# Presentation: 509469

## Case Studies and Risk Assessment Applications of Aggregate and Cumulative Risk: An Overview

**Tornero-Velez, R ****1****, Blancato, JN ****1****, Crofton, KM ****2****, Dary, C ****1****, Hertzberg, RC ****3****, DeVito, MJ ****2****,**
**Ozkaynak, H ****4****, Power, FW ****1****, Rosati J ****5****, Teuschler, LK ****3****, Setzer W ****2****, Zartarian, V ****1****   **
- 1NERL, 2NHEERL, 3NCEA, 4ORD, 5NRMRL, Office of Research and Development, U. S. Environmental Protection Agency

- The term "cumulative risk assessment" covers a wide variety of risks. Currently, EPA assessments predict qualitatively and quantitatively the risks of adverse health and ecological effects from synthetic chemicals, particulate matter, and biological stressors.  The Agency must define the dimensions of the assessment, including the characteristics of the population at risk. These include sensitive subgroups which may be highly susceptible to risks from stressors or groups of stressors due to their age, gender, or disease history*.*
- The science questions addressed by this research are:
-   How is ORD integrating its efforts in health effects research and exposure assessment to evaluate cumulative risks ?
-   How does this research provide the scientific basis to characterize and reduce human risks resulting from exposures to multiple environmental stressors ?
-   How may these research efforts, described in these case studies, serve to refine and guide future assessments ?

**Research Goals**

**Impact and Outcomes**

**Results/Conclusions**

**Future Directions**

**Science Question**

- The practice of risk assessment within the Environmental Protection Agency (EPA) is evolving away from assessments of single pollutants toward integrated assessments involving suites of pollutants in several media that may cause a variety of adverse effects on humans.
- The main research goals are as follows:
-   Elaborate approaches and methods that efficiently integrate resources within ORD to conduct aggregate and cumulative risk assessments
-  In particular, these approaches should identify the  populations that are at most risk to multiple stressors.
-  Establish mechanisms to promote discourse and refine methodology on aggregate and cumulative assessments

- The case studies described herein have produced the following results:
-  An inventory of the sources of dioxin that contribute to exposure in the general population
-  A probabilistic exposure model (SHEDS) to assess children’s exposure to CCA-treated wood
-  Toxicokinetic models of tissue dose for a variety of pollutants (DBPs, carbamates, pyrethroids, etc)
-  Development of TEF/ CRPF methodology for:
-   Drinking water disinfection byproducts
-   Organophosphate pesticides
-  Mechanisms to facilitate discourse and establish guidance on cumulative risk

- Cumulative risk assessment requires an interdisciplinary approach to manage effectively.  By including the input of stakeholders, investigators, and the front-line enforcers of regulations, ORD guidance has broad concurrence and application. These research efforts and case studies represent activities within ORD and ongoing collaboration between ORD and the regulatory offices of EPA. The impact of these efforts will be data and models that will (1) allow ORD to refine its guidance on cumulative assessments, and (2) allow the Agency to conduct state-of-the-art cumulative assessments for pollutant mixtures.

- Models of exposure, dose, and effect are being developed to describe multiple pollutants.  In general, these models assume independence and additive action among constituents.  Future models will account for correlations as well as interactions among the constituents which lead to non-additive risk.   Because of the imposition on resources, approaches in aggregate and cumulative will derive from advances in the evolving computational sciences.

**References**

- A listing of publications associated with these case studies is available under separate cover.

**Source/ Stressor**

**Transport/ **
**Transformation**

**Environmental **
**Characterization**

**Exposure**

**Tissue Dose**

**Response/ Effects**

_**Presenter: Jerry N. Blancato (NERL)**_
**Towards a Cumulative Risk Assessment of the N-Methyl Carbamate Insecticides**
- A case study was developed to consider the use of PBPK/PD models in cumulative risk assessment of the N-methyl carbamate class of insecticides.  A PBPK/PD model of carbaryl was developed as a prototype to address questions associated with the assessment.  The carbaryl PBPK/PD model was developed in NERL’s Exposure Related Dose Estimating Model (ERDEM) platform.

_**Presenter: Curtis Dary (NERL)**_
**Linking Exposure Measurements with Human Activity Data to Assess Dose in Human Tissues, Organs and Excreta through the Application of the Exposure Related Dose Estimating Model (ERDEM**)
- Can a physiologically based pharmacokinetic (PBPK) model be used to determine the interactions among, and individual contributions of, multiple chemicals from aggregate exposures on absorption, distribution, metabolism and excretion?  Can the information from model-simulated aggregate exposures be used to estimate cumulative risk?  The Exposure Related Dose Estimating Model (ERDEM) was developed to enable researchers and risk assessors to estimate dose of parent chemicals and metabolites in various organs and tissues in humans

_**Presenter: Halûk Özkaynak (ORD)**_
**Applying an ORD Probabilistic Exposure Model (SHEDS) to Help Conduct a Health Risk Assessment for Children who Contact Chromated Copper Arsenate on Treated Playsets and Decks. **
**  **
- Concerns have been raised regarding the safety of young children contacting arsenic and chromium residues while playing on and around CCA-treated wood playground structures and decks.** **Scientists in ORD conducted a probabilistic aggregate exposure and dose assessment on the arsenic (As) and chromium (Cr) components of CCA using the _S_tochastic _H_uman _E_xposure and _D_ose _S_imulation model for wood preservatives (SHEDS-Wood).

_**Presenter:**__**	**__**Matthew Lorber (NCEA)**_
**Researching Source-to-Exposure Pathways for Dioxin-Like Compounds Under the Dioxin Exposure Initiative**
- Given that U.S. background exposures to dioxin-like compounds are very high, at a level that translates approximately to a 10-3 lifetime cancer risk, can we quantify the pathways of human exposures, starting from sources of dioxin release, through the environment and into the food chain, so that we can tailor a regulatory strategy for this important class of compounds ?
- The fundamental goal of the Dioxin Exposure Initiative, DEI is to quantitatively link dioxin sources to general population exposure.  This is being accomplished by pursuing two simultaneous lines of inquiry: one line starts with identification of sources of dioxin-like compounds and works forward along their pathways of transport and deposition, and the second starts with human body burdens and works backward through the process of bioaccumulation and uptake.

_**Presenter: Kevin Crofton (NHEERL)**_
**Impacts of Selected Cumulative Pesticide Exposure/Risk Projects**
- The FQPA requires consideration of cumulative exposures in determining the risk from exposure to pesticides with a common mode of action.  Two ongoing efforts aim to decrease the uncertainties in the cumulative risk assessments for carbamate and pyrethroid pesticides. Specific aims  are: 1) To test the hypothesis of additivity; 2) Test the effects of mixtures based on environmentally relevant exposures (relative doses based on known human exposures); and, 3) Integrate the experimental neurotoxicology data with PBPK models and *in vitro* mechanistic data.

_**Presenter: R. Woodrow Setzer (NHEERL)**__ _
**Research Supporting the Relative Potency Factor Assessment of OP Pesticides**
- The strategy of the risk assessment was to develop a stochastic model for exposure to organophosphates (OPs) through diet, drinking water, and residential uses, and to combine the toxicities of different OP exposures by scaling those exposures by their estimated relative potencies, relative to the index chemical methamidophos.

_**Presenter: **__**Michael DeVito**_ _**(NHEERL)**__ _
**The Use of the Toxic Equivalency Factor (TEF) Methodology For Cumulative Risk For Dioxins**
- What are the uncertainties in the use of the TEF methodology for dioxin risk assessment?  Dioxins are a family of chemicals whose toxicities are mediated by binding and activating the Ah receptor.  2,3,7,8-Tetrachlorodibenzo-p-dioxin is the most potent of these chemicals.  Humans are exposed to complex mixtures of dioxins and the TEF methodology has been developed to provide risk assessors with a means to estimate the potential adverse health effects of exposure to these chemicals.

_**Presenter: Linda K. Teuschler (NCEA)**_
**Cumulative Risk Assessment of Drinking Water Disinfection By-Products**
- What are peoples real world aggregate exposures to drinking water disinfection by-product (DBP) mixtures?  How do we estimate cumulative risk from multiple-route exposures to DBP mixtures? This research examines the feasibility of performing a cumulative risk assessment for DBP mixtures by combining external exposure modeling and physiologically-based pharmacokinetic (PBPK) modeling results with a new mixtures risk assessment method, the Cumulative Relative Potency Factors (CRPF) approach.

_**Presenter: **_**Richard Hertzberg**  _**(NCEA)**_
**Guidance and Workshops on Aggregate and Cumulative Assessments **
- The complexity of aggregate and cumulative risk assessments is best approached by an interdisciplinary team that ranges from bench scientists, epidemiologists and mathematicians to frontline enforcers of regulations. ORD has stimulated that activity by two main vehicles: agency risk assessment guidance and open workshops.