# Presentation: 375662

## Peter W. Preuss, Ph.D.
Director, National Center for Environmental Assessment

*Director, National Center for Environmental Assessment*

***Human Health Risk Assessment at EPA:*****  Background, ****Current Practice, Future Directions**

- Presentation for the
*Board of Scientific Counselors for Human Health Risk Assessment*
- October 2, 2007

## Risk Paradigm Alignment in ORD

**National**
**Center for Computational Toxicology**

- Application of computational tools and models to improve understanding of toxicity and risks posed by environmental agents.

*Risk Paradigm Alignment in ORD*

##  Risk Assessment Linkages

- Epidemiology

**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**

- Primary
- Research

**Synthesis**
**and Guidance**

**Assessments**

- Application

- Risk
- Assessments
- and Management

- Comp. Tox;
- Labs (EPA,
- others)
- NCER

**NCEA**
- RAF

**NCEA**

- Regulatory
- Programs,
- Regions

- Methods, Models, Data

- Needs

-  **Risk Assessment Linkages**

- 3

## NCEA and Risk Assessment at EPA

## NCEA and Risk Assessment at EPA

*NCEA and Risk Assessment at EPA*

## Human Health Risk Assessment is:

*Human Health Risk Assessment is:*

- Fundamental to EPA’s approach to analysis of potential risk from exposure to environmental contaminants
- Essential for EPA regulatory decision-making
- Evolving in the face of new understandings about uncertainty, mode of action, metabolism, susceptibility, etc.
- Addressing emerging science and new science challenges

**Notes:**
Molecular/cellular to tissue
Tissue to individual
Individual to population(s)
Populations to ecosystem
Local to global

## 1990s

**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
-  Integrated Risk Information System (IRIS)

- Risk Assessment Forum’s 	 recommendations for RfD and RfC
- Examination of non-cancer methods
- Susceptible populations
- Cumulative assessment approaches
- Probabilistic approaches
- Uncertainty analysis

*        **Human Health Risk Assessment at EPA*

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

## Oversight, Interest, and Influences

- Scientific community

***Oversight, Interest, and Influences***

**NAS**
**Reports**

- Court-ordered schedules

- Statutory mandates/schedules
- Congressional concerns

-  Executive branch

- Industry
- Trade associations

- Federal Agencies
- States
- Public

- Public interest groups
- Environmental organizations
- Advocacy groups

- U.S. international agreements

## LTG 1: Integrated Risk Information System (IRIS) and other priority health hazard assessments:  Agency, state and local risk assessors use the state-of-the-science health hazard assessment information provided on priority substances in their decisions and actions to protect human health from risks posed by environmental pollutants. 

**LTG 2: **_**State-of-the-science risk assessment models, methods, and guidance**_**:**  *EPA programs, states and other risk assessors use the risk assessment models, methods, and guidance provided to enhance, through the incorporation of contemporary scientific advances, the quality and objectivity of their assessments and decision-making on environmental health risks. *

**LTG 3: **_**Air Quality Criteria Documents**_ (now called Integrated Science Assessments):  *As mandated in the Clean Air Act, the ambient air criteria pollutants are reviewed and AQCDs revised to reflect the best available scientific information on identifiable effects on public health and the environment from exposure to the pollutant, and this information is used by the EPA Office of Air and Radiation in their review and promulgation of the National Ambient Air Quality Standards (NAAQS) to protect public health with an adequate margin of safety. *

**Human Health Risk Assessment**
**Multi-Year Plan**
**August 2007**

**Executive Lead: ****	**** Peter Preuss**
**	****	****         ****	****Center Director, ORD-NCEA**
**Science Lead: ****	****John Vandenberg**
**	****	****	****Associate Center Director, ORD-NCEA**
**Author Leads:****	****Bruce Rodan**
**	****	****	****Assistant Center Director, ORD-NCEA**
**	****	****	**
**	****Stan Barone**
**	****Acting Assistant Center Director, ORD-NCEA**

## Logic Model for the Human Health Risk Assessment 

_**Outreach and Effective Transfer**_
- _Output_ via the IRIS database, NCEA websites, peer reviewed agency and journal publications, and participation at scientific society and regional risk assessment meetings.
- _Input_ through Congressional mandate, annual programmatic reviews, Federal Register solicitation, public meetings and external peer consultation.

_**Environmental Indicators**_
- _Impact Matrix_: measuring incorporation of RA-H outputs into agency risk assessment practices and decisions, including use in agency site assessments, RODs and regulations, and the benefits resulting from this use of sound science, evaluated through independent external scientific review, such as the EPA  BOSC, CASAC, SAB and NAS.

_**Resources**_
- We apply our human resources and expertise in the diverse scientific fields contributing to risk assessment  practice, supplemented through extramural funding and contractor support, and incorporating stakeholder, public and peer review input ...

_**Research Activities**_
- ... to compile, analyze and summarize the state of the science on environmental health hazards posed to humans by substances of priority concern to agency decision-makers, along with the models, methods, guidance and technical support necessary to enhance the quality of these analyses ...

_**Clients**_
- ... to risk assessors and managers in EPA client Offices and Regions dealing with air, water, land, and enforcement, in addition to other state and local risk assessors, the public and international organizations...

_**Short-term**_
_**Outcomes**_
- ... so that they have high quality health hazard information under the Integrated Risk Information System (IRIS) and Integrated Science Assessment( ISA) Documents based on sound scientific models, methods, and guidance ...

_**Immediate Outcomes**_
- ... leading to enhanced risk-based decision-making and reduced environmental pollution of the air, water, land and food to levels without appreciable risk to the public ...

_**Outputs**_
- ... to provide human health hazard assessments and quantitative risk information in a form most appropriate for decision-making, supported by peer reviewed agency reports, journal articles, and technical presentations ...

_**Long Term Outcomes**_
- ... resulting in improved health, well-being and prosperity of communities through science-based environmental decision making.

- Logic Model for the Human Health Risk Assessment
- - Multi-Year Plan

## RA LTG 1 Annual Performance Goals

- 10

- LTG 1: Integrated Risk Information System (IRIS) and other priority health hazard assessments:  Agency, state and local risk assessors are provided state-of-the-science health hazard assessment information on priority substances included in planned Agency decisions and actions.

- 06

- 07

- 09

- 11

- 08

- 12

- Provisional Toxicity Values

- IRIS
- assessments

- Complete health hazard assessments for interagency review or external peer review.
- 16 IRIS hazard/DR assessments
- +
- 25 new/         25 revised PPRTVs

- Complete health hazard assessments for interagency review or external peer review.
- 16 IRIS hazard/DR assessments
- +
- Post 4 completed hazard/DR assessments
- +
- 50 new/revised PPRTVs

**RA LTG 1 Annual Performance Goals**

- Complete health hazard assessments for interagency review or external peer review.
- 16 IRIS hazard/DR assessments
- +
- Post 6 completed hazard/DR assessments
- +
- 50 new/revised PPRTVs

- Complete health hazard assessments for interagency review or external peer review.
- 16 IRIS hazard/DR assessments
- +
- Post 10 completed hazard/DR assessments
- +
- 50 new/revised PPRTVs

- Complete health hazard assessments for interagency review or external peer review.
- 16 IRIS hazard/DR assessments
- +
- Post 14 completed hazard/DR assessments
- +
- 50 new/revised PPRTVs

- Complete health hazard assessments for interagency review or external peer review.
- 16 IRIS hazard/DR assessments
- +
- Post 16 completed hazard/DR assessments
- +
- 50 new/revised PPRTVs

- Complete health hazard assessments for interagency review or external peer review.
- 16 IRIS hazard/DR assessments
- +
- Post 16 completed hazard/DR assessments
- +
- 50 new/revised PPRTVs

## Human Health Risk Assessment LTG 2 Annual Performance Goals

**Quantitative RA models & tools**:
- Provide models and tools for improving quantitative dose-response relationships, characterizing human exposures and reducing uncertainty in risk assessments

**Integrating RA advances into quantitative frameworks:**
- Integrate PBPK, exposure, microbial and biological modeling advances into quantitative risk frameworks, thereby applying mathematical modeling and data advances to biological systems, including: application of uncertainty analysis in PBPK modeling; quantitative basis for interspecies scaling and defaults; exposure factors, dermal methods, and exposure assessment guidelines; and microbial RA models.

**Mode of Action to refine RA & extend beyond the range of data:**
- Incorporate mode of action advances to improve approaches for cancer and non-cancer RA, facilitating quantitative estimates of risk within the range of data and at environmental exposure levels, including dose-response and extrapolation implications of MoA in peroxisome proliferation, bladder tumors, mutagenesis, chemical mixtures and immunosuppression, culminating in a summary of conceptual MoA models and their application to dose-response modeling.

**Guidance on RA models &  uncertainty analysis:**
- Apply uncertainty analyses in biologically-based risk assessment models, accompanied by the development of risk assessment guidance to disseminate information, including tools to characterize uncertainty and variability in PBPK models; lifestage data and its application to children’s RA; and RfC methods guidance, less than lifetime RA guidance, and microbial RA guidance.

**Expanding single substance RA to complex environmental mixtures:**

**Integrating & synthesizing progress in RA models & methods:**
- Integrate and synthesize improvements in dose-response methods and models in risk assessment,

**Quantitative RA advances, including central tendency & uncertainty:**
- Develop mathematical models to address an expanded range of data sets, including measures of central tendency and uncertainty analysis, accompanied by dissemination for use in quantitative risk assessment, including: categorical regression, 2-stage clonal, and acute models to incorporate current standards of RA science into EPA practice; methods for central tendency and uncertainty in RA modeling; dissemination through the BMD software; BMD guidance; harmonization of uncertainty factors; and age group designations for children’s exposure assessment.

**Human Health Risk Assessment LTG 2 Annual Performance Goals**

**Synthesis of progress to improve risk assessment application for hazard and exposure information:**
- Synthesize qualitative and quantitative information contributing to uncertainty in RA for exposure and susceptibility.

**Human Health Risk Assessment LTG 3 Annual Performance Goals & Measures**

## NCEA:

**Producing Integrated Science Assessments **
- Ozone -- completed February 2006; ***proposed NAAQS June 2007***
- Lead -- completed September 2006 ***proposed NAAQS fall 2007***
**Particulate Matter -- completed October 2004; *****completed NAAQS fall 2006**** *
**Nitrogen Oxides -- underway**
**Sulfur dioxide -- underway**
- Carbon Monoxide -- completed June 2000

*NCEA:*
- Human Health Assessment* *

## Other types of assessments products include
Provisional peer reviewed toxicity values (PPRTV’s) for site specific purposes
These are hazard and dose response assessments principal for OSWER where no IRIS, ATSDR, or Cal EPA values exist.

Technical expertise in risk assessment is also requested for major disasters and emergencies. Examples include:
World Trade Center
Hurricane Katrina and Rita recovery and cleanup
DC WASA lead issue 

- Provisional peer reviewed toxicity values (PPRTV’s) for site specific purposes
- These are hazard and dose response assessments principal for OSWER where no IRIS, ATSDR, or Cal EPA values exist.
- Technical expertise in risk assessment is also requested for major disasters and emergencies. Examples include:
- World Trade Center
- Hurricane Katrina and Rita recovery and cleanup
- DC WASA lead issue

*NCEA:*
- Other Human Health Assessments* *

## NCEA:

- Uncertainty analysis
- Identification of possible modes of action
- Physiologically-Based Pharmacokinetics (PBPK) Modeling
- Approaches to quantification
- Approaches for Assessing Risk of Environmental Exposures to Age-Susceptible Populations (children, elderly)
- Less than Lifetime Assessments

*NCEA:*
- Human Health Assessment
*(continued) *

## LTG 1: Integrated Risk Information System (IRIS) and other priority health hazard assessments:

## www.epa.gov/iris

- Cancer risk: Hazard characterization, oral slope factors, and oral 	and inhalation unit risks
- Improvements in transparency, consistency, and timeliness
- EPA and OMB/Interagency group discussing revised IRIS process 	for the development of human health assessments
- Proposed process will be subjected to both Agency comment and 	public comment

*Integrated Risk Information System*

- IRIS provides qualitative and quantitative 	health effects information on over 540 	substances
- Many high-profile, first applications of risk 	assessment guidelines and science	policy

**www.epa.gov/iris**

**Notes:**
Provides EPA scientific positions on potential adverse health effects that may result from exposure to chemical substances found in the environment
Oral reference doses and inhalation reference concentrations for non-cancer endpoints
A weight of evidence description (e.g., known human carcinogen), oral slope factors, and inhalation unit risks for cancer
EPA risk assessors combine IRIS toxicity values with scenario-specific exposure values to estimate risk
Source of toxicity information to inform risk-based decision-making; founded on EPA guidelines for health risk assessment
Fosters consistent risk assessments across EPA Programs and Regions
Support NAS risk assessment paradigm

## Develops EPA positions on potential human health effects from exposure to various chemical substances found in the environment

Follows EPA guidelines for health risk assessment

Follows IRIS standard operating procedures that are updated yearly

Fosters consistent risk assessments across EPA Programs and Regions 		

- Follows EPA guidelines for health risk assessment
- Follows IRIS standard operating procedures that are updated yearly
- Fosters consistent risk assessments across EPA Programs and Regions

*Integrated Risk Information System (IRIS) Program*

## Nominations solicited by ORD Assistant Administrator from AAs and RAs of the Program Offices and Regions that use IRIS values in their assessments and from the public
Priority-based annual selection of substances for IRIS (re)assessment 
Criteria: 
Statutory, regulatory, or programmatic need
New science or methodology available to develop an assessment or update an older assessment
Public, state, other user need 
Assessment available or in progress in EPA or other federal agency (leverages resources)
Availability of EPA resources to conduct assessments
2007 agenda lists 75 assessments in progress

- Priority-based annual selection of substances for IRIS (re)assessment** **
- Criteria:
- Statutory, regulatory, or programmatic need
- New science or methodology available to develop an assessment or update an older assessment
- Public, state, other user need
- Assessment available or in progress in EPA or other federal agency (leverages resources)
- Availability of EPA resources to conduct assessments
- 2007 agenda lists 75 assessments in progress

*IRIS Agenda Development***  **

## 2007 IRIS AGENDA

- acetaldehyde
- acrolein
- acrylamide
- acrylonitrile
- aldicarb/aldicarb sulfoxide
- aldicarb sulfone
- arsenic
- asbestos
- benzene (acute)
- benzo(a)pyrene
- beryllium (cancer effects)
- bromobenzene
- butyl benzyl phthalate
- cadmium
- carbon tetrachloride
- cerium
- chloroethane
- chloroform (inhalation route)
- chloroprene
- cobalt
- copper

- dibutyl phthalate
- 1,2-dichlorobenzene
- 1,3-dichlorobenzene
- 1,4-dichlorobenzene
- 1,2-dichloroethylene
- di(2-ethylhexyl)adipate (DEHA)
- di(2-ethylhexyl)phthalate
- 1,4-dioxane
- ethanol
- ethyl tertiary butyl ether
- ethylbenzene	*	*
- ethylene dichloride
- ethylene glycol monobutyl ether
-   (cancer effects)
- ethylene oxide
-   (cancer effects; noncancer acute)
- formaldehyde
- hexachlorobutadiene
- hexachloroethane
- hexachlorocyclopentadiene

## 2007 IRIS AGENDA

- RDX (hexahydro-1,3,5-dintirotriazine)
- 2-hexanone
- hydrogen cyanide
- hydrogen sulfide**
- isopropanol
- kepone
- methanol
- methyl tert-butyl ether (MTBE)
- methylene chloride
-   (dichloromethane)
- mirex
- naphthalene (inhalation route)
- nickel (soluble salts)
- nitrobenzene
- PAH mixtures
- pentachlorophenol
- perfluorooctanoic acid -
- ammonium salt (PFOA)
- perfluorooctane sulfonate -
- potassium salt (PFOS)

- phosgene (acute exposure
- platinum
- polybrominated diphenyl ethers
- polychlorinated biphenyls (PCBs)
-   (noncancer endpoints)
-  propionaldehyde
- refractory ceramic fibers
- styrene
- 2,3,7,8-TCDD (dioxin)
- 1,1,2,2-tetrachloroethane
- tetrachloroethylene
- tetrahydrofuran
- thallium
- trichloroacetic acid
- 1,1,1-trichloroethane
- trichloroethylene
- 1,2,3-trichloropropane
- 2,2,4-trimethylpentane
- uranium compounds
- vinyl acetate

## Current Process for Assessment Development and Review

- Annual FR Notice of IRIS agenda; data call
- Literature search and review
- EPA develops draft assessment
- Internal peer review, IRIS Agency Review
- Interagency review
- External peer review with public comment period
- Interagency and Agency review of response to comments
- Final EPA and OMB approval and posting on IRIS database

## Outline of IRIS Process

- FRN Request for Nominations

- IRIS Track Entry

- Peer Review Plan

- Scoping meeting

- NCEA Center Dir Briefing

- Internal Peer Consultation

- Develop Draft Tox Review/  IRIS Summary

- FRN Annual IRIS Agenda

- Submit peer review file to IRIS helpdesk

- Final Assm Posted on IRIS

- FR Notice & Communication materials

- External Peer Review & Public Comment

- Communication Materials

- OMB/
- Interagency Review

- ORD AA Briefing

- Option for NCEA and ORD AA Briefing

**Outline of IRIS Process**

- Agency Review

- Final Agency and Inter-agency Review

## EPA Program Offices and Regional Offices
Regulatory and site-specific evaluations
Other Federal agencies
State and local agencies
International agencies
Public - including academia, regulated industries, environmental organizations, individuals
Usage: ~ 21,000 hits/day

- Regulatory and site-specific evaluations
- Other Federal agencies
- State and local agencies
- International agencies
- Public - including academia, regulated industries, environmental organizations, individuals
- Usage: ~ 21,000 hits/day

*IRIS Users*

## 2006 IRIS Web Site Hits

*2006 IRIS Web Site Hits*

## Basic Principles of Risk Assessment at EPA

- The starting point for risk assessment is a critical analysis of available scientific information.*
- Quantitative estimates of risk are, to the extent possible,
- Biologically-motivated,
- Data-driven.
- When there is insufficient data, default methods are used that**
- Protect public health,
- Ensure scientific validity (i.e., scientifically plausible and extensively peer reviewed), and
- Create an orderly and predictable process.
- Implementation of these principles involves...extensive peer review.**

*** U.S. EPA 2005, Cancer Guidelines**
****NRC 1994, “Science and Judgment in Risk Assessment”**

## NCEA:

*NCEA:*
*IRIS Example Products*

*Assessments*
**Final:  **Perchlorate, Toluene, n-Hexane...
**Interagency/External Review Draft:**  Polybrominated Diphenyl Ethers, 1,4-Dichlorobenzene, 2,2,4-Trimethylpentane, Dibutyl Phthalate, Nitrobenzene, Bromobenzene, Dioxin...and16 or more sent each year as an annual output.
**Trichloroethylene (TCE) Issue Papers: ** NCEA provided four papers on key science issues to the National Academy of Science in preparation for an NAS consultation to support the current human health assessment.
**National Academy of Sciences:  **Consultations on recurring risk assessment issues and the direction of risk assessment

- IRIS Track:  IRIS Chemical Assessment Tracking System is available. This report shows the user where the chemical assessment is in its development.

## Example: NCEA’s TCE Health Assessment

- Challenges In Assessing TCE

- TCE is inherently complex toxicologically, with multiple metabolites and multiple potential modes of action.
*Rapid absorption via inhalation and ingestion, with distribution to blood-rich organs and storage in fat*
*Metabolized by two competing pathways*
*P450-mediated oxidative pathway*
*Metabolites CH, TCA, DCA*
*Glutathione-S-transferase conjugative pathway*
*Metabolites DCVG, DCVC*
*Toxicity generally attributed to metabolites rather than parent compound*.
- ORD’s work in computational toxicology can provide significant insight into which pathways are really being turned on and about other things that are happening at the cellular level.

## MOAs and Metabolic Scheme of TCE

- TCE

- Focus of liver carcinogenicity

- Focus of kidney toxicity

- Focus of mouse lung carcinogenicity

*Source:*   Dobrev, Andersen, and Yang 2002, with modifications based on Lash et al. 2000a.

- Oxidation

- Conjugation

- --

**Notes:**
Toxicologically complex chemical with -
multiple metabolites 
tumors and toxicity observed in multiple organs
multiple modes of action contributing to toxicity
There is a large database of information on TCE modes of action, but situation is still murky.

## Liver Tumors: A Postulated Mode of Action

*Liver Tumors:* A Postulated Mode of Action

- PPARα and other MOAs for TCA, DCA and CH

**Notes:**
The three major oxidative metabolites of trichloroethylene—trichloroacetic acid, dichloroacetic acid, and chloral hydrate—can contribute to liver toxicity and cancer in rodents.
 Trichloroethylene produces hepatotoxicity in experimental animals and humans that depends on generation of reactive intermediates by the enzyme cytochrome P-450 in the liver.
The mode of action for richloroacetic acid in liver is principally as a liver peroxisome proliferator and agonist of PPARα rather than as a genotoxicant. 

A significant lack of concordance in the sensitivity of human and rodent hepatocytes to peroxisome proliferators and early events associated with liver tumor promotion has been noted, with humans being much less sensitive.

Species differences in susceptibility and phenotypic differences in tumors derived from trichloroethylene and its metabolites suggest that there are mechanistic differences in the way these chemicals cause tumors that cannot be fully explained by peroxisome proliferation. 

The mode of action for trichloroacetic acid in liver is principally as a liver peroxisome proliferator and agonist of PPARα rather than as a genotoxicant. A significant lack of concordance in the sensitivity of
human and rodent hepatocytes to peroxisome proliferators and early events associated with liver
tumor promotion has been noted, with humans being much less sensitive.
In rodents, the promotional activity of dichloroacetic acid includes a significant effect on cellular metabolism and cellular proliferation that encompasses a mitogenic mode of action. 

## Kidney Tumors: Postulated Mode of Action

- Source:  Lash et al., 2000

- Multiple potential modes of action via reactive GSH metabolites
- Genotoxicity – VHL marker
- Dose-dependent MOAs
- Example: DCVC
- High doses – lead to acute tubular necrosis
- Low doses – changes in homeostasis leading to altered gene expression and growth

*Kidney Tumors:* Postulated Mode of Action

**Notes:**
It is generally accepted that the metabolite S-(1,2-dichlorovinyl)-L-cysteine is the penultimate
	nephrotoxicant. The metabolite can undergo bioactivation by conjugation to reactive species that are genotoxic and cytotoxic and by sulfoxidation.

Multiple potential modes of action via reactive GSH metabolites 
Genotoxicity –VHL marker? Renal clear cell carcinoma, the carcinoma most often induced by trichloroethylene, was
shown to link with the homozygous inactivation of the von Hippel-Lindau (VHL) tumor
suppressor gene.

Nephro/Cytotoxicity

Trichloroethylene and some of its metabolites in the glutathione-conjugation pathway
have been shown to be nephrotoxic and nephrocarcinogenic. There is concordance between
animal and human studies.

Example: DCVC
High doses – lead to acute tubular necrosis
Low doses – changes in homeostasis leading to altered gene expression and growth

Evidence from experimental, mechanistic, and epidemiologic studies supports the conclusion that trichloroethylene is a potential kidney carcinogen.
Animal studies show that trichloroethylene acts as a complete carcinogen (at the stages of both tumor initiation and promotion and progression) in a dose-dependent manner, with nephrotoxicity as the promoter for cells initiated by a trichloroethylene metabolite.
It is not possible to predict whether humans are more or less susceptible to the carcinogenic effects than other animals, because species differences in the extent of formation of S-(1,2-dichlorovinyl)-Lcysteine have not been fully characterized. 
Furthermore, the cytochrome P-450 enzyme isoforms that metabolize trichloroethylene have polymorphisms within national populations, resulting in considerable interindividual differences in enzyme expression. 
The committee ruled out the accumulation of α2μ-globulin, peroxisome-proliferator activated receptor α (PPARα) agonism, and formic acid production as modes of action for the production of renal tumors in rodents.

## Biologically-Based Dose-Response for Formaldehyde Cancer Risk Assessment 

## Use of All Historical Controls has Significant Impact on Relevance of Mutagenic Component

**Use of All Historical Controls has Significant Impact ****on Relevance of Mutagenic Component**

## 4-orders of magnitude increase in human risk with alternative model parameters

- a “Our CIIT” used CIIT parameter estimates but differed from CIIT in human background cancer data, use of weekly average DPX, and human body weight data.

**Biologically-Based Dose-Response for Formaldehyde Cancer Risk Assessment **

## Proposed Estimates of Risk and Uncertainty Bounds

*   *
* *

| Dose | Original
data   | One tumor
moved |
| --- | --- | --- |
| 0 |  0/50 |  0/50 |
| 1 | 10/50 | 10/50 |
| 1.46 | 23/50 | 24/50 |
| 2.02 | 42/50 | 41/50 |
| MLE risk | 2.1E-10 | 1.8E-5 |
| 95th  risk | 1.8E-4 | 2.1E-4 |

- Simulated data with risk at .001ppm

- When MLE of linear term is equal to zero (left column), the MLE risk is not stable. It changes 5 orders of magnitude when just one animal is moved between two tumor groups.
- Even when MLE risk is not near zero (right column), it can be unstable. The proposed strategies allow identifying such cases.

- Proposed Estimates of Risk and Uncertainty Bounds

## Simulated Data Example
                                      Original data         One tumor moved

Estimate of expected risk        6.9E-5                    7.0E-5                          95th Confidence limit               1.9E-4                     2.0E-4

Estimate of expected risk         2.9E-5                     3.1E-5                          95th Confidence limit                1.5E-4                     1.7E-4

Both strategies provide stable results and close estimates

-                                       Original data         One tumor moved
- Estimate of expected risk        6.9E-5                    7.0E-5                          95th Confidence limit               1.9E-4                     2.0E-4
- Estimate of expected risk         2.9E-5                     3.1E-5                          95th Confidence limit                1.5E-4                     1.7E-4
*Both strategies provide stable results and close estimates*

**Bayesian estimate**

**Bootstrap estimate**

## Uncertainty Analysis Papers

_**7 papers on uncertainty topics in cancer risk assessment, including**_**:**
**  ****Uncertainty in Cancer Risk Assessments: Broad**
**      ****V****iew and Biological Assumptions and Models**
**  ****Identifiability and Prediction in a Multi-stage Clonal **
**	****	****Expansion Model**
**  ****Multiple modes of action **
**  ****A “Systems Biology” Approach for Meta-Analysis of **
**	****	****Biological Data**
**  ****Impact of Datasets, Parameter, and Modeling **
**	****	****Approaches **
**  ****A Roadmap for practical improvements.**

## Critical Analysis of Available Scientific Information

***Organ-Specific RfDs***

**LTG 2: **_**State-of-the-science risk assessment models, methods, and guidance**_**:**

## HHRA LTG2- Methods, Models & Guidance

## Major Recurring Science Issues 

- Accounting for less-than-lifetime exposure durations
- Qualitative and quantitative use of mode of action data in noncancer and cancer assessments
- Benchmark dose modeling and selection of the benchmark response
- Evaluation and use of PBPK models
- Accounting for life-stage and subpopulation susceptibility in uncertainty factors
- Use of data-derived uncertainty factors
- Characterization of uncertainty in noncancer and cancer analysis
- Quantitation of uncertainty
- Use of time-to-tumor modeling for cancer assessments

**7**

*Major Recurring Science Issues *

## As the data have improved, the limitations of current methodologies have become more apparent 

- Advances have included:
- increased chemical specific data and the willingness of stakeholders/agencies to provide these data
- improved methodologies such as benchmark dose modeling
- development of physiologically-based pharmacokinetic (PBPK) models
- development of biologically-based dose-response models (BBDR)
- increased computing power to facilitate probabilistic assessment to convey the uncertainties in different parameters and results*  *
- As the data have improved, the limitations of current methodologies have become more apparent

- Exploratory Review of the Scientific Foundation for Estimating Uncertainty in EPA Reference Values

## Use of MOA Framework in Risk Assessment

**MOA sufficiently **
**supported in animals?**

**MOA relevant to humans?**

**Flag lifestage(s) or population(s) that could be susceptible based on MOA**

**Use linear extrapolation as a default.**

**Determine extrapolation based on information about specific MOA.**

**Model using MOA or use RfD/RfC method as default.  Adjustments for susceptible...**

***No***

***Linearity due to mutagenic MOA***

***MOA can not be determined***

**Yes**

**Yes**

**Use the same linear extrapolation for all lifestages, unless have chemical-specific information on lifestages or populations.**

**No further analysis of tumors.**

***Use of MOA Framework in Risk Assessment***

***Linear, but nonmutagenic MOA***

***Nonlinear***

## MOA sufficiently supported in animals?
Identification of key events and testable hypotheses
Evidence necessary to draw conclusions and rule out alternatives
Separation of chemical-induced events from natural progression of cancer
Integration of multiple MOAs

MOA relevant to humans?
Repeat a-d
Yes/no answer or dose-response dependent
If dose-response dependent, then what kinetic and dynamic factors will drive the modeling

- Identification of key events and testable hypotheses
- Evidence necessary to draw conclusions and rule out alternatives
- Separation of chemical-induced events from natural progression of cancer
- Integration of multiple MOAs
- MOA relevant to humans?
- Repeat a-d
- Yes/no answer or dose-response dependent
- If dose-response dependent, then what kinetic and dynamic factors will drive the modeling

**Mode-of-Action**

**Issues:**

## Issues:
Determine extrapolation based on MOA?
Incorporation of susceptible lifestage(s) or population(s) 
Development of biologically-based models, or RfD/RfCs
Consideration of population variability, background additivity
Others
Application of “well-established” MOA from one chemical to another for which data are limited
Development of MOA categories; aiming at category specific model development
Incorporation into uncertainty analyses

- Determine extrapolation based on MOA?
- Incorporation of susceptible lifestage(s) or population(s)
- Development of biologically-based models, or RfD/RfCs
- Consideration of population variability, background additivity
- Others
- Application of “well-established” MOA from one chemical to another for which data are limited
- Development of MOA categories; aiming at category specific model development
- Incorporation into uncertainty analyses

**Mode-of-Action**

## NCEA:Human Health Risk Assessment LTG2

- Uncertainty analysis
- Identification of possible modes of action
- Physiologically-Based Pharmacokinetics (PBPK) Modeling
- Approaches to quantification
- Approaches for Assessing Risk of Environmental Exposures to  Age-Susceptible Populations (children, elderly)
- Less than Lifetime Assessments
- Approaches for cumulative risk assessment  	***(Fall 2007)***

*NCEA:*Human Health Risk Assessment* LTG2*

## HHRA: Methods, Models & Guidance: Example Products of LTG2

*HHRA: Methods, Models & Guidance: Example Products of LTG2*

- Cancer Guidelines and Children’s Supplemental:
- 	*Both documents are available at www.epa.gov/cancerguidelines*
- An Inventory of Sources and Environmental Releases of Dioxin-Like Compounds in the United States for the Years 1987, 1995, and 2000 *(Final Report)*
- Summary of the NCEA Colloquium on Current Use and Future Needs of Genomics in Ecological and Human Health Risk Assessment *(Final Report)*
- Approaches for the Application of Physiologically-Based Pharmacokinetic (PBPK) Models and Supporting Data in Risk Assessment *(Final Report)*
- Updates of Bench Mark Dose (BMD) software
- Development of categorical regression (CatReg) models

## NCEA:

- A Framework for Assessing Health Risk of Environmental Exposures to Children *(Final Report)*
- Child-Specific Exposure Factors Handbook 2006 *(External Review Draft)*
- Aging and Toxic Response: Issues Relevant to Risk Assessment *(Final Report)*
- Use of Physiologically Based Pharmacokinetic (PBPK) Models to Quantify the Impact of Human Age and Interindividual Differences in Physiology and Biochemistry Pertinent to Risk *(Final Report)*

*NCEA:*
*Methods, Models: Example Products*

## NCEA:

- Approaches to Estimating the Waterborne Disease Outbreak Burden in the United States: Uses and Limitations of the Waterborne Disease Outbreak Surveillance System *(External Review Draft)*
- Exposures and Internal Doses of Trihalomethanes in Humans: Multi-Route Contributions from Drinking Water *(Final Report)*
- Toxicological Reviews of Cyanobacterial Toxins: Anatoxin-a, Cylindrospermopsin and Microcystins (LR, RR, YR and LA) *(External Review Draft)*
- Concepts, methods, and data sources for health risk assessment of multiple chemicals, exposures, and effects.

*NCEA:*
*Methods, Models Example Products*

## LTG 3: Integrated Science Assessments
 (formerly called Air Quality Criteria Documents):

** ****(formerly called **_**Air Quality Criteria Documents**_):

## New Integrated Science Assessments and 

**NAAQS Development Process**

_**Integrated Plan**__:_  timeline and key policy-relevant scientific questions

_**Integrated Science Assessment**_: concise evaluation and synthesis of most policy-relevant studies

_**Risk/Exposure Assessment:**_  concise, quantitative assessment focused on key results, observations and uncertainties

- Workshop on science-policy issues

- Public hearings and comments on proposal

**EPA final decision on standards**

- Interagency review

- Interagency review

- Agency decision making and draft proposal notice

- Agency decision making and draft final notice

- Review by **CASAC** and the public

**CASAC **review and public comment

- Interagency review

- Public comment period and **CASAC **review

**EPA  proposed decision on standards**

**EPA **
**Advance Notice of Proposed Rulemaking**

- Peer-reviewed scientific studies

**Draft ANPR:**  policy assessment reflecting Agency views on range of policy options and rationales

## Slide 53

## Expert Advice and Consultation

***Committee on Improving Risk Analysis Approaches Used by the US EPA***

*Expert Advice and Consultation*

- 2006: ORD contracted with *The National Academies*’ National Research Council to convene two expert panels on risk assessment.

- What can we improve about risk assessment now?
*What methods are currently available that would allow us to make significant progress in improving current risk assessment practices?*
*How can we best incorporate these new approaches and methods into our current practice?*
- What will human health risk assessment be like in 5 - 10 years and what should we be doing to get there?
- Are there alternative risk paradigms that can be useful?

*Clarify the current state of environmental human health risk assessment*
*Envision and help prepare for the future of risk analysis*

*Questions for Consideration by the Committee:*

- To** **develop scientific and technical recommendations for improving the risk analysis approaches.  In making recommendations, the committee will indicate practical improvements that can be made in the **near term (2-5 years)** and improvements that would be made over a **longer term (10-20 years)**.

**Notes:**
- Increased role for probabilistic analysis in risk analysis, including the potential expanded role for expert elicitation- Scientific bases for and alternatives to default assumption choices made in areas of uncertainty- Quantitative characterization of uncertainty resulting from all steps in the risk analysis- Approaches for assessing cumulative risk resulting from multiple exposures to contaminant mixtures, involving multiple sources, pathways, routes - Variability in receptor populations, especially sensitive subpopulations and critical life stages- Biologically relevant modes of action for estimating dose-response relationships, and quantitative implications of different modes- Improvements in environmental transport and fate models, exposure models, physiologically based pharmacokinetic (PBPK) models, and dose-response models- How the concepts and practices of ecological risk analysis can help inform and improve the concepts and practices of human health risk analysis, and vice versa- Scientific basis for derivation of uncertainty factors- Use of value-of-information analyses and other techniques to identify priorities and approaches for research to obtain relevant data to increase the utility of risk analyses

## For more information on these NRC projects:

- The Standing Committee will plan and conduct a series of public workshops that will serve as a venue for discussion of issues critical to the development and review of objective, realistic, and scientifically based human health risk analyses for selected environmental contaminants.  The Committee, in consultation with the sponsor, will select the specific scientific issues and contaminants that will be discussed at the workshops.

******	****First workshop:**  May 3 - 4, 2007; Implications of Receptor-Mediated Events on Dose-Response
******	****Second workshop:**  June 5, 2007;  Quantitative Approaches to Characterizing Uncertainty in Human Cancer Risk Assessment Based on Bioassay Results
******	****Third workshop:**  November 8 - 9, 2007; Mouse Liver Tumors: Benefits and Constraints on Use in Human Health Risk Assessment, Qualitative and Quantitative Aspects

**For more information on these NRC projects:**
**www.dels.nas.edu/best**

- Board on Environmental Studies and Toxicology’s (BEST)
***Standing Committee on Risk Analysis Issues and Reviews***

## The Next Five To Ten Years?

- How should we prepare for them?
- Some example questions:
- What new information will the “omics” advancements provide?  How will it be useful in risk assessment?
- Will genomics change our focus to people rather than chemicals?  For example, will genetic typing to understand individual susceptibilities become the rule?
- Will “omics” information on human impacts stimulate a search for various causal factors, rather than conducting risk assessment on a chemical by chemical basis?
- How will new computational capabilities and information technologies play a role in assessments?

*The Next Five To Ten Years?*

## The Next Five To Ten Years?

- Will BBDR models coupled with PBPK models take on a more central role?
- How will the new approaches for understanding individual and community exposures help us to refine our risk estimates?
- How can we begin to focus on stressors other than chemicals to understand risk? (attributable risk)
- How do we deal better with new technologies such as nanotechnology to understand risks before they are in widespread use?
- How much information and causal linkage will be necessary to assess precursor events in the absence of overt toxicity?

*The Next Five To Ten Years?*
- (continued)

## Other Paradigm

**Other Paradigm**
***Cumulative Risk Assessment***

**Residential Location**

**Environmental Hazards and Pollutants**

**Community Stressors**

**Biologically effective dose**

**Health effects/**
**disparities**

**Community stress **

**Neighborhood Resources**

**Individual stressors**

**Exposure**

***Community ***
*** ******Level***
*** ******Vulnerability***

***Individual ***
***Level ***
***Vulnerability***

**Internal dose**

**Stress/Coping,**
**Life Stage/Style**

**Structural Factors**

*Modified from Gee & Payne-Sturges, 2004*

***Current Risk Assessment***

**Race/Ethnicity**

**Notes:**
Key Points
1.  Community factors and individual stressors may be the "vulnerability factors" specified in the traditional exposure-disease framework.

2.  Need to evaluate scientifically whether there is something intrinsic about race that causes disparities or whether race serves as a marker for some other correlated factor.

3.  Really need to examine the etiology of health from multiple-levels.   However, this way of research will involve the use of tools that are multi-level and more transdisciplinary collaborations, including greater involvement with social scientists.