Supporting Documentation for MassDEP Air Guidelines - Allowable Ambient Limits

BENZENE

CASRN: 71-43-2
Update: December 8, 2014 /
C6H6
Massachusetts Guideline Limits[1]:
AAL = 0.1 ug/m3 (0.03 ppb)[2] (annual average concentration)
TEL = 0.6 ug/m3 (0.2 ppb) (24 hour average concentration)
Chemical Properties: (ATSDR 2007)
Odor Characteristics / Aromatic
Odor Threshold: / 0.875 ppm (2.8 mg/m3) (Haley 1977)
4.68 ppm (15.3 mg/m3)
Irritant: / Yes, skin and eye
Sensitizer: / No information
Chemical Class: / Gas, VOC
Boiling Point: / 80.1oC
Melting Point: / 5.5oC
Vapor pressure: / 75 mm Hg at 20oC
Molecular Weight: / 78
Unit Conversion factor: / 3.26 ug/m3 per ppb at 20oC
Critical Effects[3]:
  • Decreased counts of B-lymphocytes in workers.
  • Target organ systems affected include: hematopoietic, neurological and reproductive/developmental systems. Impairment of immune function and/or anemia and leukemia may result from the hematologic effects.
  • Benzene is classified as a “known human carcinogen” for all routes of exposure.

Potentially Susceptible Populations:
  • Genetic polymorphism in CYP2E1 among individual humans suggests potential for differential susceptibility to benzene toxicity.
  • Females may be at greater risk than males. Gender differences result because women metabolize 23–26% more benzene than do men when subjected to the same exposure conditions.
  • Evidence from human and animal studies suggests that increases in childhood leukemia may be associated with in utero exposures and maternal and paternal exposure prior to conception.
  • Because of their smaller size, increased activity, and increased ventilation rate, as compared to adults, children may have greater exposure to benzene in air on a unit-body-weight basis.
  • Infants and children also may be vulnerable to leukemia induction from benzene because their hematopoietic cell populations are undergoing maturation and differentiation. However, the information on children is not strong enough to warrant an additional safety factor.

TEL Basis for Criteria:
Available chronic inhalation noncancer toxicity values:
RfC 30 ug/m3 (USEPA 2003)
REL 3 ug/m3 (CalEPA 2014)
MRL 10 ug/m3 (ATSDR 2007)
The REL of 3 ug/m3 derived by CalEPA (2014) was selected as the basis of the TEL. A relative source contribution factor of 0.2 was applied to derive the TEL.
TEL = 3 ug/m3 x 0.2 (RSC) = 0.6 ug/m3 (0.2 ppb)
The USEPA, CalEPA and ATSDR values are greater than a factor of 3 from each other. All values were evaluated as described in MassDEP (2011). The REL from CalEPA (2014) was selected as the basis of the TEL because the extrapolation methods are more consistent with those MassDEP uses. Both CalEPA and ATSDR use the same occupational study as the basis of the noncancer toxicity value. The Lan et al. (2004) study was large, had adequate exposure-response information and yielded statistically significant exposure-response trends for sensitive indicators of response at lower exposure concentrations than the studies available at the time the USEPA RfC was derived.
T
The CalEPA REL and ATSDR MRL are based on a cross-sectional occupational study of250 exposed workers employed for 6.1 + 2.9 years and 140 controls (Lan et al. 2004).Exposure was measured by personal monitors of workplace air and urine. Participants were divided into four groups, control (mean of sampled concentrations 0.04 ppm), <1 ppm (0.57 + 0.24 ppm), 1 to <10 ppm (2.85 + 2.11 ppm), and 10 ppm (28.73 + 20.74 ppm). Statistically significant inverse exposure-response relationships were observed for platelets, total white blood cells (WBC), and WBC subtypes, granulocytes, lymphocytes, and B cells (CalEPA 2014). Responses in the lowest exposure group, 0.57 + 0.24 ppm (1.86 + 0.78 mg/m3), were statistically significantly different from controls. Thus, 0.57 ppm (1.86 mg/m3)benzene was considered the LOAEL. Benzene-induced decreased Bcell counts were selected as the critical effect for BMD modeling as theyrepresented the largest magnitude of effect.B cell counts are a continuous endpoint, thus, the benchmark response level was defined by the standard deviation from control. CalEPA and ATSDR used similar approaches, however a number of the decisions leading to the final toxicity values differed. The approaches are summarized in the table below. The CalEPA REL was selected as the basis of the MassDEP TEL because the adjustment to human equivalent concentration was the same as would be employed by MassDEP and because the uncertainty factor for human variability included consideration of fetuses and children.
Table 1. Derivation of Benzene Noncancer Toxicity Value: Quantitative Decisions
Attribute / CalEPA (2014) / ATSDR (2007)
Benchmark Response (BMR) method / 0.5 standard deviations from the control mean (0.5SD) / 0.25 standard deviations from the control mean(0.25SD)
Benchmark Response Concentration (BMC) using Hill dose response model / 1.624 ppm
(3.29 mg/m3) / 0.42 ppm
(1.4 mg/m3)
BMCL / 0.476 ppm
(1.55 mg/m3) / 0.1 ppm
(0.325 mg/m3)
Adjustment to Human Equivalent Concentration (HEC) (workers exposed for 6 days per week) / 10 m3/20 m3, inhalation volume during work day divided by volume per day. / 8 hours/24 hours,daily duration of inhalation exposure divided by number of hour per day.
Point of Departure = BMCL adjusted to HEC / 0.2 ppm
(665 ug/m3) / 0.03 ppm
(97.8 ug/m3)
Uncertainty Factors Composite / 200 / 10
UFA (animal to human) / 1 / 1
UFH (human population variability in response) / 60(default is 30, increased to account for increased variability in toxicokinetics) / 10
UFS (subchronic to chronic) / 3 (square root of 10) / 1
UFD (combined data deficiencies) / 1 / 1
Noncancer Toxicity Value / REL = 1 ppb
(3 ug/m3) / MRL = 3 ppb
(10 ug/m3)
To calculate the REL, the BMCL0.5sd of 0.2 ppm (0.665 mg/m3)was divided by a composite uncertainty factor of 200 (CalEPA 2014).
REL = 0.2 ppm = 1 ppb = 3 ug/m3
200
Uncertainty factors:
UFH (human population variability in response) = 60
UFS (subchronic to chronic) = 3
UFD (combined data deficiencies) = 1
The USEPA (2003) RfC is based on a cross-sectional occupational epidemiological study of 44 workers exposed to benzene by inhalation for 6.3 + 4.4 years and 44 controls (Rothman et al. 1996). Exposure was measured by personal monitors of workplace air and urine. Exposed workers were divided into 2 groups; low exposure group (median exposure concentration, 13.6 ppm [43.4 mg/m3], range 1.6-30.6 ppm); and high exposure group (median exposure concentration, 91.9 ppm[294 mg/m3], range 31.6-328.5 ppm). All six blood parameters measured (absolute lymphocyte count, white blood cell count, red blood cell count, platelet count, hematocrit and mean cell volume in the low and high exposure groups were statistically different from controls. Absolute lymphocyte count (ALC) was identified as the critical effect for BMD modeling because it was the only effect that remained statistically significant in a subgroup of the low exposure group that was not exposed above 31 ppm during the study period (USEPA 2003).
Absolute lymphocyte countis a continuous endpoint, thus USEPA defined the benchmark response level as 1 standard deviations (sd) below the control mean. A BMC1sd of 13.7 ppm (43.8 mg/m3) and BMCL1sd of 7.2 ppm (23.0 mg/m3) were calculated using the study exposure concentrations. The point of departure, the duration adjusted BMCLADJis 8.2 mg/m3, where 8.2 mg/m3 =23.0 mg/m3 x 10 m3/20 m3ventilation volume x 5/7 days per week. The RfC 0.03 mg/m3was derived by dividing the BMCLADJof 8.2 mg/m3by an overall UF of 300, comprised of UFL= 3 for effect-level extrapolation, UFH= 10 for human variability, UFS= 3 for subchronictochronic extrapolation, and UFD= 3 for database deficiencies.
Cancer Classification:
USEPA (2003): known human carcinogen; Category A
NTP (2005): known human carcinogen
IARC (2007): Group 1 (carcinogenic to humans)
NTEL Basis for Cancer Assessment:
Available estimates of cancer unit risks:
2.2 x 10-6 to 7.8 x 10-6 per ug/m3 derived in 1998, posted 2000 (USEPA 2003)
2.9 x10-5 per ug/m3 derived in 1984, posted 1988 (CalEPA 2009)
6 x 10-6 per ug/m3 (WHO 2000)
1.6 x 10-5 per ug/m3 (derived for drinking water program, CalEPA 2001)[4]
The UR of 7.8 x10-6 per ug/m3 (the higher end of the range) developed by the USEPA in 1998 (USEPA 2003) and last reviewed in 2000 was selected as the basis for the NTEL. The NTEL is the ambient air concentration estimated to be associated with a 1 in a million risk of cancer.
NTEL = 1 x 10-6 / 7.8 x10-6 per ug/m3 = 0.128 ug/m3, rounded to 0.1 ug/m3 (0.03 ppb)
The USEPA (2003), CalEPA (2009) and WHO (2000) values are within a factor of 5 of each other. Because they are greater than a factor of 3 from each other, all values were evaluated as described in MassDEP (2011). All of the benzene unit risk values used for developing existing air guidelines considered the same set of studies as the basis for the unit risk. Differences in the unit risk values arise from using different cohorts, exposure metrics, and dose-response analyses.
The MassDEP (2011) updating methodology supports the selection of values that were derived using newer studies, studies with greater ability to detect effects, and the most current dosimetric extrapolation and dose-response characterization methods. The USEPA (2003) and WHO (2000) unit risks are based on more current updates of the Pliofilm cohort compared to that used for the CalEPA (2009) unit risk; and the exposure estimate (Crump 1994) used for the upper end of the USEPA (2003) unit risk is more conservative, than the mean of two exposure metrics used for the WHO unit risk. Thus, the upper range of the USEPA (2003) unit risk, 7.8 x 10-6 per ug/m3, was selected for deriving the MassDEP NTEL.
The three available unit risks are based on retrospective epidemiology studies conducted in workers occupationally exposed to benzene in rubber hydrochloride (Pliofilm) manufacturing facilities in the United States (Rinsky et al. 1981, 1987). The Rinsky et al. (1981) study and the follow-up Rinsky et al. (1987) study identified a significant positive association between leukemia mortality and exposure to benzene. The most recent update of the Pliofilm cohort by Paxton et al. (1994) supported the previous findings. Another cohort occupationally exposed to benzene, the “Chinese workers cohort” (Yin et al. 1996, Hayes et al. 1997), was not considered sufficiently studied at the time the unit risk was derived by USEPA, CalEPA and WHO. The Chinese worker cohort was included in the CalEPA 2001 evaluation and yielded unit risks within the range of the Pliofilm cohort.
To evaluate cancer risk in the Pliofilm cohort exposure metrics were developed by Rinsky et al. (1981), Crump and Allen (1984), and Paustenbach et al. (1992). The lowest exposure concentrations were estimated by Rinsky et al. (1981) assuming concentrations measured in later years represented the exposure concentrations during the early years of exposure. The highest concentrations were estimated by Paustenbach et al. (1992) that included estimates of exposure from short high concentrations and uptake from dermal exposure in addition to the estimated time weighted average. Crump and Allen (1984) considered a number of permutations for exposure estimates with most falling between those by Rinsky et al. (1981) and Paustenbach et al. (1992) under the assumption that exposure concentrations over time were associated with changes in the permissible time weighted average over the exposure period of the cohort.
All unit risks are based on dose-response models assuming risk is linear at low doses. Dose-response models differed in how latency between exposure and response was characterized and in the form of the mathematical model used.
Table 2 presents the published unit risks from each agency with the data set, endpoint, exposure estimate source, low dose assumption and approach for estimating slope (unit risk) supporting the specific values.
The most significant determinants of the magnitude of the unit risk number were the choice of mathematical model used to extrapolate risk from occupational to environmental levels of exposure and the choice of the exposure estimate for the Pliofilm workers. Additional sources of variance in the unit risk estimate are the cancer types selected and use of best estimates (i.e., mean) or upper 95th percent confidence limit (95UCL) of the estimated unit risk.

Table 2. Summary of Attributes Selected for Derivation of Benzene Unit Risk by Different Agencies

USEPA (2003) (derived 1998, posted 2000) / CalEPA (2009) (air) (derived 1984, 1988) / CalEPA (2001) (water) / WHO (2000)
Unit Risk (per ug/m3) / 2.2x10-6 to
7.8x10-6 / 2.9x10-5 / 1.6x10-5 / 6x10-6
AAL (ug/m3) / 0.13 to 0.45 / 0.03 / 0.06 / 0.17
Data Set / Rinsky et al. 1981, 1987 / Rinsky et al. 1981 / Pliofilm cohort: Rinsky et al. 1981, 1987; Paxton et al. 1994;
Chinese worker cohort (incidence data): Yin et al. 1996, Hayes et al. 1997 / Rinsky et al. 1981, 1987
End point(s) / Upper end: total leukemia
Lower end: acute myeloid and monocytic leukemia / Total leukemia / Total leukemia for Pliofilm and Chinese cohorts / Total leukemia; acute myeloid and monocytic leukemia
Exposure Estimate / Upper end: Crump & Allen 1984
Lower end: Paustenbach et al. 1992 / Rinsky et al. 1981 / Pliofilm:
Rinsky et al. 1981
Chinese:
Hayes et al. 1997 / Crump & Allen 1984
Paustenbach et al. 1992
Low dose assumption / Linear
Crump 1994 analysis / Linear
CDHS 1984 analysis / Linear
CalEPA (OEHHA) 2001 analysis / Linear
Crump 1994 analysis
Estimate of slope / Best estimate. / Upper 95% confidence limit. / Mean of the Upper 95% confidence limits of the estimates from the Pliofilm and Chinese worker cohorts. / Geometric mean of the best estimates of the slopes from both exposure estimates.
References:
ATSDR (Agency for Toxic Substances and Disease Registry). 2007. Toxicological profile for benzene. Atlanta, GA, U.S. Department of Health and Human Services, Public Health Service.
CDHS (California Department of Health Services). 1984. Report to the Scientific Review Panel on Benzene. Part B. Health Effects of Benzene. Epidemiological Studies Section, Berkeley, CA(as cited in CalEPA 2001).
CDHS (California Department of Health Services). 1988. Risk specific intake level for benzene. Department of Health Services (DHS), Reproductive and Cancer Hazard Assessment Section, State of California (as cited in CalEPA 2001).
CalEPA (California Environmental Protection Agency). 2001. Public Health Goal for Benzene in Drinking Water. Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, California.
CalEPA (California Environmental Protection Agency). 2009.Air Toxics Hot Spots Risk Assessment Guidelines Part II: Technical Support Documents for Cancer Potency Factors, Appendix B. Office of Environmental Health Hazard Assessment, California Environmental Protection Agency.
CalEPA (California Environmental Protection Agency). 2014. Air Toxics Hot Spots Program Risk Assessment Guidelines. Technical Support Documents for Noncancer Reference Exposure Levels (2008). Appendix D1 for New or Revised RELs (2014). Office of Environmental Health Hazard Assessment (OEHHA), California Environmental Protection Agency.
Crump KS. 1994. Risk of benzene-induced leukemia: a sensitivity analysis of the pliofilm cohort with additional follow-up and new exposure estimates. J Toxicol Environ Health 42(2):219-42 (as cited in USEPA 2003).
Crump KS and Allen BC. 1984. Quantitative estimates of risk of leukemia from occupational exposure to benzene. Prepared for the Occupational Safety and Health Administration, May 1984. OSHA docket H-059B, exhibit 152(as cited in USEPA 2003)
Haley TJ. 1977. Evaluation of the health effects of benzene inhalation. Clin Toxicol 11(5): 531-48 (as cited in CalEPA 2014).
Hayes RB, Yin SN, Dosemeci M, Li GL, Wacholder S, Travis LB, Li C-Y, Rothman N, Hover RN, Linet MS, for the Chinese Academy of Preventive Medicine--National Cancer Institute Benzene Study Group. 1997. Benzene and the dose-related incidence of hematologic neoplasms in China. J Natl Cancer Inst 89(14):1065-1071. (as cited in CalEPA 2001)
IARC (International Agency for Research on Cancer). 2007. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.
Lan Q, Zhang L, Li G, Vermeulen R, Weinberg RS, Dosemeci M, Rappaport SM, Shen M, Alter BP, Wu Y, Kopp W, Waidyanatha S, Rabkin C, Guo W, Chanock S, Hayes RB, Linet M, Kim S, Yin S, Rothman N and Smith MT. 2004. Hematotoxicity in workers exposed to low levels of benzene. Science 306:1774-1776.
MassDEP (Massachusetts Department of Environmental Protection). 2011. Methodology for Updating Air Guidelines: Allowable Ambient Limits (AALs) and Threshold Effects Exposure Limits (TELs). Office of Research and Standards.
NTP (National Toxicology Program). 2005. Report on carcinogens. 11th ed. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program.
Paustenbach DJ, Price PS, Ollison W, Blank C, Jernigan JD, Bass RD, Pederson HD. 1992. Reevaluation of benzene exposure for the pliofilm (rubberworker) cohort (1936-1976). J Toxicol Environ Health 36(3): 177-231 (as cited in CalEPA 2001).
Paxton MB, Chinchilli VM, Brett SM, Rodricks JV. 1994. Leukemia risk associated with benzene exposure in the pliofilm cohort: I. Mortality update and exposure distribution. Risk Anal 14(2):147-154(as cited in USEPA 2003).
Rinsky RA, Smith AB, Hornung R, Filloon TG, Young RJ, Okun AH, Landrigan PJ. 1987 Benzene and leukemia: an epidemiologic risk assessment. New England J Med 36:1004-1050(as cited in USEPA 2003).
Rinsky RA, Young RJ, Smith AB. 1981. Leukemia in benzene workers. Am J Ind Med 2:217-245(as cited in USEPA 2003).
Rothman N, Li GL, Dosemeci M, Bechtold WE, Marti GE, Wang YZ, Linet M, Xi LQ, Lu W, Smith MT, Titenko-Holland N, Zhang LP, Blot W, Yin SN, and R.B. Hayes RB.1996. Hematotoxicity among Chinese workers heavily exposed to benzene. Am J Ind Med29: 236-246 (as cited in USEPA 2003).
USEPA (U.S. Environmental Protection Agency. 1998. Carcinogenic effects of benzene: an update.National Center for Environmental Assessment, Office of Research and Development, U.S.Environmental Protection Agency, Washington, D.C., EPA/600/P-97/001F.
USEPA (U.S. Environmental Protection Agency). 2003. Integrated Risk Information System (IRIS). Available: (accessed April 28, 2011).
WHO (World Health Organization). 2000. Air Quality Guideline, Benzene. WHO Regional Office to Europe. Copenhagen, Denmark.
Yin S-N, Hayes RB, Linet MS, Li G-L, Dosemeci M, Travis LB, Li CY, Zhang ZN, Li DG, Chow WH, Wacholder S, Wang YZ, Jiang ZL, Dai TR, Zhang WY, Chao XJ, Ye PZ, Kou QR, Zhang XC, Lin XF, Meng JF, Ding CY, Zho JS, Blot WJ. 1996. A cohort study of cancer among benzene-exposed workers in China: Overall results. Am J Ind Med 29(3):227-235 (as cited in CalEPA 2001).
Update History:
TEL/AAL first listed – 1990
TEL/AAL updated and summary added 12/2013
TEL updated 1/2015

Massachusetts Department of Environmental Protection

Office of Research and Standards

Benzene1

[1] The process used for selecting and deriving Threshold Effects Exposure Limits (TELs), Non-Threshold Effects Exposure Limits (NTELs) and Allowable Ambient Limits (AALs) is described in MassDEP (2011).

[2] Guidance values are presented with 1 significant figure in units of ug/m3; for convenience, values in units of ppb are calculated based on the rounded guidance value in units of ug/m3 then rounded to 1 significant figure in units of ppb for presentation.

[3] This summary document provides information about the toxicity data supporting the available toxicity values for this chemical and the rationale for selecting among values. It is not intended to be a comprehensive summary of all toxicity information for this chemical.

[4]The unit risk developed by CalEPA in 2001 for their drinking water program, is included here for comparison, but is not considered as a candidate for the NTEL because it is not used by the CalEPA air program.