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OCR for page 169
Quantitative Assessment of Risks
Using Docketing Approaches
OVERVIEW OF TlIE SCIENCE UNDERLYING
EPA'S 2001 PROPOSED REGULATION
On January 22, 2001, following the publication of a proposed rule for
arsenic in drinking water (EPA 2000a) and a period of public comment, EPA
published a final rule for arsenic in drinking water in the Federal Register,
setting a maximum contaminant level goal (MECG) of zero for arsenic in
drinking water and a maximum contaminant level (MCL) for arsenic of 10 fig
in drinking water (EPA 2001~. Typically, when developing an MUNG and an
MCL, a risk assessment is conducted. Two important components of a risk
assessment are hazard identification and dose-response assessment ARC
1983~. Exposure assessment end risk characterization are also important steps
in a risk assessment, but they are beyond the scope of this subcommittee's
charge and, therefore, will not be discussed here. The purpose of hazard
identification is to determine whether the agent in question causes adverse
effects. Deciding which end point is the most sensitive and which studies or
data sets are most appropriate for assessing the risks from a chemical are
major conclusions from a hazard identification. In the case of EPA's assess-
ment of arsenic, the risk being assessed is the risk to the U.S. population from
consumption of arsenic in drinking water. The purpose of dose-response
assessment is to determine the relationship between the dose and the incidence
of an adverse effect in humans. Major conclusions from the dose-response
169
OCR for page 170
~ 70 ARSENIC IN DRINKING WA TER: 2001 UPDA TE
assessment include the model or models that can be used to best determine the
risks to the U.S. population from arsenic in drinking water and understanding
ofthe impacts of different model choices on the risk estimates from that analy-
sis. The details of EPA's hazard identification (choice of endpoint and choice
of study) and dose-response assessment (choice of model, selection of a com-
parison group, and adjustments for water intake, diet, and mortality versus
incidence) are discussed below.
Hazard Identification
Choice of End Point
EPA' s hazard analysis is included in Section m ofthe proposed rule (EPA
2000a) and in Section m.D. ~ of the final rule (EPA 2001~. EPA "relied upon
the NRC ~ ~ 999] report as presenting the best available, peer reviewed science
as of its completion and has augmented it with more recently published, peer
reviewed information" in its proposed rule. EPA (2000a) concludes that acute
or short-term effects are not seen at 50,ug/L (the MCL at the time of the pro-
posal) and, therefore, addresses the "Iong-term, chronic effects of exposure to
Tow concentrations of inorganic arsenic in drinking water."
With respect to Tong-term effects, EPA concludes that "arsenic is a multi-
site human carcinogen by the drinking water route," and on the basis of epide-
miological studies of Asian, Mexican, and South American populations, those
"with exposures to arsenic in drinking water generally at or above several
hundred micrograms per liter are reported to have increased risks of skin,
bladder, and lung cancer." EPA also notes that increased risk of liver and
kidney cancer have been associated with arsenic exposure and that skin cancer
has been associated with inorganic arsenic contamination in Argentina (re-
viewed by Neubauer 1947, as cited in EPA 2000a), in Poland (EPA 2000a),
and in a dose-dependent manner following exposure to arsenic in drinking
water in Taiwan (Tseng et al. 196S, Tseng 19774. Other epidemiological
studies also support an association between arsenic exposure and skin cancer
(Roth 1956; Albores et al. 1979; Cuzick et al. 1982; Cebrian et al. 1983~.
EPA discussed data from two studies in Taiwan demonstrating a statisti-
cally significant increase in mortality risks for bladder, kidney, lung, liver, and
colon cancer (Chen et al.1985), and a significant dose-response relationship
for death from bladder, kidney, skin, and lung cancer in both sexes and from
OCR for page 171
QUANTITATIVE ASSESSMENT OF RISKS USING MODELING APPROACHES ~ 71
liver and prostate cancer in males (Wu et al. ~ 989~. An increase in internal
cancers was also seen in Argentina (bladder, lung, and kidney cancer)
(Hopenhayn-Rich et al. 1996, 1998) and in Chile (bladder, kidney, and lung
cancer) (Smith et al. 1998~. Tsai et al. (1999) reported that lung, bladder,
intestinal, rectal, and laryngeal cancer were associated with chronic exposure
to arsenic in drinking water in Taiwan. EPA also reviewed a study by Lewis
et al. ~ 1999) that reported mortality of a population in Utah exposed to lower
concentrations (average, 18-191 ~g/~) of arsenic in drinking water in which
there was a statistically significant increase in prostate-cancer mortality, but
no increase in bladder or lung cancer mortality. EPA also discussed a study
by Kurttio et al. (1999) that found a significant association in a case-control
study in Finland between bladder cancer and exposure to very Tow concentra-
tions of arsenic in drinking water (odds ratio of ~ .53,95% confidence interval
(C~ = 0.75-3.09 at 0.1-0.5,ug/~; 2.44,95% C! = ~ . ~ l-5.37 at greater than 0.5
,ug/~. No association was seen for kidney cancer.
EPA reviewed noncancer effects that are observed following chronic
exposure to arsenic including dermal effects (Yeh 1973; Tseng 1977; Cuzick
et al. 1982), gastrointestinal effects (Morris et al. 1974; Nevens et al. 1990;
Mazumder et al. 1997), peripheral vascular disease (Tseng 1977; Zaldivar
~ 974; Cebrian ~ 987; Lewis et al. ~ 999), and diabetes (Lad et al. ~ 994; Rahman
and Axelson 1995; Rahman et al. 1998~.
in the final rule, EPA again summarized the acute and chronic effects of
arsenic, and added a discussion of a study from Japan (Tsuda et al. 1995~.
The study found an association between exposure to arsenic in drinking water
and lung and bladder cancer. in addition, EPA (2001) added a short discus-
sion on the potential susceptibility of children to arsenic. EPA agreed with the
conclusion of the majority of the EPA Science Advisory Board (SAB) mem-
bers (EPA 2000b) that children are generally at greater risk for a toxic re-
sponse to any agent in water because of their greater drinking-water consump-
tion (on a unit-body-weight basis), but that the available data, including a
study of infant mortality in Chile (Hopenhayn-Rich et al. 2000), do not dem-
onstrate a heightened susceptibility to arsenic.
After discussing all the toxic effects of arsenic, the water concentrations
at which they occur, and the NRC (1999) report, EPA chose cancer as the
most sensitive end point, stating that it "focused its risk assessment on the
carcinogenic effects of inorganic arsenic" (EPA 2000a). EPA (2001) states
that lung and bladder cancer are the internal cancers most consistently seen
and best characterized in epidemiological studies, and its quantitative risk
assessment is based on data for those two cancers.
OCR for page 172
72 ARSENIC IN DRINKING WA TER: 2001 UPDA TE
Choice of Study
An important decision in a quantitative risk assessment is the choice of
critical study (or studies) to be used in the dose-response assessment. At the
time of EPA's proposed rule, few animal carcinogenicity bioassays had been
conducted for arsenic, and there were no positive animal models for dose-
response modeling. There was, however, a "large data base on the effects of
arsenic on humans" (EPA 2000a, p. 38902~. EPA concluded that questions
remain about the shape of the dose-response relationship at Tow concentra-
tions. The advantages of using the studies from southwestern Taiwan (Chen
et al. 1985; Wu et al. 1989) for quantitative risk assessment, according to
EPA, are the duration of exposure and follow-up, the size of the population
(more than 40,000 individuals), the extensive pathology data, and the homoge-
nous lifestyles ofthe population. Those studies are limited, however, by their
design (i.e., they are ecological epidemiology studies), which makes quantita-
tive evaluation of dose-response relationships more difficult. EPA also stated
that the studies from Chile (Smith et al. 1998) and Argentina (Hopenhayn-
Rich et al.1996; 1998) are more limited than the Taiwanese studies (Chen et
al. 1985; Wu et al. 1989) and not suitable for quantitative dose-response as-
sessment, but that they provide supportive evidence for the effects seen in
southwestern Taiwan. EPA concluded that "tt~hese epidemiological studies
provide the basis for assessing potential risk from Tower concentrations of
inorganic arsenic in drinking water" (EPA 2000a, p.38902~. In its final rule,
EPA also concluded that the Utah study by Lewis et al. (1999) "is not power-
ful enough to estimate excess risks with enough precision to be useful for the
Agency's arsenic risk analysis."
Therefore, in its final rule, EPA (2001) still considered the southwestern
Taiwan data to be the critical data set for conducting a quantitative risk assess-
ment for exposure to arsenic in drinking water.
Dose-Response Modeling
Model Choice and Selection of a Comparison Group
In its proposed arsenic rule, EPA concluded, on the basis of the NEC
(1999) report, that there is "no basis for determining the shape of a sublinear
dose-response curve for inorganic arsenic" (EPA 2000a). Therefore, EPA
estimated the risks of cancer from exposure to arsenic in drinking water using
OCR for page 173
QUANTITA TI BE ASSESSMENT OF RISKS USING MODELING APPROA CHES ~ 73
a linear extrapolation from the data observed in the southwestern Taiwanese
epidemiological studies down to the origin. EPA's default to a linear extrapo-
lation in the absence of adequate mode-of-action data (EPA ~ 996) is in part
a policy decision. For the proposed rule, EPA used the bladder cancer risk
estimates presented in the NRC (1999) report (see Table 5-1 for examples).
EPA cited a lifetime risk estimate with a 95% upper confidence limit of ~ to
~ .347 per 1,000, calculated by a Poisson regression mode] not using any base-
line data (i.e., no comparison group) (NRC 1999), and EPA used four distribu-
tions of risk estimates (mean and 95% CT) from NRC (1999) as representative
risks in a Monte Cario analysis to estimate the potential health benefits from
the proposed rule. Those four distributions all come from analyses of the
southwestern Taiwanese data (Chen et al. 1985; Wu et al. 1989) using a Pois-
son regression model with age entered as a quadratic function and dose en-
tered as a linear function, either with or without baseline data, or a Poisson
regression mode] with a point-of-departure approach, with or without baseline
data.
On October 20, 2000, EPA published a Notice of Data Availability in the
Federal Register (EPA 2000b) in which it discussed statistical modeling
published by Morales et al. (2000) and indicated that those analyses would be
considered in its final rule for arsenic in drinking water. Morales et al. (2000)
estimated bladder, lung, and liver cancer risks for the southwestern Taiwanese
population based on the same data set that was analyzed by NRC (1999~.
Morales et al. (2000) calculated cancer risk estimates using 10 risk models and
also considered how well those models fit the data sets. Of those models,
EPA chose a single model that did not use an external comparison population
either from all of Taiwan or part of southwestern Taiwan, because most of the
models that incorporate a comparison population result in a dose-response
curve that is supralinear at low doses. EPA indicated that there is no biologi-
cal basis for a supraTinear curve. In addition, differences other than arsenic
exposure between the study population and the comparison population could
affect the results. The decision to use a dose-response model that does not
incorporate a comparison population agreed with the SAB's recommendation
that the analysis should be conducted without a comparison group (see discus-
sion below). Of the models that did not incorporate a comparison population,
mode] ~ from Morales et al. (2000), in which "the relative risk of mortality at
any time is assumed to increase exponentially, with a linear function of dose
and a quadratic function of age," was used because it best fit the data based
on the Akaike information criterion (EPA 2001~. However, EPA did not
OCR for page 174
~ 74 ARSENIC IN DRINKING WA TER: 2001 UPDA TE
TABLE 5-1 NRC's Risk Estimates for Bladder Cancer Mortality from 1999 NRC
Reporta
Margin of
Point of Risk at 50 ~g/L Exposure at
Method ofAnalysis Departure, pub (X 1,OOO) 50 ALL
Poisson model, linear
dose, no background data
Poisson model, linear
dose, background data
included
a Estimated points of departure at the 1% excess risk level, corresponding margin of exposure
at 50 ~g/L arid corresponding excess lifetime risk estimates at 50 ,ug/L for bladder cancer in
males. Figures in parentheses are 95% confidence limits (lower for the point-of-departure
estimates; upper for estimated risk at 50 vigil). Risk estimates are those predicted in Taiwan
using U.S. ingestion rates.
b Me point of departure represents an estimate or observed level of exposure or dose associated
with an increase in adverse effects in the study population. An example of a point of departure
is ail EDo~
c A margin-of-exposure analysis compares the levels of arsenic to which the U.S. population
is exposed with the point of departure to characterize the risk to the U.S. population. The larger
the ratio, the greater degree of assumed safety for the population.
Abbreviation: EDo,, 1% effective dose.
Source: Modified from NRC (1999~.
404 (323) 1.237 (1.548) 8.08 (6.46)
443 (407) 1.129 (1.229) 8.86 (8.14)
publish the theoretical risk estimates on which it based its analyses in the
Federal Register (EPA 2000a, 200 ~ ). The risk estimates that it presents (EPA
2001) are adjusted for the occurrence of arsenic in U.S. drinking water; con-
sideration of such an adjustment is beyond the charge to this subcommittee.
Because EPA did not present theoretical lifetime excess bladder or lung can-
cer risk estimates, the subcommittee used linear extrapolation from the EDo~s
presented in Morales et al. (2000) to estimate these risks at 3, 5, 10, and 20
~g/L (Table 5-2~.
Adjustments for Water Intake
To estimate cancer risks associated with a given arsenic concentration in
drinking water, assumptions must be made about water consumption in both
OCR for page 175
QUANTITATIVE ASSESSMENT OF RISKS USING MODELING APPROACHES 1 75
TABLE 5-2 Theoretical Estimates of Excess Lifetime Risk (Incidence per 10,000
people) of Lung and Bladder Cancer at Various Concentrations of Arsenic in Drinlcing
Water Based on EDo, Values from Morales et al. (2000)a
Arsenic Bladder Cancer Lung Cancer
Concentration
(,ug/L) Females Males Females Males
3 1.2 .76 1.2 0.82
5 2.0 1.3 1.9 1.4
10 4.0 2.5 3.9 2.7
20 7.9 5.1 7.8 5.5
a Excess cancer risk estimates were calculated using the EDo,s estimated by Morales et al. (2000)
using a model in which the relative risk of mortality at arty time is assumed to increase exponen-
tially, with a linear function of dose arid a quadratic function of age (i.e., a multiplicative Pois-
son linear regression); no external comparison population was used (see Model 1 of Table 8
from Morales et al. 2000~. Risk estimates are rounded to two significant figures. The Taiwar~-
ese exposure per kilogram of body weight is assumed to be 2.2 times the U.S. exposure.
the U.S. population and the study population. EPA estimated mean daily
average per capita consumption of water by individuals in the United States
is ~ L/person/day for "community tap water" and 1.2 L/person/day for "total
water" (which includes bottled water) based on data from the 1994-1996
Continuing Survey of Food Intakes by Individuals (CSF~ (EPA 20003~. The
90th percentile is 2. l L/person/day and 2.3 L/person/day for community tap
water and total water, respectively. Rather than only using a point estimate
for its risk assessment, EPA conducted a Monte Cario analysis using the
CFSU data to incorporate water intake. Those distributions take into account
age, sex, and weight. EPA assumed that the Taiwanese consumed relatively
more water per unit of body weight than Americans, estimating consumption
of 3.5 and 2.0 L/day for men and women in Taiwan, respectively. As dis-
cussed in the following section, EPA also added water consumption to account
for water used in cooking in Taiwan. It should be noted that assumptions that
increase the amount of arsenic consumed (~inking water and diet) by the
study population reduce the "potency factor" or estimated slope of the linear
dose-response function when applied to other populations, thereby decreasing
the estimated risk in other populations. Conversely, underestimation of the
OCR for page 176
~ 76 ARSENIC IN DRINKING WA TER: 2001 UPDA TE
actual arsenic intake in the study population increases risk estimates in other
populations. Therefore, assumptions about total arsenic exposure in the study
population can have a large impact on risk estimates.
Adjustments for Dietary Intake of Arsenic
The staple foods in the southwestern Taiwan region where the study popu-
lation resided were rice and sweet potatoes. Those foods absorb a great deal
of water when cooked. As part of its risk assessment of arsenic in drinking
water, EPA (200 ~ ~ adjusted its lower-bound estimates to account for exposure
to arsenic in food from cooking water. For that adjustment, EPA assumed that
people in the study population eat ~ cup of dry rice and 2 pounds of sweet
potatoes per day. To adjust for arsenic absorbed during cooking, EPA added
~ ~ of water consumption to the Taiwanese population. Therefore, in its
analyses, EPA assumed that Taiwanese men and women consumed the equiva-
lent of a total of 4.5 L/day and 3.0 L/day of water, respectively. Although
EPA used a Monte Cario analysis to account for variability in U.S. water
consumption rates, its analyses did not incorporate analogous variability in the
Taiwanese water consumption rates.
EPA also discussed the fact that the food in Taiwan contains more arsenic
than the food in the U.S., even prior to cooking. NRC (1999) presented data
indicating that individuals in Taiwan consume food containing inorganic
arsenic at 50 Gay, compared with ~ O Gay for Americans. To account for
the intake of arsenic from food, EPA multiplied the Tower-bound risk esti-
mates by the fraction of arsenic consumed per kilogram contributed by drink-
ing water (calculated by dividing the arsenic ingested from drinking water
(pa/kg/day) by the total arsenic consumed from drinking water, cooking water,
and food) (J. Bennett, EPA, personal commun. May 22, 2001).
Adjustments for Mortality Versus Incidence
EPA's dose-response assessment is derived from data on mortality from
bladder and lung cancer in the Taiwanese study (Chen et al. 1985, 1992; Wu
et al. 1989). Extrapolating the mortality-risk estimates calculated in the Tai-
wanese population to the incident risks in the U.S. population requires an
adjustment for the survival rate for bladder and lung cancer. EPA (2001)
OCR for page 177
QUANTITATIVE ASSESSMENT OF RISKS USING MODELING APPROACHES ~ 77
noted that the Taiwanese people in the study population had Tow incomes and
poor diets, and that "the availability and quality of medical care is not of high
quality, by U.S. standards." Therefore, EPA assumed that the bladder cancer
incidence was relatively close to the bladder cancer mortality in the Taiwanese
study area. EPA calculated the survival rate for bladder cancer by considering
the survival-rate data compiled by the World Health Organization (WHO) for
bladder cancer in developing countries from ~ 982 through ~ 992 (lARC ~ 999)
and by comparing the annual bladder cancer mortality and incidence for the
general population of Taiwan in 1996. From those data, EPA concluded that
"bladder cancer incidence could be no more than two-fold bladder cancer
mortality; and that an 80% mortality rate would be plausible" (EPA 2001;
page 7009~. Therefore, when calculating the bladder cancer cases avoided at
a given MCL, EPA adjusted the upper bound by a factor of 1.25 to reflect the
mortality for bladder cancer. With respect to lung cancer, EPA concluded that
"because lung cancer "mortality] rates are quite high, about 88% in the U.S.
[EPA 1998], the assumption was made that all Jung cancers in the Taiwan
study area resulted in fatalities."
OVERVIEW OF TlIE SAB'S REPORT ON THE
2001 RISK ASSESSMENT
EPA charged the SAB to review the proposed arsenic rule (EPA 2000a)
and to specifically review (1~ EPA's focus on inorganic arsenic as the princi-
ple form of arsenic causing health effects; (2) the implications of exposure to
natural arsenic through food; and (3) the appropriateness of EPA' s precaution-
ary advice to use low-arsenic water in the preparation of infant formula. They
also requested the SAB to address several questions related to treatment op-
tions for arsenic in drinking water.
On December ~ 2, 2000, the SAB issued a report on the proposed drinking-
water regulation (EPA 2000c), responding to those questions on the scientific
basis of EPA's health risk assessment and on the economic and engineering
aspects of the final rule. The exposure assessment, costs, benefits, control
technologies, and policy issues discussed by the SAB are beyond the charge
to this NRC subcommittee and will not be discussed. The SAB's responses
to EPA's three questions on the health effects of arsenic are discussed in this
section. EPA addressed some ofthe SAB's comments in its final arsenic rule
(EPA 2001~.
OCR for page 178
78 ARSENICIN DRINKING WATER: 2001 UPDATE
Inorganic Arsenic As Principal Form of Arsenic
Causing Health Effects
The SAB pointed out that new data released since the ~ 999 NRC report
indicated that inorganic forms of arsenic are not solely responsible for the
toxic effects of arsenic (see Chapter 3 for discussion of new data). Because
exposures to other forms of arsenic can produce health effects, the SAB rec-
ommended that future risk assessments provide quantitative information on
how the intake of inorganic arsenic is related to the concentration of arsenic
metabolites in the urine and to bladder cancer. However, because the princi-
pal forms of arsenic in drinking water are inorganic, the SAB believed "that
it is appropriate for the Agency tEPA] to make "inorganic arsenic] its regula-
tory focus."
Implications of Exposure to Natural Arsenic Through Food
The SAB concluded that on average, for the general U.S. population,
ingestion of inorganic arsenic via foodwas considerably greater then ingestion
of inorganic arsenic via drinking water. The SAB agreed that data were not
available to determine "a well-defined nonlinear dose-response curve." Fur-
thermore, the SAB concluded that insufficient data on the distribution of food
intakes existed to adequately consider them in the analysis. Therefore, the
SAB concluded that EPA had no choice but to calculate marginal risk reduc-
lions based solely on arsenic concentrations in drinking water. The SAB
noted that "there is a limit to the benefits that can be realized by reducing
arsenic in drinking water" as long as the concentrations in food remain un-
changed. The SAB also reiterated the recommendation in the NRC (1999)
report to obtain additional studies on the noncancer effects of arsenic and
incorporate that information into a risk-assessment and cost-benefit analysis.
Health Advisory on Low-Arsenic Water and Infant Formula
The SAB also reviewed EPA's plan to issue a health advisory for the use
of Tow-arsenic water in the preparation of infant formula. Some of SAB's
responses focused on risk communication and the public's ability to follow
such an advisory; those comments are beyond the scope of this subcommit-
tee's charge. However, the SAB also discussed the issue of children's suscep-
tibility to arsenic. Most of the SAB members agreed that special circum-
OCR for page 179
QUANTITATIVE ASSESSMENT OF RISKS USING MODELING APPROACHES ~ 79
stances make infants unique in regard to their response to drinking-water
contaminants, but the SAB did not reach consensus on endorsing EPA' s intent
to issue a health advisory.
An SAB consultant wrote and one SAB member endorsed a minority
report on the issue of infant and children's risk. The minority report stated
that differences in respiratory and circulatory flow rates, cell-proliferation
rates, enzymatic pathways, developmental process, life expectancies, and the
disposition of chemicals in infants and other differences in cells during devel-
opment can make children more susceptible to toxic chemicals, including
arsenic. It further concluded that data from Hopenhayn-Rich et al. (2000) and
Concha et al. (1998) "indicate that young children are a uniquely sensitive
population for adverse health effects of arsenic." The minority report "departs
from the majority opinion contained in the iSAB] report in strength of its
conclusions if not the general reasonableness of the need for increased con-
cern for children, which is also held by the tSAB]." The basis for increased
concern for children is uncertainty about pulmonary and cardiovascular risks
to infants, high exposure of infants on a per kilogram basis, and the longer
period of exposure and outcome relative to adults. The latter is particularly
relevant if the latency period for cancer development from low arsenic expo-
sure is long or if the appropriate dose metric involves a less-than-lifetime
exposure as discussed in Chapter 4.
Although the SAB recognized that children differ from adults in many
ways that could make them more susceptible to toxic chemicals, "the majority
of the tSAB] did not feel that data available to them on arsenic had demon-
strated an increased sensitivity to arsenic in children." The SAB concluded
that available data on U.S. drinking-water consumption indicate that infants
who consume food made from drinking water could have a higher dose of
arsenic per unit of body weight than adults. The majority ofthe SAB did not
believe that the study by Hopenhayn-Rich et al. (2000) demonstrated "a
heightened sensitivity or susceptibility to arsenic" but that the study "appears
to be a hypothesis generating study that, in light of the limitations [the SAB
described], merits and requires further study before drawing final conclu-
sions."
SAB's Comments on EPA's Interpretation of the NRC Report
The SAB also commented on EPA's interpretation of the 1999 NBC
report. The SAB, in general, agreed with the ~ 999 NRC report, which formed
OCR for page 203
QUANTITATIVE ASSESSMENT OF RISKS USING MODELING APPROACHES 203
TABLE 5-8 Theoretical Maxi Likelihood Estimates of Excess Lifetime Risk
(Incidence per 10,000 People) of Bladder Cancer for U.S. Populations Exposed at
Vanous Concentrations of Arsenic In Drinking Water Using Different Ratios for
Taiwanese-to-U.S. Drinking-Water Ingestion on a Per-Body-Weight Basisa
Taiwanese to U.S. Drinking Taiwanese to U.S. Drinking
Arsenic Water Ratio = 1.4b Water Ratio = 3c
Concentration
(pg/L) Females
Males
Females Males
3 7.7 15 3.6 6.8
5 13 25 6.0 11
10 26 50 12 23
20 51 100 24 45
a These risks are estimated using assumptions considered to be reasonable by the subcommittee;
it is possible to get higher and lower estimates using other assumptions. Estimates were calcu-
lated using data from individuals in the arsenic-endemic region of southwestern Taiwan (Chen
et al. 1985, 1992; Wu et al. 1989), and data from an external comparison group from the overall
southwestern Taiwan area. Risk estimates are rounded to two significant figures. All 95%
confidence limits are less than +/- 12% of the maximum-likelihood estimate and are not pre-
sented. Those confidence limits reflect statistical variability only, reflecting primarily the sample
size. As such, they are not indicative of the true uncertainty associated with the estimates.
b Risks were estimated assuming that the typical U.S. resident weighs 70 kg, compared with 50
kg for the typical Taiwanese, and that the typical Taiwanese drinks just over 1 L of water per
day, the same as the 1 L per day in the United States; thus, the Taiwanese exposure per kilogram
of body weight is 1.4 times the U.S. exposure, calculated using an additive Poisson model with
linear dose.
c Risks were estimated assuming that the typical U.S. resident weighs 70 kg, compared with 50
kg for the typical Taiwanese, and that the typical Taiwanese drinks just over 2 L of water per
day, compared with 1 L per day in the United States; thus, the Taiwanese exposure per kilogram
of body weight is 3 times the U.S. exposure, calculated using an additive Poisson model with
linear dose.
ing water are presented. Those values, however, should not be considered
bounds on the possible risk estimates, because other assumptions could be
made that would result in higher or lower values. When estimating the risks
to the U.S. population, assumptions must be made about body weights and
water consumption in both the United States and the Taiwanese populations.
Then, when comparing cancer risk estimates, it is important to be aware of
how those assumptions affect the estimates. For example, the higher the ratio
of water ingestion in Taiwan relative to the United States in terms of liters per
body weight per day, the smaller the U.S. cancer risk estimate will be. The
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204 ARSENIC IN DRINKING WA TER: 2001 UPDA TE
assumptions that the subcommittee used to calculate the various estimates are
discussed below and presented in the footnotes of the tables.
Table 5-7 presents estimates for the excess lifetime risk (incidence) of lung
cancer in females and mates in the U.S. population from exposure to arsenic
at 3, 5, ~ 0, and 20 ~g/L of drinking water. The estimates based on the Chilean
data (Ferreccio et al. 2000) were calculated assuming that the typical U.S. and
Chilean resident both weigh 70 kg and that the drinking-water ingestion rates
in both countries are the same that is, that exposures in Chile on a per-body-
weight basis, given the same concentration of arsenic in the drinking water,
are equal to those in the United States (i.e. a factor of 1~. The estimates based
on the southwestern Taiwanese data set (Chen et al. 198S, 1992; Wu et al.
1989), however, were calculated assuming that the typical U.S. resident
weighs 70 kg and drinks ~ ~ of water per day, and the typical Taiwanese
resident weighs 50 kg and drinks just over 2 ~ of water per day. Therefore,
given the same concentration of arsenic in drinking water, exposures in Tai-
wan on a per-body-weight basis would be three times that of a U.S. resident.
The data in Table 5-7 utilize the background rate of lung cancer in the United
States. To illustrate the importance of the background rate, Table S-9 shows
the same risk projections using the Taiwanese data set and the background
TABLE 5-9 Theoretical Maximum-Likelihood Estimates of Excess Lifetime Risk
(Incidence per 10,000 people) of Lung and Bladder Cancer for Populations Exposed
at Various Concentrations of Arsenic in Droning Water, Using the Background
Cancer Incidence Rate for Taiwana
Arsenic Bladder Cancer Lung Cancer
Concentration
(,ug/L) Females Males Females Males
3 2.3 2.0 1.8 1.7
5 3.8 3.2 3.0 3.0
10 7.5 6.8 6.2 6.1
20 15 13 12 12
.
a These risks are estimated using the assumptions noted in footnotes (a) and (c) of Table 5-8, and
assuming a Taiwanese to U.S. drinking water ratio of 3. The estimated background incidence
rates for bladder cancer in Taiwan (derived from the subcommittee's cancer risk estimates
presented in Tables 5-7 and 5-8 and adjusted by the ratio of Taiwanese incidence data (You et
al.2001) to U.S. incidence data (Ferlay et al. 2001~) are 6.9 (males) and 3.4 (females) per
100,000 and for lung cancer are 25.8 (males) and 11.9 (females) per 100,000.
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QUANTITATIVE ASSESSMENT OF RISKS USING MODELING APPROACHES 205
incidence rates for lung cancer in Taiwan, which are approximately 2- and 3-
fold lower than those in the United States for males and females, respectively.
For lung cancer, the MLEs of risk for mates based on the Chilean data
(Fernccio et al. 2000) range from 20 per 10,000 at 3 ~g/L to 130 per 10,000
at 20 ~g/L using the average arsenic concentration during the peak exposure
period of 1958 to 1970. The corresponding risk estimates in females are 14
per 10,000 to 95 per 10,000. Using the average arsenic concentration from
1930 to 1994, the risk estimates range from 75 to 500 per 10,000 males and
from 15 to 330 per 10,000 females. Using the southwestern Taiwanese data,
the risk estimates for arsenic at 3,ug/L of drinking water range from 1.7 to 4.0
per 10,000 for mares and from 1.8 to 5.4 per 10,000 for females, depending on
which assumptions are used (Tables 5-8 and 5-9~.
Different studies have estimated the risks of lung cancer following expo-
sure to arsenic, and it is possible and useful to compare the risk estimates
generated in the different analyses at a given arsenic concentration. Because
the case mortality for lung cancer is close to 100% (SEER 2001), lung cancer
incidence approximates lung cancer mortality, and the risk estimates for lung
cancer mortality can be compared with risk estimates for lung cancer inci-
dence. As can be seen in Table 5-7, the subcommittee's analysis ofthe south-
western Taiwanese data yields an estimate for lifetime lung cancer incidence
in the United States (using the U.S. background rate) at an arsenic concentra-
tion in drinking water of 10 ~g/L of approximately 14 per 10,000 and 18 per
10,000 in males and females, respectively. It is noteworthy that nearly 10
years ago, Smith et al. (1992) published a risk assessment based on the same
ecological southwestern Taiwanese data analyzed by the subcommittee. In
that risk assessment, lifetime lung cancer mortality risks at 10 ~g/L were
estimated to be 11 per 10,000 and 17 per 10,000 for males and females, re-
spectively. Therefore, lung cancer risk estimates generated by this subcom-
mittee and those published by Smith et al. (1992) are very consistent. The
lung cane. er risk estimates derived from the Taiwanese data in Table 5-7 can
be compared with those derived from the data in the recent case-control study
in northern Chile by Ferreccio et al. (2000~. When the average arsenic con-
centration in northern Chile Tom 1930 to 1994 is used as the dose-metric, the
risk estimates for lung cancer incidence in the United States calculated by the
subcommittee for an arsenic concentration of 10 ,ug/L are 250 per 10,000
mates and 170 per 10,000 females. Those estimates are approximately an
order of magnitude higher than the estimates the subcommittee derived from
the Taiwanese data. However, when the dose metric selected for the Chilean
data is the peak years of arsenic exposure from 1958 to 1970, the correspond-
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206 ARSENIC IN DRINKING WA TER: 2001 UPDA TE
ing U.S. lung cancer risk estimates are 67 per 10,000 mates and 48 per 10,000
females. Those estimates are approximately 3 to 4 times higher than the sub-
committee's estimates derived from the Taiwanese data. For comparative
purposes, the subcommittee also derived cancer risk estimates at 10 ,ug/L
using the relative risks (see Table 2-~) for lung cancer associated with the
peak period of arsenic exposure in northern Chile in the ecological study by
Smith et al. (1998~. If the same formula is applied to those relative risks, as
was used to estimate the subcommittee's other cancer estimates, the U.S. lung
cancer estimates at 10 ,ug/L are 38 per 10,000 and 21 per 10,000 in mates and
females, respectively.
Overall the peak period exposure data in northern Chile and the data from
southwestern Taiwan yield coherent lifetime excess risk estimates ranging
from 1.4 to 6.7 per 1,000 for lung cancer in the United States at a drinking-
water arsenic concentration of 10 Vigil. The finding that risk estimates de-
rived from studies of individuals exposed to arsenic in Chile are similar to
those estimated from Taiwanese data provides confidence in the validity ofthe
risk estimates.
Tables 5-8 and 5-9 present estimates for the excess lifetime risk (incidence)
for bladder cancer in females and mates in the U.S. population from exposure
to arsenic at 3, 5, ~ 0, and 20 ~g/L of drinking water based on the southwestern
Taiwanese study (Chen et al. 1985, 1992; Wu et al. 1989), using either the
U.S. background rate for bladder cancer (Table 5-~) or the Taiwanese back-
ground rate (Table 5-9~. In one water-intake scenario, the subcommittee
assumed that the typical U.S. resident weighs 70 kg and drinks ~ ~ of water
per day, and the typical Taiwanese resident weighs 50 kg and also drinks 1 L
of water per day. Therefore, given the same concentration of arsenic in drink-
ing water, exposures in Taiwan on a per-body-weight basis are 1.4 times that
of a U.S. resident. in a second water-intake scenario, calculated using the
same data set, it was assumed that the typical U.S. resident weighs 70 kg and
drinks ~ ~ of water per day, and the typical Taiwanese resident weighs 50 kg
and drinks just over 2.2 ~ of water per day. Therefore, as indicated in the lung
cancer estimates earlier at the same concentration of arsenic in drinking water,
exposures in Taiwan on a per-body-weight basis are 3 times that of a U.S.
resident.
For bladder cancer, the maximum-likelihood estimate of risk using a ratio
of 1.4 for Taiwanese-to-U.S. drinking-water rates on a per-body-weight basis
for males range from approximately 15 per 10,000 at an arsenic concentration
of 3 ,ug/L of drinking water to 100 per 10,000 at 20 ~g/L. The corresponding
estimates in females range from ~ to 5 ~ per 10,000. Using a drinking water
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QUANTITA TIVE ASSESSMENT OF RISKS USING MODELING APPROA CHES 20 7
ratio of 3.0, the corresponding ranges are approximately 7 to 45 per 10,000 in
males and 4 to 24 per 10,000 in females, using the U.S. background rate. Risk
estimates are 3-fold Tower for mates and 2-fold lower for females if the Tai-
wanese background rate is used (Table 5-9~.
Further discussion of the subcommittee's quantitative risk estimates and
comparison of them with the results of other analyses are presented in
Chapter 6.
SUMMARY AND CONCLUSIONS
· Since EPA issued a pending standard of 10 ,ug/L, based on lung and
bladder cancer data from the southwestern Taiwanese study in 2000, two
additional studies have appeared in the literature that are of sufficient size and
quality and with adequate quantification of dose to be considered in comput-
ing EDs for arsenic in drinking water. One is a study that examined urinary
tract cancer, and TCC in particular, in northeastern Taiwan (Chiou et al.
2001~; the second is a case-control study of lung cancer in Chile (Ferreccio et
al. 2000).
· Although it can be argued that an external comparison group for dose-
response analysis of the original Taiwanese data should not be used, the sub-
committee believes that such arguments are outweighed by evidence in favor
of using a comparison population. A recent paper by Tsai et al. (1999) de-
creases concerns about the potential role of confounding in using either the
southwestern Taiwanese population or the entire Taiwanese population as an
external comparison group.
· Poisson models provide a flexible and useful framework for analysis
of cohort data of the form seen in both the southwestern and northeastern
Taiwanese studies. Although dose can be entered into the model in a variety
of ways, the additive model with a linear dose effect is consistent with other
analyses that have been applied to cancer cohort data.
· The BEIR IV formula provides a useful approach to computing an
EDGE for the United States based on relative risks obtained from a different
population. The BEIR IV formula allows the incorporation of relative risk
estimates obtained from case-control studies. The simple formula presented
by Smith et al. (1992) is a close approximation to the BEIR IV approach.
· There is insufficient knowledge on the mode of action of arsenic to
justify the choice of any specific dose-response mode] the subcommittee
explored a variety of models and ultimately used the additive mode] with
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208 ARSENICIN DRINKING WATER: 2001 UPDATE
linear dose effect. Although different results might be obtained from other
reasonable model choices, the estimates do not differ by more than an order
of magnitude.
· Accounting for individual exposure rate variability causes the uncer-
tainty in the estimate to increase. Therefore, as shown in Table 5-S, the cen-
tral tendency estimates of the EDIT increase when individual variability in
drinking-water rates is considered. The corresponding lower bound estimates
for each EDIT decreases, however, because the variance about the mean be-
comes larger.
· Assumptions regarding the differences between mean drinking-water
intakes in Taiwan and the United States can have substantial impacts on the
estimated EDo,. There is evidence that drinking-water intakes in Taiwan
might be closer to U.S. intakes than previously suggested, and that is an im-
portant source of uncertainty. increasing the assumed drinking-water intakes
for Taiwan provides a suitable approach to adjusting for arsenic exposure via
cooking water, although the addition of ~ it, especially for women, seems
excessive and warrants further investigation.
· Adjusting for background arsenic exposure through food is likely to
have only a modest effect on the estimated EDIT.
· Measurement error in assigning the village-specific arsenic exposure
concentrations is also likely to have only a modest impact on the estimated
EDIT, compared with the variability associated with model uncertainty. Fur-
ther exploration of this issue, however, would be useful.
· Although there are insufficient data available for a formal combined
analysis, it is helpful to compare the results across studies and also across
various feasible assumptions to obtain a sense of the magnitude of likely
effects. Table 5-3 presents such an analysis.
· The northeastern Taiwanese study has several strengths, including
exposure assessment and data on potential confounders, which could inform
the dose-response assessment. At present, however, the follow-up time is
insufficient to provide the precision necessary for quantitative dose-response
assessment.
~ Analysis of the data from the period of peak arsenic exposure in
northern Chile and the data from southwestern Taiwan results in similar esti-
mates of lifetime lung cancer incidence in the United States. The consistency
of the results adds to the confidence in the validity of the risk estimates.
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QUANTITATIVE ASSESSMENT OF RISKS USING MODELING APPROACHES 209
RECOMMENDATIONS
· Quantitative risk assessment for arsenic in drinking water should
consider the results from the following two studies:
The data set from the southwestern Taiwanese study reported by Chen
et al. (1988, 1992;) and Wu et al. (1989), which was considered by the NRC
in the 1999 report and by EPA (lung and bladder cancer in males and fe-
males).
The Chilean case-control study (lung cancer) reported by Ferreccio et
al. (2000~.
· Dose-response analysis of the southwestern Taiwanese data should
incorporate an unexposed comparison group; the southwestern Taiwanese
region is the recommended comparison group.
· The current mode-of-action data are insufficient to guide the selection
of a specific dose-response model. The additive Poisson model with a linear
term in dose is a biologically plausible model that provides a satisfactory fit
to the epidemiological data and represents a reasonable model choice for use
in the arsenic risk assessment.
Research should be conducted on techniques for integrating the results
from many epidemiological studies into a risk assessment.
· Information on remaining uncertainties should be incorporated into
future analyses when it is acquired.
REFERENCES
Albores, A., M.E. Cebrian, I. Tellez, and B. Valdez. 1979. Comparative study of
chronic hydroarsenicism in two rural communities in the Laguna region of Mex-
ico. tin Spanish]. Boll Of~cina Sanit. Panam. 86~3~:196-205.
Breslow, N.E., and N.E. Day. 1988. Statistical Methods in Cancer Research: Vol. 2.
The Design and Analysis of Cohort Studies. New York: Oxford University
Press.
Carlin, B.P., and T.A. Louis. 1996. Bayes and Empirical Bayes Methods for Data
Analysis. New York: Chapman & Hall.
Carroll, R.J., D. Ruppert, and L.A. Stefanski. 1995. Measurement Error in Nonlinear
Models. New York: Chapman & Hall.
CDC (Centers for Disease Control and Prevention). 2001. GMWK I Total Deaths for
Each Cause by 5-Year Age Groups, United States, 1993, 1994, 1995, 1996, 1997,
OCR for page 210
2 ~ O ARSENIC IN DRINKING WA TER: 2001 UPDA TE
andl998. Mortality Tables. DataWarehouse. NationalCenterforHealthStatis-
tics, Centers for Disease Control and Prevention, U.S. Department of Health and
Human Services,Hyattsville,MD. Online. Available: http://www.cdc.gov/
nchs/datawh/statab/unpubd/mortabs/gmwki.htm. ~ Sept. 21, 2001 ~ .
Cebrian, M. 1987. Some Potential Problems in Assessing the Effects of Chronic
Arsenic Exposure in North Mexico [preprint extended abstract]. Preprint of
paper presented at the 194th National Meeting of the American Chemical Society,
Aug. 30-Sept.4, 1987, New Orleans, LA.
Cebrian, M.E., A. Albores, M. Aguilar, and E. Blakely. 1983. Chronic arsenic poi-
soning in the north of Mexico. Hum. Toxicol. 2~1~:121-133.
Chen, C.J., Y.C. Chuang, T.M. Lin, and H.Y. Wu. 1985. Malignant neoplasms
among residents of a blackfoot disease-endemic area in Taiwan: high-arsenic
artesian well water and cancers. Cancer Res. 45~11 Pt 2~:5895-5899.
Chen, C.J., M. Wu, S.S. Lee, J.D. Wang, S.H. Cheng, and H.Y. Wu. 1988.
Atherogenicity and carcinogenicity of high-arsenic artesian well water. Multiple
risk factors and related malignant neoplasms of blackfoot disease. Arteriosclero-
sis 8~5~:452460.
Chen, C.J., C.W. Chen, M.M. Wu, and T.L. Kuo. 1992. Cancer potential in liver,
lung, bladder and kidney due to ingested inorganic arsenic in drinldog water. Br.
J. Cancer 66~5~:888-892.
Chiou, H.Y., S.T. Chiou, Y.H. Hsu, Y.L. Chou, C.H. Tseng, M.L. Wei, and C.J.
Chen. 2001. Incidence of transitional cell carcinoma and arsenic in drinldng
water: a follow-up study of 8,102 residents in an arseniasis-endemic area in
nor~eastem Taiwan. Am J. Epidemiol. 153 (5) :411 -418.
Concha, G., B. Nermell, and M. Vahter. 1998. Metabolism of inorganic arsenic in
children with chronic high arsenic exposure in northem Argentina. Environ.
Health Perspect. 106~6~:355-359.
Cuzick, J., S. Evans, M. Gillman, and D.A. Price Evans. 1982. Medicinal arsenic and
intemal malignancies. Br. J. Cancer 45~6~:904-911.
EPA (U.S. Environmental Protection Agency). 1988. Special report on Ingested
Inorganic Arsenic: Skin Cancer; Nutritional Essentiality. EPA/625/3-87/013.
Risk Assessment Forum, U.S. Environmental Protection Agency, Washington,
DC. July 1988.
EPA (U.S. Environmental Protection Agency). 1996. Proposed Guidelines for Carci-
nogenic Risk Assessment. Notice. Fed. Regist. 61~79~:17960.
EPA (U.S. Environmental Protection Agency). 1998. Cost of Lung Cancer Chapter
II.V in Cost of Illness Handbook. Off~ce of Pollution Prevention and Toxics,
U.S.EnvironmentalProtection Agency. "Online]. Available: http://www.epa.
gov/oppt/ coi/. [August 17, 2001 ~ .
EPA (IJ.S. Env~ronmental Protection Agency). 2000a. 40 CFR Parts 141 and 142.
National Pr~mary Drinking Water Regulations. Arsenic and Clarif~cations to
Compliance and New Source Contaminants Monitoring. Notice of proposed
rulemalcing. Fed. Regist. 65~121~:38887-38983.
OCR for page 211
QUANT7TA TINE ASSESSMENT OF RISKS USING MODELING APPROA CHES 21~
EPA (U.S. Environmental Protection Agency). 2000b. 40 CFR Parts 141 and 142.
National Primary Drinking Water Regulations. Arsenic and Clarifications to
Compliance end New Source Contaminants Monitoring. Notice of data availabil-
ity. Fed. Regist. 65(204): 63027-63035.
EPA (U.S. Environmental Protection Agency). 2000c. Arsenic Proposed Drinking
Water Regulation: A Science Advisory Board Review of Certain Elements of the
Proposal, A Report by the EPA Science Advisory Board. EPA-SAB-DWC-01-
001. S cience Advisory B card, U. S. . Environmental Protection Agency, Washing-
ton, DC. December. "Online]. Available: http://www.epa.gov/sab/ f~scalOl.htm.
EPA (U.S. Environmental Protection Agency). 2000d. Estimated Per Capita Water
Ingestion in the United States: Based on Data Collected by the United States
Department of Agriculture's (USDA) 1994-1996 Continuing Survey of Food
Intakes by Individuals. EPA-822-00-008. Of lice of Water, Office of Standards
and Technology, U.S. Environmental Protection Agency. April 2000.
EPA (U.S. Environmental Protection Agency). 2001. 40 CFR Parts 9,141 and 142.
National Primary Drinking Water Regulations. Arsenic and Clarifications to
Compliance end New Source Contaminants Monitoring. Final Rule. Fed. Regist.
66~14~:6975-7066.
Ferlay, J., F. Bray, P. Pisani, and D. M. Parkin. 2001. GLOBOCAN 2000: Cancer
Incidence, Mortality and Prevalence Worldwide, Version 1.0. IARC CancerBase,
No.5. IARC Press, Lyons, France. "Online]. Available: http://www.dep.iarc.fr/
globocan/ globocan.ht~ tSept. 20, 2001~.
Ferreccio, C., C. Gonzalez, V. Milosavljevic, G. Marshall, A.M. Sancha, and A.H.
Smith. 2000. Lung cancer and arsenic concentrations in drinking water in Chile.
Epidemiology 11~6~:673-679.
Gail, M. 1975. Measuring the benefit of reduced exposure to environmental carcino-
gens. J. Chronic Dis. 28~3~:135-147.
Hastie, T., and R. Tibshirani.1990. Generalized Additive Models. New York: Chap-
man and Hall.
Hopenhayn-Rich, C., M.L. Biggs, A. Fuchs, R. Bergoglio, E.E. Tello, H. Nicolli, and
A.H. Smith. 1996. Bladder cancer mortality associated with arsenic in Linking
water in Argentina. Epidemiology 7~2~:117-124.
Hopenhayn-Rich, C., M.L. Biggs, and A.H. Smith. 1998. Lung and kidney cancer
mortality associated with arsenic in drinking water in Cordoba, Argentina. Int.
J. Epidemiol. 27~4~:561-569.
Hopenhayn-Rich, C., S.R. Browning, I. Hertz-Picciotto, C. Ferreccio, C. Peralta, and
H. Gibb. 2000. Chronic arsenic exposure and risk of infant mortality in two
areas of Chile. Environ. Health Perspect. 108~79:667-673.
IARC (International Agency for Research on Cancer). 1999. Cancer Survival in
Developing Countries, R. Sankaranarayanan, R.J. Black, and D.M. Parkin, eds.
Pub. No. 145. Lyon: International Agency for Research on Cancer, World
Health Organization.
OCR for page 212
212 ARSENIC IN DRINKING WA TER: 2001 UPDA TE
Kur~tio, P., E. Pukkala, H. Kahelin, A. Auvinen, and J. Pekkanen. 1999. Arsenic
concentrations in well water and risk of bladder and kidney cancer in Finland.
Environ. Health Perspect. 107~9~:705-710.
Lai, M.S., Y.M. Hsueh, C.J. Chen, M.P. Shyu, S.Y. Chen, T.L. Kuo, M.M. Wu, and
T.Y. Tail 1994. Ingested inorganic arsenic and prevalence of diabetes mellitus.
Am. J. Epidemiol. 139(5):484-492.
Lewis, D.R., J.W. Southwick, R. Ouellet-Hellstrom, J. Rench, and R.L. Calderon.
1999. Drinking water arsenic in Utah: a cohort mortality study. Environ. Health
Perspect. 107~5~:359-365.
Mazumder, D.N., J. Das Gupta, A. Santra, A. Pal, A. Chose, S. Sarkar, N.
Chattopadhaya, and D. Chakraborty. 1997. Non-cancer effects of chronic
arsenicosis with special reference to liver damage. Pp.112- 123 in Arsenic Expo-
sure and Health Effects, C.O. Abernathy, R. L. Calderon, and W. Chappell, eds.
London: Chapman & Hall.
Morales, K.H. 2001. Statistical Methods for Risk Assessment Based on Epidemio-
logical Data. Ph. D. Thesis Submitted to Harvard School of Public Health, De-
partment of Biostatistics, Boston, Mass. May 2001.
Morales, K.H., L. Ryan, T.L. Kuo, M.M. Wu, and C.J. Chen. 2000. Risk of internal
cancers from arsenic in drinking water. Environ. Health Perspect. 108~7~:655-
661.
Morris, J.S., M. Schmid, S. Newman, P.J. Scheuer, and S. Sherlock. 1974. Arsenic
and noncirrhotic portal hypertension. Gastroenterology 66~1~:86-94.
Mushak, P., and A.F. Crocetti. 1995. Risk and revisionism in arsenic cancer risk
assessment. Environ. Health Perspect. 103~7-8~:684-689.
Nevens, F., J. Fevery, W. Van Steenbergen, R. Sciot, V. Desmet, and J. De Groote.
1990. Arsenic and noncirrhotic portal hypertension: a report of eight cases. J.
Hepatol. 11~1~:80-85.
Neubauer, O. 1947. Arsenical cancer: a review. Br. J. Cancer l(June):192-251.
NRC (National Research Council). 1983. Risk Assessment in the Federal Govern-
ment: Managing the Process. Washington, DC: National Academy Press.
NRC (National Research Council). 1988. Health Risks of Radon and Other Inter-
nallyDepositedAlpha-Emitters: BEIRIV. Washington, DC: National Academy
Press.
NRC (National Research Council). 1999. Arsenic in Drinlcing Water. Washington,
DC: National Academy Press.
Rahman, M., and J.O. Axelson. 1995. Diabetes mellitus and arsenic exposure: A
second look at case-control data from a Swedish copper smelter. Occup. Environ.
Med. 52~119:773-774.
Rahman, M., M. Tondel, S.A. Ahmad, and C. Axelson. 1998. Diabetes mellitus
associated with arsenic exposure in Bangladesh. Am. J. Epidemiol.148~2~: 198-
203.
Roth, F. 1956. Concerning chronic arsenic poisoning of the Moselle wine growers
with special emphasis on arsenic carcinomas. Krebsforschung 61:287-319.
OCR for page 213
QUANTITATIVE ASSESSMENT OF RISKS USING MODELING APPROACHES 213
SEER (Surveillance, Epidemiology, and End Results). 2001. Surveillance, Epidemi-
ology, and End Results Program Public-Use Data (1973-1998), National Cancer
Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch.
"Online]. Available: http://www-seer.ims.nci.nih.gov/Publications/. [August20,
2001].
Smith, A.H., C. Hopenhayn-Rich, M.N. Bates, H.M. Goeden, I. Hertz-Picciotto, H.M.
Duggan, R. Wood, M.J. Kosnett, and M.T. Smith. 1992. Cancer risks from
arsenic in drinking water. Environ. Health Perspect. 97:259-267.
Smith, A.H., M. Goycolea, R. Haque, and M.L. Biggs. 1998. Marked increase in
bladder and lung cancer mortality in a region of northern Chile due to arsenic in
dying water. Am. J. Epidemiol. 147~7~:660-669.
Spiegelhalter, D.J., A. Thomas, N.G. Best, and W.R. Gilks. 1996. BUGS: Bayesian
inference Using Gibbs Sampling, Version 0.5. Cambridge: MRC Biostatistics
Unit. "Online]. Available: http://www.mrc-bsu.cam.ac.uk/bugs/. tAugust 20,
2001].
Tsai, S.M., T.N. Wang, and Y.C. Ko. 1999. Mortality for certain diseases in areas
with high levels of arsenic in drinking water. Arch. Environ. Health 54~3~: 186-
193.
Tseng, W.P. 1977. Effects and dose-response relationships of skin cancer and black-
foot disease with arsenic. Environ. Health Perspect. 19: 109-119.
Tseng, W.P., H.M. Chu, S.W. How, J.M. Fong, C.S. Lin, and S. Yeh. 1968. Preva-
lence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J. Natl.
Cancer Inst. 40~3~:453-463.
Tsuda, T., A. Babazono, E. Yamarnoto, N. Krumatani, Y. Mino, T. Ogawa, Y. Kishi,
and H. Aoyama. 1995. Ingested arsenic and internal cancer: A historical cohort
study followed for 33 years. Am. J. Epidemiol. 141~3~:198-209.
Wu, M.M., T.L. Kuo, Y.H. Hwang, and C.J. Chen. 1989. Dose-response relation
between arsenic concentration in well water and mortality from cancers and
vascular diseases. Am. J. Epidemiol. 130~6~: 1123-1132.
Yeh, S. 1973. Skin cancer in chronic arsenicism. Hum. Pathol. 4~4~:469-485.
You, S.L., T.W. Huang, and C.J. Chen. 2001. Cancer registration in Taiwan. Asian
Pac. J. Cancer Prev. 2( IACR suppl.~:75-78.
Zaldivar, R. 1974. Arsenic contamination of drinking water and foodstuffs causing
endemic chronic poisoning. Beitr. Pathol. 151~4~:384-400.
Representative terms from entire chapter:
lung cancer
