Introduction

The primary routes of arsenic entry into the body are ingestion and inhalation. Dermal absorption also occurs, but to a lesser extent.

The half-life of inorganic arsenic in humans is about 10 hours [Rossman 2007].

Arsenic undergoes biomethylation in the liver.

Approximately 70% of arsenic is excreted, mainly in urine [Rossman 2007].

Arsenic is excreted in the urine; most of a single, low-level dose is excreted within a few days after ingestion.

Gastro-Intestinal Tract

Lungs

Airborne arsenic in the workplace is generally in the form of arsenic trioxide [Ishinishi et al. 1986].

The amount of arsenic absorbed by inhalation has not been determined precisely, but it is thought to be within 60% to 90% [Yip and Dart 2001].

Smaller particles are deposited more deeply in the respiratory tract.

Dermal Absorption

Distribution

After absorption through the lungs or GI tract, arsenic is widely distributed by the blood throughout the body. [ATSDR 2007]

Most tissues rapidly clear arsenic, except for skin, hair, and nails [Lansdown 1995].

Two to four weeks after exposure ceases, most of the arsenic remaining in the body is found in keratin-rich tissues such as

• hair,
• nails,
• skin, and
• to a lesser extent, in bones and teeth [Yip and Dart 2001].

Metabolism

• red blood cells,
• white blood cells, and
• other cells that reduce arsenate to arsenite [Winski and Carter 1995; Wang et al. 1996].

Reduction of arsenate (As V) to arsenite (As III) is needed before methylation can occur. This reaction requires glutathione (GSH) [Miller et al. 2002; Vahter et al. 1983].

A portion of arsenite (As III) is methylated in the liver by enzymatic transfer of the methyl group from S-adenosylmethionine (SAM) to methyl arsonate (MMA V) and dimethyl arsenate (DMA V) [Aposhian et al. 2004; Styblo et al. 2002].

The resulting metabolites are more readily excreted.

Methylation has long been considered the main route of arsenic detoxification, but more recently there has been a growing body of literature supporting other detoxification mechanisms. For example, a number of animal species lack arsenic methylation and excrete inorganic arsenic [Vahter 2002]. The implication is that there may be other more important arsenic detoxification mechanisms in mammals. Other studies have suggested additional detoxification mechanisms such as

• antioxidant defenses,
• resistance to apoptosis, or
• transport [Yoshida et al. 2004].

There have also been studies of arsenic metabolism suggesting that methylation of inorganic arsenic may be a toxification, rather than a detoxification pathway and that trivalent methylated arsenic metabolites, particularly monomethylarsonous acid (MMA III) and dimethylarsinous acid (DMA III), are "unusually capable of interacting with cellular targets such as proteins and DNA" [Kitchin 2001].

Methylation efficiency in humans appears to decrease at high arsenic doses. Patterns of methylated arsenic species in urine are similar between siblings and between siblings and parents, which suggests that arsenic methylation is genetically linked [Chung et al. 2002].

When the methylating capacity of the liver is exceeded, exposure to excess levels of inorganic arsenic results in increased retention of arsenic in soft tissues.

Excretion

• Approximately 50% of excreted arsenic in human urine is dimethylated and 25% is monomethylated, with the remainder being inorganic [Buchet et al. 1981]. However, there may be individual variations in percentage. According to urinary arsenic data from the National Health and Nutrition Examination Survey 2003-2004 (also described in the "Clinical Assessment, Lab Testing" section of this document), as urinary levels of total arsenic increase, the percentage of methylated forms increases and at lower urinary total arsenic levels, the predominant form is inorganic [Caldwell et al. 2008].
• Fish arsenic is largely not biotransformed in vivo, but it is rapidly excreted unchanged in the urine.
• After a single intravenous injection of radiolabeled trivalent inorganic As (III) in human volunteers, most of the arsenic was cleared through urinary excretion within 2 days, although a small amount of arsenic was found in the urine up to 2 weeks later [ATSDR 2007].
• The biologic half-life of ingested fish arsenic in humans is estimated to be less than 20 hours, with total urinary clearance in approximately 48 hours [ATSDR 2007].
• Because arsenic is rapidly cleared from the blood, blood levels may be normal even when urine levels remain markedly elevated [ATSDR 2007].

• feces,
• incorporation into hair and nails,
• skin desquamation, and
• sweat.

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