1. Arindam Basu Presented for Doctoral Examination Saint Louis University, MO Diet, micronutrients, methylation in arsenic-caused skin lesions and health services research

2. Overview of the Presentation • Trace the arsenic epidemic • Discuss the mechanism of action of arsenic • Describe the links to health services research • Outline key studies linking arsenic exposure, diet, and micronutrients for skin lesions • Track back to health services research

3. Worldwide Arsenic Exposure

4. West Bengal and Bangladesh

5. For hundreds of years ... River Ganges begins somewhere here in the Himalayas (satellite image of the Himalayan Range). The rocks are laden with arsenic in the sediments Flows through the Indian plains Deposits the arsenic in the aquifers in the area as it enters Bay of Bengal

6. ... and over the last 30 years Villagers are digging a tubewell, shallow tubewells are the ones that reach less than 150 m deep and contain inorganic arsenic in the groundwater

7. ... dissolved in tube-well water, arsenic reached humans

8. Arsenic metabolic pathway InAsMMA5 MMA3 DMA3DMA5 MMA5 reductase GST-Omega -CH3 MMA3 methyltransferase (cyt 19) -CH3

9. Skin pigmentation changes Spotted Melanosis, very typical early appearance of arsenic poisoning

10. Keratosis of palms and soles Disfiguring loss of finger Bowen's disease

11. Lung and Bladder Cancer This chest xray shows a radioopaque large lesion in middle lobe: lung cancer Large bladder tumor

12. Patients with Skin Lesions Prevalence estimates are based on surveys Prevalence estimates are in percentages WB = West Bengal, BD = Bangladesh

13. The karma of arsenic poisoning POVERTY, SES MALNUTRITION ARSENIC HEALTH EFFECTS NEED SAFE WATER GI DISEASES, OTHERS

14. HEALTH SERVICES ARSENIC IN DRINKING WATER Prevent access; {safe water, needs assessment, policy, planning, best option} ENTERS HUMAN BODY ? FOOD INORGANIC ARSENIC MINIMIZE DAMAGE METHYLATION REQ ENZYMES METHYLATED ARSENICALS Micronutrients OUTCOMES TREAT & PLAN Expensive Inefficient LEAVES BODY THROUGH URINE

15. Diet, micronutrients, methylations DIET MICRONUTRIENTS AGE ARSENIC SKIN LESIONS SEX {METHYLATION} Genetics

16. The Building Blocks ARSENIC EXPOSURE & SKIN LESIONS DIET & SKIN LESIONS MICRONUTRIENTS & SKIN LESIONS DIET, MICRONUTRIENTS & SKIN LESIONS ARSENIC METHYLATION & SKIN LESIONS DIET, MICRONUTRIENTS & ARSENIC METHYLATION RELATING TO HEALTH SERVICES RESEARCH

17. What has been done and needed? • Dose-Response Relationship between Exposure and Skin Lesions • Diet and Arsenic-caused skin lesions • Micronutrients and arsenic-caused skin lesions • Expansion of the knowledge base: • Relationship between, diet, together with micronutrients on arsenic skin lesions • Arsenic methylation and skin lesions • Diet, together with micronutrients on arsenic methylation

18. Reina Haque, DN Guha Mazumder, Sambit Samanta and others. Epidemiology 2003;14:174-182 Arsenic in Drinking Water and Skin Lesions: Dose-Response Data from West Bengal, India

19. Arsenic exposure and skin lesions • Why Skin Lesions: • Hallmarks of chronic arsenic exposure • Can be debilitating, disfiguring, social isolation • Associated with increased risk of lung/bladder ca • Cancer risks can occur even without skin lesions • Prior evidence of arsenic and skin lesions This was a case control study nested within a larger cross-sectional survey of 7683 individuals conducted in the West Bengal State of India. Aim: To Assess the dose-response relationship between arsenic and skin lesions

20. N = 7683 Total 4815 consumed As < 500 ug/L 265 Cases 265 Controls 32 Moved 38 Moved 26 Too Ill 14 Too ill 15 DNP 213 CONTROLS 192 CASES

21. 7683 people sampled in the cross-sectional survey, house-to-house • Physicians were blinded to the status of cases and controls and they gave a complete physical examination to all people enrolled in the study • Detailed history of water intake from specific tubewells for each individual was taken IPGME & R, where the research was planned Village in Bengal about 100 miles away where study was conducted

22. Water was sampled from each tubewell that were used for at least 6 months in the last 20 years or lifetime • Average Exposure: Time-weighted average of the arsenic concentrations of different sources used for each person • Peak Exposure: Highest arsenic concentration in the source used for at least 6 months for the last 20 years or lifetime The researcher conducting the survey

23. Results table for dose-response effect Relation of the highest known arsenic concentration ingested with skin lesions Relation of the average arsenic concentration ingested with skin lesions Adjusted for age, sex, smoking, education, housing, education, occupation, BMI

24. Dose-response curve for average arsenic exposure

25. Relation between peak arsenic exposure and skin lesions

26. What came out of the dose-response study • Strong Dose-response trends for peaks and average exposure • Relationship not affected by adjustment for age, sex, housing status, smoking, body mass index • Next steps: • Would diet modify susceptibility to arsenic-caused skin lesions? • Would micronutrients impact susceptibility to arsenic-caused skin lesions?

27. Soma R Mitra, DN Guha Mazumder, Arindam Basu and others. Environmental Health Perspectives; (2004),112 (10): 1104-1109 Nutritional Factors and Susceptibility to Arsenic-Caused Skin Lesions

28. Diet and Skin Lesions • Taiwan studies suggested diet high in calories, low in protein --> increased risk • Small study Northern Chile --> risks similar if exposure comparable, in spite of good diet • Question: does diet or specific items increase susceptibility to arsenic-caused skin lesions? • First Systematic Study in Diet-As Skin Lesion

29. Sample selection: shown • House-to-house diet survey • Based on 24-hour diet recall • Plates, spoons used for measurements • 7-day average for some items • Information on arsenic caused skin lesion from physicians • Conditional and unconditional LR Dietician (background) conducting a diet survey

30. Diet Versus Skin Lesion Status Table Showing comparison between cases and controls on selected dietary variables. P-values are based on two-tailed paired T-tests. SD = Standard Deviation

31. Relationship between dietary variables and skin lesions Decrementing quintiles mean 1 = highest quintile (reference category), 2 = fourth quintile, 3 = third quintile, 4 = second quintile, 5 = lowest quintile

32. Take home for HSR: diet-skin lesion study • Deficiency of animal protein, calcium, fiber, folate, vitamin C ---> skin lesions • Why fiber? Why animal protein? • Undernutrition widespread in this population • Some evidence for diet • What are the roles of micronutrients?

33. Joyce Chung, Reina Haque, ..., Arindam Basu and others. Environmental Research (Article in Press) Blood concentrations of methionine, selenium, beta-carotene, and other micronutrients in a case-control study of arsenic-induced skin lesions in West Bengal, India

34. Micronutrients and Skin Lesions • Arsenic metabolism uses several micronutrients • What are the roles of micronutrients? • Indicators of recent nutritional status (transthyretin...) • Carotenoids (beta-carotene, retinol) • Cofactors (glutathione, methionine, homocysteine) • Antagonists (?selenium) • Nested case-control study

35. Methods • Sampling as before • Blood samples collected at the time of interview • Samples were frozen at 0 degree C @ field • Field >> Calcutta >> US for analysis • 180 samples available for analysis • If non-detectable, the data were considered as missing

36. Relationship between micronutrients and skin lesions

37. Message for HSR from micronutrient study • No hard evidence that blood micronutrients alone impact arsenic-caused skin lesions • Selenium, not associated • Next Steps: • How, diet, together with micronutrients relate to arsenic-caused skin lesions? • How diet, micronutrients, methylation, lesions interlinked

38. Diet, together with micronutrients on arsenic-caused skin lesions • Are there interactions between diet and micronutrients that are missing in individual studies? • Cases, controls from the cross-sectional survey • Diet variables from diet history • Blood micronutrients from the measurements already made • Stepwise logistic regression model building

39. Diet, together with micronutrients on arsenic methylation • Methylation known risk factor for arsenic-caused cancers • Micronutrients influence methylation (biology) • Epidemiologic evidence? • Data from spot urine samples collected at the time of interview • Little prior data available • Regression modeling Diet, Micronutrients Methylation Skin Lesions

40. Relationship between methylation and skin lesions • Methylation risk factor for skin cancers, little studied for arsenic-caused skin lesions • Outcome status obtained from survey • Methylation data from urine samples • INAS/MMA, MMA/DMA ratios Diet & Micronutrients Methylation Skin Lesions

41. What does this body of evidence mean for HSR • How likely will dietary interventions be based on epidemiological evidence? • What are the roles of micronutrient supplementation in face of diet deficiencies • Is it meaningful to invest in structures and processes that measure urine arsenic routinely? • How do we balance the cost-access-quality of care for diseases that have hidden environmental causal mechanism?

42. Paul Sanazaro, 1969 Afield that develops methodsfor improvingaccess to care,moderating the rate of medical careprices, and assuring the effectiveness of care

43. AHSR, 2000 Association of Health Services Research, June 24, 2000

44. An Emerging Model - Phase 4 Health Behavior Environment Population Characteristics Outcomes Perceived Health Status Evaluated Health Status Consumer Satisfaction Personal Health Practices Use of Health Services Health Care System External Environment Pre- Enabling Need disposing Resources Character- istics Source: Andersen, JHSB, 1995, Vol. 30 (March): 1-10

45. What's next? • Incorporate {Genes}, Environment into HSR • Bring about a cross-sectoral perspective • Look beyond traditional paradigms • Create an interface between HSR & Env Health

46. Good to the last drop?