William K. Boyes Neurotoxicology Division

Office of Research and Development, US EPAResearch Triangle Park, NC

Air Toxics: Chronic Health Research Needs

What is the Goal?

• Biologically-based dose response model “predictive tool used to estimate potential human

health risks by describing and quantifying the key steps in the cellular, tissue and organismal responses as a result of chemical exposure”

• The preferred approach, e.g. EPA new Cancer Risk Assessment Guidelines NAS research priorities for particulate matter

AppliedDose

AbsorbedDose

TargetTissueDose

MetabolicConversion

ToxicEvents

Observedoutcomes

Elimination

AppliedDose

AbsorbedDose

MetabolicConversion

Observedoutcomes

Elimination

AnimalModel

Human

Dose metric is key

Typical Dose Measures

Basis Peak Cumulative

External Exposure

Air concentration ( C )

(ppm, mg/m3)

C x t (Haber’s)

Cn x t

(ppm * yr, mg/m3 * yr)

Internal Dose Tissue Concentration (mg/l)

Tissue AUC

(mg/l * hr, mg/l * yr)

Others?

Reference Concentration (RfC)

NOAEL * [HEC]RfC = -------------------------

UF

RfC A concentration to which lifetime exposure will be without appreciable risk (w/in order of magnitude)

NOAEL*[HEC] NOAEL, or equivalent adjusted for human dosimetry

UF Uncertainty factors (up to 3000 total)

Noncancer Cancer

IRISOtherNone

Number of HAP Chemicals with Chronic Health Benchmark Values

131

5855

71

41

132

Chronic Health Benchmarks

Uncertainty Factors of HAP RfCs

• Uncertainty factors: LOAEL to NOAEL (up to) 10 Short duration to long 10 Animal to human 10 Human variability 10 Inadequate database 10 Maximum total

3000

Uncertainty Factors of HAP RfCs

Magnitude of UF (log scale)

1 10 100 1000 10000

Num

ber

of C

hem

ical

s0

5

10

15

20

Acute Health Benchmarks

Epidemiology and Temporal Patterns

• Criteria Pollutants PM

• Hourly exposure peaks linked to cardio-pulmonary mortality

Ozone• Hourly/daily

concentrations linked to reactive airway problems (asthma)

• HAPs Little epidemiology

regarding temporal exposure patterns

Exposure Patterns

• Risk assessment for chronic exposures considers only mean annual exposure levels

• Yet HAP exposures vary greatly from time to time Human activity patterns Changing weather Emission patterns and/or “upsets”

Recent Studies of Upset Emissions

• Public Citizen (Austin TX, 2005) In some cases, upset releases exceeded

annual releases several thousand fold 7,533 upset events to Texas in 2004 Some facilities report upset events on

average every other day

Concentration-Driven Health Outcomes

• Respiratory Irritants Concentration more important than C x t

• Acute CNS effects of VOCs Peak brain concentration determines outcome

and not AUC

• Development Short critical periods of development (hrs/days) Short term exposure episodes lead to life long

alterations

AppliedDose

AbsorbedDose

Target TissueDose

AdverseOutcome

Exposure-Dose-Response Model

Brain vs Blood

Blood [TCE] (mg/l)

0.1 1 10 100

Bra

in [

TC

E]

0.1

1

10

100

Time (hr)

0.0 0.5 1.0 1.5 2.0 2.5

Blo

od T

CE

Con

cent

ratio

n (m

g/lit

er)

0.01

0.1

1

10

100

1000 4000 ppm2000 ppm200 ppmsimulations

Visual Evoked Potential Amplitude as a Function of Estimated Brain TCE Concentration

Estimated Brain [TCE] (mg/l)

0 20 40 60 80 100 120 140 160

F2

Am

p (u

V)

(mea

n +

\- S

EM

)

0

1

2

3

4

5

6

7

8

9

10 0 ppm500 ppm during exposure1000 ppm during exposure2000 ppm during exposure2000 ppm after exposure3000 ppm during exposure3000 ppm after exposure4000 ppm during exposure4000 ppm after exposure5000 ppm during exposure5000 ppm after exposureSigmoidal function

Dose Metric for Neurotoxic VOCs

• Acute peak brain concentration Use to extrapolate

• across exposure durations

• Across species

• Chronic Unknown Likely cumulative in

some way• AUC?

• Other

Chronic Toluene Neurotoxicity

As a function of ppm As a function of ppm*yr

Human Toluene Studies

Study Number

0 1 2 3 4 5 6 7 8 9 10 11

Con

cent

ratio

n (p

pm)

0

20

40

60

80

100

120

140LOAEL (ppm) NOAEL (ppm) Point of Departure (34 ppm)

Human Toluene Studies

Study Number

0 1 2 3 4 5 6 7 8 9 10 11C

umul

ativ

e E

xpos

ure

(ppm

*yrs

)

0

500

1000

1500

2000

2500

3000 LOAEL Cum Dose (ppm*yr) NOAEL Cum Dose (ppm*yr) 380 ppm*yr

Toluene Neurotoxicity Rat vs Human

As a function of ppm*yr

Human Toluene Studies

Study Number

0 2 4 6 8 10 12C

umul

ativ

e E

xpos

ure

(ppm

*yrs

)0

500

1000

1500

2000

2500

3000 LOAEL Cum Dose (ppm*yr) NOAEL Cum Dose (ppm*yr) 380 ppm*yr

Rat Toluene Studies

Study Number

0 2 4 6 8 10

Cum

ulat

ive

Exp

osur

e (p

pm*y

rs)

0

100

200

300

400

What do we know?

We Know We Don’t Know

Health benchmarks (RfC, URE) for ~½ the HAPs

The other half

RfC: safe over a lifetime of exposure

Risks above the RfC

URE: linear slope factors Nonlinear mechanisms

Mean annual exposure estimates

Temporal/spatial variations in exposure

Goal: BBDR models Mode of action & dose metrics