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1 G. V. Alexeeff, K. K. Deng, R. L. Broadwin, A. G. Salmon Office of Environmental Health Hazard Assessment, California Environmental Protection Agency,

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Presentation on theme: "1 G. V. Alexeeff, K. K. Deng, R. L. Broadwin, A. G. Salmon Office of Environmental Health Hazard Assessment, California Environmental Protection Agency,"— Presentation transcript:

1 1 G. V. Alexeeff, K. K. Deng, R. L. Broadwin, A. G. Salmon Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA

2 2 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

3 3 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

4 4 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) / (UF A x UF H x UF other ) 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 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 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/ (UF A x UF H x UF other ) POD (point of departure) could be BMD, NOAEL, or LOAEL UF refers to uncertainty factor and may or may not be explicit Background (cont.)

7 7 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.)

8 8 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.)

9 9 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.

10 10 AcetaldehydeAcetophenone Acrolein Acrylic acidAcrylonitrileAllyl chloride AnilineBenzeneBenzyl chloride Beryllium compoundsButadieneCadmium compounds Carbon disulfideCarbon tetrachlorideChlorine ChloroformChloromethyl methyl etherChloroprene Cobalt compoundsCumeneDiazomethane DichloropropeneDimethylformamideDimethylhydrazine (1,1-) Dioxane (1,4-)EpichlorohydrinEpoxybutane(1,2-) Ethyl acrylateEthylbenzeneEthyl chloride Ethyl dichlorideEthyleneimineEthylene oxide FormaldehydeGlycol etherHexachloroethane Hexamethylene 1,6-diisocyanateHexaneHydrogen chloride Hydrogen fluorideIsophoroneMethanol Methyl bromideMethyl chlorideMethyl chloroform Methyl hydrazineMethyl isobutyl ketone (MIBK)Methyl isocyanate Methyl methacrylateMethyl tert-butyl etherMethylene chloride Methylene diphenyl diisocyanateNickel compoundsNitrophenol PCBsPhenolPhosgene PhosphinePhosphorus compoundsPropionaldehyde StyreneTetrachloroethyleneToluene Toluene diisocyanate (2,4-)TrichloroethyleneTriethylamine Vinyl acetateVinyl chloride Vinylidene chlorideXylenes (m, o, p-isomers)

11 11 Table 1. Studies Identified from the Literature Search for Evaluation Species Number of Studies Identified Number of Studies with Multiple Doses Human6015 Mouse6019 Rat12034 Other*3911 TOTAL27979 *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).

12 12 Table 2. Studies Identified Sorted by Endpoint Category Endpoint Category Number of Studies Identified Number of Studies with Multiple Doses Alimentary4111 Eyes496 Nervous7926 Respiratory7727 Other*3411 TOTAL31181 *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.

13 13 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.

14 14 Table 3. Study Description of Acute Inhalation Human Studies Identified Chemical Study duration/ Mean sample size Health EffectsReferences Acetophenone40 minutes/ 3 Increased sensitivity to light Imasheva, 1963 *Formaldehyde150 minutes/ 16 Conjunctival irritation and discomfort Anderson & Molhave, 1983 *Formaldehyde180 minutes/ 14Eye irritationKulle et al., 1987 MethanolMissing/ 5 Affected alpha rhythm amplitude Ubaydullayev, 1968 MIBK2 hours/ 8HeadacheHjelm et al., 1990 *Vinyl Acetate2 minutes/ 9 Eye, nose, & throat irritation Union Carbide Corporation, 1973 Vinyl Chloride5 minutes/ 6 Intoxicating effects Lester, 1963 *Mixed Xylenes15 minutes/ 6 Eye irritation/ tears Carpenter et al., 1975 *Human irritants

15 15 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

16 16 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.

17 17 Figure 1. BMD Analysis for Formaldehyde Exposure at 5% Response Rate

18 18 Figure 2. BMD Analysis for Mixed Xylenes Exposure at 5% Response Rate

19 19 Table 4. Comparing BMD 01 (Top Line) and BMDL 01 (Bottom Line) for Various BMD Models ChemicalProbitMultistageLogistic Quantal Linear Quantal Quadratic WeibullGamma Acetophenone (mg/m 3 ) 8.8 x x x x x x x x x x x x x x Formaldehyde (ppm) Formaldehyde (ppm) Methanol (mg/m 3 ) / x MIBK (mg/m 3 ) NA Vinyl Acetate (ppm) NA Vinyl Chloride (ppm) Mixed Xylenes (ppm) NA

20 20 Table 4a. Comparing BMD 01 (Top Line) and BMDL 01 (Bottom Line) for Various BMD Models ChemicalProbitMultistage Acetophenone (mg/m 3 ) 8.8 x x x x Formaldehyde (ppm) Formaldehyde (ppm) Methanol (mg/m 3 ) MIBK (mg/m 3 ) Vinyl Acetate (ppm) Vinyl Chloride (ppm) Mixed Xylenes (ppm)

21 21 Table 5. Comparing BMD 05 (Top Line) and BMDL 05 (Bottom Line) for Various BMD Models ChemicalProbitMultistageLogistic Quantal Linear Quantal Quadratic WeibullGamma Acetophenone (mg/m 3 ) 9.2 x x x x x x x x x x x x x x Formaldehyde (ppm) Formaldehyde (ppm) Methanol (mg/m 3 ) MIBK (mg/m 3 ) NA Vinyl Acetate (ppm) NA Vinyl Chloride (ppm) Mixed Xylenes (ppm) NA

22 22 Table 6. Comparing BMD 10 (Top Line) and BMDL 10 (Bottom Line) for Various BMD Models ChemicalProbitMultistageLogistic Quantal Linear Quantal Quadratic WeibullGamma Acetophenone (mg/m 3 ) 9.5 x x x x x x x x x x x x x x Formaldehyde (ppm) Formaldehyde (ppm) Methanol (mg/m 3 ) MIBK (mg/m 3 ) NA Vinyl Acetate (ppm) NA Vinyl Chloride (ppm) Mixed Xylenes (ppm) NA

23 23 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.

24 24 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.

25 25 Table 7. Comparison of BMD to BMDL at 1%, 5%, and 10% Response Rates using the Probit Model Chemical BMD 01 BMDL 01 BMD 05 BMDL 05 BMD 10 BMDL 10 Acetophenone *Formaldehyde *Formaldehyde Methanol MIBK *Vinyl Acetate1.8 Vinyl Chloride *Mixed Xylenes1.7 Note: * = Human irritants MIBK = Methyl Isobutyl Ketone

26 26 Relationship of BMC 95% Confidence Limits to Maximum Likelihood Estimates (Fowles et al., 1999)

27 27 Table 8. NOAEL and LOAEL Values, Compared to BMDL-BMD Concentrations, for 1%, 5% & 10% Response Rates, Using the Probit Model.NOAEL1 % Response5 % Response10 % Response LOAEL Acetophenone (mg/m 3 ) Formaldehyde 1 (ppm) Formaldehyde 2 (ppm) Methanol (mg/m 3 ) MIBK (mg/m 3 ) Vinyl Acetate (ppm) Vinyl Chloride (ppm) Mixed Xylenes (ppm) Note: Numbers in % response columns read as BMDL-BMD concentrations. 1: Anderson & Molhave, 1983; 2: Kulle et al., 1987

28 28 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.

29 29 Relationship of NOAEL and LOAEL to BMDL Ratio Response Rate 1%5%10% NOAEL to BMDL LOAEL to BMDL

30 30 Relationship of BMC to NOAELs & LOAELs from Acute Lethality Data – Probit (Fowles et al., 1999)

31 31 Table 9. NOAEL and LOAEL Values and BMDL Response Rates NOAEL% ResponseLOAEL% Response Acetophenone (mg/m 3 ) x Formaldehyde 1 (ppm) Formaldehyde 2 (ppm) Methanol (mg/m 3 ) MIBK (mg/m 3 ) Vinyl Acetate (ppm) Vinyl Chloride (ppm) Mixed Xylenes (ppm) : Anderson & Molhave, : Kulle et al, 1987

32 32 Estimating a Reference Level from the BMDL Assuming that the BMDL 05 represented the identified POD, we estimated a reference exposure level using a default 10-fold interindividual uncertainty factor (UF H ) for each of the data sets. BMDL response rates were calculated at the estimated reference exposure level.

33 33 Table 10. Estimated REL and BMDL Response Rate Using the Probit Model Chemical BMDL Response Rate CA REL Comment Acetophenone (mg/m 3 ) 3.6 x x NA *Formaldehyde 1 (ppm) x Used Kulle et al, 1987 *Formaldehyde 2 (ppm) x Used Kulle et al, 1987 Methanol (mg/m 3 ) x Different study, endpoint, and exposure. MIBK (mg/m 3 ) 3.24 x NA *Vinyl Acetate (ppm) x NA Vinyl Chloride (ppm) 4306 x Study with longer exposure *Mixed Xylenes (ppm) 11 4 x Study with longer exposure CA REL = Reference 1-hour exposure level; NA= not available; Note: * = Human irritants 1: Anderson & Molhave, 1983; 2: Kulle et al, 1987MIBK = Methyl Isobutyl Ketone

34 34 Estimating a Reference Level from the BMDL Results All of the estimated risk levels were at or below 4 x

35 35 Estimating the BMDL Response Rate at the AEGL We identified relevant AEGL-1 levels for four of the seven substances from: AEGL-1 is the airborne concentration (expressed as ppm or mg/m 3 ) 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.

36 36 Table 11. BMDL Reported Rates for Acute Emergency Guideline Levels (AEGLs) ChemicalAEGL-1 (ppm) BMDL Response Rate (%) *Formaldehyde *Vinyl Acetate6.739 Vinyl Chloride4509 x *Xylene Note: * = Human irritants 1: Anderson & Molhave, : Kulle et al, 1987

37 37 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.

38 38 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 BMDL 05 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).

39 39 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).

40 40 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.

41 41 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.

42 42 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

43 43 References ACGIH Worldwide 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). 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: Anderson, I., Molhave, L. (1983). Controlled human studies with formaldehyde. Formaldehyde Toxicity. Chapter 14, 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,

44 44 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, Fowles, JR Et Al. (1999). The Use of Benchmark Dose Methodology with Acute Inhalation Lethality Data. Regul Toxicol Pharmacol 29, 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: 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,

45 45 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, NRC 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 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, 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,


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