Benchmark Dose Method Beyond Science and Decisions: From Problem - PowerPoint PPT Presentation

Use of Biomarkers in the Benchmark Dose Method Beyond Science and Decisions: From Problem Formulation to Dose- Response SRA, November 2010 Rita Schoeny, Ph.D. Senior Science Advisor U.S EPA Office of Water 1/3/2011 1 1

Disclaimer  The views expressed in this presentation are those of the authors and do not represent the policy of the U.S. EPA. These are the views of Robinan Gentry, Cynthia Van Landingham, Lesa Aylward, Sean Hays 1/3/2011 2 2

MeHg Hazard Characterization  Effects of adult exposure or during development range from mortality through subtle effects on ability to learn  Not likely to be a human carcinogen  Developing nervous system has been focused on as a sensitive target for low dose MeHg exposure  Human and animal evidence of cardiovascular effects – from adult and in utero exposure  Animal evidence of immune and reproductive effects  Mode of action is not established 1/3/2011 3 3

Three State-of-the-art Studies on Children, in utero exposure Faroes Seychelles New Zealand Northern Caucasian African Multi-ethnic 900 mother child pairs 200 mother child pairs 700 mother child pairs Cord blood, maternal Maternal Hair Maternal hair hair Pilot whale Variety of fish (mostly Shark (fish and chips) small reef fish) 2006 publication on Seychelles -- Effects in 8 to 10 Authors report no Effects in “IQ” tests measures BMD similar to Faroes for a few measures effects associated with mercury in kids up to 9 CVLT Long Delay years of age Finger Tapping Preferred Hand Boston Naming Test, DDST, McCarthy Scales, DDST, McCarthy Scales, CPT Reaction Time Continuous Performance Bailey Scales, WISC III WISC R Boston Naming Test With Cues Test, Finger Tapping, California Verbal Learning 1/3/2011 4 4

MeHg Dose Response ‘01  RfD = 0.1 µ g/kg/day (about 1.1 ppm hair, 5.8 ug/L blood) neuropsychological effects (test scores) in children exposed in utero through maternal seafood consumption  BMD set at level for doubling of the number of poor performers on tests (from 5% to 10% of the population)  UF = 10  Used Boston Naming Test as example BMDL (Lowest 95% Confidence Limit on Dose) Response x = 58 ug mercury / L blood ) Environmental e Empirical t a m Exposure Levels Range of i t s of Interest E Observation l a r t n e C (  Cord blood = maternal blood x x a% x t u l a f e D Range of r a e n L i Extrapolation x 0% RfD LED a ED a UF x NOAEL Nonlinear Default Dose x LOAEL 1/3/2011 5 5

Most U.S. Exposure is from Fish  Data from a large, continuing CDC study indicate distribution of MeHg blood levels 1 0.9 Cumulative Frequency 0.8 b – 7.8% (5.7%) women of 0.7 a childbearing age were above 0.6 Effect level, 0.5 Faroes RfD 0.4 RfD c 0.3 – Blood mercury higher in some 0.2 0.1 ethnic groups 0 0 10 20 30 40 50 60 – Fish consumption was Fishers, LA Hg in Blood (ppb) associated with increased blood Hg – Data from smaller, localized surveys show higher blood mercury than NHANES – Median blood mercury was 7.1 ppb, people eating fish from AR waters – Median was 25 ppb in 6 commercial fishers and family in LA (a) – Family in WI, 37- 38 ppb (ate sea bass twice/week) (b) – High income fish-eaters had greater than 80 ppb (c) 1/3/2011 6 6

Case Study Method  Development of risk values at doses above the Reference Dose (RfD)  Methylmercury – Dose-response information in humans – BMDs estimated using biomarkers (i.e., levels in hair and cord blood) – Multiple BMDs available – Sensitive human subpopulation (children exposed in utero )  Extension of the Benchmark Dose (BMD) method 1/3/2011 7

Biomonitoring Data  National Health and Nutrition Examination Survey (NHANES) – Blood concentrations or total and inorganic mercury – Data available in children (1-19) and women of childbearing age (14-45) – Population estimates 1 0.9 Cumulative Frequency 0.8 0.7 0.6 The BMDL 0.5 from Faroes 0.4 Istudy 0.3 RfD 0.2 0.1 0 0 10 20 30 40 50 60 Hg in Blood (ppb) 1/3/2011 8

4 Approaches  Approach 1 - Straight line is drawn from both the BMDL and BMD to the RfD, RfD is considered to be zero risk  Approach 2 - The appropriate BMD model is extrapolated to the RfD, risk at the RfD is zero  Approach 3 - The appropriate BMD model is extrapolated to the RfD and this risk is allowed to stand as an upper bound  Approach 4 - The appropriate BMD model is extrapolated using a threshold term, where the threshold value is judged to be the RfD, or some higher value. 1/3/2011 9

4 Approaches Response x Environmental Empirical Exposure Levels Range of of Interest Observation x x a% x Range of Extrapolation x 0% RfD BMDL BMD UF x NOAEL Nonlinear Default Dose x LOAEL 1/3/2011 10

Estimated Adverse Events Range of Range of Range of Estimiated number of organic Associated Risks Associated Risks Adverse Events Approach RfD (ppb) Population Mercury Upper Levels Most Likely Upper Bound Most Likely Bound -3 4.8×10 -4 to 2.6×10 -4 to 3.9×10 -3 5.8 Children (1 to 19 yrs) 6.3 - 9.9 256 389 3.2×10 -3 1.9×10 -4 to 3.2×10 -4 to 4.8×10 -3 5.8 Women (14 -45 yrs) 6.0 - 10.8 1276 1936 1.3×10 1 No Organic Blood Levels above 10.5 ppb 10.5 Children (1 to 19 yrs) -5 -4 10.5 Women (14 -45 yrs) 10.8 1 9 5.0×10 3.2×10 -5 -4 2 10.5 Women (14 -45 yrs) 10.8 1 43 2.5×10 3.0×10 -3 -3 10.5 Women (14 -45 yrs) 10.8 37 122 1.3×10 4.3×10 3 -3 4.3×10 -3 to 4.5×10 -3 to 1.9×10 -2 10.5 All US pop 10.6 - 42.9 3697 13275 1.3×10 4 Estimated Threshold of 77.8 ppb 10.5 Women (14 -45 yrs) 10.8 1/3/2011 11

Impact of Approach Approaches to Deriving Risks 0.014 0.012 0.01 Risk Level 0.008 0.006 0.004 0.002 0 0 5 10 15 20 25 Blood Mercury Level (ppb) Approach 1 BMD Approach 1 BMDL Approach 2 BMD Approach 2 BMDL Approach 3 BMD Approach 3 BMDL 1/3/2011 12

Strengths  Use of a biomarker, which is typically closer to the “target tissue” concentration than the use of external exposure concentration  Ability to evaluate the potential fraction of people exposed above and below the RfD – Assess the likelihood of adverse noncancer effects at a specified internal concentration – May be extended to an exposure level if information are available.  Ability to estimate potential risk at a specific dose or biomarker concentration above the RfD. 1/3/2011 13

and Limitations  Uncertainties (for other compounds) as to the relationship between biomarker and effects of concern.  Information characterizing the potential shape of the dose-response curve below the BMD/BMDL 1/3/2011 14

Science and Decisions  Address human variability and sensitive populations? – Intraspecies variability and sensitive populations are usually addressed by the use of an intraspecies uncertainty factor of up to 10 – this method can be used if measured biomarkers of exposure in sensitive subpopulations or selected populations, such as women of childbearing years, and evaluate the relationship to the RfD or the BMD/BMDL.  Address background exposures and responses? – C onsideration of the NHANES data focuses on background levels of compounds in the general population. This method can be extended to biomarker information for specific populations as well, if data are available. 1/3/2011 15

Science and Decisions 2  Allow the calculation of risk (probability of response for the endpoint of interest) in the exposed human population? – The method allows for the estimation of risk, based on the biomarker information from individuals (if available) or subpopulations at or above the RfD.  Work practically? – It is an easy method to apply, as long as the critical data are available. 1/3/2011 16

What’s Next?  Consideration of the available information (if any) on the potential MOA for the effects that are the basis of the RfD to inform which approach would be preferred.  Consideration of other compounds in NHANES which have been considered in the estimation of Chemical-Specific Biomonitoring Equivalents (BEs) and how this information can be used for additional application of the approaches demonstrated for methylmercury. 1/3/2011 17