CADMIUM AND CADMIUM COMPOUNDS: TOXICOLOGY

  1. Toxicokinetics
  2. Target organs
  3. Reprotoxicity
  4. Genotoxicity
  5. Carcinogenicity

1.Toxicokinetics
  1. Absorption
  2. -inhalation route: 
    Inhalation exposure primarily occurs in the workplace. 
    Cadmium compounds are inhaled as particulate matter, either as fumes with very small particle size or as dust.
    After inhalation exposure, the absorption of cadmium compounds may vary greatly. and depends upon the particle sizes and their solubility. Large particles, dusts, (>10m in diameter) tend to be deposited in the upper airways, while small particles, fumes, (approximately 0.1 m) tend to penetrate into the alveoli. While some soluble cadmium compounds (CdCl2 and CdSO4) may undergo limited absorption from particles deposited in the respiratory tree, the major site of absorption is the alveoli. Only about 5% of particles > 10m in diameter will be deposited, up to 50% of particles <0.1 m will be deposited, and between 50-100% of cadmium deposited in the alveoli will ultimately be absorbed. Thus particle size, which controls alveolar deposition, is a key determinant of cadmium absorption in the lung. 
    In humans, figures of 10-30% of absorption rate according to particle size are derived for Cd dusts. For Cd fumes, based on cigarette smoke studies, it can be calculated that the respiratory absorption of Cd fumes is between 25% and 50%.
    The respiratory Cd intake can be diverted to the gastro-intestinal tract due to the clearance of Cd deposited on the mucosa of nasopharynx, trachea or bronchi. It can also be deposited in the alveoli and from there be absorbed into the blood. 

    -oral route:
    Depending on the dietary intake and the iron status, it has been estimated that a European or an American adult absorbs cadmium orally at an average rate varying between 1.4 and 25g/day.  (Elinder et al., 1985; Lauwerys et al., 1982) 
    The cadmium absorption from the gastrointestinal tract is usually about 5%. However it varies considerably and subjects with iron deficiency may absorb up to 10%.
    For a given individual, the absorption following oral exposure to cadmium is likely to depend on physiologic status (age; body stores of iron, calcium, and zinc; pregnancy history; etc.) and, also, on the presence and levels of ions (Zn) and other dietary components ingested with the cadmium. 

    -dermal route: 
    Absorption of cadmium through the skin is extremely low (0.5%) and would be of concern only in situations where concentrated solutions would be in contact with the skin for several hours or longer.

  3. Distribution 
  4. Cadmium is widely distributed in the body, with the major portion of the body burden located in the liver and kidney. Liver and kidney cadmium concentrations are comparable after short-term exposure, but the kidney concentration exceeds the liver concentration following prolonged exposure (30% of Cd body burden in the kidney)

    The concentration of cadmium in the liver of occupationally exposed workers generally increases in proportion to intensity and duration of exposures to values up to 100 g/g. The concentration of cadmium in the kidney rises more slowly than in the liver after exposure and begins to decline after the onset of renal damage at a critical concentration of 160-285 g/g

    Most non-occupationally exposed people are exposed to cadmium primarily through the diet. Cadmium can be detected in virtually all tissues in adults from industrialized countries, with greatest concentrations in the liver and kidney. 
    Average cadmium concentrations in the kidney are at birth near zero , and rise roughly linearly with age to a peak  (typically around 40-50 g/g wet weight) between ages 50 and 60, after which kidney concentrations plateau or decline. Liver cadmium concentrations also begin near zero at birth , increase to typical values of 1-2 g /g wet weight by age 20-25, then increase only slightly thereafter.

  5. Metabolism (see fig. 1)

  6. The most dangerous characteristic of cadmium is that it accumulates throughout  lifetime. Cadmium accumulates in the liver and kidneys and has a long biological half-life, from 17-30 years in man (Goyer, 1997). After uptake from the lung or the gastrointestinal tract, cadmium is transported in blood plasma initially bound to albumin, as shown in experimental animals. Cadmium bound to albumin is preferentially taken up by the liver. In the liver, cadmium induces the synthesis of metallothionein and a few days after exposure metallothionein-bound cadmium appears in the blood plasma. Because of its low molecular weight, cadmium-metallothionein is efficiently filtered through the glomeruli and thereafter taken up by the tubules. Cadmium accumulates in the human kidney over the entire lifetime (Nordberg, 1992).

     

    click here to see fig.1

    Fig.1: Metabolism of cadmium

     

  7. Elimination

    Most cadmium that is ingested or inhaled and transported to the gut via mucociliary clearance is excreted in the feces.  Almost all fecal cadmium represents material that was not absorbed from the gastrointestinal tract. Most absorbed cadmium is excreted very slowly, with urinary and fecal excretion being approximately equal. Cadmium is also eliminated through hair and breast milk, but these routes are of limited importance for total excretion and do not significantly alter the biological half-time.
    The placenta is only a partial barrier to fetal exposure to cadmium. 
  8. Several studies have shown that in the general population urinary cadmium excretion increases  with age, this increase coinciding with the increased body burden. Smokers have higher urinary excretion than non-smokers. The amount of cadmium excreted represents only a small fraction of the total body burden unless renal damage is present. 

    Following oral exposure, the major proportion of administered cadmium is found in the feces, because absorption is low.

  9. Half-life

  10. Experimental and epidemiological evidence indicates strongly that the biological half-time in the whole body is extremely long (many years)
    For the human kidney half-lives ranged between 6 and 38 years, and for the human liver between 4 and 19 years.

2.Target organs

Kidneys:  (Renal effects)
The kidney is considered to be the critical target organ for the general population as well as for the occupationally exposed population. Within the kidney, the cortex is the site where the first adverse effect occurs. 
Long-term exposure to cadmium causes renal tubular dysfunction with proteinuria, glucosuria, and aminoaciduria, as well as histopathological changes, in both experimental animals and humans. These are usually the first effects to occur after ingestion or inhalation exposure. In working environments with high cadmium exposure levels, workers have also developed hypercalciuria, phosphaturia , and polyuria and some have suffered from renal colics due to recurrent stone formation. As the renal dysfunction progresses in severity, the glomeruli may also be affected and, in a few cases,  the cadmium-induced damage may lead to renal failure. 

Bone tissues:
Case studies indicate that calcium deficiency, osteoporosis, or osteomalacia can develop in some workers after long-term occupational exposure to high levels of cadmium. Bone lesions (accompanied by renal damage) have also been reported in aged and malnourished women living in Cd-polluted areas in Japan. (Itai-Itai disease). Effects on bone generally arise only after kidney damage has occurred and are likely to be secondary to resulting changes in calcium phosphorus and vitamin D metabolism. 
The daily intakes via food and exposure levels in air at which the bone effects occur are probably in the same range as those producing kidney affects.

Respiratory system:
Long-term occupational exposure to high levels of cadmium has been reported to cause emphysema and dyspnea in humans. 
The dose needed to produce these effects  is higher than the dose needed to produce renal effects.

Chronic inflammation of the nose, pharynx, and larynx have been reported in some studies. Anosmia is a frequent symptom in cadmium workers after prolonged exposure. 

 

3.Reprotoxicity

The nervous system of developing animals appears to be a sensitive target.

Limited evidence suggests that maternal cadmium exposure may cause decreased birth weight in humans. 
Evidence is insufficient to determine an association between exposure to cadmium and reproductive effects in humans. 

4.Genotoxicity

No definitive conclusions can be drawn about the genotoxicity of cadmium compounds. Data from experimental systems indicate that cadmium, in certain forms, has genotoxic properties and it is reasonable to assume that these properties may also apply to other Cd compounds.  It cannot be excluded, based on the available data (Forni et al. 1990/1994) that cadmium might exert genotoxic effects in populations exposed to cadmium by inhalation. 

See also Mutagenic Effects

5.Carcinogenicity

Several studies  in humans have reported an excess risk of lung cancer in occupationally exposed cohorts. However,  the evidence is limited rather than conclusive due to confounding factors (smoking, simultaneous exposures to other carcinogens,). No studies have indicated that cadmium may act as a carcinogen in the general population exposed by the oral route.

Overall, in view of the sum of data collected in genotoxicity tests, long-term animal experiments and epidemiological studies, it seems reasonable to consider  Cd compounds at least as  suspected human carcinogens (lung cancer).

There is no evidence of an increased risk of prostate cancer in workers exposed to Cd compounds.

See also Carcinogenic Effects

References:

-ATSDR (1999), Toxicological profile for cadmium- Update. U.S. Department of Health & Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, U.S. Government Printing Office, 1997.

-Budavari S., ONeil M., Smith A., Heckelman P. and Kinneary J. The Merck index, an encyclopedia of chemicals, drugs, and biologicals; 12th edition, 1996.IARC. Evaluation of the carcinogenic risk of chemicals to humans, some metals and metallic compounds; IARC, 1980, 23, 205-323.

-Chang LW, "Toxicology of metals", 1996 , CRC Press. 

-Elinder CG., Exposure, dose and metabolism, in : Friberg L;, Elinder CG, Kjellstrm T., Nordberg G., Cadmium and Health: A toxicological and Epidemiological Appraisal, Floridea CRC Press, Baca Raton, 1985: 23-63 

-Goyer. Toxic and essential metal interactions; Annual reviews of nutrition, 1997, 17, 37-50.

-IARC (1993), IARC Monographs on the evaluation of carcinogenic risks to humans, Vol.58 Beryllium, Cadmium, Mercury, and Exposures in the Glass Manufacturing Industry, Lyon.

-International chemical safety cards (WHO/IPSO/ILO), 1999.

-IPCS (1992) Environmental Health Criteria 134 Cadmium, WHO, Geneva.

-Lauwerys R, Buchet JP, Roels H, Bernard A, Cadmium toxicity: summary of personal studies, Toxicol Eur Res 1982 Jan;4(1):7-17

-Nordberg. Application of the critical effect and critical concentration concept to human risk assessment for cadmium; IARC scientific publications, 1992, 3-13.

-Weast R., Astle M. and Beyer W. CRC handbook of chemistry and physics; 66th 1985.