Toxicology – Cadmium

Core concept

Cadmium is a cumulative toxic metal that primarily injures the lungs after acute inhalation and the kidneys after chronic exposure.

The major toxic syndromes are:

Acute inhalation → delayed chemical pneumonitis + noncardiogenic pulmonary edema

Acute ingestion → severe gastroenteritis ± hepatic/renal injury

Chronic exposure → proximal renal tubular dysfunction → chronic kidney disease + secondary bone disease

Cadmium is also a human carcinogen (IARC Group 1). Current OSHA and NIOSH resources identify occupational cadmium as a carcinogenic hazard.

Sources and Uses

Important occupational sources include:

• Battery manufacture, particularly nickel-cadmium batteries
• Welding or cutting cadmium-plated/coated metals
• Smelting and refining
• Electroplating
• Metal alloy production
• Pigments, paints, and glazes
• Jewelry work
• Soldering
• Plastics and stabilizers
• Mining

Important nonoccupational sources include:

• Tobacco smoke
• Contaminated food
• Environmental contamination

Smoking significantly increases cadmium body burden.

Routes of Exposure

Inhalation

The most dangerous route for acute occupational poisoning.

Heating cadmium-containing metal can generate:

• Cadmium oxide fumes
• Fine respirable particles

Approximately 10–50% of inhaled cadmium may be absorbed depending on particle size, compound solubility, and exposure circumstances.

Ingestion

Cadmium salts can cause profound local gastrointestinal irritation.

GI absorption is substantially lower than pulmonary absorption, but significant systemic poisoning can still occur after large soluble-salt ingestion.

Dermal

Systemic absorption through intact skin is generally limited.

Toxic Dose

There is no single clinically reliable toxic dose.

Historical reports describe lethal oral exposures to soluble cadmium salts in the range of approximately 30–40 mg, but these values vary widely and should not be used as absolute thresholds.

The older textbook’s use of solution concentration in mg/L is particularly misleading because toxicity depends on:

Concentration × volume ingested = actual dose

as well as:

• Chemical form
• Solubility
• Route
• Duration
• Renal function

For inhalation, clinical severity depends on airborne concentration and duration of exposure.

Pathophysiology

Cadmium is a cumulative toxin.

After absorption it binds to proteins, particularly metallothionein, and accumulates predominantly in:

• Kidneys
• Liver

Its biologic elimination is extremely slow.

Cadmium’s estimated half-life may be:

• 6–38 years in the kidney
• 4–19 years in the liver

Important mechanisms include:

• Oxidative stress
• Glutathione depletion
• Lipid peroxidation
• Inflammatory cytokine production
• Endothelial/cellular injury
• Proximal tubular toxicity

Acute Inhalational Toxicity

Key syndrome

Cadmium fumes → delayed inflammatory lung injury

This is one of the most important features of cadmium poisoning:

The patient may initially appear relatively well.

Symptoms often begin approximately:

4–10 hours after exposure

and can subsequently progress to:

• Chemical pneumonitis
• Pulmonary edema
• Acute hypoxemic respiratory failure

Early symptoms

Initially:

• Throat irritation
• Metallic or unpleasant taste
• Cough
• Headache

Several hours later:

• Fever
• Chills
• Myalgia
• Malaise
• Chest tightness
• Pleuritic chest pain
• Dyspnea
• Tachycardia
• Nausea

The initial illness may resemble metal fume fever.

Important distinction from ordinary metal fume fever

Simple metal fume fever is generally self-limited.

Cadmium exposure may instead progress to:

Chemical pneumonitis → noncardiogenic pulmonary edema → ARDS

Patients who fail to improve over the first 1–2 days require particular concern.

Severe respiratory effects

Possible complications include:

• Bronchospasm
• Hemoptysis
• Diffuse pulmonary infiltrates
• Noncardiogenic pulmonary edema
• ARDS
• Respiratory failure
• Death

Progressive lung injury has been described from several hours to days after exposure.

Acute Oral Toxicity

Cadmium salts are potent GI irritants.

Typical manifestations include:

• Severe nausea
• Vomiting
• Salivation
• Abdominal pain
• Cramping
• Diarrhea
• Tenesmus

Severe exposure may cause:

• Hematemesis
• Hemorrhagic gastroenteritis
• Dehydration
• Hypotension
• Metabolic acidosis

Systemic complications can include:

• Hepatic injury
• Acute tubular injury
• Acute kidney injury

Because vigorous vomiting often occurs, the absorbed fraction may be limited after some acute oral exposures.

Chronic Cadmium Toxicity

Kidney – Primary Target

The hallmark of chronic cadmium toxicity is:

Proximal renal tubular dysfunction

Cadmium accumulates within the renal cortex and damages proximal tubular cells.

Early abnormalities include:

• Low-molecular-weight proteinuria
• β₂-microglobulinuria
• Retinol-binding proteinuria

Later manifestations may include:

• Generalized proteinuria
• Glycosuria despite normal blood glucose
• Aminoaciduria
• Phosphaturia
• Reduced concentrating ability
• Decreased GFR
• Chronic kidney disease

ATSDR identifies urinary low-molecular-weight proteins, particularly β₂-microglobulin, as early indicators of chronic cadmium-related renal injury.

Fanconi-Like Syndrome

Severe proximal tubular dysfunction may resemble Fanconi syndrome:

Proximal tubular injury → urinary phosphate/calcium loss → metabolic bone disease

Bone Toxicity

Chronic cadmium exposure can produce:

• Osteomalacia
• Osteoporosis
• Bone pain
• Pathologic fractures

Bone disease is largely secondary to:

• Renal tubular dysfunction
• Phosphate/calcium wasting
• Altered vitamin D metabolism

Itai-Itai Disease

The classic severe chronic cadmium syndrome is:

Itai-itai disease

characterized by:

• Severe bone pain
• Osteomalacia
• Osteoporosis
• Fragility fractures
• Renal tubular dysfunction

It was historically described in heavily environmentally exposed populations in Japan.

Chronic Pulmonary Effects

Long-term occupational inhalation may contribute to:

• Chronic bronchitis
• Emphysema
• Reduced pulmonary function
• Pulmonary fibrosis

Some severe acute inhalational injuries may also leave permanent pulmonary impairment.

Carcinogenicity

Cadmium is classified as:

IARC Group 1 — carcinogenic to humans

Occupational exposure is associated particularly with lung cancer risk.

Current OSHA resources list cadmium as:

• IARC Group 1
• NIOSH occupational carcinogen
• OSHA carcinogen

Other Clinical Features

Hepatic

Acute high-dose exposure may cause:

• Elevated transaminases
• Hepatocellular injury

Severe hepatic injury is less characteristic than pulmonary or renal toxicity.

Cardiovascular

Severe acute poisoning may produce:

• Tachycardia
• Hypotension
• Shock

Associations between chronic cadmium exposure and hypertension/cardiovascular disease have been investigated, but these findings are less specific than renal toxicity.

HEENT

Chronic occupational exposure has historically been associated with:

• Anosmia
• Yellow discoloration near the gingival margin of teeth

These are not sensitive diagnostic findings.

Neurologic

Acute systemic illness may include:

• Headache
• Weakness
• Malaise

Cadmium does not typically produce a dominant neurologic toxidrome.

Diagnosis

Exposure History

A detailed occupational history is crucial.

Ask specifically about:

• Welding
• Flame cutting
• Brazing
• Battery production
• Electroplating
• Smelting
• Jewelry fabrication
• Cadmium-coated metal
• Pigment manufacture

Also ask:

• Smoking history
• Duration of exposure
• Respiratory protection
• Ventilation
• Whether coworkers developed similar symptoms

Laboratory Assessment

Acute Exposure

For significant acute poisoning consider:

• CBC
• Electrolytes
• Bicarbonate
• BUN
• Creatinine
• Urinalysis
• Liver enzymes
• Blood gas if respiratory toxicity is present

For inhalation:

• Pulse oximetry
• Chest radiograph
• Serial respiratory examination

A chest radiograph may initially be normal despite evolving lung toxicity.

Blood Cadmium

What it means

Blood cadmium primarily reflects relatively recent exposure.

It is particularly useful after:

• Recent occupational exposure
• Acute high-dose exposure

It is less useful as a direct measure of total lifetime cadmium burden.

There is no single blood cadmium concentration that reliably defines clinical poisoning.

Thus, the older simple cutoff such as “>7 μg/L = toxicity” should not be used as an absolute diagnostic threshold.

Urinary Cadmium

What it means

In the absence of established renal damage:

Urinary cadmium more closely reflects cumulative body burden and chronic exposure.

However, once tubular injury is present, urinary cadmium can increase because damaged kidneys release accumulated cadmium, making interpretation more complex.

β₂-Microglobulin

Urinary β₂-microglobulin is a marker of proximal tubular injury.

Elevated urinary β₂-microglobulin may therefore provide evidence of early cadmium nephrotoxicity.

It should be interpreted together with:

• Urinary cadmium
• Blood cadmium
• Renal function
• Occupational history

OSHA Biological Monitoring

For cadmium-exposed workers, current OSHA surveillance uses:

• Urine cadmium (CdU)
• Whole-blood cadmium (CdB)
• Urinary β₂-microglobulin

Values at or below:

• CdU 3 μg/g creatinine
• CdB 5 μg/L whole blood
• β₂-microglobulin 300 μg/g creatinine

fall within OSHA’s lowest monitoring category.

Values above these trigger enhanced occupational medical surveillance and exposure reassessment.

Important

These are:

Occupational surveillance thresholds

—not universal clinical “toxic levels.”

Differential Diagnosis

Acute inhalation

Consider:

• Ordinary metal fume fever
• Irritant gas inhalation
• Nitrogen dioxide
• Phosgene
• Hydrofluoric acid fumes
• Viral respiratory illness
• Pneumonia
• ARDS from another cause

Renal toxicity

Consider:

• Lead
• Mercury
• Other nephrotoxic metals
• Diabetes
• Hypertension
• Medication nephrotoxicity
• Primary Fanconi syndrome
• Interstitial nephritis

Bone disease

Consider:

• Vitamin D deficiency
• Hyperparathyroidism
• Renal osteodystrophy
• Other causes of osteoporosis/osteomalacia

Treatment

1. Remove from Exposure

Immediately terminate exposure.

For inhalational exposure:

• Move to fresh air
• Remove contaminated clothing when appropriate
• Prevent secondary workplace exposure

For chronic occupational toxicity:

Preventing further cadmium exposure is the most important intervention.

Acute Inhalation Management

Treatment is primarily supportive.

Provide:

• Supplemental oxygen
• Bronchodilators if bronchospasm occurs
• Close respiratory monitoring
• Mechanical ventilation when necessary

ATSDR identifies oxygen, fluid management, and mechanical ventilation as the mainstay of severe acute inhalational management.

Pulmonary Edema / ARDS

If respiratory failure develops:

• Use lung-protective mechanical ventilation
• Apply appropriate PEEP
• Manage according to standard ARDS principles
• Avoid unnecessary fluid overload

There is no proven cadmium-specific pulmonary antidote.

Observation

Because significant pulmonary toxicity may be delayed for several hours, patients with meaningful fume exposure should not be reassured solely by an initially normal examination.

Acute Oral Exposure

Mouth / GI

After ingestion:

• Rinse mouth
• Treat vomiting and fluid losses
• Correct electrolytes
• Monitor renal and hepatic function after significant exposure

Do Not Induce Vomiting

Ipecac-induced emesis is obsolete and should not be used.

Activated Charcoal

Activated charcoal has not been shown to be reliably effective for cadmium.

It is therefore not a routine cadmium-specific therapy.

Gastric Lavage

Older sources suggested gastric lavage soon after severe ingestion.

Routine gastric lavage is not part of contemporary standard poisoning management and would only be considered under exceptional circumstances with:

• A potentially life-threatening recent ingestion
• Protected airway
• Medical-toxicology consultation

Skin and Eye Exposure

For contaminated skin:

• Remove contaminated clothing
• Wash thoroughly with soap and water

For eye exposure:

• Irrigate copiously with water or saline

Persistent ocular irritation warrants examination.

Antidote

There is no established specific antidote for cadmium poisoning.

Chelation

Routine Chelation Is Not Recommended

This is an important update from the older source.

Although chelators may increase urinary cadmium excretion, they can also redistribute cadmium and increase renal cadmium delivery.

ATSDR states that chelation has no established role in routine cadmium poisoning management.

Dimercaprol (BAL)

Dimercaprol should not be used for cadmium poisoning.

It can form cadmium complexes that increase renal toxicity. ATSDR specifically identifies BAL as potentially harmful in cadmium exposure.

CaNa₂EDTA

Older references suggested CaNa₂EDTA after acute exposure.

This is now highly controversial because EDTA may:

• Increase urinary cadmium
• Mobilize cadmium toward the kidney
• Increase renal cortical cadmium concentrations
• Worsen nephrotoxicity

Therefore:

Do not routinely administer EDTA for cadmium poisoning.

Any consideration of chelation in an exceptional acute case should involve an experienced medical toxicologist.

Chronic Cadmium Toxicity

There is no established role for chelation in chronic cadmium accumulation.

Primary treatment is:

Stop further exposure

before irreversible renal injury progresses.

Hemodialysis

Hemodialysis does not effectively remove the established cadmium body burden, largely because cadmium becomes strongly bound to proteins and tissues.

Therefore:

Dialysis is not an enhanced-elimination treatment for cadmium itself.

However, dialysis should be used when conventional indications from acute kidney injury develop, such as:

• Refractory hyperkalemia
• Severe metabolic acidosis
• Fluid overload
• Uremic complications

Hypotension

Treat shock with:

• Appropriate isotonic crystalloid
• Blood products when clinically indicated
• Vasopressors if hypotension persists

Modern management does not preferentially require dopamine; vasopressor choice should follow contemporary shock physiology, with norepinephrine commonly preferred for persistent distributive hypotension.

Chronic Kidney Disease

Management includes:

• Complete removal from further cadmium exposure
• Avoidance of nephrotoxins
• Blood-pressure management
• Monitoring GFR and proteinuria
• Nephrology follow-up

Renal dysfunction may continue to progress even after exposure has stopped because of the extraordinarily long tissue half-life and irreversible tubular injury.

Bone Disease

For osteomalacia/osteoporosis:

• Correct calcium abnormalities
• Correct vitamin D deficiency
• Correct phosphate abnormalities
• Manage chronic kidney disease
• Treat osteoporosis according to standard clinical criteria

Simply administering calcium and vitamin D does not reverse the underlying cadmium body burden.

Occupational Exposure Standards

The older occupational limits are substantially outdated.

OSHA PEL

Current OSHA permissible exposure limit:

5 μg/m³ (0.005 mg/m³) as an 8-hour TWA

for cadmium compounds, dust, and fumes.

OSHA Action Level

2.5 μg/m³ as an 8-hour TWA

Exposure at or above this level can trigger additional occupational monitoring requirements.

NIOSH

NIOSH designates cadmium as an:

Occupational carcinogen (Ca)

and recommends reducing exposure to the lowest feasible concentration rather than giving a conventional numerical REL.

NIOSH IDLH

Current IDLH:

9 mg/m³ as cadmium

—not “9 mg/m².”

This corrects the unit error in the older source.

Smoking

Tobacco is an important source of cadmium exposure.

Therefore, patients with:

• Occupational cadmium exposure
• Elevated cadmium biomarkers
• Cadmium nephrotoxicity

should be strongly encouraged to avoid tobacco exposure.

Smoking can materially increase cadmium body burden.

Pregnancy

Cadmium can cross the placenta, although placental transfer is partly limited by binding within placental tissue.

Environmental and occupational exposure has been associated in epidemiologic research with adverse reproductive and fetal-growth outcomes.

Management should prioritize:

• Termination of exposure
• Occupational/environmental assessment
• Maternal renal and respiratory evaluation
• Obstetric follow-up when exposure is significant

Monitoring

Significant Acute Inhalation

Monitor:

• Respiratory rate
• Oxygen saturation
• Work of breathing
• Serial lung examination
• Chest imaging as indicated
• Blood gas if respiratory distress develops
• Renal function
• Liver enzymes after substantial exposure

Because symptoms may be delayed 4–10 hours or longer, observation duration should be guided by exposure severity rather than a rigid 4–6-hour rule.

Acute Ingestion

Monitor:

• Fluid status
• Electrolytes
• BUN/creatinine
• Urine output
• Liver function
• CBC if GI hemorrhage is suspected

Chronic Exposure

Follow:

• CdU
• CdB
• Urinary β₂-microglobulin or other tubular markers
• Creatinine/eGFR
• Urinalysis/proteinuria
• Blood pressure
• Pulmonary function when occupational inhalation is significant

Admission

Hospital admission is appropriate for:

• Significant cadmium fume inhalation
• Dyspnea
• Hypoxemia
• Pulmonary infiltrates
• Chemical pneumonitis
• Persistent severe vomiting/diarrhea
• Hemorrhagic gastroenteritis
• Significant dehydration
• Acute kidney injury
• Hepatic injury
• Hemodynamic instability

Severe respiratory toxicity warrants ICU-level care.

Prognosis

Acute Oral Exposure

Most patients who survive the initial severe GI illness recover, although significant renal or hepatic injury may require prolonged recovery.

Acute Inhalation

The prognosis depends strongly on the magnitude of exposure.

Severe chemical pneumonitis may lead to:

• ARDS
• Prolonged ventilation
• Pulmonary fibrosis
• Permanent impairment
• Death

Persistent lung dysfunction has been documented years after severe single exposures.

Chronic Exposure

Chronic cadmium-associated renal tubular damage may be irreversible.

Even after exposure stops:

Renal dysfunction may continue to progress.

Important Pitfalls

1. Mistaking cadmium fume poisoning for benign metal fume fever

Both may initially cause:

• Fever
• Chills
• Myalgia
• Cough

But cadmium can progress to:

Chemical pneumonitis + pulmonary edema + respiratory failure

2. Discharging too early after significant inhalation

Respiratory symptoms are characteristically delayed 4–10 hours.

3. Using outdated occupational limits

The old dust/fume values of 0.1–0.2 mg/m³ are far above the current general OSHA PEL.

Current OSHA PEL:

0.005 mg/m³ = 5 μg/m³

4. Misreading the IDLH unit

NIOSH IDLH is:

9 mg/m³

not 9 mg/m².

5. Treating a cadmium level as the diagnosis

Blood cadmium mainly reflects recent exposure.

Urinary cadmium more closely reflects body burden, unless tubular injury has already altered excretion.

Neither provides a perfect stand-alone measure of clinical toxicity.

6. Missing proximal tubular injury

The earliest chronic renal manifestations may be:

• β₂-microglobulinuria
• Retinol-binding proteinuria

before major creatinine elevation.

7. Giving chelation reflexively

Routine EDTA or BAL therapy is not recommended.

BAL may worsen renal toxicity, and EDTA may redistribute cadmium to the kidney.

8. Using dialysis to remove cadmium

Hemodialysis is used for complications of renal failure, not as effective cadmium decontamination.

9. Forgetting tobacco exposure

Smoking adds substantially to lifetime cadmium burden.

High-Yield Toxicology Pearls

Cadmium = lungs acutely, kidneys chronically

Think:

Welding/cutting cadmium metal → delayed fever + cough + dyspnea → chemical pneumonitis

and

Chronic exposure → proximal tubular proteinuria + osteomalacia

Key points:

• Cadmium is a cumulative heavy metal toxin
• Major occupational routes: welding, smelting, batteries, electroplating
• Tobacco is an important nonoccupational source
• Acute inhalation is the most dangerous occupational presentation
• Symptoms may be delayed 4–10 hours
• Severe inhalation can cause noncardiogenic pulmonary edema/ARDS
• Acute ingestion causes severe gastroenteritis
• Chronic target organ: kidney
• Classic chronic lesion: proximal tubular dysfunction
• Early marker: urinary β₂-microglobulin
• Bone complications: osteomalacia, osteoporosis, Itai-itai disease
• Cadmium is IARC Group 1 carcinogenic
• Blood Cd → more reflective of recent exposure
• Urine Cd → more reflective of cumulative body burden
• No specific antidote
• Main therapy: remove exposure + supportive care
• Routine chelation is not recommended
• BAL can worsen cadmium toxicity
• EDTA is controversial and potentially nephrotoxic in cadmium exposure
• Hemodialysis does not meaningfully remove tissue-bound cadmium
• Current OSHA PEL: 5 μg/m³ over 8 hours
• OSHA action level: 2.5 μg/m³
• NIOSH IDLH: 9 mg/m³
• Prevention and occupational exposure control are central because established chronic renal injury may be irreversible