Conclusions

Information presented at this meeting, in earlier CMNR reports, and other scientific literature provide evidence that military service leads to exposure to unique oxidative stresses that may have adverse health consequences. Some of these stresses are reasonably well characterized, such as those associated with strenuous exercise, work in extremes of environmental temperatures, and at altitude. Much less is known about other sources of oxidative stress, such as radiofrequency and microwave radiation hazards, exposure to blast overpressure, and psychological stress related to extreme training courses or deployment .

The multiple occupational stresses associated with military tasks often occur together in deployment situations. These stresses may have more severe effects as food intake becomes more limited; thus, those individuals with both diminished food intake and high stress would be the most likely target population. Among them, those exposed to these adverse conditions for extended periods of time might be the most vulnerable.

Military personnel living on military bases and those in deployment situations have access to diets that are formulated according to the Military Recommended Dietary Allowances (MRDA). The MRDAs provide guidance for recommended daily intakes of nutrients, based on the National Research Council's Recommended Dietary Allowances (NRC, 1980). Studies of military personnel living in garrison reveal satisfactory dietary intakes of vitamin C (averaging 2x the MRDA). Vitamin E intakes measured in four studies indicated that in three of the locations evaluated, median intakes were equal to or greater than the MRDA of 10 mg. However, one study of Army Rangers at Fort Stewart indicated a median vitamin E intake of only 6.9 mg/ day (Corey Baker Fulco, U.S. Army Research Institute of Environmental Medicine, personal communication, July 17, 1998).

Military rations formulated in accordance with the MRDAs provide nutrients in amounts consistent with meeting nutrient needs—including the antioxidant nutrients—when these rations are consumed at levels required to maintain body weight in the usual range of physical activity for military task requirements. There is little evidence that supplementation with vitamins C, E or with β-carotene in normal conditions (i.e. in garrison) would enhance overall health.

In contrast to garrison situations, the CMNR recognizes that there are circumstances where the various environmental and emotional stresses of military operations may result in a tendency to reduce ration intake. Studies carried out in field training exercises consistently demonstrate that caloric intake is reduced to approximately 75% of troops' usual intakes. In basic training, negative energy balance and weight loss also occur, probably as a result of both decreased energy intake and greatly increased energy expenditure. Such situations may be associated with intakes of vitamins C, E, and β-carotene (vitamin A) below recommended levels. In the report, Not Eating Enough (IOM, 1995), the CMNR proposed establishing a Food Doctrine with suggestions of how to minimize the underconsumption of rations in the field in order to reduce the impact of these environmental factors on food intake and consequent overall nutrient intake. The committee recognizes there may be some benefit to enhancing body reserves of these nutrients prior to deployment but at current levels of reported consumption, body stores have not been evaluated.

There is little evidence currently available to indicate that supplementation of vitamins C and E and β-carotene would be beneficial in protecting against short term, acute oxidative stress. In addition, the use of antioxidant compounds to minimize this stress is not without risk .

Trials reviewed by the committee in which supplemental β-carotene was given to smokers appeared to increase the risk of lung cancer. These data are especially relevant since a large segment of the military population still engages in smoking. Recent studies from the National Institutes of Health (NIH) indicate that daily intakes of 100 mg of vitamin C saturated circulating immune cells and was reflective of other body tissues. Furthermore, as intake exceeded 100 mg per day, bioavailability decreased and above 500 mg, the entire absorbed dose was excreted. Thus there appears to be little benefit in intakes of vitamin C above 100 mg. In fact, the value of intake levels adequate to provide saturation of tissues has not been clarified. There is also some evidence that high levels of vitamin E (400 to 800 rag/day) inhibit platelet aggregation, and when taken with non-steroidal anti-inflammatory medication can result in excessive bleeding which would be a particular concern for injured or wounded personnel. Data which the committee considered important in making recommendations are detailed in Part II, Attachment A of this report.

Future Research Considerations

The CMNR believes that the military services, through their pool of volunteer personnel, have an excellent and often unique opportunity to generate statistics about nutrition, health, and well-being of service personnel that can be directly applied toward improved health of both military personnel and the general U.S. population. Research on the following topics is recommended.

• Research focused on the protective effects of antioxidants against acute oxidative stress is strongly encouraged as information is most lacking in this area.
• Validation of a battery of biomarkers for detecting oxidative tissue damage in human subjects in ambulatory or field situations.
• Evaluation of the extent to which the presence of tissue oxidative damage impacts performance.
• The extent and duration of oxidative stress that might be associated with hyperoxia, prolonged exposure to ionizing radiation, radiofrequency, blast overpressure, and psychological stress.
• Supplementation of vitamins C, E and β-carotene in a controlled, randomized way so that their true efficacy in decreasing oxidative tissue damage based on validated biomarkers can be determined. This research is essential both with respect to optimizing health and performance of personnel, and optimizing cost effectiveness.

The CMNR is pleased to provide this review as part of the Committee's continuing response to the U.S. Army Medical Research and Materiel Command. The Committee always welcomes comments and suggestions from you or your staff regarding how these reports can better serve the Army.

Sincerely,
John E. Vanderveen, Ph.D. (Chair)
Lawrence E. Armstrong, Ph.D.
William R. Beisel, M.D
Gail E. Butterfield, Ph.D., R.D.
Wanda Chenoweth, Ph.D., R.D.
Johanna T. Dwyer, D.Sc., R.D.
John D. Fernstrom, Ph.D.
Robin B. Kanarek, Ph.D.
Orville A. Levander, Ph.D.
Esther M. Sternberg, M.D.
Douglas W. Wilmore, M.D.

Attachments

cc: LTG Ronald Blanck

LTC Karl Friedl

MAJ Vicky Thomas

Kenneth Shine

Susanne Stoiber

Allison Yates

Mary Poos

Vitamin C

Vitamin C intake in the range of 250–500 mg is very unlikely to cause adverse effects in the overwhelming majority of the population (Bendich, 1997). Possible exceptions would be individuals who form oxalates, and thus are prone to kidney stone formation (Chalmers et al., 1986).

A number of studies have been conducted on the effect of vitamin C intake on urinary oxalate excretion (Briggs, 1976; Hatch et al., 1980; Hughes et al., 1981; Fituri et al., 1983; Tsao et al., 1984). Daily doses have ranged from 1 to 10 grams. Findings have been conflicting, with some studies reporting no effects and others reporting large increases in urinary oxalate. Conflicting results may be explained in part by methodological problems in oxalate measurement since the presence of vitamin C in the urine interferes with urinary oxalate assays. No evidence clearly linking kidney stone formation to excess vitamin C intake was found (Curhan et al., 1996).

Other individuals who may be at risk include those who have iron storage diseases such as hereditary hemochromatosis or severe thalassemias. However the scientific basis for risk in these latter groups has not been firmly established (Bendich and Cohen, 1990). In the case of hereditary hemochromatosis it seems logical that increased consumption of vitamin C might increase the absorption of iron, but data are lacking on what the extent and impact of such an increase would be. Unfortunately the clinical manifestations of the disease are often not detected until middle age. In the case of severe thalassemias such as β-Thalassemia Major most of the increase in body iron is derived from repeated transfusions over a number of years and thus increased iron absorption is not considered to be the main cause of the iron overload. In vitro studies have shown that Vitamin C reduces unbound ferric iron, which in turn generates hydroxyl free radicals (Elsayed, 1997). However, virtually all iron in biological systems is in a bound state and not susceptible to this type of reaction.

There may be other potential risks. Results of one study suggested that 3 g of vitamin C per day for 6 days reduced high-altitude resistance in normal adults (Schrauzer et al., 1975). Other studies have indicated evidence of systemic conditioning (the accelerated metabolism of ascorbic acid) following abrupt discontinuation of prolonged, high dose vitamin C supplementation (Omaye et al., 1986, Schrauzer and Rhead, 1973; Tsao and Leung, 1988).

Recent research conducted at the National Institutes of Health (NIH) indicated that daily intakes of 100 mg of vitamin C saturated circulating immune cells and that this is reflective of other tissues in the body. Bioavailability of oral doses of vitamin C up to 200 mg was found to be 80%. Above that level, bioavailability declined rapidly. Consumption of vitamin C above 500 mg results in steady state conditions, the entire absorbed dose being excreted (Levine et al., 1996).

Although supplementation of up to 500 mg of vitamin C per day appears to pose little risk, data also indicate there is little benefit in providing supplements in excess of the 100 mg per day required for tissue and enzyme system saturation.

Vitamin E

Widely varying doses of vitamin E have been evaluated in numerous studies. In the α-Tocopherol, β-Carotene Cancer Prevention studies (ATBC Study Group, 1994) where subjects were given 50 mg tocopherol equivalents daily for 5 to 8 years, there was an increased risk of hemorrhagic stroke in the groups receiving vitamin E. The age of these subjects ranged from 50 to 69 yr. which is, on average, older than that of the military population. In a smaller study reported by Steiner et al. (1995), patients at high risk of stroke (as shown by transient ischemic attacks (TIA) and other transient neurologic deficits which often predate the occurrence of major strokes) were given 400 mg vitamin E plus aspirin for 2 years. Hemorrhagic stroke occurred in 2 of the 50 patients receiving vitamin E plus aspirin, while none were reported for those receiving aspirin only, although according to the investigator, this was not of statistical significance. Nevertheless it should be pointed out that the study population was selected on the basis of a tendency to form small blood clots in that they all had TIA and were therefore not likely to be classified as bleeders.

Individuals being treated with coumarin or Warfarin drugs have been reported to be at increased risk of hemorrhage if taking high doses of vitamin E (Corrigan and Ulfers, 1981). Jandak et al (1988) reported a significant reduction in platelet adhesion in healthy adults given 400 mg of d-α-tocopherol per day for 2 wk. Similar adverse effects have not been reported in other studies in healthy subjects given supplements of vitamin E as high as 800 mg to 1200 mg per day (Stampfer et al., 1988; Kitagawa and Mino, 1989; Kim and White, 1996).

Thus, supplements of vitamin E may pose a minor risk for the military population. Individuals routinely ingesting non-steroidal anti-inflammatory drugs such as aspirin, and anticoagulants may be at risk if supplemented with more than 50 mg of vitamin E.

Data supplied to the committee from Fort Hood, Texas, which houses 41,500 active duty soldiers, indicated that in 1997 44 % of soldiers were taking anti-inflammatory drugs, primarily ibuprofen, naprosyn, piroxicam, and aspirin, and that this estimate was considered to be a very conservative one (MAJ Vicky Thomas, Office of the Surgeon General, personal communication, September 22, 1998). Additional research is needed to define better any potential risk of vitamin E supplementation for those individuals who may be routinely consuming non-steroidal inflammatory drugs or anticoagulants. Concerns with respect to prolonged clotting times would be magnified in battlefield situations.

Beta Carotene

Carotenoids are widely distributed in fruits and vegetables with β-carotene being the most prevalent. For many years nutritionists have regarded high intakes of β-carotene as being innocuous and having no adverse effects other than causing skin discoloration. More recently, there have been a number of adverse effects of high levels of β-carotene reported in the scientific literature that would be of concern to military personnel.

Several reports have addressed the occurrence of amenorrhea associated with high intakes of β-carotene from fruits and vegetables (Duester et al., 1986; Frumar et al., 1979; Kemmann et al., 1983). Another study reported an interaction of ethanol with β-carotene causing delayed blood clearance of ethanol and enhanced hepatotoxicity (Leo et al., 1992).

Two recent prospective intervention trials designed to test the hypothesis that β-carotene might have a favorable chemopreventive effect against lung cancer in smokers revealed unexpected results (ATBC Study Group, 1994; Omenn et al., 1996a, b). In the ATBC trial, with a total of 29,133 male smokers, participants receiving β-carotene (20 mg per day alone, or in combination with 50mg of α-tocopherol) had an 18% increase in lung cancer and an 8% increase in mortality. In the Carotene and Retinol Efficacy Trial (CARET) (Omenn et al., 1996a, b) involving 18, 314 smokers and asbestos workers, 30 mg of β-carotene plus 25000 IU of retinol per day increased lung cancer incidence by 28% and mortality by 17%. However, in the Physicians Health Study, which included both smokers and non-smokers, no adverse effects of β-carotene were observed, nor were any benefits observed (Hennekens et al., 1996). In one long term study, Chinese subjects who were deficient in vitamin A received approximately 15 mg β-carotene daily, risk of stomach cancer decreased with no evidence of adverse effects (Blot et al., 1993). Several shorter studies with 25-90 mg of β-carotene per day showed positive effects in treating oral pre-malignant lesions, with no adverse side effects (Stich et al., 1988; Garewal et al., 1995).

The evidence suggests there may be an adverse effect of high doses of supplemental β-carotene in current heavy smokers and asbestos-exposed populations. Very recent data obtained using ferrets has demonstrated a plausible mechanism of β-carotene interaction with tobacco smoke that enhances lung tumor development (Wang et. al., 1999).

In view of these data, the committee does not recommend supplementation of β-carotene, even in high stress situations, especially since self-report data from the 1995 DoD World-wide Health Survey indicates that across all services (Army, Navy, Air Force, and Marines) 34% of males and 28% of females are smokers. Broken down by age group, 41% of males and 31% of females in the 18-25 age group are smokers. In addition, in the 18-25 age group (again by self-report which probably under-reports true incidence), 28.1% of males and 7.7% of females are heavy alcohol drinkers (defined as consuming 5 or more drinks in one day, at least one day per week).

It would appear that significant improvements in health status of military personnel could best be achieved through the promotion of healthy life-style changes.

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Antioxidants and Oxidative Stress in Military Personnel

July 29–31, 1998

National Academy of Sciences

2101 Constitution Avenue, N.W.

Washington, D.C. 20418

Workshop Participants

CMNR

Robert Nesheim

Salinas, CA

Lawrence E. Armstrong Ph.D.

Professor, Departments of Physiology and Neurobiology, and Exercise Science

Human Performance Laboratory

University of Connecticut

Storrs, CT

William R. Beisel, M.D.

Adjunct Professor, Department of Molecular

Microbiology and Immunology

The Johns Hopkins University School of Hygiene and Public Health

Baltimore, MD

Wanda Chenoweth, Ph.D., R.D.

Professor, Department of Food Science and Human Nutrition

Michigan State University

East Lansing, MI

Robin B. Kanarek, Ph.D.

Professor and Chair of Psychology

Professor of Nutrition

Tufts University

Medford, MA

Orville A. Levander, Ph.D.

Research Leader, Nutrient Requirements and Functions Laboratory

USDA-ARS Beltsville Human Nutrition Research Center

Beltsville, MD

Esther M. Sternberg, M.D.

Chief, Neuroendocrine Immunology and Behavior

National Institute of Mental Health-NIH

Bethesda, MD

John E. Vanderveen, Ph.D.

Rockville, MD

Douglas W. Wilmore, M.D.

Frank Sawyer Professor

Department of Surgery

Brigham and Women's Hospital

Boston, MA

Food and Nutrition Board Liaison

Johanna T. Dwyer, D.Sc., R.D.

Professor, Departments of Medicine and of Community Health

Tufts Medical School and School of Nutrition Science and Policy

Director, Frances Stern Nutrition Ctr., New England Medical Ctr.

Boston, MA

U.S. Army Grant Officer Representative

LTC Karl Friedl, Ph.D.

Program Director

Army Operational Medicine Research

USAMRMC

Fort Detrick, MD

Speakers

Eldon Wayne Askew, Ph.D.

Professor and Director

Division of Foods and Nutrition

University of Utah

Salt Lake City, UT

Lt. Gen. Ronald Blanck

Surgeon General, U.S. Army

Patrick Dunne, Ph.D.

U.S. Army Natick Research, Development, and Engineering Center

U.S. Army Soldier System Command

Natick, MA

Nabil M. Elsayed, Ph. D.

Chief, Pulmonary Biochemistry Section

Department of Respiratory Research

Division of Medicine

Walter Reed Army Institute of Research

Washington, D.C.

Hank Gardner, Ph.D.

Director

USARIEM

Fort Detrick, MD

Charles Hennekens, M.D., Ph.D.

Eugene Braunwald Professor of Medicine

Harvard Medical School

Chief, Div. of Preventive Medicine

Brigham and Womens Hospital

Boston, MA

MAJ William H. Karge, Ph.D.

Nutritional Biochemist

USARIEM

Natick, MA

Susan Taylor Mayne, Ph.D.

Associate Professor in Chronic Disease Epidemiology

Department of Epidemiology and Public Health

Yale University School of Medicine

New Haven, CT

Harold Schmitz, Ph.D.

Group Manager

M&M Mars Company

Hackettstown, NJ

Ronald L. Seaman, Ph.D.

Research Scientist

Microwave Bioeffects Branch,

USARMD

Brooks AFB, TX

Chandan K. Sen, Ph.D.

Staff Scientist

Biological Technologies Section

Lawrence Berkeley National

Laboratory/EETD

University of California

Berkeley, CA

Maret G. Traber, Ph.D.

Principal Investigator,

Linus Pauling Institute

Associate Professor, Dept. of Nutrition and Food Management

Oregon State University

Corvallis, OR

Steven Wood, Ph.D., R.D.

Senior Clinical Project Leader

Ross Products Division

Columbus, OH

FNB Staff

Mary Poos, Ph.D.

Sydne Newberry, Ph.D.

Melissa Van Doren

Allison Yates, Ph.D.