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Determining Risks to Background Arsenic Using a Margin – of – Exposure ApproachPresentation atSociety of Risk Analysis, New England Chapter Barbara D. Beck, Ph.D., DABT, FATS Gradient Corporation January 23, 2008
How Can Epidemiology be Used to Inform the Understanding of Background Risks from Inorganic Arsenic? • Multiple opportunities, e.g. • Identification of plausible “No Observed Effect Level” for carcinogenicity • Intake distributions, e.g. from food • Host factors that modify carcinogenicity • Evaluating plausibility of modeled dose estimates through use of urine arsenic population studies • Understanding the relationship between arsenic metabolism and disease
Background • Ingestion of inorganic arsenic (Asi) • Associated with skin, bladder, and lung cancer • Studies demonstrating carcinogenicity – Taiwan, Bangladesh, Inner Mongolia, etc. • Relatively high exposures, frequently in poorly nourished populations • No confirmed association in US populations • Challenges in developing animal model of Asi carcinogenesis
Background (cont’d) • Prior risk assessments • Cancer Slope Factors (CSFs) range from 1.5 to 23 (mg/kg-d)-1 • All based on Taiwan data • Different cancer types (skin, bladder, lung), absolute vs. relative risk models, etc. • All assume low dose linearity
Identification of NOEL Cancer Data from Taiwan Figure from: Lamm, SH; Engel, A; Penn, CA; Chen, R; Feinleib, M. January 13, 2006. "Arsenic cancer risk factor in SW Taiwan dataset." Environ. Health Perspect. 39p.
Analysis of Taiwan Data by Township ◊ = Townships 2, 4, 6 □ = Townships 0, 3, 5 Figure from: Lamm, SH; Engel, A; Penn, CA; Chen, R; Feinleib, M. 2006. “Arsenic cancer risk confounder in southwest Taiwan data set.” Environ. Health Perspect. 114: 1077-1082.
Analysis of Taiwan Data by Township • Suggests high background of bladder and lung cancer in townships 0, 3, 5 • Clear dose-response only in in townships 2, 4, 6 • SMR > 100 at median H2O concentrations > 150 µg/L (CI = 42 - 229 µg/L)
Implications • Offers alternate approach to LNT for evaluating cancer risks from ingestion of inorganic arsenic • Determine the “No Effect” Drinking Water Level based on epidemiological data and convert to a dose • Equivalent to 0.013 mg/kg-d ( “NOEL”) • Use Margin of Exposure (MOE) to compare population dose to NOEL • Approach compatible with US EPA cancer guidelines and current understanding of arsenic mode of action
Monte Carlo Exposure Analysis for US Populations • 3 main sources for background exposure • Diet • Water • Soil • Intake estimates based on population surveys
Use of Epidemiology to Evaluate Plausibility of Intakes • 50th percentile = 7.1 x 10-5 mg/kg-d • Can convert to potential urine concentration • 70kg • 0.8 – 2 L urine/day • 100% excreted in urine (our estimate) • = ~ 2.5 to 6.2 µg arsenic/L urine • Comparable to 7.5 µg/L median from Kalman
Risk Calculation Results Notes: a – MOE calculation based on Point of Departure Value of 0.013 mg/kg-day b – Calculation based on CSF value presented in EPA’s IRIS database: 1.5 (mg/kg-day)-1 c – Calculation based on alternative CSF value used in recent EPA risk assessments: 3.67 (mg/kg-day) -1
Implication of Analysis • Choice of dose-response model critical • 95th percentile risks exceed permissible criteria using recent CSF, based on LNT • 95th percentile risks do not exceed criteria using epidemiologically-based NOEL
Sensitivity Analysis • Use of alternate assumptions • Increased or decreased intake from each medium by 50% • Greatest impact was change in adult dietary intake • Changed Average Lifetime Daily Dose by +/- 23%
Sensitivity Analysis (cont’d) • Uncertainty in NOEL • Use of lower confidence unit on dose of 42 µg/L (instead of 150 µg/L) • 95th percentile MOE – 19 (versus 58) • Estimates of NOEL based on different diet and water intakes in Taiwan – more “restrictive” NOELs, MOEs all > 13
Implications • Use of epidemiological data to assess risks of ingestion of inorganic arsenic -- informative on multiple levels • Toxicity quantification • Exposure assumptions • Plausibility of results