Arsenic and our Health

arsenicStudies in animal species provide strong evidence that arsenic is an essential trace element – at least for birds and mammals. When researchers completely eliminated arsenic from the diets of animals in experiments, the animals became ill; some developed reproductive problems. The offspring of these arsenic-deprived adults were born with developmental problems. Putting a small amount of arsenic back into the animals’ diets completely reversed these effects.

Dietary requirements for arsenic in humans are still controversial. There are trace amounts of arsenic in almost all food and water, air and soil, so it is difficult to find humans who are isolated from all sources of arsenic. There are no known human health effects of arsenic deficiency, if such exist, and the effects observed in arsenic-deficient animals would be hard to detect and characterize in humans. Most investigators believe that it is likely that we receive all the arsenic we need from a normal diet, and there is currently no recommendation for a daily dietary intake for humans.

Nutritionists and toxicologists find themselves on opposite sides of an interesting question when they consider the human health effects of elements such as arsenic. In many cases an element can be toxic at one dose and healthful, even essential for health, at another. If it were somehow possible to eliminate from the environment all traces of elements known to have toxic effects, would this have a negative effect on human health? Because arsenic is ubiquitous in the environment, this question is likely to remain moot.

How does arsenic harm living things?

Arsenic’s toxic effects largely depend on its chemical and physical form and how one is exposed. A large single dose that produces an immediate effect is called an acute exposure; a smaller amount over a long period of time that produces a gradual or delayed effect is called a chronic exposure.

At acute exposures, such as in accidental or intentional poisonings, arsenic can displace elements involved in the fundamental chemical processes of cells. For example, arsenic has an affinity for binding to sulfur. Certain enzymes involved in metabolism use the sulfur atom of a cysteine amino acid to carry out their function. If arsenic binds to the sulfur at these sites, the enzymes can begin to behave in abnormal ways or lose their ability to function. Arsenic, in the form of arsenate, can also resemble phosphate, which is used by cells for energy and signaling. By displacing phosphate in enzymes or signaling proteins, arsenic can block energy production and normal cell signaling.

At lower chronic exposures, such as in most environmental or occupational exposures, arsenic appears to indirectly modify the way cells communicate. Recent studies at Dartmouth suggest that arsenic may act as an endocrine disrupter by binding to hormone receptors, interfering with normal cell signaling of hormones through those receptors. Disruption of these endocrine receptors by arsenic in this way may contribute to the development of diabetes, cancer and vascular disease.

Other Dartmouth researchers have found that arsenic may interfere with molecular signals that prompt the cells lining heart and blood vessels to grow. The subsequent build-up of these cells can narrow the passage inside blood vessels, restricting the flow of blood. This may be one of the mechanisms that enable arsenic to contribute to cardiovascular disease and other blood vessel diseases.

Dartmouth researchers are also trying to understand other ways in which arsenic increases the risk of certain kinds of cancer. Unlike many other known chemical carcinogens, arsenic does not cause damage to DNA or cause mutations in genes. Instead, it appears to indirectly modify the way cells behave in ways that increase their probability of becoming cancer cells, perhaps in combination with other carcinogens such as cigarette smoke or other environmental contaminants.

What makes some forms of arsenic more harmful to humans?

The effect arsenic has on living things is strongly governed by its form or species. Although metals are simple elements, metal atoms can combine into different forms that vary in chemical and biological properties. Some forms of arsenic are highly toxic; others are essentially non-toxic. The reasons are rooted in basic chemistry.

Atoms are made up of a nucleus – a mixture of positively charged particles called protons and neutral particles called neutrons — around which negatively charged particles called electrons orbit. The positive, negative or neutral charge on an atom, called its “ionic state,” is governed by how many electrons it has circling around it balancing the positive charges of its protons. Atoms can gain or lose electrons to change their ionic charge, and the sharing of electrons is primarily how atoms bond together to form molecules.

The most common and stable forms of arsenic in nature are arsenite, also called or arsenic (+3), and arsenate, or arsenic (+5). Arsenic (+3) is arsenic with three fewer electrons than protons, giving it a plus three positive charge; arsenic (+5) is arsenic with five fewer electrons than protons, giving it a plus five positive charge. These two forms can be readily converted back and forth both in nature and inside our bodies depending on the local chemical environment – such as changes in acidity (pH), the presence of oxygen or iron, and what other molecules are present. Arsenite is believed to be slightly more toxic than arsenate, but since they are so easily inter-converted, both forms are considered a health risk.

Once arsenic (+3) or arsenic (+5) atoms combine with other elements to form molecules, the molecules acquire chemical and biological properties of their own. When arsenic binds to elements such as sulfur, oxygen, and chlorine it forms molecules known as inorganic compounds; when arsenic binds to molecules containing carbon it forms organic compounds. Inorganic forms of arsenic are, in general, more toxic to humans since they are less stable and may allow arsenic to interact with important cellular molecules.

Both the inorganic and organic forms of arsenic are readily eliminated from the body through the urine. When we are exposed to inorganic arsenic, the body routinely changes, or metabolizes, it into one or more organic forms by successively adding carbon atoms to it. Scientists once believed that this process – known as methylamine – was a natural arsenic detoxification process for both humans and other animals.

But new findings have challenged that idea. Animal species that do not methyl ate arsenic are not only able to excrete inorganic arsenic efficiently but appear to be no more sensitive to its toxic effects than animals that methyl ate. More recently, scientists have found that a simple ethylated form of arsenic called mono-methyl arsenic (III) can cause cancer in animals. On the other hand, fish and other animals contain a highly ethylated form of arsenic called arsenobetaine or “fish arsenic” which is essentially non-toxic and is readily eliminated by our bodies. So although fish may have high amounts of arsenic in them, it is primarily in a form that is not a health risk to humans.

There is evidence that humans and other animals can build up tolerance to the toxic effects of arsenic. A society of “arsenic eaters” who deliberately consumed arsenic-laden soils in their religious practices developed a high tolerance for arsenic. Rasputin was reported to regularly ingest arsenic to build tolerance and to protect him from poisoning.

What amount of arsenic is toxic to humans?

Like any other poison, whether an exposure to arsenic is harmful largely depends on its chemical and physical form and how one is exposed. Toxicologists use the terms dose, duration and route of exposure, meaning the amount of a substance taken in, the period of time the exposure lasts, and the way the substance enters the body. One way of being exposed to arsenic is by breathing it in as a dust. This primarily occurred in workplace settings where arsenic or products containing arsenic were used, and before new knowledge led to the development of modern worker safety measures. There is normally little or no uptake of arsenic through the skin at environmental levels, though it was of concern in previous workplace exposures (such as long-term use of arsenic-containing pesticides) or through use of arsenic-containing medications applied directly to the skin. The route of exposure of most concern today is ingesting arsenic, particularly through drinking water contaminated by inorganic arsenic.

The concentrations of arsenic found in the heavily contaminated drinking water of Bangladesh are between 170 and 1500 micrograms per liter (A microgram is a millionth of a gram). By contrast, a person would have to ingest more than 70,000 micrograms of arsenic all at once to be fatally poisoned by a single dose. Nevertheless, exposure over a long period of time to concentrations of arsenic such as those found in Bangladesh is associated with a wide range of illnesses.

Much of the world’s current safe drinking water standards for arsenic are based on risk estimates using data on people exposed to very high levels of arsenic through their occupations or through drinking water in areas such as Bangladesh, Taiwan and parts of South America. Few studies have examined the effects of lower doses on people over long periods of time.

Dartmouth researchers are conducting epidemiological studies to determine the health effects of drinking water containing arsenic at the elevated levels found in certain regions of the United States. These levels -typically between 50 and 200 micrograms per liter – are much lower than those of Bangladesh but are still considered high enough to be of concern

Can arsenic cause cancer?

Like many chemicals, arsenic’s effects on cancer at first appear paradoxical. On the one hand, arsenic is one of a handful of chemicals that is well established as a human carcinogen based on direct evidence in human populations. In fact, this was evident in humans long before there was evidence for arsenic’s cancer-causing effects in laboratory animals. On the other hand, arsenic has been shown to be effective as a cancer chemotherapy drug and can be used to induce complete cures in certain forms of cancer.

The evidence that arsenic is a carcinogen comes primarily from studies of disease in regions of Taiwan, South America, India, and Pakistan where drinking water contains elevated levels of arsenic. These studies have demonstrated a strong association between high levels of arsenic in drinking water and the risk of lung, skin, bladder and other cancers. Interestingly, these studies have suggested that arsenic is unique in being the only known agent that increases lung or skin cancer risk where ingestion is the only route of exposure.

Surprisingly, it has been difficult to demonstrate that arsenic can increase the incidence of cancer in animals despite the strong human epidemiological data. This is also true of several other carcinogenic metals including chromium, cadmium and nickel. The reasons are unclear, but one view is that these agents act indirectly, by increasing the risk of cancer from other factors. This would not be evident in experiments in which animals are raised in a relatively pristine laboratory environment and exposed only to the metal in question.

Beginning around the 1970s, the Chinese began to systematically experiment with the use of arsenic to treat certain cancers. Most of these studies were published in the Chinese medical literature, which did not become accessible to the western world until the late 1980s. In particular, the Chinese demonstrated that use of arsenite -inorganic arsenic trioxide – was highly effective in treating certain leukemia. Arsenite was particularly useful for people whose leukemia were resistant to chemotherapy treatment using retinoic acid, a derivative of vitamin A. The results of these arsenic studies were recently confirmed in a small U.S. cancer trial as well. These studies suggest that arsenic may prove to be an effective anti-cancer agent for other malignancies in the coming years.

Arsenic’s paradoxical behavior as both cause and treatment for cancer is an example of an often-repeated maxim attributed to Paracelsus, a physician and alchemist who lived 500 years ago: “the right dose differentiates a poison from a remedy.”

What are the symptoms of arsenic poisoning?

Arsenic has been the poison of choice since antiquity because it is difficult to detect in food and water and because the symptoms of poisoning by arsenic can be mistakenly attributed to many other ailments.

The effects of arsenic poisoning differ depending upon whether the exposure is acute – a large dose in a short period of time – or chronic – lower doses over an extended period of time.

At a very high, single dose arsenic can cause severe shock, general paralysis, delirium and then death within a few hours. At a somewhat lower dose the primary symptoms are nausea, headache, intense gastrointestinal pain, vomiting and diarrhea. This can be followed by extensive gastrointestinal bleeding, loss of blood pressure and a decrease in brain function followed by death. These effects are rare except in cases of intentional poisoning or suicides.

Workers and others who have been exposed to arsenic over long periods of time, principally by breathing it or ingesting it, can exhibit symptoms that include melanosis, a change in pigmentation of the skin similar to freckling; hyperkeratosis, an extensive thickening of the skin, especially the palms of the hands and soles of the feet; damage to heart and blood vessels; a decrease in both red and white blood cell production; and severe inflammation of the liver.

These symptoms are also seen in people who live in regions where drinking water contains between 100 and 1,500 parts per billion of arsenic.

Drinking-water arsenic at these levels is also associated with an increased risk of diabetes mellitis (type 2 or adult-onset diabetes), with damage to heart and blood vessels and, in some areas of the world, a condition called Blackfoot disease. This causes the feet or sometimes hands to lose circulation and to turn “black.” There is also a strong association between arsenic in drinking water and an increased risk of lung, skin, bladder and other cancers.

Arsenic is cleared from the body quickly, so the most important remedy for arsenic poisoning is eliminating exposure. The most serious effects of arsenic, such as cancer and diabetes, are believed to require long, continuous exposures perhaps lasting 20 years or more.

In cases of extreme poisoning, chemical compounds called chelating agents can be used as an antidote. Chelating agents such as “British anti-lewisite” (BAL) and other more modern therapies work by binding arsenic tightly in complexes, making it inactive. This can help remove arsenic from a person’s body, averting severe toxicity and death.