# Presentation: 496006

## Cumulative Risk Assessment of Drinking Water Disinfection By-Products

- Linda K. Teuschler1, Glenn E. Rice1, John C. Lipscomb1, Richard C. Hertzberg1, Fred W. Power2, Jerry N. Blancato2, Charles Wilkes3, Jane Ellen Simmons4
- U.S. Environmental Protection Agency, Office of Research and Development, 1NCEA 2NERL, 4NHEERL,  3Wilkes Technologies, Inc.

- 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?
- Humans are exposed daily to hundreds of DBPs via oral, dermal, and inhalation routes. Some positive epidemiological studies suggest reproductive and developmental effects and cancer are associated with consumption of chlorinated drinking water. However, human health risk estimates made using animal data based only on oral exposures do not reflect the same magnitude of risks found in positive epidemiological studies. Thus, it is hypothesized that this difference may be accounted for by evaluating simultaneous exposures to multiple DBPs via all three exposure routes.

**Research Goals**

**Multiple Route Internal Dose Estimates**

**Impact and Outcomes**

**Results/Conclusions**

**Future Directions**

**Science Question**

- The Safe Drinking Water Act Amendments of 1996 require EPA to begin evaluating mixtures of contaminants in drinking water. The goal of this research was to determine the feasibility of conducting a Cumulative Risk Assessment (CRA) for DBP mixtures.  Three significant findings resulted.
- 1)  External exposure modeling was conducted and linked with Physiologically Based Pharmacokinetic (PBPK) modeling to produce internal dose measures from dermal, oral and inhalation exposures for use in risk assessment.  This new approach provided realistic human exposure distributions for integrating health risks for multi-route DBP exposures.
- 2)  These internal doses were estimated for an adult female and an adult male, each of reproductive age, and for a child (age 6), accounting  for human activity patterns that affect contact time with drinking water. Exposure distributions were estimated  for 13 major DBPs, including most of the DBPs currently regulated by EPA.
- 3)  A new risk assessment method, the Cumulative Relative Potency Factors (CRPF) approach, integrates the principles of dose addition and response addition, additivity concepts presented in Agency guidance, to produce multiple-route, chemical mixture risk estimates using internal doses.  The CRPF approach  evaluates human health risks using total internal doses and single chemical, oral toxicology dose-response data based on knowledge or assumptions regarding toxic modes of action. The CRPF approach is a new method that can be generalized for the evaluation of other environmental mixtures whose components act by more than one toxic mode of action.

- Realistic multiple route exposure estimates can be developed for specific populations  that account for human activity patterns and water use patterns, and physico-chemical properties of DBPs.
- The scientific basis for evaluating DBP mixture health risks is improved beyond methods based on individual DBP concentrations and single route risk analyses.
- The CRPF method provides a way to assess mixtures whose components cause a common health effect through different toxic MOA’s.

- This research:
- Provides data and tools supporting the evaluation of alternative drinking water treatment technologies developed to meet new promulgated standards.
- Aids EPA’s Office of Water with interpreting epidemiological studies on DBP health risks.
- Provides information and tools to key interested parties (American Water Works Association, the American Chemistry Council, stakeholder groups) who implement programs to protect human health.
- Provides methods and data that enrich the available library of cumulative risk assessment methods beyond what is currently published in EPA guidance

- This research establishes the feasibility of analyzing multi-route exposures to DBP mixtures using a CRA approach.  Important data gaps include:
- Careful treatment of MOA and common MOA subclasses for the major DBPs for developmental and reproductive effects and cancer.
- Development of physico-chemical properties and external exposure factors for several major DBPs.
- PBPK modeling of the pregnant uterus and DBP doses to the fetus.
- Improved uncertainty and sensitivity analyses.

**References**

- Teuschler, L.K., G.E. Rice, C.R. Wilkes,  J.C. Lipscomb, F.W. Power. 2004.  A Feasibility Study of Cumulative Risk Assessment Methods for Drinking Water Disinfection By-Product Mixtures. *Journal of Toxicology and Environmental Health* Part A, 2004, 67:755-777.
- U.S. EPA. 2003. The Feasibility of Performing Cumulative Risk Assessments for Mixtures of Disinfection By-Products in Drinking Water. EPA/600/R-03/051. ORD/NCEA Cincinnati, OH.

- Various dose metrics can be used for DBP mixtures depending on physicochemical characteristics and available data.  Internal dose estimates can be made beginning with environmental concentrations, and linking external exposure modeling outputs with pharmacokinetic models.

- Step 1:   	Group Chemicals into Common Toxic Mode of Action (MOA) Subclasses
- Step 2:   	Conduct Dose Response Modeling of Toxicology Data for Each Individual Chemical;
- 	Estimate Index Chemical Equivalent Doses (ICED) for DBPs Within Each Subclass
- 	Develop Relative Potency Factors (RPF) Within Each Subclass (e.g., using ratios of Effective Doses)
- Step 3:   	Estimate Each Subclass Risk Using RPF Method (assumes same toxic MOA within each subclass)
- Step 4:   	Estimate Total Mixture Risk Using Response Addition (assumes statistical and 	toxicological independence between subclasses)

**Strategy of The CRPF Approach**

**Linking External Exposure and PBPK Models**

- In this research, the **Total Exposure Model (TEM)** provided 24 hour time history simulations using data on chemical properties, human activity patterns, human drinking water intake, and building characteristics.  These time histories were joined with pharmacokinetic data and became input to the PBPK model, **ERDEM (Exposure Related Dose Estimating Model).  **Multi-route exposure, internal doses were then estimated.

| TEM Results Show it is Important for Risk Assessment to Know the  Percentage of Exposure Route Contribution for 13 of the Major DBPs |  |  |  |  |
| --- | --- | --- | --- | --- |
| Chemical                       | Contribution to Total by Route |  |  |  Dose |
|  | Dermal | Ingestion | Inhalation | (mg/day) |
| Chloroform | 9% | 9% | 81% | 1.52E+00 |
| Bromodichloromethane
(BDCM) | 4% | 13% | 83% | 4.13E-01  |
| Dibromochloromethane
(DBCM) | 5% | 15% | 80% | 2.56E-01  |
| Bromoform (CHBr3) | 7% | 27% | 67% | 1.12E-01  |
| Chloroacetic Acid  | 3% | 97% | 0% | 1.13E-02  |
| Dichloroacetic Acid (TCA) | 0% | 100% | 0% | 7.03E-02  |
| Trichloroacetic Acid (TCA) | 0% | 100% | 0% | 7.48E-02  |
| Bromoacetic Acid  | 3% | 97% | 0% | 2.22E-02  |
| Dibromoacetic Acid  | 3% | 97% | 0% | 9.54E-03  |
| Bromochloroacetic Acid  | 3% | 97% | 0% | 2.02E-02  |
| Dichloroacetonitrile  | 2% | 95% | 2% | 4.53E-03  |
| Trichloroacetonitrile  | 3% | 96% | 1% | 3.13E-04  |
| Dibromoacetonitrile  | 3% | 97% | 0% | 1.8E-03  |

- _Physico-Chemical Properties, e.g.,_
- -  Mass transfer coefficients
- -  Henry’s Law constants
- -  Octanol/water partition coefficients
- -  Chemical concentrations
- _Human Behavioral Parameters, e.g.,_
- -  Frequencies/duration of
-    showering, bathing,  faucet use
- -  Appliance factors,  flow rates,
-    water temperatures, cycles
- _Human Intake Characteristics, e.g.,_
- -  Tap water consumption
- -  Skin permeability coefficients
-   Breathing rates
- _Building Characteristics, e.g.,_
- -  Household air volume
- -  Whole house air exchange rate

-  **TEM **

**Example of ERDEM 48 Hour Absorbed Doses**
**Bromodichloromethane for Adult Female **

| 
Demographic Group | 5th Percentile | 10th Percentile | 50th Percentile | 90th Percentile | 95th Percentile |
| --- | --- | --- | --- | --- | --- |
|  |  |  |  |  |  |
| AUC Kidney (mg/L*hr) | 5.36E-05 | 0.00013 | 0.00103 | 0.00424 | 0.00723 |
| AUC Ovaries (mg/L*hr) | 7.39E-05 | 0.00018 | 0.00142 | 0.00584 | 0.00994 |
| Total Absorbed Dose (mg) | 0.0206 | 0.0328 | 0.177 | 0.703 | 1.22 |
| AUC Liver (mg/L*hr) | 3.33E-05 | 4.41E-05 | 0.000217 | 0.000794 | 0.00135 |
| AUC Venous Blood (mg/L*hr) | 4.85E-05 | 0.000107 | 0.000778 | 0.00319 | 0.00539 |

- Adjust to Internal Animal Dose
- (PBPK Modeling or Administered Dose Times % Bioavailable)

- Internal HED

*Build Human Dose*
*Response Model*

- *Estimate
- ED10’s, RPF’s

- Human Exposures in the Home via Oral, Dermal and
- Inhalation Routes

**Dose-Response Modeling Using Single Chemical, Oral Toxicology **
**Data for Each Individual DBP; Assumes No Portal of Entry Effects**

- Response

- DBCM ICED +
- CHBr3 ICED +
- BDCM Dose =
- ICED of BDCM
- (mg/Kg day)

- TCA ICED +
- DCA Dose =
- ICED of DCA
- (mg/Kg day)

**Schematic of CRPF to Illustrate DBP Mixture Cancer Risk**

- Non-Genotoxic
- DBPs:
*DCA (Index*
*Chemical)*
- TCA

- Genotoxic
- DBPs:
*BDCM  (Index Chemical),*
- DBCM, CHBr3

- _EDx(BDCM)_ * DBCM   EDx(DBCM)    TAD

- _EDx(BDCM)_  *  CHBr3 EDx(CHBr3)      TAD

- _EDx(DCA)_  *  TCA EDx(TCA)      TAD

- Group DBPs
- into Common
- MOA Subclasses

- RPFs * TADs
- (Total Absorbed Doses)

- Sum to get
- Subclass ICEDs

- Estimate
- Subclass
- Risks

- Sum to get
- Mixture Risk

- Note:  AUC = Area Under the Curve

- *Note:  EDx is the Effective Dose causing a response in x% of the population of interest.