Page 6: Guidelines for Canadian Drinking Water Quality: Guideline Technical Document – Chromium
Health Considerations
Essentiality
Only the trivalent and hexavalent forms of chromium appear to be of significance in biological systems,Footnote 30 and only the trivalent form appears to be essential.Footnote 31 Trivalent chromium is necessary for the synthesis of fat from glucose and also for the oxidation of fat to carbon dioxide. The biologically active form of the element is believed to be a nicotinic acid - amino acid (glycine, glutamic acid, and cysteine) - trivalent chromium complex, which functions as a potentiator of insulin, possibly by forming a complex between sulfhydryl groups on the cell membrane and sulfhydryl groups on the A chain of insulin.Footnote 32,Footnote 33 This complex, which occurs in a variety of foods, is termed glucose tolerance factor (GTF). The primary biochemical effect from chromium deficiency is decreased sensitivity to exogenous or endogenous insulin.Footnote 33
There is increasing evidence that chromium deficiency may also be a basic factor in atherosclerosis.Footnote 34,Footnote 35 In animals, severe deficiency results in decreased growth rates and life spans, increased concentrations of serum cholesterol, and increased formation of aortic plaques. Under certain conditions, a syndrome resembling diabetes mellitus, with fasting hyperglycaemia and glycosuria, has been produced. Low levels of chromium in plasma or hair have also been correlated with increased likelihood of coronary artery disease.Footnote 36,Footnote 37 The U.S. Food and Nutrition Board has set an adequate and safe range for chromium intake at 0.05 to 0.2 mg/day.Footnote 38
Absorption, Distribution, and Excretion
Estimates of the fraction of chromium that is absorbed by the intestine vary. It has been reported that about 2 to 10 percent of the hexavalent chromium ingested is absorbed, as is 0.1 to 3 percent of the inorganic trivalent chromium.Footnote 39,Footnote 40 Absorption of 2.1 percent of ingested chromium(VI) has been estimated in humans.Footnote 41 From studies on rats, it has been estimated that the fraction of chromium(VI) absorbed is nine times greater than that of chromium(III).Footnote 42 Other estimates put the absorption of both inorganic chromium species in the range of 0.5 to 3 percent.Footnote 43,Footnote 44 Gastric juice inhibits absorption of both trivalent and hexavalent inorganic chromium and partially reduces the hexavalent form to the trivalent.Footnote 41 Chromium is much more readily absorbed in the GTF (organic) form than in the inorganic form. At least 10 to 25 percent of ingested organic chromium is thought to be absorbed from the intestinal tract, probably the jejunum or upper ileum.Footnote 18,Footnote 34,Footnote 39 Intestinal chromium absorption in young children proceeds at a greater rate than that in adults.Footnote 45 Because the proportion of ingested chromium that is hexavalent, trivalent, inorganic, or organically bound is unknown, the amount of chromium absorbed per day cannot be reliably estimated. For example, a document published by the World Health Organization estimates that 10 percent of the chromium ingested is absorbed,Footnote 40,Footnote 46 which implies that the mean daily uptake of chromium from a Canadian diet is about 0.006 mg. However, an independent estimate of the U.S. daily uptake is 0.001 mg or less.Footnote 23
Airborne chromium-containing particles with mass greater than 0.001 mg are believed not to reach the alveoli at all, but to be trapped in the bronchi. These particles are later moved to the pharynx by ciliary action and swallowed. This route of exposure could therefore contribute to dietary intake.Footnote 47 A portion of inhaled chromium-containing aerosols deposits in the respiratory tract. Insoluble particles small enough to penetrate the alveoli may be trapped in the tissue. If the particles can be dissolved, chromium may enter the blood and be distributed throughout the body.
The metabolism of ingested chromium depends on its chemical form. Chromium chloride administered parenterally to rats disappears rapidly from the bloodstream and is most strongly absorbed by the ovaries or testes and spleen, whereas chromium administered as the organic complex, GTF, accumulates mainly in the liver. The fate of inhaled trivalent chromium differs from that of the hexavalent form. Thirty days after intratracheal injection of chromium-containing aerosol to guinea pigs, 30 percent of the trivalent chromium, but only 2.4 percent of the hexavalent chromium, remained in the lung tissue.Footnote 48 The concentration of chromium in red blood cells, liver, kidney, and spleen was greater following intratracheal administration of hexavalent chromium.
In studies using rodents, it has been shown that chromium can cross the placenta. Estimates of the fraction of the dose of inorganic chromium transferred to the foetus were 0 to 12 percent for chromium(VI) and 0.4 percent for chromium(III).Footnote 49 In contrast, 20 to 50 percent of chromium administered in the form of GTF was found in the litters.Footnote 50 This is consistent with the role of chromium as an essential trace element.Footnote 43
There seems to be a homeostatic mechanism involving hepatic or intestinal transport systems that prevents excessive accumulation of trivalent chromium.Footnote 51 In man, the largest stores of chromium are in skin, muscle, and fat; the highest concentration is in the lungs. The average total chromium content of the body is approximately 6 mg,Footnote 18 but tissue levels vary according to the sex, age, and geographical location of the individual.Footnote 34
At least 80 percent of excreted chromium is eliminated in the urine; the remainder is eliminated in the faeces. There is little agreement on the amount of daily urinary chromium excretion. A mean 24-hour excretion value of 0.0084 mg with a range of 0.002 to 0.021 mg is believed to be representative, although a recent estimate places the mean at less than 0.001 mg.Footnote 23 Very high chromium excretion appears to occur in some insulin-dependent diabetics. Absorbed chromium is eliminated from the body in a rapid phase (1 to 2 days) representing clearance from the blood, and in a slower phase representing clearance from tissues. Adipose and muscle tissues retain chromium for about two weeks, whereas the liver and spleen may store chromium for as long as 12 months.Footnote 43
Toxic Effects
The known harmful effects of chromium in man are attributed primarily to the hexavalent form; trivalent chromium is considered non-toxic. A single oral dose of 10 mg/kg body weight of hexavalent chromium will result in liver necrosis, nephritis, and death in man. A lesser dose will cause irritation and corrosion of the gastrointestinal mucosa and occasionally encephalitis and enlarged liver. No local or systemic effects have been attributed to the ingestion of trivalent chromium.
Consumption of drinking water with a hexavalent concentration of 1 to 25 mg/L for 3 years caused no ill effects in a family of four.Footnote 52
Ingestion of drinking water containing 25 mg of hexavalent chromium (potassium chromate) per litre resulted in an eightfold increase in tissue chromium concentration over that found in rats that had consumed trivalent chromium (chromic chloride) at 25 mg/L for the same six-month period.Footnote 53 Toxic effects have been observed in rats and rabbits following ingestion of drinking water with a hexavalent chromium concentration above 5 mg/L, but ingestion of water containing 11.2 mg/L for 4 years caused no ill effects in dogs. Drinking water with a chromium concentration of 25 mg/L administered to rats for six months caused no deleterious effects.Footnote 30
Inhalation of air containing high concentrations of chromium causes respiratory damage and cancer (see below).
Carcinogenicity
Hexavalent chromium can inhibit benzpyrene hydroxylase activity. It has been suggested that compounds capable of such inhibition are carcinogenic.Footnote 54
In humans, exposure to hexavalent chromium salts for periods of 2 to 26 years has been implicated as a cause of cancer of the digestive tract. High levels of chromium (and zinc) in soil have been correlated with regional incidences of stomach cancer.Footnote 55 Lead chromate is believed to have caused the deaths, from cancer, of five occupationally exposed individuals.Footnote 56 Based on exposure to chromium via inhalation, the International Agency for Research on Cancer has categorized "chromium and certain chromium compounds" in Group 1: sufficient evidence for carcinogenicity in humans and animals.Footnote 57 However, a recent report by the U.S. Environmental Protection Agency states that there are inadequate data to conclude that chromium is carcinogenic via ingestion.Footnote 39
Mutagenicity
Hexavalent chromium is mostly inactive on isolated nuclei and purified DNA but is able to induce every kind of genetic effect in intact cells and whole mammals, whereas trivalent chromium shows the opposite tendency. This behaviour is attributed to the fact that trivalent chromium usually crosses cell membranes only slowly and is therefore unlikely to reach the nucleus of intact cells. In contrast, hexavalent chromium crosses cell membranes readily, in part by active transport; once inside the cell, it is partially reduced to the trivalent state, which produces genotoxic effects.Footnote 58 Once inside the cell, trivalent chromium can form tight complexes with DNA, accounting for its mutagenic potential.Footnote 59 Compounds of both trivalent and hexavalent chromium increase non-complementary nucleotide incorporation into DNA, with hexavalent chromium being effective at lower doses.Footnote 50,Footnote 60 Exposure of cells from rat liver and kidney to hexavalent chromium leads to increased cross-linking in DNA.Footnote 39 Positive Ames tests have been reported for hexavalent chromium but not for trivalent chromium.Footnote 61,Footnote 62
Teratogenic and Reproductive Effects
There is no evidence that chromium compounds have produced birth defects or reproductive deficits in man.Footnote 43 Animal studies have attributed malformations such as cleft palate and skeletal defects to chromium, but the effects may have been the secondary result of maternal toxicity.Footnote 43