The facts on chromium
What is Chromium?
Chromium, a "transition" metal, is of intermediate atomic weight - that is, it is not considered either a heavy metal or a light metal. It is found primarily in three chemical states depending on its electrical charge. Common forms are chromium-0, which has no charge, chromium+3, which has an ionic charge of plus 3, and chromium+6, which has a charge of plus 6.
Chrome metal (the form chromium-0) is the element that makes steel "stainless." Chromium in this form is hard, stable, and resistant to chemical changes such as oxidation or rust. Steel alloyed with chromium is harder and less brittle than iron and highly rust-resistant. This form of chromium is also used to coat or "chrome plate" the surface of other metals to produce a hard, shiny, chemically resistant surface.
The primary form of chromium found in the environment is chromium+3, which is also quite stable. This common form of chromium is always found in a complex with other chemical partners such as oxygen or chlorine. In these compounds it is very "inert to substitution", that is, it is resistant to changing its form or exchanging its chemical partners.
Though small quantities of chromium+6 are found in nature, most of the chromium in this form is man-made. Chromium+6 is easily and rapidly reduced to chromium+3 by many chemicals and conditions, so it is not very stable in the environment. Like chromium+3, chromium+6 is usually found in chemical complexes with other elements, for example bound with several oxygen atoms to form chromate. It is very difficult to oxidize chromium+3 to chromium+6, though it can be done with strong oxidizing agents and very high temperatures. An industrial process called "roasting" is used to oxidize the chromium+3 derived from ores into chromium+6, a form used in a wide variety of commercial products.
Where is Chromium Found?
Chromium is widely dispersed in the environment. In the Earth's crust chromium is present at an average of 140 parts per million (ppm), but is not distributed evenly. High concentrations of chromium can be found in certain ores, which are mined commercially.
There are trace amounts of chromium in rocks and soil, in fresh water and ocean water, in the food we eat and drink and in the air we breathe. Levels of chromium in the air are generally higher in urban areas and in places where chromium wastes or "slag" from production facilities were used as landfill.
Chromium wastes have been detected in many landfills and toxic waste sites across the country, usually in combination with other metals and chemicals. In the Aberjona River watershed near Boston Massachusetts, industrial wastes containing chromium contaminated the river and pond sediments. In some areas the sediments contain as much as one to two percent chromium by weight. However, recent studies suggest that people living nearby have received very little exposure to the chromium from these sediments. The principal impact is ecological in areas such as this, where concentrations of several toxic materials collectively threaten aquatic food webs and the wildlife they support.
What are the Uses of Chromium?
Chromium is used in paints, dyes, stains, wood preservatives, curing compounds, rust inhibitors and many other products. However, the predominant use of chromium is for production of stainless steel and in chrome plating. A radioactive form of chromium is used in medicine to tag, or label, red blood cells inside the human body. The labeling is permanent for the lifetime of that cell, so it is a useful way to look at long-term patterns of blood cell turnover in the body, to look for evidence of internal bleeding and for similar studies.
Because of commercial demand, chromium-containing ores have been mined and processed intensively over the past century, and many industries manufacture or use chromium containing compounds.
Do we Need Chromium for Health?
Humans need chromium, in the form of chromium+3, for proper health. However, most people get all the daily chromium they need from a normal, well-balanced diet.
Nutritionists have learned over the past century that certain substances, such as vitamins and minerals, are essential to normal functioning and health. These substances are not made in the body, so they must come from foods. (The British Navy discovered this connection in the 1700s, when they observed that sailors on long sea voyages often developed a condition called scurvy. Adding citrus fruits such as limes to the sailors' diets prevented the condition. This is how English sailors first came to be known as "Limeys.") Since chromium is present in all foods, and is especially high in certain plants, few people are deficient in dietary chromium.
The Federal government establishes guidelines for "Essential, Safe and Adequate Daily Dietary Intake" or ESADDI (formerly called the Recommended Daily Allowance or RDA) of an essential vitamin or mineral. For chromium, the recommended ESADDI level is 50-200 micrograms per day of chromium. Chromium is a standard component of most multi-vitamin/multi-mineral pills and food supplements. Chromium is also present in all foods and is especially high in certain plants. U.S. Department of Agriculture scientists recently suggested, based on their own studies, that certain people such as the elderly, diabetics, and others with blood sugar (glucose) regulation problems can benefit from even higher levels of chromium, perhaps as high as 500-800 micrograms per day, which would normally require a supplement tablet. More controversial is whether the general public needs more chromium than they get from their diet. Several manufacturers of over-the-counter chromium supplements have claimed that high doses of chromium are beneficial for dieting and bodybuilding, but the majority of controlled, independent studies to date fail to show any benefit from chromium supplementation for normal individuals. On the other hand, there is currently no evidence that taking chromium supplements is necessarily bad for you, since chromium+3 is not very toxic even at relatively high doses.
How does Chromium Act as a Nutrient?
The best known nutritional effect of chromium is that it appears to assist insulin in regulating blood sugar (glucose) levels. Insulin is a small protein hormone that is released into the blood when blood glucose levels get too high. Insulin then binds to a receptor on the outside of cells, causing them to absorb more glucose from blood, returning blood glucose levels to normal. If glucose levels fall too low, other signals in the body prompt cells to release glucose to the blood. This "seesaw" glucose regulation is disrupted in people with diabetes, usually due to a lack of insulin production or a failure of cells to properly respond to insulin. Chromium appears to enhance the effects of insulin once insulin binds to its receptor.
Human bodies do not appear to store or absorb chromium+3 very well, taking up only 1 or 2 percent of the total chromium available in the intestines from food. But humans do have a way to take up more chromium when it is needed - the lower the body's level of chromium, the more efficiently it is taken up from the intestines. Chromium+3 does not easily cross cell membranes, and it appears to interact with cells only when needed, which suggests that it is stored in a form the body can rapidly mobilize, either in blood or nearby where blood can easily draw on it.
The form of chromium associated with enhancing insulin's effect is a complex of several chromium+3 atoms bound together with amino acids. The response of cells to insulin is much greater in the presence of this LMWCr complex (also called chromodulin). The complex appears to be different from the storage form of chromium in the blood, which is not yet well defined.
Recently, Dartmouth toxicologist, Joshua Hamilton and his colleagues discovered that chromium also affects the other side of the "seesaw" that controls blood glucose levels, increasing cell signals that offset the effects of insulin. This appears to be through interaction with another as yet unknown protein receptor on the surface of cells. The mechanism for this effect and the identity of this new receptor are intriguing research questions that remain to be answered. There may also be other uses of chromium by the body that remain to be discovered.
Is Chromium Harmful to Humans?
The most common health effect from exposure to chromium is contact dermatitis - skin inflammation or rash. A small fraction of the population, between 5 and 10 percent, has an allergic skin reaction to chromium. Much like other allergies - to foods, bee stings, cotton, wool - this allergic response is genetically based. When genetically predisposed individuals are exposed to chromium compounds their skin can become reddened and swollen; the condition clears up once exposure stops.
Avoiding skin contact with chromium - in jewelry for example - is not a problem for most of the general population but those whose occupations involve daily exposure to chromium compounds, such as cement workers, may develop chronic allergic reactions that necessitate changing or modifying their jobs. In the past, workers in the chrome ore industry who were contact-sensitive could develop a related asthma-like condition in the lungs and respiratory tract if they suddenly breathed in large amounts of chromium-containing dusts. These incidents are rare now due to modern occupational safety and health practices.
Is Chromium in the Workplace a Health Risk?
In the United States, all cement contains chromium.
Until safer workplace practices were adopted in the 1960s, large numbers of workers were exposed to high levels of chromium+3 and chromium+6 over periods of 30 to 50 years. Studies in the 1930s and others conducted after World War II found higher rates of respiratory cancers in these workers. A complicating factor in the post-war studies is that those workers- unlike the workers of the 1930s - included a very large fraction of lifelong cigarette smokers. That made it more difficult to determine whether it was exposure to cigarette smoke or to chromium that was related to higher rates of lung cancer. Analysis of the workplace studies indicates that prior to the 1960s workers exposed to high levels of chromium had four times the risk of developing lung cancer compared to unexposed people. By comparison, cigarette smoking is estimated to increase a person's risk of lung cancer ten to twenty times.
Cigarette smoking has been shown to synergistically increase the risk of lung cancer for people exposed to certain metals, such as arsenic, cadmium and nickel as well as other chemicals. That is, the risk of lung cancer in a smoker exposed to one of these agents is much higher than what would be predicted by simply adding the two individual risks together. But recent studies suggest that, unlike the case with these and many other lung carcinogen combinations, chromium and cigarette smoking do not act synergistically with each other. The reason for this is not clear, but this supports the idea that chromium is a relatively weak carcinogen even at very high occupational doses.
Recent studies indicate that people who began working in chromium industries from the 1960s on under more modern occupational hygiene conditions have levels of respiratory cancer that are not significantly different than the general population.
Is Chromium in the Environment a Health Risk?
While industrial hygiene practices have largely reduced or eliminated health risks from exposure to chromium+6 dusts, there is growing concern about environmental exposures. For example, there are sites in the U.S. where large amounts of chromium-containing wastes have been dumped or used as landfill, such as in areas of northern New Jersey in the United States. This led to concern over whether area residents were at risk of disease from inhaling chromium-contaminated dusts from these sites. However, studies comparing the health of residents near these sites to other populations have found no significant differences. Under these conditions, levels of exposure to chromium are likely to be below those of concern. However, the issue is still under active investigation.
Concerns have also been raised about possible health effects of chromium-contaminated drinking water. However, there is no evidence to date of a link between chromium exposure from drinking water and any human health effects. Even under the higher occupational exposures of the past there is no evidence for any cancers in humans other than respiratory cancers, nor is there evidence of cancer from exposures other than long-term inhalation of chromium+6 dusts. In fact, on a gram-for-gram basis, chromium is not considered particularly toxic as compared to other metals, even by ingestion. Chromium+3 has about the same relative toxicity as table salt in lab animals. Chromium+6 is about twenty times more toxic, but is still hundreds or thousands of times less toxic than other metals such as cadmium or mercury.
Can Chromium Cause Cancer?
Shortly after studies showing that workplace exposure to chromium+6 increased the risk of lung cancer, researchers began to examine how chromium behaves in the human body. In experiments using cell cultures, investigators found that chromium+6 crosses cell membranes and gets into the cell much more easily than chromium+3, which does not normally get into cells. Once inside cells, chromium+6 can damage DNA, the hereditary material of the cell, and this damage can lead to mutations. Mutations in certain cancer-associated genes of the cell are believed to be the basis for initiating cancer.
Karen Wetterhahn, Ph.D.
Scientists found that treating cells with chromium+3 did not cause DNA damage or mutations, which was not surprising since chromium+3 did not enter the cell. When cells were treated with chromium+6, chromium was found attached to the DNA molecule in various ways to cause damage. Surprisingly, the form of chromium attached to the DNA was chromium+3, not chromium+6. How to explain this apparent paradox?
The solution to this puzzle was proposed by Dartmouth chemist Karen Wetterhahn and her colleagues in what became known as the "uptake-reduction model" of chromium toxicity. The researchers found that chromium+6 could rapidly be reduced by several small molecules inside the cell to form chromium+3. During metabolism, chromium passes through several forms that are highly reactive and unstable. In addition, the process of chromium reduction can create reactive oxygen and other free radicals inside the cell. This combination of reactive intermediates was postulated to be able to attack DNA, leading to the DNA damage and the chromium binding that was observed. Since they are unstable, these intermediates are reduced to the stable chromium+3 found on the DNA at the end of the process. So although chromium+3 remains outside the cell, chromium+6 is taken up and is eventually reduced to chromium+3 inside the cell.
The Wetterhahn uptake-reduction model has served as the central paradigm for the chromium field for the past 20 years, and set the stage for a more complete understanding of how chromium behaves in the body. Wetterhahn and other researchers also found that chromium+6 could also be reduced to chromium+3 by serum components and other chemicals of the blood outside the cell. In cell culture, serum is normally added to help feed cells. However, treatment of cells with chromium+6 in the presence of serum caused a reduction of the chromium outside the cells rather than inside. This meant no uptake of the chromium, and no DNA damage or mutations. So components of the blood appeared to protect the cell from chromium+6 uptake.
Recent studies have called into question the idea that the 0primary way chromium+6 causes cancer is by damaging DNA and causing mutations. First, to produce a relatively small number of mutations researchers needed to use chromium levels that are hundreds or thousands of times higher than the levels required by other agents. Second, there appears to be a long latency time for the development of cancer in chromium-exposed workers, requiring as much as 30 to 40 years of exposure. It also appears that continuous exposure is required, since shorter or disrupted occupational exposures did not significantly increase cancer risk. These observations suggest that chromium might be acting by a mechanism other than, or in addition to causing mutations.
Another class of chemicals that can increase cancer risk slightly without causing mutations are tumor promoters. These agents push a cell along the path of cancer development by acting on mutations caused by other events. To effect cancer rates, tumor promoters also require a constant rather than single or short duration exposure. Is chromium+6 acting as a tumor promoter? It has recently been shown that treating cells with chromium causes certain cell signaling changes that are more similar to the effects of tumor promoters than to the effects of mutagens. These cell signaling events in turn lead to changes in gene expression . These alterations occur even in the absence of DNA damage, and at lower doses, suggesting that this may be a more important mechanism in humans. However, this idea will require further investigation, and it may be that chromium contributes to cancer risk by both mechanisms.
Why is Chromium Associated with Lung Cancer?
There are many agents that show a similar pattern of causing respiratory diseases, such as asbestos, fine wood dust from manufacturing furniture, grain elevator dust, coal dust from mining, and fibers or dust in cotton mills and ceramics factories. These agents all share some common characteristics. All are inhaled as dusts, tiny fibers or fine particles with a particular size and shape that allows them to penetrate into the deep recesses of the lung. Once there, they are cleared poorly by the lung, and most do not dissolve or break down readily inside the lung. This leads to a long "residence time." In continuous exposures such as workplace settings, a large build-up of these particles can occur over time. Common effects of these agents are chronic lung inflammation, or fibrotic disease and certain cancer.
The increased risk of lung cancer associated with chromium+6 has been shown to require long-term inhalation of high levels of chromium-laden dusts. Chromium+6 compounds with intermediate solubility in water are also most closely associated with lung cancer. This may be because highly insoluble forms will not readily release their chromium+6 to cells, whereas forms that are highly soluble dissolve quickly in the lung, where chromium+6 is rapidly and thoroughly reduced by the extracellular lung fluids. However, the intermediate soluble forms can sit above a cell and slowly dissolve over time.
If this process occurs throughout the lung for 30 or 40 years, it may well overwhelm the natural defenses of the lung and contribute to increased cancer risk.
How do our Bodies Protect us from the Harmful Effects of Chromium?
The body appears to have normal defense mechanisms that protect against the harmful effects of chromium. In addition to work by Karen Wetterhahn, Silvio DeFlora and his colleagues demonstrated that many of the other fluids of the body have very high levels of chromium reducing chemicals, resulting in a large capacity to reduce chromium+6 outside the cells of the body. These fluids include saliva, stomach and intestinal fluids, lung fluids, mucus, blood, and the layers of the skin. All these protective mechanisms reduce chromium+6 on the outside of cells, preventing its uptake. It has also been proposed that reduction of chromium+6 in the intestines, in the presence of amino acids, leads to formation of the natural form of chromium+3 that the body uses, which may lead to enhanced uptake of this form. Human volunteers who drank a large glass of concentrated chromium+6 had very little uptake of total chromium, and the only form that was observed in the body was chromium+3. Studies with human volunteers also showed that exposure of the skin to chromium+6-containing water in a bath or shower resulted in little or no uptake of chromium.
Laboratory animal studies have also been performed to determine the effects of chromium+6 under controlled conditions. Exposure of animals to very high doses of chromium+6 in drinking water resulted in no measurable health effects, even at extremely high doses given for the lifetime of the animals. This confirmed what had been observed in humans following ingestion.
It was initially very difficult to show that chromium is a carcinogen using animals. Initial experiments did not show any differences between control and chromium-exposed animals even at very high doses given for the lifetime of the animals, using a variety of chromium compounds and normal means of exposure. Eventually, experiments were able to show that chromium can elevate cancer rates in animals. However, to accomplish these researchers had to use extremely high doses, use solid or other non-dissolved forms of chromium compounds, and expose the animals to these agents in ways that got around the normal protective mechanisms of the body. For example, animals were injected with a large slurry of chromium directly into the muscle, or were exposed by surgically implanting a large "cage" of solid chromium directly into the respiratory tract of the animal. These studies reinforce the idea that chromium+6 is at best a weak carcinogen, and only with certain forms and by certain means of exposure. They also demonstrate that the body normally has substantial barriers to the effects of chromium+6 exposure, which must be overwhelmed before an effect is seen.
Although the human and animal evidence to date suggests that there are no adverse health effects of chromium in drinking water, there have been only a few long-term animal studies that specifically examined this issue in the laboratory. Because of recent concern about chromium in drinking water, the State of California recently petitioned the National Toxicology Program, which is overseen by the National Institute of Health's National Institute of Environmental Health Sciences, to do a long-term study as part of their ongoing assessment of environmental chemicals of concern. This study is examining effects of lifetime chromium+6 exposure in drinking water in several animal species under controlled conditions that are designed to rule out other factors. The final results of these studies will become available in two to three years.