88 CADMIUM
Stephen J. Traub and Robert S. Hoffman
Cadmium (Cd)
Atomic number = 48
Atomic weight =  112.4 Da
Normal concentrations
  Whole blood <  5 mcg/L (44.5 nmol/L)
 Urine <  3 mcg/g creatinine
<  26.7 nmol/g creatinine
HISTORY AND EPIDEMIOLOGY
Cadmium, atomic number 48, is a transition metal in IUPAC group 12 of the
modern 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.39
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 in patient and as a neutron absorber
in nuclear reactors. Cadmium salts were once also used as veterinary
antihelminthics.14
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 consump-
tion 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-contaminated soil.
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 fol-
lowed, affecting hundreds of people, particularly postmenopausal multipa-
rous women.70 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.30 These symptoms were ultimately linked to
cadmium, and the event came to be known as the Itai-Itai epidemic. Less
consequential environmental cadmium exposures are also reported from
Sweden,49 Belgium,12 and China.51 Smokers have higher blood cadmium
concentrations than nonsmokers,96 probably as a result of contamination of
soil where the tobacco is grown. This is noteworthy, in that cadmium and
tobacco are reported to be synergistic causes of chronic pulmonary disease.66
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 are at risk for 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 venti-
lation and/or improper respiratory precautions.
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TOXICOKINETICS
There is no known biologic role for cadmium. Ingested cadmium salts are
poorly bioavailable (5%–20%), whereas inhaled cadmium fumes (cadmium
oxide) are readily bioavailable (up to 90%).104 As the only data on cadmium
toxicokinetics are derived from work with cadmium salts and oxides, the
term “cadmium” in the following discussions refers to these species unless
otherwise noted.
After exposure, cadmium is absorbed into the bloodstream, where it is
bound to α2-macroglobulin and albumin.105 It is then quickly and preferen-
tially redistributed to the liver and kidney, and to a lesser extent to other
organs such as the pancreas, spleen, heart, lung, and testes.27 Cadmium
enters target organs via 3 possible mechanisms: zinc and calcium transport-
ers; uptake of cadmium–glutathione or cadmium–cysteine complexes by
transport proteins; and/or endocytosis of cadmium–protein complexes.111
After incorporation into the liver and kidney, cadmium forms a complex
with metallothionein, an endogenous thiol-rich protein that is produced in
both organs. Metallothionein binds and sequesters cadmium. Over time,
hepatic stores of the cadmium–metallothionein complex (Cd-MT) are slowly
released. Circulating Cd-MT is filtered by the glomerulus but reabsorbed and
concentrated in proximal tubular cells,21,91,92 explaining why the kidney is a
principal target organ in cadmium toxicity.
There is no evidence that cadmium ions are oxidized, reduced, methyl-
ated, 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 elimina-
tion are complex, and an 8-compartment kinetic model is proposed.57 The
slow release of cadmium from metallothionein-complexed hepatic stores
accounts for its very long biologic half-life of 10 or more years.
PATHOPHYSIOLOGY
Cellular Pathophysiology
Cadmium toxicity results from interactions of the free cations with target
cells.27,38,64,69,92 Complexation with metallothionein is cytoprotective,24,64 and
metallothionein functions as a natural chelator with a strong affinity for
cadmium.20,58 Although metallothionein plays a role in proximal tubular con-
centration of cadmium, kidney damage is attenuated by metallothionein, as
metallothionein-deficient mice are more susceptible to cadmium toxicity
than controls.64
There are several mechanisms by which cadmium interferes with cel-
lular function. Cadmium binds to sulfhydryl groups, denaturing proteins
and/or inactivating enzymes. The mitochondria are severely affected by this
process,1 which results in an increased susceptibility to oxidative stress.50
Generally, cadmium affects processes involved in DNA repair, generation of
reactive oxygen species, and induction of apoptosis.80 Specifically, cadmium
interferes with mediators of cell adhesion such as E-cadherin, N-cadherin,
and β-catenin,76-78 and interacts with other proteins such as kinesin10 and
amyloid beta protein 1-42.71 Finally, the demonstrated interference of cad-
mium with calcium transport mechanisms101,102 leads to intracellular hyper-
calcemia and, ultimately, apoptosis
Specific Organ System Injury (Table 88–1)
Kidney
The kidney damage caused by cadmium develops over years. Proteinuria is
the most common clinical finding and correlates with proximal tubular dys-
function, which manifests as urinary loss of low-molecular-weight proteins
1259
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 1260 PART C • THE CLINICAL BASIS OF MEDICAL TOXICOLOGY
  TABLE 88–1    Major Acute and Chronic Organ System Effects of Cadmium
Organ Acute Chronic
Kidney   Proteinuria
Nephrolithiasis
Bone   Osteomalacia
Lung Pneumonitis Cancer
Gastrointestinal system Caustic injury  
such as β2-microglobulin and retinol-binding protein. Cadmium also pro-
duces hypercalciuria,88 possibly also via damage to the proximal tubule.
Musculoskeletal
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.95
Pulmonary
Acute cadmium pneumonitis is characterized by infiltrates on chest radio-
graph and hypoxia. Human autopsy studies35,75,89,106 generally show degenera-
tion and/or loss of bronchial and bronchiolar epithelial cells.
Gastrointestinal Tract
Based on case reports,13,107 ingested cadmium salts are caustic with the poten-
tial 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. 95).
CLINICAL MANIFESTATIONS
Acute Poisoning
Pulmonary/Cadmium Fumes
Cadmium pneumonitis results from inhalation of cadmium oxide fumes. The
acute phase of cadmium pneumonitis mimics metal fume fever (Chap. 121),
but the 2 entities are distinctly different. Whereas metal fume fever is benign
and self-limited, acute cadmium pneumonitis progresses to hypoxia, respira-
tory insufficiency, and death.
Published case reports of patients who develop acute cadmium
p­ neumonitis4,5,34,75,89,98,106,110 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, patients often have a normal physical examina-
tion, oxygenation, and chest radiograph. This relatively mild presentation
potentially leads both to the misdiagnosis of metal fume fever and an under-
estimation of the severity of illness. As the pneumonitis progresses to acute
respiratory distress syndrome (ARDS) (Chap. 121), crackles and rhonchi
develop, oxygenation becomes impaired, and the chest radiograph develops
a pattern consistent with alveolar filling. In fulminant cases, death usually
occurs within 3 to 5 days.35,75,89,106
Patients who survive an episode of acute cadmium pneumonitis are
at increased risk for developing chronic pulmonary disorders, including
restrictive lung disease,4,5 diffusion abnormalities,4 and pulmonary fibrosis,98
although recovery without sequelae is also reported.110
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,13 a 17-year-old student ingested approximately 150 g of cad-
mium chloride that she obtained from her school science stockroom. She pre-
sented to the emergency department with hypotension and edema of the face,
124-Goldfrank_Ch88_p1259-p1263.indd 1260
pharynx, and neck. Her condition quickly deteriorated, and she suffered a
respiratory arrest. She was intubated and underwent orogastric lavage, chela-
tion with an unspecified chelator, 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 2,000 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 hemor-
rhagic gastroenteritis.107 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 spe-
cific 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 pro-
gressive multisystem organ failure and expired one week after presentation.
His blood cadmium concentrations were extraordinarily high, suggesting an
acute ingestion, although the source of cadmium was never determined.81
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,12,47,49,70,100 although this relationship weakens at low doses.42
Patients with diabetes mellitus are reported to be particularly susceptible to
the nephrotoxic effects of cadmium.40 In most cases, proteinuria is considered
to be irreversible even after removal from exposure,41,55,84 but improvement
is sometimes reported.63,99 Less clear is the question of whether kidney dys-
function progresses after removal from exposure, with studies showing both
stable41 and deteriorating45,83,84 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, lim-
iting wider applicability of any analysis. Occupational cadmium exposure is
also associated with nephrolithiasis,48,87 likely as a result of hypercalciuria.88
Pulmonary Toxicity
Large studies of workers chronically exposed to relatively low concentra-
tions 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.29 By contrast, other
studies report both restrictive19 and obstructive23,86 changes on pulmonary
­function tests. Interestingly, a follow-up study of the group with restrictive
lung d­ isease showed improvements after cadmium exposure was reduced.18
The discrepancies in these results are due in part to markedly different
doses and durations of exposure among the various groups. Cadmium is also
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 environ-
mental exposure;46 although mentioned in case reports,8,56 osteomalacia is
generally not a prominent feature of occupational exposure to cadmium.
Gender and age differences explain part of this apparent difference: victims
of the original Itai-Itai epidemic were mostly older women, whereas occu-
pational cadmium exposures typically occur in younger men. In addition,
­differences in cumulative dosing and in route of exposure (oral vs pulmonary)
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 w ­ idespread
environmental exposure is unlikely.108
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Hepatotoxicity
Although the liver stores as much cadmium as any other organ, hepatotoxic-
ity 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, 67,85,94
impaired higher
cortical function,103 and parkinsonism.72,103
Cardiovascular
Cadmium induces hypertension in rats,62 but human studies have only
yielded unconvincing and conflicting results.33,61,73,97 Cadmium is associated
with the development of atherosclerotic plaques34 as well as heart failure.11
Other Organ Systems
Although there is evidence that cadmium causes immunosuppression affect-
ing both humoral and cell-mediated immunity in animals,26 a single human
study showed no overt immunopathology in an occupationally exposed
cohort.54 The testes are clearly a target organ in animal exposures,60 but they
are not considered a major target organ in humans.
Cancer
Cadmium induces tumors in multiple animal organs, an effect that is exac-
erbated by zinc deficiency.104 In humans, cadmium exposure is principally
associated with lung cancer.74 The strength of this association is questioned,
as most studies have methodologic problems such as coexposure to arsenic,
a known pulmonary carcinogen.9,56 Despite these confounding coexposures,
cadmium is designated as a human carcinogen by the International Agency
for Research on Cancer.44
DIAGNOSTIC TESTING
Other than to confirm exposure, cadmium concentrations have limited use-
fulness in the management of the acutely exposed patient. Diagnosis and
treatment are based on the history, physical examination, and symptoms,
and in acute exposures ancillary tests (such as pulse oximetry and chest radi-
ography) are more useful than actual cadmium concentrations.
In the patient chronically exposed to cadmium, both cadmium concen-
trations and ancillary testing are recommended. Urinary cadmium con-
centrations, 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.79
Cadmium is a significant workplace toxin. In the United States, the
Permissible Exposure Limit (PEL), expressed as the concentration of
­ derived from animal models. Succimer dosing in human cadmium poisoning
cadmium in air as an 8-hour time-weighted average exposure (TWA), is
5 mcg/m3. Workers must also be provided with lunchroom facilities in which
the concentration of cadmium in air must be below 2.5 mcg/m3.
Yearly biologic monitoring plays an important role in the surveillance of
workplace cadmium toxicity, and involves testing not only for urinary and
blood levels of cadmium but for indices of renal function as well. Abnor-
malities in monitoring data require 90-day follow-up testing; if subsequent
testing meets action levels, the worker must be medically removed from
exposure to cadmium. Workers with higher cadmium indices on initial eval-
uation have lower thresholds for removal based on 90-day follow-up testing.
Testing and removal thresholds for workplace cadmium testing are noted
in Table 88–2.
The values noted for industrial hygiene are reasonable in light of the fact
that kidney dysfunction is reported to occur at cadmium concentrations as
low as 5 mcg/g urinary creatinine,22,47 a concentration significantly higher
than that of the general US population (95% of whom have concentrations
that are less than 3 mcg/g urinary creatinine).17
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CHAPTER 88 • CADMIUM 1261
  TABLE 88–2    Workplace Cadmium Exposure Risk Assessment Values
Initial Low Initial High 90-Day Medical
Biologic Index Risk Level Risk Level Removal Level
Urine Cadmium (mcg/g Cr) 3 15
  7 7
Beta2-Microglobulin (mcg/g Cr) 300 1,500
  750 750
Whole Blood Cadmium (mcg/L) 5 15
  10 10
MANAGEMENT
Acute Exposure
Oral Exposure/Cadmium Salts
After the patient’s airway, breathing, and circulation are secured, attention
should be given to GI decontamination. Although large ingestions of sol-
uble cadmium salts are rare, they are potentially fatal,13,107 with the lowest
reported human lethal dose being 5 g. In light of this, if a significant inges-
tion occurs but emesis has not occurred, gastric lavage is recommended. 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 sup-
portive care, monitoring of renal and hepatic function, and possibly evalua-
tion 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 chela-
tion in acute cadmium exposure is unproven. Multiple chelators have been
studied, 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 bur-
dens in target organs, and improves survival.2,6,53
In a patient thought to have acutely ingested potentially lethal amounts
of cadmium, treatment with succimer is reasonable but unproven. Succimer
should be given as soon as possible after the ingestion, as the effectiveness
of chelators decreases dramatically over time in experimental models of
c­ admium poisoning.16
It must be stressed, however, that supporting data for chelation are solely
is unstudied. Doses that are well tolerated (10 mg/kg/dose 3 times a day) are
reasonable.
Other chelators with potential benefits include diethylenetriaminepen-
taacetic acid (DTPA)6,15 and 2,3-dimercaptopropane sulfonate (DMPS),13,53
both of which reduce tissue burdens and increase survival but for which
­further investigation is needed.
Most other chelators are either ineffective or detrimental, including
dimercaprol (British anti-Lewisite {BAL}),15,21,52 penicillamine,15,65 cyclic tet-
ramines (such as cyclam and tACPD),93 detergent formula chelators (such
as sodium tripolyphosphate {STPP} and nitrilotriacetic acid {NTA}),31,32
CaNa2EDTA,68 and dithiocarbamates.3,35
Pulmonary/Cadmium Fumes
The patient who is ill after exposure to cadmium fumes (generally cad-
mium oxide) presents with predominantly respiratory complaints and
constitutional symptoms. The patient’s airway should be assessed and
appropriate oxygenation ensured, although hypoxia is commonly delayed.
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 1262 PART C • THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Corticosteroids are used in most reported cases (although there are no stud-
ies 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 expo-
sures 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 is not recommended as an option for patients with single acute
exposures to cadmium fumes, as these patients do not appear to develop
extrapulmonary injury.4,5,98,110
­
Chronic Exposure
Patients chronically exposed to cadmium frequently come to attention dur-
ing routine screening, as those who work with cadmium are under close
medical surveillance (Chap. 131). These patients may have developed pro-
teinuria 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.
We recommend again chelation for chronic cadmium toxicity. 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.109 Further-
more, 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.25
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 redis-
tribution 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).37 Numerous
dithiocarbamates have been synthesized and studied with regard to cad-
mium decorporation, however, and several species effectively reduce whole-
body, kidney, and liver cadmium concentrations without an increase in CNS
cadmium.59,90 Thus, at present, there is insufficient evidence to justify the use
of any chelator in the treatment of patients with chronic cadmium toxicity.

SUMMARY
■■ Cadmium toxicity is largely dependent on the route of and chronicity
of exposure.
■■ After acute oral exposure, GI injury predominates.
■■ After acute inhalation, a severe chemical pneumonitis can ensue.
■■ With chronic environmental or occupational exposure, nephrotoxic-
ity (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 support-
ive care.
■■ In the rare instance of a potentially life-threatening acute cadmium salt
ingestion, treatment with succimer is reasonable.
■■ At this time, we recommend against chelation in the patient with
chronic cadmium poisoning.

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