Dietary zinc absorption was measured by extrinsic isotopic labeling and whole-body counting. Plasma cholesterol, cholesterol fractions, and lipoproteins were reduced 7--12% with the lactoovovegetarian diet, consistent with predictions based on dietary cholesterol and fat. Blood pressure was unaffected. Calcium, copper, magnesium, and phosphorus balances were not different between diets; manganese balance tended to be greater with the lactoovovegetarian diet (P < 0.07).

The lactoovovegetarian diet was associated with a 21% reduction in absorptive efficiency that, together with a 14% reduction in dietary zinc, reduced the amount of zinc absorbed by 35% (2.4 compared with 3.7 mg/d) and reduced plasma zinc by 5% within the normal range. Zinc balance was maintained with both diets. Although there is a greater risk of zinc deficiency in persons consuming lactoovovegetarian compared with omnivorous diets, with inclusion of whole grains and legumes zinc requirements can be met and zinc balance maintained. (Am J Clin Nutr 1998; 67:421-30.)

By George A. Eby

Zinc In Genetics

Zinc is an essential element in the nutrition of human beings, animals, and plants. Zinc is required in the genetic make-up of every cell and is an absolute requirement for all biologic reproduction. Zinc is needed in all DNA and RNA syntheses and is required at every step of the cell cycle. DNA is about 5000 times less susceptible to damage by Zn2+ ion than is RNA, suggesting its role in the predominant evolutionary selection of DNA, rather than RNA, as the bearer of the primary genetic information.(1)  In prebiotic chemistry on Earth billions of years ago, zinc most likely was the first effective nonenzymatic polymerase. Zinc remains an essential component of all DNA and RNA polymerases examined today.(2) "Zinc fingers" are finger-like protrusions extending from transcription factors or gene-regulating proteins and fastening to the wide, major groove of a DNA molecule.(3)

General Zinc Biochemistry

About 2 grams of zinc is distributed throughout the body (average 10 to 200 mmg/gram) of an adult human being.(4) Absorption of dietary zinc occurs over the duodenal and jejunal regions of the gastrointestinal tract. Active transport of zinc into portal blood is mediated by metallothionein. Zinc competes with other metals for absorption, and absorption is believed greatly retarded by ingestion of fiber and phytates.(4,5)

Plasma zinc is complexed to organic ligands. Zinc-albumin complexes account for about 50 percent of the zinc, and the metal is readily exchangeable throughout the peripheral circulation. About 7 to 8 percent is loosely bound to amino acid constituents in plasma. The remaining 40+ percentage of plasma zinc is largely bound to macroglobulins and unavailable for nutritional purposes. Serum and plasma zinc concentrations in adults range from 80 to 150 mmg/dL, although circadian diurnal fluctuations occur in concentration.(4) Circadian diurnal variation peaks at 9:30 AM and reaches a low at 8 PM with differences of 19 mmg/dL.(6) Rather than an enterohepatic circulation, zinc experiences a similar enteropancreatic recycling.(4) 

Zinc is an integral component of about 200 metalloenzymes, including carbonic anhydrase, alcohol dehydrogenase, carboxypeptidase, glutamic dehydrogenase, lactic dehydrogenase, and alkaline phosphatase as well as hormones, such as thymulin, testosterone, prolactin, and somatomedin.(4) 

Zinc deficiency symptoms are nonspecific, perhaps in part because of their need in so many enzymes and their critical roles in both protein synthesis and molecular genetics. Many enzymes may become nonfunctional in the absence of zinc, even though the presence of the enzyme remains undisturbed. The integrity of cell membranes, including the integrity of red and white blood cells, depends upon loosely bound ionic zinc. Moreover, zinc deficiency is a cause of 33 percent of all olfactory disorders. In many respects, the total picture of zinc deficiency is reminiscent of essential amino acid deficits.(4) 

Zinc deficiency stunts growth and causes serious metabolic disturbances. Inadequate intake in people and animals results in serious immunodeficiency, increased numbers of infections, increased severity of infections, stunted growth, and delayed sexual maturation. As deficits become worsened, skin and orificial lesions develop only to be subjected to an unchallenged bacterial invasion, yet lesions do not mount a significant inflammatory response.(4) Therefore, severe zinc deficiency produces a patently obvious immunodeficiency in the cell-mediated (T-cell) immune system. Advanced deficiency culminates in diarrhea, severe wasting, and ultimately death. This scenario is typical of at least 12 animal species including man.(4) 

Zinc, HIV and AIDS

Zinc deficiency symptoms are similar to those of patients suffering from AIDS. Siegal and co-workers first described AIDS patients with concurrent herpes simplex infection in 1981. One impression of the disease to Siegal and co-workers was immunosuppression induced by zinc deficiency.(7) Zinc serum levels were normal. Normalcy could have been brought about by the patients' advanced state of catabolism as patients were all anorectic and cachectic. Additional zinc was administered to these first four AIDs patients of record with no effect. The amount of zinc given was not stated but was probably about 15 mg/day, the recommended daily allowance (RDA). 

Unless zinc was given at very high doses for 10 days or longer to restart the thymus in the manner of Golden and colleagues (about 150 mg/day, or about 1 mg per pound of body weight),(8) little could be expected. This amount of zinc is ten times the RDA and is essentially identical to the dosages used to treat colds. Libanore and co-workers found significantly lower (P < 0.001) zinc in serum in AIDS patients. Zinc decreased with the worsening of the clinical and immunological picture (CD4 helper inducer cells), suggesting administration of zinc to the authors.(9)

Weiner suggested administration of zinc to homosexual AIDS patients.(10) Low serum zinc, frequently found in male homosexuals,(10) IV drug abusers, and other malnourished persons will significantly impair T-cell function. Impairment would prevent complete elimination of virus after initial T-cell response or at any time during infection. Demise of T-cells and immunosufficiency, and increases in severity of HIV infection, and ultimately AIDS would result. Administration of 1 mg zinc per pound body weight per day used by Golden and colleagues,(8) or 100 mg zinc per day used by Duchateau and colleagues(11,12) given on a prophylactic basis or after the time of contracting HIV infection should restore or improve thymic function, double T-cell function, increase T-cell count, help stabilize plasma cell membranes, and have a chance of eliminating HIV infection or preventing HIV infection from progressing to AIDS. (See Chapter 2 for further information on the effects of zinc in stimulating T-cell lymphocyte function, including reduction of suppressor T-cells, and enhancement of interferon production.) 

J. M. Coffin reported that the long, clinically latent phase that characterizes human immunodeficiency virus (HIV) infection of humans is not a period of viral inactivity, but an active process in which cells are being infected and dying at a high rate and in large numbers (billions per day).(13) These results led him to a simple steady-state model in which infection, cell death, and cell replacement are in balance, and imply that the unique feature of HIV is the extraordinarily large number of replication cycles of both T-cell lymphocytes and viruses that occur during infection of a single individual. Considering the extrodinary dynamics of T-cell growth and replacement, administration of zinc in the dosages suggested seems mandatory to provide sufficient zinc to allow uninterupted T-cell growth, and more particularly transformation of T-cell lymphocytes to the activated state.

Unless all HIV are successfully eliminated by activated T-cells, coincidental severe, untreated bacterial infections after HIV infection could result in a LEM reaction by the liver temporarily withdrawing zinc from the blood and T-cells,(13,14) perhaps resulting in temporary loss of T-cell control of HIV, resulting in HIV reinfection, as would be the case with any therapeutic agent used in the treatment of HIV. In HIV infection, zinc serum concentrations should be maintained near the upper limit of the normal range (150 mmg zinc/dL), but not above the normal range. Immunosuppression and other hemopoietic side effects from twice normal or greater zinc serum concentration may result (see below and specifically references 32, and 34), particularly if serum concentrations of copper, iron, and manganese fall below their normal ranges. Conversely, notice the familial hyperzincemia discussion below.

Experimental zinc treatment was tested for immunostimulatory effects in an HIV-infected 180-pound man. T-cell function change [the resultant of T-cell count change (from 90 to 120) and the fraction of T-cells activated change (from 7 to 10 percent)], doubled within the first 30 days. As the patient left the study, follow-up was not possible. Dosage tested was 3 to 5 tablets daily with each tablet containing 30 mg zinc, 2 mg iron, 2 mg manganese, and 0.3 mg copper.(15) 

GRAS Status Assessment

Certain zinc salts are food substances and are Generally Recognized As Safe (GRAS). In 1973, the Life Sciences Research Office re-evaluated health aspects of supplementing food with certain GRAS zinc salts that were commonly used as food ingredients.(16) Their assessment was based upon information summarizing worldwide scientific literature gathered by the Food and Drug Administration from 1920 to 1970, supplemented by literature searches of Toxline and Medline available as of November 1973, and summarized in the following paragraphs. The Select Committee on GRAS Substances concluded: "There is no evidence in the available information on zinc that demonstrates, or suggests reasonable ground to suspect, a hazard to the public when they are used at levels that are now current in the manner now practiced. However, without additional data, it is not possible to determine whether a significant increase in consumption would constitute a dietary hazard."(16) 

The Select Committee found daily intake of zinc in the total diet varied considerably with age. The observed daily intake of elemental zinc per kilogram of body weight is found in Table (16). After reviewing the available data, the Select Committee commented that because of the central role of zinc as either an activator of certain enzymes or as a coenzyme in many metabolic reactions, relatively large excesses of zinc salts in the diet can lead to metabolic dysfunction. In particular, interaction of zinc with several other mineral nutrients, notably iron, copper, manganese and calcium, suggests major modification of zinc nutritional balance might lead to significant metabolic disturbances. 

Human colostrum has been measured to contain 825 mmg/dL on the first day of lactation, falling to 507 mmg/dL on the fifth day of lactation, remaining at over 200 mmg/dL until about the third month of lactation, remaining at over 200 mmg/dL until about the third month of lactation, and at 70 mmg/dL for nearly the entire first year of life.(17) Zinc from colostrum activates infant cell-mediated immunity as well as stimulates cell growth. Cell mediated immunity must remain suppressed in the fetus and uterus to prevent host-graft disorders. Human amniotic fluid contains an antibacterial amount of zinc 4.4 times serum concentration.(18) 

The Select Committee found orally ingested zinc to be absorbed largely from the duodenum. The degree of absorption is substantially affected by nutritive status with respect to zinc, dietary phytate, calcium, and phosphorus. Usually about 8 to 10 percent of zinc ingested by rats, cats, and dogs is absorbed, and the rest is excreted in feces. Retention may be higher in bone and skin than in other tissues, but the element is present and needed in every cell. The average biologic half-life of zinc in the adult man is 154 days. As happens with other metals, zinc salt ingested in toxic amounts cause a variety of metabolic changes. 

Toxic doses of zinc inhibit intestinal alkaline phosphatase, xanthine oxidase, liver catalase, cytochrome oxidase, and succinic dehydrogenase; also, toxic doses modify excretion of nitrogen, phosphorus, and sulfur. For example, feeding zinc oxide as 1 percent of the diet of rats resulted in increased urinary excretion of nitrogen, while phosphorus and sulfur excretion was reduced. Fecal excretion was also increased, resulting in decreased net retention. Urinary excretion of both uric acid and creatine was increased.(16) 

The most important adverse effect of feeding toxic doses of zinc appears to be a specific microcytic hypochromic anemia, probably related to changes in iron and copper utilization. For example, decreases in iron storage proteins were observed when rats were fed a diet containing 0.4 percent zinc as zinc oxide. In other studies, diets containing 0.75 percent zinc resulted in decreased red cell life spans and increased iron excretion. Feeding an excess of zinc oxide (0.6 percent as zinc) to rats resulted in a decrease in both iron and copper levels of all tissues, explaining most of the enzyme changes. This effect of zinc excess on iron and copper metabolism appears to be the result of interference with iron and copper utilization at the cellular level and the increased excretion of copper. 

Evidence for this interaction is observed in studies of iron and copper supplementation. Supplementation of these metals can reverse anemia caused by excess zinc feeding. A similar interaction has been found with calcium and manganese. Increasing dietary calcium increased loss of zinc in rats and resulted in decreased absorption and decreasing turnover. In other studies, high calcium and phosphorus intakes appeared to increase zinc requirement in rats. By contrast, feeding an excess (0.75 percent zinc as zinc carbonate) in diets of young rats for one week resulted in a marked decrease in bone calcium and phosphorus.(16) 

In the rat, a lethal dose in 50 percent of cases (LD₅₀) has been reported to be 1374 mg per kg for both zinc sulfate heptahydrate and for zinc acetate heptahydrate but 750 mg per kg for zinc chloride. Values of similar magnitude have been reported for mice and rabbits. One human fatality has been reported. A woman's death was attributed to zinc sulfate poisoning following accidental consumption of about 30 grams of the salt. This intake amounted to about 500 mg per kilogram of body weight, a dosage similar to dosages found to be often lethal in animal studies. 

Many short-term tests with high levels of zinc salts fed to different animal species have shown no adverse effects at levels below 100 mg of the salt per kilogram per day, but curiously, extensive studies indicate that feeding zinc oxide or zinc sulfate at levels greatly in excess of 500 mg of the salt per kilogram have no consistently adverse effects. The nature of the compound appears to play a significant role in toxicity. Limited studies of zinc sulfate intake have been conducted in human beings. There was no evidence of toxicity at levels of up to 660 mg per day of the heptahydrate (about 10 mg of the salt per kg per day) for up to 3 months.(16) 

Long-term dosages in rats have been carried out with zinc chloride, oxide, carbonate, and sulfate. These studies, extending for one year and over three generations, showed no effect at levels up to 0.25 percent of diet. In other investigations, zinc sulfate fed at dietary levels of about 100 ppm to rats and dogs was reported to cause hematologic changes including microcytosis, coupled with polychromasia in some animals and hyperchromomasis in others; in addition, more rapid turnover of red blood cells was observed.(16) 

No evidence of carcinogenicity of several zinc salts was noted in rat studies over three generations nor in feeding rats zinc oxide (equivalent to 34.4 mg of zinc daily for 29 weeks), or zinc carbonate (equivalent to 1 percent zinc in diet) for 39 weeks. No significant carcinogenic differences between zinc-treated mice (5,000 ppm zinc as zinc sulfate) and control groups were observed. These findings, the comprehensive critical analyses of the literature by experienced investigators, and recent reviews by two laboratories specializing in experimental carcinogenesis make it evident than zinc salts taken orally should not be considered a carcinogenic hazard.(16) 

Animal reproduction studies performed through several generations have disclosed no evidence of any adverse effect on fertility, gestation, and health of fetus from feeding diets of up to 0.25 percent zinc chloride, zinc oxide, zinc carbonate, or zinc sulfate to rats. In addition, specific studies of effects of excess dietary zinc fed as oxide, malate, acetate, citrate, or sulfate on chemical composition and enzymatic activities of maternal and fetal tissues have shown no adverse effects. Teratologic tests on three species of animals were negative: daily oral administration of up to 30 mg zinc sulfate per kg of body weight in mice (day 6 through day 15 of gestation), up to 42.5 mg per kg in rats (day 6 through day 15 of gestation), and up to 88 mg per kg in hamsters (day 6 through day 10 of gestation) had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities observed either in soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in sham-treated controls.(16) 

Currently several zinc compounds are listed as GRAS by the Food and Drug Administration (FDA).(19) An official USP XXI monograph for zinc acetate exists.(20)

Recent Human Safety and Toxicologic Data

In 1979, Prasad found zinc as being relatively nontoxic in comparison with other trace metals.(21) Many of the toxic effects attributed to zinc in the past are actually attributable to contaminants such as lead, cadmium, or arsenic. Zinc is noncumulative, and the proportion absorbed is thought to be inversely related to the amount ingested. Vomiting, a protective phenomenon, occurs after ingestion of large quantities of zinc. Two grams of zinc sulfate have been recommended as an emetic. The symptoms of zinc toxicity in human beings include dehydration, electrolyte imbalance, abdominal pain, nausea, vomiting, lethargy, dizziness, and lack of muscular coordination. Acute renal failure will occur within hours of ingesting large amounts of zinc chloride. Death is reported to have occurred after ingestion of 45 grams of zinc sulfate. This dose is considered massive, considering the daily requirement of zinc for man is in the range of 15 to 30 mg/day. The competition between zinc and copper for intestinal absorption and protein-binding sites is well known, and there is a high probability that copper deficiency will be induced in patients receiving daily high amounts of zinc for at least a month.(21) 

In 1979 the National Research Council sub-committee on zinc found it not to be highly toxic. Zinc toxicosis occur only when high dose levels overwhelm the homeostatic mechanisms controlling zinc uptake and excretion. Reports of zinc tolerance as well as toxicosis in human beings are sparse, but existing evidence suggests that 500 to 1,000 milligrams or more of zinc may be ingested on a daily basis without outwardly observable adverse effects. Ten or more grams of the metal taken as a single oral dose may produce gastrointestinal distress, including nausea, vomiting, and diarrhea. The committee also found ingestion of large doses of zinc to reduce beneficially toxic stores of cadmium.(22) 

By 1988, Cunnane's review had little more to offer on the toxicity of zinc. Cunnane suggested that zinc was not completely nontoxic, even in therapeutic dose range (50 to 300 mg/day) on a long-term basis. Frequently, doses of zinc in excess of 50 mg causes gastrointestinal side effects, including nausea. Zinc has biphasic and triphasic effects on many pathways and on the immune system, particularly T-cell lymphocyte function as will be discussed later in this section. Zinc's suppression of copper, iron and manganese utilization may also be an important detriment in the long run without their concurrent administration. Administration of zinc may beneficially deplete stores of iron resulting in a reduced incident of angina pectoris and ischemia. Zinc is well known to compete with these metals for gut absorption sites and blood transport proteins. Long-term doses of zinc required to deplete copper are reported to vary from 150 to 5,000 mg/day.(23)

Pharmaceutical administration and uses, adverse effects, absorption, and the fate of zinc and zinc compounds were reviewed in Martindale The Extra Pharmacopoeia in 1989.(24) No significant indications of toxicity or adverse effects were reported from therapeutic doses of zinc, although numerous pharmacologic uses of zinc were reported. Probable lethal oral doses of soluble zinc salts including zinc acetate were reported between 50 mg per kg body weight (between one teaspoon and one ounce for an adult) and 5 grams per kg body weight (between 1 ounce and one pint for an adult).

In Clinical Toxicity of Commercial Products, Gosselin reported the toxicity rating of soluble zinc salts was 3 to 4, or moderately toxic to very toxic.(25) Better estimates place probable lethal dose for a human being at 500 mg per kg, which is close to rat LD ₅₀dose of 750 mg per kg for zinc acetate. For a 175 pound man, this would mean consuming between 40 and 60 grams of zinc acetate, which is about 3 to 5 heaping tablespoons. 

Numerous other original and review articles found no toxicity at levels used to treat common colds, particularly when used only for 7 days or less.(26-31) 

The finding of reversible, adverse immune system effects and decreased plasma high-density lipoprotein-cholesterol by Chandra when zinc serum levels were increased to double normal zinc serum levels (32) needs reconciliation with evidence showing some families have chronic zinc serum concentrations 3 to 5 times normal. Heritable hyperzincemia seemed to occur without obvious harm, and family members with high zinc serum content lived normal lives.(33) 

Even in a case of extreme abuse of zinc gluconate (10- to 20-fold the recommended 23-mg zinc dosage for common colds) taken every 2 hours for 4 months, the principal clinical findings consisted of anemia, neutropenia, very high alkaline phosphatase, a serum zinc concentration 10 times higher than normal (antiviral), and copper and manganese concentrations one-tenth normal. These findings were reversed with no apparent harm after withdrawal of zinc and administration of trace amounts of copper and manganese. Also, the patient was not ill during the time of apparent toxic overdose of zinc gluconate.(34) This observation is interesting as it documents an antiviral zinc serum level nearly 10 times normal, showing that relatively normal cell life and human life at antiviral serum zinc concentrations is possible. 

With lower amounts of oral zinc supplementation, (15, 50 and 100 mg zinc per day), Freeland-Graves observed no consistent changes in either plasma cholesterol or high-density lipoprotein-cholesterol but did observe a significant negative correlation between dietary copper and plasma cholesterol.(26)  Consequently, effects of elevated zinc serum concentration on cholesterol observed by Chandra are actually caused by reductions in copper serum concentrations induced by elevated zinc, rather than being caused directly by elevated zinc. 

Lack of Toxicity in Common Cold Studies

From the perspective of treatment with zinc for 7 days, significant benefits to T-cell immune system occurred in Chandra's patients during the first 2 weeks while zinc serum levels remained in the upper normal range.(32) As demonstrated by Farr and others, zinc serum level and other indicators did not leave normal ranges during administration of 23 mg zinc from zinc gluconate administered every 2 hours for 7 days.(35) No significant differences in vital signs between patients receiving zinc and patients receiving placebo occurred. Clinical laboratory tests, including complete blood count, differential leukocyte count, metabolic profile, urinalysis, and levels of copper and zinc in serum showed no significant differences between the two groups except for an increased mean level of zinc in serum of 105 versus 88 mmg zinc/dL (P < 0.001, t = 4.40). Normal levels of zinc in serum are 70 to 150 mmg/dL in the reference laboratory.(35) 

In the English study, Al-nakib and colleagues found a minor variation in concentration of zinc in plasma of volunteers, although no values were outside reference limits.(36) All volunteers receiving zinc showed a marked increase in urinary zinc excretion.(36) Zinc acetate (150 mg elemental zinc per day) has been sponsored as an orphan drug for long-term treatment of Wilson's disease.(37) 

Possible Adverse Effect in Pregnancy

Kumar reported in an uncontrolled trial effects of supplementing 100 mg zinc sulfate daily during the third trimester of pregnancy to subjects on diets providing 6 mg zinc/day (total 31 mg zinc/day). Of the four subjects treated by Kumar, three premature births and one stillbirth occurred, compared to 20 to 30 percent considered normal for women in underdeveloped countries including India.(38) Undesirable changes in the fetus have been associated with intake of very low or excessive amounts of zinc, magnesium, and manganese.(39) 

Hambidge and associates reported no change in maternal serum status or other problems from supplemented diets providing 22 mg zinc per day in a study of 10 middle-income United States women.(40) Zinc in perinatal nutritional supplements is either absent or most often present in 25-mg dosages.(41) A comprehensive 1994 computer search indicated toxicity from supplemental zinc in human or animal pregnancy appears otherwise unreported.

Industrial Safety and Material Safety Data Sheet for Zinc Acetate

Large non-pharmaceutical acute and chronic dosages and concentrations of a number of zinc compound powders used in industry, including zinc chloride, zinc sulfate, zinc acetate, zinc oxide, and zinc gluconate, are considered toxic to extremely toxic and painful to tissues of the upper and lower respiratory system. In sufficient concentrations, the powders can increase histamine release from mast cells,(42) causing inflammation and edema. In the special case of zinc chloride, death can occur primarily from the extremely caustic effects of chloride on respiratory tissues. Zinc oxide dust has been said to relieve asthma when briefly inhaled. OSHA requires Material Safety Data Sheets (MSDS)(43,44) for chemicals used in industry.

Concluding Comments on Toxicity

Lipophilic zinc complexes easily penetrate the cell plasma membrane and were found to be cytotoxic in direct relationship to their lipophilicity by Merluzzi and colleagues,(45) and one might wonder if interference with zinc fingers is one cause of such toxicity. Conversely, some symptoms of disease, such as delayed sexual maturity, rising from insufficient dietary zinc can now be attributed to the inability of estrogen and androgen receptors to fold properly in the absence of zinc.(3)

Although the use of Zn²⁺-ion releasing zinc lozenges causes a localized extracellular rise in Zn²⁺ ions at the concentrations used, they decrease the permeability of the cell plasma membrane to exclude additional Zn²⁺ ion absorption into the interior of cells. If zinc accumulated in cells from zinc lozenge treatment, zinc would be cytotoxic. Consequently, only zinc compounds releasing 100 percent of their zinc at pH 7.4 as Zn²⁺ ions, such as zinc acetate, are believed completely free of zinc cytotoxicity. Other zinc compounds releasing neutral cell membrane-penetrating zinc complexes may result in some degree of cytotoxicity, manifested in a variety of ways from oral irritation to outright toxicity. 

References:  

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2. Kornberg A. Origin of DNA on Earth. In: 1982 Supplement to DNA Replication. San Francisco: W. H. Freeman Co.; 1982:S224. 
   
   
3. Rhodes D, Klug A. Zinc Fingers. Scientific American. 993;268: 56-65. 
   
   
4. Zapsalis C and Beck RA. Food Chemistry and Nutritional Biochemistry. New York:John Wiley & Sons; 1985:1006-1009. 
   
   
5. Oberleas D, Harland BF. Nutritional agents which affect metabolic zinc status. In: Zinc Metabolism: Current Aspects in Health and Disease. New York:Alan R. Liss, Inc.; 1977:11-24. 
   
   
6. Markowitz ME, Rosen JF, Mizruchi M. Circadian variations in serum zinc (Zn) concentrations: correlation with blood ionized calcium, serum total calcium and phosphate in humans. American Journal of Clinical Nutrition. 1985; 41:689-696. 
   
   
7. Siegal FP, Lopez C, Hammer GS, et al. Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. The New England Journal of Medicine. 1981;305:1439-1444. 
   
   
8. Golden MHN, Jackson AA, Golden BE. Effect of zinc on thymus of recently malnourished children. The Lancet. Nov. 19, 1977:1057-1059. 
   
   
9. Libanore M, Bicocchi R, Raise E, et al. Zinc and lymphocyte subsets in patients with HIV infection. Minerva Medica (Italy). 1987;78:1805-1812. 
   
   
10. Weiner RG. AIDS and Zinc Deficiency. Journal of the American Medical Association. 1984;252:1409-1410. 
    
    
11. Duchateau J, Delepesse G, Vrijens R, et al. Beneficial effects of oral zinc supplementation on the immune response of old people. The American Journal of Medicine. 1981;70:1001-1004. 
    
    
12. Duchateau J, Delespesse G, Vereecke P. Influence of oral zinc supplementation on the lymphocyte response to mitogens of normal subjects. The American Journal of Clinical Nutrition. 1981;34:88-93. 
    
    
13. Subcommittee on Zinc, Committee on Medical and Biological Effects of Environmental Pollutants, Division of Medical Sciences, Assembly of Life Sciences National Research Council. Zinc. Baltimore:University Park Press; 1979;235. 
    
    
14. Beisel WR, Pekarek RS, Wannemaker RW Jr. Homeostatic mechanisms affecting plasma zinc levels in acute stress. In: Prasad AS, Oberleas D eds. Trace Elements in Human Health and Disease. New York:Academic Press; 1976;97.
     
    
15. Weaver CA, Austin, Texas. Manuscript in progress. 
    
    
16. Select Committee on GRAS Substances. Evaluation of the Health Aspects of Certain Zinc Salts as Food Ingredients, (SCOGS-21). Bethesda, MD: Life Sciences Research Office, Federation of American Societies for Experimental Biology. 1973. 
    
    
17. Shaw JCL. Trace elements in the fetus and young infant. American Journal of Diseases of Children. 1979;133:1260-1268. 
    
    
18. Prasad AS. Zinc in Human Nutrition. Boca Raton, FL:CRC Press. 1979:24. 
    
    
19. Part 182-Substances Generally Recognized as Safe, and Part 184-Direct Food Substances Affirmed as Generally Regarded as Safe. Code of Federal Regulations Title 21:Food and Drug Administration, Department of Health and Human Services, Parts 170-199, revised April 1, 1990, Washington DC:Office of the Federal Register National Archives and Records Administration; 1990. 
    
    
20. Zinc Acetate. The United States Pharmacopoeia, Twenty-Second Revision and National Formulary XVII, Rockville, MD:United States Pharmacopoeia Convention. 1990:1462. 
    
    
21. Prasad AS. Zinc in Human Nutrition. Boca Raton, FL: CRC Press; 1979:66-68. 
    
    
22. Subcommittee on Zinc, Committee on Medical and Biological Effects of Environmental Pollutants, Division of Medical Sciences, Assembly of Life Sciences National Research Council. Zinc. Baltimore, MD:University Park Press; 1979:305. 
    
    
23. Cunnane SC. Zinc: Clinical and Biochemical Significance. Boca Raton, FL: CRC Press;1988:65-66. 
    
    
24. Zinc. In Reynolds JEF, Parfitt K, Parsons AV, et al. eds. Martindale, The Extra Pharmacopoeia, Twenty-Ninth Edition. London:The Pharmaceutical Press; 1989. 
    
    
25. Gosselin RE, Smith RP, Hodge HC, et al. Clinical Toxicology of Commercial Products. Fifth ed. Baltimore:Williams & Wilkins; 1984:II-143. 
    
    
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27. Prasad AS. Trace Elements and Iron in Human Metabolism. New York:Plenum Medical Book Company; 1978:328-329.
     
    
28. Underwood EJ. Trace Elements in Human and Animal Nutrition. 4th ed. New York:Academic Press; 1977:230-232. 
    
    
29. Lantzsch HJ, Schenkel H. Effect of specific nutrient toxicities in animals and man: Zinc. In Rechcigl, Jr. Ed. CRC Handbook Series in Nutrition and Food. West Palm Beach, FL:CRC Press, Inc., 1978. 
    
    
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34. Pfeiffer CC, Papaioannou R, Sohler A. Effect of chronic zinc intoxication on copper levels, blood formation and polyamines. Orthomolecular Psychiatry. 1980;9:79-89. 
    
    
35. Farr BM, Conner EM, Betts RF, et al. Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds. Antimicrobial Agents and Chemotherapy. 987;31: 1183-1187. 
    
    
36. Al-Nakib W, Higgins PG, Barrow I, et al. Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges. Journal of Antimicrobial Chemotherapy. 1987;20: 893-901. 
    
    
37. Zinc Acetate. In: USP Drug Information for the Health Professional, V. Orphan Drugs and Biological Listing. Rockville, MD:The United States Pharmacopoeial Convention, Inc; 1992;2:58-59. 
    
    
38. Kumar S. Effect of zinc supplementation on rats during pregnancy. Nutrition Reports International. 1976;13:33-36. 
    
    
39. Krause MV, Mahan LK. Food, Nutrition and Diet Therapy. Philadelphia:W. B. Saunders Co.; 1979: 283. 
    
    
40. Hambidge KM, Krebs NF, Jacobs MA et al. Zinc nutritional status during pregnancy: a longitudinal study. American Journal of Clinical Nutrition. 1983;37:429-442. 
    
    
41. Physicians' Desk Reference. 47th ed. Montvale, NJ: Medical Economics Data; 1993. 
    
    
42. Harisch G, Kretschmer M. Some aspects of a non-linear effect of zinc ions on the histamine release from rat peritoneal mast cells. Research Communications in Chemical and Pathological Pharmacology. 1987;55:39-48. 
    
    
43. Material Safety Data Sheet for Zinc Acetate Dihydrate. Heico Chemical, Delaware Water Gap, NJ. 1993. 
    
    
44. Zinc Acetate Dihydrate. J.T. Baker, Phillipsburg, NJ. 1990. 
    
    
45. Merluzzi VJ, Cipriano D, McNeil D, et al. Evaluation of zinc complexes on the replication of rhinovirus 2 in vitro. Research Communications in Chemical Pathology and Pharmacology. 1989;66: 425-440. 

HANDBOOK FOR CURING THE
COMMON COLD George A. Eby

Published by:
Publications Division
George Eby Research
Austin, Texas U.S.A.

Copyright (c) 1994 by George A. Eby

The Clinical Effects of Manganese (MN)
By E.Blaurock-Busch, PhD
Laboratory Director, Trace Minerals International of Boulder, Colorado

The human body contains approximately ten milligrams of manganese, most of which is found in the liver, bones, and kidneys. This trace element is a cofactor for a number of important enzymes, including arginase, cholinesterase, phosphoglucomutase, pyruvate carboxylase, mitochondrial superoxide dismutase and several phosphates, peptidases and glycosyltransferases. In certain instances, Mn2+ may be replaced by Co2+ or Mg2+. Manganese functions with vitamin K in the formation of prothrombin. 

Functions: 

• Normal skeletal growth and development 

• Essential for glucose utilization 

• ipid synthesis and lipid metabolism 

• Cholesterol metabolism 

• Pancreatic function and development 

• Prevention of sterility 

• Important for protein and nucleic acid metabolism

• Activates enzyme functions

• Involved in thyroid hormone synthesis

Sources: (Good sources include) rolled oats, whole grain, parsley and (green) tea.

Deficiency symptoms:

• Ataxia 

• Fainting 

• Hearing loss 

• Weak tendons and ligaments 

• Possible cause of diabetes. Medical studies indicate that manganese deficiency impairs glucose metabolism and reduced insulin production.

Manganese deficiency has been linked to myasthenia gravis. Manganese activates several enzyme systems and supports the utilization of vitamin C, E, choline, and other B-vitamins. Manganese and zinc therapy can reduce copper levels and therefore manganese and/or zinc may be of therapeutic value in the treatment of symptoms linked to excess copper. 

Toxicity:

Excess manganese interferes with the absorption of dietary iron. Long-term exposure to excess levels may result in iron-deficiency anemia. Increased manganese intake impairs the activity of copper metallo-enzymes. Manganese overload is generally due to industrial pollution. Workers in the manganese processing industry are most at risk. Well water rich in manganese can be the cause of excessive manganese intake and can increase bacterial growth in water. Manganese poisoning has been found among workers in the battery manufacturing industry. Symptoms of toxicity mimic those of Parkinson's disease (tremors, stiff muscles) and excessive manganese intake can cause hypertension in patients older than 40. Significant rises in manganese concentrations have been found in patients with severe hepatitis and post-hepatic cirrhosis, in dialysis patients and in patients suffering heart attacks. Water: EPA recommends a level of 0.05PPM in drinking water, based upon taste rather than health. 

Low Manganese Levels: 

• Symptoms and side-effects of manganese deficiency are: 

• Infertility 

• Impaired glucose metabolism 

• Diseases of the skeletal structure, and impaired growth 

• Pancreatic dysfunction 

• Elevated blood pressure 

• Atherosclerosis 

• Reduced protein metabolism 

• Reduced immune function 

• Ataxia 
  

Selenium deficiency 

• Depressed activity of mammary glands in nursing mothers 

• Mitochondrial abnormalities 

Manganese deficiency has been associated with cancer, rheumatic conditions, rickets, morning sickness, jaundice, and diabetes. Excessive ingestion of iron, combined with hypochlorhydria, can cause an imbalance in the Mn/Fe ratio. 

Therapeutic consideration: 

A healthy person excretes approximately four mg/day, the minimum daily amount that should be consumed. Elevated calcium and/or phosphorus intake suppress the body's ability to absorb manganese, while an increase in Vitamin C improves cellular exchange. Manganese poisoning can be treated successfully with chelation therapy. 

Literature 

Blaurock-Busch E, Mineral & Trace Element Analysis, Laboratory and Clinical Application. Tmi 1997.

Kaplan LA, Pesce AJ. Clinical Chemistry. Theory, analysis, and correlation. 2nd ed. Mosby Co. 1989. 

Thomas L. Labor & Diagnose, 4th ed Med. Verlag Marburg 1992.

The Author: E Blaurock-Busch, PhD is Laboratory Director of Trace Minerals International of Boulder, Colorado and Co-chairman of the International Association of Trace Elements and Cancer Research, an international organization officially recognized by the Chinese government. Her book, Mineral & Trace Element Analysis, Laboratory and Clinical Application is a textbook used at schools and universities, including Beijing University. E. Blaurock-Busch has written numerous articles that have been translated and published in many languages. She had several books published in the US and Germany.

By Chester Myers
Chester Myers' Nutrition Series

Information Relating to HIV & Nutrition: HIV & Zinc And Copper revisited
March 1997 (Last modified on: 01/10/2000)

Poor wound healing, anorexia, abnormal taste and smell, diarrhea, skin inflammation, skin stretch marks, nail abnormalities such as white spots or brittleness, anemia, impaired glucose tolerance, central nervous system malfunction, muscle deterioration, increased oxidative damage of cell membranes, decreased thymic hormone activity, increased apoptosis/cell death, T-helper cell dysfunction, low CD4+ cells, increased CD8+ cells, and reduced natural killer cell activity, are some possible results of zinc deficiency. (Badgley, 1986; Chandra, 1984; Cunningham-Rundles et al, 1981; Forbes, 1984; Hoffer and Walker, 1978; Hunt and Groff, 1990; Odeh, 1992; Prasad, 1984; Stites and Terr, 1991).

In HIV disease, the most poignant observation may be that zinc supplementation has been observed to improve "accretion of lean tissue rather than fat after dietary zinc supplementation in children recovering from malnutrition" (Cavan et al, 1993). Interestingly, this study also wisely included supplementation with other micronutrients. All too often micronutrient supplementation studies have examined only one micronutrient without providing a broader baseline supplementation. In such studies, consequent imbalances are all too easily interpreted as being signs of toxic overdose of the one nutrient taken as the supplement, rather than the perhaps more likely effects of nutrient imbalance that may result from failure to simultaneously boost the baseline of other interrelated nutrients.

Copper deficiencies can cause reduced monocyte function, neutropenia, leukopenia, microcytosis, failure of erythropoiesis (formation and development of erythrocytes, i.e.,red blood cells), high oxidative damage to lipids, general oxidative damage, and, when caused by high zinc intake, high serum cholesterol (Hunt and Groff, 1990; Prasad et al, 1978; Turnlund, 1988).

Zinc and copper are two minerals that are essential for our health. Absorption of these into our bodies from food varies greatly; serum levels of both are regulated by a protein called metallothionein (Cousins, 1989), so that changing the level of one modifies the other in a see-saw fashion. From 14 to 41% of dietary zinc is absorbed in healthy people (Hunt and Groff, 1990; Sandstead, 1973); percentages of copper absorption are poorly known, but 25 to 60% has been suggested (Turnlund, 1988). The role of zinc in our bodies is linked with other materials, namely copper and sulfur-containing compounds called thiols (thiols include compounds such as N-acetyl cysteine, i.e., NAC). Zinc supplementation above normal dietary levels may be beneficial in HIV disease provided there is sufficient copper and cysteine (NAC) intake. Zinc supplementation without both copper and NAC, on the other hand, in my view is not to be recommended. I feel strongly that current information substantiates the several recommendations for daily zinc supplementation at levels of 50-100 mg, provided this is based on supplementation with a general multivitamin and multimineral (add up the zinc from the various sources to make sure 100 mg is not exceeded), 3-5 mg of copper (again, add up the amounts), and 1500-3000 mg of N-acetyl cysteine.

Background

Zinc

From 70 to over 100 enzymes in the human body are reported to require zinc; "zinc is a part of more enzyme systems than the rest of the trace elements combined". These enzymes/proteins include many from both the immune and digestive systems. Thus low levels of zinc interfere with digestion of our food, as well as our immune function. Immune dysfunction from zinc deficiency has been called "profound", and "severe deficiency is produced easily and rapidly" (Beisel, 1982).

Even for apparently healthy people, available data indicate that zinc deficiencies may not be uncommon in North America (Rivlin, 1990; Sandstead, 1973). A recent US study (Baum et al, 1994) noted that HIV- homosexual males may tend to be deficient in zinc in spite of intakes consistent with RDA recommendations. Earlier work from Europe indicated a similar trend on that side of the Atlantic (Bro et al, 1988). [COMMENT: low zinc levels in men can result from a high level of sexual activity since relatively high amounts of zinc are lost in seminal fluid (cum).]

Absorption of zinc from the digestive tract occurs in sections of the small intestine known to be often deteriorated in those living with HIV. While common measurements of zinc levels in the blood serum don't necessarily make it possible to predict low body levels from low serum levels (Bogden et al, 1990), the known digestive difficulties and increased metabolism, common with HIV, make it very likely that zinc levels deteriorate early in the disease (at least in the absence of supplementation). Furthermore, serum zinc levels are lower than the levels that provide maximum function of certain cells such as the peripheral blood mononuclear cells (Harrer et al, 1992). Thus, an apparently adequate serum level may not necessarily rule out functional deficiencies, and immune dysfunction has been singled out as a functional deficiency that may be likely when serum zinc levels are still normal (Rivlin, 1990). [One reviewer has suggested that measurement of both serum zinc levels and alkaline phosphatase is currently an appropriate assessment of zinc status (Arnaud et al, 1993). More specifically, "quantitative measurement of alkaline phosphatase activity in neutrophils before and after zinc supplementation" may be beneficial (Hunt and Groff, 1990).] Thymic hormone failure, common in HIV disease, has been attributed to zinc deficiency. While total thymulin levels remain normal, the active form is low because of low zinc levels (Arnaud et al, 1993; Bro et al, 1988; Cunningham-Rundles et al, 1981; Fabris et al, 1988; Mocchegiani et al, 1992; Ott et al, 1993).

Absorption of zinc into the body decreases when foods are cooked, especially when browning occurs. Many vegetables (legumes) and cereals are high in phytic acid which binds to zinc when calcium is present, and this makes the zinc poorly available to the body. If high levels of calcium are not present, phytic acid binding of zinc is not significant (Forbes, 1984; Hunt and Groff, 1990). It may therefore be wise to minimize dairy products and calcium supplements when eating meals high in vegetable/cereal content. NOTE: the evidence indicates calcium interferes with zinc absorption only when phytic acid is present. In addition, the body doesn't store zinc. The only 'store' is made up of those many proteins /enzymes that contain zinc; when dietary zinc intake is not enough, these proteins/enzymes (including muscle proteins) are cannibalized in a sequential fashion, those holding their zinc least tightly losing their zinc the fastest. An enzyme called carbonic anhydrase which is important for respiration is given high priority, and apparently maintains its zinc content when other body stores become depleted (Beisel, 1976; Hunt and Groff, 1990). Conversely, alkaline phosphatase becomes deprived of its zinc quite readily, thus making activity of this enzyme a good monitor for body zinc status (as already noted).

Low zinc levels may be complicated by low metallothionein, the protein that regulates zinc and copper levels in the serum, liver etc. This protein is made of about 30% of the amino acid cysteine. This amino acid becomes deficient early in the course of HIV infection, so that, uncorrected, not only is zinc likely to be deficient, but its regulation within the body is also likely compromised (see HIV & Cysteine, revisited, in this series, and listed at the end of this monograph). Futhermore, absorption of zinc from the gut into the body may also rely on compounds derived from cysteine (O'Dell, 1990; Pattison and Cousins, 1986; Reeves et al, 1993).

Studies have shown that zinc deficiency or its effects can be reversed by supplementation (Beisel, 1982; Black et al, 1988; Cavan et al, 1993; Cunningham-Rundles et al, 1981; Libanore et al, 1987). These studies include reversal of immune depression, such as diminished proliferative response by lymphocytes and neutrophil dysfunction when caused by zinc deficiency. In states of malabsorption such as occurs with Crohn's disease, supplementation at levels as high as 300 mg per day has been suggested to be necessary (Chandra, 1984). In HIV disease, Shambaugh (1989) suggested levels of 150 mg per day for up to 6 months may be necessary to correct even marginal zinc deficiencies.

A well-publicized study (Chandra, 1984) of high levels of zinc supplementation (300 mg per day) in healthy males observed effects that could be interpreted as being from copper deficiency, but otherwise "none of the subjects showed evidence of any untoward side effects". This study noted that 2000 mg of zinc can cause vomiting, abdominal cramps, and diarrhea. This study also noted the importance of supplementation at levels as high as 300 mg per day for those with zinc malabsorption such as with Crohn's disease. Curiously, this study has been cited in support of an unfocussed opinion that above either 15 mg or 300 mg per day of zinc may be toxic (Galvin, 1992). Other individuals have gone one step further by indicating 25 mg per day is a toxic level (Holley et al, 1992).


Copper

Copper is also a mineral essential in small amounts for proper health. As with zinc, copper is also part of different proteins/enzymes, mostly three proteins in blood plasma. A significant feature of copper deficiency is that it is a possible source of anemia due to a resulting defective iron metabolism secondary to a defective protein, called ceruloplasmin, which mediates use of iron by the body (Hunt and Groff, 1990). Supplementation with zinc, especially at levels of 150 mg per day or higher, without a simultaneous increase in copper intake results in copper deficiencies. These are reversed by appropriate copper supplementation (Black, et al, 1988; Prasad et al, 1978; Turnlund, 1988).

Copper absorption not only occurs in the small intestine, but also in the stomach. Because of this, in the absence of supplementation, serum zinc deficiencies could be accompanied initially by a simultaneous elevation of serum copper. It is also possible that low absorption of zinc across the small intestine mucosal membrane could permit increased absorption of copper in the stomach. Subsequent supplementation with zinc without copper would be expected to rapidly reverse this, and result in copper defiency - this could be just as bad for immunity as the initial zinc deficiency and may take longer to correct.

The story for copper levels in HIV disease has not been crystal-clear. However, a study presented at the San Francisco AIDS Conference (abstract THC677) noting an increase in copper level to accompany zinc decrease is probably the most consistent, although a report the following year (Florence Conference abstract WB2098) reported the opposite, i.e., copper deficiency. Bogden et al (1990) suggested that their observation of increasing copper levels in progressing from asymptomatic to ARC to AIDS may have been the result of weight loss. Since copper absorption is less likely to be compromised (it is absorbed in both the stomach and small intestine), and since zinc requirements are more likely to be elevated to a greater extent, it is logical that in the absence of zinc supplementation copper levels will initially become elevated, especially in early HIV disease. On initiation of zinc supplementation, it is important to remember the importance of also maintaining a balance of copper intake. While from 5X RDA levels (i.e., 75 mg per day for males, or 60 mg per day for females) to 100 mg per day of zinc intake have been recommended for those living with HIV, a level of 3 to 5 mg of copper supplementation is likely to be sufficient to balance the increased zinc inctake.


HIV and Zinc and Copper

Controls    12.3±2.5 µL
Stage II     10.5±2.7 µL
Stage IV     7.9±1.4 µL.

Beach et al (1992) observed marginally lower serum zinc in HIV+ subjects compared with HIV- gay controls. The difference was not statistically significant. Interestingly, serum copper was higher in the HIV+ subjects than in the controls. Although not considered by the authors, it would seem logical that this elevation in copper may have resulted from a real zinc decline. While it seems that zinc deficiencies may become profound in advanced HIV disease (Sappey et al, 1992), so-called early disease states have been generally documented with serum zinc levels that are low, but not lower than in HIV- gays. The data from Sappey and co-workers would make it seem likely that increased zinc deficiency may start early in HIV infection, but that the currently used assays don't detect deficiency until it is more severe; functional deficiency may precede deficiencies detected by common assay.

Comments by Harrer and co-workers (1992) also would argue for this conclusion. Another factor is that serum zinc levels decrease as part of the body's normal reaction to infection (Cousins, 1988; Koj, 1989); this results when the liver takes up higher than normal levels, apparently in order to meet increased needs of zinc-requiring enzymes to fight the infection (Beisel, 1976). Thus infection is initially accompanied by the acute phase response (APR) whereby humoral immunity is activated along with fever promotion, suppression of serum zinc and iron levels, changes in glucose metabolism, changes in energy utilization, and very large changes in blood proteins (Beisel, 1976; Dezube et al, 1992; Yamada et al, 1990). While some reports of low serum zinc levels may reflect only the acute phase response in early stages of HIV disease, it is still apparent that real decline of zinc does occur (Sappey et al, 1992), and probably should be expected if HIV disease progresses without a compensating adjustment of dietary intake.

In her monograph HIV Treatment Strategy, Part II: Therapeutic Basics for People Living with HIV, Dr. Lark Lands includes a quote from Dr. Richard Beach, at the 1992 Amsterdam International Conference on AIDS: "patients who were put on AZT who had low plasma levels did not do nearly as well on the drug as those who had normal levels of zinc."

There are reports noting benefits from zinc supplementation for those living with HIV. An early such report (Libanore et al, 1978) noted increases in T4 and T8 cell counts, and the T4/T8 ratio, after 10 mg zinc sulphate supplementation for 21 days in people with ARC, but increases of T4 cells and decline of T8 cells for those with LAS (lymphadenopathy syndrome). Gordon (1992) reported marked improvements with aggressive zinc therapy that included intravenous zinc therapy. Improved cell-mediated immune response, increased life expectancy, lower incidence of Kaposi's sarcoma, and fewer opportunistic infections were reported, although unmasking of herpes infection necessitated acyclovir treatment. For the study where cell-mediated immunity was assessed, an oral dose of 220 mg of zinc sulphate (i.e., about 75 mg of zinc) was administered orally. 

Some studies have examined dietary zinc intake and disease progression (Abrams et al, 1993; Graham et al, 1991; Tang et al, 1993).

Graham and co-workers noted "neither dietary copper and zinc nor their levels in toenails were associated with HIV-1 seropositivity or progression to AIDS", but that "serum copper levels were higher... and .. serum zinc levels were lower in the seropositive progressors than the seropositive nonprogressors and the seronegatives". This study continued to note that "in a logistic regression, higher serum copper and lower serum zinc predicted progression to AIDS independently of baseline CD4+ lymphocyte level, age, and calorie-adjusted dietary intakes of both nutrients". They concluded, however, that these markers resulted from disease activity/progression, and that a lack of correlation with dietary intake did not argue for supplementation. They did, however, state that their "findings do not completely exclude [that zinc supplementation might be useful]".

Three authors of the former study are also authors with Tang and other co-workers in a 1993 report of data from 281 HIV-1 seropositive homosexual/bisexual men. In this study it is noted that "increased intake of zinc was monotonically and significantly associated with an increased risk of progression to AIDS", while disease progression was not observed to relate to copper intake (the report implies that copper levels were elevated). While the higher level of supplemental zinc intake was 155 mg per day, in fact, few in the study had intakes this high (see below). Certainly, at 155 mg per day there may have been problems from copper balance.

The time from dietary intake assessment to study completion was 6-7 years in both cases. Abrams et al did not consider their results regarding zinc intake as statistically significant due to a "lack of variation in zinc intake". They noted that their group had generally high intakes "especially as a result of supplementation", and that overall "a high nutrient intake was associated with a significant decrease in the risk of AIDS when the models were adjusted for health status at baseline". Considering that the hazard ratio appeared to decrease at the higher level of zinc intake for the Abrams et al group, and that the 95% confidence levels of the higher intake levels in the Tang et al study spans a wide range (wider than any of the other nutrients listed!) including down to a low value of 1.16, it seems likely that there may be (an)other influencing factor(s). Dr. Lands (personal communication) has pointed out that, in the Washington/Baltimore area where the Tang et al study was done, the food portion of zinc intake may have been accompanied by a corresponding high level of toxic heavy metals such as mercury and cadmium.

Furthermore, an increase in negative effect was observed when supplemental levels (up to 155 mg/day) were added to food levels. Negative effects would be expected at this level if copper intake were not adjusted accordingly; furthermore, in HIV disease, it is important to ensure cysteine/thiol levels are adequate. Without corresponding data on copper levels and body cysteine status, it is difficult to attach much significance to what might be considered as an apparent negative influence from zinc supplementation in the Tang et al study. This is an area, however, that clearly needs controlled studies to examine all the interrelated parameters.

It would seem that the two groups of people in the latter two studies may be somewhat different, although, in general, both studies concluded that disease progression was slower among those with higher intakes of a number of micronutrients. The role of copper seems not to have been assessed, so that interpretation of the apparent trends with zinc intake are difficult to interpret.


Th1 vs Th2

Higher levels of CD8+ cells, and thus lower CD4+/CD8+ ratios , have been noted to be characteristic of many long-term survivors. Furthermore, disease progression correlates with loss of cell-mediated immunity (CMI), also called delayed-type hypersensitivity (DTH). Some people feel that events that support cell-mediated immunity (the Th1 response) encourage long-term survival for those living with HIV (Lanzavecchia, 1993; Pantaleo et al, 1993; Shearer and Clerici, 1992). The Th1 response tends to see-saw with humoral immunity, the Th2 response, so that what increases one may suppress the other. Humoral immunity involves antibodies, and is believed to be a more recent evolutionary development. In general, cell-mediated immunity is more sensitive to malnutrition, especially of the protein-calorie type, than is humoral immunity (Stites and Terr, 1991). Both humoral and cell-mediated immunity are suppressed by zinc deficiency (Beisel, 1982), but it appears that cell-mediated may be the more sensitive (Harrer et al, 1992). 

Zinc deficiency has been reported to increase CD8+ counts while suppressing CD4+ counts (Stites and Terr, 1991). Odeh (1992) noted that zinc deficiency causes a decrease in T-cell function while leaving B-cell function unaltered. In a study of zinc supplementation in HIV disease, however, both CD4+ and CD8+ counts have been observed to increase (Libanore et al, 1987). The CD4+/CD8+ ratio also increased, and currently the significance of this is difficult to interpret. Some might even say that this is perhaps therefore one argument for not supplementing with zinc in HIV disease (the study did not indicate copper status which confounds reasonable interpretation of the results). Since zinc deficiency seems to become progressively worse with disease progression, at least in the absence of supplementation, then it seems reasonable to try to ensure adequate zinc levels are maintained. Keep in mind the rather long list of possible effects of zinc deficiency - first page. Surely other ways must be sought for suppression of HIV.

There are various reports of test tube studies where zinc has been shown to either have negative or positive effects on parts of the virus. Interpretation of such studies needs to be done with discretion. Use of high levels of zinc to 'hurt' the virus is unlikely to be achieved at levels of intake that would not also be harmful to you, the host. Similarly, the body's need for zinc in so many of its components and functions would also make it unwise to consider zinc deprivation in an attempt to 'hurt' the virus. 


How much zinc and copper to take?

The normal concentration of plasma zinc is in the range of 85 to 120 µg/dL, i.e., 5.5-12 mg/100mL, or 13.0-18.3 µmol/L. The normal concentration for copper is in the range of 75 to 150 µg/dL (Hunt and Groff, 1990). To maintain these levels, for healthy people RDA recommended daily intakes are 12 or 15 mg for zinc (women and men, respectively) and 1.5 to 3 mg for copper. Some seem to consider this intake of zinc low even for healthy people and 15-50 mg per day has been suggested (Weiner, 1987). 

A review of zinc issues (Odeh, 1992) suggested "treatment with zinc supplements as an adjuvent therapy" for HIV disease, and noted the role of the sulfur-containing compounds such as metallothionein in zinc regulation in the body. Odeh argues that zinc supplementation may ameliorate "the deleterious effects" of -tumour necrosis factor, a cytokine which tends to increase to excessively high levels in people living with HIV.

Shambaugh (1989) has noted that 150 mg per day of zinc supplementation may be necessary to correct even marginal zinc deficiency. Chandra notes that up to 300 mg per day may be necessary in cases of zinc malabsorption such as with Crohn's disease. There are, however, concerns at these levels of supplementation on a long-term basis. In general, it is wise to make sure that there is adequate copper intake at any level of supplemental zinc intake.

A 1990 consideration of zinc toxicity (Fosmire) gave three categories of zinc supplementation levels: (i) levels "commonly consumed in self-selected supplements" (15-100 mg per day); (ii) pharmacological dosages" (100-300 mg per day); and (iii) "amounts sufficient to induce acute toxicity" (higher amounts). Fosmire notes that reports of overt toxicity resulted from zinc intakes in the order of 12,000 mg of elemental zinc over a 2- day period, and that "all symptoms disappeared with chelation therapy". At levels of 100-300 mg per day, copper deficiency resulted. Fosmire also notes that copper deficiency from such zinc supplementation may take considerable time to reverse. At levels under 100 mg per day, "some adverse consequences" may result, but again, only copper deficiency is noted as a problem. Fosmire notes that most studies of apparent zinc toxicity failed to "evaluate copper status", but where studied the role of copper deficiency was readily evident. One study with women noted zinc might also compete with iron status. Fortunately, iron status is more readily monitored.

Keusch and Thea (1993) have suggested that some people may not report their intake of supplements, and that, as a result, this may cause apparently contradicting results from different studies. This may be a very real factor. A major influence may be a distrust of opinions from some sources, even sources that are nominally professional. For example, while there is little evidence of toxicity from high levels of vitamin/mineral supplementation, it is not uncommon for some individuals to merely recognize the greater likeliness of deficiency while emphasizing out of proportion the dangers of excess intake.

The area of HIV disease has certainly not been exempt from such distortion. One example (Galvin, 1992) reviews some of the many known deficiencies that occur with HIV, and then proceeds to emphasize the dangers of toxic overdose, even omitting major literature that claims the opposite of some of her opinions.

Many of those living with HIV have done a great deal to educate themselves and may readily sense misconstrued concern that possibly derives more from dogma than knowledge of established literature. There is a very real danger that others who are less well-informed, but who are aware that their informed friends who take a balanced supplementation do so because they feel their wellness benefits from it, may embark on a supplementation program that results in imbalance. This may be critical in certain areas such as with zinc-copper-thiols.

There is a great need for informed nutritional counseling that reflects logic based on the extensive literature regarding HIV and nutrition, and immunity and nutrition in the broader sense.

For HIV+ people, educator Dr. Lark Lands gives an excellent review of nutrients for people living with HIV (HIV Treatment Strategy, Part II: Therapeutic Basics for People Living with HIV", 1994). Dr. Lands has one of the most extensive experiences in HIV disease, working closely with a number of HIV primary care physicians and patients. For zinc, the daily intake level suggested by Dr. Lands is 25-75 mg per day, in addition to what is contained in a multivitamin/mineral (which should be the basis for supplementation). Dr. Lands also emphasizes that more than 100 mg per day on a long-term basis may be toxic. This level is in line with the 75-100 mg per day suggested by registered dietitian Jennifer Jensen (on recommendation by Dr. Chandra to a meeting of the American Dietetic Association). Ms. Jensen has both extensive experience in HIV and nutrition, and advanced graduate level education in nutritional biochemistry. Both Dr. Lands and Jennifer Jensen are emphatic about the importance of an appropriate copper level of 2-4 mg per day accompanying this zinc supplementation.

The recommendations by both Dr. Lands and Ms. Jensen are in agreement with levels of zinc supplementation of 75 mg/day recommended at the 1992 Amsterdam International AIDS Conference by University of Miami researcher Dr. Baum and colleagues (abstract PoB 3675).

It is unfortunate that studies indicating zinc toxicity, or negative effects from zinc intake above that from normal food consumption, have not done detailed study of copper as a parameter. That is, for those studies where an apparent zinc toxicity was observed, the toxicity was likely due to a resulting copper deficiency rather than excessive zinc per se. In support of this, a modern textbook on human nutrition and metabolism lists only copper and thiol deficiencies as the major concerns re zinc supplementation above 40 mg per day, for apparently healthy individuals! The requirement of copper as a companion to zinc supplementation seems quite unequivoval (Prasad et al, 1978).

For those living with HIV, it would seem equally important that zinc supplementation be accompanied by supplementation with N-acetyl cysteine (NAC). Since NAC supplementation seems an absolute recommendation for those living with HIV (the various presentations at the Conference on Oxidative Stress in HIV/AIDS, NIH, 1993), this caveat is probably a redundant reminder. It would seem reasonable to conclude that until there are well-controlled studies of zinc AND copper intake in the presence of adequate cysteine, reports of zinc toxicity should be viewed with extreme caution, particularly in a disease where it seems zinc deficiency is far more likely than EITHER zinc normalcy OR zinc excess.


References:

B Abrams, D Duncan, I Hertzpicciotto, I., "A Prospective Study of Dietary Intake and Acquired Immune Deficiency Syndrome in HIV-Seropositive Homosexual Men", J acquir immune defic syndr 6:1993:949-958. 

J Arnaud, P Chappuis, MC Jaudon, J Bellanger, "Biological Indices Used for the Assessment of Zinc, Copper and Selenium Status in Huamns", Annales de Biol Clinique 51:1993:589-604. 

L Badgley, Healing AIDS Naturally, Human Energy Press, 1986. 

MK Baum, L Cassetti, P Bonvehi, G Shor-posner, Y Lu, H Sauberlich, "Inadequate Dietary Intake and Altered Nutrition Status in Early HIV-1 Infection", Nutrition 10:1994:16-20; MK Baum, G Shorposner, Y Lu, "Normal Triglyceride Levels in Early HIV-1 Infection", letter, AIDS 8:1994:131-132; MK Baum, G Shorposner, "Nutritional Requirements in HIV-1 Infection", letter, AIDS 8:1994:715. 

RS Beach, ME Gerschwin, LS Hurley, "Gestational zinc deprivation in mice: persistence of immunodeficiency for three generations", Science 218:1982:469-471. 

RS Beach, R Morgan, F Wilkie, E Mantero-Atienza, N Blaney, G Shor-Posner, Y Lu, C Eisdorfer, MK Baum, "Plasma Vitamin B12 Level as a Potential Cofactor in Studies of Human Immunodeficiency Virus Type 1 - Related Cognitive Changes", Arch Neur 49:1992:501-506. 

WR Beisel, "Trace Elements in Infectious Processes", Med Clin N. A. 60:1976:831-849. 

WR Beisel, "Single Nutrients and Immunity", Am J Clin Nutr 35:1982:S417-S468. 

MR Black, DM Medeiros, E Brunett, R Welke, "Zinc Supplements and Serum Lipids in Young Adult White Males", Am J Clin Nutr 47:1988:970-975. 

JD Bogden, H Baker, O Frank, G Perez, F Kemp, K Bruening, D Louria, "Micronutrient Status and Immunodeficiency Virus (HIV) Infection", Micronutrients and Immune Functions: Cytokines and Metabolism, Ann N.Y. Acad Sci 587:1990:189-195. 

S Bro, M Buhl, J Jørgensen, T Kristensen, M Hørder, "Serum Zinc in Homosexual Men with Antibodies against Human Immunodeficiency Virus", Clin Chem 34:1988:1929-1930. 

KR Cavan, RS Gibson, CF Grazioso, M Isalgue, M Ruz, NW Solomons, "Growth and Body Composition of Periurban Guatemalan Children in Relation to Zinc Status: a Longitudinal Zinc Intervention Trial", Am J Clin Nutr 57:1993:344-352. 

RK Chandra, "Excessive Intake of Zinc Impairs Immune Responses", JAMA 252:1984:1443-1446. 

RJ Cousins, "Molecular Biology and Micronutrient-Disease Relationships - Zinc as a Prototype", in Nutrition and the Origins of Disease, ed. CH Halsted, RB Rucker, Academic Press, 1988. 

C Cunningham-Rundles, S Cunningham-Rundles, T Iwata, G Incefy, JA Garofalo, C Menendez-Botet, V Lewis, JJ Twomey, RA Good, "Zinc Deficiency, Depressed Thymic Hormones, and T Lymphocyte Dysfunction in Patients with Hypogammaglobulinemia", Clin Immun Immunopath 21:1981:387-396. 

S Cunningham-Rundles, "Nutritional Factors in Immune Response", pp 233-244, Malnutrition: Determinants and Consequences, ed., PL White, N Selvey, AR Liss, 1984. 

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Author, Chester Myers, holds both honours B.Sc. and M.Sc. (1969) degrees in physical chemistry from Dalhousie University, and a Ph.D. (1975) from the University of Toronto (biophysical chemistry).