Evaluating Secondary Data For Use In Chemical Risk Assessments

1. Cheryl Itkin and Susan Rieth U.S. EPA, ORD, NCEA Washington, DC U.S. EPA Annual QA Meeting San Antonio, TX May 14, 2009 Evaluating Secondary Data For Use InChemical Risk Assessments

2. Outline • Chemical Risk Assessments/IRIS Database • Study Types and Sources • Types of Secondary Data Used in Chemical Risk Assessments • Types of New Data Derived from Secondary Data • Secondary data QAPP • Literature Review Evaluation Criteria Checklist • Other Types of QA Assessments: Peer review • Case studies: Reject or Accept! You are the evaluator.

3. Chemical Risk Assessments • Report on specific environmental substances and their potential to cause human health effects. • Each report represents a concise synthesis and evaluation of the most relevant science available. ________________________________________________ This presentation is based on IRIS risk assessments. The Integrated Risk Information System (IRIS) is an electronic database of chemical risk assessments that provides both descriptive and quantitative information. http://www.epa.gov/IRIS Other chemical assessments that utilize secondary data include the Integrated Science Assessments (ISA), formerly called EPA Air Quality Criteria Documents for NAAQS pollutants.

4. Study Types and Sources • Types of studies: Epidemiological, toxicological, cancer studies, clinical, invitro studies, etc…. • Resources: • Papers from the peer-reviewed literature • NTP Study Reports • Review documents, including health reviews prepared by ATSDR, Cal EPA, Health Canada, IARC • NIH • EPA Pesticides • NIEHS • Study Reports from Industry • Unpublished studies

5. Types of Secondary Data Used in Chemical Risk Assessments Quantitative – • e.g., mean & standard deviation, incidence data • Individual animal data with all endpoints reported is sometimes available. Typically provided for histopathology findings in NTP bioassays. Qualitative – descriptive characterizations

6. Types of New Data Derived from Secondary Data • Quantitative – secondary data are used to derive values for IRIS oral RfDs and inhalation RfCs, and oral slope factors and inhalation unit risks for the carcinogenic effects of chemicals • Qualitative – secondary data used for assessment characterization (cancer weight-of-evidence characterizations)

7. Secondary Data QAPP: Document the Method for Evaluating Existing Literature (Handout) • QA Project Plan Template for data selection from Literature Reviews; describe the process of identifying and justifying content relevant to the assessment. • Checklist included in QAPP template

8. Planning Document (QAPP) • Document conducting a Literature Search: Extracting, proofing, presenting data from literature. Here’s general guidance: • Source(s) of existing data/information and rationale for selecting the sources (selection criteria) • Non-quality constraints on existing data that affect its use in this assessment (CBI, legal, programmatic) • How the data/information will be used • Procedures for determining the quality of existing data (ie. accuracy, completeness, limitations, representativeness) • Validation procedures (calculations & equations)

9. Literature Evaluation CriteriaBelongs in the QAPP • Why is this a key study? • New research • Confirms previous key study • Replaces weaker previous study • Best or only available study • Address 9 aspects: hypothesis, overall design, stat methods and reporting results, unit specification, missing data, consistent reporting, discussion of results, credible facility, published in a peer-reviewed journal, peer reviewed.

10. Literature Evaluation CriteriaQAPP: list specifics for evaluating animal studies from peer-reviewed literature • For studies in experimental animals, determine if the following are appropriately described: • Species, strain, # animals • Exposure protocol • Doses/concentration levels • Parameters monitored • All key/relevant findings • Numerical data accurately tabulated or reported in the text • NOAELs/LOAELs identified • Correct/appropriate inferences/conclusions

11. Literature Evaluation CriteriaQAPP: specifics for evaluating epidemiological studies from peer-reviewed literature • For human exposure studies, determine if the following are appropriately described: • Study design • # subjects & controls • Exposure issues addressed • All key/relevant findings • Numerical data accurately tabulated or reported in the text • Correct/appropriate inferences/conclusions

12. Other Types of Quality Assurance Activities Peer review provides independent evaluation of scientific and technical work products. • assumptions • calculations • extrapolations • interpretations • methodology • acceptance criteria • conclusions

13. Summary • Secondary data are being used effectively and frequently and can be qualitatively and/or quantitatively analyzed. • Document your methods for evaluating literature and reasons for accepting or rejecting a study. Discuss Case Studies Next

14. Case Studies for Discussion Carbon Tetrachloride (Sept ’09) Edwards, 1941 Nagano et al., 2007 Thallium (next 2 months) Wei, 1987 The external peer review drafts for both chemicals are posted on the IRIS web site under Recent Additions (2008)

15. Questions for Evaluation (Data Quality Objectives) • Is this study adequate for conducting quantitative analysis? (e.g., derive RfC, RfC, cancer slope factor) • Is this study adequate for a qualitative assessment? (develop weight of evidence characterization) • Discuss issues/concerns (for example): • Sufficient information provided for data analysis • Dosing period concerns • Reliability of incidence rate • Adequacy of study design • Strength of evidence (clear, some, equivocal, none, inadequate) • Occurrence of common vs uncommon neoplasia • Statistical significance

16. Case StudyCarbon Tetrachloride • Edwards,JE. 1941, Hepatomas in mice induced with carbon tetrachloride. J National Cancer Institute 2:197-199 • Adequate for qualitative assessment of potential to induce liver tumors • Not adequate for qualitative assessment of effect other than liver tumors • Not adequate for quantitative analysis Here’s why (issues): • Insufficient information provided to estimate administered dose • Single dose group • Dosing period too short for quantitative cancer assessment • Only liver tumor data provided • High tumor incidence in the only dose group tested (88 to 100%) does not support quantitative analysis

17. Case StudyCarbon Tetrachloride • Nagano et al., 2007b, [Japan Bioassay Research Center (JBRC), 1998] Inhalation carcinogenicity and chronic toxicity of carbon tetrachloride in rats and mice. Inhalation Toxicology 19:1089-1103 • Adequate for qualitative assessment and qualitative assessment of noncancer and cancer endpoints. Here’s why: • Two-year inhalation bioassay published in a peer-reviewed journal • Used a robust study design that included adequate group sizeds (50 animals/sex/group) and examination of a thorough set of noncancer and endpoints. • Results were adequately reported.

18. Case StudyThallium • Wei,1987,Studies on Spermotoxicity of Thallium Carbonate in Drinking Water and its Effect o Reproductive Function of Mice. Institute of Environmental Health Monitoring, Chinese Acadamy of Preventive Medicine, Beijing. Zhongua Yufang Zazhi 21 (3): 141-143. • Not adequate to use for quantitative analysis. Study findings were not considered sufficiently reliable to serve as basis for RfD derivation. Here’s why: • Low confidence in this study (non-reporting of several observations (water intake, body weights, behavior, and animal health) • # of animals examined for sperm and repro endpoints were indefinitively reported • Absence of reported sperm results and no explanation for loss of male mice • Supporting literature on the repro toxicity is limited

19. Contact Information ITKIN.CHERYL@EPA.Gov Director Quality Assurance, NCEA, ORD, USEPA, Washington, DC (Potomac Yards) (703) 347-8557 RIETH.SUSAN@EPA.Gov IRIS Team Leader, NCEA-IRIS, ORD, USEPA, Washington, DC (Potomac Yards) (703) 347-8582