Zinc ,2

Gary J Fosmire

ABSTRACI’ Although consequences of zinc deficiency Acutely toxic intakes

have been recognized for many years, it is only recently that
attention has been directed to the potential consequences of Most reports ofacute toxicity have been in response to food
excessive zinc intake. This is a review ofthe literature on mani- poisoning incidents. Several cases, described by Brown et al(4),
resulted from storage offood or drink in galvanized containers.
festations aftoxicity at several levels afzinc intake. Zinc is can-
Typically, the food or drink was somewhat acidic in nature and
sidered to be relatively nontaxic,
particularly if taken orally.
the storage period was fairly long; presumably, sufficient zinc

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However, manifestations of overt
toxicity symptoms (nausea,
vomiting, epigastric pain, lethargy, and fatigue) will occur with was leached from the galvanized coating to cause the toxic
extremely high zinc intakes. At low intakes, but at amounts manifestations. It was not possible to quantitate the amount of
well in excess ofthe Recommended Dietary Allowance (RDA) zinc actually ingested but it was reported that an emetic dose
(100-300 mg Zn/d vs an RDA of 1 5 mg Zn/d), evidence of of ZnSO4 is 1-2 g of the salt, corresponding
‘ to 225-450 mg
induced copper deficiency with attendant symptoms of anemia Zn. The presenting symptoms included nausea and vomiting,
and neutrapenia, as well as impaired immune function and ad- epigastric pain, abdominal cramps, and diarrhea (frequently
verse effects on the ratio of bow-density-lipoprotein to high- bloody). A different set of symptoms was reported for a 16-y-

density-lipoprotein (LDL/HDL) cholesterol have been re- old boy who ingested 12 g of elemental Zn over a 2-d period
ported. Even lower levels of zinc supplementation, closer in (5). Symptoms included lethargy, light-headedness, slight stag-
amount to the RDA, have been suggested to interfere with the gering of gait, and difficulty in writing; all symptoms disap-
utilization ofcopper and iron and to adversely affect HDL cho- peared with chelation therapy. Interestingly, no gastrointesti-
nal symptoms were reported in this latter study, suggesting that
lestenol concentrations. Individuals using zinc supplements
the form of zinc ingested may strongly influence which mani-
should be aware of the possible complications attendant to
their use. Am J C/in Nutr 1990;5l:225-7. festations aftoxicity will be observed. Fortunately, instances of
acute toxicity due to ingestion of very large doses of zinc re-
main quite uncommon.
KEY WORDS Zinc, zinc toxicity, supplementation

Pharmacological intakes
Introduction
Intakes of zinc in the range of 100-300 mg Zn/d may be
Far many years mast of the nutrition research an zinc has the result of physician’s orders to treat various medical prob-
focused on its essential roles in the body. Many studies have lems, ofexcessive self-supplementation, or ofparticular experi-
examined the consequences of a deficient state on growth, de- mental protocols. For example, patients being treated with 150
velapment, and health and the prevalence ofdeficiency in vari- mg Zn/d for sickle cell anemia (6) and far nonresponsive celiac
aus population groups. Relatively little attention has been di- disease (7) developed severe copper deficiency, characterized
rected toward toxic properties of zinc other than where there by the classical symptoms ofhypocupremia, anemia, leukope-
has been a clear industrial hazard, such as with metal-fume fe- nia, and neutropenia. Normal copper status was restored by
yen due to inhalation of zinc oxide fumes or as a consequence cessation of ingestion of the zinc supplements coupled with
afsevere pollution ofa localized environment ( 1 ). Indeed, most moderate doses of copper.
review texts indicate that zinc is relatively nontaxic and that Both studies (6, 7) showed that severe copper deficiency can
animals, including humans, exhibit considerable tolerance to result from prolonged therapy with zinc supplements (23 and
high intakes of zinc (2, 3). Although it is true that overt symp- 1 3 ma, respectively) and that cessation of the use of zinc sup-
toms oftoxicity require ingestion ofrelatively large amounts of plements allowed apparent normalization of copper status.
zinc, there is increasing evidence that use of zinc supplements
by humans, even at fairly modest concentrations, may have
I From the Department ofNutrition, College ofHealth and Human
adverse consequences under certain circumstances. Such pa-
Development, Penn State University, University Park, PA.
tential consequences will be examined at three somewhat arbi- 2 Address reprint requests to GJ Fosmire, Department of Nutrition,
trarily chosen intakes: amounts sufficient to induce acute toxic- Henderson Building, Penn State University, University Park, PA
ity, amounts used in pharmacological dosages (100-300 mg 16802.
Zn/d), and amounts more commonly consumed in self-se- Received August 23, 1988.
lected supplements (1 5- 100 mg Zn/d). Accepted for publication March 29, 1989.

Am J C/in Nuir l990;5 1:225-7. Printed in USA. © 1990 American Society for Clinical Nutrition 225
226 FOSMIRE

More recent reports indicate that this problem of induced cop- nonpregnant, nanlactating adults (lS)J and 100 mg Zn/d,
per deficiency is still ofconcern. In a case reported by Hoffman amounts most commonly used with self-supplementation (16),
et al (8), a woman given 440-660 mg ZnSO4 (1 10- 165 mg Zn) may also have some adverse consequences, problems similar in
daily for 10 mo for aphthaus ulcers of her mouth and tongue some ways to those seen with pharmacological dosages. Several
developed copper deficiency with anemia and neutrapenia. In- investigators (17-20) showed that the amount of zinc in the
terestingly, resolution ofthe copper deficiency was not accom- dietary supply can influence the requirement far copper. By
plished by cessation ofthe use ofthe oral zinc supplements and using balance studies with adult men, Sandstead (17) was able
the inclusion ofaral copper supplements for 2 ma, but required to show that as the amount of zinc in the diet increased, so
an intravenous administration ofcupric chloride solution over did the amount afcopper required to maintain balance. These
a 5-d period. This would suggest that elimination ofexcess zinc observations were made at quite modest levels of zinc intake,
is slow and that, until such elimination occurs, the intestinal near the RDA. Other studies also reported increased copper
absorption of copper is blocked. A report by Patterson et al requirements on increased fecal losses ofcopper as the amount
(9) of a sideroblastic anemia and leukopenia associated with of zinc in the diet increased. Festa et al (18), in their study of
copper deficiency in a young man consuming large amounts of young, adult male students, Gregen et al (19), in their study
supplemental zinc for 2 y, corrected by the cessation ofthe use of adolescent females, and Burke et al (20), studying elderly
of zinc supplements, illustrates the dangers inherent in a pro- persons, all observed increased copper excretion as zinc was
longed period of self-supplementation with large doses of zinc. increased. Nate that the amount ofzinc fed in all these studies
Studies reporting copper deficiency secondary to the use of zinc was near the RDA. However, not all studies have observed this

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supplements have utilized prolonged periods of supplementa- increased copper excretion with increasing zinc intake (2 1-23).
tion ( 10 mo) but equivalent dosages for a shorter period of Reasons fan the discrepancy in response are not readily appar-
time (6 wk) did not cause hypocupremia in a recent study by ent but there are substantial differences in experimental design,
Samman and Roberts (10). Interestingly, many subjects in that including differences in the age and sex ofsubjects, amounts of
study did report symptoms of headache, abdominal cramps, zinc and copper in the diet, and the duration ofthe experiment.
nausea, and vomiting-manifestations similar to signs of acute Ifcopper excretion or the copper requirement is increased as
toxicity. Because the study of Samman and Roberts (10) used a function afincreased zinc intake, it is logical to suppose that
healthy men and women, it is unclear whether the develop- the use of zinc supplements might impair copper status unless
ment of copper deficiency requires banger than 6 wk to mani- there is adequate or perhaps compensatory copper intakes. Few
fest on whether it is dependent in some fashion on the health of studies have addressed this question. Mast ofthe studies cited
the subjects. above either did not evaluate copper status on failed to observe
Other reported consequences of zinc intakes ranging from any significant change in status. The study of Fischer et al (24)
100 to 300 mg/d include alterations in immune response and did, however, find a decrease in erythnocyte Cu,Zn-superoxide
in blood lipid profiles. When 1 1 healthy male volunteers were dismutase, a copper metabboenzyme shown to be more sensitive
given 300 mg Zn/d for 6 wk, several indices of immune func- to copper deficiency than are plasma copper or cerulaplasmin
tion (lymphocyte stimulation index, chematactic migration, concentrations, when healthy adult males were fed two daily
and ingestion ofbacteria) were depressed when compared with doses of 25 mg Zn far 6 wk. Similar results were shown by Ya-
values obtained just before supplementation ( 1 1 ). However, drick et al (25) when adult females were fed 50 mg Zn/d for 10
lower amounts of supplementation ( I 00 mg Zn/d) given to an wk; erythrocyte superoxide dismutase activity declined to 53%
elderly population for 3 mo did not alter any ofthe indicators ofpretreatment values, although ceruboplasmin concentrations
of immune function, including delayed dermal hypersensitiv- did not differ. In addition, that study also noted an apparent
ity or in vitro lymphocyte proliferative responses to mitogens competitive interaction between zinc and iron that lead to a
and antigens (12). decrease in serum ferritin and hematocrit concentrations by 10
Because high levels of zinc intake in rats are associated with wk in women given zinc supplements without additional iron.
an increase in serum cholesterol ( 1 3), serum Iipopnotein con- Although competitive interactions between zinc and iron were
centrations have been examined in those taking zinc supple- reported for animals (26), the report by Yadrick et al (25) is
ments. Among the 1 1 subjects given the 300-mg-Zn/d regimen apparently the first with human subjects under experimental
(1 1), an increase in low-density-lipopratein (LDL) cholesterol conditions.
and a decrease in high-density-lipoprotein (HDL) cholesterol Reports of alterations in serum lipoprotein profiles may be
were observed, although triglyceride and total cholesterol con- related in some fashion to a derangement in copper metabo-
centrations did not vary significantly between baseline and val- lism as a consequence ofzinc supplementation. Black et al (27)
ues obtained after 6 wk of supplementation. This reported de- observed decreased concentrations of HDL cholesterol when
crease in HDL cholesterol is in agreement with an earlier obsen- male subjects consumed either 50 or 75 mg Zn/d for 12 wk;
vation by Hoopen et al (14), whose subjects received 160 mg with the higher amount of supplementation, HDL cholesterol
Zn/d for 6 wk. Thus, there appear to be several potential ad- was also significantly depressed at 6 wk of supplementation.
verse consequences ofsuch pharmacological doses ofzinc, pan- Serum copper concentrations did not vary significantly among
ticularly when such intakes are continued for a prolonged pe- treatment groups, although, as noted above (24, 25), this may
riod. not be the most sensitive indicator of copper status. Freeland-
Graves et al (28) reported only a transient decline in serum
Moderately excessive intakes HDL cholesterol concentrations in young women given a sup-
plement of 100 mg Zn/d for 8 wk. Using a different experimen-
Several studies indicate that use ofzinc supplements between tal approach, Goodwin et al (29) examined how cessation of
1 5 mg/d [the Recommended Dietary Allowance (RDA) for zinc supplementation affected HDL cholesterol concentra-
 ZINC TOXICITY 227

tions. In a healthy, elderly population consuming modest sup- deficiency: megamineral sideroblastic anemia. Ann Intern Med
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was associated with a significant increase in HDL cholesterol 10. Samman 5, Roberts DC. The effect ofzinc supplements on plasma
zinc and copper levels and the reported symptoms in healthy vol-
concentrations, a decrease in LDL cholesterol concentrations,
unteers. Med I Aust 1987; 146:246-9.
and an improvement in the ratio of HDL to LDL. Although
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