Case Studies & Presentations

Workshop IX Case Studies and Presentations

Welcome

  • Andrew Maier, NIOSH Environmental Research Center at the University of Cincinnati

Introduction and Opening Remarks

  • Members of the Advisory Committee and Science Panel
  • Presentation

Overview of AOPs and best practices and OECD wiki

Case Study: Vicinal Dithiol Binding Cancer Adverse Outcome Pathway: Case Study with Inorganic Arsenic
Harvey Clewell, The Hamner Institute

 

Case Study: Vicinal Dithiol Binding Noncancer Adverse Outcome Pathway: Case Study with Inorganic Arsenic
Robinan Gentry, Ramboll ENVIRON


Frameworks for evaluating chemical alternatives

Joel Tickner, University of Massachusetts, Lowell

 

Case Study: A risk assessment methodology for flame retardants – the FR framework
Smadar Admon, ICL

 

Case Study: AOP for a mutagenic MOA for Cancer (AFB1 and HCC)
Lynn H. Pottenger, TERC, The Dow Chemical Company; Martha M. Moore, Ramboll ENVIRON

 

Workshop VIII Case Studies & Presentations

May 21-22, 2014

Introduction and Opening Remarks

 

Keynote Talk: EPA’s Risk Assessment Forum activity related to the Science and Decisions Report
Rita Schoeny, U.S. Environmental Protection Agency

 

Case Study: Weight of Evidence Approach for Chemicals with Limited Toxicity Data (silanes and siloxanes)
Tiffany Bredfeldt, Texas Commission on Environmental Quality

 

Beyond Science and Decisions Dose Response Assessment Framework
Lynne Haber, Toxicology Excellence for Risk Assessment

 

Dose-response assessment of a mixture of melamine and cyanuric acid in rats: practical challenges and outcome
Gonçalo Gamboa da Costa, National Center for Toxicological Research

 

Kids and Chemical Safety
Patricia Nance, Toxicology Excellence for Risk Assessment

 

Understanding Uncertainties and Confidence in Hazard Databases: An Example Using IRIS
Nancy Beck, American Chemistry Council

 

Case Study: Practical guidance on the development of a non-cancer hazard range
Ed Pfau of Hull and Associates and Rod Thompson of Alliance for Site Closure

The method presented in the Case Study Summary (as undergoing review by the science panel) is the development of hazard ranges for non-cancer endpoints.  This method is one of several addressed in the full case study,  “Guidance for Contaminated Sites:  TCE risk assessment case study.”   Key aspects of the method for developing hazard ranges for the non-cancer endpoint (originally applied to TCE) have been refined for more general application to other chemicals in the Case Study Summary.  The file on “additional chemicals” illustrates the application of the method to chemicals that have not undergone the depth of mathematical analysis used in EPA’s TCE assessment.

 

Lessons learned from the U.S. Endocrine Disruptor Screening Programs
Ellen Mihaich, ER2

 

Case Study Proposal: Comparative risk assessment of mixtures in fish
Michael Dourson, Toxicology Excellence for Risk Assessment
Coauthor: Moiz Mumtaz, Agency for Toxic Substances and Disease Registry

 

Workshop VII Presentation

November 13, 2013, Webinar

ARA Dose Response Framework Updates
Oliver Kroner, Toxicology Excellence for Risk Assessment

 

Workshop VI Case Studies & Presentations

May 28-29, 2013, Arlington, VA, U.S. Environmental Protection Agency

Welcome – Julie Fitzpatrick, U.S. Environmental Protection Agency

 

Introduction – Lynne Haber, Toxicology Excellence for Risk Assessment

 

Case Study: Endogenous Formation Implications for Formaldehyde Carcinogenicity
Robinan Gentry, Environ International Corporation; Tom Starr, TBS Associates; Jim Swenberg, University of North Carolina Chapel Hill; Jeffry Schroeter, Applied Research Associates

 

Keynote – Ken Olden, U.S. EPA, National Center for Environmental Assessment

 

Pathway-Based Regulatory Toxicology and Alternatives to Animal Testing
Thomas Hartung, Johns Hopkins Bloomberg School of Public Health

 

Recent International Developments in Mode of Action/Adverse Outcome Pathway Analysis
Bette Meek, University of Ottawa

 

Health and Environmental Sciences Institute (HESI) RISK21 Program
Tim Pastoor, Syngenta Crop Protection, Inc.

 

The HESI RISK21 Quantitative Key Events Dose Response Framework (Q-KEDRF)
Ted Simon, Ted Simon, LLC


Case Study: Naphthalene Carcinogenicity: Hypothesis-Based Weight-of-Evidence Evaluation

Lorenz Rhomberg, Gradient; Lisa Bailey, Gradient

 

Case Study: Interpretation of 24-hour Sampling Data
Texas Commission on Environmental Quality (TCEQ): Roberta Grant; Joseph “Kip” Haney; Allison Jenkins
Ontario Ministry of Environment (MOE): Denis Jugloff; Julie Schroeder

 

Workshop V Case Studies & Presentations

November 2, 2012, Webinar

The World Health Organization Chemical Risk Assessment Network 
Becki Clark, U.S. EPA, Kathy Hughes, Health Canada

Link

 

Advancing Multi-scale Integration of Human Health and Environmental Data: Computational and Conceptual Interoperability
Annie Jarabek, U.S. EPA

Link

 

FutureTox: Building the Road for 21st Century Toxicology and Risk Assessment Practices
J. Craig Rowlands, The Dow Chemical Company

Link

 

EPA’s NexGen Program
J. Craig Rowlands, The Dow Chemical Company

Link

Preliminary Case Study Review:  Endogenous Chemical Risk Assessments using Formaldehyde as a Case Example
Robinan Gentry, ENVIRON

Link

 

Workshop IV Case Studies & Presentations

May 22-24, 2012, Austin, Texas, Texas Commission on Environmental Quality

Introductions & Updates
Dose Response Advisory Committee
Tiffany Bredfeldt, Julie Fitzpatrick, Lynn Pottenger
Presentation

 

Keynote Talk: Incorporating New Technologies into Toxicity Testing and Risk Assessment: Moving from 21st Century Vision to a Data-Driven Framework
Rusty Thomas, The Hamner Institutes for Health Sciences
Presentation

 

Presentation of Beyond Science & Decisions Dose Response Framework and Discussion
Lynne Haber, Toxicology Excellence for Risk Assessment
Presentation

EPA’s Response to NRC Framework Recommendation: Framework for Human Health Risk Assessment to Inform Decision Making
Rita Schoeny, U.S. Environmental Protection Agency
Presentation

Update: Ethylene Oxide Mode of Action
William Gulledge, American Chemistry Council
Presentation

Update: The Occupational Alliance for Risk Science (OARS)
Jimmy Perkins, University of Texas Health Science Center
Presentation

Update: Naphtalene Mode of Action (MOA)
Lorenz Rhomberg, Gradient
Presentation

Update: Structure Activity Relationships Applied to Short Term Exposures
Tiffany Bredfeldt, Texas Commission on Environmental Quality
Presentation

Combined Exposures Framework
Bette Meek, Universit of Ottawa
Presentation

Case studies

Development of Screening Tools for the Interpretation of Chemical Biomonitoring Data
Richard A. Becker, Sean M. Hays, Steven Robison, Lesa L. Aylward, Christopher R. Kirman

 

Criteria Requirements for Data-Driven Carcinogenicity Mode of Action (MOA) Determinations as Exemplified by Chloroform
Chris Borgert, Applied Pharmacology Toxicology Inc.

 

Value of Information: Approach and Case Studies
Eric Ruder, Henry Roman

 

The Human Relevant Potency Threshold: Reducing Uncertainty by Human Calibration of Cumulative Risk Assessments
Chris Borgert, Applied Pharmacology Toxicology Inc.

Methods for Deriving Inhalation Effect Levels for Comparison to Health-Protective Values
Roberta Grant

 

Workshop III Case Studies & Presentations

May 4, 5, & 6, 2011, Falls Church, Virginia; Noblis

Presentation by Ed Ohanian, U.S. Environmental Protection Agency (EPA). NRC findings and Current EPA Risk Assessment Forum Efforts

 

Presentation by Adam Finkel, University of Pennsylvania Law School & NAS Panelist. Beyond Misleading Underestimation of Carcinogenic Potency

 

Presentation by Peter Grevatt, Office of Children’s Health Protection (No Slides; presentation on issues related to children’s health)

 

Presentation by Craig Rowlands, The Dow Chemical Company. ILSI Risk21

 

Presentation by Doug Wolf, U.S. EPA National Health and Environmental Effects Research Laboratory. Dose Response Approaches for Nuclear Receptor Mediated Modes of Action Workshop Preliminary Report

 

Workshop 3 Guest Speaker Presentations

 

Workshop Overview

 

Rita Schoeny, Environmental Protection Agency. Experience at EPA in Problem Formulation Relevant to both Ecological and Human Dose-Response Analysis

 

Bette Meek, University of Ottawa. Increasing Assessment & Management Efficiency – The Importance of “Fit for Purpose” MOA/ Human Relevance Analysis

 

James Swenberg, University of North Carolina. Endogenous and Background DNA Adducts as a Means of Understanding Mode of Action (MOA) in the Low End of the Dose Response Curve

 

Resha Putzrath, U.S. Navy. Low-Dose Linearity for Noncancer Risks and Dose Additivity for Mixtures

 

Case Studies

Case studies were presented at Workshops II & III. In some instances, studies presented at Workshop II were revised and the enhanced case studies were presented at Workshop III. In such situations, the both the “initial” and the “revised” presentations are provided below.
Panel Discussion Questions

 

Lead – Dose-response relationship for effect on Children’s IQ
Carrington C.D.

 

Background/Endogenous Damage: Considerations for Dose-Response & Risk Assessment
Pottenger L.H., Bus J.S., with support from J.A. Swenberg

 

Comparison of Hattis strawman approach and BMDs/UFs for noncancer endpoints (carbonyl sulfide and tetrachlorobenzene)
Greco S.L., Hattis D.H., Lynch M.K.

 

Quantitative Assessment of Sensitivity and Variability in Humans: Modeling the Effects of Low Dose Exposure to Dietary Residues of Chlorpyrifos   
Juberg D.R., Price P.

 

Risk Assessment of Exposure to Trihalomethane Drinking Water Disinfection By-Products.  Use of Biomonitoring Equivalents and Biomonitoring Data from NHANES
Aylward L.L., Hays S.M., Kirman C.R., Becker RA

 

Risk-Risk Comparison:  Comparative Risk for Use of Perchloroethylene (Perc) or N-propyl-bromide (NPB) in Dry Cleaning
Clewell H., Finkel A.

 

BBDR model for respiratory tract carcinogenicity of inhaled formaldehyde
Allen B., Clewell H., Conolly R., Haney J., Kester J.

 

Assessment of Low-Dose Dose-Response Relationships (Non-linear or Linear) for Genotoxicity, Focused on Induction of Mutations & Clastogenic Effects
Moore M., Pottenger L., Zeiger E., and Zhou T.

 

Implications of Linear Low-Dose Extrapolation from Benchmark Dose for Noncancer Risk Assessment
Kroner O., Haber L.
Advisor: Dourson M.Initial Case Study

 

Framework for Evaluating Alternative Temporal Patterns of Exposure for Risk Characterization
Maier A., Haber L., Haney J., Kaden D.A., Carrier R., Craft E., and Hertzberg R.
Advisor: Dourson, M.

 

Review and application of data fusion methodologies for toxicological dataset analysis to resolve data quality issues in predictive toxicology and contaminated sites risk assessment.
Mohapatra A.K., Sadiq R., Zargar A., Islam S., Dyck R.

 

Use of human data in cancer risk assessment of chemicals as illustrated by the case of 1,3-Butadiene
Albertini R., Sielken Jr. R.L.

 

The Quantitative Human Health Risk Assessment for 1,3-Butadiene Based Upon Ovarian Effects in Rodents
Kirman C.R., Grant R.L.

Initial Case Study

Revised Case Study

Apply AEGL Methodology to Develop Acute Exposure Guideline Levels for Ethylbenzene
Grant R., Erraguntla N., Hinz J., Camacho I.A.

 

Deriving Health-Protective Values for Evaluation of Acute Inhalation Exposures for Chemicals with Limited Toxicity Data Using a Tiered Screening Approach
Grant R.L., Phillips T., Ethridge S.

 

Consideration of Human Kinetic Variability
Lipscomb J.C., Teuschler L.K., Swartout J., Popken D., Cox T., Kedderis G.L.

 

Multiple modes of action and risk assessment modeling
Hertzberg R.
Advisor: Dourson M.

 

Application of National Research Council “Silverbook” Methodology for Dose Response Assessment of 2,3,7,8-Tetrachlorodibenzo(p)dioxin
Simon T., Stephens M., Yang Y., Manning R.O., Budinsky R.A. and Rowlands J.C.

 

Estimate Risk Above the RfD Using Uncertainty Factor Distributions
Spalt E., Kroner O.
Advisor: Dourson M.

 

Use of biomarkers in the benchmark dose method
Gentry R., Van Landingham C., Hays S., Aylward L.

 

Sustainable Futures Screening
Becker E., Ranslow P.

 

Biologically-Informed Empirical Dose Response Modeling:  Using Linked Cause-Effect Functions to Extend the Dose-Response Curve to Lower Doses (Titanium dioxide – TiO2)
Allen B., Maier A., Willis A., Haber L.T.

 

Ethanol Case Study – Evaluating Human Dose-Response of Morbidity and Mortality from Hepatic Disease: Are the Predicted Risks from Low-Dose Linear Extrapolation to Environmentally Relevant Concentrations Biologically Plausible?
Becker R., Hays S.

 

Use of Categorical Regression – Risk Above the RfD
Danzeisen R., Krewski D., Chambers A., Baker S., Hertzberg R., and Haber L.

 

 

Workshop II Case Studies & Presentations

October 11-13, 2010, Crystal City, Virginia (In tandem with the Federal & State Risk Assessment & Toxicology Committee)

Workshop 2 Guest Speaker Presentations

Workshop Overview

Presentation by Ed Ohanian, U.S. Environmental Protection Agency (EPA). NRC findings and Current EPA Risk Assessment Forum Efforts

Presentation by Adam Finkel, University of Pennsylvania Law School & NAS Panelist. Beyond Misleading Underestimation of Carcinogenic Potency

Presentation by Peter Grevatt, Office of Children’s Health Protection (No Slides; presentation on issues related to children’s health)

Presentation by Craig Rowlands, The Dow Chemical Company. ILSI Risk21

Presentation by Doug Wolf, U.S. EPA National Health and Environmental Effects Research Laboratory. Dose Response Approaches for Nuclear Receptor Mediated Modes of Action Workshop Preliminary Report

 

 

Case Studies

Some case studies were presented at Workshops II & III. In some instances, studies presented at Workshop II were revised and the enhanced case studies were presented at Workshop III. In such situations, the updated case study is linked below.
Panel Discussion Questions

 

Lead – Dose-response relationship for effect on Children’s IQ
Carrington C.D.

 

Background/Endogenous Damage: Considerations for Dose-Response & Risk Assessment
Pottenger L.H., Bus J.S., with support from J.A. Swenberg

 

Comparison of Hattis strawman approach and BMDs/UFs for noncancer endpoints (carbonyl sulfide and tetrachlorobenzene)
Greco S.L., Hattis D.H., Lynch M.K.

 

Quantitative Assessment of Sensitivity and Variability in Humans: Modeling the Effects of Low Dose Exposure to Dietary Residues of Chlorpyrifos   
Juberg D.R., Price P.

 

Risk Assessment of Exposure to Trihalomethane Drinking Water Disinfection By-Products.  Use of Biomonitoring Equivalents and Biomonitoring Data from NHANES
Aylward L.L., Hays S.M., Kirman C.R., Becker RA
Risk-Risk Comparison:  Comparative Risk for Use of Perchloroethylene (Perc) or N-propyl-bromide (NPB) in Dry Cleaning
Clewell H., Finkel A.

 

BBDR model for respiratory tract carcinogenicity of inhaled formaldehyde
Allen B., Clewell H., Conolly R., Haney J., Kester J.

 

Assessment of Low-Dose Dose-Response Relationships (Non-linear or Linear) for Genotoxicity, Focused on Induction of Mutations & Clastogenic Effects
Moore M., Pottenger L., Zeiger E., and Zhou T.

 

Implications of Linear Low-Dose Extrapolation from Benchmark Dose for Noncancer Risk Assessment
Kroner O., Haber L.
Advisor: Dourson M.

 

Framework for Evaluating Alternative Temporal Patterns of Exposure for Risk Characterization
Maier A., Haber L., Haney J., Kaden D.A., Carrier R., Craft E., and Hertzberg R.
Advisor: Dourson, M.

 

Review and application of data fusion methodologies for toxicological dataset analysis to resolve data quality issues in predictive toxicology and contaminated sites risk assessment.
Mohapatra A.K., Sadiq R., Zargar A., Islam S., Dyck R.

 

Use of human data in cancer risk assessment of chemicals as illustrated by the case of 1,3-Butadiene
Albertini R., Sielken Jr. R.L.

 

The Quantitative Human Health Risk Assessment for 1,3-Butadiene Based Upon Ovarian Effects in Rodents
Kirman C.R., Grant R.L.

Initial Case Study

Revised Case Study

Apply AEGL Methodology to Develop Acute Exposure Guideline Levels for Ethylbenzene
Grant R., Erraguntla N., Hinz J., Camacho I.A.

 

Deriving Health-Protective Values for Evaluation of Acute Inhalation Exposures for Chemicals with Limited Toxicity Data Using a Tiered Screening Approach
Grant R.L., Phillips T., Ethridge S.

 

Consideration of Human Kinetic Variability
Lipscomb J.C., Teuschler L.K., Swartout J., Popken D., Cox T., Kedderis G.L.

 

Multiple modes of action and risk assessment modeling
Hertzberg R.
Advisor: Dourson M.

 

Application of National Research Council “Silverbook” Methodology for Dose Response Assessment of 2,3,7,8-Tetrachlorodibenzo(p)dioxin
Simon T., Stephens M., Yang Y., Manning R.O., Budinsky R.A. and Rowlands J.C.

 

Estimate Risk Above the RfD Using Uncertainty Factor Distributions
Spalt E., Kroner O.
Advisor: Dourson M.

 

Use of biomarkers in the benchmark dose method
Gentry R., Van Landingham C., Hays S., Aylward L.

 

Sustainable Futures Screening
Becker E., Ranslow P.

 

Biologically-Informed Empirical Dose Response Modeling:  Using Linked Cause-Effect Functions to Extend the Dose-Response Curve to Lower Doses (Titanium dioxide – TiO2)
Allen B., Maier A., Willis A., Haber L.T.

 

Ethanol Case Study – Evaluating Human Dose-Response of Morbidity and Mortality from Hepatic Disease: Are the Predicted Risks from Low-Dose Linear Extrapolation to Environmentally Relevant Concentrations Biologically Plausible?
Becker R., Hays S.

 

Use of Categorical Regression – Risk Above the RfD
Danzeisen R., Krewski D., Chambers A., Baker S., Hertzberg R., and Haber L.

 

Workshop I Case Studies & Presentations

March 16-18, 2010, Austin, Texas; Texas Commission on Environmental Quality

Case Study Proposals Recommend for Further Development

Breakout groups discussed the proposed case studies, suggested enhancements and modifications, and recommended whether a full case study based on the proposal should be brought to the second workshop. Breakout groups also had the opportunity to propose additional case studies. The report of the breakout group discussions can be found here. The following list groups the case study proposals by topic, but within topic, the numbering reflects the original numbering of the case study proposals. Although chemicals are named, the focus is on the principles of methodology illustrated by the case. Topics covered include the following; note that some case studies addressed multiple topics:

 

  1. Consideration of the impact of inter-individual variability in cancer susceptibility;
  • Case Study #2 – Inter-individual variability in cancer susceptibility – 4-aminobiphenyl from the Silver Book
  • Case Study #8 – Conceptual models for individual/population dose response – TCDD
  1. Evaluation of a data-rich chemical using approaches of increasing sophistication, and data intensity, from default through BBDR, potentially including sensitivity analyses to address relative uncertainty;
  • Case Study #4 – Consideration of known pathophysiology and human variability – Ethanol (maybe – lower priority, no team assigned)

See also Case Study #5, below

  1. Consideration of background and endogenous processes;
  • Case Study #3 – Consideration of Endogenous processes: 1,4-Dioxane from the Silver Book
  1. Methods for screening-level assessments;
  • Case Study #6 – Sustainable futures screening
  • Case Study #25 – Tiered screening for acute exposure- Pentene
  1. Determining the risk consequences of intermittent exceedances of short-term exposure screening levels;
  • New Case Study – Determine risk consequences of short, intermittent exceedances of 1-hour short term screening levels.
  1. A variety of methods for calculating risk at exposures exceeding or in the range of the RfD/RfC;

 

  • Case Study # 9 – Extending the dose-response curve using biomarkers of effect – TiO2
  • Case Study #11 – Estimate risk above the reference dose using the published uncertainty factor distributions of Swartout et al. (1998), applied to 10 RfDs and RfCs from EPA IRIS.
  • Case Study #17 – Calculate the probability of adverse effects at any dose at or above a threshold of one molecule, assuming a threshold of one molecule and applying linear extrapolation to zero; applied to 10 RfDs and RfCs from EPA IRIS.
  • Case Study # 18 – Calculate the risk above the RfD using categorical regression.
  • Case Study #21 – Use of biomarkers in the benchmark dose method to define risk for exposures above the RfD
  • New Case Study – A comparative toxicological reference values analysis by carrying out low dose linear extrapolations.
  1. Acute exposure limits of varying severity using the AEGL methodology;
  • Case Study #13 – Apply AEGL Methodology to Develop Acute Exposure Limit for Ethyl Benzene
  1. Applying MOA information with PBPK and BBDR modeling to quantify cancer risk, including consideration of endogenous/background exposure and background processes, as well as uncertainty, variability, and alternative modeling approaches;
  • Case Study #5 – Applying MOA information with PBPK and BBDR modeling to quantify cancer risk, including consideration of endogenous/background exposure and background processes, as well as uncertainty, variability, and alternative modeling approaches (Formaldehyde).
  • Case Study #10 – Considering uncertainty in cancer dose-response assessment – develop a method or framework for conducting comparable uncertainty analyses on both default/statistical-modeling methods and BBDR-based methods. (recommended be combined with #5)
  • Case Study #16 – Using a flexible dose-response model for describing the dose-response for a MOA that includes multiple pathways – Acrylamide
  • Case Study #26 – Consideration of nonlinearities in genotoxic modes of action – acrylamide (recommended to combine with #16)
  • New Case Study Proposal – DNA damage by intracellular generated formaldehyde has been proposed as a carcinogenic mode of action for several chemicals (e.g., methanol, MTBE).
  1. Decision tree/framework on criteria for using increasingly data-informed approaches;
  • Case Study #1A – Sufficiency of data to evaluate human relevance – Thyroid follicular tumors (maybe – no team identified)
  1. Review of data fusion methodologies to integrate data from different organizational levels;
  • Case Study #19 – Apply data fusion methodologies for toxicological dataset analysis to resolve data quality issues in predictive toxicology
  1. Incorporation of data on inter- and intra-species variability in kinetics for noncancer endpoints;
  • Case Study #23 – Incorporation of interspecies kinetic variability in metabolism – ovarian atrophy and 1,3-butadiene
  • New Case Study –Use of human data in cancer risk assessment – 1,3-butadiene and leukemia (recommend to combine with #23)
  • Case Study #24 – Consideration of human kinetic variability – Trichloroethylene
  1. Dose-response for liver tumors in rats involving receptor-mediated modes of action
  • Case Study #20 – Three nuclear receptors, AHR, CAR/PXR and PPARα, as examples for how their biology is linked to key events and dose-response for liver tumors in rodents
  • Case Study #8 – Conceptual models for individual/population dose response – TCDD
  1. Dose-response for liver tumors in rats involving receptor-mediated modes of action
  • Case Study #20 – Three nuclear receptors, AHR, CAR/PXR and PPARα, as examples for how their biology is linked to key events and dose-response for liver tumors in rodents
  • Case Study #8 – Conceptual models for individual/population dose response – TCDD
  1. Other
  • Case Study #12 – IUEBK model prediction incorporating exposure distribution and background exposure (IUEBK/Lead).