Unanswered questions in arsenic toxicology.
Arsenic (As) is one of the most important environmental global toxicants. In various countries and for decades people have been and currently are exposed to inorganic As through geogenically contaminated drinking water. An increased incidence of diseases mediated by this toxic element is the consequence of long-term exposure. Despite past extensive research on the toxicology of As, many questions remained unanswered, making risk assessment difficult. For instance, it is still not known how the carcinogenicity of As is mechanistically operative. Moreover, there is an increasing debate on whether the metabolic methylation of As has to be considered a detoxification process. Furthermore, it is historically documented that long-term intake of small amounts of As can lead to an acquired increased tolerance to its acute toxicity. It is not known whether this tolerance may be associated with a reduced chronic toxicity as well. In contrast to nonhuman cells, the selection of As-induced self-tolerance in human cells in vitro had been unsuccessful until now. However, we recently selected As-resistant human hepatoma HepG2 sublines that have low-level tolerance to As. Besides an approximately twofold elevated resistance to As cytotoxicity, this tolerance was associated with a significantly suppressed induction of As-mediated genotoxicity, which was evident in the cytokinesis-block micronucleus test. Additional questions arise when we consider several factors suspected to modulate the long-term toxicity of arsenic in vitro, variables that may either enhance or suppress the environmental genotoxicity and carcinogenicity of the metalloid. Besides malnutrition, these are single nutritional factors such as selenium and possible drinking water co-contaminants such as antimony. For instance, in the case of selenium, we could show that antimony (III) is able to suppress As genotoxicity. Taken together, research answers in many fields of As toxicology are needed in order to reduce the uncertainties in risk assessment of environmental As.
Gebel
T W
TW
Medical Institute of General Hygiene and Environmental Health, University of Goettingen, Germany.
D000965:Antimony / Q000009:adverse effects; D001151:Arsenic / Q000494:pharmacology / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004781:Environmental Exposure; D006801:Humans; D009748:Nutrition Disorders; D011634:Public Health; D018570:Risk Assessment; D012643:Selenium / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014881:Water Supply
D000965:Antimony; D012643:Selenium; D001151:Arsenic