ARA
About the Framework    
   ǀ      FAQ        ǀ    

ARA Dose-Response Framework >
Problem Formulation > In Depth Assessment


 

 





 









 

 



























 






 



___________________________________________________________________________________________________________________________________

Problem Formulation > In-Depth Assessment > Endpoint Assessment

 

 

 

 

 

Method Case Studies

expand Data Fusion
  • 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.

 

 

 

 

   


This continuum of effects is potentially associated with any exposure to xenobiotics and reflects a sequence of effects of differing severity.  From least to most severe this continuum includes:

–Adaptive effects, 
–Compensatory effects, 
–Critical effect, 
–Adverse effects, and 
–Frank effects.

This continuum starts at low dose with upstream indicators of change, or adaptive effects, where the organism’s ability to withstand a challenge is enhanced.  Doses associated with such effects are often referred to as No Observed Adverse Effect Levels (NOAELs).  The concept of hormesis may also be relevant here.

  • As dose increases, compensatory effects occur, which enable the organism to maintain overall function without further enhancement or significant cost.  Doses associated with such effects are also often NOAELs.  Some of these effects might be judged to be the critical effect. 
  • As dose further increases, the critical effect is reached.  This is the first adverse effect, or its known precursor, that occurs to the most [relevant or] sensitive species as the dose rate of an agent increases.   Note that the bracketed phrase “relevant or” is important since the most relevant specie is always preferred over the most sensitive specie (e.g., if data shows that the rat is more sensitive than the human, the human data are still preferred), but when such information is not available, data from the most sensitive specie are chosen.  Also the term “precursor” in this definition is singular, meaning the immediate precursor, not just any prior effect.  This restriction is important both because it ties the concept of critical effect into common medical practice and because the resulting dose response---such as an RfD---is more meaningful, since without the restriction any RfD can be estimated.*  Doses associated with such effects are Lowest Observed Adverse Effect Levels (LOAELs).   The highest NOAEL below this LOAEL is generally used in the dose response, and the focus is on determining this NOAEL in a sensitive population.
  • As dose further increases, the critical effect is exceeded, and adverse effects are manifested as biochemical changes, functional impairments, or pathologic lesions.  These progressively more severe effects impair the performance of the organism, and/or reduce its ability to respond to additional challenges.  At some point these adverse effects become manifestly overt and irreversible, and frank effects or disease ensues.

*Many examples of appropriate use by different groups are found on International Toxicity Estimates for Risk (ITER) database available at http://toxnet.nlm.nih.gov. An example of where this was not done appropriately is the NAS perchlorate assessment (2005, page 111).

___________________________________________________________________________________________________________________________________

Problem Formulation > In-Depth Assessment > Mode of Action Asessment

 

 

 

Method Case Studies

Sufficiency of MOA evidence/research MOAs - MOA/HRF/KEDRF Butadiene

expand Butadiene Ovarian Case Study
expand Butadiene Cancer Case Study

 

expand Ethanol Case Study
  • 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.

expand Low-Dose Evaluation for Genotoxicity
  • 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.
expand Dioxin Case Study (Key Events Dose Response Framework)
  • 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.

 

 

   

__________________________________________________________________________________________________________________________________

Problem Formulation > In-Depth Assessment > Vulnerable Populations

 

 

 

 

 

Method Case Studies

expand Human Kinetic Variability (Trichloroethylene)
expand Kinetic Variability Based on PON1 Polymorphism (Integrated with PBPK Model) for Chlorpyrifos
  • 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.

expand Sensitive Life Stages
  • 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.

expand Lead Case Study
expand Inter-Individual Variability in Cancer Susceptibility
  • BBDR model for respiratory tract carcinogenicity of inhaled formaldehyde
    Allen B., Clewell H., Conolly R., Haney J., Kester J.

 

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

expand Data Fusion
  • 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.

 

 

   



___________________________________________________________________________________________________________________________________

Problem Formulation > In-Depth Assessment > Background Exposure Assessment

 

 

 

 

 

Method Case Studies

expand Mixtures Guidance
  • Case Study
  • Case Study Summary
  • Presentation Slides
expand Cumulative Risk Guidance
  • Case Study
  • Case Study Summary
  • Presentation Slides
expand Biologically Based Dose Response for Formaldehyde to Address Endogenous
  • BBDR model for respiratory tract carcinogenicity of inhaled formaldehyde
    Allen B., Clewell H., Conolly R., Haney J., Kester J.

expand Biomonitoring Equivalents
expand Endogenous Processes or Adducts – 1,4-dioxane, Vinyl acetate, vinyl chloride, acetaldehyde
  • Background/Endogenous Damage: Considerations for Dose-Response & Risk Assessment 
    Pottenger L.H., Bus J.S., with support from J.A. Swenberg

 

 

 

 

 

   

___________________________________________________________________________________________________________________________________

Problem Formulation > In-Depth Assessment > Conceptual Model

 

 

 

Method Case Studies

 


Conceptual model

• Data availability

• Risk management needs
for form of risk characterization




 

  • Conceptual Model 1
  • Conceptual Model 2
  • Conceptual Model 3
  • Other

Nonlinear individual response, low-dose linear popopulation response with background dependence

expand Dioxin case study - Key Events Dose Response Framework
  • 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.

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

expand Biologically-Based Uncertainty Factor Distributions (Hattis approach)

Low-dose nonlinear individual and nonlinear population response; low-dose response independent of background – i.e., threshold.

expand Dioxin case study - Key Events Dose Response Framework
  • 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.

expand Acute Exposure Guidelin Levels (AEGL) for Acute Exposures
expand Safe Dose
Content 4
expand Biomonitoring Equivalents
expand Acute RfC and related – ATSDR, OECD guidance
Content 5

 

Low-dose linear individual and linear population dose-response- i.e., a non-threshold response, slope factor most appropriate).

expand Dioxin Case Study - Key Events Dose Response Framework
  • 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.

expand Ethanol Case Study
  • 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.
expand Slope Factor Calculation
Content 4
expand Margin of Exposure
Content 2
expand Lead Case Study
expand Short-Term and Intermittent Exposures to Carcinogens – Methodology for Intermittent and Short-Term Exposure to Carcinogens (MISTEC)?
Content
expand Data Fusion
  • 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.

expand Biologically-Informed Dose-Response Modeling
  • 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.

expand Modeling Multi-Pronged MOA (acrylamide)
expand Low-dose evaluation for genotoxicity
expand Biologicaly Based Dose Repsonse
  • BBDR model for respiratory tract carcinogenicity of inhaled formaldehyde
    Allen B., Clewell H., Conolly R., Haney J., Kester J.

expand PBPK model (part of butadiene, TCE)
expand Categorical Regression
expand Alternative Temporal Patterns
  • 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.

expand Risk-Risk Comparison (e.g., comparative carcinogenic and neurotoxic potencies of tetrachloroethylene and n-propyl bromide)
  • Risk-Risk Comparison:  Comparative Risk for Use of Perchloroethylene (Perc) or N-propyl-bromide (NPB) in Dry Cleaning
    Clewell H., Finkel A.

 

 

 

 

 

   
___________________________________________________________________________________________________________________________________

Problem Formulation > In-Depth Assessment > Data Availability

 

 

 

 


• Conceptual model

Data availability

• Risk management needs
for form of risk characterization

 

Method Case Studies

  • High Data Requirements
  • Moderate Data Requirements
  • Small Data Requirments
expand Dioxin Case Study - Key Events Dose-Response Framework
  • 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.

expand Biologically-Informed Dose-Response Modeling
  • 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.

expand Modeling Multi-Pronged Mode of Action (MOA)(acrylamide)
expand Low-Dose Evaluation for Genotoxicity
  • 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.

expand Biologicaly Based Dose Repsonse
  • BBDR model for respiratory tract carcinogenicity of inhaled formaldehyde
    Allen B., Clewell H., Conolly R., Haney J., Kester J.

expand PBPK Model (part of butadiene, TCE)
expand Categorical Regression
expand Lead Case Study
expand Risk-Risk Comparison (e.g., comparative carcinogenic and neurotoxic potencies of tetrachloroethylene and n-propyl bromide)
  • Risk-Risk Comparison:  Comparative Risk for Use of Perchloroethylene (Perc) or N-propyl-bromide (NPB) in Dry Cleaning
    Clewell H., Finkel A.

expand Data fusion
  • 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.

expand Ethanol Case Study
  • 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.
expand AEGL for acute exposure
expand Alternative Temporal Patterns
  • 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.

expand Linear Low Dose Extrapolation from the BMD(L)
  • Implications of Linear Low-Dose Extrapolation from Benchmark Dose for Noncancer Risk Assessment 
    Kroner O., Haber L.
    Advisor: Dourson M.

expand Safe Dose
  • Case Study
  • Case Study Summary
  • Presentation Slides
expand Slope Factor
  • Case Study
  • Case Study Summary
  • Presentation Slides
expand Margin of Exposure
  • Case Study
  • Case Study Summary
  • Presentation Slides
expand Acute RfC and related – ATSDR, OECD guidance
  • Case Study
  • Case Study Summary
  • Presentation Slides
expandShort-term and intermittent exposures to carcinogens – Methodology for Intermittent and Short-Term Exposure to Carcinogens (MISTEC)?
  • Case Study
  • Case Study Summary
  • Presentation Slides
   

___________________________________________________________________________________________________________________________________

Problem Formulation > In-Depth Assessment > Risk Management

 

 


Method Case Studies



• Conceptual model

• Data availability

Risk management needs
for form of risk
characterization

  • Acute Exposure
  • Chronic Exposure
  • Other
expand AEGL for Acute Exposures
expand Biologically Informed Dose-Response Modeling
  • 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.

expand Kinetic Variability Based on PON1 Polymorphism (integrated with PBPK model) for Chlorpyrifos
  • 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.

expand Sensitive Life Stages
  • 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.

expand Lead Case Study
expand Inter-individual variability in cancer susceptibility
  • BBDR model for respiratory tract carcinogenicity of inhaled formaldehyde
    Allen B., Clewell H., Conolly R., Haney J., Kester J.

expand Sensitive disease state/background response
  • Background/Endogenous Damage: Considerations for Dose-Response & Risk Assessment 
    Pottenger L.H., Bus J.S., with support from J.A. Swenberg

expand Data Fusion
  • 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.

expand Dioxin Cas Study - Key Events Dose Response Framework
  • 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.

expand Biologically-Informed Dose-Response Modeling
  • 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.

expand Modeling Multi-Pronged Mode of Action (MOA) (acrylamide)
expand Low-Dose Evaluation for Genotoxicity
  • 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.

expand Biologicaly Based Dose Repsonse
  • BBDR model for respiratory tract carcinogenicity of inhaled formaldehyde
    Allen B., Clewell H., Conolly R., Haney J., Kester J.

expand PBPK model (part of butadiene, TCE)
expand Categorical Regression
expand Ethanol Case Study
  • 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.
expand Low Dose Linear Extrapolation from BMD(L)
  • Implications of Linear Low-Dose Extrapolation from Benchmark Dose for Noncancer Risk Assessment 
    Kroner O., Haber L.
    Advisor: Dourson M.

expand Margin of Exposure
  • Case Study
  • Case Study Summary
  • Presentation Slides
expand Safe Dose
  • Case Study
  • Case Study Summary
  • Presentation Slides
expand Biologically-based UF distributions (Hattis approach)
expand Biomonitoring Equivalents
expand Lead Case Study
expand Alternative Temporal Patterns
  • 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.

expand Data Fusion
  • 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.

expand Risk-risk comparison (e.g., comparative carcinogenic and neurotoxic potencies of tetrachloroethylene and n-propyl bromide)
  • Risk-Risk Comparison:  Comparative Risk for Use of Perchloroethylene (Perc) or N-propyl-bromide (NPB) in Dry Cleaning
    Clewell H., Finkel A.

expand Occupational Populations
  • Case Study
  • Case Study Summary
  • Presentation Slides
expand Short-term and intermittent exposures to carcinogens – Methodology for Intermittent and Short-Term Exposure to Carcinogens (MISTEC)
  • Case Study
  • Case Study Summary
  • Presentation Slides

 

   


___________________________________________________________________________________________________________________________________

Problem Formulation > In-Depth Assessment > Results Reporting

 

 

 

 

 

Method Case Studies

  • Risk Characterization Guidance
  • Safe Dose or Effect Level
  • Slope or Risk per unit
  • Risk Specific Dose
expand Dioxin - Key Events Dose Response Framework
  • 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.

expand AEGL for Acute Exposure
expand Safe Dose
  • Case Study
  • Case Study Summary
  • Presentation Slides
expand Biologically-Based Uncertainty Factor distributions (Hattis approach)
expand Biomonitoring Equivalents
expand Acute RfC and related – ATSDR, OECD guidance
  • Case Study
  • Case Study Summary
  • Presentation Slides
expand Dioxin case study (Key Events Dose Response Framework)
  • 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.

expand Ethanol case study
  • 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.
expand Linear Low Dose Extrapolation from BMD(L)
  • Implications of Linear Low-Dose Extrapolation from Benchmark Dose for Noncancer Risk Assessment 
    Kroner O., Haber L.
    Advisor: Dourson M.

expand Modeling multi-pronged MOA (acrylamide)
expand Slope factor calculation
  • Case Study
  • Case Study Summary
  • Presentation Slides
expandMargin of Exposure
  • Case Study
  • Case Study Summary
  • Presentation Slides
expandLead Case Study
expandShort-term and intermittent exposures to carcinogens – Methodology for Intermittent and Short-Term Exposure to Carcinogens (MISTEC)
  • Case Study
  • Case Study Summary
  • Presentation Slides
expand Biologically-Informed Dose-Response Modeling
  • 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.

expand Biologically-Based Dose-Response
  • BBDR model for respiratory tract carcinogenicity of inhaled formaldehyde
    Allen B., Clewell H., Conolly R., Haney J., Kester J.

expand Categorical Regression
expand Risk-risk comparison (e.g., comparative carcinogenic and neurotoxic potencies of tetrachloroethylene and n-propyl bromide)
  • Risk-Risk Comparison:  Comparative Risk for Use of Perchloroethylene (Perc) or N-propyl-bromide (NPB) in Dry Cleaning
    Clewell H., Finkel A.