Diets, and Wilson's Disease
(Brewer G, et al, Journal
of the American College of Nutrition, 12, 1993)
It has been reported that copper is
less bioavailable from a vegetarian diet, compared to a mixed
diet, possibly because of the high content of fiber and phytate
in vegetarian diets. This finding suggests that a vegetarian
diet may be of value in the treatment of Wilson's disease,
a disorder caused by copper accumulation. Two patients with
Wilson's showed improvement on a vegetarian diet, despite
being almost totally noncompliant with anti-copper medication.
Comment: The typical American
diet contains only about 50% of the RDA for copper. Since,
as the present study indicates, the copper in a vegetarian
diet is less bioavailable, some vegetarians may be at risk
for developing copper deficiency. (Alan
R. Gaby, M.D. Copper, Vegetarian Diets, and Wilson's Disease,
Townsend Letter for Doctors, Issue 154)
(Hunt J , et al, The American
Journal of Clinical Nutrition, Volume 67 Number 3 March 1998)
Zinc absorption, mineral
balance, and blood lipids in women consuming controlled lacto-ovovegetarian
and omnivorous diets
absorption, mineral balance, and blood lipid concentrations were measured
in 21 women aged 33 ± 7 y (range: 20--42 y) consuming controlled
lactoovovegetarian and nonvegetarian diets for 8 wk each in a crossover
design. The lactoovovegetarian and nonvegetarian diets, respectively,
provided (by analysis) 973 and 995 mg Ca, 1.8 and 1.3 mg Cu, 367 and
260 mg Mg, 5.9 and 2.5 mg Mn, 1457 and 1667 mg P, 9.1 and 11.1 mg
Zn, and (by calculation) 40 and 16 g dietary fiber, 2.5 and 0.8 mmol
phytic acid, molar ratios of phytate to Zn of 14 and 5, and millimolar
ratios of (phytate × Ca) to Zn of 344 and 111.
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).
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.)
George A. Eby
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
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)
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
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
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
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
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
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
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)
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
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
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
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
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.
Butzow JL, Eichhorn GL. Different susceptibility
of DNA and RNA to cleavage by metal ions. Nature (London).
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- Rhodes D, Klug A. Zinc Fingers. Scientific
American. 993;268: 56-65.
Zapsalis C and Beck RA. Food Chemistry and
Nutritional Biochemistry. New York:John Wiley & Sons; 1985:1006-1009.
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.;
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;
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acquired immunodeficiency in male homosexuals, manifested by chronic
perianal ulcerative herpes simplex lesions. The New England
Journal of Medicine. 1981;305:1439-1444.
Golden MHN, Jackson AA, Golden BE. Effect
of zinc on thymus of recently malnourished children. The
Lancet. Nov. 19, 1977:1057-1059.
Libanore M, Bicocchi R, Raise E, et al. Zinc
and lymphocyte subsets in patients with HIV infection. Minerva
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Weiner RG. AIDS and Zinc Deficiency. Journal
of the American Medical Association. 1984;252:1409-1410.
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.
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.
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.
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.
Weaver CA, Austin, Texas. Manuscript in
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.
Shaw JCL. Trace elements in the fetus and
young infant. American Journal of Diseases of Children.
Prasad AS. Zinc in Human Nutrition. Boca
Raton, FL:CRC Press. 1979:24.
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;
Zinc Acetate. The United States Pharmacopoeia,
Twenty-Second Revision and National Formulary XVII, Rockville,
MD:United States Pharmacopoeia Convention. 1990:1462.
Prasad AS. Zinc in Human Nutrition. Boca
Raton, FL: CRC Press; 1979:66-68.
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.
Cunnane SC. Zinc: Clinical and Biochemical
Significance. Boca Raton, FL: CRC Press;1988:65-66.
Zinc. In Reynolds JEF, Parfitt K, Parsons
AV, et al. eds. Martindale, The Extra Pharmacopoeia, Twenty-Ninth
Edition. London:The Pharmaceutical Press; 1989.
Gosselin RE, Smith RP, Hodge HC, et al.
Clinical Toxicology of Commercial Products. Fifth ed. Baltimore:Williams
& Wilkins; 1984:II-143.
Fox MRS. Zinc excess. In Miles CF. Zinc
in Human Biology. New York:Springer-Verlag; 1989.
Prasad AS. Trace Elements and Iron in Human
Metabolism. New York:Plenum Medical Book Company; 1978:328-329.
Underwood EJ. Trace Elements in Human and
Animal Nutrition. 4th ed. New York:Academic Press; 1977:230-232.
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.
Abdel-Mageed AB, Oehme FW. A review of the
biochemical roles, toxicity and interactions of zinc, copper
and Iron: I. Zinc. Veterinary and Human Toxicology. 1990;
Fosmire GJ. Zinc Toxicity. American Journal
of Clinical Nutrition. 1990;51:225-227.
Chandra RK. Excessive intake of zinc impairs
immune responses. Journal of the American medical Association.
Smith JC Jr. Heritable hyperzincemia in
humans. In Brewer GJ, Prasad AS, eds. Zinc Metabolism: Current
Aspects in Health and Disease. New York: Alan R. Liss, 1977.
Pfeiffer CC, Papaioannou R, Sohler A. Effect
of chronic zinc intoxication on copper levels, blood formation
and polyamines. Orthomolecular Psychiatry. 1980;9:79-89.
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.
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:
Zinc Acetate. In: USP Drug Information for
the Health Professional, V. Orphan Drugs and Biological Listing.
Rockville, MD:The United States Pharmacopoeial Convention, Inc;
Kumar S. Effect of zinc supplementation
on rats during pregnancy. Nutrition Reports International.
Krause MV, Mahan LK. Food, Nutrition and
Diet Therapy. Philadelphia:W. B. Saunders Co.; 1979: 283.
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.
Physicians' Desk Reference. 47th ed. Montvale,
NJ: Medical Economics Data; 1993.
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.
Material Safety Data Sheet for Zinc Acetate
Dihydrate. Heico Chemical, Delaware Water Gap, NJ. 1993.
Zinc Acetate Dihydrate. J.T. Baker, Phillipsburg,
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
George Eby Research
Austin, Texas U.S.A.
Copyright (c) 1994 by George A. Eby
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.
Normal skeletal growth
Essential for glucose
ipid synthesis and lipid
Prevention of sterility
Important for protein
and nucleic acid metabolism
Activates enzyme functions
Involved in thyroid
Sources: (Good sources include)
rolled oats, whole grain, parsley and (green) tea.
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.
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.
Symptoms and side-effects
of manganese deficiency are:
Impaired glucose metabolism
Diseases of the skeletal
structure, and impaired growth
Elevated blood pressure
Reduced protein metabolism
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.
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.
Blaurock-Busch E, Mineral
& Trace Element Analysis, Laboratory and Clinical Application.
Kaplan LA, Pesce AJ. Clinical
Chemistry. Theory, analysis, and correlation. 2nd ed. Mosby Co.
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
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
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
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.
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"
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 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
As early as 1984
it was apparent that serum zinc levels were likely to be
severely stressed with HIV disease (Cunningham-Rundles,
1984); other research noted
that decreases in both T4 cells and the T4/T8 ratio correlated with
zinc deficiency (Beach et
al, 1982; abstr. ThC677, San Francisco AIDS Conf. 1990).
It was several years before there was general medical documentation
that serum zinc levels may be low in those with HIV disease (abstr.
ThC677, ThBu206, San Francisco AIDS Conf. 1990; abstr. MC3128, MB3128,
WB90, WB2098, WB2166, Florence AIDS Conf. 1991; abstr. PoB3675,
PoB3707, PuB7502, Amsterdam AIDS Conf. 1992; Bogden et al, 1990;
Libanore et al, 1987; Beach et al, 1992; Falutz, 1990; Falutz et
al, 1988; Harrer et al, 1992; Shambaugh, 1989). Furthermore,
use of AZT has been associated with still greater decreases in zinc
levels (abstr. WB2098, Florence
AIDS Conf. 1991).
In some cases, as already noted, low serum zinc may be common
among gays irrespective of HIV status. Not all studies, however,
have noted zinc reductions in those with HIV. One study noted low
levels in HIV+ people with Group IV HIV disease, but not in those
with swollen lymph glands (generalized lymphadenopathy) (Falutz
et al, 1988). Another study
failed to find any lowering of zinc status in either people with
ARC or AIDS (Walter et al,
1990). This latter study
recorded lower zinc levels for control subjects; thirty-five percent
of these were female and it is not stated whether the males were
In a study of the relative decrease in antioxidant status during
the course of HIV infection, Sappey et al (1992) compared
16 control HIV- people with 25 HIV+ people of CDC stage II status,
and 18 HIV+ people of CDC stage IV status. The following serum levels
of zinc were recorded:
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
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
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
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
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
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.
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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).