Zinc Biochemistry

Chapter 8. - Zinc Biochemistry

Chapter Executive Summary

The complete biochemistry of zinc is far outside the scope of this handbook. This survey is generally restricted to items of major interest, and items of importance in common cold research, such as toxicology. Many implications and effects of zinc nutrition and deficiency in human medicine are of significant clinical interest but are omitted or only briefly mentioned. The reader should consider a review of the many discussions by other sources regarding zinc in human nutrition, biochemistry and medicine.

July 1998, ADDENDUM: The genesis of this research and much more on zinc biochemistry can be found in the article "Zinc and Leukemia".

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) With a poly C template, Zn2+ alone can catalyze the assembly of an activated GMP derivative (guanosine 5'-phosphoimidazolide) into poly G chains 30 to 40 residues in the natural 3'-5' linkage.(2) Although other metals are catalytic, Zn2+ ion produces greater fidelity.

Zinc's function as a nonenzymatic polymerase suggests an inorganic answer to the age-old question, "Which came first the chicken or the egg?"

"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) Since the discovery of zinc fingers in 1985, over 200 proteins, many of which are transcription factors, have been found to incorporate zinc fingers. Zinc fingers rely totally upon Zn2+ ions for their form and function. Zinc fingers have been identified in species as diverse as yeast to human beings. About 1 percent of the DNA in human cells specify zinc fingers. As few as 2 and as many as 37 zinc fingers occur on gene-regulating proteins. Zinc fingers are believed to enable enzymes to transcribe a second genetic segment from DNA into RNA serving as a template for synthesis of a specific protein such as a string of amino acids or RNA itself. The finger-like projections are perfectly suited for DNA recognition by means of their three-dimensional shape. From an evolutionary standpoint, ancestral genes specifying a small protein of 30 or so amino acids would easily pick up zinc from the environment and would fold without assistance into a stable conformation where they would have the ability to bind to DNA and RNA.

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 sulfate, zinc oxide, zinc acetate, zinc carbonate, and zinc chloride 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. In consideration of the potential for metabolic disturbance by toxic doses of zinc, and currently wide nutritional use of zinc sulfate and zinc oxide in infant formulas, the committee suggested expanding knowledge of interactions of zinc salts in association with dietary levels of other essential mineral nutrients.

The committee suggested establishing maximum limits for levels of zinc salts in foods, particularly in formulas for infants, since this segment of the population now consumes the highest level of zinc salts when calculated on a daily or body weight basis.

Table 16. Possible daily intake of zinc in milligrams per kilogram of body weight


Age group   Possible daily intake in milligrams / kilogram body weight
			Average intake		Maximum intake

0-5 montths		     5.59		     10.25
6-11 months		     0.72		      3.41
12-23 months		     0.17		      0.19
2-65 years	           < 0.01		    < 0.01

The present author suggests lowering infant zinc intake may be erroneous. Lowering zinc content excessively in infant foods may contribute to infant immunosuppression, progression of HIV in infected infants to AIDS, and impaired growth. 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), but zinc acetate is not listed, although both zinc and acetic acid are listed.(19) Zinc acetate was a GRAS substance before re-evaluation by the Select Committee on GRAS substances in 1973, and was again found to be GRAS by the Select Committee in 1973.(16) Zinc acetate was not included in the GRAS list by the FDA in CFR 21 because no food use has been identified for it before development of zinc acetate lozenges, and it was not being used in foods. Zinc acetate may not be currently used in foods because (a) zinc acetate has an extremely sharp and offensive taste when not diluted with sugars, and (b) zinc acetate is extremely reactive with most food ingredients. An official USP XXI monograph for zinc acetate exists.(20)

Heico Chemicals, Inc. of Delaware Gap, Pennsylvania, appears to be the only U.S. company offering large volume sales of zinc acetate dihydrate U.S.P. suitable for use in zinc acetate lozenges. Zinc acetate dihydrate U.S.P. currently is used (a) as a component in zinc-eugenol dental cement to accelerate setting, (b) as a component of an eye lotion and eye drops in the treatment of conjunctivitis, (c) occasionally as an astringent, (d) as a styptic, and (e) as an emetic for both human and animal usage. Heico has no drug master file on zinc acetate dihydrate U.S.P. Heico's zinc acetate dihydrate U.S.P. product is currently used by only one reseller in the amount of one ton per year.

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. Three types of acute toxic reactions to zinc have been reported in human beings. The first type is "zinc fume fever" characterized by pulmonary manifestations, fever, chills, and gastroenteritis observed in industrial workers who are chronically exposed to hot zinc oxide fumes. In the second type, toxicity was observed in a 16-year-old boy who slowly ingested 12 grams of metallic zinc dust over a period of 2 days. This condition was characterized by drowsiness, lethargy, and increased serum lipase and amylase levels without additional sequela. The third type of acute zinc toxicity was observed in patients with renal failure following hemodialysis using water stored in a zinc-galvanized tank. These patients suffered from nausea, vomiting, fever, and anemia.

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, although he was more restrained than the National Research Council. 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 including zinc acetate 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, including zinc gluconate lozenge treatment for common colds, 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 LD50 dose 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 of common colds with zinc lozenges 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

As none of the clinical trials of zinc lozenges for common colds included pregnant women, caution in pregnancy may be warranted as with any treatment during 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.

October 1997, ADDENDUM: There have been no other adverse reports listed in the Index Medicus for a number of racial and ethnic populations (including Indian) using a number of MEDLINE search parameters including: zinc, pregnancy, and outcome.

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 fume fever, an acute disability, can occur when zinc fumes are inhaled from metal heated to a temperature above its melting point. This disease is most commonly associated with inhalation of recently formed zinc oxide fumes. Moderate exposure to zinc oxide dust does not cause zinc fume fever to the extent found with freshly formed zinc fumes, apparently because of the aggregation of fume particles. 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. MSDS summarize important material safety data for the manufacturer's product. MSDS reports by Heico Chemicals, Delaware Water Gap, Pennsylvania, a manufacturer of zinc acetate dihydrate USP, and by J. T. Baker, Phillipsburg, New Jersey, a manufacturer of reagent-grade zinc acetate dihydrate, show zinc acetate to be a slight health and flammability hazard and a moderate contact hazard. Zinc acetate's chemical formula is Zn.(CH3CO2)2.2H2O. Molecular weight of the dihydrate is 219.49, and 183.47 for anhydrous. CAS numbers are 5970-45-6 for dihydrate and 557-34-6 for anhydrous. The melting point is 237 C. Solubility is appreciable at 1 g/2.3 ml water, and 1.6 ml boiling water. One gram dissolves in 30 ml alcohol or about 1 ml of boiling alcohol. Specific gravity is 1.735. The pH of zinc acetate is 6.3. Zinc acetate's oil/water partition coefficient was not available, but is expected to be zero. Zinc acetate dihydrate is a white crystal, and the anhydrous form is amorphous. Both have a faint acetic acid odor. Vapor density is 6.3 (air = 1).

Zinc acetate is not volatile and essentially does not evaporate. The dihydrate may be dehydrated at 105 C. Zinc acetate is not combustible and is not a fire hazard, although excessive heating may release acetic acid fumes. Zinc acetate is a stable chemical when unheated, and hazardous polymerization does not occur at any temperature. Zinc acetate is incompatible with alkalies and strong oxidizing agents and will chemically react with many organic and inorganic substances. Zinc acetate decomposes upon severe heating to zinc oxide, carbon monoxide, and carbon dioxide. In both acute and chronic industrial overexposures, zinc acetate is an eye irritant and respiratory hazard.

Overexposure causes eye redness and irritation. Continuous inhalation of dust, concentrated mists, or aerosols may cause irritation of upper respiratory tract, tightness and pain in chest, and coughing. Ingestion causes nausea, vomiting, gastrointestinal irritation, and burns to the mouth and throat. Inhalation of concentrated mists aggravates respiratory disorders such as emphysema and asthma. Zinc acetate is not carcinogenic, and teratologic tests on three species of animals were negative. Oral rat LD50 is 2460 mg/kg. Dry zinc acetate is not absorbed through the skin, but hot, concentrated solutions can cause severe skin irritation or burns. No chronic effects of overexposure have been identified.

Bulk zinc acetate is considered a hazardous, but not extremely hazardous industrial chemical and is regulated by several governmental agencies. No special industrial protective equipment is needed other than good ventilation, safety goggles, clothing, and gloves. First aid for oral ingestion, if the person is conscious, is to give large amounts of water and induce vomiting. If inhaled, the person is to move to fresh air. If the victim is not breathing, artificial respiration is indicated. In case of eye or skin irritation, the area should be washed with water.

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.

Zinc, in the form of zinc gluconate or zinc acetate lozenges, used at doses of 23 mg zinc or less, 9 times per day for 1 week, does not raise zinc serum levels and has a record of safety with no unreported side effects known to exist since their use began in 1979.

Chapter 8. - References

Chapter 9 - Conclusions and Recommendations

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