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