Arsenic. No other element has such a complex and variegated past. As
early as 500 B.C. the ancients knew about arsenic, whose name comes from
the
Greek word for
potent. Through the centuries, this “king of
poisons” was a common means of homicide. And yet, arsenic’s
image has not always been so morbid. People in the Middle Ages wore arsenic
amulets around their necks to ward off the bubonic plague, and women in
Victorian times applied arsenic compounds to their faces to whiten their
complexions. Hippocrates, the father of western medicine, recorded arsenic’s
usefulness as a topical remedy for skin ulcers.
Today, arsenic compounds are still used for pharmaceutical purposes. Arsenic
trioxide is known for its use in the treatment of acute promyelocytic leukemia
in patients who are unresponsive to, or have relapsed from, certain chemotherapy
agents. Research published in the 1 April 2005 issue of the Journal
of Clinical Oncology suggests that arsenic trioxide may have therapeutic
uses in other malignancies as well, and that it may be used in combination
with other chemotherapy drugs to expand their benefits.
And yet, no toxicologist would deny that chronic arsenic exposure places
people at risk for a host of adverse health effects, from skin and internal
cancers (of the bladder, kidney, liver, lung, colon, uterus, prostate,
and stomach) to diabetes mellitus and vascular, reproductive, developmental,
and neurological effects. Studies have shown arsenic to be a potent endocrine
disruptor, altering hormone-mediated cell signaling at extremely low concentrations.
Joshua Hamilton, program director of the Dartmouth College Superfund Basic
Research Program, and colleagues published papers on the latter topic in
the March 2001 issue of EHP and the August 2004 issue of Chemical
Research in Toxicology. “We demonstrated this with the glucocorticoid receptor
and subsequently showed that arsenic has similar effects on all five steroid
receptors,” says Hamilton. “Furthermore, we recently found similar
effects on other members of the nuclear receptor signaling family, including
retinoic acid and thyroid hormone receptors.” Since these receptors
are central to so many biological processes, Hamilton suggests that this
may be an important way by which chronic arsenic exposure contributes to
so many malignancies as well as nonmalignant diseases.
The noncancer effects of arsenic arise from both acute and chronic exposures.
Among those symptoms linked with acute exposure to arsenic-laced well water
(typically containing more than 1,200 micrograms per liter [µg/L])
are abdominal pain, vomiting, diarrhea, muscular weakness and cramping, pain
to the extremities, erythematous skin eruptions, and swelling of the eyelids,
feet, and hands. A progressive deterioration in the motor and sensory responses
may also result, finally leading to shock and death.
The effects of chronic arsenic poisoning (also called arsenicosis) are
more complex. Aside from cancer, these chronic effects include atherosclerosis,
diabetes, hypertension, anemia, liver disorders, kidney damage, headache,
confusion, peripheral neuropathy, and a variety of skin lesions, notably
hyperkeratosis, or thickening of the skin, and both hypo- and hyperpigmentation.
Skin lesions are the most common outward sign of chronic arsenic exposure,
though many dermatologic symptoms are thought to be mediated by nutritional
factors. Studies conducted in Taiwan, India, and Bangladesh have linked high-arsenic
well water with the incidence of both skin lesions and diabetes in a dose-responsive
pattern. One recent population study in West Bengal, India, published in
the March 2003 issue of Epidemiology, showed that the lowest peak
arsenic ingested by a confirmed case of arsenic-induced skin lesions was
115 µg/L.
Among children, chronic arsenic exposure has also been reported to cause
adverse effects on the digestive, respiratory, cardiovascular, and nervous
systems. An article in the September 2004 issue of EHP reported
intellectual impairment occurring when arsenic in drinking water exceeded
50 µg/L.
There is evidence that arsenic-exposed people who are predisposed to noncancerous
skin lesions may be more vulnerable to other cancers. “During our long
field experience in West Bengal and Bangladesh we observed that those who
are suffering from severe keratosis appear more likely to develop cancer
later on,” says Dipankar Chakraborti, director of the School of Environmental
Studies at Jadavpur University in Calcutta. “Not only skin cancer but
internal cancers also may arise in people who show such noncancerous lesions.”
The lung, too, seems to be a major site of action of ingested arsenic. “Lung
cancer is the main cause of arsenic-related death,” says Allan Smith,
director of the Arsenic Health Effects Research Program at the School of
Public Health, University of California, Berkeley. “But we’re
also seeing many noncancer [lung] effects, such as a tenfold [increase in
the] rate of bronchiectasis in people with skin lesions in India.”
The prevalence and incidence of these noncancer manifestations of arsenic
exposure is highly variable from one country to the next. For example, whereas
skin pigmentation and hyperkeratosis are common indicators of arsenic exposure
in Taiwan, it may be more common in India to see respiratory stress, polyneuropathy,
and peripheral vascular disease linked with habitual ingestion of high-arsenic
drinking water. This topic remains a very active area for epidemiologic research.
A World Exposed
Globally, millions of people are at risk for the adverse effects of arsenic
exposure. The majority of harmful arsenic exposure comes from drinking water
from wells drilled through arsenic-bearing sediments. Drinking water contains
primarily inorganic arsenic, which is more acutely toxic than the organic
form. The other major sources of arsenic exposure are through food, soil,
and air. For most people, in fact, the primary exposure to arsenic comes
from food, but dietary arsenic includes primarily organic forms, which are
relatively nontoxic and contribute little, if any, to the overall risk associated
with exposure. (Unless otherwise indicated, all mentions of arsenic in the
remainder of this article refer to the inorganic form.)
Rebecca Calderon, chief of the Epidemiology and Biomarker Branch at the
Environmental Protection Agency (EPA) National Health and Environmental Effects
Research Laboratory, says that preparing foods in arsenic-containing water
increases the arsenic content by 10-30% for most foods, and by 200-250% for
beans and grains, which absorb cooking water. Moreover, arsenic-laced irrigation
water can substantially increase the arsenic content of rice and vegetables,
as recently shown in several studies in Southeast Asia, including a February
2005 Chemosphere report on West Bengal crops and soil.
Soil- and waterborne arsenic does not readily permeate the skin, though
soil can be a key source of exposure in young children who show significant
hand-to-mouth activity. People are also exposed on a more sporadic basis
through a hodgepodge of human activities, such as the burning of fossil fuels,
waste incineration, smelting of ores, pesticide and herbicide use, coal burning,
semiconductor production, and other manufacturing processes. The public health
impact of these exposures is largely unknown as the epidemiologic focus has
been on exposure via drinking water.
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Good intentions gone awry. Villagers
drill a tubewell in Bangladesh (left). Encouraged as a solution to
pathogenic
contamination of surface waters, such wells have resulted in exposure
of millions to arsenic, leading to the need for alternative water sources
(right).
images: Left to right: David Kinniburgh/BGS; Joseph Graziano/Columbia
University
|
For most U.S. citizens who are on piped water systems, drinking water is
not a major source for arsenic exposure. Nonetheless, in certain areas in
the West, Midwest, Southwest, and Northeast, people drinking well water may
be exposed to arsenic levels ranging from 50 to 90 µg/L, well above
the EPA’s guideline of 10 µg/L. To date, no statistically significant
relationships have been found between arsenic exposure and cancer in these
areas.
The situation in Bangladesh and West Bengal is radically different: arsenic
exposure through drinking naturally contaminated groundwater is widespread
and often excessive. This situation began in the 1970s, when the United Nations
Children’s Fund, in response to epidemics of cholera, dysentery, and
other waterborne infectious diseases, spearheaded an effort to switch the
region’s population from drinking surface waters to groundwater. Millions
of tubewells were drilled into arsenic-rich sediments; as a result, in many
of these wells arsenic levels reach 500-1,000 µg/L and even higher.
Field studies have shown that many people living in a vast geological zone
known as the Ganga-Meghna-Brahmaputra plain are being exposed to high arsenic
levels in the water. A large portion of this plain, an area totaling 500,000
square kilometers and spanning all of Bangladesh and most of India, shows
significant groundwater arsenic contamination, putting more than 500 million
people at risk of chronic arsenic poisoning, says Chakraborti. He published
these alarming estimates in the June 2004 issue of the Journal of Environment
Monitoring. With 80% of Bangladeshis estimated to be at risk of arsenic-related
diseases, the World Health Organization (WHO) has labeled this “the
worst mass poisoning in history.”
Large areas of China also face severe arsenic exposure from groundwater
contamination, with more than 3 million people affected, based on estimates
in the August 2004 issue of Toxicology and Applied Pharmacology. In
Shanxi Province alone, an estimated 900,000 people are at risk of arsenicosis.
Among the investigated villages in Shanxi, an average of 52% of wells give
water containing arsenic concentrations higher than 50 µg/L, according
to a recent report from the School of Public Health at China Medical University
in Shenyang.
A unique type of exposure, resulting from the burning of arsenic-rich coal,
is found in Guizhou Province, an area of endemic arsenicosis. Guizhou inhabitants
commonly use this coal for cooking, heating, and drying their dietary staples
of corn and hot peppers. The coal is burned in open stoves without chimneys,
resulting in contamination of both the indoor air and the foods being prepared.
At this time, arsenicosis is known to affect eight provinces, but most of
China has not been studied, and new endemic areas are continuously emerging.
Reports on arsenicosis in China actually preceded those from Bangladesh and
India, but have been overlooked due to limited scientific exchange and publication.
Other countries with arsenic-rich groundwaters include Argentina, Chile,
Mexico, Cambodia, Vietnam, Thailand, Nepal, and Ghana. In the Obuasi area
of Ghana, arsenic contamination of food and water has been linked with gold-mining
activities. Much of the gold in the Obuasi mines is locked in pyrite and
arsenopyrite, both associated with arsenic and sulfur. The extraction of
the gold results in the release of airborne particles that include large
concentrations of arsenic. At least 10% of Ghana’s rural borehole wells
have arsenic concentrations exceeding 10 µg/L. In the Terai region
of Nepal, inhabited by half the country’s total population, hundreds
of thousands of shallow tubewells have been installed by various agencies,
and groundwater is the primary source of drinking water. According to Chakraborti,
around 500,000 people in Terai are at risk of arsenic poisoning from drinking
this water, and up to 1 in 20 people may show skin lesions indicative of
arsenicosis.
The Arsenic-Cancer Equation
Today, researchers around the world are racing against the clock to unravel
the secrets of arsenic’s workings, including how it influences the
cancer process and thereby increases cancer risk. Although inorganic arsenic
is generally held to be more acutely toxic, some researchers argue that the
organic metabolites of arsenic may be the ultimate carcinogens. One of these
metabolites, DMA, has been shown in rodents to induce bladder cancer and
to promote tumor growth in several other organs. A review article focusing
on induced disturbances of calcium homeostasis, genomic damage, and apoptotic
cell death caused by arsenic and its organic metabolites appears in the June
2005 issue of EHP.
There is general agreement that arsenic does not directly interact with
DNA, and that its toxic effects occur through indirect alteration of gene
expression, such as via the perturbation of DNA methylation, inhibition of
DNA repair, oxidative stress, and altered modulation of signal transduction
pathways. Many of these mechanisms are overlapping, interdependent, and heavily
influenced by factors in the cellular environment. For example, arsenic promotes
both oxidative stress and impaired DNA repair, and yet both of these effects
tend to amplify mutation rates, thus increasing the likelihood of cancer.
|
Coal catastrophe. Cyclists on their way to work in
Guizhou Province, China, pass through smoke pouring out of a coal-burning
cooking stove. Exposure to the arsenic-rich coal burned in this region
has resulted in endemic arsenicosis.
images: Mark Henley/Panos Pictures
|
Another indirect mechanism is the influence of growth-stimulating chemicals
or cytokines generated in response to arsenic exposure. Dori Germolec, a
research scientist at the NIEHS Laboratory of Molecular Toxicology, has been
approaching the arsenic question from the standpoint of cytokine biology. “Arsenic
alters the production of inflammatory cytokines and does so persistently
over time,” Germolec says. “These effects on cytokines seem to
relate to its effects on the skin. Arsenic seems to stimulate progenitor
cells that could ultimately be responsible for tumor formation. This is just
one of a number of mechanisms that has biological plausibility.” Research
published in the April 2004 issue of EHP by Toby Rossman, an
environmental science professor and program director of the Molecular and
Genetic Toxicology Program at New York University, has demonstrated similar
relationships in animal models as well as in cultured human cells.
Studies of differences in arsenic metabolism between individuals have led
to further insights--and further questions. The importance of individual
arsenic metabolites in terms of cancer induction is still being determined.
All of the human populations studied thus far have been found to methylate
inorganic arsenic, but the patterns of arsenic metabolites in urine show
substantial interindividual variation. Within any given population, individuals
differ in the quantity and distribution of the various metabolites of arsenic
excreted by the kidney. If some happen to excrete more of the carcinogenic
metabolites or are unable to metabolize arsenic efficiently, they may be
more vulnerable to cancer. This variation may be affected by a variety of
factors, including dose level, route(s) of exposure, diet, and the particular
type of arsenic to which the individual is exposed. Polymorphisms in genes
that code for the enzymes important in metabolism, such as arsenic methyltransferase,
have also been implicated as accounting for some of this variability.
No one yet knows how this interindividual variation in arsenic metabolism
actually affects cancer risk. “This is a difficult question since when
you deal with the carcinogenicity of inorganic arsenic you are dealing with
six or more distinct [metabolites],” says H. Vasken Aposhian, a molecular
and cell biology professor at the University of Arizona. Aposhian is involved
in studies in New England, Mongolia, Romania, Mexico, and Kazakhstan to identify
unique or abnormal arsenic urine profiles in people who develop cancer in
areas of high arsenic exposure. Once studies reveal which of these metabolites
are promoters and/or carcinogens, it will be possible to better answer the
riddle of interindividual variation in vulnerability to arsenic-induced effects.
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Fool’s gold? Gold mining in areas of Ghana such
as the Ashanti Goldfields in Obuasi results in the release of airborne
arsenic particles that also have been linked to food and water contamination..
images: Jacob Silberberg/Panos Pictures
|
The metabolite MMAIII presently is one of the leading candidates as a potential
cancer inducer. If MMAIII turns out to be carcinogenic, an increased or decreased
amount in the urine might prove useful as a marker for potential future arsenic-mediated
cancer.
In time, the identification of reliable exposure markers could help identify
groups that may be more susceptible to cancer at the levels of arsenic exposure
typically found in the United States (less than 50 µg/L). At the present
time, the carcinogenic risk of such exposures is unclear. Biomarkers would
provide a more detailed picture of individual arsenic exposure and how the
body is responding to that exposure. “The low-dose extrapolations used
for risk assessment purposes may be subject to error in part because they
are based more on ecologic data than on individual measures of exposure,” says
Margaret Karagas, an epidemiology professor at Dartmouth College. “Use
of relevant markers in human tissue samples eventually may help us sort out
the risk at lower levels of exposure.”
One practical biological marker identified by Karagas is toenail clippings,
with arsenic content measured via instrumental neutron activation analysis.
Using this measure, she and her colleagues reported in the June 2004 issue
of Cancer Causes & Control on a case-control study in New
Hampshire suggesting an increased cancer risk associated with moderate arsenic
exposure, but only in smokers.
An Emerging Consensus: Arsenic Does Not Act Alone
Studies such as Karagas’s point to the growing recognition that arsenic
does not always operate alone. Rather, arsenic appears to work with other
factors to promote cancer, at least at some target sites. “Animal models
indicate it takes a promoter or some genotoxic carcinogen to get arsenic
to produce skin cancers,” says Michael Waalkes, section chief of the
Inorganic Carcinogenesis Section at the National Cancer Institute Laboratory
of Comparative Carcinogenesis, housed at the NIEHS. “When you always
see this kind of cotreatment effect, it makes it harder to nail down the
precise contribution of arsenic to the final tumor.”
The classic cofactor in this regard may be tobacco smoke. “There
is mounting evidence of a malignant synergy between smoking and arsenic,” says
Smith. “Smokers are at an increased risk from arsenic in drinking water
and appear to comprise a susceptible subpopulation.” A study by Smith
and colleagues, published in the November 2000 issue of Epidemiology,
found that the relative risk of lung cancer for Chileans who smoked and had
high arsenic in their water was 32 times that of nonsmokers with low arsenic
concentrations in their water. In contrast, the lung cancer risk of smokers
without arsenic in their water was about 6 times that of nonsmokers. Similar
findings have come from studies in Taiwan and New Hampshire.
Other cofactors are also gaining attention. Rossman’s group was among
the first to hypothesize that arsenic requires a carcinogenic partner--in
their April 2004 EHP article and another in the 1 August 2004 issue
of Toxicology and Applied Pharmacology, they reported finding that
arsenic plus ultraviolet (UV) radiation exposure led to a dose-related increase
in skin cancers in mice compared with mice exposed to UV light alone. The
tumors in mice treated with arsenite plus UV light also appeared earlier
and were larger and more invasive than those in mice exposed to UV light
alone. At the 2004 Third International Conference on Comparative Physiology
and Biochemistry, Rossman reported that selenium deficiency also enhanced
the carcinogenic effects of arsenic.
Such insights may carry over to the epidemiological realm. In Bangladesh
and West Bengal, for example, the most likely cofactors for arsenicosis include
malnutrition (with resulting deficiency of selenium and other nutrients that
can affect arsenic metabolism) and agricultural activities that lead to frequent
sun exposure. Not only does selenium seem to help protect against the toxic
effects of chronic arsenic exposure, but high levels of chronic arsenic ingestion
from well water may accelerate the excretion of selenium, according to research
published in the 5 May 2004 issue of Science of the Total Environment.
“We need to find out whether Bangladesh and other poverty-stricken
countries with arsenic-tainted groundwater may benefit by this relatively
cheap strategy of supplementing the diet with selenium,” says Floyd
Frost, an epidemiologist at the Lovelace Respiratory Research Institute in
Albuquerque. “We need solutions that are cheap and doable. If you’re
in Bangladesh, there just isn’t much money for expensive mitigation
strategies.”
However, Smith notes that he and colleagues found only modest increased
risks in West Bengal with some dietary deficiencies. He and others contend
that the top priority should be to reduce arsenic exposure. Other approaches
being explored include rainwater collection, novel filtration systems, chelation,
and deep community wells, as well as the use of antioxidants, methionine
(an amino acid), and other dietary supplements that may limit arsenic’s
toxicity. [For more information on remediation strategies, see “Columbia
Center Digs Deeper into Arsenic Dilemma” and “Metal Attraction:
An Ironclad Solution to Arsenic Contamination?” p. A374 and A398 this
issue.]
A Special Population: The Very Young
Infants and children are deemed to be more susceptible than adults to the
adverse effects of arsenic and other toxic substances. Chakraborti has observed
that arsenical skin lesions show up sooner in children than they do in adults.
If the child’s nutrition is poor, outward signs of arsenic toxicity
manifest even sooner and at less extreme levels of exposure. An additional
concern is the potential for increased sensitivity of children to arsenic-associated
neuropsychological effects such as reduced verbal IQ scores, as reported
in the September 2004 issue of EHP.
Chakraborti speculates that infants and children may be intrinsically more
susceptible than adults due to differences in metabolism, a view supported
by some preliminary studies. “In one of our studies on an arsenic-affected
population in Bangladesh, we found that the second step in arsenic metabolic
pathways is more active in exposed children in comparison with exposed adults,” he
says. In the June 2005 issue of EHP, Maria Mercedes Meza and colleagues
identified a developmentally restricted component of arsenic metabolism,
a genetic association with urinary arsenic metabolites that applied only
to children.
Complicating this scenario is the special threat posed by in utero exposure
to arsenic. One of the concerns here is that low-level exposures may have
a greater impact if experienced in utero than if experienced in childhood
or adulthood. Waalkes and his colleagues were the first to identify the transplacental
carcinogenic potential of arsenic. They duplicated this finding in several
rodent studies, reported in the 1 August 2004 issue of Toxicology and
Applied Pharmacology and the 20 May 2004 issue of Toxicology.
“The critical window of exposure for mice equates to about the middle
three months of pregnancy in humans,” says Waalkes. “This could
lead to a fifty percent increase in the risk of hepatocellular carcinoma
for adults. This is a reproducible phenomenon, and it has alarming implications
for in utero exposures in humans.” The first half of fetal
development is a period of very high sensitivity because of a high rate of
cell proliferation, cell differentiation, and gene imprinting, all of which,
when disrupted, can lead to carcinogenesis.
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Special
victims. New information indicates that children metabolize arsenic differently
than adults, and provides compelling reason to further study the effects
of the element in vulnerable populations. |
images: Left to right: Joseph Graziano/Columbia
University; Jim Holmes/Panos Pictures
|
Smith’s studies of bladder and lung cancers also have indicated that
there may be a long latency--40 years or more for these cancers--from arsenic
exposure to the manifestation of malignant disease. For example, he has found
very high lung cancer risks in Chilean adults who were exposed as children
or in utero. He notes that it is critically important to study large
populations with significant and well-documented arsenic exposure. Smith
says Chile has the best-documented exposure in the world.
“In any country where people are exposed to high levels of arsenic,
if nothing else is done, they should focus on protecting pregnant women,
providing them with low-arsenic water,” says Waalkes. “That would
be my top priority if I could advise the governments of those countries on
what to do.”
How Much Protection Is Enough?
Although the effects of severe arsenic contamination are well established,
there is much debate about the risk associated with chronic ingestion of
drinking water that contains arsenic levels lower than regulatory standards.
The WHO adopted a standard of 10 µg/L in 1993. Bangladesh and many
other developing countries use a guideline of 50 µg/L. Beginning in
January 2006 the maximum contaminant level for inorganic arsenic permitted
in U.S. drinking water will be 10 µg/L, although scientists still debate
this standard.
Part of the uncertainty regarding the 10 µg/L standard stems from
the absence of epidemiologic data to help determine the exact shape of the
dose-response curve, particularly at exposures under 10 µg/L. Cancer
risks at these levels of exposure may be about 1 in 300 people, according
to the National Research Council report Arsenic in Drinking Water: 2001
Update. However, says Smith, epidemiology will never prove such risks
are real. He points to the fact that large numbers of studies throughout
the world were required to eventually demonstrate that nonsmokers married
to smokers had an increased risk of lung cancer, even though such risk involves
about 1 in 100 persons.
Still, some argue that different study designs and larger sampling will,
in time, provide adequate data to answer the question of whether there is
a level of arsenic exposure below which health effects do not develop. In
the interim, the precautionary principle holds sway; policy makers assume
that the burden of proof for potentially harmful actions or policies rests
on the assurance of safety, and that when there are threats of cancer or
other serious diseases, scientific uncertainty must be resolved in favor
of prevention.
Acceptance of the limitations of epidemiologic research in detecting the
risk associated with low-level exposures lies at the very heart of this principle. “It
is possible that the effects may be nonlinear, with certain extremely low
levels of arsenic exposure posing no excess risk,” says Karagas. “In
epidemiologic studies, however, it is important to distinguish between ‘no
effect’ and ‘inability to detect an effect’ due to various
methodological limitations.”
There is also, she says, a critical need for further data on other health
outcomes and in potentially susceptible subgroups such as pregnant women
and children, and those particularly at risk due to genetic or lifestyle
factors. By studying the whole population but not susceptible subgroups,
scientists may be missing key pieces to the arsenic puzzle.
Hamilton concurs but emphasizes a more mechanism-based rationale. He theorizes
that arsenic at different doses may act by different mechanisms, perhaps
producing different patterns of disease. For example, the patterns of disease
in areas such as Bangladesh that have high and endemic arsenic contamination
may be quite different than the patterns seen at the lower doses encountered
elsewhere. “We have observed an almost completely nonoverlapping pattern
of gene expression changes with a low versus a high dose of arsenic, almost
as if they were two different agents,” says Hamilton.
“At the lower, noncytotoxic dose,” he explains, “we saw
an approximately equal number of genes that were increased as were decreased,
whereas at the higher, cytotoxic dose, virtually all of the significant changes
involved activation of genes.” Most of the genes in the latter case
were members of stress response and apoptosis pathways. Taken together with
Hamilton’s studies of the endocrine-disrupting effects of low to moderate
arsenic levels, this indicates the importance of examining arsenic at doses
that are directly relevant to the end point of interest.
On the Threshold of a New Understanding
A major challenge for future research is the issue of linking genetic polymorphisms
with arsenic-related disease susceptibility. “Since arsenic metabolism
seems to be a key to the carcinogenic process, sorting out these polymorphisms
will be important, but this is extremely difficult to do,” says Julian
Preston, director of the EPA’s Environmental Carcinogenesis Division
and a member of the committee that produced Arsenic in Drinking Water:
2001 Update. “You need to see a very strong association between
a particular polymorphism and the cancer end point in order to establish
a link.” To date, a few polymorphisms have been identified in an indigenous
population in Chile that may confer protection against the carcinogenic effects
of arsenic exposure, but the findings are only suggestive.
Given that humans appear to be substantially more sensitive than experimental
animals to arsenic-induced cancers, more epidemiologic research will be needed
to assess the effects of early-life exposures for child as well as adulthood
cancers. “Humans remain the most sensitive species when it comes to
understanding the toxicity of arsenic,” says Calderon. “Despite
several attempts to use rodents and other animal species, those assays and
experiments have had limited success in explaining what appears to be a rather
unique response on the part of Homo sapiens to arsenic. This
represents a unique challenge, and perhaps the keys reside in emerging areas
of genomics, proteomics, or molecular epidemiology.” Childhood exposure
to arsenic has emerged as a potential regulatory concern.
Arsenic contamination of drinking water is among the most awesome environmental
health challenges of our time. With hundreds of millions of people affected
in Southeast Asia and elsewhere, the need for effective arsenic mitigation
strategies has never been greater. Thus the focus is moving beyond exposure
to include those physiologic variables that may mediate the effects of exposure
and that correlate with adverse effects in humans.
Exposures associated with arsenic due to cooking and agricultural activities
(including herbicide and pesticide use) should be explored, along with the
identification and control of other carcinogenic compounds that may act as
cocarcinogens. Such efforts could, in time, result in profound public health
benefits and alleviate a great deal of suffering.
For people living in areas where arsenic exposure is less extreme, the
question of whether arsenic is safe below a certain dosage level remains
central. Many scientists assert that only biological data based on measurements
of the variation in human metabolic responses to arsenic will resolve the
low-dose controversy. Such data will pave the way for developing biologically
based dose-response models that should greatly enhance our understanding
of arsenic’s carcinogenic potential. Only with persistent inquiry and
innovative investigation will the elemental mystery of arsenic be solved.