Background information on cadmium poisoning in support of a "fact sheet" for lay adjudicators
Prepared for the Occupational Disease Panel (Industrial Disease Standards Panel)
Ministry of Labour
The following report "Background information on cadmium poisoning in support of a "fact sheet" for "lay adjudicators" was commissioned by the Occupational Disease Panel. The Panel has not entered into deliberations on this subject and takes no official position on the findings of this researcher.
|TABLE OF CONTENTS|
|Part 1. Sources of Cadmium Exposure|
| Occupational exposures
|Part 2. Health Outcomes of Cadmium Exposure|
| Acute effects
Chronic respiratory effects
|Part 3. Biological Testing Methods For Cadmium Exposures|
| Cadmium in the blood
Cadmium in the urine
Markers of early renal effects of cadmium exposure
Direct measurement of cadmium concentration
in liver and kidneys
|Part 4. Cadmium Exposure Limits|
This paper accompanies a prototype "fact sheet" intended to help lay adjudicators dealing with claims for industrial disease or "poisoning" as a result of occupational exposure to cadmium. It provides the rationale for the information included on the fact sheet, as well as further references which an adjudicator might consult in the process of making a decision.
SOURCES OF CADMIUM EXPOSURE
Cadmium has a large array of uses, and its production has climbed steadily during the last forty years, although certain applications have recently declined. Industrial exposure levels in some industries were very high through the 1950's and 60's.  In the last two decades, however, occupational exposures have dropped, following the dramatic reduction of exposure limits in most industrialized nations.  Many scientists and policy makers acknowledge the need to continue reducing exposures to this very toxic metal. Some jurisdictions have prohibited specific uses of cadmium.
Cadmium may be encountered in work other than that listed below. Because of the wide variety of uses for cadmium, it is not possible to provide an exhaustive list. Industries are listed in order of potential exposures, from higher to lower.
A. OCCUPATIONAL EXPOSURES
Industries Associated with Cadmium Exposures
1. Nickel-cadmium battery manufacturing [1, 36, 75]
Significant exposures to cadmium dusts appear to be generated at all stages in the manufacture of both industrial and household nickel-cadmium batteries, including plate-making, impregnation, plate preparation and assembly. Cadmium health effects may be confounded by associated exposures to nickel in this environment.
2. Zinc refining/Cadmium smelting and production [32, 36, 75]
Deposits of cadmium occur naturally in zinc ores. Cadmium is therefore produced as a byproduct of zinc refining. A small amount of cadmium is also recovered from cadmium-bearing scrap and waste products. Significant exposures to cadmium fume and dusts as well as aerosols of cadmium sulphate are generated at several stages in cadmium production.
3. Cadmium-containing pigment production [22, 75, 89, 98]
Cadmium pigments (mainly cadmium sulfide and cadmium selenosulfide) are produced as powders, pellets, pastes and liquids and are primarily used for the colouring of plastics. About 25% of worldwide production of cadmium is used in pigments. High inhalation exposures may occur in calcining, crushing and milling operations [75, 98] especially when the cadmium product is present in powder form. However, wet system operations with lower inhalation exposures may be associated with increased ingestion exposure, resulting in high cadmium-blood levels even where air levels are not excessive. 
4. Dry colour formulating [75, 98]
Cadmium pigments may be formulated into custom colour concentrates prior to use in plastics, ceramics and specialty coatings by dry colour formulators. These producers are generally very small companies, who produce custom materials in batch operations. Intermittent and highly variable exposures to cadmium occur in material handling, mixing of dry pigments with other materials (blending or compounding), grinding, or cleaning.
5. Cadmium-based stabilizer production [75, 98]
Cadmium stabilizers are used primarily in the production of poly-vinyl chloride and other plastics. Exposures -- to dry and wet products -- are described by OSHA as intermittent. High exposures occur in cadmium oxide charging, drying, crushing and blending operations.
6. Metal plating with cadmium-containing materials [22, 75]
Cadmium is highly corrosion resistant, and is widely used to plate metal parts used in general industrial hardware as well as in the automotive, electronics, marine and aerospace industries. (As much as 35% of worldwide cadmium production is used in plating.) Cadmium plating is done by means of electroplating or mechanical plating operations. Plating may be done in independent industrial operations, or as an element of production in larger production facilities. OSHA reports that at mechanical plating operations, less than 10% of the
workforce is exposed to cadmium, though exposures tend to be higher than those in electroplating. During electroplating, plating operators and maintenance technicians are most likely to be exposed. Other chemical exposures which may contribute to health effects also occur in plating.
7. Production of cadmium alloys [16, 22, 36, 75, 98]
Cadmium is used in some copper alloys to increase the mechanical strength and wear resistance of copper wire conductors. It is also used in the production of solders, and in alloys with zinc, lead, silver or tin. Workers may be exposed to cadmium fume during melting and casting operations.
8. Lead smelting and refining 
Lead concentrates which are processed in lead smelting and refining operations contain cadmium contaminants, found naturally in the ores. Cadmium exposures occur in material handling, sinter plants, furnace areas, refining and casting, and maintenance operations. Workers have combined exposures to lead, cadmium and other materials.
9. Iron and steel production 
Cadmium is present as a trace contaminant in the raw materials used for steelmaking. Exposures to cadmium may occur during furnace operations, welding, and maintenance work on pollution control equipment.
10. Coal-fired electrical utilities and garbage incineration [75, 98]
The fly ash, cinders and flue gases produced by coal burning utilities and garbage incineration may contain problematic levels of cadmium. Exposures generally occur during malfunctions, inspection and maintenance of boilers, ovens and filters, and in the transport of ash and cinders. Problematic exposures to several other metals also occur in these situations.
Occupations in General Industry which may be Associated with Cadmium Exposure 
1. Chemical mixers
Where chemical or mechanical mixing involves cadmium compounds such as stabilizers, pigments, metallic coatings or substances used for fungicides, exposure to cadmium may occur.
Electroplaters may be employed in industries which plate with cadmium-containing materials, to provide decorative or protective surfaces.
3. Furnace operators and moulders
These workers may be exposed to cadmium fumes released from molten metal during smelting, refining, casting, forging and moulding operations.
4. Kiln or kettle operators
Workers who operate, load or tend kilns, kettles, ovens or furnaces for annealing, roasting or converting processes, may be exposed when heating materials with cadmium-containing glazes, paints or other coatings.
5. Heat treaters
Work with flame-hardening machines, electronic induction machines, furnaces and baths used to harden, anneal or heat treat metal parts may expose workers when materials coated with, or containing cadmium, are involved.
6. Equipment cleaners
Workers who clean baghouses, electrostatic precipitators, process equipment and process areas may be exposed when these are contaminated with cadmium-containing dusts.
7. Metal machine operators
Machinists, grinders, filers, machine tool operators and others may be exposed when grinding or forming metals coated with cadmium-containing products, or bearing cadmium as a component.
Because cadmium is used in some metal sprays and paints, workers may be exposed during spray painting or non-electrolytic metal coating. Hot dip lines, metal spraying machines and hand held power tools are used to coat metal, plastic and other materials with cadmium-containing coatings.
9. Mechanics, maintenance and industrial installation workers
Workers who maintain, repair, install or dismantle machinery and heavy equipment, automotive, motorcycle, aircraft, farm and heavy equipment mechanics, plumbers, pipefitters, steamfitters and boilermakers may be exposed to cadmium.
10. Welders, brazers and solderers 
Wherever welding, brazing or soldering is done with cadmium-bearing base metals, brazing rods or solders, exposure to cadmium occurs. In addition to welders, brazers and solderers, exposed workers include structural steel workers, metal pattern makers, metal fabricators, and assemblers who carry out metal joining or cutting functions.
Other Occupational Exposures 
1. Ceramists 
Ceramists and ceramics teachers may be exposed to cadmium used as a colouring compound in glazes.
2. Artists, Theatre and Television Crafts 
Cadmium and compounds are found in dry pigments, paints, pastels, pottery and enamelling colorants, low melting silver solders, and metal alloys used in artwork and theatre crafts.
3. Jewellery producers
Solders used by jewellery workers may contain cadmium.
B. NON-OCCUPATIONAL EXPOSURES
Non-occupational exposures to cadmium may give rise to cadmium-related disease, but, other than smoking, usually contribute relatively little to the body burden of an occupationally-exposed person. [25, 91, 93]
Exposures from Ambient Air, Water and Soil 
Cadmium levels have increased in the general environment ever since metal ores containing cadmium have been refined.  Very little cadmium is recycled. General environmental levels are much higher in industrial areas, particularly in the vicinity of cadmium-producing industries such as zinc smelters and cadmium-copper alloy factories. A number of studies are currently underway to determine the effects of environmental cadmium on exposed populations. Cadmium released from these sources finds its way into the air, water and soil in the surrounding areas.  Environmental contamination has led to severe cadmium-related disease in Japanese populations who consumed rice grown in cadmium-contaminated irrigation water. [54, 56, 57, 70]
Cadmium is found in water in areas where there are zinc-bearing mineral formations, and where water flows through galvanized pipes.
Cadmium in Food Products
A major non-occupational source of cadmium exposure is in foods. High cadmium concentrations may be found in kidneys and livers of adult animals and certain seafoods such as mussels, oysters and crabs. Intermediate levels may be found in grains.
The use of sewage sludge or phosphate fertilizers can increase cadmium content of soils and uptake of cadmium in food products.
Cadmium Exposures Due to Cigarette Smoking
Cadmium is found in small amounts in tobacco. Although the cadmium content of cigarettes is much lower than that of food, cadmium is absorbed much more effectively by the lung than the gut. For smokers who are not occupationally exposed to cadmium, smoking is usually the main source of exposure. Cadmium intake from smoking can substantially increase total cadmium exposure for occupationally-exposed workers.  Absorption of cadmium in tobacco smoke is mainly through the lung, although occupationally-exposed smokers may also ingest some cadmium from contamination of hands and cigarettes. 
HEALTH OUTCOMES OF CADMIUM EXPOSURE
A. ACUTE EFFECTS
Acute effects in workers occur mainly as a result of exposures to cadmium fume in welding or soldering, especially when this takes place in a poorly ventilated workspace.
1. Metal Fume Fever
Exposures to cadmium fume may give rise to a type of metal fume fever. [3, 12, 28, 48] Flu-like symptoms occur, with chills, fever and muscular pain in the back and limbs. If the respiratory system has not been damaged, symptoms may resolve within a week.
2. Acute Respiratory Effects
Overexposure to cadmium fume (usually from welding or cutting materials containing cadmium) can cause tracheo-bronchitis (inflammation in the trachea and bronchial tubes), pneumonitis (inflammation of the lungs) and pulmonary edema (accumulation of fluid in the lungs). 
A severe inflammatory response accompanied by edema is usually fatal.  The ACGIH has estimated that 20% of those who experience acute pulmonary responses to cadmium fume die as a result.  Even a couple of hours of exposure to a few milligrams per cubic meter can have fatal results. 
Inflammation may not become evident until a few hours after exposure.  Initial symptoms include irritation and dryness of the nose and throat, cough, headache, dizziness, weakness, chills, fever, and chest pain.
Respiratory effects may also occur as a result of high exposures to cadmium dust, but are usually less severe than those due to cadmium fume. 
Survivors of cadmium-related pneumonitis may go on to develop emphysema several years later. [12, 28]
3. Gastrointestinal Effects
Ingestion of cadmium can be associated with salivation, choking attacks, persistent vomiting, abdominal pains, spasms of the anal sphincter, vertigo and loss of consciousness. These effects have been observed mainly in individuals exposed to high levels of cadmium in food.  Gastrointestinal effects may occur in workers exposed to cadmium dust of a large particle size, which is deposited on the mucous membranes and ingested.  Ingestion may be increased by smoking in the cadmium-contaminated workplace.
B. CHRONIC RESPIRATORY EFFECTS
Substantial data -- both animal and human -- is available to demonstrate chronic respiratory effects resulting from high levels of cadmium exposure. Some of these effects have not been replicated in recent studies of workers with lower exposures of shorter duration. Chronic pulmonary effects appear to be associated with high exposures of long duration and/or intermittent high peak exposures. Unfortunately, good dose-response information is not available for pulmonary effects. 
Kidney effects occur at lower levels of exposure than chronic respiratory problems and usually occur in workers before cadmium-related pulmonary effects. [21, 60] However, the impact of cadmium on mortality is greater from respiratory disease than other effects. 
Pulmonary effects due to cadmium exposure may vary depending on whether exposure is to a fume or dust, the size of particles, and solubility of the compound involved.
A large number of studies have identified emphysema as an outcome of chronic cadmium exposure. However, a prominent research scientist in this field suggests that much of the emphysema attributed to cadmium exposure is more appropriately classified as chronic nonspecific lung disease, characterized by chronic airflow obstruction.  Restrictive patterns of lung functioning may also occur, because of fibrotic changes associated with cadmium exposure.
1. Chronic Obstructive Lung Disease (Emphysema and Chronic Bronchitis)
Emphysema was first associated with cadmium exposure in the last century.  A number of morbidity studies have identified shortness of breath, obstructive patterns of lung function, bronchitis and emphysema in cadmium exposed workers. [1, 12, 17, 19, 28, 39] Pulmonary function tests have shown that decreases in forced vital capacity may occur in workers exposed to cadmium for six years or more, at levels greater than 0.2 mg/m3 of cadmium. 
Significant increases in deaths caused by chronic obstructive lung disease, specifically emphysema and chronic bronchitis, have been observed in several independent studies of workers exposed for long periods of time to high levels of cadmium in air. [5, 39, 52] In most of these studies, workers had been exposed for a decade or more. However, fatal cases of emphysema have been reported for workers with less than two years exposure.  These workers were exposed to general levels of 0.1 to 0.4 mg/m3 in air, and also to unmeasured peak exposures.
2. Pulmonary Fibrosis
Mild to moderate pulmonary fibrosis has been diagnosed in chronically highly exposed cadmium oxide workers. [28, 74, 83] This effect has been replicated in animal studies. It appears to result from an inflammatory reaction in the lung from inhalation exposure to soluble cadmium compounds such as cadmium oxide and cadmium sulfide. 
3. Olfactory Impairment
Olfactory impairment (loss of a sense of smell) associated with cadmium exposure has been reported by a number of investigators. [1, 81] Workers with olfactory impairment due to cadmium exposure are likely to have renal effects -- proteinuria -- as well.
C. KIDNEY EFFECTS
The kidney is considered the critical organ in long-term, low-level exposure to cadmium. Kidney effects from exposure to cadmium have been recognized since the late 1940's. [12, 39] Dozens of human and animal studies have demonstrated these effects. [9, 15, 23, 34, 38, 49, 50, 78, 90, 92]
1. Tubular Proteinuria
About half the cadmium absorbed by the body is stored in the kidneys where it produces structural and functional changes.  The first sign of cadmium-related damage to the kidneys is usually an increase of low molecular weight proteins in the urine (proteinuria). Marker proteins include beta2-microglobulin and retinol-binding protein. These proteins are normal constituents of plasma, and are normally filtered through the glomerular membrane and then reabsorbed from the proximal tubules of the kidney. Proteinuria is a sign of damage to the tubules. The damage is permanent, and may progress even after retirement or removal from exposure. [77, 90] This damage may lead to other complications, including skeletal effects. A Japanese study demonstrates increased mortality in a cadmium-exposed population suffering from tubular dysfunction.  However, in the absence of other effects, proteinuria may not result in any subjective symptoms of ill health. Tubular proteinuria does not often progress to kidney failure. 
2. Glomerular Dysfunction
Long-term exposure to cadmium may also damage the glomerular membrane of the kidney, leading to the excretion of high molecular weight proteins such as albumin, gamma globulins (IgG and IgA), and alpha2-macroglobulin.  A decrease in the glomerular filtration rate and increase in serum creatinine concentration are related to cadmium dose, and indicate glomerular dysfunction. [65, 90] Glomerular dysfunction can progress after exposure has ended.  While most investigators suggest that tubular proteinuria occurs before glomerular dysfunction in cadmium-exposed workers, a recent study argues that subtle defects in glomerular barrier function may precede tubular impairment.  Some investigators believe that increased urinary concentrations of albumin in cadmium-exposed workers are not a sign of glomerular damage, but result mainly from tubular dysfunction. 
3. Chronic Renal Failure
Most investigators believe that the incidence of kidney failure in cadmium-exposed workers is low, but this is difficult to determine because of the serious under-reporting of impaired renal function on death certificates, even when the disease is severe enough to require dialysis.  Renal tubular dysfunction may progress and result in aminoaciduria, glycosuria, wasting of calcium and phosphate and altered calcium metabolism leading to bone disease. [5, 65, 90] OSHA cites three studies which suggest increased mortality from kidney diseases, genito-urinary diseases or kidney cancer in cadmium-exposed workers.  Increased mortality from chronic nephritis and nephrosis has been observed in Swedish battery workers.  A British study also found suggestive evidence of increased risk for nephritis and nephrosis after high exposures.  The loss of kidney functional reserve which occurs as a result of tubular and glomerular effects of cadmium exposure may also make affected workers succumb more rapidly to other illnesses or drugs which affect kidney function. 
4. Kidney Stones
A number of studies have reported elevated incidence of kidney stones in cadmium-exposed populations. [1, 23, 47, 60] One reviewer suggests that lifetime prevalence rates of 18 to 44% are found in cadmium-exposed workers as compared to rates under 5% in control populations. 
D. SKELETAL EFFECTS
Environmental exposures in Japan and long-term heavy occupational exposures to cadmium in a number of countries have been associated with effects on bone. [54, 56, 59, 70] Cadmium can affect bone directly, through deposition and storage in this tissue, and indirectly, by its effects on calcium and Vitamin D metabolism. These effects are also demonstrated in animal studies.  Cadmium-related bone effects are most likely to occur in individuals with nutritional deficiencies, and in postmenopausal women.
Osteomalacia is a condition of defective mineralization of bone, characterized by pains, softening and bending of the bone resulting in skeletal deformities, spontaneous fractures, pseudofractures, and low serum and urine calcium. There have been at least eight reports of osteomalacia in more than 50 cadmium-exposed workers. The incidence appears to have peaked about thirty years ago.  These effects are associated with kidney damage and increased urinary calcium excretion. Most of the cases reported are from France, Japan and Britain. Investigators suggest that nutritional habits in relation to Vitamin D and calcium intake play a role. [10, 70, 84] However, poor nutrition alone does not explain the effects. Treatment with Vitamin D, calcium and other supplements has been reported to be effective in relieving symptoms and strengthening bone, although recovery is slower than if the osteomalacia were due purely to a nutritional deficiency. 
Osteoporosis involves the reduction in bone mass exceeding that which occurs naturally with aging. It can result in bone fractures on impact. Less research has been carried out on osteoporosis than osteomalacia in cadmium-exposed humans due to the lack of suitable equipment to measure bone density.  Nevertheless, some investigators argue that it may be a more common effect of cadmium-exposure than osteomalacia.  In some cadmium-exposed populations osteomalacia and osteoporosis are found together. [55, 57] Animal experiments confirm osteoporotic effects due to cadmium exposure.
The IARC recently updated its assessment of cadmium, and determined that there is limited evidence for carcinogenicity to humans and sufficient evidence for carcinogenicity to animals.  Overall, the IARC classifies cadmium as probably carcinogenic to humans. Elevated levels of respiratory, prostate, and other cancers have been reported in cadmium-exposed workers. The evidence is strongest for lung cancer.
1. Pulmonary Cancer
Small but statistically-significant increases in lung cancer have been reported in several studies of cadmium-exposed workers. [24, 75, 52, 73, 87, 91] There is some controversy about how much of the excess mortality from lung cancer in cadmium-exposed workers is due to cadmium and how much due to confounding exposures to arsenic or to nickel. Insufficient data is available on smoking among exposed workers. Recent studies demonstrate an increase in cancer incidence with cumulative dose.  Also, the lung cancer effects of cadmium are confirmed in rats at exposure levels below the current occupational limits. 
2. Prostatic Cancer
Several studies in the 1970's associated cadmium exposure with statistically significant increases in prostatic cancers.  There have been a number of more recent studies, some with larger cohorts which demonstrated no increase in expected prostatic cancers, or small increases which are not statistically significant. [5, 85] Pooled data from several of these studies, on workers with "high" or "medium" levels of exposure, show an excess in prostate cancer which doesn't reach statistical significance.  Recent studies detecting prostatic cancers in rodents, following systematic exposure to cadmium, add credence to the link between cadmium and cancer of the prostate.
3. Other Cancers
Tumours of the kidney have been associated with cadmium exposure in one study. There was also a good correlation with smoking, suggesting the possibility of carcinogenesis due to multiple agents.  Cadmium has also recently been associated with stomach cancer in exposed workers. 
F. OTHER EFFECTS
Effects of cadmium on the liver, blood-forming system, blood pressure and reproductive organs have been investigated in animals and humans. [18, 29, 33, 40, 62, 86] Although effects have been seen in some studies, the evidence is not strong enough to link occupational levels of exposure to cadmium with specific effects in these systems.
BIOLOGICAL TESTING METHODS FOR CADMIUM EXPOSURES
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. Some of these are mentioned in Part II. They will not be described further here.
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. [79, 92] Evidence of subtle kidney effects are demonstrated at levels a low as 2 ug Cd/g creatinine. [15, 79] 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, [22, 78] although levels as low as 200 or as high as 500 ug/g creatinine have been suggested as abnormal. [32, 60] 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; [8, 78, 79]
- N-acetyl-D-glucosaminidase (NAG) in urine; [15, 50, 65, 79, 92]
- metallothionein (MT) in urine; [34, 50, 60]
- urinary transferrin; [8, 79]
- 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. [15, 50, 55]
D. 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. [14, 30, 31, 37] 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. [13, 53, 67, 91] 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 not 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.
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FACT SHEET FOR ADJUDICATORS ON OCCUPATIONAL CADMIUM EXPOSURE AND DISEASE
A. Sources of Exposure (The following list not exhaustive. Industries are ranked from most to least exposed.)
1. Nickel-cadmium battery manufacturing
2. Zinc refining/cadmium smelting and production
3. Cadmium pigment production
4. Dry colour formulating for plastics
5. Cadmium-based stabilizer production
6. Metal plating with cadmium-containing materials
7. Production of cadmium alloys
8. Lead smelting and refining
9. Iron and steel production
10. Coal-fired electrical utilities (ash, flue gases)
11. Garbage incineration (ash, flue gases)
II. Occupations in General Industry
1. Chemical mixers
3. Furnace operators and moulders
4. Kiln, kettle or furnace operators
5. Heat treaters
6. Equipment cleaners
7. Metal machine operators
8. Metals and plastics painters
9. Mechanics, maintenance and industrial installation workers
10. Welders, brazers and solderers
III. Other Occupations
2. Artists, theatre and televition crafts using cadmium pigments
3. Jewellry producers
IV. Non-occupational Exposures
Cadmium levels may be significant in the immediate vicinity of cadmium-producing industries. In Ontario, a major contributor to non-occupational exposures is smoking. Smoking also contributes significantly to the body burden of occupationally-exposed workers.
B. Health Effects of Cadmium Exposure
I. Acute Effects (from short-term, high-level exposures)
1. Metal fume fever
2. Tracheo-bronchitis, pneumonitis, pulmonary edema usually from exposures to cadmium
welding fume; may cause death
3. Vomiting, abdominal pain and other gastro-intestinal effects, mainly from ingestion of
II. Chronic Respiratory Effects
1. Chronic obstructive lung disease, emphysema and chronic bronchitis from long-term,
high-level exposures to cadmium (usually more than 10 years at levels of 0.1 to 0.4 mg/m3 in
2. Mild to moderate pulmonary fibrosis from chronically highly-exposed workers,
especially to cadmium oxide and cadmium sulfide
3. Olfactory impairment (loss of sense of smell)
III. Kidney Effects
1. Dysfunction of the proximal tubules of the kidneys, resulting in tubular proteinuria (loss of
low molecular weight proteins in the urine); can occur at exposures below the current
occupational exposure limit; early stages symptomless; can lead to other kidney and skeletal
2. Dysfunction of the glomerular membrane, usually considered to follow on tubular damage,
leading to excretion of high molecular weight proteins in urine
3. Chronic renal failure as a result of progressive kidney damage; relatively rare result
4. Kidney stones
IV. Skeletal Effects
Skeletal effects are rare at current exposure levels. Other risk factors are usually present.
1. Osteomalacia (defective mineralization of bone, resulting in pain, skeletal deformities, and
fractures); cadmium exposure contributes to this condition mainly in post-menopausal women
withpoor early nutrition
2. Osteoporosis (reduction in bone mass resulting in fractures); may be found together with
osteomalacia in cadmium-exposed workers.
1. Lung cancer is reported in highly-exposed workers; exposures to nickel and arsenic may
contribute to the effect; data on smoking among affected workers is poor
2. Prostatic cancer in workers with high or medium exposure
C. Biological Testing Methods
I. Cadmium in Blood
Reflects recent exposure and body burden. Normal values are less than 1 ug/l in non-smokers, vary from 1.4 to 4.2 ug/l in smokers. The Ontario Ministry of Labour recommends medical assessment of workers above 11 ug/l.
II. Cadmium in Urine
More reflective of body burden. Normal values are 0.1 to 1 ug/g creatinine. Evidence of kidney effects demonstrated at levels as low as 2 ug Cd/g creatinine.
III. Markers of Early Renal Effects
1. Levels of beta2-microglobulin in urine above 300 ug/g creatinine are elevated and indicate
tubular dysfunction and proteinuria. Elevated levels of B2M may indicate the
cadmium-relatedness ofother diseases in an exposed worker.
2. Other markers of kidney effects include elevated excretion of retinol-binding protein, albumin,
NAG, metallothionein, transferrin and tubular antigens in urine.
IV. Direct Measurement of Cadmium Concentration in Liver and Kidney
Neutron activation analysis of cadmium in the liver and kidneys can provide a direct measure of cadmium body burden. Levels of 40 ppm in the liver are associated with kidney damage. At present the only Canadian facility with the equipment to carry out this analysis is McMaster University.
D. Occupational Exposure Limits
The current Ontario occupational exposure limit is 0.05 mg/m3. Ontario is currently considering a new limit of 0.02 mg/m3. These limits do not protect against proteinuria and may not protect against cancer. Other jurisdictions are considering, or have adopted new limits ranging from 0.005 mg/m3 to 0.01 mg/m3, to protect against kidney disease and cancer.