Arsenic Data from E.P.A.
These excerpts have been taken from the E.P.A. Federal Register. For a full version of the article please visit;
E.P.A. Federal Register
``No human studies of sufficient statistical power or scope have examined whether consumption of arsenic in drinking water at the current MCL results in an increased incidence of cancer or noncancer effects (NRC, 1999, pg. 7).''
There have only been a few studies of inorganic arsenic exposure
via drinking water in the U.S., and most have not considered cancer as
an endpoint. People have written EPA asking that the new MCL be set
considering that these U.S. studies have not seen increases in cancers
at the low levels of arsenic exposure in U.S. drinking water.
A large number of adverse noncarcinogenic effects have been
reported in humans after exposure to drinking water highly contaminated
with inorganic arsenic. The earliest and most prominent changes are in
the skin, e.g., hyper pigmentation and keratoses (callus-like growths).
Other effects that have been reported include alterations in
gastrointestinal, cardiovascular, hematological (e.g., anemia),
pulmonary, neurological, immunological and reproductive/developmental
function (ATSDR, 1998).
The most common symptoms of inorganic arsenic exposure appear on
the skin and occur after 5-15 years of exposure equivalent to 700
µg/day for a 70 kg adult, or within 6 months to 3 years at
exposures equivalent to 2,800 µg/day for a 70 kg adult (pg. 131
NRC, 1999). They include alterations in pigmentation and the
development of keratoses which are localized primarily on the palms of
the hands, the soles of the feet and the torso. The presence of
hyper pigmentation and keratoses on parts of the body not exposed to the
sun is characteristic of arsenic exposure (Yeh, 1973, Tseng, 1977). The
same alterations have been reported in patients treated with Fowler's
solution (1% potassium arsenite; Cuzick et al., 1982), used for asthma,
psoriasis, rheumatic fever, leukemia, fever, pain, and as a tonic (WHO
1981 and NRC 1999).
Although peripheral neuropathy (numbness, muscle weakness, tremors,
ATSDR 1998) may be present after exposure to short-term, high doses of
inorganic arsenic (Buchanan, 1962; Tay and Seah, 1975), there are no
studies that definitely document this effect after exposure to levels
of less than levels (50 µg/L) of inorganic arsenic in drinking
There have been a few, scattered reports in the literature that
inorganic arsenic can affect reproduction and development in humans
(Borzysonyi et al., 1992; Desi et al., 1992; Tabacova et al., 1994).
After reviewing the available literature on arsenic and reproductive
effects, the National Research Council panel (NRC 1999) wrote that
``nothing conclusive can be stated from these studies.''
Based on the studies mentioned in this section, it is evident that
inorganic arsenic contamination of drinking water can cause dermal and
internal cancers, affect the GI system, alter cardiovascular function,
and increase risk of diabetes, based on studies of people exposed to
drinking water well above the current arsenic MCL. EPA's MCL is chosen
to be protective of the general population within an acceptable risk
range, not at levels at which adverse health effects are routinely seen
(see section III.F.7. on risk considerations).
In terms of implications for the risk assessment, the panel noted
that risk per unit dose estimates from human studies can be biased
either way. For the Taiwanese study, the ``* * * biases associated with
the use of average doses and with the attribution of all increased risk
to arsenic would both lead to an overestimation of risk (US EPA, 1997d,
May 1999 Utah Mortality Study
EPA scientists conducted an epidemiological study of 4,058 Mormons
exposed to arsenic in drinking water in seven communities in Millard
County, Utah (Lewis et al., 1999). The 151 samples from their public
and private drinking water sources had arsenic concentrations ranging
from 4 to 620 µg/L with seven mean (arithmetic average)
community exposure concentrations of 18 to 191 µg/L and all
seven community exposure medians (mid-point of arsenic values) 200
µg/L. Observed causes of death in the study group (numbering
2,203) were compared to those expected from the same causes based upon
death rates for the general white male and female population of Utah.
Several factors suggest that the study population may not be
representative of the rest of the United States. The Mormon church, the
predominant religion in Utah, prohibits smoking and consumption of
alcohol and caffeine. Utah had the lowest statewide smoking rates in
the U.S. from 1984 to 1996, ranging from 13 to 17%. Mormon men had
about half the cancers related to smoking (mouth, larynx, lung,
esophagus, and bladder cancers) as the U.S. male population from 1971
to 1985 (Lyon et al., 1994). The Utah study population was relatively
small (4,000 persons) and primarily English, Scottish, and
Scandinavian in ethnic background.
While the study population males had a significantly higher risk of
prostate cancer mortality, females had no significant excess risk of
cancer mortality at any site. Millard County subjects had higher
mortality from kidney cancer, but this was not statistically
significant. Both males and females in the study group had less risk of
bladder, digestive system and lung cancer mortality than the general
Utah population. The Mormon females had lower death rates from breast
and female genital cancers than the State rate. These decreased death
rates were not statistically significant.
Although deaths due to hypertensive heart disease were roughly
twice as high as expected in both sexes, increases in death did not
relate to increases in dose, calculated as the years of exposure times
the median arsenic concentration. The Utah data indicate that heart
disease should be considered in the evaluation of potential benefits of
U.S. regulation. Vascular effects have also been reported as an effect
of arsenic exposure in studies in the U.S. (Engel et al. 1994), Taiwan
(Wu et al., 1989) and Chile (Borgono et al., 1977). The overall
evidence indicating an association of various vascular diseases with
arsenic exposure supports consideration of this endpoint in evaluation
of potential noncancer health benefits of arsenic exposure reduction.
Study of Bladder and Kidney Cancer in Finland
Kurttio et al. (1999) conducted a case-cohort design study of 61
bladder and 49 kidney cancer cases and 275 controls to evaluate the
risk of these diseases with respect to arsenic drinking water
concentrations. In this study the median exposure was 0.1 µg/L,
the maximum reported was 64 µg/L, and 1% of the exposure was
greater than 10 µg/L. The authors reported that very low
concentrations of arsenic in drinking water were significantly
associated with being a case of bladder cancer when exposure occurred
2-9 years prior to diagnosis. Arsenic exposure occurring greater than
10 years prior to diagnosis was not associated with bladder cancer
risk. Arsenic was not associated with kidney cancer risk even after
consideration of a latency period.
The NRC report examined the question of essentiality of arsenic in
the human diet. It found no information on essentiality in humans and
only data in experimental animals suggesting growth promotion
(arsenicals are fed to livestock for this reason). Inorganic arsenic
has not been found to be essential for human well-being or involved in
any required biochemical pathway. Given this and the fact that arsenic
occurs naturally in food, consideration of essentiality is not
necessary for public health decisions about water.
The NRC report concluded: ``For arsenic carcinogenicity, the mode
of action has not been established, but the several modes of action
that are considered plausible (namely, indirect mechanisms of
mutagenicity) would lead to a sublinear dose-response curve at some
point below the point at which a significant increase in tumors is
observed. * * * However, because a specific mode (or modes) of action
has not yet been identified, it is prudent not to rule out the
possibility of a linear response.''
Given the current outstanding questions about human risk at low levels of exposure, decisions about safe levels are public health policy judgments.
In 1983 the National Academy of Sciences (NAS, 1983) defined risk
assessment as containing four steps: hazard identification, dose-
response assessment, exposure assessment, and risk characterization.
Risk characterization is the process of estimating the health effects
based on evaluating the available research, extrapolating to estimate
health effects at exposure levels, and characterizing uncertainties. In
risk management, regulatory agencies such as EPA evaluate alternatives
and select the regulatory action. Risk management considers
``political, social, economic, and engineering information'' using
value judgments to consider ``the acceptability of risk and the
reasonableness of the costs of control (NAS, 1983).''
Unlike most chemicals, there is a large data base on the effects of
arsenic on humans. Inorganic arsenic is a human poison, and oral or
inhalation exposure to the chemical can induce many adverse health
conditions in humans. Specifically oral exposure to inorganic arsenic
in drinking water has been reported to cause many different human
illnesses, including cancer and noncancer effects, as described in
Section III. The NRC panel (1999) reviewed the inorganic arsenic health
effects data base. The panel members concluded that the studies from
Taiwan provided the current best available data for the risk assessment
of inorganic arsenic-induced cancer. (There are corroborating studies
from Argentina and Chile.) They obtained more detailed Taiwanese
internal cancer data and modeled the data using the multistage Weibull
model and a Poisson regression model. Three Poisson data analyses
showed a 1% response level of male bladder cancer at approximately 400
µg of inorganic arsenic/L. The 1% level was used as a Point of
Departure (POD) for extrapolating to exposure levels outside the range
of observed data.
For an agent that is either acting by reacting directly with DNA or
whose mode of action has not been sufficiently characterized, EPA's
public health policy is to assume that dose and response will be
proportionate as dose decreases (linearity of the extrapolated dose-
response curve). This is a science policy approach to provide a public
health conservative assessment of risk. The dose-response relationship
is extrapolated by taking a straight line from the POD rather than by
attempting to extend the model used for the observed range. This
approach was adopted by the NRC report which additionally noted that
using this approach for arsenic data provides results with alternative
models that are consistent at doses below the observed range whereas
extending the alternative models below the observed range gives
inconsistent results. Drawing a straight line from the POD to zero
gives a risk of 1 to 1.5 per 1,000 at the current MCL of 50 µg/
L. Since some studies show that lung cancer deaths may be 2- to 5-fold
higher than bladder cancer deaths, the combined cancer risk could be
even greater. The NRC panel also noted that the MCL of 50 µg/L
is less than 10-fold lower than the 1% response level for male bladder
cancer. Based on its review, the consensus opinion of the NRC panel was
that the current MCL of 50 µg/L does not meet the EPA's goal of
public-health protection. Their report recommended that EPA lower the
MCL as soon as possible.
A factor that could modify the degree of individual response to
inorganic arsenic is its metabolism. There is ample evidence (NRC,
1999) that the quantitative patterns of inorganic arsenic methylation
vary considerably and that the extent of this variation is unknown. It
is certainly possible that the metabolic patterns of people affect
their response to inorganic arsenic.
There are studies underway in humans and experimental animals under
the EPA research plan and other sponsorships. Over the next several
years these will provide better understanding of the mode(s) of
carcinogenic action of arsenic, metabolic processes that are important
to its toxicity, human variability in metabolic processes, and the
specific contributions of various food and other sources to arsenic
exposure in the U.S. These are important issues in projecting risk from
the observed data range in the epidemiologic studies to lower
environmental exposures experienced from U.S. drinking water.
Until further research is completed, questions will remain regarding the dose-response relationship at low environmental levels.
The several Taiwan studies have strengths in their long-term observation of exposed persons and coverage of very large populations
(>40,000 persons). Additionally, the collection of pathology data was
unusually thorough. Moreover, the populations were quite homogeneous in
terms of lifestyle. Limitations in exposure information exist that are
not unusual in such studies. In ecological epidemiology studies of this
kind, the exposure of individuals is difficult to measure because their
exposure from water and food is not known. This results in
uncertainties in defining a dose-response relationship. The studies in
Chile and Argentina are more limited in extent, (e.g., years of
coverage, number of persons, or number of arsenic exposure categories
analyzed), but provide important findings which corroborate one another
and those of the Taiwan studies.
These epidemiological studies provide the basis for assessing potential risk from lower concentrations of inorganic arsenic in drinking water, without having to adjust for cross-species toxicity interpretation. Ordinarily, the characteristics of human carcinogens can be explored and experimentally defined in test animals. Dose-response can be measured, and animal studies may identify internal transport, metabolism, elimination, and subcellular events that explain the carcinogenic process. Arsenic presents unique problems for quantitative risk assessment because there is no test animal species in which to study its carcinogenicity. While such studies have been undertaken, it appears that test animals, unlike humans, do not respond to inorganic arsenic exposure by developing cancer. Their metabolism of inorganic arsenic is also quantitatively different than humans.
Inorganic arsenic does not react directly with DNA. If it did, it would
be expected to cause similar effects across species and to cause response in a proportionate relationship to dose. Moreover, its metabolism, internal disposition, and excretion are different and vary
across animal and plant species and humans--in test studies and in
Until more is known, EPA will take a traditional, public health
conservative approach to considering the potential risks of drinking
water containing inorganic arsenic. EPA recognizes that the traditional
approach may overestimate risk, as explained in the next section.
Most of the 25-States data had reporting limits of less than 2
µg/L. In addition, the database includes multiple samples from
the water systems over time and from multiple sources within the
systems. The multiple samples provide for a more accurate estimate of
the arsenic levels in the systems, than a survey with one sample per
system. The arsenic compliance monitoring data provides point-of-entry
or well data within systems from eight States, which is used for
intrasystem variability analysis (discussed in Section V.G).
Intrasystem variability analysis provides an understanding of the
variation of arsenic levels within a system, from well to well or entry
point to entry point.