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