The toxicity of zinc is dependent on the route of exposure. Each zinc compound has similar toxic manifestations following oral and dermal exposure. However, they have unique inhalational toxicities. The metallic form of zinc is not toxic per se, and only the salt forms are considered here unless otherwise specifically mentioned.
The hallmark of acute oral zinc (Zn2+) toxicity is gastrointestinal (GI) distress, including nausea, vomiting, abdominal pain, and gastrointestinal hemorrhage.9 In initial studies that evaluated the oral use of zinc sulfate (ZnSO4) as an acne therapy, epigastric distress was noted in 33% of patients.28,36 Zinc chloride solutions in concentrations greater than 20% are particularly corrosive when ingested. Partial- and full-thickness burns to the oral mucosa, pharynx, esophagus, and stomach, as well as to the laryngotracheal tree, can occur even following small unintentional ingestions of zinc chloride by children.22,56,71 Delayed gastric stricture may occur after acute71 or chronic zinc chloride consumption.20,98 Pancreatitis was noted in a piglet model34 and also in a 24 year-old man who inadvertently ingested liquid zinc chloride.22
Hyperamylasemia, acute respiratory distress syndrome (ARDS), hypotension, vomiting, diarrhea, jaundice, anemia, thrombocytopenia, and subsequent death occurred following an unintentional intravenous infusion of 7.4 g of zinc sulfate (via total parenteral nutrition) over 60 hours. The patient’s serum zinc concentration was 4184 μg/dL.13 A 14 week premature neonate received a 1000 fold increased concentration of zinc in her total parenteral nutrition. Rather than 330 μg/dL, she received 330 mg/dL, which resulted in hypotension, respiratory failure, and death despite the administration of CaNa2EDTA.38
Inhalational toxicity will often depend on the type of zinc compound involved in the exposure. The water solubility of the various zinc salts plays an important role in the extent and time to onset of pulmonary toxicity. The solubility of zinc chloride in water at 77°F (25°C) is 432 g/100 mL, whereas that of zinc oxide at 84°F (29°C) is 0.00016 g/100 mL.85 Acute inhalation of zinc chloride from smoke bombs produces lacrimation, rhinitis, dyspnea, stridor, and retrosternal chest pain. Upper respiratory tract inflammation, and ARDS may occur, generally without renal or hepatic manifestations of systemic absorption.35,47,48,68 Morbidity and mortality increase when the exposure to a zinc chloride smoke bomb occurs in an enclosed space.88 Of 70 individuals exposed to a zinc chloride smoke bomb in a tunnel during World War II, 10 died within 4 days. Ambient zinc concentrations in the tunnel were measured at 33,000 mg/m.3,30 Inhalation of zinc oxide, a far less water soluble zinc salt, is associated with metal fume fever (Chap. 124) and not pneumonitis or ARDS despite similar ambient zinc concentrations.9 See below for further discussion on metal fume fever.
Despite the importance of zinc in gustatory function, there appears to be an association of intranasal zinc use and anosmia.93 Animal research suggests that intranasal zinc sulfate use can cause transient or persistent anosmia as a consequence of disruption of functional connections between the olfactory bulb and the olfactory epithelium.69 Topical zinc sulfate is used experimentally in both rat and mouse models to induce anosmia.102 Multiple patients, ages 31 to 55 years, who developed a burning sensation after intranasal zinc gluconate application to the olfactory epithelium later developed either a long lasting or permanent anosmia and olfactory dysfunction.53 The mechanism of zinc-induced hyposmia and anosmia is thought to be a direct result of proteolytic destruction of the olfactory receptor cells.25
US pennies (91.5% Zn and 2.5% Cu) lodged in the distal esophagus release zinc ions following exposure to gastric acids and can damage the local esophageal tissue.17 The phenomenon of acid dissolution is demonstrated in animal4 and in vitro models.74
Rare reports of renal complications exist. Hematuria was observed in a 24 year-old man who ingested liquid zinc chloride but whose kidney function remained otherwise normal.22 Intravenous zinc sulfate administration can result in acute tubular necrosis and acute kidney injury.13
Certain zinc salts, such as zinc oxide, found in baby powders and calamine lotion, are usually nonirritating for intact skin.5 Although older studies suggested the possibility of pruritic, pustular rashes in workers who are exposed to zinc oxide, other causative factors, including personal hygiene, were not considered.100 One case report describes urticaria and angioedema in a 34 year-old welder following contact with zinc oxides fumes at a smelting plant.31 The patient was asymptomatic once he was removed from the environment and had no further difficulty during the welding process when personal protective equipment was employed.
Several individual cases report the significant implication of chronic zinc exposure. Chronic zinc toxicity following nutritional supplements and the ingestion of coins can produce a reversible sideroblastic anemia manifested by anemia and granulocytopenia associated with bone marrow-demonstrated vacuolated precursors and ringed sideroblasts.14 The mechanism for this reversible myelodysplastic syndrome appears to be a zinc-induced copper deficiency.32
A 55 year-old schizophrenic patient with a 15 year history of pica typically of metal objects and frequently zinc containing pennies, presented with pancytopenia, including a hemoglobin of 3 g/dL and a white blood cell count of 1300/mm3. He had a serum zinc concentration of 280 μg/mL and low serum copper concentration of <0.05 μg/mL.57 The patient refused surgery to remove the coins, which formed a massive bezoar in his GI tract. The patient continued to ingest coins and ultimately died of sepsis and multiorgan failure. An autopsy revealed a coin mass weighing 1870 g in his stomach and another bezoar at the site of a sigmoid volvulus.
Over a 6 to 7 month period, a 17 year-old boy used significant doses of oral vitamins and mineral supplements containing zinc to treat acne and developed copper deficiency and anemia, leukopenia, and neutropenia.87 A 28 month-old boy developed anemia, neutropenia, and developmental delay after 11 months of parental administration of 314 mg/d of oral zinc gluconate (3.6 mg/kg/d of elemental zinc).96 Hyperzincemia and hypocupremia were present and improved after discontinuation of zinc without copper supplementation.
It is suggested that zinc and other transition metals may be important in the pathogenesis of demyelinating diseases.59,81 Clusters of cases of multiple sclerosis (MS) were described in northern New York in a factory where zinc was the primary occupational exposure. One hypothesis is that the allele frequency for transferrin (an iron- and zinc-binding protein) may differ in these MS subjects.89,95 Another cluster was found in Canada where excess metals, including zinc, were found in the soil and water.39,51,52 A conclusive link to MS, however, has not been established.
Since the prostate contains the highest concentration of zinc in the human body, the role of zinc in the development of prostate cancer has been investigated. Specifically, American men participating in the Health Professionals Follow-Up Study were followed for 14 years, from 1986 to 2000. Of the 46,974 in the cohort, 2901 new cases of prostatic cancer were diagnosed, with 434 of them considered to be in an advanced stage.63 Men who used zinc supplementation at a dose >100 mg/d had a relative risk of 2.29 for advanced prostate cancer, and those using zinc for longer than 10 years had a relative risk of 2.37. Neither the International Agency for Research on Cancer (IARC) nor the Environmental Protection Agency (EPA) currently classify zinc as a carcinogen.
The Third National Health and Nutrition Examination Survey examined the association of higher dietary zinc intake on the risk of kidney stone disease. Dietary zinc intake of greater than 15 mg/d was associated with a significantly increased risk of kidney stones compared to those with a dietary zinc intake less than 7 mg/d. More rigorous studies are required to determine causality and a potential underlying mechanism for this association.97
A neurologic syndrome of progressive myeloneuropathy called “swayback” is defined by a spastic gait, usually a prominent sensory ataxia, and hematologic manifestations.58,59,61,62 These cases involve patients with copper deficiency and typically elevated serum zinc concentrations. A history of excess zinc exposure is obtained in some but not all patients. The potential of an inherited zinc overload syndrome has been considered.41 A 46 year-old man presented with evidence of bone marrow suppression followed by sensory ataxia and a progressive myelopathy. His neuroimaging evaluation was normal. His only remarkable laboratory studies included an elevated serum zinc concentration of 184 μg/dL (28.2 µmol/L) and a low copper concentration of <10 μg/dL (<1.57 µmol/L). There was no known occupational exposure or supplementation of zinc by history. Although his copper deficit improved with copper therapy, hyperzincemia persisted for more than the 3 years that he was followed. More recently, an unusual source of high zinc concentrations was related to denture creams, which may contain as much as 34 g of zinc per gram of cream. Four patients with chronic exposure to excess denture cream developed neurological abnormalities in the setting of hyperzincemia with associated hypocupremia.73 Multiple other reports have confirmed the relationship between denture cream, hyperzincemia, hypocupremia, and the development of this progressive myeloneuropathy. The history in these patients often reveals poor fitting dentures as well as use of dentures during sleep.3,11,42,94
Patients with underlying Wilson disease are also at risk for chronic zinc overload syndromes due to treatment. Recent reports have raised increased concerns for the use of zinc in the treatment of Wilson disease with recommendations for more frequent monitoring of zinc and copper blood concentrations.49,84,106
Chronic inhalation of zinc oxide can lower blood copper and serum calcium concentrations. However, no long term effect on ventilatory function or chest radiography is reported.29
Since 1983, the US penny is composed of 97.5% zinc and 2.5% copper.101 Zinc is widely used in industry because it enhances the durability of iron and steel alloys; it also is commonly used in construction. Galvanization involves coating an iron product with metallic zinc to prevent it from oxidizing (rusting). Electroplaters, smelters, jewelers, artists working on stained glass or sculpting metal, as well as aircraft manufacturing workers, are routinely exposed to zinc. Zinc chloride is an essential component of flux, which can be used for soldering of galvanized iron.
Zinc is present in drinking water and beverages stored in metal containers or that flow through pipes coated with zinc. Zinc concentrations in air are typically low; average zinc concentrations in the United States are<1 μg/m3. Air concentrations near industrial zones can be higher, and may be substantially greater in certain occupational settings. The currently accepted occupational threshold limit value (TLV)-time-weighted average (TWA) is 1 mg zinc/m3.85
Metal fume fever typically occurs within 12 hours after an exposure to metal oxide fumes. Patients can develop fever, chills, cough, myalgias, muscle cramping, chest pain, dyspnea, dry throat, and a metallic taste in the mouth. Although exposure to zinc oxide fumes is the commonest zinc etiology, other zinc compounds may be implicated. The chest radiograph is often normal, but may show an infiltrate. Hypoxia and tachycardia are rare, but may occur. Overall, however, the syndrome is relatively benign, with tolerance developing within days.29 An immune mechanism is suggested, and chronic exposure may lead to sensitization (Chap. 124).23