métodos de investigación en epidemiología ambiental
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Craig Steinmaus MDUniversity of California Berkeleycraigs@berkeley.eduCoquimbo, Chile December 2016
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
Mining and smelting
Cr-Cu arsenate treated woodArsenic
pesticidesRoxarsone Most rice
Arsenic: common sources
#1 Natural arsenic in water
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
Region City or Town Population
Average Arsenic Concentration (g/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 <10Population data are based on the most recent Chile census
Concentrations of Arsenic in Drinking Water (µg/L) in Northern Chile by Year
Highly exposed in utero and early life
40+ YEARS
Long term impacts of early-life exposure: Antofagasta
Born here
Can
cer?
Smith et al., 1998 Am J Epidemiol 147:660-9
ECOLOGIC STUDIES OF CANCER MORTALITY IN REGION II VS. REST OF CHILE
ECOLOGIC STUDIES: Criticisms
Ecologic bias: no exposure information at the individual level
Confounding by…SmokingOccupationDietOther
In and out migration
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)
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 DoeYear City As (ug/L) % bottled Adjusted
Birth 1967 Antofagasta 860 0 8601968 Antofagasta 860 0 8601969 Antofagasta 860 0 8601970 Antofagasta 860 0 8601971 Antofagasta 860 0 8601972 Antofagasta 100 0 1001973 Antofagasta 100 0 1001974 Arica 8 0 81975 Arica 8 0 81976 Arica 8 0 81977 Arica 8 0 81978 Arica 8 0 81979 Arica 8 0 81980 Arica 8 0 81981 Arica 8 0 81982 Arica 8 0 81983 Arica 8 0 81984 Santiago 3 0 31985 Santiago 3 0 31986 Santiago 3 0 31987 Santiago 3 0 31988 Santiago 3 0 31989 Santiago 3 0 31990 Santiago 3 0 31991 Santiago 3 0 31992 Santiago 3 0 31993 Santiago 3 0 31994 Santiago 3 0 31995 Santiago 3 0 31996 Santiago 3 0 31997 Santiago 3 0 31998 Santiago 3 0 31999 Santiago 3 0 32000 Santiago 3 0 32001 Iquique 60 50 302002 Iquique 60 50 302003 Iquique 10 0 102004 Iquique 10 0 102005 Iquique 10 0 102006 Iquique 10 0 102007 Iquique 10 0 102008 Iquique 10 0 102009 Iquique 10 0 10
Interview 2010 Iquique 10 0 10
Arsenic water concentrations
Residential history
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 AcevedoSandra CortesMany others
Craig Steinmaus
Fenna Sille
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 cancerOR = 11.1 (3.60--34.2)#
Transitional cell
Bladder cancer OR = 6.88 (3.84-12.3)
Relative risks (RR) of lung cancer in former smokers
RR
Future Directions: Susceptibility
Highly exposed in utero and early life
Born here
40+ YEARS
Long term impacts of early-life exposure: Antofagasta
Born here
Can
cer?
Highly exposed as adults
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
LUNG CANCER ODDS RATIOS (OR)
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
OBESITY
ARSENIC
CANCERINFLAMATION
TNF-alphaIL-6CRP
Other possible mechanisms: oxidative stress, immune dysfunction, altered lipid metabolism
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
Odds ratios for arsenic and lung and bladder cancer: People with low BMI (<90th percentile)
Odds ratios for arsenic and lung and bladder cancer: People with high BMI only after age 40
Odds ratios for arsenic and lung and bladder cancer: People with high BMI only at age 20, not after
Odds ratios for arsenic and lung and bladder cancer: People with high BMI at age 20 and after
ENVIRONMENTAL EPIDEMIOLOGY
MOLECULAR BIOLOGY
Disease mechanisms
Surveillance
Disease screening
Early detection
Treatment
Breast cancer mortality in Region II (Antofagasta) vs. Region V
Smith et al., E Biomedicine [In press]
Breast cancer mortality in Region II (Antofagasta) vs. Region V
Breast cancer mortality in Region II (Antofagasta) vs. Region V
Breast cancer mortality in Region II (Antofagasta) vs. Region V
Biologic plausibilityArsenic is an effective treatment for promyelocytic leukemiaIn vitro experiments with cancerous and noncancerous breast cells
Environmental exposure
F2 germline
F1
F2
F3
Adult disease in the offspring (1st generation)
Health effect
Health effect (transgenerational)
FUTURE STUDIES?
TRANSGENERATIONAL EFFECTS
Epigenetics: Fetal and early-life is a time of major epigenetic (DNA methylation) programming
Anway et al., Science 308: 2005
Transgenerational impacts in humans: in Antofagasta?
1958-70High exposure
F0
F2
F1
F32016
Ages 0-22 years
cancer
cancer
???
???
SummaryEcologic and case-control studiesWho is most susceptible? Obesity and early-life exposureBreast cancer: complimentary epidemiologic and laboratory studies
Public Health RelevanceCurrent regulations do not incorporate susceptibility factorsMechanisms: 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 AntofagastaSuperfund: hypertension, diabetes, prostate cancer, stress in Region IIOther chemical exposures in northern Chile?
Research TeamCatterina FerreccioAllan H SmithMartyn SmithGuillermo MarshallJohanna AcevedoYan YuanSandra CortesLuoping ZhangFenna SilleJane LiawViviana DuránJohn BalmesSusana CuevasLee MooreJosé GarciaKen CantorRodrigo MezaDavid KalmanRodrigo ValdésRoxana ParraGustavo ValdésVania Villagra Hugo BenitezFrancisca GonzálezTeresa BarlaroVania VanderLindeJuan José AguirreMaria Isabel VásquezLiliana PérezJacqueline Calle
NIEHS P42ES04705, R01CA129558, R01ES014032
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