NUATRC/TCEQ Air Toxics Workshop

October 2005

Air Toxics

Air Toxics: What We Know, What we Don’t Know, and What We Need to Know

Human Health Effects – Chronic

Human Health Effects – Chronic

• 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 ?

Perspectives

• Importance to chemical industry – Responsible Care®

• Chemical hazards versus chemical risks• Approaches• Opportunities

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.

Chemical hazards versus chemical risks

Elements to risk assessment (Source NAS, 1983)

Hazard identificationHazard evaluationExposure assessmentRisk characterization

Chemical hazards versus chemical risks

Elements to risk assessment (Source NAS, 1983)

Hazard identificationHazard evaluationExposure assessmentRisk characterization

Getting People ExposedGetting People Exposed – Fate and transport models:

Source: Mel Andersen, CIIT Centers for Health Research

Public Health Paradigm

SOURCE / STRESSOR

FORMATION

TRANSPORT/ TRANSFORMATIO

N

ENVIRONMENTAL CHARACTERIZATI

ON

EXPOSURE

EXPOSURE CHARACTERIZATI

ON

* Factors/criteria Example:•Temporal context- Constant or intermittent•Source(s)

*Factors/criteriaExamples:•Comparative toxicokinetics•Uncertainty•Short half-life

RISK CHARACTERIZATI

ON

DOSE

•Individual•Community•Population

EARLY BIOLOGICAL

EFFECT

ALTERED STRUCTURE FUNCTION

ADVERSE OUTCOME

*Factors/criteria * Factors/criteria

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 evaluationExposure assessmentRisk characterization

Risk assessment

Source: US EPA

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

Approaches to risk assessment

• Approaches, assumptions, and values vary, sometimes significantly: – Europe – ACGIH TLVs® – EPA– Individual States

• WHY ???– Policy, including history– Uncertainty

Dose Response AssessmentDose Response Assessment

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.

What tools help us evaluate these What tools help us evaluate these relationships?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

Physiologically Based Pharmacokinetic (PBPK) ModelingPhysiologically Based Pharmacokinetic (PBPK) Modeling

Define Realistic Model

Collect NeededData

Refine Model Structure

Make Predictions

Metabolic ConstantsTissue SolubilityTissue Volumes

Blood and Air FlowsExperimental System

Model EquationsX

X

X

X

XX

X X

Tiss

ue C

once

ntra

tion

Time

You can be wrong!

Liver

Fat

Body

Lung

Air

Source: Mel Andersen, CIIT Centers for Health Research

Models for Cellular ResponsesModels for Cellular Responses

Normal Epithelia

l Cell

Adaptive

State

StressedState

Pathology

Necrosis

Atrophy

MolecularBiochemicalHistologic

Physiological

DosimetryDosimetryInhaled Stressors

VentilationVentilation Tissue Phase ReactionsCl2 HOCl + HClCH2O HCOOH

Source: Mel Andersen, CIIT Centers for Health Research

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

Source: US EPA ORD

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

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.