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Toxicokinetics of Arsenic and its Effects on Human Health

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Arsenic and its compounds are ubiquitous in nature and exhibit both metallic and non metallic properties. It is known that arsenic has different toxicological properties dependent upon both its oxidation state for inorganic compounds as well as the different toxicity levels exhibited for organic arsenic compounds. Arsenic appears in nature primarily in the form of sulfides in association with ores of silver, lead, copper, nickel, antimony, cobalt and iron. Trace amount of arsenic are found in soils and other environmental media.  Arsenic is released to the atmosphere from both natural and anthropogenic sources. The principal source is volcanic activity. Man-made emissions to air arise from the smelting of metals, the contribution of fuels and use of pesticides. World production of arsenic kept rising mid-1940s. As arsenic pesticides, especially insecticides, were gradually replaced by the other preparations, the production of arsenic declined. Arsenic is still used in production of agricultural chemicals. Arsenic is an active component of antifungal wood preservatives. It is also used in the pharmaceutical and glass industries and in the manufacture of poisonous baits.  Arsenicals are used in the manufacture of pigments while metallic arsenic is used in the manufacture of alloys. Gallium arsenide and indium arsenide are used in the production of certain semiconductor devices. This article describes toxicity and some currently used chromatographic mass spectrometry applications to detect and quantify arsenic in its various chemical forms.

Forms of Arsenic

The trivalent and pentavalent forms are the most common oxidation states. From both the biological and the toxicological points of view, arsenic compounds can be classified into three major groups

  • Inorganic arsenic compounds
  • Organic arsenic compounds
  • Arsenic gas

The most common trivalent inorganic arsenic compounds are arsenic trioxide, sodium arsenite and arsenic trichloride. Pentavalent inorganic compounds include arsenic peroxide, arsenic acid and arsenates such as lead arsenate and calcium arsenate. Common organic arsenic compounds are arsanilic acid, methylarsonic acid, dimethylarsinic acid (cacodylic acid) and arsenobetaine. Arsenic trioxide is only slightly soluble in water, in sodium hydroxide it forms arsenite and with concentrated hydrochloric acid it forms arsenic trichloride. Sodium arsenite and sodium arsenate are highly soluble in water. Interchange of valence state may occur in aqueous solutions depending on the pH and on the presence of other substances which can be reduced or oxidized. Arsenic is mainly transported in the environment by water. In oxygenated water arsenic usually occurs as arsenate but under reducing conditions e.g. in deep well-water, arsenates predominates. In water the methylation of inorganic arsenic to methyl and dimethyl arsenic acids (DMA) is associated with biological activity. In oxygenated soil inorganic arsenic is present in the pentavalent form. Under reducing conditions it is in the trivalent form.

Toxicokinetics

The major routes of arsenic absorption in the general population are ingestion and inhalation. Human and animal data indicate that over 90 % of the ingested dose of dissolved inorganic trivalent or pentvalent arsenic is absorbed from the gastrointestinal tract. Organic arsenic compound in sea food are also readily absorbed. Factors affecting the extent of absorption from the lungs includes the chemical form , particles size ad solubility. Air borne arsenic is usually in the forms of arsenic trioxide.  Particles of more than 10 micrometer in aerodynamic diameter are predominantly deposited in the upper airways (nasopharynx), particles of between 5 and 10 micrometer are deposited in the airways cleaned by mucociliary action and particles with diameter of less than 2 micrometer penetrate significantly into the alveoli. The overall absorption as a proportion of the inhaled dose was about 30-35 % while the amount of arsenic excluded in urine was about 40-60 % of the estimated inhaled dose.

Blood is the main vehicle for the transport of arsenic following absorption and arsenic is cleared relatively rapidly from it. In humans, skin, excretory and storage organs such as nails and hair, have the highest concentration. Arsenic in the kidneys, liver, bile, brain, skeleton, skin and blood are 2-2.5 times higher for the trivalent than for the pentavalent form, and are greatly increased at higher doses.

Trivalent inorganic arsenic is oxidized in vivo in animals and human exposed to arsenite. The reduction of arsenate to arsenite, has been demonstrated in mice and rabbits. Both arsenite and arsenate are methylated in the liver. Both methylated species MMA and DMA are considered to be less toxic and to bind to tissues and are eliminated more rapidly than the unmethylated form. On average, 20-25% of inorganic arsenic remains unmethylated.

Effects on Human Health

As a consequence of the many different uses of arsenic and arsenicals, there is wide spectrum of situation in which human may be exposed to the element. Arsenic in air is present mainly in particulate forms as inorganic arsenic. Particulate arsenic compounds may be inhaled, deposited in the respiratory tract and absorbed into the blood. Inhalation of arsenic from ambient air is usually a minor exposure route for the general population. Tobacco smoke may contain arsenic especially when the tobacco plants have been treated with lead arsenate insecticide. The use of arsenic pesticides is now prohibited in most countries. Occupation exposure to arsenic occurs primarily among workers in the copper smelting industry, at power plant burning arsenic-rich coal and using or producing pesticides containing arsenic. Inhalation exposure to arsenic can also take place during production of gallium arsenide in the microelectronics industry and metals ore mining.

Drinking water may contribute significantly to oral intake in regions where there are high arsenic concentrations in well-water or river-water or mine drainage areas. The concentration in ground water depends on the arsenic content of the bed-rock.  With the exception of some kind of sea food, most foods contain low levels of arsenic, normally less than 0.25 mg/kg. Marine organisms may contain large amount of organo-arsenicals (arsenobetaine). These arsenic derivatives are not acutely toxic because of their low biological reactivity and their rapid excretion in urine. Hence, the amount of arsenic ingested daily by humans via food is greatly influenced by the amount of sea food in the diet.

Recently,  the research done by the Indian Council of Agricultural Research (ICAR) of India was published showing that 90 % of arsenic-laden water in affected areas (96 districts) was used for irrigation and it was found that some vegetables such as brinjal, potato, radish, cauliflower had high quantity of arsenic. Arsenic contamination is spreading fast and entering the food chain through farm products in the region. As people take contaminated water along with contaminated food, the chances of damage become greater. The report says total number of deaths so far is one lakh people, with over three lakh suffering from arsenic-related disease.

There are three population groups at high exposure risk:

  • People drinking water and food products with abnormally high concentrations of arsenic
  • The occupationally exposed people
  • Children living in close vicinity of smelters

The clinical picture of chronic poisoning with arsenic varies widely. It is usually dominated by changes in the skin and mucous membranes and by neurological, vascular and haematogical lesions. Arsenic and its inorganic compounds have been known to be neurotoxic. The skin is a common critical organ in people exposed to inorganic arsenical compounds. Eczematoid symptoms develop with varying degrees of severity.  Hyperkerotosis, warts and melanosis of the skin are the most commonly observed lesions in chronic exposure. There is sufficient evidence that inorganic arsenic compounds are skin and lung carcinogen in human. There are many arsenic compounds both organic and inorganic in the environment. Inorganic arsenic can have acute, subacute and chronic effects which may be wither local or systemic. Lung cancer is considered to be critical effect following inhalation. A WHO working group on arsenic conducted a quantitative risk assessment for arsenic, assuming a linear relationship between the cumulative arsenic dose and the relation risk of developing lung cancer from inorganic arsenic exposure were based on the study by Pinto et al.

Speciation Analysis

This is the analytical activity of identifying and/or measuring in a sample the quantity of one or more individual chemical species. The need to define and measure chemical species of an element lies in the fact that physiological factors such as toxicity, bioavailability, mobility and reactivity are dependent on the specific form of an element. Chemical species can be free ions, inorganic complexes, organometallic compounds, biomolecules and structures of high molecular mass. The field of arsenic speciation analysis has grown rapidly in recent years, especially with the utilization of high-performance liquid chromatography (HPLC) coupled to ICP-MS, a highly sensitive and robust detector system. Complete characterization of arsenic compounds is necessary to understand intake, accumulation, transport, storage, detoxification and activation of this element in the natural environment and living systems.

Conclusions

As a consequence of the many different uses of arsenic and arsenicals, there is wide spectrum of situation in which human may be exposed to the element. The clinical picture of chronic poisoning with arsenic varies widely. Arsenic has different toxicological properties dependent upon both its oxidation state for inorganic compounds as well as the different toxicity levels exhibited for organic arsenic compounds. The field of arsenic speciation analysis has grown rapidly in recent years, especially with the utilization of high-performance liquid chromatography (HPLC) coupled to ICP-MS.

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