Epidemiology and toxicity of cadmium

INTRODUCTION — Cadmium (Cd) is a metal that can cause severe acute or chronic toxicity in humans. Most cases of cadmium toxicity are due to chronic exposure. Chronic, low-level cadmium exposure can affect a variety of organs, with the kidneys and bones being the principal targets [1-3]. Acute cadmium toxicity is less common. Depending upon the route of exposure, acute cadmium toxicity primarily affects the lungs and gastrointestinal tract.

This topic reviews chronic and acute cadmium toxicity. Other heavy metal toxicities are discussed elsewhere:

●(See "Mercury toxicity".)

●(See "Lead nephropathy and lead-related nephrotoxicity".)

●(See "Childhood lead poisoning: Clinical manifestations and diagnosis".)

●(See "Arsenic exposure and chronic poisoning".)

CHRONIC HUMAN EXPOSURE

Source of exposure — Cadmium is a relatively rare heavy metal that occurs naturally in combination with zinc. Environmental contamination and consequent human exposure to cadmium have dramatically increased during the past 100 years [4,5]. Used in electroplating and battery manufacturing, cadmium commonly contaminates the environment via household waste, industrial emissions, and soil. As examples:

●Cadmium-containing products are frequently thrown out with the household garbage; the metal is then released into the atmosphere if the waste is burned.

●Cadmium emissions are released from mining and nonferrous smelters.

●Soil may become contaminated via atmospheric emissions and sewage sludge. Land used for farming can also contain cadmium due to the use of phosphate fertilizers containing the metal. Cadmium is readily absorbed by plants grown in cadmium-containing soil, particularly grain, rice, and vegetables.

Exposure to cadmium principally results from eating contaminated food, smoking cigarettes, and working in cadmium-contaminated workplaces.

Food intake — The daily intake of cadmium through food varies in part by geographic region. As an example, intake is reported to be approximately 8 to 30 mcg in Europe and the United States versus 59 to 113 mcg in various areas of Japan [6]. There is also a wide individual variation in cadmium intake based upon the type and amount of food consumed. Since this variation follows a log-normal distribution, most individuals ingest between 4 and 60 mcg per day (eg, ±2 standard deviations [SDs]) if the average individual intake is 15 mcg per day [7,8].

The average gastrointestinal absorption is 5 percent. Thus, the net absorbed amount of cadmium is approximately 1 to 2 mcg per day in Europe and the United States and up to 5 mcg in areas in Japan. In certain areas of Japan, such as the Jinzu river basin and Kakehashi river basin, which are considered highly contaminated with cadmium, the net ingestion is higher [9].

The gastrointestinal absorption of dietary cadmium is increased by mild iron deficiency [10]. As a result, chronically iron-deficient individuals are at higher risk for environmental cadmium exposure. (See 'Risk factors' below.)

Smoking — Smoking is a potentially important route of cadmium exposure. Individuals who smoke 20 cigarettes a day absorb nearly 1 mcg of cadmium via the lungs, an amount similar to the quantity absorbed via food in Europe and the United States [8].

Occupational exposure — The workplace constitutes the most important source of cadmium exposure among individuals engaged in cadmium production and the industrial use of cadmium. Major industrial applications for cadmium are in the production of alloys, galvanizing pigments, and nickel-cadmium batteries. Over one million individuals worldwide are believed to be occupationally exposed to cadmium.

The permissible occupational threshold limit values range from 0.005 to 0.05 mg Cd/m³ in air in various countries. The Occupational Safety and Health Administration (OSHA) of the United States has set the permissible exposure limit for cadmium in air to 0.005 mg Cd/m³ [1,11].

Metabolism after exposure — Gastrointestinal absorption following oral intake is relatively poor, with the highest estimates for bioavailability listed at approximately 10 percent [12]. Inhalational absorption is far more efficient, with a bioavailability of up to 50 percent. However, total absorbed cadmium dose is also dependent on inhaled particle size. Small particles (<0.1 micrometer) are more likely to penetrate to the alveoli, where cadmium absorption occurs [13]. After ingestion of contaminated food or inhalation via cigarette smoking or at the workplace, cadmium is transported to the liver, where metallothionein, a cadmium- and zinc-binding protein, is synthesized [8]. Metallothionein serves as a detoxifying protein by binding cadmium and preventing free cadmium ions from disturbing normal cellular functions. It is also responsible for the pronounced accumulation of cadmium in the liver and kidneys.

Metallothionein, which has a molecular weight of approximately 7000 daltons, migrates slowly from the liver cells into the blood stream, where it is transported to the kidneys. As with other small proteins, it is freely filtered across the glomerulus and then reabsorbed by the proximal tubular cells via pinocytosis. In the tubular cells, metallothionein enters the lysosomes, where it is degraded by lysozymes, releasing free cadmium ions into the tubular cell cytoplasm.

The renal tubular cells have a considerable capacity to synthesize metallothionein, which binds the toxic cadmium ions. At some point, however, the kidneys' detoxifying capacity is surpassed, and free cadmium causes tubular damage, interstitial inflammation, and eventually fibrosis and glomerular injury [1,11].

Disease associations — Chronic cadmium exposure causes toxicity of the kidney and bones. Chronic exposure may also be associated with lung cancer and may cause emphysema.

Kidney disease

Manifestations — The majority of patients with cadmium-associated kidney disease have isolated tubular defects that are only detected by specific testing [14,15]. Early manifestations include an increased excretion of low-molecular-weight proteins, such as beta2-microglobulin [11]. In almost all cases, tubular proteinuria is irreversible, even if exposure has ceased [16-18].

Some workers exposed to cadmium have a slightly increased urinary excretion of albumin, which may be related to a glomerular lesion or represent decreased tubular reabsorption of the small amount of albumin that is normally filtered through the glomerulus [19].

In more severe cases of cadmium toxicity, patients present with evidence of kidney interstitial injury, including the following [1,11,20,21]:

●Renal glucosuria

●Aminoaciduria

●Renal phosphate wasting

●Hypercalciuria

●Polyuria due to decreased concentration capacity

●Diminished ability to handle an acid (NH₄Cl) load

●Decreased glomerular filtration rate (GFR)

Despite tubular damage, kidney disease does not appear to progress in most individuals if exposure ceases. In a five-year follow-up study of nearly 600 Belgian individuals with initially mild evidence of tubular damage and decreasing exposure to cadmium, there was no evidence of progressive kidney damage [22]. Thus, patients with isolated tubular defects rarely have symptoms or clinically evident disease. However, there are several exceptions to this:

●Some individuals develop kidney stones as a result of hypercalciuria, which is a known risk factor for stone development (see "Kidney stones in adults: Epidemiology and risk factors", section on 'High urine calcium'). The prevalence of symptomatic kidney stones is increased among individuals occupationally exposed to cadmium [1,11,23]. In one report, for example, a dose-response relationship was demonstrated between cumulative cadmium exposure among a group of battery workers and the age-adjusted cumulative incidence of kidney calculi (figure 1). Hypercalciuria is thought to be a primary determinant of stone formation in such patients [24,25].

●Some individuals, presumably those with more severe exposure to cadmium, present with a decreased estimated GFR (eGFR) [11,26-28]. There is an association among the degree of tubular dysfunction, the cadmium dose, and a decrease in GFR (figure 2).

●Some individuals who have significant environmental cadmium exposure progress to end-stage kidney disease (ESKD). As an example, uremia was a common cause of death among Japanese farmers suffering from cadmium-induced osteomalacia (see 'Bone disease' below) and has been observed in workers previously heavily exposed to cadmium [1]. Additionally, in a large cohort study from a cadmium-polluted area of Sweden, the age-standardized incidence rate ratio (SRR) of requiring kidney replacement therapy over an 18-year period was higher among those with increased exposure to cadmium [27]. The SRR among those with low, moderate, and high cadmium exposure was 1.4, 1.9, and 2.3, respectively.

Pathology — Few reports of kidney biopsies from cadmium-poisoned individuals have been published. Tubular atrophy, ischemic and degenerative glomerular lesions, interstitial fibrosis, and marked subcapsular lymphocytic infiltration were found in the kidneys of a man who died from cadmium-induced uremia [29]. In a study of kidney biopsies from 109 healthy kidney donors, tissue concentrations of cadmium were associated with mild tubular atrophy [30]; these histopathologic changes were consistent with those previously found in the kidneys of horses who had a higher degree of cadmium exposure [31].

Risk factors — In addition to cadmium exposure, risk factors for cadmium-induced nephrotoxicity include age, diabetes mellitus, and iron deficiency.

●Cadmium exposure – Multiple epidemiologic studies have associated endemic outbreaks of cadmium-induced kidney disease in Japan with consumption of cadmium-contaminated rice [1,9,11]. Other studies from certain areas of Belgium, China, Japan, and Sweden demonstrated an association between high body cadmium burdens and kidney dysfunction [9,32-34].

Chronic exposure of the kidney to cadmium is reflected in the urinary cadmium excretion. The threshold urinary cadmium excretion that is associated with toxicity is not known but is probably lower than was initially suggested (5 to 10 mcg per gram of creatinine) [35].

Subsequent reports, however, indicate that toxicity may occur at much lower urinary cadmium concentrations [5,7,34]. A number of studies have suggested that increased secretion of tubular proteins may occur at urine cadmium concentrations exceeding a level of only 1 to 5 mcg Cd/g creatinine (or 2 to 3 nmol Cd/mmol creatinine) [32,34,36,37]. In one study, depending upon age, the prevalence of beta2-microglobulinuria was 5 to 15 percent at urinary cadmium concentrations of 3 nmol/mmol creatinine (figure 2). Among 820 environmentally exposed postmenopausal females (aged 53 to 64 years), cadmium levels in blood and urine were associated with reduced eGFR and increased markers of tubular injury; these associations were seen at a mean urinary cadmium level as low as 0.8 nmol/mmol creatinine [38]. However, associations between eGFR and cadmium were only recorded when smokers were included in the multiple regression analysis, which suggests that confounding from smoking may be a problem in the interpretation of the findings.

Even lower urinary cadmium concentrations have been associated with proteinuria in some studies [39]. However, these associations appear to be largely driven by current smoking, variations in diuresis, and probably also the co-excretion in urine of Cd with proteins [40]. The assessment of data of a large cohort of nickel-cadmium battery workers revealed that the kidney effects of chronic smoking substantially distort the dose effect/response relationships [41]. On the basis of associations undistorted by smoking and adjusted for covariates, the threshold for low-molecular-weight proteinuria induced by occupational exposure to Cd was estimated between 5.5 and 6.6 nmol/mmol creatinine [41].

A review of the literature combined with an analysis of the risks from environmental cadmium exposure concluded that there is a low margin of safety between current levels of exposure to cadmium and that which may cause kidney toxicity [7]. If the average daily intake of cadmium is increased from 15 to 30 mcg, approximately 1 percent of the adult population would be expected to develop renal tubular damage (as detected by tubular proteinuria). In certain high-risk groups, such as females with poor iron stores, the percentage affected would be even higher.

●Age – Older individuals are more likely to develop kidney toxicity at a given level of cadmium exposure [34]. In an examination of Swedish battery workers, a 10 percent prevalence of tubular proteinuria associated with a cadmium level of 1.5 nmol/mmol creatinine was found in the older age group versus 5 nmol/mmol creatinine in the younger subjects (figure 2).

Several reasons have been advanced as to why older individuals have a higher prevalence of kidney dysfunction when exposed to cadmium. Older individuals may have an increased cadmium body burden with age due to higher amounts of cadmium accumulated in the kidney from both occupational exposure and environmental sources (food, tobacco). Degenerative changes in the renal tubules with age may predispose to cadmium-induced tubular injury and accelerate the rate of cadmium-induced kidney dysfunction.

●Diabetes – Observational data suggest that individuals with diabetes mellitus also have a higher risk of developing kidney dysfunction from cadmium exposure [16,42].

●Iron deficiency – Individuals with iron deficiency may be at higher risk for cadmium toxicity. This is because iron deficiency results in higher gastrointestinal cadmium absorption.

Bone disease — Cadmium toxicity is associated with bone disease. Bone disease due to prolonged exposure to cadmium was first reported among exposed individuals living in the Jinzu river basin in Japan, an area that is highly contaminated with cadmium. Exposure to cadmium was caused by contaminated river water used for irrigation of rice fields. Cadmium toxicity resulted in Itai-Itai ("Ouch-Ouch") disease, an illness characterized by multiple fractures, a mixed pattern of osteoporosis and osteomalacia, and kidney damage [1,11,43,44]. The diagnosis of osteomalacia was made by clinical manifestations including multiple fractures, vertebral compressions, shortening of stature, and other radiograph and autopsy findings. Bone biopsies were generally not performed. A few additional reports have described similar bone disorders in workers with kidney damage and a history of heavy exposure to cadmium [1,11,45].

A dose-dependent association of cadmium exposure with osteoporosis and bone fractures is described in numerous observational studies [2,3,46-55]. These studies, which included individuals who had lower-intensity cadmium exposure than those in the original case series, ascertained cadmium exposure using blood and/or urine levels or an estimation of dietary intake.

The following examples illustrate the range of findings:

●A prospective cohort of 506 individuals living in proximity to zinc smelters in Belgium underwent baseline measurement of urinary cadmium excretion with assessments of forearm bone mineral density and fracture incidence a mean of 6.6 years later [47]. Urinary cadmium excretion was inversely correlated with future bone mineral density. In addition, a twofold higher urinary cadmium excretion was associated with a 73 percent increased risk of fracture in females after controlling for other variables and a 60 percent increased risk of height loss in males.

●A cross-sectional study of 1021 individuals who resided near or worked in two battery plants in Sweden had measurements of blood cadmium and forearm bone mineral density [49]. Among those aged ≥60 years, blood cadmium was independently and inversely correlated with bone mineral density in females. In both males and females ≥60 years, a blood cadmium of ≥10 nmol/L was associated with a threefold higher prevalence of osteoporosis (defined as a z-score <-1) compared with those who had a blood cadmium <5 nmol/L.

●Another cross-sectional study of 2688 females examined the association of the urine cadmium-to-creatinine ratio with bone mineral density and the prevalence of fractures [52]. After controlling for potential confounders, a higher urine cadmium-to-creatinine ratio was significantly and inversely correlated with bone mineral density and positively associated with the prevalence of osteoporosis. This relationship was stronger in females who had never smoked compared with females who smoked. In addition, the prevalence of fractures was twofold higher in nonsmoking females whose cadmium-to-creatinine ratio was >0.75 mcg/g compared with nonsmoking females whose ratio was <0.5 mcg/g. A 1 nmol Cd/mmol creatinine equals 1 mcg Cd/g creatinine.

●The association of estimated dietary cadmium intake and incidence of fractures was analyzed in a prospective, population-based cohort of Swedish males followed for 10 years [53]. Males in the highest compared with lowest tertile of cadmium intake had an increased risk of developing a fracture (hazard ratio [HR] 1.19, 95% CI 1.06-1.34) after controlling for potential confounders.

●Using multivariable-adjusted linear regression, dietary cadmium exposure and urinary cadmium were related to total-body bone mineral density and risk of osteoporosis and fractures in 2676 females aged 56 to 69 years. High dietary cadmium exposure (≥13 mcg/day, median) compared with lower exposures (<13 mcg/day) was associated with a 32 percent increased risk of osteoporosis (95% CI 2-71 percent) and 31 percent increased risk for any first incident fracture (95% CI 2-69 percent) [55].

●In an analysis of data from 10,978 subjects (aged 30 to 90 years) from the Third National Health and Nutrition Examination Survey (NHANES), the multivariable adjusted risk of osteopenia and osteoporosis increased at each level of urinary cadmium in both males and females [54].

Not all studies have found such an association, however. As an example, a Japanese cross-sectional study of more than 1300 individuals with long-term cadmium exposure from food reported no significant association of cadmium with bone density [56]. However, the assessment of dietary cadmium intake in this study was potentially biased since it did not correlate with urinary cadmium excretion.

Potential mechanisms — The mechanism underlying cadmium-associated bone disease is not well understood. One hypothesis suggests that the accumulation of cadmium in kidney tubular cells causes a reduction in the activation of calcidiol to calcitriol, resulting in decreased calcium absorption from the gut and impaired bone mineralization and eventually osteoporosis or osteomalacia [57].

Other mechanisms, however, may also be involved. A direct toxic effect from cadmium on the bone is suggested by several epidemiologic studies that documented associations between cadmium exposure and lower bone mineral density in the absence of any evidence for renal tubular injury [2,3].

Lung toxicity and cancer — There is experimental and epidemiologic evidence linking exposure to cadmium to respiratory cancer [58]. In 1993, the International Agency for Research on Cancer (IARC) concluded that inhaled cadmium should be considered a human carcinogen [59]; this interpretation, however, has been challenged [60,61]. Nevertheless, a summary evaluation of existing studies found that both lung cancer and kidney dysfunction should be considered "critical effects" from exposure to cadmium [1].

The relationship between cadmium and lung cancer was explored in an epidemiologic study from Belgium. Lung cancer incidence among 521 individuals residing in a cadmium-contaminated zinc smelter area was compared with that in 473 individuals with low environmental exposure [62]. During a median follow-up of 17 years, 3 and 16 lung cancers occurred in the low- and high-exposure areas, respectively, for an incidence of 0.4 versus 1.8 per 1000 patient-years at risk, respectively. In multivariate analyses adjusted for smoking, age, and sex, the hazard ratio was 4.2 (95% CI 1.2-14) for high- versus low-exposure areas, respectively, and 1.7 (95% CI 1.1-2.6) for doubling of 24-hour urinary cadmium excretion. However, concomitant exposure to arsenic, a well-known human carcinogen, occurred in the exposed area. This was adjusted for in the epidemiologic analyses, but the possibility for residual confounding from arsenic, or some other contaminant in the zinc smelter area, cannot be ruled out completely [63].

Continued inhalational exposure to cadmium can give rise to obstructive lung disease and emphysema [1,8].

Clinical presentation — Most patients with chronic cadmium toxicity are asymptomatic for kidney disease, although they may have symptoms and/or a previously established diagnosis of osteoporosis. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men", section on 'Clinical manifestations'.)

Patients with cadmium-associated kidney disease may have mild laboratory abnormalities that are detected as part of evaluation of unrelated presentation. Such laboratory abnormalities include mildly increased protein excretion (reflecting decreased tubular reabsorption of beta2-microglobulin, retinol binding protein, and human complex-forming glycoprotein HC [protein HC]), as well as a mild metabolic acidosis and glucosuria, amino aciduria, or phosphaturia, consistent with a proximal tubular defect with Fanconi syndrome. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA' and "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Diagnosis'.)

Although patients with cadmium-associated kidney disease may have increased excretion of low-molecular-weight proteins (such as beta2-microglobulin), this is not detected by urine dipstick, which detects only albumin [11]. However, mild increases in protein excretion (ie, <500 mg/day) may be detected by protein quantitation of a 24-hour urine collection or by protein-to-creatinine ratio in a spot urine. As noted above, occasional patients with cadmium toxicity may have increased albumin excretion, which is detectable by urine dipstick; however, this is uncommon.

Some patients present with symptoms of a concentrating defect with complaints of nocturia or polyuria. (See "Evaluation of patients with polyuria", section on 'Arginine vasopressin resistance (AVP-R)' and "Nocturia: Clinical presentation, evaluation, and management in adults", section on 'Polyuria'.)

Some patients come to attention because of recurrent calcium-containing stones, and the evaluation reveals hypercalciuria. (See "Nephrolithiasis in renal tubular acidosis", section on 'Proximal (type 2) RTA' and "Kidney stones in adults: Epidemiology and risk factors", section on 'High urine calcium'.)

A small number of patients may present with reduced eGFR that is detected as a part of evaluation for an unrelated presentation or, rarely, with symptoms and laboratory manifestations of ESKD. (See "Overview of the management of chronic kidney disease in adults", section on 'Treatment of the complications of severe CKD'.)

Diagnosis — The diagnosis of chronic cadmium toxicity should be considered in patients with a history of exposure who present with signs of interstitial kidney disease or signs or symptoms of osteoporosis.

The diagnosis of chronic cadmium toxicity is made by determination of increased cadmium in urine and by the demonstration of increased excretion of tubular proteins in the appropriate clinical setting. Cadmium in urine reflects the cumulative cadmium exposure. The urine cadmium should be adjusted for dilution by calculating the cadmium/creatinine ratio [7,64]. There is no absolute cadmium/creatinine ratio that is considered diagnostic, but, in clear cases of cadmium nephrotoxicity, it is usually >5 nmol Cd/mmol creatinine. In the setting of a history of exposure to cadmium or clinical evidence of toxicity (such as a Fanconi syndrome and increased urinary excretion of beta2-microglobulin), abnormally increased blood cadmium concentration and urinary cadmium/creatinine ratio should be considered evidence of chronic toxicity [65].

Increased excretion of at least one tubular protein should be demonstrated to confirm the diagnosis of cadmium nephrotoxicity. Several highly sensitive indicators of tubular damage have been developed and used in cross-sectional and epidemiologic studies in cadmium-exposed groups. We first measure the urinary excretion of beta2-microglobulin. Among patients who have increased blood and urinary cadmium concentrations, an increase in beta2-microglobulin excretion >0.3 mg/g creatinine is considered diagnostic. Beta2-microglobulin is a low-molecular plasma protein with a molecular weight of 12,000 and is easily detected using radioimmunoassays. Beta2-microglobulin is freely filtered by the glomerulus and almost completely (>99.9 percent) reabsorbed in the proximal tubule. Even small changes in tubular reabsorptive capacity result in a marked increase in urinary beta2-microglobulin excretion [1]. The United States OSHA requires that an employer take action if a cadmium-exposed worker demonstrates a urinary beta microglobulin concentration exceeding 750 mcg/g creatinine, though nonmandatory levels for removal from work exposure are advised for concentrations between 300 and 750 mcg/g creatinine. A table outlining OSHA recommendations in response to elevated surveillance levels for blood or urine cadmium, or beta2-microglobulin excretion, is available (table 1).

However, measurement of beta2-microglobulin is less sensitive for diagnosis among patients who have acidic urine since the protein degrades in an acid pH. Thus, among patients who have acidic urine (pH <5.6) and do not have or have only a mild increase in urinary beta2-microglobulin, we measure either retinol binding protein, human complex-forming glycoprotein (protein HC or alpha-1-microglobulin), or apolipoprotein. These are equally sensitive but less widely used indicators of cadmium-induced tubular damage.

These plasma proteins are all filtered through the glomerulus. Other urinary markers indicative of a subtle tubulotoxic effect are increased excretion of N-acetyl-beta-D-glucosaminidase (NAG), an enzyme localized in lysosomes of the tubular cells, and kidney injury molecule-1 (KIM-1), a transmembrane protein expressed in proximal tubule cells after injury [36,66]. However, these are generally not used clinically.

Prevention of chronic toxicity — Minimizing exposure to cadmium is the most important therapeutic measure. To reduce the risk of cadmium toxicity, as for many other reasons, we recommend stopping smoking (see "Cardiovascular risk of smoking and benefits of smoking cessation", section on 'Summary and recommendations'). In addition, occupational exposure should be kept as low as technically feasible, preferably below 0.005 mg/m³. Exposure via food should be kept well below 30 mcg Cd/day [67].

There is very little margin of safety between levels of cadmium found in human kidneys and the levels in which early kidney dysfunction can occur in susceptible individuals. Subtle kidney and bone effects likely still occur in certain areas where cadmium pollution is severe. As a result, actions aimed at decreasing pollution from and human exposure to cadmium are well founded.

Treatment of chronic toxicity — There is no specific therapy for cadmium-associated chronic kidney disease (CKD) [11]. Cadmium-induced osteomalacia has been treated with large doses of vitamin D [11]. Sources of cadmium exposure should be avoided as much as possible.

Prognosis of chronic toxicity — Increased mortality among Japanese farmers with proteinuria due to chronic environmental exposure to cadmium has been observed in several epidemiologic studies [7,68-76]. A 15-year follow-up of 3178 inhabitants in a cadmium-polluted area of Japan revealed a dose-related increase in the overall age-adjusted mortality with increasing urinary excretion of beta2-microglobulin [72]. People with an initial examination showing urine beta2-microglobulin exceeding 1 to 10 mg/g creatinine had more than twice the mortality compared with those with normal values (<0.3 mg/g creatinine) [72,73]. The elevated mortality rate is associated with cardiovascular and kidney diseases [73,74]. Another study followed 3281 inhabitants (1544 males and 1737 females) of a separate cadmium-contaminated region from Japan; kidney disease and kidney disease-associated mortality were increased, and among females, all-cause mortality was elevated [75].

Taken together, available epidemiologic evidence indicates that the initial, rather subtle kidney effects from cadmium in the form of a tubular proteinuria eventually may develop, or at least contribute, to more severe kidney disease and increased mortality [27,73].

ACUTE CADMIUM TOXICITY — Acute cadmium toxicity is rare but occurs in the setting of both inhalational [77,78] and oral [79,80] exposure.

Acute inhalational (pulmonary) exposure — Inhalational exposure to cadmium may cause severe pneumonitis, which can progress to acute respiratory distress syndrome (ARDS) and pulmonary hemorrhage. Acute pulmonary exposure to cadmium oxide occurs when welders use cadmium-containing solders or braze cadmium-containing objects without appropriate pulmonary precautions [77,81-85]. In these scenarios, the liberation of cadmium oxide at first produces only mild irritant symptoms (if any), which may facilitate ongoing exposure [86,87]. The initial symptoms of cadmium pneumonitis usually occur hours after the initial exposure, and include sore throat, cough and dyspnea [87]. Early cadmium pneumonitis resembles metal fume fever, a more common condition caused by the inhalation of oxides of other metals such as zinc or magnesium. However, metal fume fever is almost always benign and self-limited, whereas cadmium pneumonitis may progress to severe dyspnea, hypoxia, and respiratory failure. The initial chest radiograph in cadmium pneumonitis may be normal but in severe cases will progress to an ARDS pattern (see "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults"). In such patients, cadmium pneumonitis is often fatal [77,78,88]. Although chronic pulmonary sequelae after cadmium pneumonitis are reported [82,83,85], the extent to which cadmium is the causative agent is unclear.

Inhalational cadmium toxicity also can cause renal and hepatic injury [86,87].

Acute oral exposure — Acute exposure to oral cadmium is very rare but significant; ingestion of cadmium salts results in substantial local tissue injury. In two documented cases of single-dose cadmium poisoning, oropharyngeal edema and gastrointestinal bleeding were prominent clinical findings [79,80]. A third case of suspected oral exposure, which may have occurred over months, presented with an anemia that was initially suspected to be autoimmune hemolytic in nature [89].

Prevention of acute toxicity — Avoiding exposure to cadmium is the most important preventive measure. Occupational exposure should be kept as low as technically feasible. Inhalational exposure may be avoided by wearing appropriate protective equipment.

Diagnosis of acute toxicity — The diagnosis of acute cadmium toxicity rests entirely on the clinical presentation and a history of exposure to cadmium. The diagnosis is usually confirmed by analysis of cadmium in blood, which reflects recent cadmium exposure. We also check urine cadmium to determine whether there is concomitant chronic exposure to cadmium. Cadmium in urine (adjusted for dilution by calculating the cadmium/creatinine ratio) indicates accumulation or kidney burden of cadmium [7,64].

Treatment of acute toxicity — Other than general supportive therapy, there are no specific methods available for treating acute cadmium ingestion or inhalation. Although various chelating agents have been tried in animals, none have been shown to be efficient in humans. In the event of an acute cadmium exposure (inhalation or oral), the provider should contact a poison control center immediately. (See 'Additional resources' below.)

Additional resources — Regional poison control centers in the United States are available for consultation on patients who are critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have clinical and/or medical toxicologists available for bedside consultation and/or inpatient care. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for regional poison centers around the world is available here.

Prognosis of acute toxicity — Based on limited data from case reports, the morbidity and mortality associated with acute cadmium toxicity are very high.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Cadmium toxicity (The Basics)")

SUMMARY

●Overview – Cadmium (Cd) may cause severe chronic or acute toxicity. Prolonged cadmium exposure principally affects the kidneys and bones. Acute toxicity is mainly via inhalation. (See 'Introduction' above and 'Disease associations' above.)

●Sources of exposure – Exposure to cadmium principally results from eating contaminated food, smoking cigarettes, and working in cadmium-contaminated workplaces. (See 'Source of exposure' above.)

●Chronic toxicity

•Clinical manifestations

-Kidney disease – The earliest sign of cadmium nephrotoxicity is tubular proteinuria. Other manifestations include glucosuria, aminoaciduria, phosphate wasting, hypercalciuria, polyuria due to decreased concentration capacity, decreased glomerular filtration rate (GFR), and a mild metabolic acidosis. Some patients may present with kidney stones from hypercalciuria. Patients may present with or progress to end-stage kidney disease (ESKD), but this is uncommon. In addition to cadmium exposure, risk factors for nephrotoxicity include age, diabetes mellitus, and iron deficiency. (See 'Kidney disease' above and 'Risk factors' above.)

-Bone disease – Cadmium toxicity is associated with osteoporosis and fractures, which appears to be dose related. The mechanism by which cadmium causes bone disease is not completely clear. (See 'Bone disease' above.)

-Lung disease – Cadmium exposure may cause significant toxicity of the lungs, including lung cancer. (See 'Lung toxicity and cancer' above.)

•Diagnosis – The diagnosis of chronic cadmium toxicity should be considered in patients with a history of exposure who present with signs and/or symptoms of interstitial kidney disease or osteoporosis. The diagnosis of chronic cadmium toxicity is made by analysis of cadmium in urine in the appropriate clinical setting. The increased excretion of at least one tubular protein should be demonstrated to confirm the diagnosis of cadmium nephrotoxicity. (See 'Diagnosis' above.)

●Acute toxicity

•Clinical manifestations – Acute cadmium toxicity is rare but may occur after inhalational exposure and give rise to influenza-like symptoms including fever and pains in muscles and joints shortly (less than 12 hours) after exposure. A severe and fatal chemical pneumonitis may develop. Acute oral exposure is very rare but may cause oropharyngeal edema and gastrointestinal bleeding. (See 'Acute cadmium toxicity' above.)

•Diagnosis, treatment, and prognosis – The diagnosis of acute cadmium toxicity rests entirely on the clinical presentation and a history of exposure to cadmium. The diagnosis is usually confirmed by analysis of cadmium in blood. Other than general supportive therapy, there are no specific methods available for treating acute cadmium ingestion or inhalation. The morbidity and mortality associated with acute toxicity are very high. (See 'Acute cadmium toxicity' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen Traub, MD, who contributed to earlier versions of this topic review.