Transcript Benchmark Dose Evaluations for Acute Inhalation Exposures to Human Toxicants G.V. Alexeeff, K. K. Deng, R. L. Broadwin, A. G. Salmon

G. V. Alexeeff, K. K. Deng, R. L. Broadwin, A. G. Salmon
Office of Environmental Health Hazard Assessment,
California Environmental Protection Agency, Oakland, CA
1
Purpose
To evaluate the application of the
USEPA benchmark dose (BMD)
methodology to acute inhalation
exposure risk assessment using human
data.
– To refine BMD methodology.
– To inform the standard method: no
observed adverse effect level (NOAEL)
divided by uncertainty factor (UF)s
2
Background
• Approaches to describe human risks and/or reference
levels from acute inhalation exposures have been
developed by:
– American Conference of Governmental Industrial Hygienists
Inc. (ACGIH) short-term exposure limits (STELs) and Ceiling
values (ACGIH Worldwide, 2006).
– National Research Council /USEPA acute emergency guidance
levels (AEGLs) (NRC, 2000).
– USEPA acute reference exposures (Strickland et al., 2002).
– California acute reference exposure levels (Collins et al., 2004).
3
Background (cont.)
• Traditional NOAEL or LOAEL approach
– empirically analyzes effects at discrete concentrations
– does not infer about the exposure group response rates.
– Usually is described as follows (Collins et al., 2004):
Reference value = NOAEL (or LOAEL) / (UFA x UFH x UFother)
• LOAEL refers to lowest observed adverse effect level
• UF refers to uncertainty factor and may or may not be explicit
– Remains the predominant methodology due to data
available.
4
Background (cont.)
• BMD methodology is generally seen as an
improvement of the NOAEL/LOAEL approach since:
– reflects the shape of the dose-response curve
– is not an artifact of the choice of experimental
concentration.
– takes into account some variability in the test population.
• e.g., the choice of a 95% lower confidence limit (LCL).
– increases the minimum quality of an acceptable study.
5
Background (cont.)
• BMD methodology
– considers data consistency over a range of exposures
– estimates a concentration at a defined response level
– provides an estimate of toxicological response that could
replace the NOAEL as the point of departure (POD) in
health risk assessments.
– described as follows (Collins et al., 2004):
Reference value = POD/ (UFA x UFH x UFother)
• POD (point of departure) could be BMD, NOAEL, or LOAEL
• UF refers to uncertainty factor and may or may not be explicit
6
Background (cont.)
• BMD methodology requires the user to input the desired response
rate. Usually the response rate chosen is 1, 5 or 10 %.
• In 1999 we published a paper evaluating 100 acute inhalation
lethality datasets using a BMD approach (Fowles et al.). From this
analysis we decided on some preferred approaches for use in
BMD evaluation.
– Use of the probit model
– Use of a 5% response rate
– Equate the 5% response rate with the NOAEL
• While we may deviate from these approaches, they generally
represent our starting point.
7
Background (cont.)
• Caveat:
– The Fowles et al. analysis is based on acute
inhalation animal lethality evaluations.
– There is little acute inhalation exposure
information regarding
• human endpoints or
• non-lethal animal endpoints
• The USEPA BMD software has a wide range of
models to consider.
• We considered whether other models may be
superior to the probit model for a default approach.
8
Approach
• Literature search of all hazardous air
pollutants to identify data sets reporting
– mild acute effects (Alexeeff et al., 2002)
– NOAEL
– LOAEL
– sufficient information to conduct a BMD
analysis
• Relevant NOAEL and LOAEL information
was identified for 70 chemicals.
9
Acetaldehyde
Acetophenone
Acrolein
Acrylic acid
Acrylonitrile
Allyl chloride
Aniline
Benzene
Benzyl chloride
Beryllium compounds
Butadiene
Cadmium compounds
Carbon disulfide
Carbon tetrachloride
Chlorine
Chloroform
Chloromethyl methyl ether
Chloroprene
Cobalt compounds
Cumene
Diazomethane
Dichloropropene
Dimethylformamide
Dimethylhydrazine (1,1-)
Dioxane (1,4-)
Epichlorohydrin
Epoxybutane(1,2-)
Ethyl acrylate
Ethylbenzene
Ethyl chloride
Ethyl dichloride
Ethyleneimine
Ethylene oxide
Formaldehyde
Glycol ether
Hexachloroethane
Hexamethylene 1,6-diisocyanate
Hexane
Hydrogen chloride
Hydrogen fluoride
Isophorone
Methanol
Methyl bromide
Methyl chloride
Methyl chloroform
Methyl hydrazine
Methyl isobutyl ketone (MIBK)
Methyl isocyanate
Methyl methacrylate
Methyl tert-butyl ether
Methylene chloride
Methylene diphenyl diisocyanate
Nickel compounds
Nitrophenol
PCBs
Phenol
Phosgene
Phosphine
Phosphorus compounds
Propionaldehyde
Styrene
Tetrachloroethylene
Toluene
Toluene diisocyanate (2,4-)
Trichloroethylene
Triethylamine
Vinyl acetate
Vinyl chloride
Vinylidene chloride
Xylenes (m, o, p-isomers)
10
Table 1. Studies Identified from the Literature
Search for Evaluation
Number of Studies
Identified
Number of Studies
with Multiple Doses
Human
60
15
Mouse
60
19
Rat
120
34
Other*
39
11
TOTAL
279
79
Species
*Other refers to animal studies consisting of: baboon (N= 2), dog (N= 4), guinea pig (N= 19),
hamster (N= 4), monkey (N= 1), prairie dog (N=2), and rabbit (N= 6), and rock dove (N=1).
11
Table 2. Studies Identified Sorted by Endpoint
Category
Endpoint
Category
Number of Studies
Identified
Number of Studies
with Multiple Doses
Alimentary
41
11
Eyes
49
6
Nervous
79
26
Respiratory
77
27
Other*
34
11
TOTAL
311
81
*Other refers to ratios based on endpoints of: cardiovascular (N= 4), hematologic (N=18), immune (N= 12), and
reproductive (N=1).
Total N> 279 because some studies showed multiple effects.
12
Human Studies Identified
• 60 human studies contained data which met
the criteria of mild acute effects and
reported NOAEL and LOAEL values.
– 15 studies reported multiple doses.
• For this BMD analysis, we focused on those
studies based on dichotomous (quantal or
effect/no effect) responses.
• Eight data sets, for seven chemicals, met
the additional criteria: dichotomous with at
least three dose levels for BMD analysis.
13
Table 3. Study Description of Acute Inhalation Human Studies Identified
Chemical
Study duration/
Mean sample size
Health Effects
References
Acetophenone
40 minutes/ 3
Increased
sensitivity to light
Imasheva, 1963
*Formaldehyde
150 minutes/ 16
Conjunctival
irritation and
discomfort
Anderson & Molhave,
1983
*Formaldehyde
180 minutes/ 14
Eye irritation
Kulle et al., 1987
Methanol
Missing/ 5
Affected alpha
rhythm amplitude
Ubaydullayev, 1968
MIBK
2 hours/ 8
Headache
Hjelm et al., 1990
*Vinyl Acetate
2 minutes/ 9
Eye, nose, &
throat irritation
Union Carbide
Corporation, 1973
Vinyl Chloride
5 minutes/ 6
Intoxicating
effects
Lester, 1963
*Mixed Xylenes
15 minutes/ 6
Eye irritation/
tears
Carpenter et al.,
1975
14
*Human irritants
Data Analysis
• We analyzed and compared each data set
using seven different BMD models for
dichotomous data:
– Probit
– Quantal linear
– Multistage
– Weibull
– Logistic
– Quantal quadratic
– Gamma
15
Data Analysis (cont.)
• For each data set, comparisons among
the BMDL and BMD values made at 1%,
5%, and 10% response rates are shown
on the following slides.
16
Figure 1. BMD Analysis for Formaldehyde
Exposure at 5% Response Rate
Probit Model with 0.95 Confidence Level
Probit
1 BMD Lower Bound
0.8
0.6
0.4
0.2
0
BMDL
0
0.5
BMD
1
1.5
dose
12:25 03/01 2006
2
2.5
3
17
Figure 2. BMD Analysis for Mixed Xylenes
Exposure at 5% Response Rate
Probit Model with 0.95 Confidence Level
0.8
Probit
BMD Lower Bound
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
BMDL
0
100
BMD
200
300
400
dose
13:52 07/28 2006
500
600
700
18
Table 4. Comparing BMD01 (Top Line) and
BMDL01 (Bottom Line) for Various BMD Models
Chemical
Probit
Multistage
Logistic
Quantal
Linear
Quantal
Quadratic
Weibull
Gamma
Acetophenone
(mg/m3)
8.8 x 10-3
2.4 x 10-3
1.2 x 10-3
7.1 x 10-5
8.0 x 10-3
1.8 x 10-3
1.2 x 10-4
5.7 x 10-5
1.2 x 10-3
7.7 x 10-4
8.1 x 10-3
8.5 x 10-4
5.8 x 10-3
6.4 x 10-4
Formaldehyde
(ppm)
0.24
0.097
0.030
0.014
0.14
0.010
0.021
0.014
0.21
0.16
0.067
0.015
0.11
0.015
Formaldehyde
(ppm)
0.51
0.26
0.32
0.039
0.42
0.17
0.026
0.019
0.21
0.18
0.36
0.13
0.44
0.16
Methanol
(mg/m3)
1.0
0.84
0.14
0.014
0.92/
0.74
0.017
9.5 x 10-3
0.14
0.10
0.93
0.65
0.65
0.44
MIBK
(mg/m3)
28
16
5.4
2.6
5.9
1.9
5.4
2.6
30
21
NA
NA
Vinyl Acetate
(ppm)
1.7
0.93
1.4
0.17
1.2
0.15
0.37
0.16
1.5
0.99
NA
NA
Vinyl Chloride
(ppm)
5900
3000
4400
310
5400
2400
160
100
1400
1100
4600
1700
5500
2300
Mixed Xylenes
(ppm)
97
58
32
9.9
52
8.1
20
9.8
110
69
NA
NA
19
Table 4a. Comparing BMD01 (Top Line) and BMDL01
(Bottom Line) for Various BMD Models
Chemical
Acetophenone
(mg/m3)
Formaldehyde
(ppm)
Formaldehyde
(ppm)
Methanol
(mg/m3)
MIBK
(mg/m3)
Vinyl Acetate
(ppm)
Vinyl Chloride
(ppm)
Mixed Xylenes
(ppm)
Probit
Multistage
8.8 x 10-3
2.4 x 10-3
1.2 x 10-3
7.1 x 10-5
0.24
0.097
0.030
0.014
0.51
0.26
0.32
0.039
1.0
0.84
0.14
0.014
28
16
5.4
2.6
1.7
0.93
1.4
0.17
5900
3000
4400
310
97
58
32
9.9
20
Table 5. Comparing BMD05 (Top Line) and
BMDL05 (Bottom Line) for Various BMD Models
Probit
Multistage
Logistic
Quantal
Linear
Quantal
Quadratic
Weibull
Gamma
Acetophenone
(mg/m3)
9.2 x 10-3
3.6 x 10-3
2.6 x 10-3
3.6 x 10-4
8.8 x 10-3
3.2 x 10-3
6.3 x 10-4
2.9 x 10-4
2.6 x 10-3
1.7 x 10-3
8.9 x 10-3
2.1 x 10-3
7.0 x 10-3
1.7 x 10-3
Formaldehyde
(ppm)
0.43
0.19
0.15
0.074
0.33
0.055
0.11
0.074
0.47
0.36
0.23
0.074
0.29
0.074
Formaldehyde
(ppm)
0.73
0.44
0.64
0.20
0.69
0.39
0.13
0.094
0.47
0.40
0.67
0.35
0.69
0.37
Methanol
(mg/m3)
1.07
0.92
0.31
0.073
1.00
0.87
0.085
0.049
0.31
0.24
1.0
0.82
0.79
0.60
MIBK
(mg/m3)
55
32
28
13
27
10
28
13
67
46
NA
NA
Vinyl Acetate
(ppm)
3.2
1.8
3.3
0.86
3.00
0.76
1.9
0.82
3.36
2.23
NA
NA
Vinyl Chloride
(ppm)
7200
4300
6600
1600
7200
4100
820
530
3200
2500
6800
3600
7100
3900
Mixed Xylenes
(ppm)
190
110
140
51
160
42
100
50
250
160
NA
NA
Chemical
21
Table 6. Comparing BMD10 (Top Line) and
BMDL10 (Bottom Line) for Various BMD Models
Probit
Multistage
Logistic
Quantal
Linear
Quantal
Quadratic
Weibull
Gamma
Acetophenone
(mg/m3)
9.5 x 10-3
4.4 x 10-3
3.8 x 10-3
7.5 x 10-4
9.2 x 10-3
4.2 x 10-3
1.3 x 10-3
6.0 x 10-4
3.8 x 10-3
2.5 x 10-3
9.3 x 10-3
3.2 x 10-3
7.7 x 10-3
2.6 x 10-3
Formaldehyde
(ppm)
0.58
0.28
0.29
0.15
0.49
0.12
0.22
0.15
0.67
0.51
0.39
0.15
0.46
0.15
Formaldehyde
(ppm)
0.87
0.59
0.86
0.40
0.87
0.56
0.27
0.19
0.68
0.57
0.87
0.54
0.87
0.54
Methanol
(mg/m3)
1.10
0.97
0.45
0.15
1.0
0.93
0.17
0.010
0.45
0.37
1.1
0.90
0.87
0.54
MIBK
(mg/m3)
79
46
57
27
55
21
57
28
96
66
NA
NA
Vinyl Acetate
(ppm)
4.6
2.6
4.8
1.8
4.5
1.6
3.8
1.7
4.8
3.2
NA
NA
Vinyl Chloride
(ppm)
8100
5300
4500
2600
8300
5300
1700
1100
4500
3600
8100
4900
8100
5000
Mixed Xylenes
(ppm)
280
160
260
100
260
89
210
100
350
220
NA
NA
Chemical
22
Reviewing Model Results
• Data analyses via Weibull and Gamma
dichotomous models were eliminated due to
calculation failure for one or more chemicals.
• For each data set, we considered whether
the Chi-square p-value indicated that the
fitted model adequately described the data,
using a 0.05 rejection criterion. The quantal
linear, multistage, and quantal quadratic
models did not fit the data sets in all cases.
23
Reviewing Model Results (cont.)
• Remaining models (probit and logistic) were
compared using the goodness-of-fit statistics
presented in the analsyis of deviance table. In
almost all cases, there was little difference in the
parameters evaluated.
• The probit model yielded an adequate fit overall for
all the data sets, particularly in the low dose region.
We concluded that it served as useful default
approach, particularly in light of extensive
experience with the model in acute toxicology.
• The remaining evaluations use the probit model.
24
Table 7. Comparison of BMD to BMDL at 1%, 5%,
and 10% Response Rates using the Probit Model
BMD01
BMDL01
BMD05
BMDL05
BMD10
BMDL10
2.6
2.2
2.2
2.1
*Formaldehyde
3.7
2.5
2.0
1.6
1.5
Methanol
1.2
1.2
1.1
MIBK
1.8
1.7
1.7
*Vinyl Acetate
1.8
1.8
1.8
Vinyl Chloride
2.0
1.7
1.5
*Mixed Xylenes
1.7
1.7
1.7
Chemical
Acetophenone
*Formaldehyde
Note: * = Human irritants
MIBK = Methyl Isobutyl Ketone
25
Relationship of BMC 95% Confidence Limits
to Maximum Likelihood Estimates
(Fowles et al., 1999)
26
Table 8. NOAEL and LOAEL Values, Compared to BMDL-BMD
Concentrations, for 1%, 5% & 10% Response Rates, Using the Probit Model
NOAEL
1 % Response
5 % Response
Acetophenone
(mg/m3)
0.007
0.0024 0.0088
0.0036 0.0092
0.0044 0.0095
0.01
Formaldehyde1
(ppm)
0.50
0.097 - 0.24
0.19 - 0.43
0.28 - 0.58
1
Formaldehyde2
(ppm)
0.51
0.26 - 0.51
0.44 - 0.73
0.59 - 0.87
1.01
Methanol
(mg/m3)
1.01
0.84 - 1.0
0.92 - 1.07
0.97 - 1.10
1.17
MIBK
(mg/m3)
10
16 - 28
32 - 55
46 - 79
100
Vinyl Acetate
(ppm)
1.3
0.93 - 1.7
1.8 - 3.2
2.6 - 4.6
4
Vinyl Chloride
(ppm)
4000
3000 - 5900
4300 - 7200
5300 - 8100
8000
Mixed Xylenes
(ppm)
110
58 - 97
110 - 190
160 - 280
230
Note: Numbers in % response columns read as BMDL-BMD concentrations.
1: Anderson & Molhave, 1983; 2: Kulle et al., 1987
10 % Response
LOAEL
.
27
NOAEL and LOAEL Values
Compared to BMDL-BMD Concentrations
• The relationship among the NOAEL, LOAEL, BMDL
and BMD values were evaluated at the 1%, 5% and
10% response rates.
• The 1% and 5% BMDL-BMD range is more closely
associated with the NOAEL than the 10% range.
• The 10% BMDL-BMD range may be associated with
the LOAEL.
28
Relationship of NOAEL and LOAEL
to BMDL
Response Rate
Ratio
1%
5%
10%
NOAEL to
BMDL
2.1
1.3
0.93
LOAEL to
BMDL
4.6
2.6
1.9
29
Relationship of BMC to NOAELs & LOAELs
from Acute Lethality Data – Probit (Fowles et
al., 1999)
30
Table 9. NOAEL and LOAEL Values and
BMDL Response Rates
NOAEL
% Response
LOAEL
% Response
Acetophenone
(mg/m3)
0.007
1.0 x 10-7
0.01
34
Formaldehyde1
(ppm)
0.50
8.0
1
28
Formaldehyde2
(ppm)
0.51
1.0
1.01
16
Methanol
(mg/m3)
1.01
0.42
1.17
49
MIBK
(mg/m3)
10
0.042
100
15
Vinyl Acetate
(ppm)
1.3
0.45
4
7.8
Vinyl Chloride
(ppm)
4000
0.018
8000
9.4
Mixed Xylenes
(ppm)
110
1.4
230
7.2
31
1: Anderson & Molhave, 1983
2: Kulle et al, 1987
Estimating a Reference Level from
the BMDL
• Assuming that the BMDL05 represented
the identified POD, we estimated a
reference exposure level using a default
10-fold interindividual uncertainty factor
(UFH) for each of the data sets.
• BMDL response rates were calculated at
the estimated reference exposure level.
32
Table 10. Estimated REL and BMDL
Response Rate Using the Probit Model
Chemical
BMDL05
10
Response Rate
CA
REL
Comment
Acetophenone
(mg/m3)
3.6 x 10-4
1 x 10-7
NA
NA
*Formaldehyde1
(ppm)
0.019
4 x 10-5
0.076
Used Kulle et al, 1987
*Formaldehyde2
(ppm)
0.044
2.5 x 10-6
0.076
Used Kulle et al, 1987
Methanol
(mg/m3)
0.092
1 x 10-7
28
Different study, endpoint,
and exposure.
MIBK
(mg/m3)
3.2
4 x 10-5
NA
NA
*Vinyl Acetate
(ppm)
0.18
4 x 10-5
NA
NA
Vinyl Chloride
(ppm)
430
6 x 10-9
72
Study with longer exposure
*Mixed Xylenes
(ppm)
11
4 x 10-5
5
Study with longer exposure
CA REL = Reference 1-hour exposure level;
1: Anderson & Molhave, 1983;
NA= not available;
2: Kulle et al, 1987
Note: * = Human irritants
MIBK = Methyl Isobutyl Ketone
33
Estimating a Reference Level from
the BMDL Results
• All of the estimated risk levels were at or
below 4 x 10-5.
34
Estimating the BMDL Response
Rate at the AEGL
• We identified relevant AEGL-1 levels for four of the
seven substances from: http://www.epa.gov/oppt/aegl
• AEGL-1 is the airborne concentration (expressed as
ppm or mg/m3) of a substance above which it is
predicted that the general population, including
susceptible individuals, could experience notable
discomfort, irritation, or certain asymptomatic
nonsensory effects. However, the effects are not
disabling and are transient and reversible upon
cessation of exposure.
• We calculated the BMDL response rate at the AEGL-1.
35
Table 11. BMDL Reported Rates for Acute
Emergency Guideline Levels (AEGLs)
Chemical
AEGL-1 (ppm)
BMDL
Response Rate (%)
*Formaldehyde
0.9
242 - 461
*Vinyl Acetate
6.7
39
Vinyl Chloride
450
9 x 10-7
*Xylene
130
6.5
Note: * = Human irritants
1: Anderson & Molhave, 1983
2: Kulle et al, 1987
36
Estimating the BMDL Response
Rate at the AEGL Results
• Expected risk levels from the AEGL-1
values appear to be significant for the
irritants vinyl acetate and
formaldehyde.
37
Discussion and Conclusion
• The probit model consistently provides an adequate fit
for these dichotomous acute human exposure data; this
is consistent with the results for acute inhalation lethality
animal data (Fowles et al., 1999).
• Among 1%, 5% and 10% response rates, 5% overall is
more closely associated with the NOAEL; therefore,
human inhalation data sets at BMDL05 are considered to
be similar to a NOAEL in estimating a concentration
associated with a low level of risk. This is consistent
with the results for acute inhalation lethality animal data
(Fowles et al., 1999).
38
Discussion and Conclusion
(cont.)
• The BMD 10% response rate may be associated with the
LOAEL. This may require consideration of an additional
uncertainty factor if the 10% response level is assumed.
• The average ratio of the BMD to the BMDL was fairly
constant across chemicals. This indicates that no
significant divergence between the BMD and BMDL for
most chemicals in the 1% to 10% range. This is
consistent with the results for acute inhalation lethality
animal data (Fowles et al., 1999).
39
Discussion and Conclusion
(cont.)
• BMD approach provides a more consistent basis
for estimating a point of departure. The
estimated response rates at the NOAEL and
LOAEL can vary substantially.
• At the LOAEL, response rates above 25% can
occur.
• At the NOAEL, response rates are generally
very low, although several in the 1% to 10%
range were calculated.
40
Discussion and Conclusion
(cont.)
• Using the BMD approach to estimate of
the response rate of a guidance level may
provide useful insight to the level of
protection of the guidance level.
41
Contributors
OEHHA Staff
Students
•
•
•
•
•
•
•
•
George V. Alexeeff
Rachel Broadwin
James F. Collins
Melanie A. Marty
Andrew Salmon
Kitty K. Deng
Dora Wang
Melisa Masuda
Other Contributors
Support Staff
•
Jefferson R. Fowles
• Laurie Bliss
42
References
•
ACGIH Worldwide. 2006. 2006 TLVs and BEIs, Based on the
Documentation of the Threshold Limit Values for Chemical Substances and
Physical Agents & Biological Exposure Indices. Cincinnati, OH: ACGIH
Worldwide.
•
Acute Emergency Guidelines Levels (AEGLs). (2005). U.S. Environmental
Protection Agency (EPA). http://www.epa.gov/oppt/aegl/chemlist.htm
•
Alexeeff, G.V., Broadwin, R., Liaw, J., and Dawson, S.V. (2002)
Characterization of the LOAEL-NOAEL Uncertainty Factor for Mild Adverse
Effects from Acute Inhalation Exposure. Reg. Toxicol. Pharmacol. 36:96105.
•
Anderson, I., Molhave, L. (1983). Controlled human studies with
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