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20 As noted above, noncancer health effects associated with of an additional cancer per unit concentration (micrograms chronic inhalation exposure to the airport-related HAPs per cubic meter [g/m3]) in air (USEPA 1992). IURs are reviewed include alterations of the respiratory epithelium, derived by extrapolating the concentration-response rela- neurological effects, developmental toxicity, and reproduc- tionship modeled in the range of observed concentrations to tive toxicity. For example, effects on respiratory epithelium lower concentrations associated with lower, more acceptable have been observed in rats exposed to acrolein (USEPA risk. Noncancer hazards due to inhalation exposure are char- 2003b). Exposure to n-hexane is associated with peripheral acterized by a reference concentration (RfC), which is an air neuropathy in both rats and humans (USEPA 2005a). Expo- concentration, in milligrams per cubic meter [mg/m3], at sure to styrene and toluene has been associated with various which no adverse biological effects are expected to occur, neurological effects in humans, and exposure to xylenes is as- even in susceptible subpopulations (Barnes and Dourson sociated with neurological effects in rats (USEPA 1993, 2003c, 1988). RfCs are typically derived by identifying a lowest or 2005b). Both ethylbenzene and xylenes have been associated no-observed-adverse-effect-level (LOAEL or NOAEL), which with developmental abnormalities4 in laboratory animals is then divided by uncertainty factors to account for inter- (USEPA 1991c, 2003b). In addition, Silman et al. (1990) and intraspecies variability, as well as uncertainties relating to observed a clustering of scleroderma5 associated with prox- study design or database deficiencies. RfCs can also be devel- imity to two different airports. The biological basis for this oped using a benchmark concentration (BMC), which is a observation is not known, however. concentration associated with a specified change in response Acute (<24 hr) and short-term (130 days) exposure to above background (typically 5% to 10%), based on the HAPs can also cause adverse health effects. For example, concentration-response relationship for all concentrations reactive compounds such as acrolein and formaldehyde can tested. With the BMC approach, uncertainty factors are cause irritation of the eyes and respiratory tract; while volatile applied to the lower 95% confidence limit on the BMC organic compounds, such as toluene and xylenes, can cause (BMCL). headaches, nausea, and dizziness (ATSDR 1999, 2000, 2005; Toxicity criteria listed on EPA's IRIS database were used USEPA, 2005c). for all HAPs, if available. Toxicity criteria on the IRIS data- base typically undergo an extensive evaluation and peer review process before being added to the database. If the IRIS 4.2 Evaluation of Chronic Health toxicity criteria are up to date, they are generally considered Effects for Aviation-Related to represent the best science available. If toxicity criteria were Hazardous Air Pollutants not available on the IRIS database, alternatives for toxicity In order to evaluate both carcinogenic and noncarcino- criteria listed in California EPA's Office of Environmental genic aviation-related HAPs according to their potential to Human Health Assessment (OEHHA) Toxicity Database; the cause adverse health effects, RBCs for both cancer and Agency for Toxic Substances and Disease Registry (ATSDR); noncancer endpoints were developed for this report, using Health Canada; the Total Petroleum Hydrocarbon Criteria toxicity criteria for the HAPs along with standard assump- Working Group (TPHCWG), and the National Institute for tions for evaluating exposure to carcinogens and noncar- Public Health and the Environment of the Netherlands cinogens. These RBCs represent air concentrations that an (RIVM) were used, giving preference to values developed individual could be exposed to for a prolonged period of time most recently and thus incorporating the most current eval- that would be associated with a negligible risk of developing uation of available scientific data. This analysis used IURs cancer or other adverse health effects. Using RBCs allows a and chronic reference exposure levels (RELs) listed in the side-by-side evaluation of both carcinogenic and noncar- OEHHA database, chronic minimal risk levels (MRLs) cinogenic aviation-related HAPs in terms of their potential to developed by ATSDR, tolerable concentrations (TCs) de- cause adverse health effects. veloped by Health Canada, and RfCs developed by the TPHCWG. Chronic RELS, chronic MRLs and TCs are analogous to RfCs, both in their derivation (i.e., as a 4.2.1 Identification of Toxicity Criteria LOAEL/NOAEL or BMCL divided by uncertainty factors) Cancer due to inhalation exposure is characterized using and in their representation of a concentration that the gen- an IUR, which represents the incremental upper-bound risk eral population, including sensitive subpopulations, can be exposed to with a negligible risk of experiencing adverse 4 Developmental abnormalities occur during growth and development of the health effects (ATSDR 2007a; Health Canada 1996). Table 6 embryo and fetus. lists toxicity criteria used to evaluate chronic health effects for 5 Scleroderma involves abnormal growth of connective tissue supporting the skin and internal organs, which can cause hard, tight skin, and can also affect blood airport-related HAPs. For several of the HAPs which have un- vessels and internal organs including the heart, lung, and kidneys (NIAMS 2006). dergone a review that is more current than that on the IRIS

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21 Table 6. Summary of chronic toxicity criteria. Criteria Value Source Basis Acetaldehyde IUR 2.2 x 10-6 USEPA Nasal squamous cell carcinoma and adenocarcinoma in 3 -1 (g/m ) 1991a rats (Woutersen and Appleman 1984) (IRIS) RfC 0.009 USEPA Degeneration of olfactory epithelium in rats exposed for four 3 (mg/m ) 1991a weeks (Appleman et al. 1986, 1982) (IRIS) TC 0.39 Health Degeneration of olfactory epithelium in rats exposed for four 3 (mg/m ) Canada 2000 weeks (Appleman et al. 1986, 1982) Acetone Chronic MRL 3.1 x 101 ATSDR Neurological effects in humans (Stewart et al. 1975) 3 (mg/m ) 1994 Acrolein RfC 2.0 x 10-5 USEPA Slight histopathological lesions in nasal cavity in 1/12 rats 3 (mg/m ) 2003c exposed (whole body) 6 hr/day, 5 days/week, 13 weeks at (IRIS) 0.4 ppm (Feron et al. 1978). In study by Cassee et al. (1996) disarrangement of respiratory/transitional epithelium was observed in 4/5 rats, and slight focal proliferative response observed in 3/5 rats exposed (nose only) to 0.25 ppm, 6 hrs/day for 3 days. Benzene -6 IUR 7.8 x 10 USEPA Increased incidence of leukemia in pliofilm workers (Rinsky 3 -1 (g/m ) 2003a et al. 1981, 1987). (IRIS) -3 Chronic MRL 9.7 x 10 ATSDR Decreased lymphocyte count in humans (Lan et al. 2004). 3 (mg/m ) 2007b 1,3-Butadiene -5 IUR 3.0 x 10 USEPA 2002 Increased incidence of leukemia among male styrene- 3 -1 (g/m ) (IRIS) butadiene rubber production workers (Delzell et al. 1995). -3 RfC 2.0 x 10 USEPA 2002 Ovarian atrophy in mice (NTP 1993). (mg/m3) (IRIS) Ethylbenzene IUR 2.5 x 10-6 CalEPA, Increased incidence of renal tubule carcinomas and (g/m3)-1 2007 adenomas in male rats (NTP 1999). RfC 1.0 USEPA Skeletal variations, slightly reduced litter size, and elevated 3 (mg/m ) 1991c maternal liver, kidney and spleen weight (Andrew et al. (IRIS) 1981). Effects considered mild. Formaldehyde -5 IUR 1.3 x 10 USEPA Nasal squamous cell carcinoma in rats. 3 -1 (g/m ) 1991b Note: This is the value currently listed in EPA's IRIS database. 5.5 x 10-9 USEPA Nasal squamous cell carcinoma in rats; IUR for humans 2005d incorporates mechanistic/dosimetric information (CIIT 1999). Note: This value is used by EPA in their National Air Toxics Assessment, and in the Emissions Standard for Plywood and Composite Wood Products. MRL (mg/m3) 9.8 x 10-3 ATSDR 1999 Mild damage to nasal epithelium (Holmstrom et al. 1989). n-Hexane -1 RfC 7.0 x 10 USEPA Peripheral neuropathy in rats (Huang et al. 1989). 3 (mg/m ) 2005b (IRIS) Naphthalene -5 IUR 3.4 x 10 CalEPA Respiratory epithelial adenomas and olfactory epithelial (g/m3)-1 2004a neuroblastomas in male rats. Note: This value is currently used by EPA for screening assessments. -4 1.0 x 10 USEPA Respiratory epithelial adenomas and olfactory epithelial 2004a neuroblastomas in male rats. Note: This is a draft value currently undergoing review for inclusion in EPA's IRIS database. -3 RfC 3.0 x 10 USEPA Nasal lesions in respiratory and olfactory epithelium in mice 3 (mg/m ) 2004a (NTP 1992). Phenol -1 Chronic REL 2.0 x 10 CalEPA Systemic effects including liver and nervous system effects 3 (mg/m ) 2004b in mice, rats and monkeys (Sandage, 1961; Dalin and Kristofferson 1974). (continued on next page)

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22 Table 6. (Continued). Criteria Value Source Basis Polycyclic Aromatic Hydrocarbons IUR 5.5E-05 USEPA 2001 Value represents 5% of the IUR for benzo[a]pyrene. (g/m3)-1 Propene Chronic REL 3.0 CalEPA, Inflammation and effects on epithelial cells of the nasal (mg/m3) 2000 cavity in rats (Quest et al. 1984). Styrene RfC 1.0 USEPA 1993 Neuropsychological (CNS) effects in workers (Mutti et al. 3 (mg/m ) (IRIS) 1984). Toluene RfC 5.0 USEPA Neurological effects in workers (multiple studies). (mg/m3) 2005c (IRIS) Xylene RfC 1.0 x 10-1 USEPA Impaired motor coordination in male rats (Korsak et al. (mg/m3) 2003b 1994). (IRIS) Total Petroleum Hydrocarbons C>8-C16 Aromatics (1-methylnapthalene, 2-methylnaphthalene, dimethylnaphthalene) RfC 2.0 x 10-1 TPHCWG Reduced weight gain in rats (Douglas et al. 1993). 3 (mg/m ) 1997 Total Petroleum Hydrocarbons C5-C8 Aliphatics (n-pentane, n-heptane, 2,2,4-trimethylpentane) RfC 1.8E+01 TPHCWG Increased liver weight, nephropathy, respiratory tract 3 (mg/m ) 1997 irritation, reduced body weight gain in offspring, liver tumors (various studies). Total Petroleum Hydrocarbons C9-C16 Aliphatics (n-octane, n-nonane, n-decane, n-undecane, n-dodecane, C13-alkane, c14-alkane) RfC 1.0 TPHCWG No significant adverse effects observed at highest 3 (mg/m ) 1997 concentration tested (Mattie et al. 1991). Notes: IUR Inhalation unit risk g/m3 Micrograms per cubic meter 3 mg/m Milligrams per cubic meter TC Tolerable concentration MRL Minimal risk Level RfC Reference concentrations RBC Risk-based concentration database, both the IRIS and the more current toxicity criteria cussed in a Health Canada priority substances list assessment are listed. report on formaldehyde (Health Canada 2001), induction of For formaldehyde we used an IUR of 5.5 10-9 per g/m3 nasal tumors by formaldehyde likely occurs subsequent to (USEPA 2005d), based on an analysis by the Chemical In- cytotoxicity, which results in a sustained increase in nasal dustry Institute of Toxicology (CIIT), as well as the formalde- epithelial cell regeneration. The CIIT value has undergone hyde IUR listed on EPA's IRIS database of 1.3 10-5 per peer review sponsored by EPA and Health Canada and is used g/m3 (USEPA 1991b).6 Both values are based on increased by EPA in its National Air Toxics Assessment as well as in the incidence of nasal cavity squamous cell carcinoma in rats, as Emissions Standard for Plywood and Composite Wood observed in a study by Kerns, Pavkov, and Donofrio et al. Products as representing the "best available peer-reviewed (1983). The CIIT value accounts for rat versus human differ- science at this time." (USEPA 2004b, 2005d). Nonetheless, we ences in deposition of formaldehyde in the respiratory tract note that some scientists have expressed concerns regarding and formation of DNA-protein cross links, which are con- assumptions and choice of parameter values for the CIIT sidered a critical lesion for nasal tumor formation. The CIIT model. In addition, evidence from several epidemiology stud- value also accounts for the nonlinear dose-response for nasal ies suggests that formaldehyde exposure may be associated cavity tumors as observed by Kerns et al. and others As dis- with increased incidence of lymphohematopoietic malignan- cies, in addition to nasopharyngeal cancer. EPA is currently 6The relative health impact, based on the risk-based concentration and the emis- updating the IRIS file for formaldehyde, with an expected sion factor (discussed above in Section 2), was calculated using both IUR values. The rationale for including both values is to provide a sense of the magnitude of release date of July 2008, to consider the CIIT value in light of uncertainty associated with the cancer potency estimate for formaldehyde. the concerns regarding model assumptions and parameter

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23 values, as well as the potential that formaldehyde may be a Ethene leukemogen. For ethene we identified a noncancer toxicity criterion For acetaldehyde we used Health Canada's TC for non- from a two-year inhalation study in rats by Hamm, Guest, cancer toxicity, as well as EPA's RfC for acetaldehyde.7 At the and Gent (1984), in which rats were exposed for 6 hr/day, request of Health Canada, the acetaldehyde TC has under- 5 days/week, to ethene concentrations of 0, 300, 1,000 and gone independent peer review sponsored by Toxicology Ex- 3,000 parts per million (ppm) (0, 345, 1,150, 3,450 mg/m3).9 cellence in Risk Assessment (TERA). Both the Health Canada Rats were evaluated for clinical signs of toxicity including TC and the IRIS RfC are based on degenerative changes in effects on liver, kidney, and blood, and tissues were evaluated nasal epithelium as observed in a subchronic study in rats. for histopathological lesions. No effects were observed at the The IRIS value, however, includes an uncertainty factor to highest concentration (3,450 mg/m3), which is hence consid- account for use of a subchronic rather than a chronic expo- ered a NOAEL. If this concentration were adjusted to repre- sure study that was not used by Health Canada. With respect sent a continuous, exposure (24 hr/day, 7 days/week),10 the to the subchronic-to-chronic uncertainty factor, the TERA resulting adjusted NOAEL would be 616 mg/m3. Accounting peer review panel concluded this factor is not necessary as for uncertainty regarding inter- and intraspecies variability, there is no indication that severity of the critical effect would as well as database deficiencies, an acceptable exposure level increase with a longer study duration (TERA 1997). More- in humans could be anywhere from 300- to 1,000-fold lower, over, effects on the respiratory epithelium of the structurally or approximately 0.6-2.0 mg/m3. Considering potential non- similar HAP formaldehyde are more closely related to expo- cancer toxicity of ethene relative to emissions, it does not sure concentration than exposure duration (Health Canada appear that ethene would pose a substantial health concern 2001). The IRIS value also includes a full 10-fold interspecies relative to the prioritized HAPs identified in Table 1. variability factor, whereas a partial interspecies variability fac- There is also some concern that exposure to high levels of tor of 3 should be sufficient because EPA had converted the ethene may be associated with an increased risk of cancer. NOAEL from the rat study to a human equivalent concen- This concern stems from the in vivo metabolism of ethene to tration (HEC) NOAEL, which accounts for interspecies dif- ethylene oxide (EtO), which has been classified as a human ferences in toxicokinetics for respiratory tract toxicants.8 carcinogen by the International Agency for Research on Cancer (IARC 1994). There is uncertainty regarding the 4.2.2 Toxicity Evaluation for HAPs shape of the dose-response for EtO-induced tumors at low Without Existing Criteria exposure concentrations, however, and hence, uncertainty whether exposure to any level of ethene would produce suf- Published toxicity criteria were not available for several of ficient levels of EtO, due to saturation of the metabolic path- the airport-related HAPs, including the alkenes butene, way that converts ethene to EtO. In addition, while EtO is ethene, and hexene; the aldehydes butanal, propanal (propi- mutagenic, there is no evidence that ethene is mutagenic onaldehyde), glyoxal and methylglyoxal, and the 2-alkenal (Rusyn, Shoji, et al. 2005). Nonetheless, several researchers crotonaldehyde. Here we present a semiquantitative assess- have suggested that the lack of an increase in tumors in ment regarding their potential toxicity and impact relative to ethene-exposed laboratory animals may be due to the lack of HAPs with established toxicity criteria. This assessment sensitivity of typical carcinogenicity bioassays to detect very indicates that glyoxal, methylglyoxal, propanal (propi- small, but potentially biologically significant increases in onaldehyde), and crotonaldehyde may be important HAPs tumor incidence (Tornqvist 1994; Walker, Yuh, et al. 2000). to consider, based on their potential toxicity and relative To address the potential that exposure to ethene may be emissions. associated with an increased risk of cancer, we considered results from an epidemiological study by Steenland, Stayner, 7 While we believe the Health Canada TC value represents the most current sci- and Deddens (2004), who observed a positive exposure entific understanding of acetaldehyde's noncancer toxicity for the purposes of response trend for lymphoid tumors among workers exposed establishing a prioritized research agenda, any quantitative health risk assess- to ethylene oxide. There was no increase in tumor incidence ment of airport exposures should rely on the most appropriate toxicity value for the specific purposes of the risk assessment. for workers in the lowest exposure group (> 1199 ppm-days). 8 The full interspecies uncertainty factor of 10 includes partial uncertainty fac- 9Based on a molecular weight for ethene of 28.0536, according to the following tors of 3 each to account for interspecies differences in toxicokinetics (i.e., ab- sorption, distribution, metabolism, and elimination) and toxicodynamics (i.e., conversion formula: interaction of chemicals with target sites in the body and subsequent reactions MW causing adverse health effects). A partial uncertainty factor of 3 can be used if ei- mg / m 3 = ppm 24.45 ther toxicokinetics or toxicodynamics are expected to be similar between labo- ratory animals and humans, or if the RfC is based on a human equivalent con- 5 days 6 hours 10 3450 mg / m 3 = 616mg / m 3 centration that accounts for differences in toxicokinetics. 7 days 24 hours