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Toxicity, Arsenic

Author: Steven Marcus, MD, Professor, Department of Preventive Medicine and Community Health, Associate Professor, Department of Pediatrics, New Jersey Medical School, University of Medicine and Dentistry of New Jersey; Executive and Medical Director, New Jersey Poison Information and Education System; Consulting Staff, Departments of Pediatrics and Internal Medicine, University Hospital, University of Medicine and Dentistry of New Jersey; Consulting Staff, Department of Pediatrics, Newark Beth Israel Medical Center
Contributor Information and Disclosures

Updated: Apr 21, 2009

Introduction

Background

Arsenic, element 33, has a long and nefarious history; its very name has become synonymous with poison. In the 15th and 16th centuries, the Italian family of Borgias used arsenic as their favorite poison for political assassinations. Some even have suggested that Napoleon was poisoned by arsenic-tainted wine served to him while in exile.

Arsenic is ubiquitous in the environment. It ranks 20th in abundance in the earth's crust, 14th in seawater and 12th in the human body.¹  In nature, arsenic exists in the metallic state in 3 allotropic forms (alpha or yellow, beta or black, gamma or grey) and several ionic forms. Arsenic has been used as a medicinal agent, a pigment, a pesticide, and an agent of criminal intent. It is typically considered a heavy metal and shares many toxic characteristics with the other heavy metals (eg, lead, mercury). Arsenic is primarily used in the production of glass and semiconductors. It is also found in certain water supplies and seafood and often contaminates fruits and vegetables particularly rice.

Today, arsenic poisoning occurs through industrial exposure, from contaminated wine or moonshine, or because of malicious intent. The possibility of heavy metal contamination of herbal preparations and so-called nutritional supplements must also be considered.

Because arsenic has been involved in geopolitics, an estimated 100 million people are at risk of exposure to unacceptable arsenic levels in either well water or ground water. There have been numerous "outbreaks" of excessive arsenic in water and food from an assortment of natural and anthropological causes. This has become a major public health issue in the developing world, primarily Bangladesh and surrounding countries, where many thousands of individuals are suffering from precancerous arsenic-related disease.

Pathophysiology

Inorganic forms of arsenic are more toxic than organic forms. The trivalent forms are more toxic and react with thiol groups, while the pentavalent forms are less toxic but uncouple oxidative phosphorylation. Very few organ systems escape the toxic effects of arsenic.

Trivalent inorganic arsenic inhibits pyruvate dehydrogenase by binding to the sulfhydryl groups of dihydrolipoamide. Consequently, conversion of pyruvate to acetyl coenzyme A (CoA) is decreased, citric acid cycle activity is decreased, and production of cellular ATP is decreased. Trivalent arsenic inhibits numerous other cellular enzymes through sulfhydryl group binding. Trivalent arsenic inhibits cellular glucose uptake, gluconeogenesis, fatty acid oxidation, and further production of acetyl CoA; it also blocks the production of glutathione, which prevents cellular oxidative damage.

Effects of pentavalent inorganic arsenic occur partially because of its transformation to trivalent arsenic; toxicity proceeds as outlined above. More importantly, pentavalent arsenic resembles inorganic phosphate and substitutes for phosphate in glycolytic and cellular respiration pathways. High-energy phosphate bonds are not made, and uncoupling of oxidative phosphorylation occurs. For example, in the presence of pentavalent arsenic, adenosine diphosphate (ADP) forms ADP-arsenate instead of ATP; the high-energy phosphate bonds of ATP are lost.

Arsenic is listed as a presumed carcinogenic substance based on the increased prevalence of lung and skin cancer observed in human populations with multiple exposures (primarily through industrial inhalation).

Frequency

United States

According to the American Association of Poison Control Centers' (AAPCC) National Poisoning Data System (NPDS), 1,165 reported human exposures not related to arsenic-containing pesticides and 379 exposures related to arsenic-containing pesticides were reported. No mortalities occurred in either group; however, outcome documented as major reportedly occurred in 10 nonpesticide and 1 pesticide exposures. The bulk of the pesticide exposures occurred in children younger than 6 years of age while more than 50% of the nonpesticide exposures occurred in adults.²

International

Worldwide, up to 100 million people are at risk of exposure to arsenic from excessive arsenic in drinking water. In Bangladesh, more than 95% of the water supply to over 138 million people is potentially arsenic contaminated at levels exceeding the US EPA and WHO action limits.³ If international efforts at elimination of the risk are unsuccessful, it is estimated that a substantial proportion of the Bangladesh population will develop arsenic-related diseases such as pulmonary and skin cancers and cardiovascular and renal disease.

In addition to the concentration of arsenic in the water, the prevailing diet existing in the affected areas may place the citizens at increased risk for toxicity from the arsenic. The population was recently surveyed and those individuals who had diets deficient in certain B vitamins and antioxidants appeared to have greater risk of arsenic dermatoses. An inverse correlation was found between consumption of vitamins A, C, and E, riboflavin and folic acid, and the existence of dermatological manifestations or chronic arsenic exposure.⁴

Mortality/Morbidity

According to the American Association of Poison Control Centers' (AAPCC) National Poisoning Data System (NPDS), 1,165 reported human exposures not related to arsenic-containing pesticides and 379 exposures related to arsenic-containing pesticides were reported. No mortalities occurred in either group; however, outcome documented as major reportedly occurred in 10 nonpesticide and 1 pesticide exposures. The bulk of the pesticide exposures occurred in children younger than 6 years of age while more than 50% of the nonpesticide exposures occurred in adults.²

Sex

Men are more likely to experience industrial arsenic exposure than women.

Age

As in many reported cases of poisoning, the majority of reports of exposure to arsenic-containing pesticides occur with children younger than 6 years as the victim (274 of 379 in the NPDS 2007 data), whereas, when nonpesticide arsenic exposure is involved, the majority are in adults older than 19 years (645 of 1165).²

Clinical

History

• Arsenic exposure is usually suicidal, malicious, homicidal, or occupational.
• To reveal the exposure, record a careful work history on individuals with symptoms of a painful peripheral neuropathy. If the setting is not occupational, a careful epidemiological history of those affected and those unaffected must be undertaken.
• Exposure to arsine gas is usually the result of an occupational accident; in most cases, the worker presents rapidly and is brought in with the material safety data sheet (MSDS).
• Determining unusual cases requires a careful history regarding dietary and nutritional habits, particularly the use of nutritional supplements and ayurvedic medicines, hobbies, and alcohol abuse.
• Often, patients with neurological symptoms are subjected to "heavy metal screens" by their primary care practitioners or even neurologists. Often, the laboratories used are not the standard medical reference laboratories, and the results are of questionable reliability. In other cases, the results are reported in concentration of total arsenic in urine or blood, and this is not generally accepted as valuable in the determination of possible exposure or toxicity.

Physical

• Frequently, patients exposed to arsenic will have a garlic smell to their breath and tissue fluids.
• In trivalent arsenic poisoning, clinical effects depend on the chronicity of exposure.
  • Acute exposures generally manifest with the choleralike gastrointestinal symptoms of vomiting (often times bloody) and severe diarrhea (which may be rice-watery in character and often bloody); these patients will experience acute distress, dehydration (often), and hypovolemic shock.
  • Chronic toxicity is more insidious and may manifest as a classical dermatitis (hyperkeratosis with a classical "dew drops on a dusty road" appearance) or peripheral neuropathy (usually a painful paresthesia that is symmetrical and stocking-glove in distribution).
  • Also, whitish lines (Mees lines) that look much like traumatic injuries are found on the fingernails.
  • Multiple reports of cardiac arrhythmias exist in the literature. Reports of prolongation of the QT and ventricular fibrillation after acute arsenic intoxication make careful attention to cardiac status imperative.
  • Chronic hepatic and renal damage is common with chronic exposure.
• Arsine gas exposure manifests with an acute hemolytic anemia and striking chills. Hemoglobinuria causes the urine to appear black (see Media file 1), and the patient becomes rapidly obtunded and shocky. Shaking chills are often described in these patients.

Causes

• Children may encounter arsenic trioxide as a rodenticide or herbicide. Examine for both arsenic and cholinesterase-inhibitor exposure. Possible transdermal absorption from exposure to pressure-treated wood, now banned for use by the US EPA, has been reported.
• Adults may be exposed through work in a metal foundry, mining, glass production, or the semiconductor industry.
• Arsenic has been found to contaminate such common items as wine, glues, and pigments. Arsenic is commonly found in many foods both in its apparently nontoxic organic form and also in the more toxic inorganic form. Such arsenic has been reported in milk and dairy products, beef, pork, poultry, and cereal. Arsenic is also often found in rice, representing a potentially serious source of exposure in certain at-risk populations.
• Arsenic exists in significant concentrations in some shallow wells dug for provision of clean water in some underdeveloped countries.

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