Genetic toxicology of a paradoxical human carcinogen, arsenic: a review

Abstract

Arsenic is widely distributed in nature in air, water and soil in the form of either metalloids or chemical compounds. It is used commercially, as pesticide, wood preservative, in the manufacture of glass, paper and semiconductors. Epidemiological and clinical studies indicate that arsenic is a paradoxical human carcinogen that does not easily induce cancer in animal models. It is one of the toxic compounds known in the environment. Intermittent incidents of arsenic contamination in ground water have been reported from several parts of the world. Arsenic containing drinking water has been associated with a variety of skin and internal organ cancers. The wide human exposure to this compound through drinking water throughout the world causes great concern for human health. In the present review, we have attempted to evaluate and update the mutagenic and genotoxic effects of arsenic and its compounds based on available literature.

Introduction

Arsenic is a naturally occurring metalloid that exists in inorganic as well as organic forms. The major inorganic forms of arsenic include the trivalent meta arsenite and the pentavalent arsenate. The majority of arsenic in surface water exists as As⁵⁺ and in ground water in deep anoxic wells as As³⁺. The trivalent arsenic is more toxic than the pentavalent form. The organic forms are the methylated metabolites-monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), and trimethylarsine oxide (TMAO). The source of arsenic is geological. Arsenic is released to the environment through natural weathering of arsenic-rich geological forms, pesticide use, mining, manufacturing, burning of fossil fuels and incineration. The majority of humans are chronically exposed to low levels of arsenic, principally through ingestion of food and water and to some extent due to inhalation of arsenic in the ambient air.

Incidents of arsenic contamination in the ground water have been reported from widespread areas such as Taiwan, Mexico, Chile, Argentina, Thailand, Bangladesh and India. Minor cases of chronic arsenic toxicity have occurred in Poland, USA (Minnesota and California), Canada (Ontario), Hungary and Japan. It has been reported that earth arsenic concentration increases with depths of less than 22 m and decreases at depths of over 22 m [1]. According to WHO, the preferred level of arsenic in water is ≤10 μg/l and the maximum permissible limit accepted by the WHO is 50 μg/l. Arsenic has been found to be above the permissible limit in seven districts of West Bengal, India, with concentrations ranging from 200–600 μg/l according to latest reports. It has been regarded as the biggest arsenic calamity in the world [2]. In contrast to most other carcinogens, vast human epidemiological studies on arsenic poisoning are available. Treatment with arsenic alone, however, does not easily induce cancer in animals. Chronic ingestion of high levels of inorganic arsenic in drinking water is associated with increased incidence of human cancer at various sites such as skin, lung, bladder and other internal organs [3]. In the six arsenic affected districts of West Bengal, India about 175,000 people are showing arsenical skin lesions that are the late stages of manifestation of arsenic toxicity [2]. The clinical manifestations of chronic arsenic poisoning are many but the most commonly observed symptoms include arsenical skin lesions, melanosis, conjunctivities, keratosis and hyperkeratosis. Cases of gangrene in limbs and malignant neoplasms have been observed [2].

We have been working on the mutagenic and genotoxic effects of different environmental chemicals and drugs [4], [5], [6], [7], [8], [9]. There is no report on the genetic damage induced by arsenic through drinking water from West Bengal, India. Very recently we started working on the assessment of the cytogenetic damage in the patients showing arsenical skin lesions from the populations exposed to arsenic through drinking water in West Bengal, India. Considering the widespread reports of carcinogenicity in human beings, we recognised the need to review and update the mutagenic and genotoxic effects of arsenic based on available literature. This review takes into account in vivo and in vitro experimental studies as well as human observational studies.