Category: Toxicity
Affected System: Multi system
| Synonyms and Related Keywords |
Cadmium Toxicity, Cadmium Intoxication
| Introduction |
Definition:
Cadmium has no constructive purpose in the human body. It and its compounds are extremely toxic even in low concentrations, and will bioaccumulate in organisms and ecosystems.The itai-itai disease ("ouch-ouch disease") was caused by cadmium poisoning.
Diagnosis:
Cadmium poisoning is usually diagnosed by its symptoms, particularly if there is reason to believe that the patient has been exposed to cadmium. Because patients may not request treatment for up to a day following cadmium exposure, diagnosticians should carefully question any patient who shows symptoms consistent with this condition.
Signs and Symptoms:
Acute exposure to cadmium fumes may cause flu like symptoms including chills, fever, and muscle ache. Symptoms may resolve after a week if there is no respiratory damage. More severe exposures can cause tracheo-bronchitis, pneumonitis, and pulmonary edema. Symptoms of inflammation may start hours after the exposure and include cough, dryness and irritation of the nose and throat, headache, dizziness, weakness, fever, chills, and chest pain.
Inhaling cadmium-laden dust quickly leads to respiratory tract and kidney problems which can be fatal (often from renal failure). Ingestion of any significant amount of cadmium causes immediate poisoning and damage to the liver and the kidneys. Compounds containing cadmium are also carcinogenic.
The bones become soft (osteomalacia), lose bone mass and become weaker (osteoporosis). This causes the pain in the joints and the back, and also increases the risk of fractures. In extreme cases of cadmium poisoning, the mere body weight causes a fracture.
The kidneys lose their function to remove acids from the blood in proximal renal tubular dysfunction. The kidney damage inflicted by cadmium poisoning is irreversible and does not heal over time. The proximal renal tubular dysfunction creates low phosphate levels in the blood (hypophosphatemia), causing muscle weakness and sometimes coma. The dysfunction also causes gout, a form of arthritis due to the accumulation of uric acid crystals in the joints because of high acidity of the blood (hyperuricemia). Another side effect is increased levels of chloride in the blood (hyperchloremia). The kidneys can also shrink up to 30%.
Other patients lose their sense of smell (anosmia).
Pathogenesis:
In the 1950s and 1960s industrial exposure to cadmium was high. But as the toxic effects of cadmium became apparent, industrial limits on cadmium exposure have been reduced in most industrialized nations and many policy makers agree on the need to reduce exposure further. While working with cadmium it is important to do so under a fume hood to protect against dangerous fumes. Silver solder, for example, which contains cadmium, should be handled with care. Serious toxicity problems have resulted from long-term exposure to cadmium plating baths.
Buildup of cadmium levels in the water, air, and soil has been occurring particularly in industrial areas. Environmental exposure to cadmium has been particularly problematic in Japan where many people have consumed rice that was grown in cadmium contaminated irrigation water.
Food is another source of cadmium. Plants may only contain small or moderate amounts in non-industrial areas, but high levels may be found in the liver and kidneys of adult animals.
Cigarettes are also a significant source of cadmium exposure. Although there is generally less cadmium in tobacco than in food, the lungs absorb cadmium more efficiently than the gut. This goes for marijuana as well as tobacco.
Aside from tobacco smokers, people who live near hazardous waste sites or factories that release cadmium into the air have the potential for exposure to cadmium in air. However, numerous state and federal regulations in the United States control the amount of cadmium that can be released to the air from waste sites and incinerators so that properly regulated sites are not hazardous. The general population and people living near hazardous waste sites may be exposed to cadmium in contaminated food, dust, or water from unregulated releases or accidental releases. Numerous regulations and use of pollution controls are enforced to prevent such releases.
Workers can be exposed to cadmium in air from the smelting and refining of metals, or from the air in plants that make cadmium products such as batteries, coatings, or plastics. Workers can also be exposed when soldering or welding metal that contains cadmium. Approximately 512,000 workers in the United States are in environments each year where a cadmium exposure may occur. Regulations that set permissible levels of exposure, however, are enforced to protect workers and to make sure that levels of cadmium in the air are considerably below levels thought to result in harmful effects.
Some sources of phosphate in fertilizers contain Cadmium in amounts of up to 100 mg/kg, which can lead to an increase in the concentration of Cadmium in soil. (for example in New Zealand) Nickel-cadmium batteries are one of the most popular and most common cadmium-based products.
Pathophysiology:
The pathophysiology of the heavy metal toxidromes remains relatively constant. For the most part, heavy metals bind to oxygen, nitrogen, and sulfhydryl groups in proteins, resulting in alterations of enzymatic activity. This affinity of metal species for sulfhydryl groups serves a protective role in heavy metal homeostasis as well. Increased synthesis of metal binding proteins in response to elevated levels of a number of metals is the body´s primary defense against poisoning. For example, the metalloproteins are induced by many metals. These molecules are rich in thiol ligands, which allow high-affinity binding with cadmium, copper, silver, and zinc among other elements. Other proteins involved in both heavy metal transport and excretion through the formation of ligands are ferritin, transferrin, albumin, and hemoglobin.
Although ligand formation is the basis for much of the transport of heavy metals throughout the body, some metals may compete with ionized species such as calcium and zinc to move through membrane channels in the free ionic form.
The study of health effects of cadmium with respect to the cardiovascular system and calcium metabolism disproved the hypothesis that exposure to cadmium would lead to an increase in blood pressure and in the prevalence of hypertension and other cardiovascular diseases. On the other hand, there was a positive relationship between urinary cadmium (Cd-U) and both serum alkaline phosphatase activity and urinary excretion of calcium. The regression coefficients obtained after adjustment for significant co-variates indicated that, when Cd-U increased two-fold, serum alkaline phosphatase and urinary calcium rose by 4% and 0.25 mmol/24 h, respectively. These findings suggest that calcium metabolism is gradually affected as cadmium accumulates in the body. The morbidity associated with the latter phenomenon is still unknown, and requires further investigation, preferably in a longitudinal prospective population study, in which the incidence of morbid events would be monitored in relation to the cadmium body burden.
Cadmium derives its toxicological properties from its chemical similarity to zinc an essential micronutrient for plants, animals and humans. Cadmium is biopersistent and, once absorbed by an organism, remains resident for many years (over decades for humans) although it is eventually excreted.
In humans, long-term exposure is associated with renal disfunction. High exposure can lead to obstructive lung disease and has been linked to lung cancer, although data concerning the latter are difficult to interpret due to compounding factors. Cadmium may also produce bone defects (osteomalacia, osteoporosis) in humans and animals. In addition, the metal can be linked to increased blood pressure and effects on the myocardium in animals, although most human data do not support these findings.
The average daily intake for humans is estimated as 0.15µg from air and 1µg from water. Smoking a packet of 20 cigarettes can lead to the inhalation of around 2-4µg of cadmium, but levels may vary widely.
The organ systems affected and the severity of the toxicity vary with the particular heavy metal involved, the age of the individual, and the level of toxicity.
Also see Signs and Symptoms.
Toxico-Kinetics
Absorption
Approximately 2-7% of ingested cadmium is absorbed through the gastrointestinal tract, and its absorption is enhanced when the diet is deficient in calcium, iron, or protein (Lauwerys 1994). Absorption through the respiratory tract is more efficient, ranging from 15% to as much as 50% of an inhaled dose (Lauwerys 1994, Goyer 1996). Both these routes are potential sources of exposure in children.
Metabolism
Cadmium binds to red blood cells, plasma albumin, and metallothionein, which is synthesized in the liver and also by the placenta. Methallothionein may serve as a barrier to protect the fetus (Goyer 1996); however, in cases of excessive maternal exposure, it appears that some cadmium will cross the placenta (Frery 1993).
Cadmium is initially detoxified in the liver through the formation of a metallothionein-cadmium complex, which is slowly released from that organ. Although initially non-toxic, the cadmium-metallothionein complex can be nephrotoxic as it accumulates in the kidneys (Goyer 1996, Dorian 1995).
The average blood level of cadmium in adults without excessive or occupational exposure is about 1 mg/dL or less, as is the amount excreted in the urine in the adult population. Blood and/or urinary cadmium excretions exceeding 5 mg/dL generally indicate excessive exposure (Barnhart 1984). Human breast milk concentrations of cadmium are usually very low.
Frequency/Epidemiology:
Cases of severe acute cadmium poisoning are rare.
Mortality/Morbidity:
Heavy metal toxicities are relatively uncommon. However, failure to recognize and treat heavy metal toxicities can result in significant morbidity and mortality.
Race:
It affects all races.
Age:
Several points are of concern in heavy metal toxicity with respect to age. Generally, children are more susceptible to the toxic effects of the heavy metals and are more prone to accidental exposures. However, company workers, comprising of adults, are no exception.
Sex:
* Little or no difference in prevalence exists.
* Occupations with heavy metal exposure that predominantly involve a particular sex are associated with higher rates of exposure in that sex.
| Clinical |
History:
* A history of ingestion or exposure is the most critical aspect of diagnosing heavy metal toxicity. A complete history, including occupational, hobby, recreational, and environmental exposure is crucial in diagnosing heavy metal toxicity.
* Most acute presentations involve industrial exposure.
* A history of ingestion often leads to the diagnosis in children.
Physical Assessment:
- Metallic taste and increased salivation
- Irritation of respiratory and gastrointestinal tracts.
- Inhalation can cause respiratory toxicity after a latency period of several hours, including a mild, self-limited illness of fever, cough, malaise, headaches and abdominal pain, similar to metal fume fever.
- At higher doses, chemical pneumonitis may occur, with labored breathing, chest pain, and a sometimes fatal hemorrhagic pulmonary edema.
- Ingested cadmium causes nausea, vomiting, diarrhea, abdominal pain and tenesmus.
Chronic symptoms may include:
- Kidney damage (proteinuria and azotemia) anemia, liver injury (jaundice) and defective bond structure. Chronic obstructive pulmonary disease for those chronically exposed by inhalation.
Causes:
Bioaccumulation of Cadmium in the system.
| Test/Studies |
Lab Studies:
Three main tests are used for measuring cadmium exposures: cadmium in whole blood, cadmium in urine, and measurement of plasma proteins in urine. A number of other tests may be employed in investigating cadmium-related health effects.
A. Cadmium in Blood
Mainly because of ease of analysis, cadmium in whole blood has been used as a biological indicator of occupational exposures. Cadmium concentrations in blood are mainly a reflection of recent exposure. The ACGIH suggests that monitoring in blood is preferred during the initial year of exposure and whenever changes in the degree of exposure are suspected. In workers not currently exposed, cadmium in blood decreases substantially. When declining blood cadmium levels reach a steady state, they are considered to reflect body burden from previous exposures.
Normal values of cadmium in blood of non-smokers are generally less than 1 ug/l. Higher average values of 1.4 to 4.2 ug/l are found in smokers, though individual blood cadmium levels in smokers may exceed these values.
In 1991, the Ontario Ministry of Labour suggested medical assessment for exposed workers whose blood cadmium level reaches 11 ug/l. However, OSHA recently chose 5 ug Cd/l of whole blood as a level at which further medical surveillance is required of American workers. If this level of cadmium in blood is accompanied by protein in the urine, then OSHA requires workers to be medically removed. A level of 15 ug Cd/l is cause for removal without proteinuria. The ACGIH has also recently proposed a Biological Exposure Index of 5 ug/l of cadmium in blood. The BEI "is intended to prevent the potential for increased urinary excretion of markers of renal dysfunction in almost all workers".
B. Cadmium in Urine
Cadmium concentration in urine is considered to be more reflective of body burden in currently-exposed workers than cadmium in blood, and is the most widely used biological measure of chronic exposure to cadmium. Cadmium in urine increases with age, cigarette smoking, and exposures in the general and occupational environments.
The normal concentration of cadmium in urine is from 0.1 to 1 ug/g creatinine. Until recently, a measure of 10 ug Cd/g creatinine has been regarded as a threshold for kidney effects. However, a number of recent studies have cast doubt on this figure. Evidence of subtle kidney effects are demonstrated at levels a low as 2 ug Cd/g creatinine. Levels of 5 to 1ug Cd/g creatinine are associated with a 10% risk of increased excretion of enzymes and proteins. OSHA recently chose a level of 3 ug Cd/g creatinine as a trigger for enhancing medical surveillance of cadmium. If this level of cadmium in urine is accompanied by proteinuria, then OSHA requires medical removal of the affected worker. A level of 15 ug/g creatinine is cause for removal without proteinuria. The ACGIH has recommended a new Biological Exposure Index (BEI) of 5 ug/g creatinine for cadmium in urine.
C. Markers of early Renal Effects from Cadmium Exposure
While not a measure of cadmium exposure per se, the increase of proteins in urine is a marker of damage to the kidneys which precedes or accompanies most health effects associated with cadmium exposure. One particular protein -- beta2-microglobulin (BMG) -- has been extensively used as an indicator of cadmium-related damage to the proximal tubules of the kidney. BMG excretion may be elevated due to other causes: anti-cancer drugs, antibacterial antibiotics such as streptomycin, anti-inflammatory compounds, myeloma, flu and upper respiratory tract infections. These factors can be readily identified, and need not confound the diagnosis of cadmium-related proteinuria.
Levels of BMG are considered elevated by most investigators at 300 ug/g creatinine, although levels as low as 200 or as high as 500 ug/g creatinine have been suggested as abnormal. OSHA mandates a removal level of 1500 ug BMG/g creatinine, if cadmium levels in blood or urine are elevated.
Exposures to cadmium for 20 years at a level 50 ug/m3 (0.05 mg/m3), the current Ontario limit, give rise to a greatly increased incidence of tubular proteinuria as indicated by output of BMG.
In recent years, a number of other markers for cadmium effects have been recommended. Several of these markers appear to be more sensitive to the early effects of cadmium on the kidney, and/or more stable than BMG in urine. The following markers have been assessed and shown to have significant association with cadmium exposure:
- retinol-binding protein (RBP) in urine;
- albumin in urine;
- N-acetyl-D-glucosaminidase (NAG) in urine;
- metallothionein (MT) in urine;
- urinary transferrin;
- most tubular antigens.
Conventional indicators of renal function such as total urinary protein, serum urea, and serum creatinine are considered insensitive indicators of early renal dysfunction, but may indicate the progression of cadmium-related damage.
Other Tests:
Direct Measurement of Cadmium Concentration in Liver and Kidney
Neutron activation analysis is a new method which allows for the direct measurement of the cadmium burden in the liver and kidney. The technique involves use of an ultrasonic scan to precisely locate the target organs, followed by irradiation with a neutron beam which allows assessment of organ burden by measurement of cadmium-specific gamma rays. The radiation dosage is less than most conventional x-rays.
For workers who have been out of exposure for some time or who have suffered kidney damage, this technique can provide a more accurate measure of body burden and may help in determining if non-specific diseases such as emphysema are cadmium-related. This equipment has been employed in England to resolve compensation disputes. Only one Canadian facility is currently equipped to carry out this kind of analysis -- at McMaster University in Hamilton.
Estimation of liver burden is considered more appropriate because once renal damage occurs, cadmium excretion increases and the kidneys lose their cadmium burden. Liver and kidney burdens increase until a 40 ppm concentration is reached in the liver, after which kidney levels decrease while liver burden continues to rise. One study measured a mean liver cadmium burden of 0.6 ppm in non-exposed controls.
X-ray fluorescence, another technique for in vivo measurement of cadmium body burden, has also been developed recently, but is not generally available at this time.
Cadmium Exposure Limits:
Exposure limits for cadmium and its compounds have declined steadily over time, as the knowledge about cadmium-related diseases has grown. The current Ontario time-weighted average limit of 0.05 mg/m3 is considered too high by many scientists. Ontario is currently considering a new limit of 0.02 mg/m3, to match the lower Dutch limit. The Dutch Working Group of Experts which reviewed cadmium's toxicity in 1980, actually proposed a health-based limit of 0.01 mg/m3. However, this limit was not considered feasible at the time. The cadmium limit is again under review in the Netherlands.
In Sweden, a limit of 0.01 mg/m3 is in effect for all new industries employing cadmium or its compounds.
In 1990, the American Conference of Governmental Industrial Hygienists (ACGIH), an influential body which produces a list of Threshold Limit Values adopted by many governments as enforceable occupational exposure limits, proposed a new total dust limit of 0.01 mg/m3 for cadmium, and a 0.002 mg/m3 respirable dust limit.
In 1992, after an exhaustive review of occupational exposures, toxicity and feasibility issues, the U.S. Occupational Safety and Health Administration adopted a new cadmium limit of 0.005 mg/m3, one-tenth of the current Ontario limit, in order to prevent kidney effects and cancer in exposed workers.
In 1991 and 1992, a lively debate occurred in the scientific literature on the question of a protective occupational exposure limit. Proposed protective limits varied from a low of 0.001 mg/m3 through 0.01 mg/m3. One author suggested a limit in the range of 0.01 - 0.1 mg/m3 might be protective, but put some emphasis on 0.02 mg/m3. Although there is no consensus on the level of a protective limit, there is considerable agreement in the scientific community that a limit of 0.05 mg/m3 does not provide sufficient protection, and that kidney effects occur at this level of exposure.
| Treatment/Management |
Independent Interventions/First Aid:
NOTE! PREVENT DISPERSION OF DUST! STRICT HYGIENE! | General First Aid: IN ALL CASES CONSULT A DOCTOR! | ||
Route of Exposure | Symptoms | First Aid | |
|---|---|---|---|
| Inhalation | Cough. Headache. Symptoms may be delayed (see Notes). | Fresh air rest. Half-upright position. Artificial respiration if indicated. Refer for medical attention. | |
| Skin | Remove contaminated clothes. Rinse and then wash skin with water and soap. | ||
| Eyes | Redness. Pain. | First rinse with plenty of water for several minutes (remove contact lenses if easily possible) then take to a doctor. | |
| Ingestion | Abdominal pain. Diarrhoea. Headache. Nausea. Vomiting. | Rest. Refer for medical attention. | |
| Notes for ICSC Information | |||
| Reacts violently with fire extinguishing agents such as water foam carbon dioxide and halons. Depending on the degree of exposure periodic medical examination is indicated. The symptoms of lung edema often do not become manifest until a few hours have passed and they are aggravated by physical effort. Rest and medical observation are therefore essential. Do NOT take working clothes home. | |||
Consultations:
If intentional ingestion or overdose is suspected, place patient in closely a monitored unit and consult a medical toxicologist and psychiatrist.
* Contact a certified poison control center or medical toxicologist.
* Consult a gastroenterologist if the possibility of corrosive GI effects is present.
Diet:
Eat a balanced diet that provides enough calcium, iron, protein, and zinc.
Medication:
No treatment has been proven effective for cadmium poisoning.
| Follow Up Treatment/Management |
Further inpatient care:
Encourage patient to eat foods rich in calcium, iron, protein, and zinc.
Further outpatient care:
* Care must be taken to remove the source of heavy metal contamination.
* Report industrial-related toxicities to OSHA or; report childhood cases to the local health department.
Deterrence/Prevention:
· Avoid Smoking.
· Avoid hazardous areas or hazardous work such as welding.
Complications:
Complications include pneumonitis and pulmonary edema. Chronic exposure may cause anemia, emphysema or renal failure, and cadmium may be a risk factor in the development of prostate or lung cancer.
Prognosis:
The prognosis depends on the nature and severity of the cadmium load. Most cases of mild exposure resolve spontaneously after a few days. In other cases, cadmium can lead to permanent damage with shortened lifespan, or even death.
Cadmium may be carcinogenic.
Long-term exposure may also result in bone defects including osteoporosis.
Patient Education:
Teach the patient on how to prevent cadmium poisoning.
| Miscellaneous |
Medical/Legal Pitfalls:
· Failure to report such toxicity to the local health authorities.
| References |
NCBI
Healthatoz.com
eMedicine
Pesticideinfo.org
Canoshweb.org
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