Determining Risks to Determining Risks to Background Arsenic Using a Background Arsenic Using a

Margin – of – Exposure Margin – of – Exposure ApproachApproach

Presentation atPresentation atSociety of Risk Analysis, New England Society of Risk Analysis, New England

ChapterChapterBarbara D. Beck, Ph.D., DABT, FATSBarbara D. Beck, Ph.D., DABT, FATSGradient CorporationGradient Corporation

January 23, 2008January 23, 2008

How Can Epidemiology be Used to How Can Epidemiology be Used to Inform the Understanding of Inform the Understanding of

Background Risks from Inorganic Background Risks from Inorganic Arsenic?Arsenic?

Multiple opportunities, Multiple opportunities, e.g. e.g. Identification of plausible “No Observed Identification of plausible “No Observed

Effect Level” for carcinogenicityEffect Level” for carcinogenicity Intake distributions, Intake distributions, e.g. e.g. from foodfrom food Host factors that modify carcinogenicityHost factors that modify carcinogenicity Evaluating plausibility of modeled dose Evaluating plausibility of modeled dose

estimates through use of urine arsenic estimates through use of urine arsenic population studiespopulation studies

Understanding the relationship between Understanding the relationship between arsenic metabolism and disease arsenic metabolism and disease

BackgroundBackground

Ingestion of inorganic arsenic (AsIngestion of inorganic arsenic (Asii)) Associated with skin, bladder, and lung Associated with skin, bladder, and lung

cancercancer Studies demonstrating carcinogenicity – Studies demonstrating carcinogenicity –

Taiwan, Bangladesh, Inner Mongolia, Taiwan, Bangladesh, Inner Mongolia, etc.etc. Relatively high exposures, frequently in Relatively high exposures, frequently in

poorly nourished populations poorly nourished populations No confirmed association in US populationsNo confirmed association in US populations Challenges in developing animal model of AsChallenges in developing animal model of Asi i

carcinogenesiscarcinogenesis

Background (Background (cont’dcont’d))

Prior risk assessmentsPrior risk assessments Cancer Slope Factors (CSFs) range Cancer Slope Factors (CSFs) range

from 1.5 to 23 (mg/kg-d)from 1.5 to 23 (mg/kg-d)-1-1

All based on Taiwan dataAll based on Taiwan data Different cancer types (skin, bladder, Different cancer types (skin, bladder,

lung), absolute lung), absolute vs.vs. relative risk models, relative risk models, etc.etc.

All assume low dose linearityAll assume low dose linearity

Identification of NOEL Identification of NOEL Cancer Data from TaiwanCancer 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 Analysis of Taiwan Data by TownshipTownship

◊ =

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 Analysis of Taiwan Data by TownshipTownship

Suggests high background of Suggests high background of bladder and lung cancer in bladder and lung cancer in townships 0, 3, 5townships 0, 3, 5

Clear dose-response only in in Clear dose-response only in in townships 2, 4, 6townships 2, 4, 6

SMR > 100 at median HSMR > 100 at median H22O O concentrations > 150 concentrations > 150 µµg/L (CI = 42 - g/L (CI = 42 - 229 229 µµg/L)g/L)

ImplicationsImplications Offers alternate approach to LNT for evaluating Offers alternate approach to LNT for evaluating

cancer risks from ingestion of inorganic arseniccancer risks from ingestion of inorganic arsenic Determine the “No Effect” Drinking Water Level Determine the “No Effect” Drinking Water Level

based on epidemiological data and convert to a based on epidemiological data and convert to a dosedose

Equivalent to 0.013 mg/kg-d (Equivalent to 0.013 mg/kg-d ( “NOEL”) “NOEL”) Use Margin of Exposure (MOE) to compare Use Margin of Exposure (MOE) to compare

population dose to NOELpopulation dose to NOEL Approach compatible with US EPA cancer Approach compatible with US EPA cancer

guidelines and current understanding of arsenic guidelines and current understanding of arsenic mode of actionmode of action

Monte Carlo Exposure Monte Carlo Exposure Analysis for US PopulationsAnalysis for US Populations

3 main sources for background 3 main sources for background exposureexposure DietDiet WaterWater SoilSoil

Intake estimates based on Intake estimates based on population surveyspopulation surveys

Drinking WaterDrinking Water

Key Input Distributions

Parameter GM GSD 95th%

As Concentrations in Drinking Water (µg/L)

Groundwater 0.78 4.85 10.5

Surface Water 0.19 5.70 3.26

Drinking Water Intake (L/day)

Child 0.41 2.06 1.25

Adult 1.19 1.91 3.19

SoilSoil

Key Input Distributions

Parameter GM GSD 95th%

Soil Intake (mg/L)

Groundwater 45 1.85 124

Surface Water 22.5 1.85 61.9

As Concentration in Soil (mg/kg)

Child 5.2 2.23 19.5

Bioavailability

Vertices at 0.01, 0.16, 0.5

FoodFood

Key Input Distributions

Parameter GM GSD 95th%

Dietary Intake (µg/kg-day)

Child (1 to 6 years) 0.18 1.70 0.41

Adult 0.032 2.36 0.13

Summary of Results of Summary of Results of Probabilistic Exposure Probabilistic Exposure

Analysis Analysis

0.0E+00

5.0E-05

1.0E-04

1.5E-04

2.0E-04

2.5E-04

5th 25th 50th 75th 95th

Percentiles

AL

DD

(m

g/k

g-d

y)

Total

diet

water

soil

Intake at 50Intake at 50thth Percentile Percentile

Soil1.1%

Water35.4%

Diet63.5%

Use of Epidemiology to Use of Epidemiology to Evaluate Plausibility of Evaluate Plausibility of

IntakesIntakes 5050thth percentile = 7.1 x 10 percentile = 7.1 x 10-5-5 mg/kg-d mg/kg-d Can convert to potential urine Can convert to potential urine

concentrationconcentration 70kg70kg 0.8 – 2 L urine/day0.8 – 2 L urine/day 100% excreted in urine (our estimate)100% excreted in urine (our estimate)

= = ~ 2.5 to 6.2 µg arsenic/L urine~ 2.5 to 6.2 µg arsenic/L urine Comparable to 7.5 µg/L median from Comparable to 7.5 µg/L median from

KalmanKalman

Risk Calculation ResultsRisk Calculation Results

Mean 5th Percentile

50th Percentile

95th Percentile

MOE Estimatea 140 450 180 58

LICR Estimate – Based on IRIS CSFb of 1.5

1.4 x 10 -4 4.4 x 10 -5 1.1 x 10 -4 3.4 x 10 -4

LICR Estimate – Based on Alternative Valuec of 3.67

3.5 x 10 -4 1.1 x 10 -4 2.6 x 10 -4 8.3 x 10 -4

Notes:a – MOE calculation based on Point of Departure Value of 0.013 mg/kg-dayb – 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 AnalysisImplication of Analysis

Choice of dose-response model Choice of dose-response model criticalcritical 9595thth percentile risks exceed permissible percentile risks exceed permissible

criteria using recent CSF, based on LNTcriteria using recent CSF, based on LNT 9595thth percentile risks do not exceed percentile risks do not exceed

criteria using epidemiologically-based criteria using epidemiologically-based NOELNOEL

Sensitivity AnalysisSensitivity Analysis

Use of alternate assumptionsUse of alternate assumptions Increased or decreased intake from Increased or decreased intake from

each medium by 50%each medium by 50% Greatest impact was change in adult Greatest impact was change in adult

dietary intakedietary intake Changed Average Lifetime Daily Changed Average Lifetime Daily

Dose by +/- 23%Dose by +/- 23%

Sensitivity Analysis Sensitivity Analysis ((cont’dcont’d))

Uncertainty in NOELUncertainty in NOEL Use of lower confidence unit on dose of Use of lower confidence unit on dose of

42 µg/L (instead of 150 µg/L)42 µg/L (instead of 150 µg/L) 9595thth percentile MOE – 19 (versus 58) percentile MOE – 19 (versus 58)

Estimates of NOEL based on different Estimates of NOEL based on different diet and water intakes in Taiwan – more diet and water intakes in Taiwan – more “restrictive” NOELs, MOEs all > 13“restrictive” NOELs, MOEs all > 13

ImplicationsImplications

Use of epidemiological data to Use of epidemiological data to assess risks of ingestion of inorganic assess risks of ingestion of inorganic arsenic -- informative on multiple arsenic -- informative on multiple levelslevels Toxicity quantificationToxicity quantification Exposure assumptionsExposure assumptions Plausibility of resultsPlausibility of results