1. NUATRC/TCEQ Air Toxics Workshop October 2005

2. Air Toxics Air Toxics: What We Know, What we Don’t Know, and What We Need to Know Human Health Effects – Chronic

3. Questions: –1) Do better exposure estimates yield stronger associations with health effects ? –2) What is the appropriate proportion of attention that should be given to chronic and acute outcomes. –3) Do mortality, cancer, exacerbation of asthma, and other respiratory and cardiovascular diseases correlate with exposure ?

4. Perspectives Importance to chemical industry – Responsible Care® Chemical hazards versus chemical risks Approaches Opportunities

5. Chemical industry: Responsible Care® A global, voluntary initiative to improve the environment, improve and protect the health and safety of our employees and community members. Responsible Care is more than a set of principles and declarations. It is implementing world-class management systems, verified through independent auditors; tracking performance through established environment, health, safety and security measures; and extending these best practices to business partners through the industry supply chain.

6. Chemical hazards versus chemical risks Elements to risk assessment (Source NAS, 1983) Hazard identification Hazard evaluation Exposure assessment Risk characterization

7. Chemical hazards versus chemical risks Elements to risk assessment (Source NAS, 1983) Hazard identification Hazard evaluation Exposure assessment Risk characterization

8. Getting People Exposed Getting People Exposed – Fate and transport models: Source: Mel Andersen, CIIT Centers for Health Research

9. Public Health Paradigm SOURCE / STRESSOR FORMATION TRANSPORT/ TRANSFORMATION ENVIRONMENTAL CHARACTERIZATION EXPOSURE EXPOSURE CHARACTERIZATION * Factors/criteria Example: Temporal context - Constant or intermittent Source(s) *Factors/criteria Examples: Comparative toxicokinetics Uncertainty Short half-life RISK CHARACTERIZATION DOSE Individual Community Population EARLY BIOLOGICAL EFFECT ALTERED STRUCTURE FUNCTION ADVERSE OUTCOME *Factors/criteria

10. Chemical hazards versus chemical risks Elements to risk assessment (Source NAS, 1983) Hazard identification Chronic human health effects: cancer, developmental, reproductive, neurotoxicity,respiratory toxicity,.. Hazard evaluation Exposure assessment Risk characterization

11. Risk assessment Source: US EPA

12. Approaches to risk assessment Europe (EU) –Margin of Safety (MOS) ACGIH TLVs® for worker protection –‘represent concentrations that nearly all workers may be repeatedly exposed, day after day, over a working lifetime, without adverse health effects’ –Note: NOT meant to be a legal standard EPA –Several factors for uncertainty – some with more scientific basis than others. –Probabilistic cancer risk Individual States –Texas - TCEQ

13. Approaches to risk assessment Approaches, assumptions, and values vary, sometimes significantly: –Europe –ACGIH TLVs® –EPA –Individual States WHY ??? –Policy, including history –Uncertainty

14. Dose Response Assessment

15. Opportunities Best available science: Dosimetry – for a given exposure in test animals and humans how do tissue doses vary between species Tissue Response – for a specified tissue dose, how will the response vary between test animals and humans.

16. What tools help us evaluate these relationships? Pharmacokinetic Models – calculate the tissue dose of active forms of the toxic chemical for various doses, dose- routes, and animal species Pharmacodynamics Models – calculate the degree of response for any level of tissue dose in different species

17. Physiologically Based Pharmacokinetic (PBPK) Modeling Define Realistic Model Collect Needed Data Refine Model Structure Make Predictions Metabolic Constants Tissue Solubility Tissue Volumes Blood and Air Flows Experimental System Model Equations X X X X X X X X Tissue Concentration Time You can be wrong! Liver Fat Body Lung Air Source: Mel Andersen, CIIT Centers for Health Research

18. Models for Cellular Responses Normal Epithelial Cell Adaptive State Stressed State Pathology Necrosis Atrophy Molecular Biochemical Histologic Physiological Dosimetry Inhaled Stressors Ventilation Tissue Phase Reactions Cl 2 HOCl + HCl CH 2 O HCOOH Source: Mel Andersen, CIIT Centers for Health Research

19. Computational, High Content Biology Biological models of cellular responses, using high content data collection (genomics), focusing on computational biology of target cell signaling modules and dose responses related to activation of circuits and specific cellular responses

20. Source: US EPA ORD

21. Human Health Effects – Chronic Questions: –1) Do better exposure estimates yield stronger associations with health effects ? Exposure estimates are an important element, but the public health paradigm requires an understanding of health effects, including (particularly) dose response. –2) What is the appropriate proportion of attention that should be given to chronic and acute outcomes. Chemical (nature of hazards) and situation (exposure) specific. –3) Do mortality, cancer, exacerbation of asthma, and other respiratory and cardiovascular diseases correlate with exposure ? Depends on dose

22. Conclusions Air Toxics: Health Effects Chronic –What We Know High dose hazard identification A sense of the uncertainty. –What we Don’t Know Certainty about uncertainty. –What We Need to Know Biologically based pharmacokinetic and pharmacodynamic models.