# Presentation: 499464

## Slide 1

## Two days of Focus on “Staff Paper”:

- Many interesting science presentations and discussion of issues regarding uncertainty factors, extrapolation, methods such as PBPK and BBDR
- Staff paper underscores important risk assessment issues

- Need to understand “Staff Paper” in *time and place* and thus recognize that a broader view allows us to see where we have come from and where we are going

- 2

## 2000s

**1990s**

**1970s**

- Beginnings of the field of risk assessment
- Emphasis on oral route per FDA precedent
- General acceptance of Safety Factors (10x10)
- Beginnings of cancer guidelines

**1980s**

-  Adopt NRC RA/RM paradigm
-  EPA publishes five risk assessment guidelines
-  First paper on Reference Dose
-  Data bases (IRIS)

- Inhalation RfC methodology
- Oral RfD methodology
- Applications of PBPK models
- BBDR models developed
- BMD models developed and applied

**2000s**

- Risk Assessment Forum’s 	 	recommendations for RfD and RfC
- “Staff Paper”
- Examination of non-cancer methods
- Probabilistic approaches

- Evolution of Risk Assessment at EPA

- 3

## 4

## Research	    Assessment         Application

**Toxicity **
**Testing**

**Risk Assessment**
**Methods, Models **
**for Extrapolation**

**Research on**
**Exposure**

**Research on Mode**
** ****of Action (TK/TD), **
**dose-response, etc**

** **
**Dose-Response Assessments **
**(IRIS,Criteria Docs); **
**Communication, support**

**Guidelines for**
**Interpretation**

**Data **
**Generation**

**Data Synthesis**
**And Modeling**

**Assessments**

**Application**

**Risk **
**Assessments**
**and Management**

**EPA Labs **
**NCER**
**Others **
**(e.g., NTP, NCI)**

**NCEA/**
**RAF, **
**NCER**

**NCEA**

**Regulatory**
**Programs,**
**Regions**

**Methods, Models, Data**

**Needs**

- Research	    Assessment         Application

- 5

## National Health and Environmental Effects Research Laboratory 

- National Health and Environmental Effects Research Laboratory
*Human Health Risk Assessment Research*

- Mechanistic Data in Risk Assessment
*Arsenic, PM, atrazine, disinfectant/DBPs, haloacetic acids, perchlorate*
- Fundamental Research on Models
*Route-to-route extrapolation models (e.g., 1,1,2-trichloroethane, methanol, ethanol, 1,2-dichloroethane)*
- Aggregate/Cumulative Risk
*Organophosphate cumulative risk - data to support additivity model *
*Carbamate cumulative risk - PBPK model for cumulative risk*
- Susceptible Subpopulations
*Pharmacokinetic modeling (e.g., Life-stage dependent effects of PFOA risk assessment) **	**    *
*Risk assessment methods (e.g., National Children’s Study pilots)*

- 6

## National Exposure Research Laboratory Exposure Assessment Research

- National Exposure Research Laboratory *Exposure Assessment Research*

- Tools for Characterizing Risk Based on Activity Levels and Exposure Factors
*Consolidated Human Activity Database (CHAD) - database of real-world activities by age, sex, etc. *
- Tools to Characterize Internal Dose Associated with Exposures
*Exposure Related Dose Estimating Model (ERDEM) - TCE reassessment with NCEA*
- Exposure Tools Supporting Environmental Epidemiology
- Tools Supporting the National Children’s Study
- Methods, Protocols for Characterizing Exposures
- Tools for Characterizing Cumulative Risk

- 7

## National Center for Environmental Research 

- National Center for Environmental Research
*Funding Environmental Research*

- Human Health
*Computational, statistical, and predictive strategies to assess impacts*
*Vulnerable populations including tribes, children, elderly*
- Particulate Matter
*Impacts on human health *
*Risks to sensitive populations*
- Endocrine Disruptors
*Computational tools for rapid prediction of estrogenic effects*
*Novel screening methods*
- Drinking Water
*Understanding waterborne pathogens such as Cryptosporidium and Norwalk virus*
*Risks from microorganisms in source and drinking water*
*Occurrence and effects of antibiotics, hormones, and pharmaceuticals in water*

- 8

## How to Incorporate Research 

- When are new methods “ready”?
*Example:  immunotoxicity testing*
*New models?*
- Do they answer our needs?
- Is scientific basis sound?
*Peer review?*
*Consensus in the scientific community?*
- Are methods too complex?
*Are models becoming so complex that only a few people understand and can work with them?*
*Are new methods so complex that cascading errors and uncertainties become critical?*

- How to Incorporate Research
- into Assessments?

- 9

## Risk Assessment Issues Discussed 

- Intra individual
- Cross species
- High to Low
- Susceptible populations
- Mode of Action

- Risk Assessment Issues Discussed
- at This Workshop

- 10

## Default Assumption Using Uncertainty Factors

**M. Dourson**

**Default Assumption Using Uncertainty Factors**

- Meek et al., 1994; IPCS, 1994, 2001; Rademaker and Linders, 1994; Pohl and Abdin, 1995; EPA multiple references

- 11

## Review of the Foundation for Estimating Uncertainty in EPA Reference Values

- The role and application of uncertainty factors is a specific focus.
- Scoping questions for this exercise:
*Is there a common understanding as to what constitutes the current process for deriving a reference value?*
*What is the scientific foundation for this process?*
*What problems and issues are evident?*

- 12

## Issues Related to Current Approaches 

- Examination of the current application of uncertainty factors
- Exploration of alternative methods for assigning values to uncertainty factors
- Analysis of the result of multiplying individual factors together

**RfD/RfC Methodology for **
**Non-Cancer Risk Assessment**
_*Application of Uncertainty Factors*_

- Issues Related to Current Approaches
- that are Being Reevaluated

- 13

## oron IRIS Assessment

- Data were used to replace the kinetic portions of default uncertainty factors for inter-species and intra-species uncertainty factors.
*The value for animal to human toxicokinetic variability was based on quantitative data describing species differences in the renal elimination of boron between rats and pregnant women (studies funded voluntarily by the borax industry)*
*The toxicokinetic component of the human intra-species uncertainty factor was based on differences in renal function among humans.*
- Defaults were used for the dynamic portion of uncertainty factors because appropriate dynamic information was not available.

**oron IRIS Assessment**

- Data-Derived Uncertainty Factors

- 14

## 15

## Examples of Application of PBPK Models 

- Examples of Application of PBPK Models
- in IRIS Assessments

- Vinyl Chloride (posted on IRIS in 2000)
*Using the human equivalent exposure derived using the model, instead of the NOAEL as POD produced a 3-fold higher RfD, mainly because the interspecies uncertainty factor was reduced from 10 to 3*
- Dichloromethane (methylene chloride)
*PBPK modeling reduced unit risk approximately 9-fold in the 1995 assessment*
*EPA is currently updating the model to include more compartments, exercise parameters, and capability to assess risks to children.*
- Tetrachloroethylene (PERC)
*Three human PBPK models with similar model structures, but different parameters*
- Trichloroethylene (TCE)
*Two different model structures, each with two alternative parameterizations*

- 16

## EPA’s Approach to 

- EPA’s Approach to
- High-to-Low Dose Extrapolation

- Both model-independent and model-dependent approaches used in EPA’s current and future risk assessments.
- Major issues with choosing and implementing different approaches include:
*Knowledge of mode-of-action, biological relationships at low dose*
*Characterization of uncertainty and variability*
*Degree of confidence and consistency in results*
- EPA is working both to advance the science and methods in this area as well as to make use of the best science that is available for its current risk assessments.

- 17

## 18

**Rory Conolly**

## EPA’s Focus on Formaldehyde BBDR

- 19

- There are substantial new data on formaldehyde dosimetry, toxicity, and epidemiology.
*State-of-the-Art PBPK/BBDR models developed by CIIT for point of contact tumors.*
*Recent epidemiology studies show associations between formaldehyde exposures and increased point of contact *_*and*_* systemic tumors; systemic tumors are not considered in CIIT model.*
- Data and approaches (BBDR *vs.* observational) are complex and seemingly contradictory.
- Thus, EPA is evaluating both the strengths and limitations of the epidemiology studies and the parameters, assumptions, and decisions made in the development of the CIIT model to develop our new risk assessment.

## Summary

- Products of human health research and risk assessment are still fundamental to the Agency’s regulatory decision-making process
- Innovative and cutting-edge approaches to risk assessment issues are being developed by EPA
- Between research and methods development at EPA and other places, we are moving forward on all these fronts, and we seem to be well positioned to make significant progress in the next few years.
- Finally, the future...

- 20

## Genomics  Proteomics  Metabonomics

- Genomics  Proteomics  Metabonomics

- Genomics  / Proteomics  / Metabonomics

- 21

## Science Challenges in 

- Issues related to current approaches that are being refined and/or reevaluated
- 		***Examples:****	**Non-Cancer Human Health Risk Assessment **	**	**	**	**	**	**	**	**Uncertainty Factors Approach*
*	**	**	**	*

- Issues that are with us today that are being examined and Agency-wide approaches developed
- 		***Examples:****	**Aggregate/Cumulative Risk *
*	**	**	**	**	**Probabilistic Risk Assessment and Expert Elicitation*
*	**	**	**	**	*

- Emerging science areas that need to be factored into human health risk assessment
*	**	****Examples:******	****Systems Biology*
*	**	**	**New materials, e.g., nanomaterials* *	**	**	*

- Science Challenges in
- Human Health Risk Assessment

- 22

## Thank you 

- Thank you

- www.epa.gov
- www.epa.gov/ord
- www.epa.gov/ncea
- www.epa.gov/iris