Chemistry Reference
In-Depth Information
18.2 Carcinogenicity and Cocarcinogenicity
Predominant tumours in humans exposed chronically via inhalation or the gastroin-
testinal tract are lung and skin cancers, respectively. Additionally, case reports and
epidemiological studies indicate increased incidences of tumours in the skin, the
liver and the digestive tract after chronic arsenic inhalation, as well as increased
risks of internal tumours (mainly bladder, lung, and to a lesser extent liver, kidney
and prostate) after chronic arsenic ingestion (reviewed in references 3-6). Numer-
ous scientifi c commissions and regulatory agencies have classifi ed arsenic as a human
carcinogen; among these are the International Agency for Research on Cancer
(IARC), the German Commission for the Investigation of Health Hazards of
Chemical Compounds in the Work Area (MAK commission) and the United
States Environmental Protection Agency (USEPA).
2,7 - 11
In contrast to humans, where the carcinogenic potential is clearly evident,
experimental animals usually fail to demonstrate increased tumour incidences, with
the exception of studies in mice demonstrating transplacental carcinogenesis.
2,12 - 14
Nevertheless, cocarcinogenic effects have been observed in several experimental
settings. Thus, early animal studies have shown that lung adenoma incidences were
increased by benzo[
a
]pyrene and arsenic cotreatment, as compared to treatment
with each chemical alone.
15
More recently, arsenite has been demonstrated to
enhance the carcinogenicity of UV radiation in mice, thus combined exposure to
arsenite-enriched drinking water and solar UV radiation strongly increased skin
tumour incidences, as compared to mice given UV alone.
16,17
Similar cocarcinogenic
effects were also seen in humans. The results from several epidemiological studies
suggest more than additive effects on respiratory tract cancer incidences in smokers
that were exposed to arsenic occupationally or via drinking water.
18,19
Additionally,
epidemiological studies provide some evidence that arsenite acts as a cocarcinogen
in skin cancer (reviewed in reference 20).
With respect to organic methylated arsenic metabolites, oral treatment of
animals with dimethylarsinic acid (DMA
V
) has been shown to act as a tumour pro-
moter in several organs and as a complete carcinogen in the rat bladder; however
it is questionable whether the applied DMA
V
concentrations could be attained
in
vivo
after exposure to nonacutely toxic inorganic arsenic doses (summarized in
references 21 and 22 ).
18.3 Metabolism of Inorganic Arsenic
After inhalation or ingestion of inorganic arsenic, humans and many other mammals
have the ability to metabolize inorganic arsenic into organic arsenic forms that are
more readily excreted via urine. After reduction of arsenate, arsenite is converted
to its trivalent and pentavalent methylated metabolites, monomethylarsonous
(MMA
III
) and dimethylarsinous (DMA
III
) acid, monomethylarsonic (MMA
V
) and
dimethylarsinic (DMA
V
) acid. To date, the individual steps of biomethylation, which
