California, Nevada Arsenic Lung Cancer Case-Control Study


Millions of people are exposed to drinking water contaminated with arsenic, and extensive epidemiological evidence has demonstrated that these exposures can cause cancer. In fact, at high concentrations the levels of risk exceed those of any other known environmental carcinogen. At relatively low exposures such as those commonly found in the U.S., cancer risks from lifetime exposure could be above 1 in 1000 people, even at the newly proposed drinking water standard of 10 µg/L. In certain susceptible sub-populations, such as those who smoke or have poor diets, the risks may be even greater. Furthermore, our studies in Chile suggest particularly high risks for those drinking arsenic-contaminated water as children. Unfortunately, cancer risks at low exposures are uncertain since risk estimates to date involve extrapolation from high dose levels to lower exposures where the shape of the dose-response relationship is unknown. Such extrapolations are highly controversial. We therefore propose a population-based case-control study to assess the association of lung cancer with low to moderate levels of arsenic in drinking water. Current evidence indicates that lung cancer may be responsible for more deaths due to ingested arsenic than all other cancer sites combined, including bladder cancer. It is therefore particularly important to obtain a clear picture of the dose-response relationship for this cancer. The study area includes Kings County, California, and six counties in Nevada. These counties incorporate the largest population in the U.S. exposed to water supplies containing between 50 and 100 µg/L of arsenic. Most other water supplies in the study region contain less than 5 µg/L and thus provide a marked contrast in exposure. A total of 271 lung cancer cases diagnosed in the study area between 2002 and 2004 will be identified with rapid case ascertainment from local hospitals. Tumor biopsies will be archived for a potential subsequent study of DNA alterations. Random digit dialing and the rolls of the Health Care Financing Administration will be used to identify two controls for each case, frequency-matched by age and sex. Telephone interviews of all study subjects will be conducted to gather information on lifetime residential history and drinking water sources which will be used in conjunction with water arsenic measurements to construct exposure histories. A strength of the study is that exposure can be reliably ascertained retrospectively since it is largely dependent on residential history. Information on cigarette smoking will also be obtained and synergistic effects with arsenic assessed. Dietary information, medical history, and demographic data will be collected and analyzed for potential susceptibility factors. The proposed study has over 83% statistical power to detect a relative risk of 1.7, the risk predicted by linear extrapolation from high dose studies. The study has public health importance since finding the hypothesized relative risk would identify important health effects from low levels of exposure, whereas not finding increased risks would contribute to assurance about public health protection from the new drinking water standard.





University of California

Perchlorate and thyroid hormones in pregnancy and infants in southern California


The study is an analysis of perchlorate exposure and thyroid hormone levels in 2,300 pregnant women and their newborns in San Diego County, an area with known perchlorate drinking water contamination. Perchlorate is a highly stable oxidizing chemical used in many industrial applications, and millions of people in the US are exposed to perchlorate through contaminated food or water. Perchlorate competitively inhibits iodide uptake into the thyroid gland. Since iodide is required for thyroid hormone synthesis, this can cause a decrease in thyroid hormone production. This is a public health concern since adequate supplies of thyroid hormone are vital for proper brain and neurodevelopment, and even small decreases in this hormone during development have been linked to decreased IQ and other adverse neurological effects.


Intriguing new evidence from several human studies suggests that common environmental levels of perchlorate could alter thyroid function in certain susceptible subgroups, including the developing fetus, young children, pregnant women, or those with low intake of iodine or high intake of thiocyanate. (Thiocyanate is a chemical commonly found in food which, like perchlorate, can also competitively inhibit thyroid iodide uptake). Currently, despite widespread exposure, there is no US drinking water regulatory standard for perchlorate. But if these new findings are true, public health intervention might be needed to protect infants, children, and other potential susceptibility groups. Importantly, the new evidence on perchlorate is mostly based on studies with small sample sizes, ecologic data, or limited information on potential confounders or effect modifiers. Because of this, this new evidence must be confirmed.


The ongoing study takes advantage of thousands of blood and urine samples and questionnaire data already collected from pregnant women and their infants as part of a previous study in a perchlorate exposed area. We are using these samples to measure urine concentrations of perchlorate, thiocyanate, and iodide, and serum concentrations of thyroxine, thyroid stimulating hormone (TSH), free-thyroxine, and thyroid antibodies in 2,300 pregnant women. Bloodspot TSH levels have already been measured in all 2,300 of the newborns of these women (increased TSH is a highly sensitive marker of decreased thyroid hormone production). Umbilical cord blood in 857 mother-infant pairs are being used to measure perchlorate, thiocyanate, iodide, and thyroid hormones. All of these measurements will be used to investigate associations between perchlorate and thyroid hormones in pregnant women and their infants and examine interactions with iodide, thiocyanate, and thyroid antibodies. Data on maternal age, education, infant gender, birth weight, socioeconomic status, race/ethnicity, smoking, and other questionnaire information will be used to adjust for potential confounding and to investigate effect modification.


This study is the largest to date in pregnant women and infants with individual data on perchlorate exposure. It is also be the first to include large numbers of pregnant women with low iodine and high thiocyanate levels commonly found in the US. A major advantage of our study is the availability of thousands of biologic samples and questionnaire data that have already been collected in a large group of pregnant women and infants, from an area with known perchlorate contamination. The availability of these samples and data in a defined exposed community offers a unique opportunity to investigate perchlorate toxicity in important susceptibility groups, with accurate information on perchlorate exposure and potential confounding factors, and with good statistical power. The public health importance of this research lies in the widespread extent of perchlorate exposure, the finding that even small changes in thyroid hormones may alter neurodevelopment, and the intriguing, albeit preliminary, new evidence that infants, fetuses, and pregnant women may be particularly susceptible to perchlorate. Our ultimate goal is to provide information that can be used to help determine whether a US drinking water regulatory standard is needed protect these susceptible groups, and if one is needed, provide dose-response and other information that might be useful in developing a safe and effective public health standard.

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