1. Key Concepts on Health Risk Assessment of Chemical Mixtures

2. Dose-Response Assessment Hazard Identification Exposure Assessment Risk Characterizatio n Risk Assessment Paradigm for Mixtures: In Addition to Issues for Single Chemicals Hazard identification: - consider potential interaction effects - identify effects from total mixture dose. Exposure assessment: - account for internal dose of several mixture components at target tissue - evaluate changes in mixture over time (e.g., environmental degradation) Dose-response: - consider potential for effects below individual chemical thresholds - incorporate toxicologic judgment of similar toxicity within or between mixtures. Risk characterization: - evaluate data support for assumptions about interactions, exposure, and similar toxicity of mixtures or their components. Note: Dose-response & exposure assessment are interdependent

3. Origins of Multiple Chemicals Coincidental  Urban air  Superfund sites -VOCs -radionuclides, metal mixtures  Mine tailings -metal mixtures Intentional  Manufactured products -PCBs -brominated flame retardants  Pesticide formulations -technical grade toxaphene  Fuels -gasoline -jet fuel Incidental (Generated)  Byproducts -drinking water disinfection byproducts -volatile organic compounds  Combustion -dioxins -PAHs -diesel exhaust  Product degradation -weathered toxaphene ATSDR (2004) From different, multiple sources of pollutants that co- exist in the same medium

4. Mixture RfD/RfC; Slope Factor Interaction-Based Hazard Index, Interaction Profiles, Weight of Evidence, PBPK Models Relative Potency Factors Hazard Index Response Addition, Whole Mixture Data Available Sufficiently Similar Mixture Whole Mixture of Concern Component Data Available Toxicologically Similar Components Toxicologically Independent Components Epidemiological Evaluations, Toxicity Profiles Dose Addition Mix of Toxicologically Similar & Independent Components Integrated Additivity Methods Health Evaluations Hazard Quotient; Risk Estimate Index Chemical-Based Risk Estimate; Hazard Quotient Risk Estimate Available Interactions Data Whole Mixture Exposure Assessment Component Exposure Assessment Flow Charts for Evaluating Chemical Mixtures Whole Mixture Methods in supplemental materials at the end of this Section

5. Mixture RfD/RfC; Slope Factor Interaction-Based Hazard Index, Interaction Profiles, Weight of Evidence, PBPK Models Relative Potency Factors Hazard Index Response Addition, Whole Mixture Data Available Sufficiently Similar Mixture Whole Mixture of Concern Component Data Available Toxicologically Similar Components Toxicologically Independent Components Epidemiological Evaluations, Toxicity Profiles Dose Addition Mix of Toxicologically Similar & Independent Components Integrated Additivity Methods Health Evaluations Hazard Quotient; Risk Estimate Index Chemical-Based Risk Estimate; Hazard Quotient Risk Estimate Available Interactions Data Whole Mixture Exposure Assessment Component Exposure Assessment Flow Charts for Evaluating Chemical Mixtures Whole Mixture Methods in supplemental materials at the end of this Section

6. Additivity (effect of mixture estimated using component data) –Simple similar action Dose Addition - sum of doses, scaled for relative toxicity Assumes same mode-of-action across components e.g., Hazard Index, Toxicity Equivalence Factors, Relative Potency Factors –Simple dissimilar action Response Addition - sum of probabilistic risks Assumes toxicological and statistical independence Key Concept: Additive Joint Toxic Action of Mixture Components

7. Key Concept: Similarity of Toxicologic Action High Level of knowledge Low Mechanism-of- Action Mode-of-ActionToxicologic Similarity Knowledge of the details of the molecular basis of the toxic effect Knowledge of the sequence of key cellular and biochemical events (measurable parameters) that result in a toxic effect Knowledge of Toxicological Effect at the Target Organ Level Low Likelihood of knowledge High

8. Appropriate Risk Assessment Method High Level of knowledge Low Mechanism-of- Action Mode-of-ActionToxicologic Similarity Specific Methods, e.g., Toxicity Equivalence Factors (TEFs) General Methods, Limited by Route, Endpoint, Exposure Time, Chemical Groups, e.g., Relative Potency Factors (RPFs) Screening Level Assessments, e.g., Hazard Index (HI) e.g., Dioxins (binding to Ah receptor) e.g., Organophosphorus Pesticides (cholinesterase inhibition) e.g., Contaminated Site Assessment (liver effects) Low Likelihood of knowledge High

9. Toxicologic Interactions –Defined here as any toxic responses that are greater than or less than those observed under additivity Interaction Effects –Myriad of applicable terms (e.g., inhibition, masking, etc.) –Most common and general terms refer to effects that are: greater than additive (i.e., synergism) less than additive (i.e., antagonism) Key Concept: Toxicological Interactions

10. Key Concept: Exposure Assessment Key Concept: Exposure Assessment Risk Assessment Paradigm NAS,1983 Exposure – when a person contacts a pollutant; occurs at body’s outer boundary Exposure Pathway – physical course pollutant takes from source to exposed person Exposure Route – the way a pollutant enters an exposed person after contact Primary exposure routes for environmental agents:  ingestion  dermal absorption  inhalation U.S. EPA (1992) Humans are exposed concurrently and sequentially to many chemicals  various routes of exposure  multiple sources  over varying periods of time Dose-Response Assessment Hazard Identification Risk Characterization Exposure Assessment