Toenail arsenic and bladder cancer: findings from a cohort study of male smokers Dominique S....
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Transcript of Toenail arsenic and bladder cancer: findings from a cohort study of male smokers Dominique S....
Toenail arsenic and bladder cancer: Toenail arsenic and bladder cancer: findings from a cohort study of male findings from a cohort study of male smokerssmokers
Dominique S. MichaudAssistant Professor
Department of EpidemiologyHarvard School of Public Health, Boston
OutlineOutline
Arsenic and bladder cancer– High dose studies– Low dose studies
Arsenic measurements in toenails Methods: ATBC study Results Discussion Future directions
High arsenic levels and bladder cancerHigh arsenic levels and bladder cancer
Ecological studies have consistently reported elevated mortality rates of bladder cancer in arsenic endemic areas: – Taiwan– Argentina– northern Chile
High arsenic levels and bladder cancerHigh 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)
Risk levels in U.S.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
Extrapolation studies--limitationsExtrapolation 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
Low-level arsenic and bladder cancerLow-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
Low-level arsenic and bladder cancerLow-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
Low-level arsenic and bladder cancerLow-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
Low-level arsenic and bladder cancerLow-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
Low-level arsenic and bladder cancerLow-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
Low-level arsenic and bladder cancerLow-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
Low-level arsenic and bladder cancerLow-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
Shorter1.0 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
Low-level arsenic and bladder cancerLow-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
Low-level arsenic and bladder cancerLow-level arsenic and bladder cancer
Steinmaus et al.
<10 10-80 >80 µg/L
Highest 20-year average, 40-year lag160 10 111.0 1.28 1.70 (0.73-3.96)
Exposure 51-60 yr prior to diagnosis166 3 12
1.0 0.73 1.86 (0.80-4.33)
AJE 2003,158:1193-1201
Low level arsenic studies: limitationsLow 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
Use of toenails to measure arsenicUse 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)
ATBC studyATBC study
Alpha-Tocopherol and Beta-Carotene (ATBC) Prevention Trial
29,133 male smokers
50-69 years old
Living in southwestern Finland
ATBC studyATBC study
Alpha-tocopherol (50 mg/day)
Beta-carotene (20 mg/day)
2x2 factorial design
Double-blind, placebo-controlled
Incidence of lung cancer
ATBC studyATBC 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
Baseline characterisicsBaseline characterisics
Health statusSmoking historyHeight and weight EducationOccupationPhysical activityDietary questionnaire
Toenail samplesToenail 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
Case ascertainmentCase ascertainment
Finnish Cancer Registry (FCR)– 95% complete within 0.8-years
Hospital Discharge RegistryDeath CertificatesHistologically confirmed incident bladder
cancer cases – 331 cases with toenail clippings
Nested case-control designNested 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)
Arsenic determinationArsenic 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
Arsenic determinationArsenic 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
Detection limit and exclusionsDetection 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.
Statistical analysisStatistical 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
Toenail arsenic levelsToenail 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
Baseline characteristicsBaseline 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 16.0Urban residence, % 45.4 38.9Education 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)
Arsenic and bladder cancer riskArsenic and bladder cancer risk
Median Cases Controls OR 95% CI arsenic level (g/g)
Quartile1 0.033 65 74 1.02 0.079 71 73 0.89 0.55-1.423 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).
Arsenic and bladder cancer riskArsenic and bladder cancer risk
Median Cases Controls OR* 95% CI arsenic level (g/g)
Percentile<50 0.050 136 147 1.050.1 – 75 0.130 73 72 1.10 0.73-1.6475.1 – 90 0.198 37 44 0.93 0.56-1.5490.1 – 95 0.333 20 16 1.38 0.68-2.8095.1 –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).
Arsenic and bladder cancer, by smoking Arsenic and bladder cancer, by smoking durationduration
Tertile of arsenic (g/g) 0.017 – 0.070 0.071 – 0.137 > 0.137
OR* OR 95% CI OR 95% CIYrs smoked <35 1.0 1.14 0.5-2.9 1.30 0.6-3.136-45 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).
Interpretation of toenail arsenic levelsInterpretation 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.
Interpretation of toenail arsenic levelsInterpretation 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
Potential biological mechanismsPotential biological mechanisms
Induction of oxidative damage to DNAInhibition of DNA repairAltered DNA methylation and gene
expressionChanges in intracellular levels of p53
proteinInduction of apoptosis
StrengthsStrengths
Biomarker– Reflects internal exposure– Long-term marker
Prospective study– Samples collected prior to disease– Data on smoking, other potential
confoundersReasonable power
LimitationsLimitations
Measurement error– Relevant time period 30-40 years earlier– Mobility
Range of exposure
Generalizability– Men– Smokers
Previous findings among smokersPrevious 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
SummarySummary
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
Future directionsFuture directions
Studies with toenail arsenic levels in the U.S.
Larger case numbersLonger latency periodsData on selenium levelsGenetic susceptibility