of radiation-induced acute leukemia, breast cancer, thyroid cancer and other somatic and heritable mutations.

Claims

1. A formulation consisting essentially of antioxidants, said antioxidants are selected from the group consisting essentially of Vitamin A, Vitamin C, Vitamin E, L-cysteine, N-acetylcysteine, R-alpha-lipoic acid, Selenium, Natural mixed carotenoids and mixtures thereof.

2. The formulation of claim 1 wherein said the formulation comprises at least one glutathione elevating agent.

3. The formulation of claim 1 wherein a dosage level of antioxidants is proportionate to the radiation level exposed to by a human.

4. The formulation of claim 1 wherein said formulation is designed for a human who exposed to an effective dose of ionizing radiation of 0.5 mSv or less, radon, smoking, biological agents, or radiation.

5. The formulation of claim 1 wherein said formulations is for health care, aviation, military, and government employees.

5. The formulation of claim 4 wherein the antioxidants consist essentially of 5,000 IU of Vitamin A, 500 mg of vitamin C, 400 international units of d-alpha tocopheryl acid succinate, 200 mg of L-cyteine, 30 mg of R-alpha-lipoic acid, and 250 mg of N-acetyl cysteine, 100 mcg of Selenium, and 15 mg of natural mixed carotenoids.

6. The formulation of claim 1 wherein said formulation is designed for a human who is consistently exposed to an effective dose of ionizing radiation of 0.5-5 mSv, radon, smoking, occupational chemicals, pesticides, cellular phone technology, air pollution and biological agents.

7. The formulation of claim 6 wherein the antioxidants consist essentially of 3,00 IU of Vitamin A, 1,000 mg of buffered vitamin C, 400 international units of d-alpha tocopheryl acid succinate, 200 mg of L-cysteine, 250 mg of N-acetyl cysteine, 800 IU of Vitamin D, 4 mg of Vitamin B1, 5 mg of Vitamin B2, 30 mg of Vitamin B3, 5 mg of Vitamin B6, 800 mcg of Folic acid, 10 mcg of Vitamin B12, 200 mcg of Biotin, 10 mg or Pantothenic acid, 250 mg calcium, 125 mg of Magnesium, 15 mg of Zinc, 200 mcg of Selenium, 50 mcg of Chromium, 30 mg R-alpha-lipoic acid, 100 mg of L-carnitine, and 15 mg of natural mixed carotenoids.

8. The formulation of claim 1 wherein said formulation is designed for a human who receives an effective dose of ionizing radiation of 5-250 mSv, nuclear accidents, terror attacks, or potentially lethal doses of radiation.

9. The formulation of claim 8 wherein said antioxidants consist essentially of 3,00 IU of Vitamin A, 1,000 mg of buffered vitamin C, 400 international units of d-alpha tocopheryl acid succinate, 200 mg of L-cysteine, 250 mg of N-acetyl cysteine, 800 IU of Vitamin D, 4 mg of Vitamin B1, 5 mg of Vitamin B2, 30 mg of Vitamin B3, 5 mg of Vitamin B6, 800 mcg of Folic acid, 10 mcg of Vitamin B12, 200 mcg of Biotin, 10 mg or Pantothenic acid, 250 mg calcium, 125 mg of Magnesium, 15 mg of Zinc, 200 mcg of Selenium, 50 mcg of Chromium, 30 mg R-alpha-lipoic acid, 100 mg of L-carnitine, and 15 mg of natural mixed carotenoids.

10. The formulation of claim 1 wherein said antioxidants consist essentially of: TABLE-US-00028 Vitamin A (retinyl palmitate, fish oil or natural 500-5,000 IU mixed carotenoids) Vitamin C (calcium ascorbate, citrus, rose or berry 50-500 mg products) Vitamin E (d-alpha tocopheryl succinate and/or 50-400 IU d-alpha tocopherol, vegetable or wheat germ products or natural tocopheryl) L-cysteine (or natural food sources-e.g. soy 0.01-300 mg extracts, sesame or flaxseeds, oat bran, wheat germ, Swiss cheese, peas or whole grain extracts) N-acetylcysteine 0.01-250 mg R-alpha-lipoic acid (R+, R, yeast or liver 5-60 mg sources) Selenium (L-selenomethionine, sodium selenite/ 25-300 mcg selenate or natural forms) Natural mixed carotenoids (sea, algal, plant or 0.01-45 mg other natural sources)

11. The formulation of claim 1 further consisting essentially of Vitamin D, Vitamin B1, Vitamin B2, Vitamin B3, Vitamin B6, Folic Acid, Vitamin B12, Biotin, Pantothenic acid, Calcium, Magnesium, Zinc, Selenium, Chromium, Coenzyme Q10, L-carnetine, and mixtures thereof.

12. The formulation of claim 11 wherein said antioxidants consist essentially of: TABLE-US-00029 Vitamin D (cholecalciferol-D3 or fish oils) 100-4000 IU Vitamin B1 (thiamine mononitrate or yeast 1-10 mg sources) Vitamin B2 (riboflavin or yeast sources) 1-20 mg Vitamin B3 (niacinamide, nicotinic acid, 1-100 mg nicotinamide or yeast sources) Vitamin B6 (pyridoxine or yeast sources) 1-50 mg Folic acid (folate, yeast or liver source) 100-2,000 mcg Vitamin B12 (cyanocobalamin, methylcobalamin 1-50 mcg or yeast sources) Biotin (d-biotin or liver sources) 50-600 mcg Pantothenic acid (d-calcium pantothenate, rice 1-50 mg bran, yeast or liver sources) Calcium (citrate, ascorbate, lactate or plant based 50-1,000 mg sources) Magnesium (citrate, lactate, gluconate, oxide, 25-500 mg carbonate, hydroxide, chloride, sulphate, lactic acid, Jay phosphate, tribasic phosphate or natural forms) Zinc (glycinate, gluconate, oxide, sulphate or 2-45 mg natural forms) Selenium (L-selenomethionine, sodium selenite/ 25-300 mcg selenate or natural forms) Chromium (picolinate, chromic chloride or natural 10-200 mcg forms) Coenzyme Q10 (ubiquinone, organ meat or natural 0.01-100 mg ingredient sources-e.g. Agrobacterium tumefaciens, Paracoccus denitrificans or Pseudomonas aeruginosa) L-carnitine (fumarate or natural forms) 20-400 mg

13. A method of manufacturing a formulation, said method comprising admixing antioxidants, said antioxidants consist essentially of: TABLE-US-00030 Vitamin A (retinyl palmitate, fish oil or natural 500-5,000 IU mixed carotenoids) Vitamin C (calcium ascorbate, citrus, rose or berry 50-500 mg products) Vitamin E (d-alpha tocopheryl succinate and/or 50-400 IU d-alpha tocopherol, vegetable or wheat germ products or natural tocopheryl) L-cysteine (or natural food sources-e.g. soy 0.01-300 mg extracts, sesame or flaxseeds, oat bran, wheat germ, Swiss cheese, peas or whole grain extracts) N-acetylcysteine 0.01-250 mg R-alpha-lipoic acid (R+, R, yeast or liver sources) 5-60 mg Selenium (L-selenomethionine, sodium selenite/ 25-300 mcg selenate or natural forms) Natural mixed carotenoids (sea, algal, plant or 0.01-45 mg other natural sources)

14. The method of claim 13 wherein a dosage level of antioxidants is proportionate to the radiation level exposed to by a human.

15. A method of manufacturing the formulation of claim 14, said method comprising admixing antioxidants, said antioxidants consist essentially of: TABLE-US-00031 Vitamin D (cholecalciferol-D3 or fish oils) 100-4000 IU Vitamin B1 (thiamine mononitrate or yeast 1-10 mg sources) Vitamin B2 (riboflavin or yeast sources) 1-20 mg Vitamin B3 (niacinamide, nicotinic acid, 1-100 mg nicotinamide or yeast sources) Vitamin B6 (pyridoxine or yeast sources) 1-50 mg Folic acid (folate, yeast or liver source) 100-2,000 mcg Vitamin B12 (cyanocobalamin, methylcobalamin 1-50 mcg or yeast sources) Biotin (d-biotin or liver sources) 50-600 mcg Pantothenic acid (d-calcium pantothenate, rice 1-50 mg bran, yeast or liver sources) Calcium (citrate, ascorbate, lactate or plant based 50-1,000 mg sources) Magnesium (citrate, lactate, gluconate, oxide, 25-500 mg carbonate, hydroxide, chloride, sulphate, lactic acid, Jay phosphate, tribasic phosphate or natural forms) Zinc (glycinate, gluconate, oxide, sulphate or 2-45 mg natural forms) Selenium (L-selenomethionine, sodium selenite/ 25-300 mcg selenate or natural forms) Chromium (picolinate, chromic chloride or 10-200 mcg natural forms) Coenzyme Q10 (ubiquinone, organ meat or 0.01-100 mg natural ingredient sources-e.g. Agrobacterium tumefaciens, Paracoccus denitrificans or Pseudomonas aeruginosa) L-carnitine (fumarate or natural forms) 20-400 mg

16. The method of claim 15 wherein a dosage level of antioxidants is proportionate to the radiation level exposed to by a human.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0105] The accompanying drawings are included to provide a further understanding of the present invention. These drawings are incorporated in and constitute a part of this specification, illustrate one or more embodiments of the present invention and together with the description, serve to explain the principles of the present invention.

[0106] FIGS. 1A and 1B shows immune function of participants in study taking supplements; and

[0107] FIG. 2 is a summary of the average value of MDA levels in plasma and urine as well as TLT in participants n the study.

[0108] FIG. 3 Lung damage in rabbits exposed to CNS syndrome-causing radiation dose (9.011Gy).

[0109] Among those benefits and improvements that have been disclosed, other objects and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying drawings. The drawings constitute a part of this specification and include exemplary embodiments of the present invention and illustrate various objects and features thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0110] As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various forms. The examples disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention.

[0111] Although brief medical x-rays themselves may not cause detectable damage, serial imaging, future screening studies (the importance of which cannot be currently predicted), flight exposures, military operations exposures, occupational exposures, and other factors, such as diet, disease status, and environmental exposure, and the like may be clinically significant.

[0112] Relevant findings from basic scientific studies underscore this clinical concern. For example, a dose of 2 rem does not cause detectable mutations in normal human lymphocytes in culture. However, if the cells are irradiated with the same dose and treated with caffeine for a few hours after radiation exposure, an increased rate of cellular mutations is observed. This suggests that radiation-induced changes could be repaired in the normal course of events, but that subsequent exposure to caffeine impairs this normal cellular protective mechanism. In addition, a radiation dose that by itself would not be sufficient to induce cancer in an in vitro experimental system is able to do so in the presence of tumor promoters, such as phorbol ester, estrogen, and others. Furthermore, x-rays increase the incidence of cancer in cell culture by several folds when combined with chemical carcinogens, certain DNA viruses, ultraviolet radiation, or ozone exposure. Clearly, the potential hazard of even small radiation doses should not be ignored, since the target population readily interacts with agents present in the diet and environment, as well as other factors present in individual lifestyles.

Risk Categories

[0113] The following risk categories are general guidelines only and refer to acute exposures. The examples listed are not totally inclusive. The actual risk for any particular person may be modified by age and health status. The actual designation for all persons should be determined by healthcare or radiation physics professionals.

[0114] Population groups experiencing chronic radiation exposure risk, such as radiation workers (including commercial and military flight crews and field combat personnel), should maintain a higher baseline antioxidant load by taking a multiple antioxidant formulation (SEVAK) two times a day. They should then take the appropriate radioprotective formulation when the acute risk of exposure is expected (daily necessary). Categories 2-4 are equivalent with respect to formulation and can be regarded to be adequate for exposures less than 15 sMv effective dose when used for acute exposures only.

Category 1: Effective Dose 0.5 mSv or Less

[0115] For example: chest x-ray, dental x-ray, abdominal x-ray, skeletal plain films, most commercial flight passengers.

Category 2: Effective Dose 0.5-5 mSv

[0116] For example: diagnose/screening computed tomography, urologic imaging, mammography, flight crews (commercial and military) and other radiation workers.

Category 3: Internal Radionuclide Exposures

[0117] For example: radionuclide imaging.

Category 4: Effective Dose 5-15 mSv

[0118] For example: limited diagnostic fluoroscopy (upper GI series, cholangiography, brain enema).

Category 5: Effective Dose Greater than 15 mSv-250 mSv

[0119] For example: prolonged fluoroscopy/interventional radiology (coronary angiography, cerebral angiography, transluminal angioplasty) and some military personnel in combat operations (ground troops and seamen).

Category 6: Effective Dose 1000-2000 mSv

[0120] For example: radiation workers, civilian populations at risk near nuclear reactor sites in the event of an accident, and at risk military personnel in overseas theatres of operation.

Category 7: Effective Dose Greater than 2000 mSv (not Exceeding Bone Marrow Syndrome Doses)

[0121] For example: radiation workers, civilian populations at risk near nuclear sites in the event of an accident, and at risk military personnel in overseas theatres of operation.

[0122] Hereinafter, the term imaging study will be employed to include chest x-ray, dental x-ray, abdominal x-ray, skeletal plain films, diagnostic/screening computed tomography, urologic imaging, mammography, radionuclide imaging, limited diagnostic fluoroscopy, prolonged fluoroscopy/interventional radiology and the like.

[0123] The specific example below will enable the invention to be better understood. However, they are given merely by way of guidance and do not imply any limitation.

Example 1: Baseline Formulation (SEVAK)

[0124]

TABLE-US-00013 Vitamin A (palmitate) 5,000 I.U. Natural mixed carotenoids 15 mg Vitamin D-3 (cholecalciferol) 400 I.U. Natural source Vitamin E (d-alpha tocopherol) 100 I.U. (d-alpha tocopheryl acid succinate) 100 I.U. Buffered Vitamin C (calcium ascorbate) 500 mg Thiamine mononitrate 4 mg Riboflavin 5 mg Niacinamide ascorbate 30 mg d-calcium pantothenate 10 mg Pyridoxine hydrochloride 5 mg Cyanocobalamin 10 g Folic acid (Folacin) 800 g D-Biotin 200 g Selenium (1-seleno methionie) 100 g Chromium picolinate 50 g Zinc glycinate 15 mg Calcium citrate 250 mg Magnesium citrate 125 mg

Radioprotective Formulations: (Boost Formulations)

Example 2: For Category 1 Personnel

[0125]

TABLE-US-00014 Vitamin C (calcium ascorbate) 250 mg Natural source vitamin E 200 I.U. (d-alpha tocopheryl acid succinate) N-acetyl cysteine 250 mg Complete dosage to be taken 1 hour prior to an imaging study.

Example 3: For Category 2 Personnel

[0126]

TABLE-US-00015 Vitamin C (calcium ascorbate) 500 mg Natural source vitamin E 400 I.U. (d-alpha tocopheryl acid succinate) N-acetyl cysteine 250 mg Natural mixed carotenoids 15 mg Alpha lipoic acid 30 mg Complete dosage to be taken 1 hour prior to an imaging study or prior to each flight.

Example 4: For Category 3 Personnel

[0127]

TABLE-US-00016 Vitamin C (calcium ascorbate) 500 mg Natural source vitamin E 400 I.U. (d-alpha tocopheryl acid succinate) N-acetyl cysteine 250 mg Natural mixed carotenoids 15 mg Alpha lipoic acid 30 mg Complete dosage to be taken 1 hour prior to an imaging study and 24 hours and 48 hours after the imaging study.

Example 5: For Category 4 Personnel

[0128]

TABLE-US-00017 Vitamin C (calcium ascorbate) 500 mg Natural source vitamin E 400 I.U. (d-alpha tocopheryl acid succinate) N-acetyl cysteine 250 mg Natural mixed carotenoids 15 mg Alpha lipoic acid 30 mg Complete dosage to be taken 24 hours and 1 hour prior to an imaging study 24 hours after the imaging study.

Example 6: For Category 5 Personnel

[0129]

TABLE-US-00018 Vitamin C (calcium ascorbate) 500 mg Natural source vitamin E 400 I.U. (d-alpha tocopheryl acid succinate) N-acetyl cysteine 500 mg Natural mixed carotenoids 30 mg Alpha lipoic acid 60 mg Complete dosage to be taken 48 hours, 24 hours and 1 hour prior to an imaging study 24 hours after the imaging study.

Example 7: For Category 6 Personnel

[0130]

TABLE-US-00019 Vitamin C (calcium ascorbate) 1000 mg d-alpha tocopheryl acid succinate 400 I.U. alpha tocopherol 200 I.U. N-acetyl cysteine 500 mg Natural mixed carotenoids 40 mg Alpha lipoic acid 100 mg Complete dosage to be taken prior to anticipated exposure or as soon as possible after actual exposure. Continue complete dosage daily for seven days after exposure.

Example 8: For Category 7 Personnel

[0131]

TABLE-US-00020 Vitamin C (calcium ascorbate) 2000 mg d-alpha tocopheryl acid succinate 600 I.U. alpha tocopherol 200 I.U. N-acetyl cysteine 1000 mg Natural mixed carotenoids 50 mg Alpha lipoic acid 150 mg Complete dosage to be taken prior to anticipated exposure or as soon as possible after actual exposure. Continue complete dosage daily for seven days after exposure.

[0132] It has been estimated that approximately 70-80% of the cellular damage induced by ionizing radiation is caused by free radicals. Therefore, it would be prudent to use agents that would quench these substances formed during x-ray exposure and protect the cells, organs, and total body from such injury.

[0133] Since World War II, extensive studies have been undertaken to identify radioprotective compounds that have been shown to be effective when administered before exposure to irradiation. It is important to note that such compounds do not protect cells or organisms if they are administered after the ionizing radiation exposure. For modest radiation dose levels, the protective agents can be absorbed rapidly enough that they could be effective when given immediately before the exposure (within an hour or two). For enough levels of radiation dosage, it might be more desirable to achieve an established steady state of antioxidant concentration in the tissues initially, an then provide a booster dose of radioprotective agent immediately prior to exposure.

[0134] Research has determined that sulfhydryl (SH) compounds such as cysteamine, cystamine, and glutathione are among the most important and active intracellular antioxidants. Cysteamine protects animals against bone marrow and gastrointestinal radiation syndromes. The rationale for the importance of SH compounds is further supported by observations in mitotic cells. These are the most sensitive to radiation injury in terms of cell reproductive death and are noted to have the lowest level of SH compounds. Conversely, S-phase cells, which are the most resistant to radiation injury using the same criteria, have demonstrated the highest levels of inherent SH compounds. In addition, when mitotic cells were treated with cysteamine, they became very resistant to radiation. It has also been noted that cysteamine may directly protect cells against induced mutations. Unfortunately, cysteamine is extremely toxic when administered to human beings and, therefore, cannot itself be utilized in a radioprotective antioxidant regimen.

[0135] Thus, other SH compounds sharing the same antioxidant characteristics must be considered. Glutathione is a very effective antioxidant. However, when ingested by human beings it is completely hydrolyzed in the intestine and, therefore, can not be used as a radioprotective agent. However, N-acetylcysteine (NAC) and alpha lipoic acid actively increase the intracellular levels of glutathione without causing any toxicity. These rapidly absorbed compounds are tolerated by humans very well and would provide protection against ionizing radiation damage when given prior to the exposure. Indeed, these agents have also been shown to be of radioprotective value in experimental systems. Additional antioxidants such as vitamin E (d-alpha tocopheryl succinate), vitamin C (as calcium ascorbate) and the carotenoids (particularly natural beta-carotene) have been shown to be of marked radioprotective value in animals and in humans. A very recent report by the Armed Forces Radiobiology Research Institute showed good protection by vitamin E against lethal doses of cobalt-60 in mice.

[0136] The natural beta-carotene was selected because it most effectively reduces radiation-induced transformation in mammalian cells in culture. The d-alpha tocopheryl succinate form of vitamin E was selected because it is the most effective form of this micronutrient and also actively reduces the incidence of radiation-induced transformation in mammalian cells. This form of vitamin E is a more effective antioxidant than the more commonly utilized alpha tocopherol or other mixtures of tocopherols. Vitamin C as calcium ascorbate is beneficial because it is the most effective nonacidic form available for human use and, therefore, is less likely to cause stomach upset, diarrhea, and other problems that are observed in some individuals when taking therapeutic doses of vitamin C.

[0137] The most effective antioxidant approach to the free radical damage related to ionizing radiation-induced injury must utilize multiple micronutrients. It has been determined that multiple antioxidants are more effective than the individual agents themselves, and we propose this approach for several reasons. It is known that vitamin C and vitamin E are synergistic as antioxidants against free radicals because they are able to protect both the aqueous and lipid environments of the cells respectively. Indeed, one study has shown that oral intake of both vitamin C and vitamin E reduces the levels of fecal mutagens formed during digestion more than that produced by either of the individual antioxidants. It also must be recognized that oxygen level may vary widely within the tissues of whole organs or within the individual cells. This is especially true during the biologic insults that may occur with radiation-induced damage. It is known that beta-carotene acts more effectively as an antioxidant in high oxygen pressures, whereas vitamin E is a more effective antioxidant at reduced oxygen pressures.

[0138] Finally the body produces several types of free radicals (a myriad of oxygen-derived and nitrogen-derived species) during exposure to ionizing radiation. Clearly, each antioxidant has a different affinity for each specific class of free radicals. In a parallel manner, a combination of antioxidants is more effective in reducing the growth of tumor cells than the individual agents themselves. Therefore, to provide the most effective overall micronutrient approach to protect against radiation injury, a multiple component protocol utilized with a risk-based strategy seems essential and rational.

[0139] Most commercially available multiple supplement formulations contain iron, copper, and/or manganese. It is well known that these substances actively generate free radicals when combined with vitamin C. In addition, these minerals are more easily absorbed from the intestinal tract in the presence of antioxidants, such as vitamin C, and thereby increase the body stores of these minerals. Increased iron stores have been associated with many chronic human conditions, including heart disease, cancer and neurological diseases. Therefore, the addition of iron, copper or manganese to any multiple antioxidant preparation has no scientific merit for optimal health or disease prevention. Only in cases where a person has iron-deficiency anemia is a short-term iron supplement essential.

[0140] Many commercially available preparations contain heavy metals such as boron, vanadium, zirconium and molybdenum. Sufficient amounts of these metals are obtained from the diet and the daily consumption of excess amounts over long periods of time can be neurotoxic.

[0141] Many commercial preparations contain inositol, methionine and choline in varying amounts, e.g., 30 mg to 60 mg. These small doses serve no useful purpose for improving health because 400 mg to 1,000 mg of these nutrients are obtained daily from even the most minimal diet.

[0142] Para-aminobenzoic acid (PABA) is present in some multiple vitamin preparations. PABA has no biologic function in mammalian cells and can block the antibacterial effect of sulfonamides. Therefore, the effectiveness of a sulfonamide may be reduced in some patients being treated for bacterial infection.

[0143] Commercially sold multiple antioxidant preparations often contain varying amounts of N-acetyl cysteine or alpha lipoic acid. These nutrients are utilized because they are known to increase glutathione levels in cells. Reduced glutathione is a powerful antioxidant and actively protects both normal and cancer cells against radiation damage. Many cancer patients take antioxidant supplements without the knowledge of their oncologists. Therefore, the consumption of antioxidant preparations containing N-acetyl cysteine or alpha lipoic acid by these patients undergoing radiation therapy could interfere with important anti-cancer treatment.

[0144] The addition of both natural mixed carotenoids and vitamin A to any multiple vitamin preparation is essential, because beta-carotene not only acts as a precursor of vitamin A, but also performs important biological functions that cannot be performed by vitamin A. Beta-carotene increases the expression of the connexin gene, which codes for a gap junction protein that is necessary for maintaining the normal cellular phenotype. While other carotenoids, such as, lycopene, xanthophylls, and lutein, are also important for health, they can be obtained from an adequate diet with tomato (lycopene), spinach (lutein), and paprika (xanthophylls) in amounts are higher than those that can be supplied from supplements. Therefore, the addition of a few milligrams of lycopene, xanthophylls, and lutein to any multiple vitamin preparation serves no useful purpose for health or disease prevention.

[0145] The proper ratio of two forms of vitamin E, d-alpha tocopherol, which is normally present in the body, and d-alpha succinate, to a multiple antioxidant preparation is essential. Alpha tocopheryl succinate is the most effective form of vitamin E inside the cells, where as alpha tocopherol can readily act as an antioxidant in the intestinal tract and in the extracellular environment of the body. Alpha-tocopherol at doses of 20-60 g/ml can stimulate the immune system, while the beta, gamma, and delta forms at similar doses can inhibit the immune system. This effect of these forms of tocopherol may not be related to their antioxidant action and, since they are less effective than alpha tocopherol, their supplementation is not recommended.

[0146] Tocotrienols are also antioxidants, but they may inhibit cholesterol synthesis. Since this activity is not beneficial in healthy individuals, prolonged consumption of tocotrienols as a supplement is not optimal.

[0147] Vitamin C is usually administered as ascorbic acid, which can cause stomach upset, diarrhea and other complications in some individuals. However, using the calcium ascorbate form is most suitable because it is non-acidic and has not been shown to produce negative side effects. The use of potassium ascorbate and magnesium ascorbate in any vitamin preparation is unnecessary. Also, any multiple micronutrient preparation should include adequate amounts of B-vitamins (2-3 times of RDA) and appropriate minerals.

[0148] The risk of chronic illness may depend upon the relative consumption of protective versus toxic substances. If the daily intake of protective substances is higher than toxic agents, the incidence of chronic illness may be reduced. Since we know very little about the relative levels of toxic and protective substances in any diet, a daily supplement of micronutrients including antioxidants would assure a higher level of preventive protection.

[0149] The present invention also provides for the following formulation examples:

Example 9: BioshieldR1 in Two Capsules

[0150]

TABLE-US-00021 Vitamin C (calcium ascorbate) 500 mg d-alpha tocopheryl succinate 400 IU Natural mixed carotenoids 15 mg Selenomethionine 100 mcg n-acetylcysteine 250 mg Alpha-lipoic acid 30 mg

Example 10: BioshieldR2 in Four Capsules Daily

[0151]

TABLE-US-00022 Vitamin A (as palmitate) 5,000 Vitamin C (as calcium ascorbate) 1,000 mg Vitamin E (as d-alpha-tocpheryl succinate) 200 IU (as d-alpha-tocopherol) 200 IU Vitamin D (as cholocalciferol) 400 IU Vitamin B-1 (thiamine mononitrate) 4 mg Vitamin B-2 (riboflavin) 5 mg Niacin (as niacinamide ascorbate) 30 mg Vitamin B-6 (as pyrodioxine HCl) 5 mg Folate (Folic acid) 800 mcg Vitamin B-12 (as cyanocobalamin) 10 mg Biotin 200 mcg Pantothenic acid (as d-calcium pantothenate) 10 mg Calcium citrate 250 mg Magnesium citrate 125 mg Zinc (as zinc glycinate) 15 mg Selenium (as selenomethionine) 200 mcg Chromium (as chromium picolinate) 50 mcg Coenzyme Q10 30 mg N-acetylcysteine 250 mg Alpha-lipoic acid 30 mg Natural mixed carotenoids 15 mg

Example 11: BioshieldR3 in Six Capsules/Daily

[0152]

TABLE-US-00023 Vitamin A (as palmitate) 5,000 Vitamin C (as calcium ascorbate) 1,000 mg Vitamin E (as d-alpha-tocpheryl succinate) 400 IU (as d-alpha-tocopherol) 200 IU Vitamin D (as cholocalciferol) 400 IU Vitamin B-1 (thiamine mononitrate) 4 mg Vitamin B-2 (riboflavin) 5 mg Niacin (as niacinamide ascorbate) 30 mg Vitamin B-6 (as pyrodioxine HCl) 5 mg Folate (Folic acid) 800 mcg Vitamin B-12 (as cyanocobalamin) 10 mg Biotin 200 mcg Pantothenic acid (as d-calcium pantothenate) 10 mg Calcium citrate 250 mg Magnesium citrate 125 mg Zinc (as zinc glycinate) 15 mg Selenium (as selenomethionine) 200 mcg Chromium (as chromium picolinate) 50 mcg Coenzyme Q10 30 mg N-acetylcysteine 500 mg Alpha-lipoic acid 90 mg Natural mixed carotenoids 60 mg

[0153] The formulation of claim 1 BioShield E1 is designed for humans who are or may be episodically exposed to radon, smoking, biological agents, or are workers in health care, military, government or aviation, including frequent flyers. It may also be appropriate for proactive consumers who utilize emergency survivor kits. In addition, the formulation has relevance for people receiving chest x-rays, dental x-rays, abdominal x-rays, skeletal plain films, computed tomography (CT) scanning, urologic imaging, and mammography; radionuclide imaging, diagnostic fluoroscopy (upper GI series, cholangiography, barium enema), or prolonged fluoroscopy/interventional radiology (coronary angiography, cerebral angiography and transluminal angioplasty).

[0154] For humans who may be episodically exposed, the ideal primary dosing schedule consists of one dose consumed orally one to two hours prior to the anticipated exposure. For medical and dental imaging, such as chest x-rays, dental x-rays, abdominal x-rays, skeletal plain films, CT scanning, urologic imaging, or mammography, the primary dosing schedule consists of one dose administered orally from 30 minutes to one hour before the study. The maintenance dosing schedule consists of from one oral dose 2-4 hours after the study to twice daily oral doses for 14 days. Those who are frequent flyers should take one oral dose of BioShield E1 from 30 minutes to two hours before takeoff and another dose 4-6 hours after reaching destination.

[0155] For humans who receive radionuclide imaging or prolonged fluoroscopy/interventional radiology (coronary angiography, cerebral angiography and transluminal angioplasty), the primary dosing schedule consists of one dose administered orally from 30 minutes to one hour before the study. The maintenance dosing schedule consists of from one oral dose 2-4 hours after the study and twice a day (morning and evening) for a 5-day period after the study, up to a total of 14 days after the study, depending on the half-life of the radionuclide employed for the procedure.

[0156] For humans who receive diagnostic fluoroscopy (upper GI series, cholangiography, barium enema), the primary dosing schedule consists of one dose administered orally from 30 minutes to one hour before the study. The maintenance dosing schedule consists of from one oral dose 2-4 hours after the study and twice a day (morning and evening) for from a 2-day period after the study, up to a total of 14 days after the study.

[0157] The formulations for Bioshield E1 are as follows:

Formulation for Adults, Ages 14 and Older, Consisting Essentially of:

[0158]

TABLE-US-00024 primary dose Vitamin A (retinyl palmitate, fish oil or natural mixed 5,000 IU carotenoids) Vitamin C (calcium ascorbate, citrus, rose or berry 500 mg products) Vitamin E (d-alpha tocopheryl succinate and/or d-alpha 400 IU tocopherol, vegetable or wheat germ products or natural tocopheryl) L-cysteine (or natural food sources-e.g. soy extracts, 200 mg sesame or flaxseeds, oat bran, wheat germ, Swiss cheese, peas or whole grain extracts) N-acetylcysteine 250 mg R-alpha-lipoic acid (R+, R, yeast or liver sources) 30 mg Selenium (L-selenomethionine, sodium selenite/selenate 100 mcg or natural forms) Natural mixed carotenoids (sea, algal, plant or other 15 mg natural sources)

Formulation for Children (4-13 Years of Age) Consisting Essentially of:

[0159]

TABLE-US-00025 primary dose Vitamin A (retinyl palmitate, fish oil or natural 2,500 IU mixed carotenoids) Vitamin C (calcium ascorbate, citrus, rose or berry 150 mg products) Vitamin E (d-alpha tocopheryl succinate and/or 100 IU d-alpha tocopherol, vegetable or wheat germ products or natural tocopheryl) L-cysteine (or natural food sources-e.g. soy extracts, 100 mg sesame or flaxseeds, oat bran, wheat germ, Swiss cheese, peas or whole grain extracts) N-acetylcysteine 50 mg R-alpha-lipoic acid (R+, R, yeast or liver sources) 15 mg Selenium (L-selenomethionine, sodium selenite/ 50 mcg selenate or natural forms) Natural mixed carotenoids (sea, algal, plant or other 5 mg natural sources)

[0160] The formulation of BioShield E2 is designed for individuals who are workers in or reside near the area of radiation equipment, such as x-ray or gamma-ray machines, nuclear plants, or other technology operated by nuclear power, flight crews (pilots and flight attendants), government installations and military personnel, health care and those who are consistently exposed to radon, smoking, occupational chemicals, pesticides, cellular phone technology, air pollution and biological agents. It is also relevant for proactive consumers who utilize emergency survival kits.

[0161] For individuals who are occupationally or consistently exposed to these environments, the primary dosing schedule consists of one dose consumed orally twice a day (morning and evening) for the entire lifespan. In some circumstances of particularly high chronic exposure levels, it may be appropriate for certain individuals to additionally consume the supplemental booster list of compounds listed with the BioShield E3 formulation.

[0162] The formulation2 for Bioshield E2 is as follows:

Environmental-Daily, E2 Formulation for Adults, Ages 14 and Older

[0163]

TABLE-US-00026 primary dose Vitamin A (retinyl palmitate, fish oil or natural mixed 3,000 IU carotenoids) Vitamin C (calcium ascorbate, citrus, rose or berry 1,000 mg products) Vitamin E (equally d-alpha tocopheryl succinate and 400 IU d-alpha tocopherol acetate, vegetable or wheat germ products or natural tocopheryl) L-cysteine (or natural food sources-e.g. soy extracts, 200 mg sesame or flaxseeds, oat bran, wheat germ, Swiss cheese, peas or whole grain extracts) N-acetylcysteine 250 mg Vitamin D (cholecalciferol-D3 or fish oils) 800 IU Vitamin B1 (thiamine mononitrate or yeast sources) 4 mg Vitamin B2 (riboflavin or yeast sources) 5 mg Vitamin B3 (niacinamide, nicotinic acid, nicotinamide 30 mg or yeast sources) Vitamin B6 (pyridoxine or yeast sources) 5 mg Folic acid (folate, yeast or liver source) 800 mcg Vitamin B12 (cyanocobalamin, methylcobalamin or 10 mcg yeast sources) Biotin (d-biotin or liver sources) 200 mcg Pantothenic acid (d-calcium pantothenate, rice bran, 10 mg yeast or liver sources) Calcium (citrate, ascorbate, lactate or plant based 250 mg sources) Magnesium (citrate, lactate, gluconate, oxide, 125 mg carbonate, hydroxide, chloride, sulphate, lactic acid, Jay phosphate, tribasic phosphate or natural forms) Zinc (glycinate, gluconate, oxide, sulphate or natural 15 mg forms) Selenium (L-selenomethionine, sodium selenite/ 200 mcg selenate or natural forms) Chromium (picolinate, chromic chloride or natural 50 mcg forms) Coenzyme Q10 (ubiquinone, organ meat or natural 30 mg ingredient sources-e.g. Agrobacterium umefaciens, Paracoccus denitrificans or Pseudomonas aeruginosa) R-alpha-lipoic acid (R+, R, yeast or liver sources) 30 mg L-carnitine (fumarate or natural forms) 100 mg Natural mixed carotenoids (sea, algal, plant or other 15 mg natural sources)

[0164] No iron, copper or manganese would be included because these trace minerals are known to interact with vitamin C to produce free radicals. These minerals are also absorbed more readily from the intestinal tract in the presence of antioxidants, and this could result in potentially harmful increased body stores of unbound minerals.

[0165] BioShield E3 is recommended for individuals exposed to high, or potentially lethal doses of hazardous environments (e.g. pollution levels, biological agents, space travel, government, military) or those related to unexpected events, such as nuclear accidents (e.g. Chernobyl nuclear power plant leak, Russia, 1986; Fukushima Daiichi nuclear power plant weather-related damage, Japan, 2011) or deliberate terrorist attacks. In ionizing radiation exposure, these doses are associated with development of acute radiation sickness (ARS), represented by bone marrow syndrome (adverse effects on blood cells) that can cause up to 100% lethality within 60 days in humans, depending upon the dose; gastrointestinal syndrome (adverse symptoms of intestinal injury) that can cause 100% lethality within 14 days in humans; and central nervous system syndrome (adverse neurological effects) that can cause 100% lethality within 24 hours. The survivors of these high radiation doses have increased risk of cancerous and non-cancerous diseases and heritable mutations that appear in future generations.

[0166] BioShield E3 is intended to be consumed daily for a limited time period depending on the level and severity of exposure. For those who develop diagnosed serious medical conditions as a result of the exposure, it is to be used as an adjunct to standard therapy that may include fluid and electrolyte replacement, antibiotics, blood transfusion, growth factors, such as granulocyte colony-stimulating factor, and consideration of bone marrow or stem cell transplantation.

[0167] The BioShield E3 formulation should be taken orally and divided into two doses, half in the morning and the other half in the evening preferably with meals. This is because the biological half-lives of micronutrients (water-soluble and fat-soluble) are highly variable which can create marked fluctuations in tissue levels, differences in gene profile expression and cellular stress.

[0168] Consumption of the formulation should be started 24 hours after exposure and continued for up to 60 days depending on the judgment of the health care provider. The 24-hour post-exposure waiting period is desirable because immediately after exposure, pro- and anti-inflammatory cytokines are released in response to cellular injuries. During this period, the proportion of anti-inflammatory cytokines responsible for repair of injury may be higher than that of pro-inflammatory cytokines that further damage cells and tissues. Inhibition of the inflammatory response by the high doses of antioxidants too soon after exposure may prevent the release of both anti- and pro-inflammatory cytokines, and thereby prevent the repair of injury. However, after 24 hours, pro-inflammatory cytokines are expected to dominate. Therefore, inhibition of inflammation at this time may help to prevent progression of damage. The 60-day consumption period is appropriate because by this time, those who would succumb to the exposure will have likely died. Since survivors of will have increased risk of neoplastic and non-neoplastic diseases, it is recommended that when the BioShield R3 supplementation has stopped after 60 days, the BioShield R2 formulation should be consumed twice daily for the remainder of the individual's lifespan in order to reduce the risk of the late adverse health effects of hazardous exposures.

[0169] Hazardous environmental exposures are implicated in many adverse health conditions worldwide and antioxidants are protective agents involving many cellular processes that must be considered as targets for therapeutic intervention (1). The present invention relates to the use of multiple micronutrients including dietary and endogenous antioxidants with glutathione-elevating agents to reduce the adverse health effects on humans during episodic, occupational or accidental exposures to hazardous environmental factors or potentially toxic agents. This includes the relevant affected groups listed in Sections 1.1, 2.1 and 3.1 above. In addition to the oral mode of consumption that is outlined in Sections 1.2, 2.2 and 3.3 above, the BioShield formulations may be provided in several alternative platforms including, but not limited to liquids, aerosols, dissolvable disks, injectable forms, those absorbed through the skin, lipid-encased and droplet forms and delayed absorption technologies.

[0170] The formulation for Bioshield E3 is as follows:

BioShield Environmental-Catastrophic, E3 for Adults, Ages 14 Years and Older

[0171]

TABLE-US-00027 primary dose Vitamin A (retinyl palmitate, fish oils or natural 3,000 IU mixed carotenoids) Vitamin C (calcium ascorbate, citrus, rose or berry 1,000 mg products) Vitamin E (2:1 ratio: d-alpha tocopheryl succinate to 400 IU d-alpha tocopherol acetate, vegetable or wheat germ products or natural tocopheryl) L-cysteine (or natural food sources-e.g. soy extracts, 400 mg sesame or flaxseeds, oat bran, wheat germ, Swiss cheese, peas or whole grain extracts) N-acetylcysteine 500 mg Vitamin D (as cholecalciferol-D3 or fish oils) 800 IU Vitamin B1 (thiamine mononitrate or yeast sources) 4 mg Vitamin B2 (riboflavin or yeast sources) 5 mg Vitamin B3 (niacinamide, nicotinic acid, 30 mg nicotinamide or yeast sources) Vitamin B6 (pyridoxine or yeast sources) 5 mg Folic acid (folate, yeast or liver sources) 800 mcg Vitamin B12 (cyanocobalamin, methylcobalamin or 10 mcg yeast sources) Biotin (d-biotin or liver sources) 200 mcg Pantothenic acid (d-calcium pantothenate, rice bran, 10 mg yeast or liver sources) Calcium (citrate, ascorbate, lactate or plant based 250 mg sources) Magnesium (citrate, lactate, gluconate, oxide, 125 mg carbonate, hydroxide, chloride, sulphate, lactic acid, Jay phosphate, tribasic phosphate or natural forms) Zinc (glycinate, gluconate, oxide, sulphate or natural 15 mg forms) Selenium (L-selenomethionine, sodium selenite/ 200 mcg selenate or natural forms) Chromium (picolinate, chromic chloride or natural 50 mcg forms) Coenzyme Q10 (ubiquinone, organ meat or natural 45 mg ingredient sources-e.g. Agrobacterium tumefaciens, Paracoccus denitrificans, Pseudomonas aeruginosa) R-alpha-lipoic acid (R+, R, yeast or liver sources) 90 mg Natural mixed carotenoids (sea, algal or plant 60 mg sources) L-carnitine (fumarate or natural forms) 200 mg

[0172] Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the attendant claims attached hereto, this invention may be practiced otherwise than as specifically disclosed herein.

REFERENCES

[0173] 1. Okunieff, P., Swarts, S., Keng, P., Sun, W., Wang, W., Kim, J., Yang, S., Zhang, H., Liu, C., Williams, J. P., Huser, A. K., Zhang, L. Antioxidants reduce consequences of radiation exposure. Adv Exo Med Biol, 614: 165-178, 2008. [0174] 2. Roston, B. L., Chang, C. M., Pechacek, T. F. Estimation of Cigarette Smoking-Attributable Morbidity in the United States. JAMA Intern Med doi: 10.1001/jama intern med. 2014. 5219. Epub Oct. 13, 2014. [0175] 3. Coppes, Z., De Vecchi, S., Coppes, P., Prasad, K. A multiple micronutrient supplement increases immune competency and decreases oxidative stress in healthy volunteers: a pilot study. Montevideo, Uruguay: University of Uruguay; 2006. [0176] 4. Hodgdon, J., Prasad, K. N., Cole, W. C. Beneficial effects of micronutrients on oxidative damage during intense military training. San Diego (Calif.): Naval Health Research Center; 2008. [0177] 5. Gottshall, K. R., Hoffer, M. E., Balough, B. J. Characterizing vestibular deficits and function after blast injury; effects of antioxidant intervention. Presented at the 24.sup.th meeting, the Barany Society. Sweden: Uppsala; 2006. [0178] 6. Kleinerman, R. A. Cancer risks following diagnostic and therapeutic radiation exposure in children. Pediatr Radiol, 36 Suppl 14: 121-125, 2006. [0179] 7. Prasad, K. N. Handbook of Radiobiology, Second Edition. CRC Press, Boca Raton, Fla., 1995. [0180] 8. Shah, N. B. and Platt, S. L. ALARA: is there a cause for alarm? Reducing radiation risks from computed tomography scanning in children. Curr Opin Pediatr, 20: 243-247, 2008. [0181] 9. ICRP 1990 recommendations of the International Commission on radiological protection. Vol. 21, pp. 1-3: Ananals of the ICRP, 1991. [0182] 10. Hall, E. J. Radiation biology for pediatric radiologists. Pediatr Radiol, 2008. [0183] 11. Brody, A. S., Frush, D. P., Huda, W., and Brent, R. L. Radiation risk to children from computed tomography. Pediatrics, 120: 677-682, 2007. [0184] 12. Chodick, G., Ronckers, C. M., Shalev, V., and Ron, E. Excess lifetime cancer mortality risk attributable to radiation exposure from computed tomography examinations in children. Isr Med Assoc J, 9: 584-587, 2007. [0185] 13. Brenner, D. J. and Sachs, R. K. Estimating radiation-induced cancer risks at very low doses: rationale for using a linear no-threshold approach. Radiat Environ Biophys, 44: 253-256, 2006. [0186] 14. Radiation, N. R. C. o. t. N. A. C. t. A. H. R. f E. t. L. L. o. i. BEIR VII,

[0187] Phase 2. The National Academies Press, Washington, D.C., 2006. [0188] 15. Robbins, E. Radiation risks from imaging studies in children with cancer. Pediatr Blood Cancer, 51: 453-457, 2008. [0189] 16. Hall, E., J. Garcia, A J Radiobiology for Radiologist. Lippincott Williams & wilkins, Philadelphia, 2006. [0190] 17. Rice, H. E., Frush, D. P., Farmer, D., and Waldhausen, J. H. Review of radiation risks from computed tomography: essentials for the pediatric surgeon. J Pediatr Surg, 42: 603-607, 2007. [0191] 18. Hall, E. J. Lessons we have learned from our children: cancer risks from diagnostic radiology. Pediatr Radiol, 32: 700-706, 2002. [0192] 19. Brenner, D., Elliston, C., Hall, E., and Berdon, W. Estimated risks of radiation-induced fatal cancer from pediatric CT. AJR Am J Roentgenol, 176: 289-296, 2001. [0193] 20. Wan, M. J., Krahn, M., Ungar, W. J., Caku, E., Sung, L., Medina, L. S., and Doria, A. S. Acute Appendicitis in Young Children: Cost-effectiveness of US versus CT in DiagnosisA Markov Decision Analytic Model. Radiology, 2008. [0194] 21. Picano, E., Vano, E., Semelka, R., and Regulla, D. The American College of Radiology white paper on radiation dose in medicine:deep impact on the practice of cardiovascular imaging. Cardiovasc Ultrasound, 5: 37, 2007. [0195] 22. Picano, E. Risk-benefit balance in cardiovascular imaging: the radiation issue. G Ital Cardiol (Rome), 9: 808-814, 2008. [0196] 23. Berrington de Gonzalez, A. and Darby, S. Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries. Lancet, 363: 345-351, 2004. [0197] 24. Bedetti, G., Botto, N., Andreassi, M. G., Traino, C., Vano, E., and Picano,

[0198] E. Cumulative patient effective dose in cardiology. Br J Radiol, 81: 699-705, 2008. [0199] 25. Amis, E. S., Jr., Butler, P. F., Applegate, K. E., Birnbaum, S. B., Brateman, L. F., Hevezi, J. M., Mettler, F. A., Morin, R. L., Pentecost, M. J., Smith, G. G., Strauss, K. J., and Zeman, R. K. American College of Radiology white paper on radiation dose in medicine. J Am Coll Radiol, 4: 272-284, 2007. [0200] 26. Andreassi, M. G., Cioppa, A., Manfredi, S., Palmieri, C., Botto, N., and Picano, E. Acute chromosomal DNA damage in human lymphocytes after radiation exposure in invasive cardiovascular procedures. Eur Heart J, 28: 2195-2199, 2007. [0201] 27. BEIR VII, p. Health risks from exposure to low levels of ionizing radiation. Washington D.C.: The national Academies Press, 2006. [0202] 28. Mettler, F. A., Jr., Huda, W., Yoshizumi, T. T., and Mahesh, M. Effective doses in radiology and diagnostic nuclear medicine: a catalog. Radiology, 248: 254-263, 2008. [0203] 29. Angelieri, F., de Oliveira, G. R., Sannomiya, E. K., and Ribeiro, D. A., DNA damage and cellular death in oral mucosa cells of children who have undergone panoramic dental radiography, Pediatr Radiol 37 (6), 561-5, 2007. [0204] 30. Ribeiro, D. A. and Angelieri, F., Cytogenetic biomonitoring of oral mucosa cells from adults exposed to dental X-rays, Radiat Med 26 (6), 325-30, 2008. [0205] 31. Holland, N., Bolognesi, C., Kirsch-Volders, M., Bonassi, S., Zeiger, E., Knasmueller, S., and Fenech, M. The micronucleus assay in human buccal cells as a tool for biomonitoring DNA damage: the HUMN project perspective on current status and knowledge gaps. Mutat Res, 659: 93-108, 2008. [0206] 32. Hamzany, Y., Feinmesser, R., Shpitzer, T., Mizrachi, A., Hilly, O., Hod, R., Bahar, G., Otradnov, I., Gavish, M., Nagler, R. M. Is human saliva an indicator of the adverse health effects of using mobile phones? Antioxidants Redox Signal 18 (6): 622, 2013. doi: 10.1089/ars.2012.4751 [0207] 33. Desai, N. R., Kesari, K. K., Agarwal, A. Pathophysiology of cell phone radiation: oxidative stress and cardinogenesis with focus on male reproductive system. Reproductive Biol Endocrinol 7:114-122, 2009 [0208] 34. Han, Y. Y., Kano, H., Davis, D. L., Niranjan, A., and Lunsford, L. D., Cell phone use and acoustic neuroma: the need for standardized questionnaires and access to industry data, Surg Neurol 72 (3): 216-222, 2009. [0209] 35. Hardell, L. and Sage, C., Biological effects from electromagnetic field exposure and public exposure standards, Biomed Pharmacother 62 (2), 104-9, 2008. [0210] 36. Hardell, L., Carlberg, M., Soderqvist, F., Mild, K. H., and Morgan, L. L., Long-term use of cellular phones and brain tumours: increased risk associated with use for > or =10 years, Occup Environ Med 64 (9), 626-32, 2007. [0211] 37. Hardell, L., Carlberg, M., Soderqvist, F., and Hansson Mild, K., Meta-analysis of long-term mobile phone use and the association with brain tumours, Int J Oncol 32 (5), 1097-103, 2008. [0212] 38. Takebayashi, T., Akiba, S., Kikuchi, Y., Taki, M., Wake, K., Watanabe, S., and Yamaguchi, N., Mobile phone use and acoustic neuroma risk in Japan, Occup Environ Med 63 (12), 802-7, 2006. [0213] 39. Croft, R. J., McKenzie, R. J., Inyang, I., Benke, G. P., Anderson, V., and

[0214] Abramson, M. J., Mobile phones and brain tumours: a review of epidemiological research, Australas Phys Eng Sci Med 31 (4), 255-67, 2008. [0215] 40. Sadetzki, S., Chetrit, A., Jarus-Hakak, A., Cardis, E., Deutch, Y., Duvdevani, S., Zultan, A., Novikov, I., Freedman, L., and Wolf, M., Cellular phone use and risk of benign and malignant parotid gland tumorsa nationwide case-control study, Am J Epidemiol 167 (4), 457-67, 2008. [0216] 41. Abdel-Rassoul, G., El-Fateh, O. A., Salem, M. A., Michael, A., Farahat, F., El-Batanouny, M., and Salem, E., Neurobehavioral effects among inhabitants around mobile phone base stations, Neurotoxicology 28 (2), 434-40, 2007. [0217] 42. Tillmann, T., Ernst, H., Ebert, S., Kuster, N., Behnke, W., Rittinghausen, S., and Dasenbrock, C., Carcinogenicity study of GSM and DCS wireless communication signals in B6C3F1 mice, Bioelectromagnetics 28 (3), 173-87, 2007. [0218] 43. Kim, J. Y., Hong, S. Y., Lee, Y. M., Yu, S. A., Koh, W. S., Hong, J. R., Son, T.,

[0219] Chang, S. K., and Lee, M., In vitro assessment of clastogenicity of mobile-phone radiation (835 MHz) using the alkaline comet assay and chromosomal aberration test, Environ Toxicol 23 (3), 319-27, 2008. [0220] 44. Buja, A., Lange, J. H., Perissinotto, E., Rausa, G., Grigoletto, F., Canova, C., and Mastrangelo, G. Cancer incidence among male military and civil pilots and flight attendants: an analysis on published data. Toxicol Ind Health, 21: 273-282, 2005. [0221] 45. Band, P. R., Le, N. D., Fang, R., Deschamps, M., Coldman, A. J., Gallagher, R. P., and Moody, J. Cohort study of Air Canada pilots: mortality, cancer incidence, and leukemia risk. Am J Epidemiol, 143: 137-143, 1996. [0222] 46. Gunderstrup, M., Storm, H. H. Radiation-induced acute myeloid leukemia and other cancers in commercial jet cockpit crew: a population-based cohort study. Lancet 354: 2029-2031, 1999. [0223] 47. Ballard, T., Lagorio, S., De Angelis, G., Verdecchia, A. Cancer incidence and mortality among flight personnel: a meta-analysis. Aviation Space Environment Med 71: 216-224, 2000. [0224] 48. Sigurdson, A. J. and Ron, E. Cosmic radiation exposure and cancer risk among flight crew. Cancer Invest, 22: 743-761, 2004. [0225] 49. Rafnsson, V., Tulinius, H., Jonasson, J. G., and Hrafnkelsson, J. Risk of breast cancer in female flight attendants: a population-based study (Iceland). Cancer Causes Control, 12: 95-101, 2001. [0226] 50. Pukkala, E., Auvinen, A., and Wahlberg, G. Incidence of cancer among Finnish airline cabin attendants, 1967-92. BMJ, 311: 649-652, 1995. [0227] 51. Grayson, J. K., Lyons, T. J. Cancer incidence in United States Air Force aircrew, 1975-89. Aviation Space Environment Med 67: 101-104, 1996 [0228] 52. Heimers, A. Chromosome aberration analysis in Concorde pilots. Mutation Res 467:169-176, 2000. [0229] 53. Romano, E., Ferrucci, L., Nicolai, F., Derme, V., De Stefano, G. F. Increase of chromosomal aberrations induced by ionizing radiation in peripheral blood lymphocytes of civil aviation pilots and crew members. Mutation Res 377: 89-93, 1997. [0230] 54. Ben-Amotz, A., Yatziv, S., Sela, M., Greenberg, S., Rachmilevich, B., Shwarzman, M., and Weshler, Z. Effect of natural beta-carotene supplementation in children exposed to radiation from the Chernobyl accident. Radiat Environ Biophys, 37: 187-193, 1998. [0231] 55. Korkina, L. G., Afanasef, I. B., and Diplock, A. T. Antioxidant therapy in children affected by irradiation from the Chernobyl nuclear accident. Biochem Soc Trans, 21 (Pt 3): 314S, 1993. [0232] 56. Unreleased Federal Study, U.S. Government, reported in USA Today, 2005. [0233] 57. Stone, R. Russian cancer study adds to the indictment of low-dose radiation. Science 310:959, 2005. [0234] 58. Mangano, J., Sherman, J., Busby, C. Changes in confirmed plus borderline cases of congenital hypothyroidism in California as a function of environmental fallout from the Fukushima nuclear meltdown. O J Pediatr 3 (4): 370-376, 2013. doi:10.4236/ojped.2013.34067 [0235] 59. Frumkin, H, Samet, J. M., Radon. CA Cancer J Clin 51: 337-344, 2001. [0236] 60. Peacock, M, Radon gas more deadly than carbon monoxide poisoning. U.S. Environmental Protection Agency, news release, January, 2008. [0237] 61. Wheeler, B. W., Skin cancer rate may be higher in high-radon areas. Epidemiology Online, Nov. 10, 2011. [0238] 62. Kelly, F. J., Oxidative stress: its role in air pollution and adverse health effects. Occup Environ Med 60: 612-616, 2003. [0239] 63. Kuehn, B. M., WHO: more than 7 million air pollution deaths each year. JAMA 311: 1486, 2014. [0240] 64. Patz, J. A, Frumkin, H., Holloway, T., Vimont, D. J., Haines, A. Climate change: challenges and opportunities for global health. JAMA 312: 1565-1580, 2014. [0241] 65. Perera, F., Faraone, S. ADHD linked to expectant mom's smog exposure. Pub Libr Sci PLoS One, Online, Nov. 5, 2014. [0242] 66. Hashemi, N., Boskabady, M. H., and Nazari, A. Occupational Exposures and Obstructive Lung Disease: A Case-Control Study in Hairdressers. Respir Care, 55 (7): 895-900, 2010. [0243] 67. Borek, C., Ong, A., Mason, H., Donahue, L., and Biaglow, J. E. Selenium and vitamin E inhibit radiogenic and chemically induced transformation in vitro via different mechanisms. Proc Natl Acad Sci USA, 83: 1490-1494, 1986. [0244] 68. Radner, B. S. and Kennedy, A. R. Suppression of X-ray induced transformation by vitamin E in mouse C3H/10T1/2 cells. Cancer Lett, 32: 25-32, 1986. [0245] 69. Kennedy, A. R. and Krinsky, N. I. Effects of retinoids, beta-carotene, and canthaxanthin on UV- and X-ray-induced transformation of C3H10T1/2 cells in vitro. Nutr Cancer, 22: 219-232, 1994. [0246] 70. Gaziev, A. I., Podlutsky, A., Panfilov, B. M., and Bradbury, R. Dietary supplements of antioxidants reduce hprt mutant frequency in splenocytes of aging mice. Mutat Res, 338: 77-86, 1995. [0247] 71. Konopacka, M., Widel, M., and Rzeszowska-Wolny, J. Modifying effect of vitamins C, E and beta-carotene against gamma-ray-induced DNA damage in mouse cells. Mutat Res, 417: 85-94, 1998. [0248] 72. Kumar, B., Jha, M. N., Cole, W. C., Bedford, J. S., and Prasad, K. N. D-alpha-tocopheryl succinate (vitamin E) enhances radiation-induced chromosomal damage levels in human cancer cells, but reduces it in normal cells. J Am Coll Nutr, 21: 339-343, 2002. [0249] 73. Ni, Q. G. and Pei, Y. [Effect of beta-carotene on 60Co-gamma-induced mutation at T-lymphocyte hypoxanthine-guanine phosphoribosyl transferase locus in rats]. Zhongguo Yao Li Xue Bao, 18: 535-536, 1997. [0250] 74. O'Connor, M. K., Malone, J. F., Moriarty, M., and Mulgrew, S. A radioprotective effect of vitamin C observed in Chinese hamster ovary cells. Br J Radiol, 50: 587-591, 1977. [0251] 75. Okunieff, P., Swarts, S., Keng, P., Sun, W., Wang, W., Kim, J., Yang, S., Zhang, H., Liu, C., Williams, J. P., Huser, A. K., and Zhang, L. Antioxidants reduce consequences of radiation exposure. Adv Exp Med Biol, 614: 165-178, 2008. [0252] 76. Ushakova, T., Melkonyan, H., Nikonova, L., Afanasyev, V., Gaziev, A. I., Mudrik, N., Bradbury, R., and Gogvadze, V. Modification of gene expression by dietary antioxidants in radiation-induced apoptosis of mice splenocytes. Free Radic Biol Med, 26: 887-891, 1999. [0253] 77. Weiss, J. F. and Landauer, M. R. Radioprotection by antioxidants. Ann N Y Acad Sci, 899: 44-60, 2000. [0254] 78. Weiss, J. F. and Landauer, M. R. Protection against ionizing radiation by antioxidant nutrients and phytochemicals. Toxicology, 189: 1-20, 2003. [0255] 79. Ramakrishnan, N., Wolfe, W. W., and Catravas, G. N. Radioprotection of hematopoietic tissues in mice by lipoic acid. Radiat Res, 130: 360-365, 1992. [0256] 80. Blumenthal, R. D., Lew, W., Reising, A., Soyne, D., Osorio, L., Ying, Z., and Goldenberg, D. M. Anti-oxidant vitamins reduce normal tissue toxicity induced by radio-immunotherapy. Int J Cancer, 86: 276-280, 2000. [0257] 81. El-Habit, O. H., Saada, H. N., Azab, K. S., Abdel-Rahman, M., and El-Malah, D. F. The modifying effect of beta-carotene on gamma radiation-induced elevation of oxidative reactions and genotoxicity in male rats. Mutat Res, 466: 179-186, 2000. [0258] 82. Ershoff, B. H. and Steers, C. W., Jr. Antioxidants and survival time of mice exposed to multiple sublethal doses of x-irradiation. Proc Soc Exp Biol Med, 104: 274-276, 1960. [0259] 83. Harapanhalli, R. S., Yaghmai, V., Giuliani, D., Howell, R. W., and Rao, D. V. Antioxidant effects of vitamin C in mice following X-irradiation. Res Commun Mol Pathol Pharmacol, 94: 271-287, 1996. [0260] 84. Mills, E. E. The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer, 57: 416-417, 1988. [0261] 85. Mutlu-Turkoglu, U., Erbil, Y., Oztezcan, S., Olgac, V., Toker, G., and Uysal, M. The effect of selenium and/or vitamin E treatments on radiation-induced intestinal injury in rats. Life Sci, 66: 1905-1913, 2000. [0262] 86. Narra, V. R., Harapanhalli, R. S., Howell, R. W., Sastry, K. S., and Rao, D. V. Vitamins as radioprotectors in vivo. I. Protection by vitamin C against internal radionuclides in mouse testes: implications to the mechanism of damage caused by the Auger effect. Radiat Res, 137: 394-399, 1994. [0263] 87. Umegaki, K., Uramoto, H., Suzuki, J., and Esashi, T. Feeding mice palm carotene prevents DNA damage in bone marrow and reduction of peripheral leukocyte counts, and enhances survival following X-ray irradiation. Carcinogenesis, 18: 1943-1947, 1997. [0264] 88. Seifter E, R., A, Padawar, J, Levenson, S M. Vitamin A abd beta-carotene as adjunctive therapy to tumor excision, radiation therapy and chemotherapy. In: Vitamins, Nutrition and Cancer, Karger, Basel, 1984, pp. 1-19. [0265] 89. Guan, J., Wan, X. S., Zhou, Z., Ware, J., Donahue, J. J., Biaglow, J. E., and Kennedy, A. R. Effects of dietary supplements on space radiation-induced oxidative stress in Sprague-Dawley rats. Radiat Res, 162: 572-579, 2004. [0266] 90. Kennedy, A. R., Zhou, Z., Donahue, J. J., and Ware, J. H. Protection against adverse biological effects induced by space radiation by the Bowman-Birk inhibitor and antioxidants. Radiat Res, 166: 327-332, 2006. [0267] 91. Wan, X. S., Ware, J. H., Zhou, Z., Donahue, J. J., Guan, J., and Kennedy, A. R. Protection against radiation-induced oxidative stress in cultured human epithelial cells by treatment with antioxidant agents. Int J Radiat Oncol Biol Phys, 64: 1475-1481, 2006. [0268] 92. Kocer, I., Taysi, S., Ertekin, M. V., Karslioglu, I., Gepdiremen, A., Sezen, O., and Serifoglu, K. The effect of L-carnitine in the prevention of ionizing radiation-induced cataracts: a rat model. Graefes Arch Clin Exp Ophthalmol, 245: 588-594, 2007. [0269] 93. Sezen, O., Ertekin, M. V., Demircan, B., Karslioglu, I., Erdogan, F., Kocer, I., Calik, I., and Gepdiremen, A. Vitamin E and L-carnitine, separately or in combination, in the prevention of radiation-induced brain and retinal damages. Neurosurg Rev, 31: 205-213, 2008. [0270] 94. Altas, E., Ertekin, M. V., Gundogdu, C., and Demirci, E. L-carnitine reduces cochlear damage induced by gamma irradiation in Guinea pigs. Ann Clin Lab Sci, 36: 312-318, 2006. [0271] 95. Sminia, P., van der Kracht, A. H., Frederiks, W. M., and Jansen, W. Hyperthermia, radiation carcinogenesis and the protective potential of vitamin A and N-acetylcysteine. J Cancer Res Clin Oncol, 122: 343-350, 1996. [0272] 96. Krinsky, N. I. Antioxidant functions of carotenoids. Free Radic Biol Med, 7: 617-635, 1989. [0273] 97. Hazuka, M. B., Edwards-Prasad, J., Newman, F., Kinzie, J. J., and Prasad, K. N. Beta-carotene induces morphological differentiation and decreases adenylate cyclase activity in melanoma cells in culture. J Am Coll Nutr, 9: 143-149, 1990. [0274] 98. Zhang, L. X., Cooney, R. V., and Bertram, J. S. Carotenoids up-regulate connexin43 gene expression independent of their provitamin A or antioxidant properties. Cancer Res, 52: 5707-5712, 1992. [0275] 99. Carter, C. A., Pogribny, M., Davidson, A., Jackson, C. D., McGarrity, L. J., and Morris, S. M. Effects of retinoic acid on cell differentiation and reversion toward normal in human endometrial adenocarcinoma (RL95-2) cells. Anticancer Res, 16: 17-24, 1996. [0276] 100. Meyskens Jr, F. L. Role Of Vitamin A and Its Derivatives In The Treatment Of Human Cancer. In: K. N. Prasad, L. Santamaria, and R. M. Williams (eds.), Nutrients In Cancer Prevention And Treatment, pp. 349-362. New Jersey: Humana Press, 1995. [0277] 101. Vile, G. F. and Winterbourn, C. C. Inhibition of adriamycin-promoted microsomal lipid peroxidation by beta-carotene, alpha-tocopherol and retinol at high and low oxygen partial pressures. FEBS Lett, 238: 353-356, 1988. [0278] 102. McCay, P. B. Vitamin E: interactions with free radicals and ascorbate. Annu Rev Nutr, 5: 323-340, 1985. [0279] 103. Prasad, K. N., Kumar, B., Yan, X. D., Hanson, A. J., and Cole, W. C. alpha-Tocopheryl Succinate, the Most Effective Form of Vitamin E for Adjuvant Cancer Treatment: A Review. J Am Coll Nutr, 22: 108-117, 2003. [0280] 104. Schwartz, J. L. Molecular and Biochemical Control of Tumor Growth Following Treatment with Carotenoids or Tocopherols. In: K. N. Prasad, L. Santamaria, and R. M. Williams (eds.), Nutrients in Cancer Prevention and Treatment, pp. 287-316. New Jersey: Humana Press, 1995. [0281] 105. Prasad, K. N. and Edwards-Prasad, J. Vitamin E and cancer prevention: recent advances and future potentials. J Am Coll Nutr, 11: 487-500, 1992. [0282] 106. Witschi, A., Reddy, S., Stofer, B., and Lauterburg, B. H. The systemic availability of oral glutathione. Eur J Clin Pharmacol, 43: 667-669, 1992. [0283] 107. Niki, E. Mechanisms and dynamics of antioxidant action of ubiquinol. Mol Aspects Med, 18 Suppl: S63-70, 1997. [0284] 108. Hiramatsu, M., Velasco, R. D., Wilson, D. S., and Packer, L. Ubiquinone protects against loss of tocopherol in rat liver microsomes and mitochondrial membranes. Res Commun Chem Pathol Pharmacol, 72: 231-241, 1991. [0285] 109. Abate, A., Yang, G., Dennery, P. A., Oberle, S., and Schroder, H. Synergistic inhibition of cyclooxygenase-2 expression by vitamin E and aspirin. Free Radic Biol Med, 29: 1135-1142, 2000. [0286] 110. Devaraj, S. and halal, I. Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients. Free Radic Biol Med, 29: 790-792, 2000. [0287] 111. Guenechea, G., Albella, B., Bueren, J. A., Maganto, G., Tuduri, P., Guerrero, A., Pivel, J. P., and Real, A. AM218, a new polyanionic polysaccharide, induces radioprotection in mice when administered shortly before irradiation. Int J Radiat Biol, 71: 101-108, 1997. [0288] 112. Patchen, M. L., MacVittie, T. J., Solberg, B. D., D'Alesandro, M. M., and Brook, I. Radioprotection by polysaccharides alone and in combination with aminothiols. Adv Space Res, 12: 233-248, 1992. [0289] 113. Ross, W. M. and Peeke, J. Radioprotection conferred by dextran sulfate given before irradiation in mice. Exp Hematol, 14: 147-155, 1986. [0290] 114. Kuefner, M. A., Brand, M., Ehrlich, J., Brga, L., Uder, M., and Semelka, C. Effect of antioxidants on X-ray-induced gamma-H2AX foci in human blood lymphocytes: preliminary onservations. Radiology 264: 59-67, 2012. [0291] 115. Prasad, K. N. Rationale for using multiple antioxidants in protecting humans against low doses of ionizing radiation. Br J Radiol, 78: 485-492, 2005.