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Toenail arsenic and bladder cancer: findings from a cohort study of male smokers

Toenail arsenic and bladder cancer: findings from a cohort study of male smokers. Dominique S. Michaud Assistant Professor Department of Epidemiology Harvard School of Public Health, Boston. Outline. Arsenic and bladder cancer High dose studies Low dose studies

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Toenail arsenic and bladder cancer: findings from a cohort study of male smokers

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  1. Toenail arsenic and bladder cancer: findings from a cohort study of male smokers Dominique S. Michaud Assistant Professor Department of Epidemiology Harvard School of Public Health, Boston

  2. Outline • Arsenic and bladder cancer • High dose studies • Low dose studies • Arsenic measurements in toenails • Methods: ATBC study • Results • Discussion • Future directions

  3. High arsenic levels and bladder cancer • Ecological studies have consistently reported elevated mortality rates of bladder cancer in arsenic endemic areas: • Taiwan • Argentina • northern Chile

  4. High arsenic levels and bladder cancer • Elevated bladder cancer incidence and mortality rates have also been observed in cohort studies: • in arsenic endemic areas (Taiwan) • industrially contamination water (Japan) • Fowler’s solution (potassium arsenite)

  5. Risk levels in U.S. • EPA • 50 g/L in water supplies • 10 g/L by January 2006 • used extrapolation models to determine risk levels • National Research Council Subcommittee “Arsenic in Drinking Water Report”, 1999 and 2001 • reviewed the literature, used extrapolation models to assess risk • estimated that there are lifetime excess cancer risks in the U.S. for bladder and lung cancers at arsenic drinking water levels between 3-20 g/L

  6. Extrapolation studies--limitations • Risk assessment models make assumptions about dose-response curves • different models result in different risk estimates • Relied heavily on Taiwan data • differences in environment, diet and genetic susceptibilities in U.S. and Taiwan • Studies used for extrapolations had few bladder cancer cases

  7. Low-level arsenic and bladder cancer Chiou et al. (northeastern Taiwan) • arsenic in well-water: <0.15 g/L to >3,000 g/L • 8,102 residents were recruited • information on hx of well water intake, residential hx, smoking, disease hx, other characteristics collected by interview • obtained well water samples from 85% of households • incidence data obtained from annual interviews, community hospitals, cancer registry profiles, and national death certifications AJE 2001,153:411-18

  8. Low-level arsenic and bladder cancer Chiou et al. • 18 incident urinary tract cancers • 11 were transitional cell carcinoma • adjusted for age, smoking, gender, duration of well water drinking <10 10-50 50-100 >100 g/L 1.0 1.6 (0.3-8.4) 2.3 (0.4-14) 4.9 (1.2-20) 1.0 1.9 (0.1-32) 8.1 (0.7-98) 15.1 (1.7-139) AJE 2001,153:411-18

  9. Low-level arsenic and bladder cancer Bates et al. (Argentina) • arsenic levels: 0 to >200 µg/L, mean 164 µg/L • 114 case-control pairs, matched on age, sex, and county • water measurements for each residence • individual data on smoking, occupation, beverages • no association between exposure and bladder cancer risk overall • elevated risk among those with exposures 51-70 years prior to diagnosis (smokers only) AJE 2004,159:381-389

  10. Low-level arsenic and bladder cancer Bates et al. (Utah) • arsenic levels: 0.5 to 160 µg/L, mean 5 µg/L • case-control study • arsenic levels in public drinking water available from 88 community supplies in Utah • information on residential hx, drinking water source at each residence, hx smoking, occupation • cumulative exposure index (water intake/total fluid intake x duration residence x mean arsenic level town) AJE 1995,141:523-30

  11. Low-level arsenic and bladder cancer Bates et al. • 71 cases, 160 controls (lived in study town >½ lives) <33 33-52 53-73 >73 mg/L x yrs 1.0 0.69 (0.3-1.5) 0.54 (0.3-1.2) 1.00 (0.5-2.1) 30-39 years prior to 1978: <8 8-9 10-12 >13 mg/L x yrs 1.0 1.27 (0.4-3.6) 1.26 (0.4-3.6) 3.07 (1.1-8.4) AJE 1995,141:523-30

  12. Low-level arsenic and bladder cancer Kurttio et al. (Finland) • arsenic levels: <0.05 to 64 µg/L, median 0.14 µg/L • case-cohort study design • cohort: towns where <10% of water from municipal supplies, born 1900-1930, same address 1967-1980 • 884 incident bladder cases using Finnish Cancer Registry (1981-1995) • 4,590 persons selected in the reference cohort • sampled wells for 509 subjects (1996) • 275 controls available; 61 cases • 183 controls; 42 cases with questionnaire data Environ Health Perspect 1999,107:705-10

  13. Low-level arsenic and bladder cancer Kurttio et al. Relative risks adjusted for age, sex, smoking Latency <0.1 0.1-0.5 >0.5 µg/L Shorter 1.0 1.53 2.44 (1.11-5.37) Longer 1.0 0.81 1.51 (0.67-3.38) Environ Health Perspect 1999,107:705-10

  14. Low-level arsenic and bladder cancer Steinmaus et al. (Nevada and CA) • arsenic levels: 0 to >120 µg/L • controls frequency matched by age and gender • interview by telephone: residential hx, fluid intake hx, tap water from home and work, occupation, smoking hx • arsenic measurements obtained from Health Services, included historical measurements • linked residence to water arsenic measurement for each residence • 181 cases, 328 controls AJE 2003,158:1193-1201

  15. Low-level arsenic and bladder cancer Steinmaus et al. <10 10-80 >80 µg/L Highest 20-year average, 40-year lag 160 10 11 1.0 1.28 1.70 (0.73-3.96) Exposure 51-60 yr prior to diagnosis 166 3 12 1.0 0.73 1.86 (0.80-4.33) AJE 2003,158:1193-1201

  16. Low level arsenic studies: limitations • Water arsenic sources only • Changes in arsenic levels in water over time (not taken into account) • Selection biases: • healthier controls • restricted to those with available water measurements • Arsenic levels outside of study area (negligible) • Small numbers of bladder cancers • largest study had 181 cases • multiple sub-analyses

  17. Use of toenails to measure arsenic • Toenails grow slowly (several months to a year)—reflect internal dose 9-18 months prior to collection • Reproducibility over 6-year period • correlation for arsenic r=0.54 • Toenails used in study on arsenic and skin cancer (Karagas et al. AJE 2001)

  18. METHODS

  19. ATBC study • Alpha-Tocopherol and Beta-Carotene (ATBC) Prevention Trial • 29,133 male smokers • 50-69 years old • Living in southwestern Finland

  20. ATBC study • Alpha-tocopherol (50 mg/day) • Beta-carotene (20 mg/day) • 2x2 factorial design • Double-blind, placebo-controlled • Incidence of lung cancer

  21. ATBC study • Timeline Recruitment Trial Follow-up 1993 1985 1986 1987 1988 1998

  22. ATBC study • Exclusions at baseline: • smoked <5 cigarettes per day • history of cancer • a serious disease (limiting long-term participation) • users of vitamins E, A or beta-carotene supplements in excess of predefined doses

  23. Baseline characterisics • Health status • Smoking history • Height and weight • Education • Occupation • Physical activity • Dietary questionnaire

  24. Toenail samples • Toenails were collected from all participants at the time of recruitment (1985-1988) • A number of samples had been pulverized for previous studies; the remaining whole toenails were cleaned for external contamination

  25. Case ascertainment • Finnish Cancer Registry (FCR) • 95% complete within 0.8-years • Hospital Discharge Registry • Death Certificates • Histologically confirmed incident bladder cancer cases • 331 cases with toenail clippings

  26. Nested case-control design • 1:1 matching: • age (within 2-years interval) • date at toenail collection (+/- 1 month) • intervention group • smoking level (< or >35 years smoked)

  27. Arsenic determination • Nuclear Reactor Program, North Carolina State University • Neutron Activation Analysis (NAA): • Irradiated for 14 hrs each in the PULSTAR reactor at a power of 900 kW (with rotating exposure ports) and were left to decay for 5-6 days • Gamma spectroscopy system to analyze for arsenic

  28. Arsenic determination • Quality control: • Dogfish muscle and liver (certified by the National Research Council Canada) • Tuna (certified by the US National Institute for Standards and Technology) • Coefficient of variation (CV) % • 6.98 overall using reference material • 1.13 for three duplicate samples

  29. Detection limit and exclusions • 51 cases and 38 controls were excluded because they had non-detectable levels of arsenic (and when the detection limit was greater than 0.09 μg/g) • For 59 cases and 69 controls which also had non-detectable values but had detection limits equal or less than 0.09 μg/g, we assigned an arsenic value equal to the detection limit divided by 2. • The final sample size was 280 cases and 293 controls.

  30. Statistical analysis • Unconditional logistic regression models: • matching factors • smoking cessation • smoking inhalation • education level • place of residence • Tests for trend were conducted by using the median values for each quartile and modeling it as a continuous variable

  31. RESULTS Michaud et al. AJE 2004,160:853-859

  32. Toenail arsenic levels Cases (n=280) Controls (n=293) Median (range) Median (range) Arsenic level, g/g 0.110 (0.014-2.62) 0.105 (0.017-17.5) Karagas et al. 2001 0.089 (0.01 to 0.81) Nichols et al. 1998 0.088 (0.01 to 2.57) Garland et al. 1993 0.083

  33. Baseline characteristics Cases (n=280) Controls (n=293) Mean (SD) Mean (SD) Age, years 59.4 (5.1) 59.5 (5.0) Years smoked regularly 39.8 (7.4) 39.1 (8.0) Cigarettes per day 20.2 (7.8) 19.5 (7.8) Smoking inhalation, % Never/seldom 6.1 5.8 Often/always 93.9 94.2 Smoking cessation, % 15.4 16.0 Urban residence, % 45.4 38.9 Education level, % Primary school 67.5 70.0 High school 7.5 5.5 Vocational 20.4 20.8 University 4.6 3.7 Beverage intake, mL/d 1534 (471) 1569 (523)

  34. Arsenic and bladder cancer risk Median Cases Controls OR 95% CI arsenic level (g/g) Quartile 1 0.033 65 74 1.0 2 0.079 71 73 0.89 0.55-1.42 3 0.130 73 73 0.97 0.60-1.55 4 0.245 71 73 1.00 0.63-1.60 p trend=0.65 *Unconditional logistic regression models adjusted for matching factors, cigarettes/day (continuous) and years smoked (continuous).

  35. Arsenic and bladder cancer risk Median Cases Controls OR* 95% CI arsenic level (g/g) Percentile <50 0.050 136 147 1.0 50.1 – 75 0.130 73 72 1.10 0.73-1.64 75.1 – 90 0.198 37 44 0.93 0.56-1.54 90.1 – 95 0.333 20 16 1.38 0.68-2.80 95.1 –100 0.757 14 14 1.14 0.52-2.51 p trend=0.61 *Unconditional logistic regression models adjusted for matching factors, cigarettes/day (continuous) and years smoked (continuous).

  36. Arsenic and bladder cancer, by smoking duration Tertile of arsenic (g/g) 0.017 – 0.070 0.071 – 0.137 > 0.137 OR* OR 95% CI OR 95% CI Yrs smoked <35 1.0 1.14 0.5-2.9 1.30 0.6-3.1 36-45 1.0 0.90 0.5-1.5 1.16 0.7-1.9 >45 1.0 1.46 0.5-4.1 2.30 0.8-6.9 *Unconditional logistic regression models adjusted for matching factors, cigarettes/day (continuous) and years smoked (continuous).

  37. DISCUSSION

  38. Interpretation of toenail arsenic levels • Karagas et al. AJE 2000 • Collected data on water arsenic levels and compared them to toenail arsenic • N=280 • Water level range: 0.002 to 66.6 µg/L • Toenail arsenic: <0.01 to 0.81 µg/g • Correlations: 0.46 overall, 0.65 for > 1 µg/L • A 10-fold increase in water arsenic was associated with a doubling in toenail conc.

  39. Interpretation of toenail arsenic levels • Toenail arsenic levels in terms of water concentrations: 50th percentile = ~ 2 µg/L 75th percentile = ~ 10 µg/L 90th percentile = ~ 50 µg/L 95th percentile = ~ 100 µg/L

  40. Potential biological mechanisms • Induction of oxidative damage to DNA • Inhibition of DNA repair • Altered DNA methylation and gene expression • Changes in intracellular levels of p53 protein • Induction of apoptosis

  41. Strengths • Biomarker • Reflects internal exposure • Long-term marker • Prospective study • Samples collected prior to disease • Data on smoking, other potential confounders • Reasonable power

  42. Limitations • Measurement error • Relevant time period 30-40 years earlier • Mobility • Range of exposure • Generalizability • Men • Smokers

  43. Previous findings among smokers • Bates et al., U.S. • No association among never smokers • OR = 8.70 (90% CI = 1.7- 44) for high vs. low cumulative arsenic exposure 30-39 yrs prior to diagnosis • Kurttio et al., Finland • No association among never or ex-smokers • RR 6.9 (95% CI = 1.2-93) for >0.5 vs. <0.1 µg/L water arsenic levels • Steinmaus et al., U.S. • No association among never smokers • OR = 4.01 (95 % CI = 1.16-13.9) for >80 vs. <10 µg/day highest 20-year average

  44. Summary • No association between toenail arsenic and bladder cancer risk in ATBC study • Low level arsenic exposure is unlikely to explain a substantial excess bladder cancer risk

  45. Future directions • Studies with toenail arsenic levels in the U.S. • Larger case numbers • Longer latency periods • Data on selenium levels • Genetic susceptibility

  46. Acknowledgements • National Cancer Institute • Demetrius Albanes • Ken Cantor • Margaret Wright • Phil Taylor • National Public Health Institute, Finland • Jarmo Virtamo • Dept. Nuclear Engineering, North Carolina State University • Scott Lassell

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