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Métodos de investigación en epidemiología ambiental
- 1. Craig Steinmaus MD University of California Berkeley craigs@berkeley.edu Coquimbo, Chile December 2016
- 2. ENVIRONMENTAL EPIDEMIOLOGY: METHODS Arsenic: studies in northern Chile •Ecologic studies •Case control studies •Other aspects of study design Current focus and future directions: •Susceptibility: early-life exposure, obesity •Future studies: mechanisms, low doses, transgenerational effects
- 3. Mining and smelting Cr-Cu arsenate treated woodArsenic pesticides Roxarsone Most rice Arsenic: common sources #1 Natural arsenic in water
- 4. Few individual water sources, so few measurements needed Why Do Arsenic Studies In Northern Chile? Region II, Chile: “The driest habitable place on earth” Other Areas Worldwide: Most water from small private wells Thousands of water sources, so its hard to assess the everyone’s exposure
- 5. Region City or Town Population Average Arsenic Concentration (µg/L) Years 1930-57 1958-70 1971-77 1978-79 1980-87 1988-94 1995+ I Arica 168,594 10 10 10 10 10 10 9 Putre 1,799 1 1 1 1 1 1 1 Iquique 196,941 60 60 60 60 60 60 10 Huara 2,365 30 30 30 30 30 30 30 Pica 5,622 10 10 10 10 10 10 10 Pozo Almonte 9,855 40 40 40 40 40 40 40 II Tocopilla 21,827 250 250 636 110 110 40 10 Maria Elena 6,852 250 250 636 110 110 39 39 Calama 125,946 150 150 287 110 110 40 38 San Pedro 4,522 600 600 600 600 600 600 600 Antofagasta 270,184 90 860 110 110 70 40 10 Mejillones 7,660 90 860 110 110 70 37 10 Taltal 10,101 60 60 60 60 60 60 60 Recent migrants 82,312 <10 <10 <10 <10 <10 <10 <10 Population data are based on the most recent Chile census Concentrations of Arsenic in Drinking Water (µg/L) in Northern Chile by Year
- 6. Highly exposed in utero and early life 40+ YEARS Long term impacts of early-life exposure: Antofagasta Bornhere Cancer?
- 7. Smith et al., 1998 Am J Epidemiol 147:660-9 ECOLOGIC STUDIES OF CANCER MORTALITY IN REGION II VS. REST OF CHILE
- 8. ECOLOGIC STUDIES: Criticisms Ecologic bias: no exposure information at the individual level Confounding by… Smoking Occupation Diet Other In and out migration
- 9. CASE-CONTROL STUDY: METHODS Study design: Case-control study Study area: Regions 1 and 2 in Northern Chile Outcome: Lung (n=302), bladder (n=232), and kidney cancer (n=123) Time frame: All incident cases from 2007-2010 Case ascertainment: All pathology and radiology departments in the Regions Control ascertainment: Chile Electoral Registry (frequency matched on age and sex) Data collection: In home interviews, structured study questionnaire Exposure assessment: Lifetime residential history linked to an arsenic concentration in the public water supply of each city in Chile (90% coverage) Other data: Occupations, smoking, second hand smoke, medical history, diet, blood, sputum, rna-later, nails, urine Funding: NIH/NIEHS (R01 ES014032-01 and P42 ES04705) Ethics approval: UCB, PUC, Region II (Informed consent obtained)
- 10. 22. ¿En qué lugares ha vivido Ud. A LO MENOS 6 MESES? Período Lugares Fuente de agua potable en ese lugar Comuna Compañía de Agua municipal Embotellada Otra: Desde Hasta Localidad % % % a. 19 _____ 19 _____ b. 19 _____ 19 _____ c. 19 _____ 19 _____ d. 19 _____ 19 _____ Subject: John Doe Year City As (ug/L) % bottled Adjusted Birth 1967 Antofagasta 860 0 860 1968 Antofagasta 860 0 860 1969 Antofagasta 860 0 860 1970 Antofagasta 860 0 860 1971 Antofagasta 860 0 860 1972 Antofagasta 100 0 100 1973 Antofagasta 100 0 100 1974 Arica 8 0 8 1975 Arica 8 0 8 1976 Arica 8 0 8 1977 Arica 8 0 8 1978 Arica 8 0 8 1979 Arica 8 0 8 1980 Arica 8 0 8 1981 Arica 8 0 8 1982 Arica 8 0 8 1983 Arica 8 0 8 1984 Santiago 3 0 3 1985 Santiago 3 0 3 1986 Santiago 3 0 3 1987 Santiago 3 0 3 1988 Santiago 3 0 3 1989 Santiago 3 0 3 1990 Santiago 3 0 3 1991 Santiago 3 0 3 1992 Santiago 3 0 3 1993 Santiago 3 0 3 1994 Santiago 3 0 3 1995 Santiago 3 0 3 1996 Santiago 3 0 3 1997 Santiago 3 0 3 1998 Santiago 3 0 3 1999 Santiago 3 0 3 2000 Santiago 3 0 3 2001 Iquique 60 50 30 2002 Iquique 60 50 30 2003 Iquique 10 0 10 2004 Iquique 10 0 10 2005 Iquique 10 0 10 2006 Iquique 10 0 10 2007 Iquique 10 0 10 2008 Iquique 10 0 10 2009 Iquique 10 0 10 Interview 2010 Iquique 10 0 10 Arsenic water concentrations Residential history
- 11. UC Berkeley Arsenic Health Effects Research Group UC Berkeley Superfund Research Program US Collaborators Allan Smith Dave Kalman (University of Washington) Lee Moore (NCI) John Balmes (UCSF) Ken Cantor (NCI) Meera Smith Christine Skibola Luoping Zhang Chile PUC, Region II Catterina Ferreccio Guillermo Marshall Yan Yuan Jane Liaw Martyn Smith Johanna Acevedo Sandra Cortes Many others Craig Steinmaus Fenna Sille
- 13. 38 YEARS LONG LATENCY: Lived in Antofagasta during the high exposure period Lung cancer OR = 4.35 (2.57-7.36) No confounding by age, gender, mining work, SES, smoking, diet Steinmaus et al. Cancer Epidemiol Biomarkers Prev. 2013 22(4):623; Ferreccio et al. Am J Epidemiol. 2013 1;178(5):813-8 Kidney cancer OR = 11.1 (3.60-- 34.2)# Transitional cell Bladder cancer OR = 6.88 (3.84-12.3)
- 14. Relative risks (RR) of lung cancer in former smokers RR
- 16. Highly exposed in utero and early life Bornhere 40+ YEARS Long term impacts of early-life exposure: Antofagasta Bornhere Cancer? Highly exposed as adults
- 17. BLADDER CANCER ODDS RATIOS (OR) Steinmaus., Cancer Epidemiol Biomarkers Prev. 2014 23:1529-38 Cancer odds ratios comparing subjects exposed > 800 ug/L to those exposed ≤110 ug/l by each age of exposure
- 18. LUNG CANCER ODDS RATIOS (OR)
- 19. Smith et al. Environ Health Perspect. 2012;120:1527-31 Ecologic Mortality Study of Early life Exposure: SMRs for Antofagasta for subjects born during or just before the high exposure period
- 21. OBESITYOBESITY ARSENICARSENIC CANCER INFLAMATION TNF-alpha IL-6 CRP Other possible mechanisms: oxidative stress, immune dysfunction, altered lipid metabolism
- 22. Born BMI age 20 BMI age 40 BMI 10 years preceding interview ¿Cuál es su talla de adulto? _____”_____” Mtro. Cms. ¿Cuál ha sido su peso más frecuente en su vida de adulto? (En el caso de las mujeres no incluir peso durante el embarazo) a. en los últimos 10 años________Kgr. b. a los 20 años _________Kgr. c. a los 40 años (si es > de 590 años) _____Kgr. AGE
- 23. Odds ratios for arsenic and lung and bladder cancer: People with low BMI (<90th percentile)
- 24. Odds ratios for arsenic and lung and bladder cancer: People with high BMI only after age 40
- 25. Odds ratios for arsenic and lung and bladder cancer: People with high BMI only at age 20, not after
- 26. Odds ratios for arsenic and lung and bladder cancer: People with high BMI at age 20 and after
- 28. Breast cancer mortality in Region II (Antofagasta) vs. Region V Smith et al., E Biomedicine [In press]
- 29. Breast cancer mortality in Region II (Antofagasta) vs. Region V
- 30. Breast cancer mortality in Region II (Antofagasta) vs. Region V
- 31. Breast cancer mortality in Region II (Antofagasta) vs. Region V
- 32. Biologic plausibility Arsenic is an effective treatment for promyelocytic leukemia In vitro experiments with cancerous and noncancerous breast cells
- 33. Environmental exposure F2 germline F1 F2 F3 Adult disease in the offspring (1st generation) Health effect Health effect (transgenerational) FUTURE STUDIES? TRANSGENERATIONAL EFFECTS
- 34. Epigenetics: Fetal and early-life is a time of major epigenetic (DNA methylation) programming
- 35. Anway et al., Science 308: 2005
- 36. Transgenerational impacts in humans: in Antofagasta? 1958-70 High exposure F0 F2 F1 F3 2016 Ages 0-22 years cancer cancer ??? ???
- 37. Summary Ecologic and case-control studies Who is most susceptible? Obesity and early-life exposure Breast cancer: complimentary epidemiologic and laboratory studies Public Health Relevance Current regulations do not incorporate susceptibility factors Mechanisms: surveillance, prevention, screening, treatment Where To From Here? Epigenetics: current studies with Northwestern University (DNA methylation) and NCI (mRNA) Multi- and transgenerational? Other susceptibility: stress? Exhaled breath study in Antofagasta Superfund: hypertension, diabetes, prostate cancer, stress in Region II Other chemical exposures in northern Chile?
- 38. Research Team Catterina Ferreccio Allan H Smith Martyn Smith Guillermo Marshall Johanna Acevedo Yan Yuan Sandra Cortes Luoping Zhang Fenna Sille Jane Liaw Viviana Durán John Balmes Susana Cuevas Lee Moore José Garcia Ken Cantor Rodrigo Meza David Kalman Rodrigo Valdés Roxana Parra Gustavo Valdés Vania Villagra Hugo Benitez Francisca González Teresa Barlaro Vania VanderLinde Juan José Aguirre Maria Isabel Vásquez Liliana Pérez Jacqueline Calle NIEHS P42ES04705, R01CA129558, R01ES014032
Notes de l'éditeur
- I’ll use examples from our studies in Chile and elsewhere to discuss: 1. commonly used study designs in environmental epidemiology; the strengths and weaknesses of these designs, and what I see as some of the future directions in this field and where our research is heading
- Provide a little introductory information. Arsenic is a toxic element and there are a number of different exposure sources including…
- Arsenic in water causes a variety of health effects including cancer, heart disease, and skin lesions, and much of what we know about the toxicity of arsenic comes from research done in northern Chile, specifically Region II. This area has a number of very important features for doing arsenic research. First, because there is so little rainfall, there are few individual drinking water sources, with most water coming from a small number of rivers that flow down from the Andes Mountains. This is in contrast to other arsenic exposed areas worldwide (US, Bangladesh, Taiwan, India) where most water comes from small private wells, that is, wells used by only a few people or families. In these areas there are thousands of wells and arsenic levels can vary dramatically from well to well. Because of this, in order to have a good idea of the exposures in these populations arsenic must be measured in thousands or tens of thousands of different wells, a task that is incredibly time consuming and expensive, and usually impossible.
- Another major advantage for doing arsenic research in northern Chile is that arsenic levels have been measured in all the major water sources, with many records available from the distant past. This chart shows the arsenic levels in the larger cities and towns in Regions I and II since the 1950’s. Because we have such good records here records we simply need to know what city a person has lived in during what years to have a good idea of that person’s arsenic exposure, even from the distant past. This is important because as I will show you, we’ve found that these past exposures are the most important determinants of arsenic-associated cancer risks.
- An advantage of studying arsenic in this area is the distinct high exposure period that occurred in Antofagasta. In 1958 two rivers with high arsenic concentrations were diverted to the city for drinking. Then in 1970 an arsenic treatment plant was installed. Overall, this lead to a 13 period of high exposure in the city. Because there was no other major water source in the city, essentially everyone was exposed. This unique exposure scenario has allowed us a rare opportunity to examine the long-term impacts of being exposed in utero or in early childhood. That is, by looking at the health risks now, in people who were born during the high exposure period, we can assess the specific impacts that early-life exposure may have on the risks of adult diseases like cancer, diabetes, and hypertension.
- Our first studies in this area were “ecological”, that is, studies in which we simply compared the overall cancer rates in Region II to those in the rest of Chile. In this study design we only had data on whether or not people died of cancer and where they lived at the time of death. When looking at these data we found very high rates of bladder cancer, lung cancer, and skin cancer mortality in Region II compared to the rest of the country. This work was done in collaboration with Drs. Marshall and Ferreccio at PUC.
- The previous slides I showed on arsenic were from ecologic studies. Again, we only had information on the rates of death and the cities where the people lived at the time of death. We did not have data on their long-term residential history, where they were born, or data on potential confounders like smoking, diet, or other exposures.
- To respond to these criticisms we applied to and received funding from the National Institutes of Health in the US to do research in which we did collect individual data on arsenic exposure and potential confounding variables like smoking. Here we chose the case-control study design. This began with establishing a rapid case ascertainment system in which we identified all incident cases of bladder, lung, and kidney cancer in Regions I and II for the years 2007-2010. For a comparison group, we randomly selected people without these cancers from the Chile Electoral Registry, matched to cancer cases by age and gender. Each subject was then interviewed regarding their full residential history, smoking history, jobs, and other potential confounders.
- Each residence the subjects lived in throughout their lives was then linked to arsenic water records we had available for all the cities in Regions I and II so that we could assign an arsenic level to each year of each subject’s life, beginning at birth and ending at the time of interview.
- We assembled a team of Chilean and US researchers including…
- Under the leadership of Dr. Ferreccio we established a research infrastructure that included offices, laboratory facilities, research staff, and collaborators in the four largest cities in Regions I and II.
- Here are our findings. First, we focused on people who had lived in Antofagasta. This was done because this city had a very high arsenic exposure period beginning in 1958 when two rivers with high arsenic concentrations were diverted to the city for drinking, and ending in 1970 when an arsenic treatment plant was installed. As in our ecologic studies, we found very high rates of lung, bladder, and kidney cancer almost 40 years after the high exposure period ended.
- The prolonged high risks we saw for arsenic is unusual. For other carcinogens, like tobacco smoke, the risks of cancer drop fairly rapidly after the exposure ends. With arsenic we are finding something different: cancer risks are remaining high many years after the high exposures have ended. This highlights the importance of having data on exposure from the distant past when examining some environmental toxins like arsenic. That is, if we want to assess the true risks of certain environmental contaminants, we may need to examine exposure patterns over a period of decades.
- More and more research is not just focusing on whether or not environmental chemicals cause disease, but also if they do cause disease, who is most susceptible. This is important, because most current environmental regulations are based on the toxic effects seen in “normal” healthy individuals. If some groups are more susceptible to these chemicals then others, then these current regulations may not be adequately protective in these particular groups.
- An advantage of studying arsenic in this area is the distinct high exposure period that occurred in Antofagasta. In 1958 two rivers with high arsenic concentrations were diverted to the city for drinking. Then in 1970 an arsenic treatment plant was installed. Overall, this lead to a 13 period of high exposure in the city. Because there was no other major water source in the city, essentially everyone was exposed. This unique exposure scenario has allowed us a rare opportunity to examine the long-term impacts of being exposed in utero or in early childhood. That is, by looking at the health risks now, in people who were born during the high exposure period, we can assess the specific impacts that early-life exposure may have on the risks of adult diseases like cancer, diabetes, and hypertension.
- One potential susceptibility factor is age of exposure. In our Chile study, because we had data on lifetime exposure we could examine this issue. Here we looked at risks by age of exposure. These figures show the lung and bladder cancer odds ratios comparing high to low arsenic exposure groups for each age at which the exposure occurred. As can be seen, for both lung and bladder cancer, the odds ratios of cancer were higher when exposures occurred at younger vs. older ages. Data like this highlight the importance of having exposure data not just at one point in time but also over the entire period of a person’s life.
- Lung cancer had a slightly different pattern. Risks were still higher with earlier vs. later exposures, but the high risks continued for exposures throughout childhood. This period corresponds to the period of lung development (ages 0-20 years) suggesting that any time while the lung is growing is a period of potential susceptibility
- First set of studies Ecologic analyses of mortality Comparing Region II (Antofagasta) to the rest of Chile No info on migration (bias to the null) No info on confounders like smoking
- Next I’d like to talk about obesity. The topic of obesogens has received considerable attention recently. These are chemicals that are thought to increase obesity, and a variety of chemicals like pesticides, BPA and phthalates in plastics have been implicated (although data are somewhat inconsistent).
- In our Chile study, we’ve looked at obesity in a different way. Instead of looking at it as an effect of arsenic, we examined it as a potential susceptibility factor. Our decision to look at it this way was based on findings that both arsenic and obesity increase cancer, and both increase factors such as inflammation and oxidative stress that are also linked to cancer.
- Our questionnaire included questions about body mass index (BMI) for ages 20, 40, and for the 10 years before interview
- We had data on BMI at three points in time. Here is what we found. In people who had low BMI at all three time points we assessed, the risk (or odds) of cancer increased with increasing arsenic exposure, but only slightly (up to an odds ratio of about 3 at the highest arsenic exposure)
- In people who only had an elevated BMI at age 40 or afterwards (but not at age 20), the risks for arsenic-related cancer increased a little bit more
- In people with elevated BMIs at age 20, but not later, risks were even greater
- The strongest arsenic-cancer association was see in people with elevated BMIs both early (age 20) and later, with cancer odds ratios approaching 30.
- Another expanding area is the combination of basic epidemiology studies with laboratory studies aimed at helping to identify the mechanisms for the epidemiologic findings that are seen. An example of this is our work on arsenic and breast cancer.
- In this study we compared breast cancer rates in high arsenic Region II with those in Region V, a sociodemographically similar region with very little arsenic in drinking water. Before the high exposure period in Antofagasta (before 1958 when the high exposures started), the Region II and V breast cancer mortality rates were similar (relative risk = 1)
- However, during the high exposure period (1958-70), breast cancer rates dropped dramatically: about 50% overall, and about 60% drop for breast cancers in women under age 60.
- Since the high exposure period ended, the rates of breast cancer in Region II have begun to rise, slowly back up to those in Region V.
- The interesting features of these findings are that the rates dropped so much, and that they almost perfectly tract the high and low arsenic concentrations in Antofagasta. This makes it highly unlikely that some factor other than arsenic was the cause of this drop. In interviews we have had with physicians and public health officials we can find no reason to believe this drop is related to differences in screening, treatment, or known breast cancer risk factors.
- To help verify our epidemiologic findings we worked with laboratory scientists at Stanford University who dosed normal breast cells (black diamond) and breast cancer cells (others) with varying levels of arsenic. They found that some breast cancer cell lines (especially SKBR3 and MDA468) were killed at lower arsenic doses than normal (non-cancer) breast cells, suggesting that arsenic may preferentially kill breast cancer cells. This is an example of how bio-molecular laboratory data can be used to help add plausibility or clarity to new epidemiologic findings.
- Another topic that is receiving increasing attention in environmental epidemiology is the transgenerational effects of chemical exposures. In other words, can the adverse effects of environmental exposures be transferred across multiple generations so that your health is not just determined by your exposures but also those of your parents and grandparents. F0 = the exposed pregnant animal, F1 is the fetus, and F2-3 are subsequent generations.
- If this does occur, the most likely mechanism would be through epigenetics, and the most likely critical exposure period would be the fetal or early-life periods since these are times of major epigenetic re-structuring of the human genome. Epigenetics: factors like DNA methylation that controls the expression of genes DNA methylation may be a target site of early-life and fetal exposures because these early periods are periods of major reorganization of DNA methylation patterns in the human genome. As shown here, there is a major demethylation and re-methylation of the human genome in the developing gametes and in the early embryo.
- In fact, these types of transgenerational effects have been seen in animal studies. In this study, vinclozolin (a toxic pesticide) was given to pregnant rats whose offspring were then followed for up to four generations. As seen here, evidence of adverse impacts on sperm were not only seen in the immediate offspring (F1 generation) of the exposed rats, they were also seen up to four generations later, that is in the exposed rats grandchildren (F2), great grandchildren (F3), and great-great grandchildren (F4).
- Leads to the question: could we do a study of arsenic and transgenerational effects in northern Chile? In other words, our studies todate have involved people who were directly exposed during the high exposure period, either as an adult (F0) or as a fetus (F1). To date we have found high cancer rates in F0 and F1. But what about these peoples children or grandchildren? The F3 generation would have never been high highly exposed. But if adverse effects can be transferred through epigenetic effects in their grandparents, these ffects could potentially influence their health. There are few situations in the world like Antofagasta: where we have a very well documented period of high exposure, in the distant past, in a very large population, to a well known highly toxic agent like arsenic. This unusual scenario would be a rare and perfect situation to study to confirm the animal findings and see whether transgenerational toxicity may actually occur in humans.