Argentina:
Bladder cancer case-control
study in Córdoba, Argentina
This study was based in Villa María, Córdoba.
The study is defined by 3 major components for which final data analysis and report
preparation is currently underway:
- Arsenic and bladder
cancer dose-response: Bladder cancer cases and age- and sex-matched
population controls from the County
of Unión have been
interviewed in detail including lifelong residential histories, sources of
drinking water and smoking histories. Water samples have been collected
from both the current residences and where possible, from previous
residences. Historical data on arsenic measurements in public water
supplies have also been collected. We are currently analyzing these data
to assess the relationship between arsenic exposure and bladder cancer
risk. This will include an examination of the possible synergistic
effect of cigarette smoking.
- Metabolism:
First-morning urine samples were collected from cases and controls.
Analyses for inorganic arsenic and its methylated metabolites were
conducted in the laboratory of Professor David Kalman, University of Washington.
Cases and controls are being compared to see if they differ in arsenic
methylation patterns.
Molecular epidemiology: Tumor DNA has been analyzed for genetic
alterations using a three-tiered approach:
- screening of the
entire genome for gains and losses using comparative genomic
hybridization (CGH);
- specific analyses of
chromosomes 9 and 17p for loss of heterozygosity using PCR- based
methods;
- analysis of the p53
gene for mutations, using polymerase chain reaction-single-strand
conformation (PCR-SSCP).
The frequency and
pattern of these genetic alterations in bladder tumors of arsenic-exposed and
unexposed cases is being compared. The potential synergistic action of arsenic
on genotoxic effects of cigarette smoking is currently being assessed. In
addition, susceptibility differences between cases and controls is being
investigated by identifying the presence or absence of the glutathione
S-transferases GSTM1 and GSTT1 null genotypes in buccal cells and by comparing
urinary arsenic methylation patterns.
Argentina mortality study
Mortality from internal cancers was identified in
areas of the Province of Córdoba, Argentina, which in the past had
high levels of arsenic in drinking water. The results concerning bladder cancer
have been published. The analyses concerning
mortality from other cancers has also been published.
Increased risks for kidney and lung cancers were found in the exposed areas.
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Bangladesh:
Arsenic and Child
Respiratory Health in Bangladesh
The lung is a
surprisingly important target for the long term health effects of ingestion of
inorganic arsenic in drinking water, but the impact of exposure during
childhood is largely unknown. Children are likely to be especially susceptible
since the development of the lung continues into childhood. In Chile, we have found that people
who were exposed to arsenic in drinking water as children have 10-fold
increased risks of lung cancer and chronic respiratory disease mortality when
they become adults. In West Bengal, India we have found that adults with
arsenic-caused skin lesions and high arsenic drinking water exposures have
impaired lung function and increased rates of chronic respiratory disease. To
date however, the impact of arsenic ingestion on lung function and respiratory
health has not so far been studied in children.
This study takes advantage of the fact that our collaborators in Bangladesh have
examined 167,000 people for skin lesions and measured the arsenic
concentrations in their drinking water. We plan to study 300 children aged 6-16
years living in the families having tube well water arsenic concentration
mostly over 300 ug/L, and in which at least one member of the family has
developed arsenic-related skin lesions. An unexposed comparison group of 300
children will be selected from families with no skin lesions, and whose water
contains less than 50 ug/L. Lung
function and respiratory symptoms, including chronic cough and shortness of
breath, will be assessed in relation to current and past arsenic concentrations
in all sources of drinking water throughout childhood, including in utero
exposure. Potential susceptibility and interactions associated with indoor air
pollution, diet, and nutritional status, will be investigated. Differences in
susceptibility due to individual variability in the degree to which children
metabolize arsenic to highly toxic methylated compounds identified in urine
samples will also be assessed. The children in these exposed and unexposed
families provide a unique opportunity to identify the effects of arsenic
exposure during critical time periods of lung growth and development. The public health impact of adverse
respiratory effects due to arsenic exposure in early life could be substantial
given the large number of children exposed to arsenic in drinking water
worldwide and the relevance of these outcomes for future population morbidity
and mortality.
Chile:
Incident Cancer Studies in a
Unique Arsenic-exposed Area of Chile
Our new ecologic
evidence from Northern Chile suggests that
arsenic exposure in childhood or in utero could cause up to a 10-fold
increase in lung cancer in young adults. This may be the first time that
early-life exposure to a common environmental agent has been linked to high
risks of an adult cancer in humans. Importantly, these data are preliminary and
need to be confirmed. The highly unique arsenic exposure scenario in Northern Chile offers a rare opportunity to do this.
Because almost everyone in Northern Chile
obtains their water from large municipal sources, and past arsenic levels in
all of these sources are well documented, arsenic carcinogenicity can be
studied using exposure data that are much more accurate than anywhere else in
the world. In addition, a very distinct 14-year period of high exposure in this
area, with low exposure before and after, has created a population where tens
of thousands of people were exposed to high arsenic levels only in utero or
as young children offering a unique opportunity to study the long-term impacts
of an early-life carcinogen with excellent data on past exposure. We propose a
case-control study of 675 cases of lung and bladder cancer obtained over a
three-year period using a rapid case ascertainment system involving all local
pathologists. Controls will be obtained from the Chile electoral register containing
94% of the Chilean population. Dose-response relationships and other aspects of
susceptibility will also be investigated. For example, we have found evidence
that people producing high levels of monomethylated arsenic (MMA) have 2-5
times higher cancer risks than others, perhaps due to the highly toxic
trivalent form (MMA3). Biological samples will be collected on all subjects and
susceptibility related to metabolism, diet, genetics, and other factors will be
investigated. Millions of people in the US are exposed to drinking water
arsenic. But, current US
arsenic regulations do not incorporate information on potentially susceptible
subgroups despite the fact that cancer risks in these groups could be
exceedingly high. The information gained from this project may help to
determine if some groups, such as children, those who metabolize arsenic
poorly, or those with poor nutrition, may need special consideration in
regulatory standard setting. Information on MMA3, diet, and the future genetic
and proteomic studies we will plan could add further insight into the
co-factors and mechanisms of environmental carcinogenesis.
Cross-sectional survey
of arsenic-induced skin lesions in Chiu-Chiu, Northern
Chile
In March 1999 a cross-sectional survey
was conducted of families from two small remote villages in Region II of Chile.
One village, Chiu- Chiu, was exposed to drinking water containing 800 ug/L of
arsenic. The second village, Caspana, has low concentrations of arsenic in its
water supply (15 ug/L). A total of 11 families participated from Chiu-Chiu and
8 from Caspana, each consisting of two adults and two children. The families
were examined for skin lesions and nutritional status and the findings are currently
being prepared for publication.
Impact of arsenic on
mortality in Chile
from 1950-2000
The purpose of this study is to investigate
mortality in Region II of Chile, from 1950 to 2000. This region, currently with
a population of close to a half million people, experienced a peak exposure to
arsenic, with a population-weighted average drinking water arsenic
concentration of 580 ug/L, from 1955 to 1970. In contrast, water supplies
for the rest of Chile
mostly contained arsenic levels of less than 10 ug/L. Following the
installation of arsenic treatment plants, arsenic concentrations were reduced,
so that the average is now less than 50 ug/L. Region II is unique in the
world in the way a large population experienced a sudden increase in arsenic
exposure and then a corresponding decrease in exposure more than a decade
later. This “natural experiment” affords an opportunity to
investigate latencies of arsenic-associated diseases, particularly
cancers. A particular advantage of carrying out epidemiological studies
in Region II is the high quality of exposure information, since everyone in
this region obtained their water from municipal water supplies, for which
regular monitoring has been carried out. By contrast, in most other high
arsenic areas of the world the arsenic came from many individual wells, for
which historical monitoring data do not usually exist.
An investigation of mortality in Region II during 1989-1993 indicated that
rates for bladder, skin, lung, and kidney cancer were increased compared to the
rest of Chile.
Bladder cancer mortality was markedly elevated [men, SMR = 6.0, 95% confidence
interval (CI), 4.8-7.4; women, SMR = 8.2, 95% CI, 6.3-10.5] as was lung cancer
mortality [men, SMR = 3.8, 95% CI, 3.5-4.1; women, SMR = 3.1, 95% CI, 2.7-3.7].
It was estimated that arsenic might account for 7% of all deaths among those
aged 30 years and over. If so, the impact of arsenic on the population
mortality in Region II of Chile would be greater than that reported anywhere to
date from environmental exposure to a carcinogen in a major population.
The study underway is constructing a longitudinal mortality profile, by cause
of death for Region II between the years 1950 and 2000. A similar mortality
profile is being constructed for Region V, as an unexposed control region. As
well as cancer, increased mortality might be expected from non-cancer outcomes,
including cardiovascular, peripheral vascular and cerebrovascular diseases. The
impact of arsenic exposure during childhood on pulmonary disease mortality in
young adults, and on childhood cancer mortality, is also being assessed.
This study is taking advantage of a unique opportunity to investigate
arsenic-caused mortality, including latency patterns, for one of the world's
most significant environmental toxic exposures. The study is expected to
be completed in the first half of 2004.
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India:
Dose-response study of
arsenic-caused skin lesions in West Bengal, India
Our group is conducting research in
collaboration with Professor D. N. Guha Mazumder and his research team at
the Institute of Post
Graduate Education and Research (IPGMER) in Calcutta, India.
We analyzed data from a large cross-sectional survey of about 7000 people in an
arsenic-exposed region in West Bengal. The
dose-response analysis linking cases of skin keratoses and
hyperpigmentation to arsenic water levels has been recently published.
We recently completed data collection for a
case-control study nested in the same survey, which focuses on participants
with skin lesions who had drinking water arsenic levels of less than 500 ug/L.
Detailed interviews concerning water sources and fluid consumption, diet,
smoking and medical history were completed for over 400 participants. Water samples
were obtained from all known drinking water sources. Each participant received
a physical examination for skin lesions and other signs, and portable
spirometry was conducted. Blood and urine samples were also collected to assess
micronutrient status and arsenic metabolism. Data from this study are currently
being analyzed.
Studies on the effect of
arsenic on respiratory, reproduction and child development in West Bengal
In addition to the dose-response study, we
recently launched two new studies in West Bengal.
The first new study was generated by our
preliminary findings from a cross-sectional study in which we examined the
respiratory effects associated with ingesting arsenic (see Guha Mazumder et
al., 2001). The prevalence of cough, chest sounds, and shortness of breath were
dramatically elevated among individuals with skin lesions. These findings
raised the possibility that respiratory effects are largely present only in
people with skin lesions. We, therefore, set out to confirm these results in a
more focused study. Participants will include 135 individuals who have
arsenic-induced skin lesions, and were exposed to high arsenic levels (>500
ug/L) through their primary water sources. The comparison group will include
individuals with normal skin, but consumed water with low arsenic levels
(<50 ug/L). Data collection for this detailed study commenced April
2001.
The second investigation examines the potential
effects of arsenic on reproduction and child development. Extensive
studies have been conducted concerning various effects of ingestion of
inorganic arsenic in drinking water, and health effects in adults. So far
little has been done to investigate reproductive effects in pregnancy and
effects on child development. The goal of the proposed study is to investigate
pregnancy outcomes in a retrospective study of 100 women already known to have
been drinking water containing more than 500 ug/L of arsenic. These women will
be compared to 100 women whose drinking water contained less than 50 ug/L of
arsenic. Live births, birth spacing, spontaneous abortion, and stillbirths will
be compared between exposed and unexposed mothers. Children aged 5-15 will
receive a medical examination, and their cognitive abilities and learning
achievements will be evaluated. Detailed nutritional assessment of each family
will be undertaken to search for potential effect modifying role of nutrition
on arsenic effects. Urine samples will be collected from women and their
children to identify metabolic susceptibility. Interviews for this study
commenced April 2001.
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United States:
Bladder cancer case-control study in Nevada
and California
The California/Nevada bladder cancer
study is a population-based, case-control study that will examine the
hypothesis that bladder cancer is caused by ingestion of arsenic in drinking
water at relatively low concentrations. The study population includes residents
of Kings County
in California, and six counties in Nevada (Churchill, Mineral, Lyon, Douglas, Storey and Carson). These counties
were chosen because they include water supplies which had close to 100 ug/L of
arsenic, the highest level of arsenic found in major water supplies in the U.S. Other
water supplies in the study region contain less than 10 ug/L and thus provide a
marked contrast in exposure. Two hundred bladder cancer cases diagnosed between
1994 and 2000 are being identified from the California and Nevada Tumor Registries.
Random digit dial (RDD) is being used to identify 400 controls who will be
frequency matched to cases by sex and 5-year age groups. Structured personal
telephone interviews are being administered to obtain lifetime residential
history and detailed information on current and past water consumption
patterns. Information is also being obtained regarding cigarette smoking (which
may be synergistic with arsenic in causing bladder cancer), chlorination of
drinking water, diet, and occupational history. Although the effect of arsenic
at 100 ug/L is uncertain, this study has over 90% statistical power to detect a
relative risk of 2.0, which was predicted by linear extrapolation of data from
studies in Taiwan.
California Arsenic Methylation Study
Increasing evidence suggests that
arsenic in drinking water is an important cause of human cancer, including
bladder cancer. Methylation of inorganic arsenic after ingestion reduces its
toxicity, but little is known about the impact of diet on arsenic methylation,
nor about variation between people in the fraction of inorganic arsenic
methylated in the body. The specific aims of this project are: 1.To assess the
influence of diet on the extent of methylation of inorganic arsenic. 2.To
quantify intra-individual and inter-individual variability in arsenic
methylation. 3.To compare arsenic methylation patterns between bladder cancer
patients and controls. The study population involves a subset of the bladder
cancer cases and frequency matched controls who are being selected as part of
an on-going case-control study on the cancer risks associated with moderate
levels of arsenic in drinking water. Study participants are residents of Kings County, California
where a large proportion of the current water supply contains arsenic at
concentrations close to 50 ug/l. Cases are being ascertained from the Cancer
Registry of Central California, and controls are randomly selected from the
general population. Detailed information encompassing residential history,
water sources, fluid consumption, typical diet, plus lifestyle and demographic
factors including smoking, is being obtained using validate questionnaire and
telephone interview methods. The study takes advantage of the opportunity to
study arsenic methylation in this study population. First morning urine samples
will be obtained from 50 of the bladder cancer patients and 100 of the
controlprogram, with a new focus on
malignant and non-malignant pulmonary disease resulting from ingestion of
inorganic arsenic in drinking water. The reason for this new focus is the fact
that risk estimation based on findings from three countries, including our own
studies in Argentina and Chile, show
that lung cancer contributes more to increased cancer mortality due to arsenic
ingestion than all other arsenic-caused cancers combined, including bladder,
kidney and skin cancer. Improving population cancer risk estimation is
therefore critically dependent on a better understanding of arsenic-induced
lung cancer. In addition to causing lung cancer, ingested arsenic may also
cause non-malignant respiratory effects as evidenced by our studies in West
Bengal, India, and our finding of increased mortality from chronic respiratory
disease in persons exposed to arsenic as children in Chile. We therefore plan to
investigate both malignant and non-malignant pulmonary disease originating from
ingestion of inorganic arsenic in drinking water. We will conduct a lung cancer
case-control study in Córdoba,
Argentina with
dose-response examination using individual exposure data based on measured
water arsenic concentrations. Individual susceptibility will be assessed by
arsenic methylation patterns in urine and glutathione transferase and MTHFR
genotypes determined from buccal cell DNA. The study will include an
examination of genetic alterations in tumors including p53 mutations, DNA
methylation, and comparative genomic hybridization, and will investigate
synergy with cigarette smoking. The lung cancer DNA study will be supplemented
with DNA of tumors from a highly exposed population in Chile, where we
will also conduct a case-control study of chronic respiratory disease mortality
focusing on effects of arsenic exposure during childhood. Chronic respiratory
disease, arsenic-caused skin lesions, and nutritional susceptibility will be the
focus of a study in West Bengal, India. Arsenic effects in children will be
part of this study, plus a study of children with skin lesions in Bangladesh and further study of two children
with skin lesions in Chile.
Our overall goal is to investigate both malignant and non-malignant pulmonary
disease effects of inorganic arsenic to enable better assessment of population
risks, including the health effects resulting from childhood exposures.
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|
University of California,
Berkeley ~ School of Public Health ~ 140 Warren
Hall MC7360 ~ Berkeley, CA 94720-7360
|
Telephone:
510/843-1736 ~ Facsimile: 510/843-5539 ~ E-mail: asrg@berkeley.edu
|
