Zinc - Toxicology of Metals - page 917

1977), it might be expected that Zn competes with Cu
for binding to some Cu-dependent proteins. However,
specifi c examples of such a phenomenon have appar-
ently not been published in recent years.
Other studies not listed in Table 7 also found adverse
effects of high oral intakes of Zn. A study of 778 adults,
aged 22-80 years, who were administered suffi cient Zn
to increase serum Zn concentration, found increased
serum total and LDL cholesterol, and triglyceride con-
centrations (Hiller et al ., 1995). A study of ambulatory
men and women, aged >60 years found Zn intakes
from over-the-counter supplements adversely affected
serum HDL cholesterol concentrations (Goodwin
et al ., 1985). The 180 subjects not taking Zn showed an
increase in serum HDL cholesterol when participating
in an exercise program, while 90 subjects taking Zn did
not. Stopping Zn in 22 subjects taking >15 mg Zn daily
was followed by an increase in serum HDL cholesterol.
Consistent with these fi ndings, a study of 12 men given
150 mg Zn daily for 5 weeks found a 75% decrease in
serum HDL cholesterol, which was restored to baseline
when Zn administration stopped (Hooper et al ., 1980).
Similarly, a 12-week double-blind study of 31 men
found that 75 mg Zn daily decreased serum HDL cho-
lesterol signifi cantly after 6, 8, and 12 weeks, although
50 mg Zn daily decreased serum HDL cholesterol sig-
nifi cantly after 12 weeks (Black et al ., 1988). Changes in
serum total cholesterol, LDL cholesterol, and triglycer-
ides were not signifi cant. In contrast, an 8-week study
of 32 young women found little effect of 15, 50, or 100
mg Zn daily on serum HDL cholesterol, except for a
decrease in the 100 mg group after 4 weeks (Freeland-
Graves et al ., 1982).
Effects of excess Zn on immunity were measured
in 11 men administered 300 mg Zn daily for 6 weeks.
Serum Zn increased twofold, although in vitro phyto-
hemagglutinin induced lymphocyte transformation,
polymorphonuclear leukocyte chemotaxis, and phago-
cytosis of bacteria, and serum HDL cholesterol con-
centration decreased (Chandra, 1984). The absolute
number of lymphocytes and the proportions of T and
B lymphocytes were not signifi cantly different from
baseline.
On the other hand, Zn is an important relatively new
treatment for patients with the genetic Cu overload
disease, known as Wilson's disease (Brewer, 2000). The
treatment is highly effi cacious (Brewer et al ., 1998).

suggested RfD was, in some instances, similar to or
less than the 1989 Food and Nutrition Board's Recom-
mended Dietary Allowance for Zn (Committee, 1989)
and less than the provisional Zn requirement sug-
gested by a World Health Organization Expert Com-
mittee when Zn bioavailability is 15% (Committee,
1973). Because of this unsatisfactory outcome, alterna-
tive RfDs of 1.66 and 0.83 mg/kg/day were suggested
for bioavailability of 15% and 30%, respectively (Sand-
stead, 1993). For Zn supplements that might be 95%
absorbed, an RfD of 0.25 mg/kg/day was suggested.
The following is speculation. Perhaps estimation of
the LOAEL and the upper limit (UL) for Zn should be
related to the intake Zn/Cu molar ratio. On the basis
of the study of relationships between diet Zn, Cu, and
protein (Table 7), a LOAEL for Zn might occur when
the Zn intake is 13.7 mg and the intake of Cu is 0.83
mg (Zn/Cu molar ratio = 16.1). Perhaps the UL for Zn
should be determined in light of the intake of Cu. For
example, at an intake of 1.5 mg Cu and 13.7 mg Zn
(Zn/Cu ratio = 8.9), the Zn intake would be safe and
adequate. If a Zn supplement of 10 mg were added,
thus increasing the Zn intake to 23.7 mg (Zn/Cu
ratio = 15.4), the safety of the Zn might be in question.
Inclusion of bioavailability data might also improve
the estimate of safety.

8.7.3 Poisoning from Ingestion of Zinc-Contaminated
Food, Drink, and Other Substances

High concentrations of Zn in drinks, up to 2500
mg/L, caused nausea, abdominal cramping, vomiting,
tenesmus, and diarrhea with or without bleeding. The
estimated dose was 325-650 mg (Brown et al ., 1964).
Zinc chloride ingestion severely injured the exocrine
pancreas, causing insuffi ciency (McKinney, Brent, and
Kulig, 1995). The fi nding was similar to the effect of
Zn poisoning in other species (Hill et al ., 1983; Smith
and Embling, 1993; Gabrielson, Remillard, and Huso,
1996). Ingestion of >1800 g of coins over a period of
years caused Cu defi ciency with severe sideroblastic
anemia and leukopenia and high plasma Zn in a men-
tally ill patient (Kumar and Jazieh, 2001).

8.7.4 Poisoning from Inhalation

8.7.4.1 Zinc Chloride Fume
Zinc chloride inhalation causes severe chemical pneu-
monia. Effects on two soldiers are illustrative (Homma
et al ., 1992). After a relative brief exposure, injury
seemed minor for 10 days. Then severe respiratory
distress and pulmonary hypertension were diagnosed.
Death occurred on the 25th and 32nd days, respectively.
Autopsy found interstitial and intraalveolar fi brosis,
endothelial proliferation, and vascular occlusions.

8.7.2 Reference Dose (RfD)

The US Environmental Protection Agency (Dourson
1994) used the Zn intake and erythrocyte Cu/Zn SOD
data from Yadrick (Yadrick, Kenney, and Winterfeldt,
1989) as the basis for a LOAEL of 60 mg. A reference
dose (RfD) of 0.33 mg/kg/day was proposed. The