1 g. v. alexeeff, k. k. deng, r. l. broadwin, a. g. salmon office of environmental health hazard...
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G. V. Alexeeff, K. K. Deng, R. L. Broadwin, A. G. Salmon
Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA
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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
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• 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).
Background
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• 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.
Background (cont.)
5
• 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.
Background (cont.)
6
• 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
Background (cont.)
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• 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.
Background (cont.)
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• 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.
Background (cont.)
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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.
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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)
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Table 1. Studies Identified from the Literature
Search for Evaluation
SpeciesNumber of Studies
IdentifiedNumber of Studies with Multiple Doses
Human 60 15
Mouse 60 19
Rat 120 34
Other* 39 11
TOTAL 279 79
*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).
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Table 2. Studies Identified Sorted by Endpoint
Category EndpointCategory
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.
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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.
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Table 3. Study Description of Acute Inhalation Human Studies Identified
ChemicalStudy duration/
Mean sample sizeHealth Effects References
Acetophenone 40 minutes/ 3Increased
sensitivity to lightImasheva, 1963
*Formaldehyde 150 minutes/ 16Conjunctival irritation and discomfort
Anderson & Molhave, 1983
*Formaldehyde 180 minutes/ 14 Eye irritation Kulle et al., 1987
Methanol Missing/ 5Affected alpha
rhythm amplitudeUbaydullayev, 1968
MIBK 2 hours/ 8 Headache Hjelm et al., 1990
*Vinyl Acetate 2 minutes/ 9Eye, nose, &
throat irritationUnion Carbide
Corporation, 1973
Vinyl Chloride 5 minutes/ 6Intoxicating
effectsLester, 1963
*Mixed Xylenes 15 minutes/ 6Eye irritation/
tearsCarpenter et al.,
1975
*Human irritants
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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
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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.
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Figure 1. BMD Analysis for Formaldehyde Exposure at 5% Response Rate
0
0.2
0.4
0.6
0.8
1
0 0.5 1 1.5 2 2.5 3
Fra
ction A
ffecte
d
dose
Probit Model with 0.95 Confidence Level
12:25 03/01 2006
BMDL BMD
ProbitBMD Lower Bound
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Figure 2. BMD Analysis for Mixed Xylenes Exposure at 5% Response Rate
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0 100 200 300 400 500 600 700
Fra
ctio
n A
ffe
cte
d
dose
Probit Model with 0.95 Confidence Level
13:52 07/28 2006
BMDL BMD
ProbitBMD Lower Bound
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Table 4. Comparing BMD01 (Top Line) and
BMDL01 (Bottom Line) for Various BMD Models Chemical Probit Multistage Logistic
Quantal Linear
QuantalQuadratic
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)
0.240.097
0.0300.014
0.140.010
0.0210.014
0.210.16
0.0670.015
0.110.015
Formaldehyde(ppm)
0.510.26
0.320.039
0.420.17
0.0260.019
0.210.18
0.360.13
0.440.16
Methanol(mg/m3)
1.00.84
0.140.014
0.92/0.74
0.0179.5 x 10-3
0.140.10
0.930.65
0.650.44
MIBK(mg/m3)
2816
5.42.6
5.91.9
5.42.6
3021 NA NA
Vinyl Acetate(ppm)
1.70.93
1.40.17
1.20.15
0.370.16
1.50.99 NA NA
Vinyl Chloride(ppm)
59003000
4400310
54002400
160100
14001100
46001700
55002300
Mixed Xylenes(ppm)
9758
329.9
528.1
209.8
11069 NA NA
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Table 4a. Comparing BMD01 (Top Line) and BMDL01
(Bottom Line) for Various BMD Models Chemical Probit Multistage
Acetophenone(mg/m3)
8.8 x 10-3
2.4 x 10-3
1.2 x 10-3
7.1 x 10-5
Formaldehyde(ppm)
0.240.097
0.0300.014
Formaldehyde(ppm)
0.510.26
0.320.039
Methanol(mg/m3)
1.00.84
0.140.014
MIBK(mg/m3)
2816
5.42.6
Vinyl Acetate(ppm)
1.70.93
1.40.17
Vinyl Chloride(ppm)
59003000
4400310
Mixed Xylenes(ppm)
9758
329.9
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Table 5. Comparing BMD05 (Top Line) and BMDL05 (Bottom Line) for Various BMD Models
Chemical Probit Multistage LogisticQuantal Linear
QuantalQuadratic
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)
0.430.19
0.150.074
0.330.055
0.110.074
0.470.36
0.230.074
0.290.074
Formaldehyde(ppm)
0.730.44
0.640.20
0.690.39
0.130.094
0.470.40
0.670.35
0.690.37
Methanol(mg/m3)
1.070.92
0.31 0.073
1.000.87
0.0850.049
0.310.24
1.00.82
0.790.60
MIBK(mg/m3)
5532
2813
2710
2813
6746
NA NA
Vinyl Acetate(ppm)
3.21.8
3.30.86
3.000.76
1.90.82
3.362.23
NA NA
Vinyl Chloride(ppm)
72004300
66001600
72004100
820530
32002500
68003600
71003900
Mixed Xylenes(ppm)
190 110
14051
16042
10050
250160
NA NA
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Table 6. Comparing BMD10 (Top Line) and BMDL10 (Bottom Line) for Various BMD Models
Chemical Probit Multistage LogisticQuantal Linear
QuantalQuadratic
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)
0.580.28
0.290.15
0.490.12
0.220.15
0.670.51
0.390.15
0.460.15
Formaldehyde(ppm)
0.870.59
0.860.40
0.870.56
0.270.19
0.680.57
0.870.54
0.870.54
Methanol(mg/m3)
1.100.97
0.450.15
1.00.93
0.170.010
0.450.37
1.10.90
0.870.54
MIBK(mg/m3)
7946
5727
5521
5728
9666
NA NA
Vinyl Acetate(ppm)
4.62.6
4.81.8
4.51.6
3.81.7
4.83.2
NA NA
Vinyl Chloride(ppm)
81005300
45002600
83005300
17001100
45003600
81004900
81005000
Mixed Xylenes(ppm)
280160
260100
26089
210100
350220
NA NA
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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.
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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.
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Table 7. Comparison of BMD to BMDL at 1%, 5%, and 10% Response Rates using the Probit Model
ChemicalBMD01
BMDL01
BMD05
BMDL05
BMD10
BMDL10
Acetophenone 3.7 2.6 2.2
*Formaldehyde 2.5 2.2 2.1
*Formaldehyde 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
Note: * = Human irritants MIBK = Methyl Isobutyl Ketone
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Relationship of BMC 95% Confidence Limits to Maximum Likelihood Estimates
(Fowles et al., 1999)
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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 10 % Response LOAEL
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
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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.
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Relationship of NOAEL and LOAEL to BMDL
RatioResponse Rate
1% 5% 10%
NOAEL to BMDL
2.1 1.3 0.93
LOAEL to BMDL
4.6 2.6 1.9
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Relationship of BMC to NOAELs & LOAELs from Acute Lethality Data – Probit (Fowles
et al., 1999)
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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
1: Anderson & Molhave, 19832: Kulle et al, 1987
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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.
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Table 10. Estimated REL and BMDL Response Rate Using the Probit Model
ChemicalBMDL05
10Response Rate
CAREL
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; NA= not available; Note: * = Human irritants1: Anderson & Molhave, 1983; 2: Kulle et al, 1987 MIBK = Methyl Isobutyl Ketone
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Estimating a Reference Level from the BMDL Results
• All of the estimated risk levels were at or below 4 x 10-5.
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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.
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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 irritants1: Anderson & Molhave, 19832: Kulle et al, 1987
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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.
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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).
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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).
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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.
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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.
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Contributors
OEHHA Staff• George V. Alexeeff• Rachel Broadwin• James F. Collins• Melanie A. Marty• Andrew Salmon
Support Staff• Laurie Bliss
Students• Kitty K. Deng• Dora Wang• Melisa Masuda
Other Contributors• Jefferson R. Fowles
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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. 36:96-105.
• Anderson, I., Molhave, L. (1983). Controlled human studies with formaldehyde. Formaldehyde Toxicity. Chapter 14, 154-164.
• Carpenter, C. P., Kinkead, E. R., Geary, Jr., D. L., Sullivan, L. J., King, J. M. (1975). Petroleum hydrocarbon toxicity studies. V. Animal and human response to vapors of mixed xylenes. Toxicology Applied Pharmacology. 33, 543-558.
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References (cont.)• Collins, JF Et Al. (2004). Development of Acute Inhalation Reference
Exposure Levels (RELs) to Protect the Public from Predictable Excursions of Airborne Toxicants. Journal of Appl Toxicol. 24, 155-166.
• Fowles, JR Et Al. (1999). The Use of Benchmark Dose Methodology with Acute Inhalation Lethality Data. Regul Toxicol Pharmacol 29, 262-278.
• Hjelm, E.W, Hagberg, M., Iregren, A., and Lof, A. (1990) Exposure to methyl isobutyl ketone: toxicokinetics and occurrence of irritative and CNS symptoms in man. Int Arch Occup Environ Health 62:19-26.
• Imasheva, N.B. (1963) The Substantiation of the Maximal Permissible Concentration of Acetophenon in the Atmospheric Air. Hyg Sanit 28:57-63
• Kulle, J. T., Sauder, L. R., Hebel, J. R., Green, D., and Chatham, M. D. (1987). Formaldehyde dose-response in healthy nonsmokers. J. Air Pollution Control Assoc. 37, 919-924.
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References (cont.)• Lester, D., Greenberg, L. A., and Adams, W. R. (1963). Effects of
single and repeated exposures of humans and rats to vinyl chloride. Am. Ind. Hyg. Assoc. J. 3, 265-275.
• NRC. 2000. Acute Exposure Guideline Levels for SElected Airborne Chemicals. Washington, DC: National Academy Press.
• Smyth, H.F. and Carpenter, C.P. (1973) Vinyl Acetate Single Animal Inhalation and Human Sensory Response. Special Report 36-72. Union Carbide Corp. Danbury, CT.
• Strickland, J.A. Et. Al. (2002). US EPA’s Acute Reference Exposure Methodology for Acute Inhalation Exposures. The Science of the Total Environment. 288, 51-63.
• Ubaydullayev, R. (1968). A study of hygienic proper ties of methanol as an atmospheric air pollutant. USSR Lit. Air Pollut. Relat. Occup. Dis. – A Survey. 17, 39-45.
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