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The Relationships of Arsenic Exposure from Drinking Water with the Risks of As-related Skin Lesions and High Blood Pressure in Bangladesh Yu Chen, PhD, MPH. Background. Early / Intermediate Arsenicosis -Skin lesions -Respiratory lesions -Edema -Neurological symptoms

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slide1

The Relationships of Arsenic Exposure from Drinking Water with the Risks of As-related Skin Lesions and High Blood Pressure in BangladeshYu Chen, PhD, MPH

health effects of chronic arsenic exposure from drinking water
Early / Intermediate

Arsenicosis

-Skin lesions

-Respiratory lesions

-Edema

-Neurological symptoms

Others

-Reproductive outcomes

-Children’s cognitive function

Late

Cancer

-Skin

-Bladder

-Lung

-Liver / Spleen

Neuro-vascular/Endocrine

-Hypertension

-Stroke

-Black-foot disease

-Neuropathy

-Diabetes mellitus

Health Effects of Chronic Arsenic Exposure from Drinking Water
health effects of arsenic longitudinal study heals
Health Effects of Arsenic Longitudinal Study (HEALS)
  • Source population created by well surveys
    • Well owners were interviewed to create a roster of all users of the tube wells (n=65,876)
  • Population-based sampling (7/2000-11/2001)
    • Eligibility criteria: 1) married, aged 18-65 years, 2) 5 years residency in the study area, and 3) users of one of the existing study tube wells for 3+ years.
  • 11,746 participants; 97.5% response rate (12,050 approached)
    • Demographics, lifestyle factors, water dinking patterns
    • A FFQ was administered and completed for 11,395 subjects.
    • Biological samples
    • Physical examination

Ahsan et al, J Expo Anal Environ Epidemiol. 2005

slide10

Population Survey

66,000 People

Descriptive

Studies

12,000 Cohort Members

Cross-sectional, Case-control Studies

Baseline Data

Interview

Clinical Examination

Tube-Well Water, Blood & Urine

Randomized Clinical Trial

Community Intervention Trial

Follow-up Data

Interview

Clinical Examination

Urine

Blood & Tumor Tissue (for Cases)

Case-cohort

& Nested Case-control Studies

Main Cohort Study

slide11
Cross-sectional and Case-control Analysis of Arsenic Exposure and Risk of Arsenic-induced Skin Lesion
arsenic induced skin lesions
Arsenic induced skin lesions
  • Hallmark of arsenic poisoning
  • Short latency, 6 mos to 10 yrs
  • Precursors of arsenic-related basal/squamous cell skin cancer
  • Four grades : melanosis -> spotted keratosis on palms/soles->diffuse keratosis on palms/soles->dorsal keratosis (Saha, 2003).
cross sectional and case control analysis of the baseline data
Cross-sectional and Case-control Analysis of the Baseline Data
  • Cross-sectional analysis
    • Comparison of 714 skin lesion cases and 10,724 non-cases
    • Dose-response relationship
    • Influences of lifestyle factors
  • Case-control analysis
    • Comparison of 600 skin lesion cases and 1000 controls
    • Influences of genetic factors
    • Influences of urinary As metabolites profile
  • Analysis methods
    • Logistic regression with generalized estimating equations (GEE)Adjusted prevalence odds ratios (PORs) and odds ratios (ORs)
measurements of arsenic exposure
Measurements of Arsenic Exposure
  • Well arsenic concentration (µg /l)
    • Measured in water samples from 5,966 wells by graphite furnace atomic absorption (GFAA)
    • water samples < 5 µg/L were reanalyzed by ICP-MS
  • Urinary arsenic concentration (µg /l)
    • Measured in spot samples of urine by GFAA, a detection limit of 1 mg/l
  • Cumulative arsenic index (CAI)
    • Function of duration of well usage in years, water consumption per day, and well arsenic concentration.
    • Example: 5 yrs 100 µg/L for 2L/day
          • (5*365.25*100*2)/1000 = 365.25 mg
  • Time-weighted As exposure measure (TWA)
    • Function of duration of well usage in years and well arsenic concentration.
    • Example: 5 yrs 100 µg/L and 5 yrs 200 µg/L → 150 µg/L
relative excess risk for interaction reri
Relative Excess Risk for Interaction (RERI)
  • Presence of interaction on the additive scale :

(Risk due to both high As and a susceptible factor) >

(Risk due to high As) + (Risk due to a susceptible factor) ?

ORboth – (ORAs only + ORsusceptible factor only)+1 > 0?

RERI, Synergy : RERI > 0 , 95% CI > 0

CIs will be constructed using standard delta method (Hosmer and Lemeshow 1992)

extension dose specific reri
Extension: Dose-specific RERI

RERI ≈POR31– (POR30 + POR01) +1 > 0?

slide19

Joint Effect of As Exposure and Low BMI

RERI =5.3- (0.8+3.3) + 1 = 2.2 (0.5-3.9)

5.3 (3.1-8.9)

Adjusted PORs for skin lesions***

0.8 (0.4-1.5)

3.3 (1.9-5.8)

BMI*

1.0 (Ref)

Time-weighted As concentration (µg/L)**

Ahsan et al., American Journal of Epidemiology In Press

slide20

Joint Effect of As Exposure and Male Gender

18.5 (8.7-39.1)

12.4 (5.8-26.5)

10.4 (4.8-22.2)

7.1 (3.3-15.3)

3.8 (2.0-7.4)

Adjusted PORs for skin lesions***

2.7 (1.2-6.1)

4.7 (2.1-10.2)

2.8 (1.2-6.3)

1.2 (0.5-2.9)

1.0 (Ref)

Time-weighted As concentration (µg/L)**

Ahsan et al., American Journal of Epidemiology In Press

slide22

Joint Effect of Arsenic and Tobacco Smoking in Men

RERI 1.7 (0.2-3.4)*

5.3 (2.8-10.0)

Adjusted PORs for skin lesions***

1.4 (0.7-2.7)

3.2 (1.5-6.5)

1.0 (Ref)

Time-weighted As concentration (µg/L)**

Chen Y et al., Epidemiology, In press

slide23

Joint Effect of Arsenic and Tobacco Smoking in Women

RERI = -0.1 (-4.4-4.2)

5.1 (2.0-13.2)

2.9 (1.0-8.8)

Adjusted PORs for skin lesions***

3.4 (1.7-6.8)

1.0 (Ref)

Time-weighted As concentration (µg/L)**

Chen Y et al., Epidemiology, In press

slide24

Joint Effect of As Exposure and Tobacco Smoking in Men

5.5 (2.8-10.9)

RERI = 2.8 (0.1-5.6)*

6.3 (3.1-13.0)

Adjusted PORs for skin lesions***

1.3 (0.6-2.9)

RERI = 2.0 (0.1-4.0)*

1.4 (0.7-2.7)

3.2 (1.5-6.5)

1.0 (Ref)

Time-weighted As concentration (µg/L)**

Chen Y et al., Epidemiology, In press

slide26

Joint Effect of As Exposure and Fertilizer use in Men

RERI = 1.3 (-0.2-2.9)

RERI = 1.0 (-0.2-2.2)

5.3 (3.1-9.1)

3.7 (2.2-6.4)

Adjusted PORs for skin lesions***

1.5 (0.8-2.6)

3.5 (2.1-6.1)

2.3 (1.3-4.0)

Ever use of Fertilizer

1.0 (Ref)

Time-weighted As concentration (µg/L)**

Chen Y et al., Epidemiology, In press

slide27

Joint Effect of As Exposure and Pesticide use in Men

2.3 (1.4-3.5)

3.7 (2.4-5.6)

Adjusted PORs for skin lesions***

1.0 (0.7-1.7)

3.0 (2.0-4.6)

3.7 (2.4-5.7)

Ever use of Pesticide

1.0 (Ref)

Time-weighted As concentration (µg/L)**

**As categories were based on quintiles in the overall

***PORs were adjusted for age, gender, BMI, and smoking status.

Chen Y et al., Epidemiology, In press

slide28

Joint Effect of As and Excessive Sun Exposure in Men

5.3 (3.0-9.3)

4.5 (2.6-7.8)

2.0 (1.0-3.9)

Adjusted PORs for skin lesions***

3.8 (2.8-5.1)

Work outside uncoverred

2.5 (1.9-3.5)

1.0 (Ref)

Time-weighted As concentration (µg/L)**

**As categories were based on quintiles in the overall

***PORs were adjusted for age, gender, BMI, and smoking status.

Chen Y et al., Epidemiology, In press

summary
Summary
  • Consistent dose-response relationships were found between As exposure and risk of skin lesions.
  • Male and/or thinner participants were more likely to be affected by As exposure.
  • Use of fertilizer and excessive sun exposure increase the susceptibility to risk of skin lesions due to As exposure.
  • Tobacco smoking and high level of As exposure synergistically increase the risk of skin lesions.
metabolism of arsenic
Metabolism of Arsenic

InAsV

GSH

InAsIII

SAM  SAH

MMAV

GSH

MMAIII

SAM  SAH

DMAV

(SAM)

MTHFR (Vitamin B2-dependent enzyme)

(SAH)

methods
Methods
  • Case control analysis of 594 cases of prevalent skin lesions and 1041 controls randomly selected from non-cases.
  • Urinary arsenic metabolites were speciated using a method by Heitkemper that employs HPLC separation of arsenobetaine (AsB), arsenocholine (AsC), As (III), As (V), MMA and DMA, followed by ICP-MS analysis.
  • Genotyping of SNPs in MTHFR and GSTO1 genes was performed using fluorescence polarization technique. 10% of samples were duplicated after re-labeling.
  • Haplotype pairs (diplotypes) were constructed using PHASE version 2.1 which is based on Bayesian statistical method.
associations of risk of skin lesions with urinary as metabolites
Associations of Risk of Skin lesions with Urinary As Metabolites

Ahsan et al., in preparation

slide35

Relationship between MTHFR Genotypes and Risk of Skin Lesions

Ahsan et al., in preparation

slide36

Joint Effect of As and MTHFR 677C→T Genotype

6.8 (1.5 - 30.5)

1.3 (0.4-4.3)

Adjusted PORs for skin lesions***

2.7 (1.7- 4.1)

1.1 (0.8-1.7)

MTHFR

(677 C/T mutation)

2.1 (1.6-2.7)

1.0 (Ref)

Time-weighted As concentration (µg/L)**

Ahsan et al., in preparation

slide37

Joint Effect of As and MTHFR 1298A→C Genotype

2.8 (1.8-4.3)

1.4 (0.9-2.1)

2.2 (1.5-3.4)

Adjusted PORs for skin lesions***

1.0 (0.6-1.5)

2.1 (1.2-3.7)

MTHFR

(1298 C/A mutation)

1.0 (Ref)

Time-weighted As concentration (µg/L)**

Ahsan et al., in preparation

slide40

Joint Effect of As and GSTO1 Genotypes

3.4 (1.3-8.9))

2.0 (0.8-4.9)

2.3 (1.6-3.4)

Adjusted PORs for skin lesions***

0.9 (0.6-1.4)

2.1 (1.5-2.8)

GSTO1 rs# 4925

1.0 (Ref)

Time-weighted As concentration (µg/L)**

Ahsan et al., in preparation

slide41

Joint Effect of As and GSTO1 Genotypes

2.6 (0.7-9.4)

1.2 (0.3-4.4)

2.4 (0.6-9.4)

Adjusted PORs for skin lesions***

1.2 (0.3-4.0)

GSTO1 rs# 11509438

1.0 (Ref)

0.4 (0.1-4.8)

Time-weighted As concentration (µg/L)**

Ahsan et al., in preparation

slide42

Joint Effect of As and GSTO1 Genotypes

3.0 (0.8-12.3)

1.4 (0.4-5.8)

3.0 (0.7-12.7)

Adjusted PORs for skin lesions***

1.0 (0.2-4.4)

GSTO1 rs# 11509437l

1.0 (Ref)

0.5 (0.03-5.9)

Time-weighted As concentration (µg/L)**

Ahsan et al., in preparation

other genes of interest
Other Genes of Interest
  • Oxidative Stress Genes
    • Myeloperoxidase (MPO)
    • Catalase (CAT)
    • Glutathione Peroxidase (GPX1)
    • Manganese Superoxide Dismutase (MnSOD)
  • DNA Repair Genes
    • 8-hydroxyguanine DNA Glycosylase (OGG1)
    • X-ray Repair Cross-complementing Protein 1 (XRCC1)
    • X-ray Repair Cross-complementing Protein 3 (XRCC3)
    • Xeroderma Pigmentosum of Complementation Group D (XPD)
    • DNA Ligase I (LIG1)
    • DNA ligase IV (LIG4)
summary45
Summary
  • Genes such as MTHFR and GSTO1 responsible for methylation of As can modulate As metabolism and also its health effects.
interaction between se and as
Interaction between Se and As
  • Metabolic interaction
    • As promotesbiliary excretion of Se,and vice versa
    • Detection of seleno-bis(S-glutathionyl) arsinium ion [(GS)2AsSe]-in bile (Gailer 2000).
  • Direct interaction/precipitation
    • Biologically antagonistic to each other
    • Insoluble selenide (As2Se) deposits in lysosomes.

Zeng et al, 2005

advantage of a case cohort study design
Advantage of A Case-Cohort Study Design
  • Direct calculation of a risk ratio without the collection of full information on every member of a cohort.
selection of study population for the case cohort study
Selection of Study Population for the Case-cohort study

HEALS Cohort 11,746 participants

9,727 both urine/blood samples, clinical examination

712 prevalent skin lesion cases

A random sample of 923 were used for genetics study; blood was used up.

8092 free of skin lesions

303 were taken as the case series

Baseline

Follow-up

11%

31 incident cases identified at follow-up 1, part of the 303

Subcohort 850

Follow-up

measurements of baseline as and se
Measurements of Baseline As and Se
  • Blood As and Se
    • In whole blood, by ELAN DRC II inductively coupled plasma-mass spectrometry (ICP-MS) equipped with AS 93plus Autosampler (Perkin Elmer, Norwalk, CT)
    • Blood Se is a indicator of long-term selenium intake (Willett WC 1996)
  • Water As
    • by graphite furnace atomic absorption (GFAA)
    • water samples < 5 µg/L were reanalyzed by ICP-MS
  • Total urinary As
    • by GFAA, a detection limit of 1 mg/l
measurements of dietary intakes
Measurements of Dietary Intakes
  • A validated semi-quantitative food frequency questionnaire (FFQ)
  • Validation study of the FFQ have shown moderate validity in measuring
    • Long-term intakes of nutrients including total fat, monounsaturated fat, polyunsaturated fat, saturated fat, protein, carbohydrate, dietary fiber, sodium, potassium, vitamin B6, vitamin B12, vitamin B2, folate, manganese, thiamine.
    • Specifically, correlations for Vitamin B2, B6, B12, and folate were 0.37, 0.39, 0.57, and 0.30 respectively
statistical analysis
Statistical Analysis
  • Follow-up time: baseline visit to follow-up visit
  • A Cox proportional hazards model (SAS procedure PHREG) to estimate rate ratios (RR)
  • Variance correction: Barlow’s robust variance estimator
  • Risk-set method: cases and subcohort were matched on age at the time of follow-up.
baseline nutrient intakes by quintile of blood se in subcohort
Baseline Nutrient Intakes by Quintile of Blood Se in Subcohort

Chen Y et al., Submitted.

slide61

Joint Effect of As Exposure and Low Blood Se on Risk of Skin Lesion

4.58 (2.33-8.99)

2.62 (1.30-5.28)

2.11 (1.01-4.34)

Adjusted IRRs for skin lesions***

3.40 (1.75-6.63)

1.85 (0.92-3.74)

1.00 (Ref)

Blood Se (µg/L)

Time-weighted water As (µg/L)

***Categories of blood Se and time-weighted water As were determined based on tertile and median values, respectively, in the subcohort. IRRs were adjusted for age, BMI, gender, and smoking status

summary62
Summary
  • Consistent dose-response relationships between the risk of skin lesions and all the As measures.
  • First prospective study that shows a protective effect of Se on risk of skin lesions.
  • Higher blood Se level was related to as much as 50% reduction in risk of skin lesions.
  • Participants with higher blood Se levels had lower urinary As levels.
  • Higher Se intake reduces the risk of As-related skin lesions at any given level of As exposure.
metabolism of arsenic64
Metabolism of Arsenic

InAsV

GSH

InAsIII

SAM  SAH

MMAV

GSH

MMAIII

SAM  SAH

DMAV

(SAM)

MTHFR (Vitamin B2-dependent enzyme)

(SAH)

measurements of blood pressure
Measurements of Blood Pressure
  • Measured for 97% of the study participants (n=11,458) using an automatic sphygmomanometer (Omorn HEM 712-C) at baseline.
  • A 2nd and a 3rd measurements for those with >=140/90 mm Hg for SBP/DBP at the 1st measurement.
  • Reliability study of 61 subjects have shown
    • Correlations among three measurements are 0.92 for SBP/DBP
  • Current hypertension medicine use
    • Extracted from questionnaire, 114 were identified
slide66

Methods

  • Association between As exposure and BP
    • Linear regression for SBP, DBP, and PP.
    • PORs for
      • Systolic hypertension (SBP ≥ 140 mmHg)
      • Diastolic hypertension (DBP ≥ 90 mmHg)
      • General hypertension (SBP ≥ 140 and/or DBP≥ 90 mmHg)
      • High pulse pressure (SBP-DBP ≥ 55 mmHg)
  • Interaction between As exposure and nutrient intakes on BP
    • Intake levels (low/high) of individual nutrients.
    • Combined intake level of folate, Vitamin B2, B12, and B6.
  • Subpopulation with longer-term of time-weighted As concentration (well As known for ≥ 5 years).
arsenic exposure and high pp by intake levels of vitamin folate and b12
Arsenic Exposure and High PP by Intake Levels of Vitamin Folate and B12

Folate intake

B12 intake

Low

Low

High

High

arsenic exposure and high pp by composite measure of folate and b vitamins
Arsenic Exposure and High PP by Composite Measure of Folate and B Vitamins

2.1 (1.3-3.4)

2.0 (1.3-3.2)

1.9 (1.2-3.0)

Low

Medium

1.3 (0.9-1.7)

1.2 (0.9-1.6)

1.2 (0.9-1.6)

High

arsenic exposure and high systolic bp by composite measure of folate and b vitamins
Arsenic Exposure and High Systolic BP by Composite Measure of Folate and B Vitamins

2.1 (1.3-3.4)

2.1 (1.3-3.4)

Low

2.1 (1.3-3.4)

Medium

High

summary74
Summary
  • Arsenic exposure from drinking water, even at lower levels (<50 µg/L and <100 µg/L), was positively associated with the risk of systolic hypertension and high pulse pressure.
  • The associations were stronger in the subpopulation with 11.2 years of known well As on average (≥ 5 years).
  • This risk was more apparent among those with lower intake of Vitamin B2, B6, B12, and folate.
components of the multidisciplinary as mitigation program
Components of the Multidisciplinary As Mitigation Program
  • In-person Health Education
    • At the end of baseline visit, all study participants received person-to-person health education messages.
  • Well Labeling and Education Campaign at the Village Level
    • Metal placards with As concentrations were posted on each well after well-testing. In addition, an education campaign was launched at the village level. Covered 83% of study population.
  • Installations of Community wells
    • From 2001 to 2004, a total of 50 deep, low-arsenic community wells were installed in villages with high As exposure.
methods78
Methods
  • The first two-yearly follow-up visits took place between June, 2002 and June, 2004.
    • Extensive interview data, clinical data, and urine samples were collected at the follow-up visits.
  • Urinary As
    • All urine samples collected at baseline and at follow-up visits were analyzed for total As concentration by GFAA, using the Aanalyst 600 graphite furnace system.
  • Cox proportional hazard regression
    • 1) switching versus non-switching in participants with safe wells at baseline
    • 2) switching to safe wells versus non-switching or switching to unsafe/new wells in participants with unsafe wells at baseline.
slide82

Urinary As Reduction by Baseline Well As and Switching Status

Participants with an Unsafe Well at Baseline

-12%

-28%

-48%

-34%

-65%

-41%

Urinary creatinine-adjusted As (µg/g creatinine)*

Participants with a Safe Well at Baseline

+23%

-5%

-17%

-2%

-12%

*Additional adjustments were made for age, gender, and BMI

slide85

Summary

  • Total urinary As decreased by 22.1 % in the overall cohort and by 27.3 % in those with an unsafe well at baseline.
  • A total of 27% of the participants with an unsafe well at baseline switched to a safe well and their urinary As concentration decreased by 45.5 %.
  • Switching to a safe well was positively related to educational attainment, shorter distance to the nearest safe well, and well-labeling/village-level health education campaign
  • The reduction in urinary As was positively related to educational attainment, body mass index, never-smoking, absence of skin lesion, and time since switching.
future directions of heals
Future Directions of HEALS
  • Prospective evaluation of relationships between As exposure and incidence of skin lesions/skin cancer, cancer-related mortality, and CVD mortality.
  • Relationships of As exposure with biomarkers of cancer and preclinical CVD.
  • Effectiveness of remediation program.
  • Intervention trials of folate, Vitamin E, and selenium supplements.
slide87

Other Related Research Projects of HEALS

  • CC16
  • EGFR
  • Child IQ
  • Folate intervention
  • Selenium
acknowledgements
Columbia University

Health Sciences

Habibul Ahsan, MD

Joseph Graziano, PhD

Geoffrey Howe, PhD

Faruque Parvez, MS, MPH

Paul Brandt-Rauf, MD, DrPH

Earth Sciences

Lex van Geen, PhD

Yan Zheng, PhD

James Simpson, PhD

Martin Stute, PhD

Social Sciences

Alex Pfaff, PhD

Bangladesh

Dr. Mahmudur Rahman

Dr. AZM Iftikhar Hussain

Dr. Tariqul Islam

&

32 Member Field Team

Acknowledgements

Special Thanks to:Residents of Araihazar

Supported by U.S. National Institute of Environmental Health Sciences Grants # P42 ES10349 and # P30 ES09089.