91: Cadmium

Cadmium, atomic number 48, is a transition metal in group IIB of the periodic table. In its pure atomic form, it is a bluish solid at room temperature. It is readily oxidized to a divalent ion, Cd²⁺. Naturally occurring cadmium commonly exists as cadmium sulfide (CdS), a trace contaminant of zinc-containing ores.³⁶

Cadmium sulfide, cadmium oxide, and other cadmium-containing compounds are refined to produce elemental cadmium, which is used for industrial purposes. When combined with other metals, cadmium forms alloys of relatively low melting points, which accounts for its extensive use in solders and brazing rods. Today, cadmium is primarily used as a reagent in electroplating and in the production of nickel-cadmium batteries. Other uses of cadmium include as a pigment and as a neutron absorber in nuclear reactors. Cadmium salts have also been used as veterinary antihelminthics.¹²

As cadmium processing has increased, so has the incidence of cadmium toxicity. Cadmium toxicity usually occurs after environmental, occupational, or hobby work exposure.

Environmental Exposure

Environmental exposure to cadmium generally occurs through the consumption of foods grown in cadmium contaminated areas. Because cadmium is fairly common as an impurity in ores, areas where mining or refining of ores takes place are the most likely to contain cadmium contamination.

In the 1950s, a mine near the Jinzu River basin in Japan discharged large amounts of cadmium into the environment, contaminating the rice that was a staple of the local food supply. An epidemic of painful osteomalacia followed, affecting hundreds of people, with postmenopausal multiparous women being most affected.⁶⁷ The afflicted were prone to develop pathologic fractures, and were reported to call out “itai-itai” (“ouch-ouch”) as they walked, because of the severity of their pain.²⁸ These symptoms were ultimately linked to the cadmium. Less consequential environmental cadmium exposures have also occurred in Sweden,⁴⁶ Belgium,¹⁰ and China.⁴⁸ Additionally, smokers have higher blood cadmium concentrations than nonsmokers,⁹¹ probably as a result of contamination of soil where the tobacco is grown. This is noteworthy, in that cadmium and tobacco may be synergistic causes of chronic pulmonary disease.⁶³

Occupational and Hobby Exposure

Welders, solderers, and jewelry workers who use cadmium-containing alloys are at risk for developing acute cadmium toxicity due to inhalation of cadmium oxide fumes. Other workers who do not work with metals per se may develop significant chronic cadmium toxicity through exposure to cadmium-containing dust.

Hobbyists who work with cadmium solders have exposures similar to occupational metalworkers. Significant cadmium toxicity in this population is usually the result of metalworking in a closed space with inadequate ventilation and or improper respiratory precautions.

There is no known biologic role for cadmium or its salts. Orally ingested cadmium salts are poorly bioavailable (5%–20%); however, inhaled cadmium fumes (cadmium oxide) are readily bioavailable (up to 90%).⁹⁹ As the only data on cadmium toxicokinetics are derived from work with cadmium salts and oxides, the term “cadmium” in the following discussion refers to these species unless otherwise noted.

After exposure, cadmium is absorbed into the bloodstream, where it is bound to α₂-macroglobulin and albumin.¹⁰⁰ It is then quickly and preferentially redistributed to the liver and kidney, and to a lesser extent to other organs such as the pancreas, spleen, heart, lung, and testes.²⁵ Cadmium may enter target organs via three mechanisms: zinc and calcium transporters, uptake of cadmium–glutathione or cadmium–cysteine complexes by transport proteins, or endocytosis of cadmium–protein complexes.¹⁰⁶

After incorporation into the liver and kidney, cadmium is complexed with metallothionein, an endogenous thiol-rich protein that is produced in both organs. Metallothionein binds and sequesters cadmium. Slowly, hepatic stores of the cadmium–metallothionein complex (Cd-MT) are released. Circulating Cd-MT is then filtered by the glomerulus. A significant amount is reabsorbed and concentrated in proximal tubular cells,^19,86,87 explaining why the kidney is a principal target organ in cadmium toxicity.

There is no evidence that cadmium ions are oxidized, reduced, methylated, or otherwise biotransformed in vivo. The volume of distribution (Vd) of cadmium is unknown, but is presumably quite large as a consequence of significant hepatic sequestration. Cadmium distribution and elimination are complex, and an eight-compartment kinetic model has been proposed.⁵⁴ The slow release of cadmium from metallothionein-complexed hepatic stores accounts for its very long biologic half-life of 10 or more years.

Cellular Pathophysiology

Cadmium toxicity results from interaction of the free cation with target cells.^{25,35,61,66,87} Complexation with metallothionein is cytoprotective,^22,61 and metallothionein functions as a natural chelator with a strong affinity for cadmium.^18,55 Although metallothionein may play a role in proximal tubular concentration of cadmium, kidney damage is attenuated by metallothionein, as metallothionein-deficient mice are more susceptible to cadmium toxicity than controls.⁶¹

There are several mechanisms by which cadmium interferes with cellular function. Cadmium binds to sulfhydryl groups, denaturing proteins and or inactivating enzymes. The mitochondria are severely affected by this process,¹ which may result in an increased susceptibility to oxidative stress.⁴⁷ Cadmium also interferes with mediators of cell adhesion such as E-cadherin, N-cadherin, and β-catenin.^{72,73, and 74} Finally, the demonstrated interference of cadmium with calcium transport mechanisms^96,97 might lead to intracellular hypercalcemia and, ultimately, apoptosis (Table 91–1).

Specific Organ System Injury

Kidney.

The kidney damage caused by cadmium develops over years. Proteinuria is the most common clinical finding and correlates with proximal tubular dysfunction, which manifests as urinary loss of low-­molecular-weight proteins such as β₂-microglobulin and retinol-binding protein. Cadmium also produces hypercalciuria,⁸³ possibly also via damage to the proximal tubule.

Bone.

Cadmium-induced osteomalacia is a result of abnormalities in calcium and phosphate homeostasis, which, in turn, result from renal proximal tubular dysfunction. In one autopsy study, the severity of osteomalacia in cadmium exposed subjects correlated with a decline in the serum calcium-phosphate product.⁹⁰

Lung.

Acute cadmium pneumonitis is characterized by infiltrates on chest radiograph and hypoxia. Human autopsy studies^32,71,84,101 generally show degeneration and or loss of bronchial and bronchiolar epithelial cells.

Gastrointestinal Tract.

Based on case reports,^11,102 ingested cadmium salts are caustic with the potential to induce significant nausea, vomiting, and abdominal pain, and result in GI hemorrhage, necrosis, and perforation. With respect to their effect on the GI mucosa, cadmium salts act similar to mercuric salts (Chap. 98).

Acute Poisoning

Pulmonary/Cadmium Fumes.

Cadmium pneumonitis results from inhalation of cadmium oxide fumes. The acute phase of cadmium pneumonitis may mimic metal fume fever (Chap. 124), but in fact, the two entities are distinctly different, with regard to both mechanism and clinical consequences. Whereas metal fume fever is benign and self-limited, acute cadmium pneumonitis can progress to hypoxia, respiratory insufficiency, and death.

Published case reports of patients who develop acute cadmium pneumonitis^{4,5,32,71,84,93,101,105} are strikingly similar in their presentation. Within 6 to 12 hours of soldering or brazing with cadmium alloys in a closed space, patients typically develop constitutional symptoms, such as fever and chills, as well as a cough and respiratory distress.

On initial presentation these patients may have a normal physical examination, oxygenation, and chest radiograph. This relatively benign presentation may lead both to the misdiagnosis of metal fume fever and the underestimation of the severity of illness. As the ­pneumonitis progresses to acute respiratory distress syndrome (ARDS) (Chap. 124), crackles and rhonchi develop, oxygenation becomes impaired, and the chest radiograph develops a pattern consistent with alveolar filling. Despite aggressive supportive care, death may occur, usually within 3 to 5 days.^32,71,84,101

Patients who survive an episode of acute cadmium pneumonitis may develop chronic pulmonary disorders, including restrictive lung disease,^4,5 diffusion abnormalities,⁴ and pulmonary fibrosis,⁹³ although recovery without sequelae is also reported.¹⁰⁵

Oral/Cadmium Salts.

Most acute cadmium exposures are inhalational, and acute ingestions are rare. Based on case report data, GI injury is likely to be the most significant clinical finding after acute ingestion, although other presentations are possible.

In one case,¹¹ a 17 year-old student ingested approximately 150 g of cadmium chloride that she obtained from her school science stockroom. She presented to the emergency department with hypotension and edema of the face, pharynx, and neck. Her condition quickly deteriorated, and she suffered a respiratory arrest. She was intubated and underwent orogastric lavage, chelation with an unspecified agent, and charcoal hemoperfusion. Multisystem organ failure ensued, and she died within 30 hours of presentation. At autopsy, the most significant finding was hemorrhagic necrosis of the upper GI tract. Her blood cadmium concentration was more than 2000 times normal.

In a second reported case a 23 year-old man ingested approximately 5 g of cadmium iodide in a suicide attempt and presented with acute hemorrhagic gastroenteritis.¹⁰² His condition deteriorated, and despite treatment with calcium disodium ethylenediaminetetraacetic acid (CaNa₂EDTA) and supportive measures, he died on hospital day 7. Autopsy did not reveal a specific cause of death.

A 51 year-old man taking multiple nutritional supplements who had no history to suggest cadmium exposure presented with a one month history of fatigue, with laboratory findings suggestive of autoimmune hemolytic anemia. He was treated aggressively for that condition, but developed progressive multisystem organ failure and expired one week after presentation. His blood cadmium concentrations were extraordinarily high, suggesting an acute ingestion, although the source of the cadmium was never determined.⁷⁶

Chronic Poisoning

Nephrotoxicity.

The most common finding in chronic cadmium poisoning is proteinuria. Low-molecular-weight proteinuria is usually more significant than, and generally precedes, glomerular dysfunction, although some cadmium exposed workers manifest predominantly glomerular proteinuria.⁷ There is a dose–response relationship between total body cadmium burden and kidney dysfunction,^{10,44,46,67,95} although this relationship may not be as strong at low doses.³⁹ Patients with diabetes mellitus may be particularly susceptible to the nephrotoxic effects of cadmium.³⁷ In most cases, proteinuria is generally considered to be irreversible even after removal from exposure,^38,52,79 but improvement is sometimes reported.^60,94 Less clear is the question of whether kidney dysfunction progresses after removal from exposure, with studies showing both stable³⁸ and deteriorating^42,78,79 function in cadmium exposed workers who are removed from exposure. The routes and duration of exposure, as well as blood and urine cadmium concentrations, differ markedly among these studies, limiting wider applicability of any analysis.

Occupational cadmium exposure is also associated with nephrolithiasis,^45,82 likely as a result of hypercalciuria.⁸³

Pulmonary Toxicity.

Large studies of workers chronically exposed to relatively low concentrations of cadmium fail to demonstrate consistent effects on the lung. In one study of 57 workers with sufficient exposure to cadmium oxide to produce kidney dysfunction, there was no evidence of pulmonary dysfunction, even in those with the greatest cumulative cadmium exposure.²⁷ In contrast, other studies have reported both restrictive¹⁷ and obstructive^21,81 changes on pulmonary function tests. Interestingly, a follow-up study of the group with restrictive lung disease showed improvements after cadmium exposure was reduced.¹⁶ The discrepancies in these results may be partly a result of markedly different doses and durations of exposure among the various groups.

Cadmium is associated with pulmonary neoplasia; the carcinogenicity of cadmium is discussed separately (see Cancer below).

Musculoskeletal Toxicity.

Cadmium-induced osteomalacia usually occurs in the setting of environmental exposure, as was true in Japan and Sweden.⁴³ Although mentioned in case reports,^8,52 osteomalacia is generally not a prominent feature of occupational exposure to cadmium. Gender and age differences may explain part of this apparent difference: victims of the original Itai-Itai epidemic were mostly older women, whereas occupational cadmium exposures typically occur in younger men. In addition, differences in cumulative dosing and in route of exposure (oral vs. pulmonary) may partly account for the unique prominence of osteomalacia in patients with environmental exposures. Cadmium exposure is associated with osteopenia and osteoporosis even in areas (such as the United States) where widespread environmental exposure is unlikely.¹⁰³

Hepatotoxicity.

Although the liver stores as much cadmium as any other organ, hepatotoxicity is not a prominent feature in humans with cadmium exposure, probably because hepatic cadmium is usually complexed to metallothionein.⁴⁰ The liver is a potential target organ, however, as hepatotoxicity is easily inducible in animals.^1,25,26,77

Neurologic Toxicity.

Cadmium exposure is linked to olfactory disturbances,^64,80,89 impaired higher cortical function,⁹⁸ and parkinsonism.^68,98

Other Organ Systems.

Cadmium induces hypertension in rats,⁵⁹ but human studies have only yielded unconvincing and conflicting results.^31,58,69,92 Although there is evidence that cadmium may cause immunosuppression affecting both humoral and cell-mediated immunity in animals,²⁴ a single human study showed no overt immunopathology in an occupationally exposed cohort.⁵¹ The testes are clearly a target organ in animal exposures,⁵⁷ but they are not considered a major target organ in humans.

Cancer.

Cadmium induces tumors in multiple animal organs, an effect that is exacerbated by zinc deficiency.⁹⁹ In humans, cadmium exposure is associated with lung cancer.⁷⁰ The strength of this association has been questioned because most studies have methodologic problems, such as coexposure to arsenic, a known pulmonary carcinogen.^9,53 Despite these confounding coexposures, cadmium is officially designated as a human carcinogen by the International Agency for Research on Cancer.⁴¹

Other than to confirm exposure, cadmium concentrations have limited usefulness in the management of the acutely exposed patient. Diagnosis and treatment are based on the history, physical examination, and symptoms. In a patient exposed to cadmium oxide fumes, ancillary tests, such as pulse oximetry and chest radiography, are more useful than actual cadmium concentrations.

In the patient chronically exposed to cadmium, both cadmium concentrations and ancillary testing may prove helpful. Urinary cadmium concentrations, which reflect the slow, steady-state turnover and release of metallothionein-bound cadmium from the liver, are a better reflection of the total body cadmium burden than are whole blood concentrations. In a 22-year follow up study, mortality was higher in those with elevated urine cadmium concentrations, although it was impossible to determine if the cadmium was causative or served as a marker for another process.⁷⁵

Workers at high risk for cadmium toxicity should routinely have urinary protein testing, supplemented with urine and or blood cadmium testing when urinary protein testing is abnormal. Workers with a urinary cadmium concentration greater than 7 µg/g urinary creatinine or a whole blood cadium concentration greater than 10 µg/L require immediate reassignment to a cadmium-free area. Workers with significant proteinuria (β₂-microglobulin concentrations of 750 µg/g urinary creatinine) should also be reassigned if additional testing confirms cadmium exposure (as defined by a urinary cadmium concentration greater than 3 µg/g urinary creatinine or a whole blood cadium concentration greater than 5 µg/L). These numbers are reasonable in light of the fact that kidney dysfunction can occur at cadmium concentrations as low as 5 µg/g urinary creatinine,^20,44 a concentration significantly higher than that of the general US population, 95% of whom have concentrations that are less than 2 µg/g urinary creatinine.¹⁵

Acute Exposure

Oral Exposure/Cadmium Salts.

After the patient’s airway, breathing, and circulation are secured, attention can be given to GI decontamination. Although large ingestions of soluble cadmium salts are rare, they frequently prove fatal.^11,102 The lowest reported human lethal dose is 5 g. In light of this, if a significant ingestion occurs but emesis has not occurred, gastric lavage is appropriate. In this situation, a small nasogastric tube should suffice, as inorganic cadmium salts are powders, not pills.

Given the relative lack of experience with acute oral cadmium poisoning, all patients with known exposures and/or abnormal findings consistent with cadmium toxicity or exposure should be admitted to the hospital for supportive care, monitoring of renal and hepatic function, and possibly evaluation of the GI tract for injury.

Although it seems logical to use chelation therapy in any patient with an acute life-threatening ingestion of a metal compound, the benefit of chelation in acute cadmium exposure is unproven. Multiple chelators have been used, all in animal models, with inconsistent results.

The ideal chelator for treatment of oral cadmium toxicity would be well tolerated, and would decrease GI absorption of cadmium and decrease the concentration of cadmium in organs such as the kidney and liver, while not increasing cadmium concentrations in other critical organs such as the brain. Of the chelators studied for cadmium toxicity, succimer comes closest to fulfilling these criteria. In models of acute oral cadmium toxicity, succimer decreases the GI absorption of cadmium,^3,6 without increasing cadmium burdens in target organs, and improves survival.^2,6,50

In a patient thought to have ingested potentially lethal amounts of cadmium, treatment with succimer is reasonable. Succimer should be given as soon as possible after the ingestion, as the effectiveness of chelators decreases dramatically over time in experimental models of cadmium poisoning.¹⁴

It must be stressed, however, that supporting data for chelation are promising, but not definitive, and are only derived from animal models. Succimer dosing in human cadmium poisoning is unstudied. Doses that are well tolerated (10 mg/kg/dose three times a day) are reasonable.

Other chelators that may be beneficial, but for which further investigation is needed, include diethylenetriaminepentaacetic acid (DTPA)^6,13 and 2,3-dimercaptopropane sulfonate (DMPS),^13,50 both of which reduce tissue burdens and increase survival.

Most other chelators are either ineffective or detrimental, including 2,3-dimercaptopropanol (British anti-Lewisite, BAL),^13,19,49 penicillamine,^13,62 cyclic tetramines (such as cyclam and tACPD),⁸⁸ detergent formula chelators (such as sodium tripolyphosphate {STPP} and nitrilotriacetic acid {NTA}),^29,30 CaNa₂EDTA,⁶⁵ and dithiocarbamates.^3,33

Pulmonary/Cadmium Fumes.

The patient who is ill after exposure to cadmium fumes (generally cadmium oxide) presents with predominantly respiratory complaints and possibly also with constitutional symptoms. The patient’s airway should be assessed and appropriate oxygenation ensured, although hypoxia may not be a problem acutely. Steroids are used in most reported cases (although there are no studies to support their efficacy), and a standard dose of methylprednisolone (1 mg/kg up to 60 mg) is reasonable. Because cadmium inhalation injuries are neither benign nor self-limited, all patients with acute inhalational exposures to cadmium should be admitted to the hospital for observation and supportive care until respiratory symptoms have resolved. All such patients should have long-term follow-up arranged with a pulmonologist to assess the possibility of chronic lung injury, even following a single exposure.

Chelation should not be entertained as an option for patients with single acute exposures to cadmium fumes, as these patients do not appear to develop extrapulmonary injury.^4,5,93,105

Chronic Exposure

Patients chronically exposed to cadmium frequently come to attention during routine screening, as those who work with cadmium are under close medical surveillance (Chap. 123). These patients may have developed proteinuria or, less commonly, chronic pulmonary complaints.

Management is challenging. Cessation of cadmium exposure is the first intervention. However, as mentioned earlier, chronic cadmium-induced kidney and lung changes are largely irreversible.

Chelation for chronic cadmium toxicity is not currently recommended. There is no evidence that chelation of chronically poisoned animals improves long term outcomes, and one study in humans found no improvement in cadmium-induced kidney dysfunction with periodic CaNa₂EDTA chelation.¹⁰⁴ Furthermore, in a chronically exposed patient, the majority of cadmium is bound to intracellular metallothionein, which greatly reduces its toxicity. Any attempt to remove cadmium from these deposits risks redistributing cadmium to other organs, possibly exacerbating toxicity, as is known to occur with BAL therapy.²³

Of all the chelators tested thus far in animal models of chronic cadmium toxicity, the dithiocarbamates have shown the most success in reducing total body cadmium burdens. Unfortunately, these chelators tend to cause redistribution of cadmium to the brain; the lipophilicity that allows them to cross cell membranes into hepatocytes (to access stored cadmium) also promotes their uptake into the lipid-rich central nervous system (CNS).³⁴ Numerous dithiocarbamates have been synthesized and studied with regard to cadmium decorporation, however, and several species effectively reduce whole-body, kidney, and liver cadmium concentrations without an increase in CNS cadmium.^56,85

At present, there is insufficient evidence to justify the use of any chelator in the treatment of chronic cadmium toxicity.

• Cadmium toxicity is largely dependent on route of and chronicity of exposure.

• After acute oral exposure, GI injury predominates.

• After acute inhalation, a severe chemical pneumonitis may ensue.

• With chronic environmental or occupational exposure, nephrotoxicity (usually manifested by proteinuria) is the most significant finding, although other organ systems, such as the lungs, can be affected.

• Treatment for all patients with suspected cadmium poisoning consists of removal from the source, decontamination if possible, and supportive care.

• In the rare instance of exposure from acute cadmium salt ingestion, treatment with succimer may be warranted.

• At this time there is insufficient evidence to recommend chelation in the patient with chronic cadmium poisoning.

References