Project 3 Update Archive

2014

We established a new connection between low-dose arsenic exposure and lung cancer. We also demonstrated the persistence of lung and bladder cancer risks after exposure to high levels of arsenic in drinking water in utero or in early life; these risks remain markedly elevated even 40 years after high exposures end. This information can be used to inform the need for policies regarding prevention, treatment, and other mortality reduction efforts in arsenic-exposed regions even decades after exposure. We found biologically plausible major reductions in breast cancer mortality during high exposure to inorganic arsenic in drinking water which could not be attributed to bias or confounding. We followed a Chilean population inadvertently exposed to high levels of arsenic, a naturally occurring element found in many minerals. Instead of an increase in mortality, as with many other cancer sites, the study found that breast cancer deaths were cut in half during the period that coincided with high arsenic exposure. The effect was more pronounced among women under age 60, with mortality in these women reduced by 70 percent. While the medicinal use of arsenic is not entirely new; arsenic trioxide was approved in 2000 by the Food and Drug Administration as an effective treatment for a rare type of leukemia; further study of arsenic as a potential breast cancer treatment may prove useful. Our Project Well work has shown that safe drinking water can be provided in developing countries, with the help of aid organizations, for modest cost and that these wells are self-sustaining. Based in part on research conducted for the UC Berkeley Superfund Research Program, our nonprofit partner Project Well (based in California, http://projectwellusa.org/index.php), together with sister NGO Aqua Welfare Society (based near Kolkata, West Bengal), continue to provide clean, arsenic-safe drinking water to villages in West Bengal, India.

2013

In Bangladesh, we collected questionnaire data, conducted physical examinations and spirometry measurements, and collected biological samples, including blood, urine, and buccal cells by cytobrush from 200 study participants. We also collected tubewell water samples for the goal of assessing participant arsenic exposure levels from drinking water. These samples were shipped to our UC Berkeley lab and analysis. We found that children who had been exposed in utero or in early life to high levels of arsenic were significantly more likely to suffer from chronic respiratory symptoms such as wheezing when not having a cold and shortness of breath when walking on level ground. Previous to our study, information on pulmonary health effects on children after early life arsenic exposure was very limited.

We published some important findings that resulted from our work in Chile showing that lung and bladder cancer risks after exposure to high levels of arsenic in drinking water remain very high even 40 years after exposures end. These results have significant public health implications, as they point to a need for prevention, treatment, and other mortality reduction efforts in arsenic-exposed regions even decades after exposure.

We published a comprehensive review of the immunotoxic effects of arsenic exposure (Dangleben et al, 2013) and considered the epigenetic effects of arsenic in its carcinogenic mechanism (Herceg et al, 2013).

Based in part on research conducted for the UC Berkeley Superfund Research Program, Project Well (based in California, http://projectwellusa.org/index.php), together with sister NGO Aqua Welfare Society (based near Kolkata, West Bengal), commenced work to develop a sustainable, community-based water program in 2001, to provide arsenic-safe water to the villagers of North 24 Parganas, Nadia and Murshidabad districts, in West Bengal, India. Project Well is a pioneering water program that has three major components: 1) construction, 2) monitoring & maintenance and 3) training & education until sustainability is developed amongst general public. To complete the sustainability part of this program, last year 53 water communities were handed the ownership of their water supply. “Taking charge” means the communities maintain the wells, including applying chlorine based disinfectant. The field workers in charge of these wells inspect these wells quarterly and continue monthly visits of the other wells. This method of nano-management has now become web-based through partnering with Peer Water Exchange, PWX, (http://peerwater.org/) where individual reports are uploaded including direct from the field via mobile texting. This enables both the funders and implementers access the reports from anywhere in the world with internet access which is open to public.

Significance

We added to the body of information on pulmonary health effects on children after early life arsenic exposure, which was very limited and we demonstrated the persistence of lung and bladder cancer risks after exposure to high levels of arsenic in drinking water, which remain very high even 40 years after exposure end. This information can be used to inform the need for policies regarding prevention, treatment, and other mortality reduction efforts in arsenic-exposed regions even decades after exposure. Our Project Well work has shown that safe drinking water can be provided in developing countries, with the help of aid organizations, for modest cost and that these wells are self-sustaining.

Future Plans

We will continue collection and analysis of data and samples collected in Bangladesh and Chile.

2012

Currently under review.

2011

Currently under review.

2010

Investigators from the Superfund Research Program at Berkeley have contributed greatly to our understanding of the many diseases and disorders caused by arsenic. They were the first to discover that exposure to arsenic in childhood causes disease later in life, an example of a critical window for exposure. Dr. Allan Smith and his colleagues have also worked tirelessly to acquaint public health and governmental officials with the importance of taking actions to control arsenic in drinking water around the world, giving many presentations every year and serving on expert committees. Arsenic contaminates groundwater in many countries, including parts of the U.S.

Overall goals
Investigators are conducting epidemiology studies in several countries around the world and using advanced methods including biological markers of human exposure (such as arsenic metabolites in the urine) in order to:

learn more about what diseases are caused or worsened by arsenic exposure;
better understand the critical windows of exposure to arsenic during early life and childhood and the concentrations or doses of arsenic that cause disease.
find out how arsenic acts in the body to causes diseases.

Important discoveries so far

Early life exposure to arsenic, even at relatively low levels, causes disease in adulthood more than 30 years later. This finding was first reported by Superfund researchers at Berkeley.
Arsenic exposure contributes to susceptibility to tuberculosis. This finding was first reported by Superfund researchers at Berkeley.

Highlight for last year
The most important things we discovered over the last year were that death from tuberculosis is more likely following arsenic exposure. This is a novel finding. A paper on this is in press in the American Journal of Epidemiology.

What we plan to do next
Investigators will continue their studies in Chile and Bangladesh to find out how early life exposure to arsenic causes disease during adulthood.

In Chile, investigators are looking at people who were exposed to arsenic in drinking water during childhood to see if they are more likely to develop lung cancer as adults. This “case-control” study is collecting data on arsenic exposure, occupational history, smoking status and diet for people who have the disease (cases) and others who are matched by age and gender (controls).

In Chile, investigators are also starting to study lung function, using a technique called “spirometry.” This study will determine if those with early life exposure to arsenic have reduced lung function many years later.

In Bangladesh, investigators have already collected data for their study of lung function in children who were exposed to arsenic. Their earlier studies in West Bengal, India, showed major lung function deficits in adults with evidence of high arsenic exposure. In this new study, they are now investigating if these lung function deficits also occur in children. The next thing they will do is to analyze their data.

In another line of research, investigators are considering how arsenic causes adverse effects and why these may be different for different people. Some people appear to be more susceptible to arsenic. Past research suggests that this greater susceptibility to arsenic may be related to how well people metabolize or methylate arsenic. In both the Chile and Bangladesh study, we are investigating susceptibility related to methylated forms of arsenic in urine samples with our collaborators at the University of Washington.

2009

Arsenic is ranked first on the most recent priority list of Superfund site hazardous substances. In addition, millions of people are exposed to arsenic through naturally contaminated groundwater. This project explores the effects of childhood arsenic exposure and the mechanisms that may confer susceptibility to these effects.

We have continued our investigations of early life exposure to arsenic in studies in Chile and Bangladesh. In Chile, we have continued a lung cancer case-control study, which includes interviewing patients with lung cancer who had exposure to high concentrations of arsenic in their drinking water when they were young children. Subjects from unexposed regions who have been diagnosed with lung cancer at young ages are also included. Data on arsenic exposure, occupational history, smoking status and diet are being collected in cases and age and gender matched controls. In Bangladesh we have continued the study of lung function in arsenic-exposed children. Our earlier studies in West Bengal, India showed major lung function deficits in adults with evidence of high arsenic exposure. In this new investigation, we are now examining how these lung function changes also occur in children. We have been very pleased with the quality of spirometry our collaborators are achieving in the field.

Several studies have shown that susceptibility to arsenic could be related to how well people metabolize or methylate arsenic. In both the Chile and Bangladesh studies, we are investigating susceptibility related to methylated forms of arsenic in urine samples with our collaborators at the University of Washington. Unfortunately new methods to detect the highly unstable metabolite of arsenic (MMA3) have not been successful. MMA3 is highly toxic in vitro and some data suggests it could be the primary toxic species. However MMA3 is likely to be correlated with total MMA (MMA3+MMA5), so the speciation of arsenic in urine is continuing by measuring inorganic arsenic, total MMA and total DMA.

During 2009, The Arsenic Health Effects Research Program published their findings showing that lung cancer risks depend on the absorbed dose of arsenic, whether arsenic is ingested or inhaled. We also published an invited paper for the Annual Reviews of Public Health in which we reported recent findings concerning arsenic and human health, including findings related to arsenic methylation, and findings form studies involving early life exposure. We also published our kidney cancer findings showing that early-life exposure resulted in increased mortality rate ratios of 7.1 (3.1–14) for young adults aged 30 –39 years, born just before or during the high exposure period.

2008

Drs. Allan Smith and Martyn Smith have continued their investigations of early life exposure to arsenic in studies in Chile and Bangladesh. In Chile, they have continued a lung cancer case-control study, which includes interviewing patients with lung cancer who had exposure to high concentrations of arsenic in their drinking water when they were young children. Subjects from unexposed regions who have been diagnosed with lung cancer at young ages are also included. Data on arsenic exposure, occupational history, smoking status and diet are being collected in cases and age- and gender- matched controls. In Bangladesh the researchers have continued their study of lung function in arsenic-exposed children. Earlier studies in West Bengal, India showed major lung function deficits in adults with evidence of high arsenic exposure. In this new investigation, they are now investigating if these lung function changes also occur in children. The group has been very pleased with the quality of spirometry their collaborators are achieving in the field.

Several studies have shown that susceptibility to arsenic could be related to how well people metabolize or methylate arsenic. In both the Chile and Bangladesh study they are investigating susceptibility related to methylated forms of arsenic in urine samples with collaborators at the University of Washington. New methods to detect the highly unstable metabolite of arsenic (MMA3) are being developed. MMA3 is highly toxic in vitro and some data suggests it could be the primary toxic species. Levels of MMA3 and other arsenic forms will be assessed in both the Chile and Bangladesh studies.

During 2008 the researchers reported their findings concerning mortality from childhood liver cancer in northern Chile for children who have high exposure to arsenic in early life. Those exposed as young children had a ten-fold increase in liver cancer mortality.

2007

Drs. Allan Smith and Martyn Smith have shown that in utero and early childhood exposure to arsenic results in major increases in lung cancer and bronchiectasis mortality in young adults aged 30-49. During this last year, Smith and Smith also reported their findings of more than a 3-fold increase in mortality from acute myocardial infarction in young adults who had early life exposure to arsenic in drinking water. Based on these findings, the Berkeley researchers involved in this project believe that arsenic in drinking water is the first known common early life exposure to be strongly linked to disease incidence and mortality in adulthood.

Smith, Smith and their research team have commenced further investigations of early life exposure to arsenic in studies in Chile and Bangladesh. In Chile, the research group has commenced a lung cancer case-control study, which includes interviewing patients with lung cancer who had exposure to high concentrations of arsenic in their drinking water when they were young children. Subjects from unexposed regions who have been diagnosed with lung cancer at young ages are also included. Data on arsenic exposure, occupational history, smoking status and diet is being collected in cases and age and gender matched controls. In Bangladesh project leaders have commenced a study of lung function in arsenic-exposed children. Earlier studies in West Bengal, India showed major lung function deficits in adults with evidence of high arsenic exposure. In this new investigation, Dr. Allan Smith and Dr. Martyn Smith will now investigate if these lung function changes also occur in children.

Several studies have shown that susceptibility to arsenic could be related to how well people metabolize or methylate arsenic. In both the Chile and Bangladesh study the researchers are investigating susceptibility related to methylated forms of arsenic in urine samples with collaborators at the University of Washington. New methods to detect the highly unstable metabolite of arsenic (MMA3) are being developed. MMA3 is highly toxic in vitro and some data suggests it could be the primary toxic species. Levels of MMA3 and other arsenic forms will be assessed in both the Chile and Bangladesh studies.

The project investigators are also proceeding with the analysis of stored samples from previous Superfund projects in Nevada, Chile, and Argentina. Proteomic analyses of urine from subjects from the US have revealed differences in protein patterns between arsenic exposed and unexposed subjects. These differences have been confirmed using samples from arsenic exposed and unexposed subjects from Chile. Genetic analyses of the Argentina samples have revealed associations between several genetic polymorphisms and arsenic metabolism patterns. Both the projects, proteomic and genetic work, could lead to new information on mechanisms and arsenic susceptibility.

2006

Arsenic is ranked first on the most recent priority list of Superfund site hazardous substances. This project explores the effects of childhood arsenic exposure and the mechanisms that may confer susceptibility to these effects.

Project investigators are still in the planning stages of the project and achieved considerable success in finalizing their studies.

For the Chile lung cancer case-control study, the investigators have prepared the final study design details, tested the selection of controls, and established protocols for case ascertainment, seeking IRB approval, organizing arsenic exposure data, and locating potential staff and offices. As per the investigators timetable, project investigators expect to complete study set-up at the end of Year 1.

In the project investigators cross-sectional study in West Bengal of childhood and in utero exposure to arsenic and respiratory health and lung function in children the investigators expect to obtain R01 funding to conduct a larger study in Bangladesh with a similar study design, and are finalizing the details of that study. The investigators would then like to supplement the neighboring Bangladesh study with the children from West Bengal who were in the projects Superfund proposal.

Project investigators are also proceeding with the analysis of stored samples from their previous Superfund projects. Proteomic analysis of urine comparing subjects highly exposed to arsenic with unexposed subjects has begun in the Toxicogenomics laboratory. Aliquots from these same samples have also been sent to UC Davis for a pilot study of metabolomics. Genetic analyses from arsenic exposed and unexposed lung cancer cases and controls from Argentina have been completed and the statistical analyses comparing polymorphisms in cases and controls and in those with different arsenic methylation (metabolic) patterns are currently underway. Procedures for optimizing the proteomic analysis of urine from our subjects have been developed.

2005

Dr. Smith and his research team are now in the fifth year of their NIEHS Superfund program renewal focusing on the respiratory and early life effects of drinking water arsenic. During the last year, they found further evidence that some of the most serious consequences from exposure to arsenic in drinking water involve the lung, the reproductive system, and health impacts on children. The following paragraphs list some of the researchers’ key findings.

Their work in West Bengal includes the following: 1. They identified lung function deficits in men consuming high concentrations of arsenic in drinking water. These impacts were so strong, they exceeded those due to smoking (Am J Epidemiol 2005 Sep;162(6):533-41). These data are currently being used to evaluate dose-response relationships and susceptibility time-windows. 2. They used CT scans to show that bronchiectasis is greatly increased in subjects with arsenic-caused skin lesions (Epidemiology 2005 Nov; 16(6);760-5). 3. They identified increased rates of stillbirth in women with arsenic exposure (Am J Epidemiol, in press).

The research team’s work in Northern Chile, Argentina, and the US includes the following: 1. They have confirmed that mortality rates of lung cancer and bronchiectasis in subjects exposed to drinking water arsenic in utero or as young children are very high (SMRs: Lung cancer = 6.1, p < 0.001; Bronchiectasis = 46.2, p < 0.001). Because these findings are based on ecological data, they are currently gathering medical records on all bronchiectasis deaths in order to confirm diagnosis and residence in arsenic-exposed areas. 2. They performed two pilot studies (43 subjects in Chile and the US) of their new method for identifying MMA3, a highly toxic, but highly unstable, arsenic metabolite. 3. In a study of 175 Argentina and 87 US subjects, the researchers found that those who metabolize arsenic poorly have greater risks of bladder cancer than others (accepted, J Occup Environ Med). 4. In 175 Argentina subjects, researchers found that genetic polymorphisms in GSTM1 and MTHFR are associated with inter-individual differences in arsenic metabolism. 5. In a project involving 130 water sources in Nevada, they have found that two arsenic field test kits can be highly accurate compared to laboratory measurements (R = 0.97, p<0.001). 6. The researchers are in the final stages of data collection in their Argentina lung cancer case-control study and are currently doing planning work for a lung cancer case-control study of early life arsenic exposure in Chile.

They are continuing to explore the use of various biomarkers to explore arsenic exposure, toxicity, childhood exposure, and other susceptibility factors. For example, DNA is being extracted from lung tumors obtained in the team’s lung cancer study in Argentina and they are exploring genetic susceptibility in the highly arsenic-exposed population in India, taking advantage of new methods to study the human genome. Each advance in knowledge of arsenic health effects has led to further important questions for research including identifying important susceptible subgroups such as children and helping to determine why humans are 100-1000 times more susceptible to inorganic arsenic than experimental animals.

2004

Dr. Allan Smith and his research team are now in the fourth year of the renewal in which they made respiratory system effects of arsenic the main focus of their work for the NIEHS Superfund program. During the last year they have found further evidence that some of the most serious consequences of human exposure to arsenic in drinking water involve the lung. Indeed, the overall findings exceeded their expectations as far as the degree of pulmonary impact of arsenic is concerned, and they find that children are especially susceptible. Some key findings for the past year, or added to in the past year, include the following:

In West Bengal, India, the researchers have found major lung function deficits especially in men consuming high concentrations of arsenic in drinking water. The impact of arsenic in drinking water on lung function in this population exceeds that of smoking. The researchers have also shown in the same population using high resolution computed tomography (HRCT) that the occurrence of bronchiectasis is greatly increased in men with arsenic caused skin lesions.

In the North of Chile, where extensive drinking water contamination exposed a population of more than 300,000 people, lung cancer continues to be the major cause of death even many years after reductions in exposure. The researchers have now shown that lung cancer mortality is increased more than ten-fold in adults aged 30-39 who had high exposure as very young children. Also in the north of Chile the researchers have confirmed increased mortality from chronic obstructive pulmonary disease related to arsenic, and demonstrated that the mortality rates are markedly increased in those who had exposure in utero when their mothers were drinking the highly contaminated water.

In each of these study populations project investigators are continuing to explore the use of various biomarkers. DNA is being extracted from lung tumors obtained in our lung cancer study which continues in Argentina. In India, the researchers have been measuring micronutrients in blood samples, to see if malnourishment might increase the impact of arsenic. The investigators also obtain blood and urine samples from exposed populations and continue exploring genetic susceptibility to arsenic, taking advantage of new methods to study the human genome. In recent pilot work the investigators are exploring the measurement of arsenic in urine in the highly toxic methylated form known as MMA3. Each advance in knowledge of arsenic health effects has led to further important questions for research, and the researchers are yet to work out why humans are 100-1000 times more susceptible to the effects of chronic exposure to inorganic arsenic than experimental animals.

2003

Arsenic is ranked first on the priority list of Superfund site hazardous substances by the Agency for Toxic Substances and Disease Registry (ATSDR). Dr. Smith’s team has found that some of the most serious consequences of human exposure to arsenic involve the lung, and during the last year they continued to make further discoveries of the extent of pulmonary disease resulting from arsenic in drinking water. In the North of Chile, where extensive drinking water contamination exposed a population of more than 300,000 people, lung cancer continues to be the major cause of death even many years after reductions in exposure occurred after the installation of special water treatment plants. The researchers have now confirmed that there is a particularly high rate of mortality from both lung cancer and chronic obstructive respiratory disease (CORD) in young adults aged 30-39 who had very high exposure to arsenic in utero and in infancy, just before water treatment commenced. Since smoking does not usually cause such mortality until much older ages, these investigators think it probable that the cause is arsenic exposure of the mother during pregnancy, or exposure during infancy and early childhood of those who later developed lung cancer as young adults.

These findings of lung effects in Chile are now supported by results of the team’s studies in West Bengal, India. Here, millions of people in rural villages are exposed to arsenic in their wells. Currently, the team is completing the first respiratory function investigation of an arsenic-exposed population, which includes measurements with a portable spirometer in their homes, along with detailed arsenic exposure assessment, including testing of all wells from which participants have been drinking over the last 20 years. Remarkable reductions in pulmonary function have been found, especially in men who are exposed to arsenic in water and have developed classic arsenic-caused skin disease. Pulmonary effects of arsenic are found in both smokers and non-smokers, but why men are affected more than women in both skin and respiratory disease outcomes is a mystery. Given these findings in Chile concerning those exposed in pregnancy or childhood, the investigators are now turning attention to pulmonary development and respiratory function in arsenic-exposed children in the study population in India.

In each of these study populations, the researchers continue to explore the use of various biomarkers. DNA is being extracted from lung tumors obtained in the lung cancer study in Argentina. In India, they have been measuring micronutrients in blood samples, to see if malnourishment might increase the impact of arsenic. Project investigators also obtain blood samples from exposed populations and continue exploring genetic susceptibility to arsenic, taking advantage of new methods to study the human genome.

While there is still a long way to go, the past year has seen important progress in investigating both malignant and non-malignant pulmonary effects of inorganic arsenic, including health effects resulting from childhood exposure.

2002

The goal of this project is to examine populations exposed to high concentrations of arsenic in drinking water. The focus is on carcinogenic effects of arsenic in drinking water. The investigators hope to better define the exposure-response relationship of arsenic in water at concentrations of around 100 ug/L or lower. Most associations between arsenic and cancer involve higher concentrations of arsenic. Two bladder cancer case-control studies in areas with water sources around this level of arsenic have been completed in areas of California/Nevada and in Argentina. Both studies produced similar findings – associations with arsenic occurred only in smokers in association with arsenic exposures occurring more than 40 years ago. This adds to the evidence that arsenic may have a long cancer latency, and that it may require other factors to exert a carcinogenic effect.

Dr. Smith’s study in Chile, where the population was highly exposed to arsenic, particularly between 1957 and 1970, found high mortality rates for lung and bladder cancers in 1994-98, especially in those most highly exposed–which is additional evidence that the carcinogenic effects of arsenic have a long latency. A lung cancer study is also underway in Cordoba Province, Argentina; efforts are being made to obtain exposure data representative of periods further back than 40 years. To date, nearly half the desired 120 case-control pairs have been recruited. However, case identification has been slower than anticipated, possibly partly due to lower incidence rates than anticipated and possibly due to Argentina’s economic problems. Following the successful California/Nevada bladder cancer study, a lung cancer study will begin in the same area. It will use similar methods as the bladder cancer study, with refinements based on experience gained. The mortality study in Chile with our collaborators at the Catholic University of Chile is proceeding satisfactorily.

The findings of likely long latency in these studies emphasize the need to consider arsenic exposures occurring many years before cancer diagnosis; the findings of an interaction between arsenic and smoking suggest that the reason why arsenic has not been found to be a carcinogen in animal toxicology studies may be because most toxicology studies do not involve any co-carcinogen.

The ingestion of inorganic arsenic in drinking water is an established cause of skin lesions including alterations in skin pigmentation and keratoses of the palms and soles. People in West Bengal, India, along with neighboring Bangladesh, constitute the largest population in the world exposed to arsenic from drinking water. The objective was to determine whether nutritional deficiencies are associated with increased risks of arsenic-induced skin lesions. After taking into account an individual’s education, body size, and socioeconomic status, the strongest relationship with arsenic-induced lesions was found among people who had low vegetable fiber and low animal protein intake. This study suggests that low intake of animal protein and vegetable fiber increases susceptibility to arsenic-caused skin lesions. The finding concerning vegetable fiber is not necessarily specific to vegetable fiber itself, which is an indicator of overall vegetable consumption.

2001

The goal of this project is to examine populations exposed to high concentrations of arsenic in drinking water. In Argentina, researchers are performing a lung cancer case-control study that includes investigation of genetic polymorphisms in lung tumor biopsies. Case-recruitment has been slowed by Argentina’s economic problems. In West Bengal, we are following-up with individuals who participated in a survey in an arsenic affected region to study the relationship of non-malignant respiratory disease with ingested arsenic. In another West Bengal population, we will investigate the effects of arsenic on pregnancy and child development. Our study of chronic obstructive pulmonary disease in Chile has not yet begun. However, another NIH-funded study is well underway. This involves investigating the longitudinal mortality profile from diseases in a region where high arsenic exposure occurred during the 50’s and 60’s. This study will provide information on latent periods between arsenic exposure and mortality.

1997

A highlight of the year is the completion of a mortality analysis in an arsenic-exposed region of Chile whose results demonstrate a dramatic increase in mortality from bladder and lung cancer. The impact of arsenic on mortality in this region has been so great that it surpasses mortality from all environmental causes, including smoking. Between 5% and 10% of all deaths in those over the age of 30 could be attributed to arsenic in drinking water. These results provide further evidence that arsenic causes bladder, lung, and kidney cancer, and that ingestion of arsenic in drinking water can pose serious environmental cancer risks at high exposures. They also increase concerns about the current drinking water standard in the U.S. since the exposures in Chile are only about one order of magnitude above the U.S. drinking water standard.

Another highlight has been the development of a major arsenic research project in India. A large population in West Bengal has been ingesting arsenic from well water with tens of thousands having developed skin lesions due to arsenic. Project investigators collaborated on a cross-sectional study of about 7,000 people that showed a dose-response pattern between arsenic levels and skin lesions. This led to a proposal to E.P.A. (now funded) to investigate the dose-response relationship in greater detail with more extensive exposure data, and to examine susceptibility factors. The case-control study nested in the cross-sectional study is now commencing and includes dietary data and measurement of blood micronutrients. Both this and other projects planned in India are a direct spin-off from our Superfund support for arsenic research.

1996

This project has continued research into the risk of bladder cancer from drinking water contaminated with arsenic. During this year, analyses and published papers on the Chile intervention study, in which low arsenic water was provided to 40 homes in the town of San Pedro, located in a remote region of the Atacama desert of northern Chile, were completed. This unique study is the first intervention study involving arsenic exposed populations. Urinary arsenic levels decreased dramatically from over 700 ug/L to a little over 200 ug/L during the eight week period when water was trucked 100 kilometers and delivered twice a week to each home. One important finding is that the level of arsenic intake has little effect on arsenic methylation, and as a result of this study, it is now clear that methylation cannot be assumed to protect from the effects of inorganic arsenic at low levels of exposure (water containing about 45 ug-As/L).

This study was also the first study to examine the effects of intervention on a biomarker of effect of arsenic in bladder cells using the micronucleus assay. Biomarkers of effect offer a unique opportunity to examine the results of intervention in a relatively short period of time. In this instance, bladder cells, which turn over every two to three weeks, were examined for genetic damage (as determined by micronucleus formation) before and after the intervention. The findings are very important in that they demonstrate a reduction in genetic damage following the reduction in arsenic exposure.

1995

Application of the micronucleus assay in a population exposed to arsenic in Chile has shown that chromosome damage occurs in humans at relatively low levels of exposure. Methylation analysis on the same population demonstrated that humans are not protected by methylation at low levels of exposure. Both of these findings contribute significantly to scientific knowledge about the health effects of arsenic and provide important information relevant to policy makers. The current study in Argentina should continue to expand knowledge on these areas and others, including arsenic-related genetic changes, arsenic-smoking interactions, and genetic susceptibility to arsenic-related health effects.