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Arsenic (As) exposure: diagnosis and treatment.

General Information

Arsenic is a semi-metal element in the periodic table, and considered highly toxic to animals and man. It is one of the oldest poisons known to man. Its applications throughout history are wide and varied: murderers used it because it is odorless and tasteless. Only one tenth of one gram can lead to death.

Chronic arsenic toxicity is a global environmental health problem, affecting millions of people worldwide. Arsenic is released into the environment by the smelting of various metals, combustion of fossil fuels, as herbicides, pesticides and fungicides in agricultural products. The drinking water in many countries, which is tapped from natural geological resources, is often contaminated as a result of the high level of arsenic in groundwater.

Arsenic exists in both organic and inorganic form, and long-term health effects can be severe and highly variable: skin and lung cancer, neurological effects, hypertension and cardiovascular diseases.

Neurological effects of arsenic may develop within a few hours after ingestion, but usually are seen in 2-8 weeks after exposure. It is usually a symmetrical sensorimotor neuropathy, often resembling the Guillain-Barre syndrome where the predominant clinical features of neuropathy are paresthesias, numbness and pain, particularly in the soles of the feet.

Most of the adverse effects of arsenic are caused by inactivated enzymes in the cellular energy pathway, whereby arsenic reacts with the thiol groups of proteins and enzymes and inhibits their catalytic activity. Furthermore, As-induced neurotoxicity, like many other neurodegenerative diseases, causes changes in cytoskeletal protein composition and hyperphosphorylation. These changes may lead to disorganization of the cytoskeletal framework, which is a potential mechanism of As-induced neurotoxicity. (1)

Arsenic exposure can easily be detected, especially in hair--even after many years. In the past, arsenic was ascribed miraculous properties, and it was prescribed to enhance absorption of nutrients and help gaining weight. It was also given to prevent skeletal problems and to treat anemia. Not too many years ago, it was suggested that small doses increase energy levels. In the Tyrolean region of Austria, the well known 'arsenic-eaters' were reported to ingest small doses of arsenic at specific intervals to increase physical strength.

Interestingly, the body can build up a resistance to the toxic effect after small doses are ingested over a long time. In fact, some of the arsenic-eaters were known to tolerate up to four times the lethal dose. History does not tell us much about those arsenic-eaters who had a lower tolerance and succumbed. However, one of the documented manifestations included a decreased iodine absorption by the thyroid and reduced thyroid hormone production, which is known to cause cretinism.

Common Sources

In addition to arsenic from air, water and food, tobacco treated with arsenate sprays may also be a route of exposure. Soil can be a source of exposure. Children love to play with dirt, and studies indicate that children living near smelting areas showed signs of high cadmium, lead and arsenic exposure, all due to soil. (2), (3) Water can be a source of arsenic contamination, and while WI-I0 (World Health Organisation) recommends setting national standards, not all are the same. In 2006, the EPA (US Environmental Protection Agency) has reduced its previous standard of 50mcg/L to a limit of 10mcg/1, (4) though the American Council on Science and Health (ACSH) reported in 2002 that there are no adverse health effects (in the United States) from arsenic in drinking water at or below the limit of 50[micro]g/L. This is curious, because governments generally do not lower standards unless research indicates the need. (See table 1 on next page.)
Table 1: Currently accepted national standards for
arsenic in drinking water (5)

Standard      Countries

Countries     Australia (7 mcg/L, 1996)
whose
standard is
lower than
10 mcg/L

Countries     European Union (1998), Japan (1993), Jordan (1991),
whose         Laos (1999), Laos, Mongolia (1998), Namibia, Syria
standard is   (1994) U
10 mcg/L

Countries     Canada (1999) 0.025 mg/l
whose
standard is
lower than
50 mcg/l but
higher than
10 mcg/l

Countries     Mexico (1994)
considering
to lower the
standard
from 50
mcg/L

Countries     Bahrain, Bangladesh (unknown), Bolivia (1997), China
whose         (unknown), Egypt (1995), India (unknown), Indonesia
standard is   (1990), Oman, Philippines (1978), Saudi Arabia, Sri
50 mcg/l      Lanka (1983), Viet Nam (1989),


The toxicity of arsenic to insects, bacteria and fungi led to its use as a wood preservative. (6) Arsenic was found in herbicides and pesticides (and still is in some countries), and it was not uncommon for children to show symptoms of poisoning after touching Fly traps or coils.

Roxarsone--Arsenic Supplement for Animals

Arsenic was added to animal food, as a method of disease prevention and growth stimulation. (7), (8)One example is Roxarsone, a controversial arsenic compound, which was approved in 1944 and has been largely used as a nutritional supplement for chicken. About 70% of the US chicken farmers have used it since 1995. (9) In 2009, the Poison-Free Poultry Act proposed to ban the use of roxarsone in industrial swine and poultry production. (10) In 2011, Pfizer, the manufacturer of roxarsone voluntarily withdrew the product from the US market, but continues to sell it internationally. (11)

The dietary arsenic intake of humans varies widely, and is estimated to range from less than 10 [micro]g/day to 200 [micro]g/day. In the UK and elsewhere, fish is the main contributor of arsenic in the diet of humans. With the exception of fish, most foods contain less than 0.25 [micro]g/g arsenic. Many species of fish contain between 1 and 10 g/g. Arsenic levels at or above 100[micro]g/g have been found in bottom feeders and shellfish. (12)

Arsenic intakes by high fish consumers can reach several thousand [micro]g per day. (13) The levels of inorganic arsenic are generally higher in shellfish. However, there are no reports of acute toxicities in man resulting from the consumption of organoarsenicals in seafood.

Is there a safe Arsenic intake?

One approach to determining safe levels of As in food is by comparing safety standards for drinking water. This comparison is made on the basis of inorganic As species as these are considerably more toxic than organic As species.

Several countries, including the UK and Australia currently use a 1 ppm limit for arsenic in food. In 1989, the FAO and WHO jointly established a provisional tolerable dietary intake of 0.015 mg inorganic As/kg body weight/week, or 130 [micro]g/day for a 60 kg adult. This level is already exceeded by the intake of 200 [micro]g/day from drinking 4 L of water containing 50ppb (=mcg/L) arsenic.

Rice can be a source of arsenic overexposure, especially if it is grown in water containing more than 10mcg/L of arsenic, as is the case in Bangladesh and other rice-growing countries. (14)

Symptoms of Toxicity

Patients exposed to arsenic will frequently have a garlic smell to their breath and to tissue fluids. In trivalent arsenic poisoning the clinical effects depend on the chronicity of the exposure. Acute exposures generally present with gastrointestinal symptoms that mimic cholera: vomiting and severe diarrhea (which may be rice-watery in character, often bloody). The acutely intoxicated patient will be in acute distress, often dehydrated and in hypovolemic shock.

Chronic toxicity is more insidious and may present as a classical dermatitis: hyperkeratosis with a classical dew drops on a dusty road appearance or peripheral neuropathy: classically a painful paresthesia which is symmetrical and stocking-glove in distribution. Also, whitish lines (Mees lines) which look very much like traumatic injuries are found on the fingernails.

Arsenic intoxication is known to produce symptoms such as dark gray skin color, wart-like keratosis on palms and soles, Mees bands, acne-like skin eruptions, skin cancer, liver and kidney disease, and cerebral changes. Symptoms of a severe acute poisoning are nausea, vomiting, gastrointestinal inflammation with severe diarrhea, shock due to severe loss of fluid and electrolytes, kidney failure, respiratory failure, and coma.

A chronic arsenic exposure or overload has been associated with alopecia, dermatitis, myalgia, lethargy, exhaustion, mental confusion, diarrhea, headache, burning sensation of extremities, constipation, stomatitis, epilepsy and convulsions, slow wound healing, edema due to electrolyte imbalance, and neuropathy.

Inorganic arsenic crosses the placenta and may cause neonatal death.

Diagnosing Arsenic Exposure

BLOOD: Due to rapid excretion through the kidneys, serum and whole blood arsenic levels are often not helpful in diagnosing acute arsenic poisoning, unless samples are obtained soon after exposure. Moderately elevated blood levels may only be an indication of an excessive arsenic intake due to diet or other sources. Avoid arsenic-containing food such as fish and chlor-ella, plus other potentially high arsenic sources for three days, before repeating the test. Repeat results should be within the expected range. If not, a serious and immediate exposure may be present. Evaluate potential sources.

URINE: Mildly to moderately elevated urinary arsenic excretion levels may he due to an increased intake of dietary arsenic. Evaluate potential sources and if you suspect a dietary involvement, avoid arsenic-containing food and other potentially high arsenic sources for three days, before repeating the test. Collect urine for 24hrs. If the urine concentration is above 50mcg/L, check with a physician trained in clinical metal toxicology (see www.ibcmt.com). Or compare morning urine results with those of a DMSA or DMPS provocation urine. Both of these chelators have a good arsenic binding ability.

HAIR/NAILS: hair and nails are good diagnostic indicators of a chronic arsenic exposure. Both of these tests are known to locate long term arsenic exposure long before symptoms of intoxication are obvious. This fact was known in forensic medicine for quite some time.

Treatment of Arsenic Intoxication

The chelating agent BAL (British Anti Lewisite) was developed as an emergency treatment for chemical warfare-based arsenic poisoning during World War II. BAL (chemical name: dimercaprol; 2,3-dimercaptopropanol) has been in use in the medical community for over 60 years, but since it causes serious side effects, it has now been. replaced by equally effective chelating agents such as DMPS, which causes few side effects and DMSA, which is well tolerated even among children.

For more information about chelating agents, see the IBCMT Textbook on Clinical Metal Toxicology by P.J. Van der Schaar, or Toxic Metals and Antidotes by Blaurock-Busch.

DMPS and DMSA

DMPS is considered a stronger chelating agent than DMSA, but side effects may be more prominent. DMPS is administered intravenously and orally, but for children DMSA is considered a safer choice.

DMPS has a strong affinity to bind copper and zinc, and continued administration can interfere with the copper and zinc metabolism. When DMPS is used for long term treatment, the copper and zinc status must be carefully observed and supplementation between treatments is recommended. Treatments should be spaced carefully.

Both medications have a strong odor, not unlike rotten eggs. To cover up some of the nasty odor, wrap the capsules into bread or other food and take as directed by a physician. It is best to take oral chelators on an empty stomach with 1-2 cups of water. The urine collection should be 4 hours after intake. After the urine collection is completed, patients are advised to drink sufficient water for better renal clearance.

Side Effects to DMSA or DMPS: Nausea, vomiting, diarrhea or loose stools, metallic taste in mouth, stomach and abdominal cramps (these happen more likely When the digestive tract is highly toxic), flu like symptoms, headache and a temporarily impaired vision. The latter symptoms are often reported by patients suffering neurological problems, possibly due to heavy metal intoxication. If any of these symptoms appear, consult a physician.

Clinical cases provide strong evidence that DMSA side effects lessen considerably when the toxic load is reduced. It is not unusual that, initially, an adult strongly reacts to a relatively low dose of DMSA (500 mg or less), but report no side effects after successful treatment. It is not unusual that such a patient tolerates 3 times the initial amount without noticing .any problem. We do not know of comparable reports involving children.

It is often stated that one of the advantages of using DMSA is its ability to pass the blood-brain barrier. Unfortunately, there is only one animal study that supports that claim. No human study has yet proven it. However, studies indicate that symptoms and behaviour improved after chelation.

There may be other explanations in support of using either one of the chelating substances for detoxifying the brain and the central nervous system.

Both chelating agents have similar chemical properties. Both are hydrophilic, meaning water soluble, meaning DMPS and DMSA do not easily move into fatty tissue. Brain and nerves consist of fatty tissue.

Blood Brain Barrier

While the Blood Brain Barrier prevents toxins from passing, the hypotheses is discussed that magnetic fields such as the ones emitted from mobile phones, microwaves, even radiation exposure temporarily open the BBB, allowing passage of foreign substances such as toxins or chelating agents. Fever and infections, trauma to the brain, hypertension and hyperosmolarity (i.e. the presence of a high concentration of a substance in the blood) can open the BBB, or developmental problems prevented the full development at birth. (15)

Spacing Treatments & Homeostasis

There may be another reason why detoxification improves neurological problems. Homeostasis may take place, attempting to bring order to a highly challenged system. In other words, after a chelating agent has removed toxic and vital metals from soft tissue, homeostasis may rebalance the body's biochemistry and redistribute from metal-loaded fatty tissue to the already detoxed soft tissue.

The author sees an indication that this might be the case, and it seems wise to space chelation treatments weeks apart instead of attempting too many treatments in quick succession. More is not necessarily better, and it might be wise to allow the body to adjust and rearrange its internal biochemistry. This redistribution of toxic and vital metals may, in fact, cause metals to be released from organs that are otherwise difficult to detoxify.

Therapeutic Consideration

When a chronic arsenic overload has been diagnosed through hair or nail analysis, and when an immediate exposure has been ruled out, nutritional detoxification may be sufficient. Supplement the sulfur-containing amino acids (cysteine, methionine), along with B-vitamins, increase the vitamin E intake (of all tocopherols), and check the selenium status. Arsenic suppresses iodine and selenium, and adequate selenium intake can support the body's natural elimination of arsenic.

Check thyroid function (especially 13 and TSH) and the iodine status through blood, urine or hair testing. A low blood and/or urine level indicates an inadequate nutritional supply, whereas a low hair concentration reflects a chronically low intake. An excess iodine intake (through iodine-rich supplements such as chlorella and algae) may also disrupt the thyroid metabolism. Algae products can be high in arsenic. (16)

Research

The relationship between cognitive functions and hair mineral concentrations of lead, arsenic, cadmi urn, and aluminum was tested on a random selection of 69 children. The data obtained, showed a significant correlation between reading and writing skills and elevated arsenic levels, as well as the interaction between arsenic and Pb. Children with reduced visual-motor skills had clearly elevated Al and Pb levels.

Moon C. et al: Main and interactive effects of metallic pollutants on cognitive function. J. Learning Disabilities (18(4):217-21. 1985

References

(1.) Vahidnia A. Human & Experimental Toxicology (2007) 26,823-832

(2.) Carrizales L et al. Exposure to arsenic and lead of children living near a copper-smelter in San Luis Potosi, Mexico: Importance of soil contamination for exposure of children. Environmental Research Vol 101, Issue 1, May 2006, Pages 1-10

(3.) Diazbarriga F et al. Arsenic and Cadmium Exposure in Children Living Near a Smelter Complex in San Luis Potosi, Mexico. Environmental Research. Vol 62, Issue 2, August 1993, Pages 242-250

(4.) http://water.epa..gov/lawsregs/rulesregs/sdwa/arsenic/index.cfm

(5.) http://www.who.int/water_sanitation_health/dwq/arsenicun5.pdf

(6.) Rahman, FA; Allan, DL; Rosen, CJ; Sadowsky, MJ (2004). "Arsenic availability from cltromated copper arsenate (CCA)-treated wood". Journal of environmental quality 33 (1): 173-80.

(7.) Nachman, Keeve E; Graham, Jay P.; Price, Lance B.; Silbergeld, Ellen K. (2005). "Arsenic: A Roadblock to Potential Animal Waste Management Solutions". Environmental Health Perspective 113 (9): 1123-1124.

(8.) Arsenic. Section 5.3, p. 310. Agency for Toxic Substances and Disease Registry. http://www.atsdr.cdc.gov/toxprofiles/tp2-c5.pdf.

(9.) Jones, F. T. (2007). "A Broad View of Arsenic". Poultry Science 86 (1): 2-14

(10.) Bottemiller, Helena (September 26, 2009). "Bill Introduced to Ban Arsenic Antibiotics in Feed". Food Safety News. http://www.foodsafetynews.com/2009/09/bill-introduced-to-ban-arsenic-antibiotics-in-feed/. Retrieved 2011-01-10.

(11.) http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm258313.htm

(12.) http://www.inchem.org/documents/jecfa/jecmono/v024je08.htm

(13.) Friberg et al. 1986; WHO, 1981; Ministry of Agriculture, Fisheries and Food, 1982; Dabeka et al., 1987

(14.) http://arsenic.tamu.edu/pub/pubpres/DHAKAdhaka3.pdf

(15.) http://faculty.washington.edu/chudler/bbb.html

(16.) http://www.springerlink.com/contentu8264p61h56r6116/

br: E. Blaurock-Busch PhD

About the author:

Dr. E.Blaurock-Busch PhD is the research director of Micro Trace Minerals Laboratory in Germany an Trace Minerals International of Boulder, Colorado. She is a member of the British Society of Ecological Medicine and the European Academy for Environmental Medicine (EUROPEAM) and Scientific Advisor to the German Medical Association of Clinical Metal Toxicology (KMT) and the International Board of Clinical Metal Toxicology (IBCMT). She can be reached at ebb@microtrace.de or service@tracemin.com.
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Author:Blaurock-Blesch, E.
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Article Type:Disease/Disorder overview
Geographic Code:1USA
Date:Dec 1, 2013
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