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6 - 1 

## Chapter 6 **Health and Envir onm**  **ental Effects Associated with** 

**Exposur e to Criteria and**  **To xic Pollutants**  **6.1 Health Effects of Criteria and Toxic Pollutants**  Motor vehicles emit pollutants that contribute to ambient concentrations of ozone, PM, NO 2, SO 2 , CO, and air toxics. A discussion of the health effects of these pollutants is included in this section of the RIA. Children may be more vulnerable to air pollution and other environmental exposures than adults because their bodily s ys tems are still developing, they breathe more in proportion to their body size than adults and their behavior can expose them more to chemicals than adults. Early lifestages (e.g., children) are thought to be more susceptible to tumor development than adults when exposed to carcinogenic chemicals that act through a mutagenic mode of action. 1 6.1.1 Particulate Matter

6.1.1.1 Background Particulate matter (PM) is a highl y complex mixture of solid particles and liquid droplets distributed among numerous atmospheric gases which interact with solid and liquid phas es. Particles range in size from those smaller than 1 nanometer (10 - 9 meter) to over 100 micrometer (μm, or 10 - 6 meter) in diameter (for reference, a t ypical strand of human hair is 70 μ m in diameter and a grain of salt is about 100 μm). Atmospheric partic les can be grouped into several classes according to their aerod ynamic and ph ys ical sizes, including ultrafine particles (<0.1 μm), accumulation mode or ‘fine’ particles (< 1 to 3 μm), and coarse particles (>1 to 3 μm). For regulatory

purposes, fine partic les are measured as PM 2.5 and inhalable or thoracic coarse particles are measured as PM 10 - 2.5 , corresponding to their size (diameter) range in micrometers. The EPA currently

has standards that measure PM 2.5 and PM 10 . 2 Particles span man y sizes and shapes and may consist of hundreds of different chemicals . Particles are emitted directly from sources and are also formed through atmospheric chemical reactions; the former are often referred to as “primary” particles, and the latter as “secondary” particles. Particle concentration and composition varies b y time of ye ar and location , and in addition to differences in source emissions, is affected by several weather - related factors, such as temperature, clouds, humidity , and wind. A further lay er of complexity comes from particles ’ ability to shift between solid/liquid and gaseous phases, which is influenced by concentration and meteorology , especially temperature. Fine particles are produced primaril y b y combustion processes and b y transformations of gaseous em issions (e.g., sulfur oxides ( SO X ) , nitrogen oxides (NO X ) and volatile organic compounds ( VOCs ) ) in the atmosphere. The chemical and phy sical properties of PM 2.5 may vary greatl y with time, region, meteorology and source category. Thus, PM 2.5 may include a complex mixture of different components including sulfates, nitrates, organic compounds, elemental***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 2 carbon and metal compounds. These particles can remain in the atmosphere for day s to weeks and travel through the atmosphere hundreds to thousands of kilom eters. 3

6.1.1.2 Health Effects of PM Scientific studies show ambient PM is associated with a broad range of health effects. These health effects are discussed in detail in the December 2009 Integrated Science Assessment for Particulate Matter (PM I SA) . 4 The PM IS A summarizes health effects evidence associated with both short - and long - term exposures to PM 2.5 , PM 10 - 2.5 , and ultrafine particles. The PM I SA concludes that human exposures to ambient PM 2.5 concentrations are associated with a number of adverse heal th effects and characterizes the weight of evidence for these health outcomes. 5 The discussion below highlights the PM I SA’s conclusions pertaining to health effects associated with both short - and long - term PM exposures. Further discussion of health eff ects associated with PM 2.5 can also be found in the rulemaking documents for the most recent review of the PM NAAQS completed in 2012 . 6 , 7 The EPA concludes that a causal relationship exists between both long - and short - term exposures to PM 2.5 and premature mortality and cardiovascular effects and a likely causal relationship exists between long - and short - term PM 2.5 exposures and respiratory effects. Further, there is evidence suggestive of a causal relationship between long - term PM 2.5 exposures and other health effects, including developmental and reproductive effects (e.g., low birth weight, infant mortality) and carcinogenic, mutagenic, and genotoxic effects (e.g., lung cancer mortality). 8 As summarized in the Final PM NAAQS rule, and discussed extensive ly in the 2009 PM ISA, the scientific evidence available since the completion of the 2006 PM NAAQS review significantl y strengthens the link between long - and short - term exposure to PM 2.5 and premature mortality , while providin g indications that the magnitude of the PM 2.5 - mortality association with long - term exposures may be larger than previousl y estimated. 9 , 10 The strongest evidence comes from recent studies investigating long - term exposure to PM 2.5 and cardiovascular - related mortality . The evidence supporting a causal relationship between long - term PM 2.5 exposure and mortality also includes consideration of new studies that demonstrated an improvement in community

health following reductions in ambient fine particles. 11 Sever al studies evaluated in the 2009 PM I SA have examined the association between cardiovascular effects and long - term PM 2.5 exposures in multi - city studies conducted in the U.S. and Europe. While studies were not available in the 2006 PM NAAQS review with regard to long - term exposure and cardiovascular - related morbidity , studies published since then have provided new evidence linking long - term exposure to PM 2.5 with an array of cardiovascular effects such as heart attacks, congestive heart failure, stroke, and mortality . This evidence is coherent with studies of short - term exposure to PM 2.5 that have observed associations with a continuum of effects ranging from subtle changes in indicators of cardiovascular health to serious clinical event s, such as increased hospitalizations and emergency department visits due to cardiovascular disease and cardiovascular mortality. 12***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 3 As detailed in the 2009 PM I SA, e xtended anal ys es of studies available in the 2006 PM NAAQS review as well as epidemiolo gical studies conducted in the U.S. and abroad published since then provide stronger evidence of respiratory - related morbidit y effects associated with long - term PM 2.5 exposure. The strongest evidence for respiratory - related effects is from studies that ev aluated decrements in lung function growth (in children) , increased respiratory s ymptoms, and asthma development. The strongest evidence from short - term PM 2.5 exposure studies has been observed for increased respiratory - related emergency department visits and hospital admissions for chronic obstructive pulmonary disease (COPD) and respiratory infections. 13 The body of scientific evidence detailed in the 2009 PM I SA is still limited with respect to associations between long - term PM 2.5 exposures and developme ntal and reproductive effects as well as cancer, mutagenic, and genotoxic effects, but is somewhat expanded from the 2006 review The strongest evidence for an association between PM 2.5 and developmental and reproductive effects comes from epidemiological studies of low birth weight and infant mortality , especially

due to respirat ory

causes during the post - neonatal period (i.e., 1 month to 12 months of age). With regard to cancer effects, ‘‘[m]ultiple epidemiologic studies have shown a consistent positive association between PM 2.5 and lung cancer mortality, but studies have genera lly not reported associations between PM 2.5 and lung cancer incidence.’’ 14 , 15 Specific groups within the general population are at increased risk for experiencing adverse health effects related to PM exposures. 16 , 17 , 18 , 19 The evidence de tailed in the 2009 PM ISA expands our understanding of previousl y identified at - risk populations and lifestages (i.e., children, older adults, and individuals with pre - existing heart and lung disease) and supports the i dentification of additional at - risk p opulations (e.g., persons with lower socioeconomic status, genetic differences). Additionally , there is emerging, though still limited, e vidence for additional potentially

at - risk populations and lifestages , such as those with diabetes, people who are obese, pregnant women, and the developing fetus. 22 For PM 10 - 2.5 , the 2009 PM I SA conclude d that available evidence was suggestive of a causal relationship between short - term exposures to PM 10 - 2.5 and cardiovascular effects (e.g., hospital admissions and ED visits, changes in cardiovascular function), respiratory effects (e.g, ED visits and hospital admissions, increase in markers of pulmonary in flammation), and premature mortality . Data we re inadequate to draw conclusions regarding the relationships between long - term exposure to PM 10 - 2. 5 and various health effects. 23 , 24 , 25 For ultrafine particles, the 2009 PM I SA conclude d that the evidence wa s su ggestive of a causal relationship between short - term exposures and cardiovascular effects, including changes in heart rh ythm and vasomotor function (the ability of blood vessels to expand and contract) . It also conclude d that there wa s evidence suggestive of a causal relationship between short - term exposure to ultrafine particles and respiratory effects , including lung function and pulmonary inflammation, with limited and inconsistent evidence for increases in ED visits and hospital admissions . Data we re i nadequate to draw conclusions regarding the relationship between short term exposure to ultrafine particle and additional health effects including premature mortality as well as long - term exposure to ultrafine particles and all health outcomes evaluated . 26 , 27***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 4 6.1.2 Ozone

6.1.2.1 Background Ground - level ozone pollution is ty pically formed through reaction s involving VOCs and NO X in the lower atmosphere in the presence of sunlight. These pollutants, often referred to as ozone precursors, are emitted by man y t ypes of polluti on sources such as highway and nonroad motor vehicles and engines, power plants, chemical plants, refineries, makers of consumer and commercial products, industrial facilities, and smaller area sources. The science of ozone formation, transport, and accumulation is complex. Ground - level ozone is produced and destroy ed in a cyclical set of chemical reactions, many of which are sensitive to temperature and sunlight. When ambient temperatures and sunlight levels remain high for several day s and the air is r elativel y stagnant, ozone and its precursors can build up and result in more ozone than ty picall y occurs on a single high - temperature day. Ozone and its precursors can be transported hundreds of miles downwind of precursor emissions, resulting in elevated ozone levels even in areas with low VOC or NO X emissions. The highest levels of ozone are produced when both VOC and NO X emissions are present in significant quantities on clear summer day s. Relatively small amounts of NO X enable ozone to form rapidly

when VOC levels are relativel y high, but ozone production is quickly limited by removal of the NO X . Under these conditions NO X reductions are highl y effective in reducing ozone while VOC reductions have little effect. Such conditions are called “NO X - limit ed.” Because the contribution of VOC emissions from biogenic (natural) sources to local ambient ozone concentrations can be significant, even some areas where man - made VOC emissions are relativel y low can be NO X - limited. Ozone concentrations in an area al so can be lowered by the reaction of nitric oxide (NO) with ozone, forming nitrogen dioxide (NO 2 ) . A s the air moves downwind and the cy cle continues, the NO 2 forms additional ozone. The importance of this reaction depends, in part, on the relative concentrations of NO X , VOC, and ozone, all of which change with time and location. When NO X levels are relatively high and VOC levels relativel y low, NO X forms inorganic nitrates (i.e., particles) but relatively little ozone. Such conditions are called “VOC - li mited . ” Under these conditions, VOC reductions are effective in reducing ozone, but NO X reductions can actuall y increase local ozone under certain circumstances. Even in VOC - limited urban areas, NO X reductions are not expected to increase ozone levels if the NO X reductions are sufficientl y large. Rural areas are usually NO X - limited, due to the relativel y large amounts of biogenic VOC emissions in such areas. Urban areas can be either VOC - or NO X - limited, or a mixture of both, in which ozone levels exhib it moderate sensitivity to changes in either pollutant.

6.1.2.2 Health Effects of Ozone This section provides a summary of the health effects associated with exposure to ambient concentrations of ozone . 28 The information in this section is based on the information and conclusions in the February 2013 Integrated Science Assessment for Ozone (Ozone I SA)***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 5 prepared b y EPA’s Office of Research and Development (ORD) . 29 The Ozone I SA concludes that human exposures to ambient concentrations of ozone are associated with a number of adverse health effects and characterizes the weight of evidence for these health effects. 30 The discussion below highlights the Ozone I SA’s conclusions pertaining to health effects associated with both short - term and long - term periods of exposure to ozone. For short - term exposure to ozone, the Ozone I SA concludes that respiratory effects, including lung function decrements, pulmonary inflammation, exacerbation of asthma, respiratory - related hospital admissions, and mortality , are causally associate d with ozone exposure. It also concludes that cardiovascular effects, including decreased cardiac function and increased vascular disease, and total mortality are likely to be causall y associated with short - term exposure to ozone and that evidence is sugg estive of a causal relationship between central nervous s ys tem effects and short - term exposure to ozone. For long - term exposure to ozone, the Ozone I SA concludes that respiratory effects, including new onset asthma, pulmonary inflammation and injury , are likel y to be a causally related with ozone exposure. The Ozone ISA characterizes the evidence as suggestive of a causal relationship for associations between long - term ozone exposure and cardiovascular effects, reproductive and developmental effects, central nervous s ys tem effects and total mortality . The evidence is inadequate to infer a causal relationship between chronic ozone exposure and increased risk of lung cancer. Finally , interindividual variation in human responses to ozone exposure can result in some groups being at increased risk for detrimental effects in response to exposure. The Ozone ISA identified several groups that are at increased risk for ozone - related health effects. These groups are people with asthma, children and older adults, i ndividuals with reduced intake of certain nutrients (i.e., Vitamins C and E), outdoor workers, and individuals having certain genetic variants related to oxidative metabolism or inflammation. Ozone exposure during childhood can have lasting effects through adulthood. Such effects include altered function of the respiratory

and immune sy stems. Children absorb higher doses (normalized to lung surface area) of ambient ozone, compared to adults, due to their increased time spent outdoors, higher ventilation rates relative to body size, and a tendency

to breathe a greater fraction of air through the mouth. Children also have a higher asthma prevalence compared to adults. Additional children’s vulnerability

and susceptibility

factors are listed in Section XII.G o f the preamble. 6.1.3 Nitrogen Oxides and Sulfur Oxides

6.1.3.1 Background Sulfur dioxide (SO 2 ), a member of the sulfur oxide (SO X ) family of gases, is formed from burning fuels containing sulfur (e.g., coal or oil), extracting gasoline from oil, or extracting metals fr om ore. Nitrogen dioxide (NO 2 ) is a member of the nitrogen oxide (NO X ) famil y of gases. Most NO 2 is formed in the air through the oxidation of nitric oxide (NO) emitted when fuel is burned at a high temperature. SO 2 and NO 2 and their gas phase oxidation products can dissolve in water droplets and further oxidize to form sulfuric and nitric acid which react with***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 6 ammonia to form sulfates and nitrates, both of which are important components of ambient PM. The health effects of ambient PM are discussed in S ection 6.1.1.2 . NO X along with VOCs are the two major precursors of ozone. The health effects of ozone are covered in Section 6.1.2.2 .

6.1.3.2 Health Effects of Sulfur Oxides This section provides an over view of the health effects associated with SO 2 . Additional information on the health effects of SO 2 can be found in the 2008 Integrated Science Assessment for Sulfur Oxides (SO 2 ISA) . 31 Following an extensive evaluation of health evidence from epidemiolog ic and laboratory studies, the U.S. EPA has concluded that there is a causal relationship between respiratory health effects and short - term exposure to SO 2 . The immediate effect of SO 2 on the respiratory s ys tem in humans is bronchoconstriction. Asthmatics are more sensitive to the effects of SO 2 likely resulting from preexisting inflammation associated with this disease. In addition to those with asthma (both children and adults), potentially sensitive groups include all children and the elderl y. In labor atory studies involving controlled human exposures to SO 2 , respiratory effects have consistently been observed following 5 - 10 min exposures at SO 2 concentrations ≥ 0. 4 ppm in asthmatics engaged in moderate to heav y levels of exercise , with more limited evi dence of respiratory effects among exercising asthmatics exposed to concentrations as low as 0.2 - 0.3 ppm . A clear concentration - response relationship has been demonstrated in these studies following exposures to SO 2 at concentrations between 0.2 and 1.0 p pm, both in terms of increasing severity of respiratory

s ymptoms and decrements in lung function, as well as the percentage of asthmatics adversel y affected. In epidemiologic studies, respiratory effects have been observed in areas where the mean 24 - hour SO 2 levels range from 1 to 30 ppb, with maximum 1 to 24 - hour average SO 2 values ranging from 12 to 75 ppb. Important new multicity studies and several other studies have found an association between 24 - hour average ambient SO 2 concentrations and respirato ry s ymptoms in children, particularly

those with asthma. Generally consistent associations also have been observed between ambient SO 2 concentrations and emergency department visits and hospitalizations for all respiratory causes, particularly

among children and older adults ( ≥ 65 ye ars), and for asthma. A limited subset of epidemiologic studies ha s examined potential confounding b y copollutants using multipollutant regression models. These anal ys es indicate that although copollutant adjustment has varyi ng degrees of influence on the SO 2 effect estimates, the effect of SO 2 on respiratory health outcomes appears to be generall y robust and independent of the effects of gaseous and particulate copollutants, suggesting that the observed effects of SO 2 on resp iratory endpoints occur independent of the effects of other ambient air pollutants. Consistent associations between short - term exposure to SO 2 and mortality have been observed in epidemiologic studies, with larger effect estimates reported for respiratory mortalit y than for cardiovascular mortality . While this finding is consistent with the demonstrated effects of SO 2 on respiratory

morbidity , uncertaint y remains with respect to the interpretation of these associations due to potential confounding b y vari ous copollutants. The U.S. EPA has therefore concluded that the overall evidence is suggestive of a causal relationship between short - term***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 7 exposure to SO 2 and mortality. Significant associations between short - term exposure to SO 2 and emergency

department visits and hospital admissions for cardiovascular diseases have also been reported. However, these findings have been inconsistent across studies and do not provide adequate evidence to infer a causal relationship between SO 2 exposure and cardiovascular morbidity . 6.1.3.3 Health Effects of Nitrogen Oxides The most recent review of the health effects of oxides of nitrogen completed by the EPA can be found in the 2008 Integrated Science Assessment for Nitrogen Oxides (NO X IS A) . 32 The EPA concluded that the findings of epidemiologic, controlled human exposure, and animal toxicological studies provide evidence that is sufficient to infer a likel y causal relationship between respiratory

effects and short - term NO 2 exposure. The 2008 NO X ISA conclude d that the strongest evidence for such a relationship comes from epidemiologic studies of respiratory effects including increased respiratory sy mptoms, emergency

department visits, and hospital admissions. Based on both short - and long - term exposure studies, the 2008 NO X ISA concluded that individuals with preexisting pulmonary conditions (e.g., asthma or COPD), children, and older adults are potentially at greater risk of NO 2 - related respiratory effects. Based on findings from controlled human exposure studies , the 2008 NO X ISA also dr e w two broad conclusions regarding airway

responsiveness following NO 2 exposure. First, the NO X ISA conclude d that NO 2 exposure may

enhance the sensitivity

to allergen - induced decrements in lung function and increase the allergen - induced airway inflammatory response following 30 - minute exposures of asthmatic adult s to NO 2 concentrations as low as 26 0 pp b . Second, exposure to NO 2 has been found to enhance the inherent responsiveness of the airway to subsequent nonspecific challenges in controlle d human exposure s tudies of healthy and asthmatic adults. S mall but statistically significant increases in nonspecific airway hy perresponsiveness were reported for asthmatic adults following 30 - minute exposures to 200 - 300 ppb NO 2 and following 1 - hour expo sures of asthmatics to 1 00 pp b NO 2 . Enhanced airway responsiveness could have important clinical implications for asthmatics since transient increases in airway responsiveness following NO 2 exposure have the potential to increase s ymptoms and worsen asthm a control. Together, the epidemiologic and experimental data sets form a plausible, consistent, and coherent description of a relationship between NO 2 exposures and an array of adverse health effects that range from the onset of respiratory

sy mptoms to ho spital admission. In evaluating a broader range of health effects, the 2008 NO X ISA concluded evidence was “suggestive but not sufficient to infer a causal relationship” between short - term NO 2 exposure and premature mortality and between long - term NO 2 exposure and respiratory effects. The latter was based largely on associations observed between long - term NO 2 exposure and decreases in lung function growth in children. Furthermore, the 2008 NO X ISA concluded that evidence was “inadequate to infer the pres ence or absence of a causal relationship” between short - term NO 2 exposure and cardiovascular effects as well as between long - term NO 2 exposure and cardiovascular effects, reproductive and developmental effects, premature mortality, and cancer. 33 The conclus ions for these health effect categories were informed by uncertainties in the evidence base such as the independent effects of NO 2 exposure within the broader mixture of***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 8 traffic - related pollutants, limited evidence from experimental studies, and/or an over all limited literature base. 6.1.4 Health Effects of Carbon Monoxide In formation on the health effects of carbon monoxide (C O ) can be found in the January 2010 Integrated Science Assessment for Carbon Monoxide (CO I SA) . 34 The CO I SA concludes that ambient concentrations of CO are associated with a number of adverse health effects. 35 This section provides a summary of the health effects associated with exposure to ambient concentrations of CO . 36 Controlled human exposure studies of subjects with coronary artery d isease show a decrease in the time to onset of exercise - induced angina (chest pain) and electrocardiogram changes following CO exposure. In addition, epidemiologic studies show associations between short - term CO exposure and cardiovascular morbidity , part icularl y increased emergency room visits and hospital admissions for coronary heart disease (including ischemic heart disease, my ocardial infarction, and angina). Some epidemiologic evidence is also available for increased hospital admissions and emergenc y room visits for congestive heart failure and cardiovascular disease as a whole. The CO I SA concludes that a causal relationship is likely to exist between short - term exposures to CO and cardiovascular morbidity . It also concludes that available data ar e inadequate to conclude that a causal relationship exists between long - term exposures to CO and cardiovascular morbidity . Animal studies show various neurological effects with in - utero CO exposure. Controlled human exposure studies report central nervo us s ys tem and behavioral effects following low - level CO exposures, although the findings have not been consistent across all studies. The CO I SA concludes the evidence is suggestive of a causal relationship with both short - and long - term exposure to CO an d central nervous s ys tem effects. A number of studies cited in the CO I SA have evaluated the role of CO exposure in birth outcomes such as preterm birth or cardiac birth defects. The epidemiologic studies provide limited evidence of a CO - induced effect on preterm births and birth defects, with weak evidence for a decrease in birth weight. Animal toxicological studies have found perinatal CO exposure to affect birth weight, as well as other developmental outcomes. The CO ISA concludes the evidence is sugg estive of a causal relationship between long - term exposures to CO and developmental effects and birth outcomes. Epidemiologic studies provide evidence of associations between ambient CO concentrations and respiratory morbidity

such as changes in pulmonary function, respiratory sy mptoms, and hospital admissions. A limited number of epidemiologic studies considered copollutants such as ozone, SO 2 , and PM in two - pollutant models and found that CO risk estimates were generall y robust, although this limited evi dence makes it difficult to disentangle effects attributed to CO itself from those of the larger complex air pollution mixture. Controlled human exposure studies have not extensively evaluated the effect of CO on respiratory morbidity . Animal studies at levels of 50 - 100 ppm CO show preliminary evidence of altered***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 9 pulmonary

vascular remodeling and oxidative injury . The CO ISA concludes that the evidence is suggestive of a causal relationship between short - term CO exposure and respiratory morbidit y, and in adequate to conclude that a causal relationship exists between long - term exposure and respiratory

morbidit y. Finally , the CO I SA concludes that the epidemiologic evidence is suggestive of a causal relationship between short - term concentrations of CO and mortality . Epidemiologic studies provide evidence of an association between short - term exposure to CO and mortality , but limited evidence is available to evaluate cause - specific mortality outcomes associated with CO exposure. In addition, the attenuation of CO risk estimates which was often observed in copollutant models contributes to the uncertainty as to whether CO is acting alone or as an indicator for other combustion - related pollutants. The CO I SA also concludes that there is not likely to be a caus al relationship between relevant long - term exposures to CO and mortality . 6.1.5 Health Effects of Air Toxics

6.1.5.1 Benzene The EPA’s IRIS database lists benzene as a known human carcinogen (causing leukemia) by all routes of exposure, and concludes that exposure is as sociated with additional health effects, including genetic changes in both humans and animals and increased proliferation of bone marrow cells in mice. 37 , 38 , 39 EPA states in its IRIS database that data indicate a causal relationship between benzene exposure and acute ly mphocy tic leukemia and suggest a relationship between benzene exposure and chronic non - ly mphocy tic leukemia and chronic ly mphocy tic leukemia. EPA’s IRI S documentation for benzene also lists a range of 2.2 x 10 - 6 to 7.8 x 10 - 6 as the unit risk estimate (URE) for benzene. 40 , 41 The International Agency for Research on Carcinogens (IARC) has determined that benzene is a human carcinogen and the U.S. Department of Health and Human Services (DHHS) has characterized benzene as a known human carcinogen. 42 , 43 A number of adverse noncancer health effects including blood disorders, such as preleukemia and aplastic anemia, have also been associated with long - term exposure to benzene. 44 , 45 The most sensitive noncancer effect observed in humans, based on curr ent data, is the depression of the absolute ly mphocy te count in blood. 46 , 47 EPA’s inhalation reference concentration (RfC) for benzene is 30 μg/m 3 . The RfC is based on suppressed absolute ly mphocy te counts seen in humans under occupational exposure conditi ons. In addition, recent work, including studies sponsored b y the Health Effects Institute (HE I), provides evidence that biochemical responses are occurring at lower levels of benzene exposure than previousl y known. 48 , 49 , 50 , 51 EPA’s IRI S program has not y et evaluated these new data. EPA does not currentl y have an acute reference concentration for benzene. The Agency for Toxic Substances and Disease Registry

(ATSDR) Minimal Risk L evel (MRL) for acute exposure to benzene is 29 μg/m 3 for 1 - 14 day s exposure. 52 , 53***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 10 6.1.5.2 1,3 - Butadiene EPA has characterized 1,3 - butadiene as carcinogenic to humans by inhalation. 54 , 55 The IARC has determined that 1,3 - butadiene is a human carcinogen and the U.S. DHHS has characterized 1,3 - butadiene as a known human carcinogen. 56 , 57 , 58 There are numerous studies consistently

demonstrating that 1,3 - butadiene is metabolized into genotoxic metabolites by experimental animals and humans. The specific mechanisms of 1,3 - butadiene - induced carcinogenesis are unknown; however, the scientific evidence stro ngly suggests that the carcinogenic effects are mediated b y genotoxic metabolites. Animal data suggest that females may be more sensitive than males for cancer effects associated with 1,3 - butadiene exposure; there are insufficient data in humans from whic h to draw conclusions about sensitive subpopulations. The URE for 1,3 - butadiene is 3 × 10 - 5 per μg/m 3

. 59 1, 3 - butadiene also causes a variet y of reproductive and developmental effects in mice; no human data on these effects are available. The most sensiti ve effect was ovarian atrophy observed in a lifetime bioassay of female mice. 60 Based on this critical effect and the benchmark concentration methodology , an RfC for chronic health effects was calculated at 0.9 ppb (approximately 2 μg/m 3 ). 6.1.5.3 Ethanol EPA is p lanning to develop an assessment of the health effects of exposure to ethanol, a compound which is not currentl y listed on EPA’s IRIS database. Extensive health effects data are available for ingestion of ethanol, while data on inhalation exposure effects are sparse. In developing the assessment, EPA is evaluating pharmacokinetic models as a means of extrapolating across species (animal to human) and across exposure routes (oral to inhalation) to better characterize the health hazards and dose - response re lationships for low levels of ethanol exposure in the environment.

6.1.5.4 Formaldeh yd e In 1991, EPA concluded that formaldeh yde is a carcinogen based on nasal tumors in animal bioassay s. 61 An Inhalation Unit Risk for cancer and a Reference Dose for oral noncancer effects were developed by the Agency

and posted on the Integrated Risk Information Sy stem (IRI S) database. Since that time, the National Toxicology Program (NTP) and International Agency for Research on Cancer (IARC) have concluded that formaldehyde is a known human carcinogen. 62 , 63 , 64 The conclusions b y IAR C and NTP reflect the results of epidemiologic research published since 1991 in combination with previous animal, human and mechanistic evidence. Research conducted b y the National Cancer Institute report ed an increased risk of nasophary

ngeal cancer and specific l ymphohematopoietic malignancies among workers exposed to formaldeh yde. 65 , 66 , 67 A National Institute of Occupational Safety and Health study

of garment workers also reported increased risk of death d ue to leukemia among workers exposed to formaldeh yde. 68 Extended follow - up of a cohort of British chemical workers did not report evidence of an increase in nasophary ngeal or l ymphohematopoietic cancers, but a continuing statistically

significant excess in lung cancers was reported. 69 Finall y, a study of embalmers***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 11 reported formaldeh yd e exposures to be associated with an increased risk of my eloid leukemia but not brain cancer. 70 Health effects of formaldehyde in addition to cancer were reviewed b y the Agenc y for Toxics Substances and Disease Registry in 1999 71 and supplemented in 2010 , 72 and by the World Health Organization. 73 These organizations reviewed the literature concerning effects on the ey es and respiratory

s ys tem, the primary

point of contact for inh aled formaldehyde, including sensory irritation of ey es and respiratory tract, pulmonary

function, nasal histopathology , and immune sy stem effects. In addition, research on reproductive and developmental effects and neurological effects were discussed. EPA released a draft Toxicological Review of Formaldehyde

– Inhalation Assessment through the IR IS program for peer review by the National Research Council (NRC) and public comment in June 2010. 74 The draft assessment reviewed more recent research from ani mal and human studies on cancer and other health effects. The NRC released their review report in April 2011 75 (http://www.nap.edu/catalog.php?record_id=13142). The EPA is currentl y revising the draft assessment in response to this review.

6.1.5.5 Acetaldeh yd e Ac etaldeh yd e is classified in EPA’s IRI S database as a probable human carcinogen, based on nasal tumors in rats, and is considered toxic by the inhalation, oral, and intravenous routes. 76 The URE in IRIS for acetaldeh yd e is 2.2 × 10 - 6 per μg/m 3

. 77 Acetaldehyde is reasonabl y anticipated to be a human carcinogen by the U.S. DHHS in the 12 th Report on Carcinogens and is classified as possibly carcinogenic to humans (Group 2B) b y the IARC. 78 , 79 EPA is currentl y conducting a reassessment of cancer risk from inhalat ion exposure to acetaldeh yde. The primary

noncancer effects of exposure to acetaldehy de vapors include irritation of the ey es, skin, and respiratory tract. 80 Inshort - term (4 week) rat studies, degeneration of olfactory epithelium was observed at various c oncentration levels of acetaldehyde exposure. 81 , 82 Data from these studies were used b y EPA to develop an inhalation reference concentration of 9 μg/m 3 . Some asthmatics have been shown to be a sensitive subpopulation to decrements in functional expiratory volume (FEV1 test) and bronchoconstriction upon acetaldehyde inhalation. 83 The agency is currentl y conducting a reassessment of the health hazards from inhalation exposure to acetaldeh yde.

6.1.5.6 Acrolein EPA most recently

evaluated the toxicological and health effects literature related to acrolein in 2003 and concluded that the human carcinogenic potential of acrolein could not be determined because the available data were inadequate. No information was available on the carcinogenic effects of acrolein in humans and the animal data provided inadequate evidence of carcinogenicity . 84 The IARC determined in 1995 that acrolein was not classifiable as to its carcinogenicity

in humans. 85***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 12 Lesions to the lungs and upper respiratory tract of rats, rabbits, and hamste rs have been observed after subchronic exposure to acrolein. 86 The Agency has developed an RfC for acrolein of 0.02 μg/m 3 and an RfD of 0.5 μg/kg - day . 87 EPA is considering updating the acrolein assessment with data that have become available since the 2003 assessment was completed. Acrolein is extremely

acrid and irritating to humans when inhaled, with acute exposure resulting in upper respiratory tract irritation, mucus hy persecretion and congestion. The intense irritancy of this carbonyl has been demonstrated during controlled tests in human subjects, who suffer intolerable ey e and nasal mucosal sensory reactions within minutes of exposure. 88 These data and additional studies regarding acute effects of human exposure to acrolein are summarized in EPA’s 20 03 IR IS Human Health Assessment for acrolein. 89 Studies in humans indicate that levels as low as 0.09 ppm (0.21 mg/m 3 ) for five minutes may elicit subjective complaints of ey e irritation with increasing concentrations leading to more extensive ey e, nose an d respiratory

s ymptoms. Acute exposures in animal studies report bronchial hy per responsiveness. Based on animal data ( more pronounced respiratory irritancy in mice with allergic airway

disease in comparison to non - diseased mice 90 ) and demonstration of s imilar effects in humans (e.g., reduction in respiratory rate), individuals with compromised respiratory function (e.g., emph ys ema, asthma) are expected to be at increased risk of developing adverse responses to strong respiratory irritants such as acrolei n. EPA does not currently have an acute reference concentration for acrolein. The available health effect reference values for acrolein have been summarized by EPA and include an ATSDR MRLfor acute exposure to acrolein of 7 μg/m 3 for 1 - 14 day s exposure; and Reference Exposure L evel ( REL ) values from the California Office of Environmental Health Hazard Assessment ( OEHHA ) for one - hour and 8 - hour exposures of 2.5 μg/m 3 and 0.7 μg/m 3 , respectively. 91

6.1.5.7 PAN PAN (perox y acet yl nitrate) has not been evaluated by EPA’s IRIS program. Information regarding the potential carcinogenicit y of PAN is limited. As noted in the EPA air quality criteria document for ozone and related photochemical oxidants, cy togenetic studies indicate that PAN is not a potent mutagen, cla stogen (a compound that can cause breaks in chromosomes), or DNA - damaging agent in mammalian cells either in vivo or in vitro. Some studies suggest that PAN may be a weak bacterial mutagen at concentrations much higher than exist in present urban atmospher es. 92 Effects of ground - level smog causing intense ey e irritation have been attributed to photochemical oxidants, including PAN. 93 Animal toxicological information on the inhalation effects of the non - ozone oxidants has been limited to a few studies on PAN. Acute exposure to levels of PAN can cause changes in lung morphology , behavioral modifications, weight loss, and susceptibility

to pulmonary

infections. Human exposure studies indicate minor pulmonary function effects at high PAN concentrations, but lar ge inter - individual variability precludes definitive conclusions. 94***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 13 6.1.5.8 Poly cy clic Organic Matter The term pol yc yclic organic matter (POM) defines a broad class of compounds that includes the poly cy clic aromatic hydrocarbon compounds (PAHs). One of these compo unds, naphthalene, is discussed separately below. POM compounds are formed primarily from combustion and are present in the atmosphere in gas and particulate form. Cancer is the major concern from exposure to POM. Epidemiologic studies have reported an increase in lung cancer in humans exposed to diesel exhaust, coke oven emissions, roofing tar emissions, and cigarette smoke; all of these mixtures contain POM compounds. 95 96 Animal studies have reported respiratory

tract tumors from inhalation exposure to benzo[a]py rene and alimentary

tract and liver tumors from oral exposure to benzo[a]py rene. 97 In1997 EPA classified seven PAHs (benzo[a]py

rene, benz[a]anthracene, chry sene, benzo[b]fluoranthene, benzo[k]fluoranthene, dibenz[a,h]anthracene, and indeno[1,2,3 - cd]py rene) as Group B2, probable human carcinogens. 98 Since that time, studies have found that maternal exposures to PAHs in a population of pregnant women were associated with several adverse birth outcomes, including low birth weight and reduced length at birth, as well as impaired cognitive development in preschool children (3 years of age). 99 , 100 These and similar studies are being evaluated as a part of the ongoing IRIS assessment of health effects associated with exposure to benzo[a]py rene. 6.1.5.9 Naphthalene Naphthalene is found in small quantities in gasoline and diesel fuels. Naphthalene emissions have been measured in larger quantities in both gasoline and diesel exhaust compared with evaporative emissions from mobile sources, indicating it is primaril y a product of combustion. Acute (short - term) exposure of humans to naphthalene b y inhalation, ingestion, or dermal contact is associated with hemoly tic anemia and damage to the liver and the nervous sy stem. 101 Chronic (long term) exposure of workers and rodents to naphthalene has been reported to cause cataracts and retinal damage. 102 EPA released an external review draft of a reassessment of the inhalation carcinogenicity of naphthalene based on a number of recent animal carcinogenicit y studies. 103 The draft re assessment completed external peer review. 104 Based on external peer review comments received, a revised draft assessment that considers all routes of exposure, as well as cancer and noncancer effects, is under development. The external review draft does n ot represent official agency opinion and was released solely for the purposes of external peer review and public comment. The National Toxicology Program listed naphthalene as "reasonably anticipated to be a human carcinogen" in 2004 on the basis of bioas say s reporting clear evidence of carcinogenicity in rats and some evidence of carcinogenicity

in mice. 105 California EPA has released a new risk assessment for naphthalene, and the IARC has reevaluated naphthalene and re - classified it as Group 2B: possibly carcinogenic to humans. 106 Naphthalene also causes a number of chronic non - cancer effects in animals, including abnormal cell changes and growth in respiratory and nasal tissues. 107 The current EPA IRI S assessment includes noncancer data on h yperplasia and metaplasia in nasal tissue that form the***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 14 basis of the inhalation RfC of 3 μg/m 3

. 108 The ATSDR MRLfor acute exposure to naphthalene is 0.6 mg/kg/day .

6.1.5.10 Other Air Toxics In addition to the compounds described above, other compounds in gaseous hy drocarbon and P M emissions from vehicles w ill be affected by this proposal . Mobile source air toxic compounds that would potentially be impacted include eth yl benzene, propionaldehyde, toluene, and x yl ene. Information regarding the health effects of these compounds can be found in EPA’s IR IS database. 109 6.1.6 Traffic - associated health effects In addition to health concerns resulting from specific air pollutants, a large number of studies have examined the health status of populations near major roadways. These studies frequent ly

have employ ed exposure metrics that are not specific to individual pollutants, but rather reflect the large number of different pollutants found in elevation near major roads. In this section of the RIA, information on health effects associated with air quality near major roads or traffic in general is summarized. Generally , the section makes use of publications that sy stematically

review literature on a given health topic. In particular, this section makes frequent reference of a report of by the Heal th Effects Institute (HEI) Panel on the Health Effects of Traffic - Related Air Pollution, published in 2010 as a review of relevant studies. 110 , 111 Other sy stematic reviews of relevant literature are cited were appropriate.

6.1.6.1 Populations near major roads Numerou s studies have estimated the size and demographics of populations that live near major roads. Other studies have estimated the number of schools near major roads, and the populations of students in such schools. Every two y ears, the U.S. Census Bureau’s American Housing Survey (AHS) has reported whether housing units are within 300 feet of an “airport, railroad, or highway with four or more lanes.” The 2009 survey reports that over 22 million homes, or 17 percent of all housing units in the U.S., were located in such areas. Assuming that populations and housing units are in the same locations, this corresponds to a population of more than 50 million U.S. residents in close proximity

to high - traffic roadway s or other transportation sources. According to th e Central Intelligence Agency ’s World Factbook, in 2010, the United States had 6,506,204 km or roadway s, 224,792 km of railway s, and 15,079 airports. As such, highways represent the overwhelming majorit y of transportation facilities described b y this fact or in the AHS. The AHS reports are published every two y ears, and until 2011 recorded whether homes were located near highway s with four or more lanes, railroads, or airports. As such, trends in the AHS can be reported to describe whether a greater or les ser proportion of homes are located near major roads over time. Figure 6 - 1 depicts trends in the number and proportion of homes located***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 15 near major transportation sources, which generally indicate large roadway s. As the figure in dicates, since 2005, there has been a substantial increase in the number and percentage of homes located near major transportation sources. As such, the population in close proximity to these sources, which may be affected b y near - road air quality and hea lth concerns, appears to have increased over time.

0. 0% 2. 0% 4. 0% 6. 0% 8. 0% 10. 0% 12. 0% 14. 0% 16. 0% 18. 0%

10 12 14 16 18 20 22 24

1997 1999 2001 2003 2005 2007 2009PercentNearInfrastructureMillionHomes

Ye ar o f Amer ic an Housi ng S ur vey Mi llion H ousi ng Units Ne ar 4+ Lan e Hig hw ay, Ra ilroad, o r Air por

t

**Figure 6 -**  **1 Trends**  **in Populations**  **Near Large Highways, Railroads, and Airports** Furthermore, according to data from the 2008 American Time Use Survey (ATUS), conducted b y the Bure au of Labor Statistics (BTS), Americans spend more than an hour traveling each day , on average. 112 Although the ATUS does not indicate their mode of travel, the majority of trips undertaken nationally is by motor vehicle. 113 As such, daily travel activit y br ings nearl y all residents into a high - exposure microenvironment for part of the day .

6.1.6.2 Premature mortalit y The HEI panel report concluded that evidence linking traffic - associated air pollution with premature mortality

from all causes was “suggestive but not sufficient” to infer a causal relationship. This conclusion was based largel y on several long - term studies that “qualitativel y” examined whether or not someone was exposed to traffic - associated air pollution. In addition, based on several short - term stu dies of exposure, the panel concluded that there was evidence that***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 16 there was “suggestive but not sufficient” evidence to infer a causal relation between traffic related exposure and cardiovascular mortalit y.

6.1.6.3 Cardiovascular effects 6.1.6.3.1 Cardiac physiology Expo sure to traffic - associated pollutants has been associated with changes in cardiac phy siology , including cardiac function. One common measure of cardiac function is heart rate variability

(HRV), an indicator of the heart’s ability to respond to variations in stress, reflecting the nervous s ys tem’s ability to regulate the heart. 114 Reduced HRV is associated with adverse cardiovascular events, such as myocardial infarction, in heart disease patients. The HEI panel concluded that available evidence provides ev idence for a causal association between exposure to traffic - related pollutants and reduced control of HRV by the nervous s ys tem. Overall, the panel concluded that the evidence was “suggestive but not sufficient” to infer a causal relation between traffic - related pollutants and cardiac function. Studies suggest that the HRV changes from traffic - related air pollution result in changes to heart rh ythms, which can lead to arrh ythmia. 115 , 116

6.1.6.3.2 Heart attack and atherosclerosis The HEI panel concluded that epidemiolog ic evidence of the association between traffic related pollutants and heart attacks and atherosclerosis was “suggestive but not sufficient” to infer a causal association. In addition, the panel concluded that the toxicology studies they reviewed provided “suggestive evidence that exposure to traffic emissions, including ambient and laboratory - generated [PM] and diesel - and gasoline - engine exhaust, alters cardiovascular function.” The panel noted there are few studies of human volunteers exposed to real - wo rld traffic mixture, which were not entirel y consistent. The panel notes that the studies provide consistent evidence for exposure to PM and impaired cardiovascular responses. In addition to the HEI stud y, several other reviews of available evidence conc lude that there is evidence supporting a causal association between traffic - related air pollution and cardiovascular disease. 117 A number of mechanisms for cardiovascular disease are highlighted in the HEI and AHA report, including modified blood vessel endo thelial function (e.g, the ability to dilate), atherosclerosis, and oxidative stress. The HEI review cites “two well executed studies” in which hospitalization for acute my ocardial infarction (i.e., heart attack) were associated with traffic exposures and a prospective study finding higher rates of arterial hardening and coronary heart disease near traffic.***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 17 6.1.6.4 Respiratory

effects 6.1.6.4.1 Asthma Pediatric asthma and asthma sy mptoms are the effects that have been evaluated by the largest number of studies in the epidem iologic literature on the topic. In general, studies consistently

show effects of residential or school exposure to traffic and asthma sy mptoms, and the effects are frequentl y statistically significant. Studies have employ ed both short - term and long - term exposure metrics, and a range of different respiratory measures. HEI Special Report 17 (HEI Panel on the Health Effects of Traffic - Related Air Pollution, 2010) concluded that there is sufficient evidence for a causal association between exposure to traff ic - related air pollution and exacerbation of asthma sy mptoms in children. While there is general consistency in studies examining asthma incidence in children, the available studies emplo y different definitions of asthma (e.g., self - reported vs. hospital records), methods of exposure assessment, and population age ranges. As such, the overall evidence, while supportive of an association between traffic exposure and new onset asthma, are less consistent than for asthma sy mptoms. The HEI report determined that there is “sufficient” or “suggestive” evidence of a causal relationship between exposure to traffic - related air pollution and incident (new onset) asthma in children (HEI Panel on the Health Effects of Traffic - Related Air Pollution, 2010). A recent m eta - anal ys is of studies on incident asthma and air pollution in general, based on studies dominated by traffic - linked exposure metrics, also concluded that available evidence that exposures is consistent with a effect of exposure on asthma incidence (Ander son et al., 2011). The study reported excess main risk estimates for different pollutants ranging from 7 - 16 percent per 10  g/m 3 of long - term exposure (random effects models). Other qualitative reviews (Salam et al., 2008; Braback and Forsberg, 2009) conclude that available evidence is consistent with the hy pothesis that traffic - associated air pollutants are associated with i ncident asthma.

6.1.6.4.2 Chronic obstructive pulmonary disease (COPD) The HEI panel reviewed available studies examining COPD in the context of traffic associated air pollution. Because of how the panel selected studies for inclusion in review, there were onl y two studies that they used to review the available evidence. Both studies reported some positive associations, but not for all traffic metrics. The small number of studies and lack of consistency

across traffic metrics led the panel to conclude that there i s insufficient evidence for traffic - associated air pollution causing COPD.

6.1.6.4.3 Allergy There are numerous human and animal experimental studies that provides strongl y suggestive evidence that traffic - related air pollutants can enhance allergic responses to common allergens. 118 , 119 , 120 However, in its review of 16 epidemiologic studies that address traffic - related air pollution’s effect on allergies, the HEI expert panel (HEI, 2010) reported that only two such studies showed consistently positive associations. As a result, despite the strong experimental***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 18 evidence, the panel concluded that there is “inadequate/insufficient” evidence of an association between allergy

and traffic - associated air pollution. As noted above, the HEIpanel considered toxicological evidence only based on whether or not they provide mechanistic support for observations and inferences derived from epidemiology .

6.1.6.4.4 Lung function There are numerous measurements of breathing (spirometry) that indicate the presence or degree of airway

disease, such as asthma and chronic obstructive pulmonary disease (COPD). Forced vital capacit y (FVC) is measured when a patient maximally fills their lungs and then blows their hardest in completely exhaling. The peak expiratory flow (PEF) is the maximum air flow achie vable during exhalation. The forced expiratory volume in the first second of exhalation is referred to as FEV 1 . FEV 1 and PEF reflect the function of the large airway s. FVC and FEV 1 , along with their ratio (FVC/FEV 1 ) are used to classify airway obstructi on in asthma and COPD. Measurements of air flow at various times during forced exhalation, such as 25 percent, 50 percent, and 75 percent, are also used. The flow at 75 percent of forced exhalation (FEF 75 ) reflects the status of small airway s, which asthma and COPD affect. The HEI panel concluded that the available literature suggests that long - term exposure to traffic - related air pollution is associated with reduced lung function in adolescents and young adults and that lung function is lower in populat ions in areas with high traffic - related air pollutant levels. However, the panel noted the difficulty of disentangling traffic - specific exposures from urban air pollution in general. The studies reviewed that were more specifically oriented toward traffi c were not consistent in their findings. As a result, the panel found that the evidence linking lung function and traffic exposure is “inadequate and insufficient” to infer a causal relationship.

6.1.6.5 Reproductive and developmental effects Several studies hav e reported associations between traffic - related air pollution and adverse birth outcomes, such as preterm birth and low birth weight. At the time of the HEI review, the panel concluded that evidence for adverse birth outcomes being causall y associated with traffic - related exposures was “inadequate and insufficient.” Onl y four studies met the panel’s inclusion criteria, and had limited geographic coverage. One study provided evidence of small but consistently

increased risks using multiple exposure metric s. No studies were at the time available that examined traffic - specific exposures and congenital abnormalities. Since then, several studies investigating birth outcomes have been published, but no new s ys tematic reviews. One new meta - analy sis of air pol lution and congenital abnormalities has been published, though none of the reviewed studies includes traffic - specific exposure information. The HEI panel also reviewed toxicological studies of traffic - related air pollutants and fertility . While numerous s tudies examining animal or human exposure and sperm count have been published, the panel concluded that the generally high exposure concentrations employ ed in the studies limited the applicability to ty pical ambient concentrations. Because there was no***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 19 ov erlap in the effects studied by epidemiology

and toxicology

studies, no sy

nthesis review of the combined literature was undertaken. Since the HEI panel’s publication, a sy stematic review and meta - anal ys is of air pollution and congenital abnormalities was p ublished. 121 In that review, onl y one stud y directly included nearb y traffic in its exposure anal ys is. As such, there are so s ys tematic reviews that specifically address traffic’s impact on congenital abnormalities.

6.1.6.6 Cancer 6.1.6.6.1 Childhood cancer A number of stud ies examining various t ypes of childhood cancer have been published with mixed results. The HEI panel concluded that the available epidemiologic evidence was “inadequate and insufficient” to infer a causal relationship between traffic - related air pollutio n and childhood cancer. An earlier review article on the topic noted that studies reporting positive effects tended to be small, while those with null effects tended to be larger, suggesting the potential for publication bias in the available literature. 122

6.1.6.6.2 Adult cancer Several studies have examined the risk of adult lung cancers in relation to exposure to traffic - related air pollutants. The HEI panel evaluated four such studies, and rated the available evidence as “inadequate and insufficient” to infer a causal relation for non - occupational lung cancer. 6.1.6.7 Neurological effects The HEI panel found that current toxicologic and epidemiologic literature on the neurotoxicity

of traffic - related air pollution was inadequate for their evaluation. The panel noted that there were a number of toxicologic studies of traffic - associated pollutants, but found them to have diverse exposure protocols, animal models, and endpoints, making them unsuitable for sy stematic evaluation. **6.2 Environmental Effects of Criteria and Toxic Po**  **llutants** 6.2.1 Visibility

Degradation Visibility can be defined as the degree to which the atmosphere is transparent to visible light. 123 Visibility impairment is caused by light scattering and absorption by suspended particles and gases. Visibility is important because it has direct significance to people’s enjoy ment of daily

activities in all parts of the country . Individuals value good visibility for the well - being it provides them directl y, where they live and work, and in places where they enjo y recreationa l opportunities. Visibility is also highly

valued in significant natural areas, such as***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 20 national parks and wilderness areas, and special emphasis is given to protecting visibility in these areas. For more information on visibility see the final 2009 PM I SA. 124 EPA is working to address visibility impairment. In 1999 , EPA finaliz ed the regional haze program (64 FR 35714) to protect the visibility in Mandatory

Class I Federal areas. There are 156 national parks, forests and wilderness areas categorized as Mandatory Class I Federal areas (62 FR 38680 - 38681, July 18, 1997). These areas are defined in CAA section 162 as those national parks exceeding 6,000 acres, wilderness areas and memorial parks exceeding 5,000 acres, and all international parks which were in existence on August 7, 1977. Figure 6 - 2 shows the location of the 156 Mandatory Class I Federal areas.

**Figure 6**  **- 2**  **Mandatory Class I Federal Areas in the U.S.** EPA has also c oncluded that PM 2.5 causes adverse effects on visibility in other areas that are not protected b y the Regional Haze Rule, depending on PM 2.5 concentrations and other factors that control their visibility impact effectiveness such as dry chemical compositio n and relative humidity

(i.e., an indicator of the water composition of the particles) . EPA revised the PM 2.5 standards in December 2012 and established a target level of protection that is expected to be met through attainment of the existing secondary s tandards for PM 2.5 . 6.2.1.1 Visibility

Monitoring In conjunction with the U.S. National Park Service, the U.S. Forest Service, other Federal land managers, and State organizations in the U.S., the U.S. EPA has supported visibility monitoring in national parks an d wilderness areas since 1988. The monitoring network was originall y established at 20 sites, but it has now been expanded to 110 sites that represent all but***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 21 one of the 156 M andatory Federal Class I areas across the country (see Figure 6 - 2 ). This long term visibility

monitoring network is known as IMPROVE (Interagency Monitoring of Protected Visual Environments). IMPROVE provides direct measurement of fine particles that contribute to visibility impairment. The IMPROVE network employ s aerosol measurements at all sites, and optical and scene measurements at some of the sites. Aerosol measurements are taken for PM 10 and PM 2.5 mass, and for key

constituents of PM 2.5 , such as sulfate, nitrate, organic and elemental carbon OC and E C) , soil dust, and several other elements. Measurements for specific aerosol constituents are used to calculate "reconstructed" aerosol light extinction by multiplying the mass for each constituent b y its empirically - derived scattering and/or absorption e fficiency , with adjustment for the relative humidity . Knowledge of the main constituents of a site's light extinction "budget" is critical for source apportionment and control strategy development. In addition to this indirect method of assessing light e xtinction, there are o ptical measurements which directl y measure light extinction or its components. Such measurements are made principally

with either a nephelometer to measure light scattering, some sites also include an aethalometer for light absorptio n, or at a few sites using a transmissometer, which measures total light extinction . Scene characteristics are typically recorded usi ng digital or video photograph y and are used to determine the quality of visibility

conditions (such as effects on color and contrast) associated with specific levels of light extinction as measured under both direct and aerosol - related methods. Directl y measured light extinction is used under the IMPROVE protocol to cross check that the aerosol - derived light extinction leve ls are reasonable in establishing current visibility conditions. Aerosol - derived light extinction is used to document spatial and temporal trends and to determine how changes in atmospheric constituents would affect future visibility

conditions. Annual av erage visibility conditions (reflecting light extinction due to both anthropogenic and non - anthropogenic sources) vary regionally

across the U.S. Visibility is ty picall y worse in the summer months and the rural East generally has higher levels of impairme nt than remote sites in the West . Figures 9 - 9 through 9 - 11 in the PM I SA detail the percent contributions to particulate light extinction for ammonium nitrate and sulfate, EC and OC, and coarse mass and fine soil, by

season. 125 6.2.2 Particulate Matter Deposition Particulate matter contributes to adverse effects on vegetation and ecos ys tems, and to soiling and materials damage. These welfare effects result predominately from exposure to excess amounts of specific chemical species, regardless of their source or pr edominant form (particle, gas or liquid). The following characterizations of the nature of these environmental effects are based on info rmation contained in the 2009 PM I SA and the 2005 PM Staff Paper as well as the 2008 Integrated Science Assessment for Oxides of Nitrogen and Sulfur - Ecological Criteria (secondary

NO X/SO X IS A) . 126 , 127 , 128***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 22 6.2.2.1 Deposition of Nitrogen and Sulfur Nitrogen and sulfur interactions in the environment are highly complex. Both nitrogen and sulfur are essential, and sometimes limiting, nutr ients needed for growth and productivity of ecos ys tem components (e.g. algae, plants). In terrestrial and aquatic ecos ystems excesses of nitrogen or sulfur can lead to acidification and nutrient enrichment. 129 The process of acidification affects both fre shwater aquatic and terrestrial ecosy stems. Acid deposition causes acidification of sensitive surface waters. The effects of acid deposition on aquatic s ys tems depend largel y upon the ability of the ecos ys tem to neutralize the additional acid. As acidit y increases, aluminum leached from soils, flows into lakes and streams and can be toxic to both terrestrial and aquatic biota. The lower pH concentrations and higher aluminum levels resulting from acidification make it difficult for some fish and other aquatic organisms to survive, grow, and reproduce. Research on effects of acid deposition on forest ecos ys tems has come to focus increasingly on the biogeochemical processes that affect uptake, retention, and cy cling of nutrients within these ecos ys tems. D ecreases in available base cations from soils are at least partl y attributable to acid deposition. Base cation depletion is a cause for concern because of the role these ions play in acid neutralization, and because calcium, magnesium and potassium are es sential nutrients for plant growth and phy siology . Changes in the relative proportions of these nutrients, especiall y in comparison with aluminum concentrations, have been associated with declining forest health. At current ambient levels, risks to vegetation from short - term exposures to dry deposited particulate nitrate or sulfate are low. However, when found in acid or acidifying deposition, such particles do have the potential to cause direct leaf injury . Specificall y, the responses of forest trees to acid precipitation (rain, snow) include accelerated weathering of leaf cuticular surfaces, increased permeability

of leaf surfaces to toxic materials, water, and disease agents; increased leaching of nutrients from foliage; and altered reproductive proces ses — all which serve to weaken trees so that they are more susceptible to other stresses (e.g., extreme weather, pests, pathogens). Acid deposition with levels of acidity associated with the leaf effects described above are currentl y found in some location s in the eastern U.S. 130 Even higher concentrations of acidity can be present in occult depositions (e.g., fog, mist or clouds) which more frequently impacts higher elevations. Thus, the risk of leaf injury occurring from acid deposition in some areas of the eastern U.S **.** is high. Nitrogen deposition has also been shown to impact ecos ys tems in the western U.S. For example, a study conducted in the Columbia River Gorge National Scenic Area (CRGNSA), located along a portion of the Oregon/Washington border, i ndicates that lichen communities in the CRGNSA have shifted to a higher proportion of nitrophilous species and the nitrogen content of lichen tissue is elevated. 131 Li chens are sensitive indicators of nitrogen deposition effects to terrestrial ecos ys tems an d the lichen studies in the Columbia River Gorge clearl y show that ecological effects fro m air pollution are occurring. Some of the most significant detrimental effects associated with excess nitrogen deposition are those associated with a condition known as nitrogen saturation. Nitrogen saturation is the condition in which nitrogen inputs from atmospheric deposition and other***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 23 sources exceed the biological requirements of the ecos ys tem. The effects associated with nitrogen saturation include: (1) decrease d productivity , increased mortalit y, and/or shifts in plant community

composition, often leading to decreased biodiversity in many natural habitats wherever atmospheric reactive nitrogen deposition increases significantly above background and critical thre sholds are exceeded; (2) leaching of excess nitrate and associated base cations from soils into streams, lakes, and rivers, and mobilization of soil aluminum; and (3) fluctuation of ecos ys tem processes such as nutrient and energy cy cles through changes in the functioning and species composition of beneficial soil organisms. 132 In the U.S. numerous forests now show severe s ymptoms of nitrogen saturation. These forests include: the northern hardwoods and mixed conifer forests in the Adirondack and Catskill Mo untains of New York; the red spruce forests at Whitetop Mountain, Virginia, and Great Smoky Mountains National Park, North Carolina; mixed hardwood watersheds at Fernow Experimental Forest in West Virginia; American beech forests in Great Smoky Mountains National Park, Tennessee; mixed conifer forests and chaparral watersheds in southern California and the southwestern Sierra Nevada in Central California; the alpine tundra/subalpine conifer forests of the Colorado Front Range; and red alder forests in the Cascade Mountains in Washington. Excess nutrient inputs into aquatic ecosy stems (i.e. streams, rivers, lakes, estuaries or oceans) either from direct atmospheric deposition, surface runoff, or leaching from nitrogen saturated soils into ground or surface waters can contribute to conditions of severe water ox ygen depletion; eutrophication and algae blooms; altered fish distributions, catches, and phy siological states; loss of biodiversity ; habitat degradation; and increas es in the incidence of disease. Atmo spheric deposition of nitrogen is a significant source of total nitrogen to many estuaries in the United States. The amount of nitrogen entering estuaries that is ultimately attributable to atmospheric deposition is not well - defined. On an annual basis, atmospheric nitrogen deposition may

contribute significantly

to the total nitrogen load, depending on the size and location of the watershed. In addition, episodic nitrogen inputs, which may be ecologically important, may

play a more important role than i ndicated by the annual average concentrations. Estuaries in the U.S. that suffer from nitrogen enrichment often experience a condition known as eutrophication. Sy

mptoms of eutrophication include changes in the dominant species of phy toplankton, low level s of ox ygen in the water column, fish and shellfish kills, outbreaks of toxic alga, and other population changes which can cascade throughout the food web. In addition, increased ph yt oplankton growth in the water column and on surfaces can attenuate light causing declines in submerged aquatic vegetation, which serves as an important habitat for many estuarine fish and shellfish species. Severe and persistent eutrophication often directly impacts human activities. For example, losses in the nation’s fishery resources may be directl y caused by fish kills associated with low dissolved oxygen and toxic blooms. Declines in tourism occur when low dissolved oxygen causes noxious smells and floating mats of algal blooms create unfavorable aesthetic conditions. R isks to human health increase when the toxins from algal blooms accumulate in***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 24 edible fish and shellfish, and when toxins become airborne, causing respiratory problems due to inhalation. According to a National Oceanic and Atmospheric Administration report , more than half of the nation’s estuaries have moderate to high expressions of at least one of these s ymptoms

– an indication that eutrophication is well developed in more than half of U.S. estuaries. 133

6.2.2.2 Deposition of Heav y M etals Heav y metals, including ca dmium, copper, lead, chromium, mercury , nickel and zinc, have the greatest potential for impacting forest growth . 134 Investigation of trace metals near roadway s and industrial facilities indicate that a substantial load of heavy metals can accumulate on veg etative surfaces. Copper, zinc, and nickel have been documented to cause direct toxicity to vegetation under fie ld conditions . Trace metals are associated with ambient PM, however l ittle research has been conducted on the effects associated with mixtures of contaminants. While metals ty

pically exhibit low solubility , limiting their bioavailabilit y and direct toxicity , chemical transformations of metal compounds occur in the environment, particularl y in the presence of acidic or other oxidizing species. These chemical changes influence the mobility and toxicity

of metals in the environment. Once taken up into plant tissue, a metal compound can undergo chemical changes, exert toxic effects on the plant itself, accumulate and be passed along to herbivores or can re - enter the soil and further cycle in the environment. Although there has been no direct evidence of a ph ys iological association between tree injury and heav y m etal exposures, heav y metals have been implicated because of similarities between metal deposition patterns and f

orest decline . This hy

pothesized relationship/correlation was further explored in high elevation forests in the northeastern U.S. These studies measured levels of a group of intracellular compounds found in plants that bind with metals and are produced b y plants as a response to sublethal concentrations of heav y metals. These studies indicated a systematic and significant increase in concentrations of these compounds associated with the extent of tree injury . These data strongl y imply that metal stress causes tree injury and contributes to forest decline in the northeastern United States. 135 Contamination of plant leaves b y heav y metals can lead to elevated soil levels. Trace metals absorbed into the plant frequentl y bind to the leaf tissue, and then are lost when the leaf drops . As the fallen leaves decompose, the heav y metals are transferred into the soil. 136 , 137 Upon entering the soil environment, PM pollutants can alter ecological processes of energy flow and nutrient cycling, inhibit nutrient uptake, change ecos ys tem structure, and affect ecos ys tem biodiversity . Man y of the most important effects occur in the soil. The soil environment is one of the most dy namic sites of biological interaction in nature. It is inhabited by mi crobial communities of bacteria, fungi, and actinomycetes. These organisms are essential participants in the nutrient cycles that make elements available for plant uptake. Changes in the soil environment that influence the role of the bacteria and fungi in nutrient cy cling determine plant and ultimately ecosy stem response. 138 The environmental sources and cy cling of mercury are currentl y of particular concern due to the bioaccumulation and biomagnification of this metal in aquatic ecos ys tems and the potent toxic nature of mercury

in the forms in which is it ingested by people and other animals. Mercury is unusual compared with other metals in that it largel y partitions into the gas phase (in elemental form), and therefore has a longer residence time in the atmosphere than a metal found***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 25 predominantly

in the particle phase. This propert y enables mercury to travel far from the primary source before being deposited and accumulating in the aquatic ecosy stem. The major source of mercury

in the Great Lakes is fr om atmospheric deposition, accounting for approximately

eight y percent of the mercury in Lake Michigan. 139 , 140 Over fifty percent of the mercury in the Chesapeake Bay

has been attributed to atmospheric deposition. 141 Overall, the National Science and Technolog y Council identifies atmospheric deposition as the primary source of mercury

to aquatic sy stems. 142 Fort y - four states have issued health advisories for the consumption of fish contaminated b y mercury; however, most of these advisories are issued in areas wi thout a mercury

point source. Elevated levels of zinc and lead have been identified in streambed sediments, and these elevated levels have been correlated with population density and motor vehicle use. 143 , 144 , 145 Zinc and nickel have also been identified in urb an water and soils. In addition, platinum, palladium, and rhodium, metals found in the catalysts of modern motor vehicles, have been measured at elevated levels along roadsides. 146 Plant uptake of platinum has been observed at these locations.

6.2.2.3 Deposition o f Poly cy clic Organic Matter Poly cy clic organic matter (POM) is a by product of incomplete combustion and consists of organic compounds with more than one benzene ring and a boiling point greater than or equal to 100 degrees centigrade. 147 Poly cy clic aromatic hydrocarbons (PAHs) are a class of POM that contains compounds which are known or suspected carcinogens. Major sources of PAHs include mobile sources. PAHs in the environment may be present as a gas or adsorbed onto airborne particulate matter. Since th e majority of PAHs are adsorbed onto particles less than 1.0 μm in diameter, long range transport is possible. However, studies have shown that PAH compounds adsorbed onto diesel exhaust particulate and exposed to ozone have half lives of 0.5 to 1.0 hours . 148 Since PAHs are insoluble, the compounds generally are particle reactive and accumulate in sediments. Atmospheric deposition of particles is believed to be the major source of PAHs to the sediments of Lake Michigan. 149 , 150 Anal ys es of PAH deposition in C hesapeake and Galveston Bay

indicate that dry

deposition and gas exchange from the atmosphere to the surface water predominate. 151 , 152 Sediment concentrations of PAHs are high enough in some segments of Tampa Bay

to pose an environmental health threat. EPA f unded a study

to better characterize the sources and loading rates for PAHs into Tampa Bay . 153 PAHs that enter a water bod y through gas exchange likely partition into organic rich particles and can be biologicall y rec ycled, while dry deposition of aerosols containing PAHs tend to be more resistant to biological recycling. 154 Thus, dry

deposition is likely

the main pathway

for PAH concentrations in sediments while gas/water exchange at the surface may lead to PAH distribution into the food web, leading to incr eased health risk concerns. Trends in PAH deposition levels are difficult to discern because of highly variable ambient air concentrations, lack of consistency in monitoring methods, and the significant***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 26 influence of local sources on deposition levels. 155 Van Metre et al. noted PAH concentrations in urban reservoir sediments have increased b y 200 - 300 percent over the last forty y ears and correlate with increases in automobile use. 156 Cousins et al. estimate that more than ninet y percent of semi - volatile organ ic compound (SVOC) emissions in the United Kingdom deposit on soil. 157 An analy sis of PAH concentrations near a Czechoslovakian roadway indicated that concentrations were thirt y t imes greater than background. 158

6.2.2.4 Materials Damage and Soiling The effects of the deposition of atmospheric pollution, including ambient PM, on materials are related to both phy sical damage and impaired aesthetic qualities. The deposition of PM (especiall y sulfates and nitrates) can ph ys ically affect materials, adding to the effects o f natural weathering processes, by potentiall y promoting or accelerating the corrosion of metals, by degrading paints, and by deteriorating building materials such as concrete and limestone. Only chemicall y active fine particles or h ygroscopic coarse part icles contribute to these phy sical effects. In addition, the deposition of ambient PM can reduce the aesthetic appeal of buildings and culturall y important articles through soiling. Particles consisting primarily of carbonaceous compounds cause soiling o f commonly used building materials and culturally important items such as statues and works of art. 6.2.3 Plant and Ecosy stem Effects of Ozone The welfare effects of ozone can be observed across a variet y of scales, i.e. subcellular , c ellular, leaf, whole plant , population and ecos ys tem. Ozone effects that begin at small spatial scales, such as the leaf of an individual plant, when they occur at sufficient magnitudes (or to a sufficient degree) can result in effects being propagated along a continuum to larger and larger spatial scales. For example, effects at the individual plant level, such as altered rates of leaf gas exchange, growth and reproduction can , when widespread, result in broad changes in ecos ys tems, such as productivity , carbon storage, water cyc ling, nutrient cycling, and community composition. Ozone can produce both acute and chronic injury in sensitive species depending on the concentration level and the duration of the exposure. 159 Inthose sensitive species, o zone effects also tend to accumul ate over the growing season of the plant, so that even low concentrations experienced for a longer duration have the potential to create chronic stress on vegetation. Ozone damage to sensitive species includes visible injury to leaves and impaired p hotos ynthesis, both of which can lead to reduced plant growth and reproduction, resulting in reduced crop yi elds, forestry

production, and use of sensitive ornamentals in landscaping. In addition, the impairment of photosy

nthesis, the process by

which the plant makes carbohydrates (its source of energy and food), can lead to a subsequent reduction in root growth and carbohydrate storage below ground, resulting in other, more subtle plant and ecos ys tems impacts. These latter impacts include increased susce ptibility of plants to insect attack, disease, harsh weather, interspecies competition and overall decreased plant vigor. The adverse effects of ozone on areas with***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 27 sensitive species could potentially lead to species shifts and loss from the affected ecos ys tems, resulting in a loss or reduction in associated ecosystem goods and services. L astl y, visible ozone injury to leaves can result in a loss of aesthetic value in areas of special scenic significance like nationa l parks and wilderness areas. T he Integrated Science Assessment (I SA) for Ozone presents more detailed information on how ozone effects vegetation and ecos ys tems. 160 The I SA concludes that ambient concentrations of ozone are associated with a number of adverse welfare effects and characterizes the weight of evidence for different effects associated with ozone. 161 The I SA concludes that visible foliar injury effects on vegetation, reduced vegetation growth, reduced productivity

in terrestrial ecos ys tems, red uced yield and quality

of agricultural crops, and alteration of below - ground biogeochemical cycles are causall y associated with exposure to ozone. It also concludes that reduced carbon sequestration in terrestrial ecosy stems, alteration of terrestrial eco sy stem water cy cling, and alteration of terrestrial community composition are likely to be causall y associated with exposure to ozone. 6.2.4 Environmental Effects of Air Toxics Emissions from producing, transporting and combusting f uel contribute to ambient levels of pollutants that contribute to adverse effects on vegetation. Volatile organic compounds (VOCs), some of which are considered air toxics, have long been suspected to play a role in vegetation damage. 162 Inlaboratory experiments, a wide range of tolerance to VOCs has been observed. 163 Decreases in harvested seed pod weight have been reported for the more sensitive plants, and some studies have reported effects on seed germination, flowering and fruit ripening. Effects of individual VOCs or their role in conjunction with other stressors (e.g., acidification, drought, temperature extremes) have not been well studied. In a recent study of a mixture of VOCs including ethanol and toluene on herbaceous plants, significant effects on seed producti on, leaf water content and photosy nthetic efficiency

were reported for some plant species. 164 Research suggests an adverse impact of vehicle exhaust on plants, which has in some cases been attributed to aromatic compounds and in other cases to nitrogen oxide s. 165 , 166 , 167 The impacts of VOCs on plant reproduction may have long - term implications for biodiversity and survival of native species near major roadway s. Most of the studies of the impacts of VOCs on vegetation have focused on short - term exposure and few studies have focused on long - term effects of VOCs on vegetation and the potential for metabolites of these compounds to affect herbivores or insects.***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 28 **References** 1 U.S. Environmental Protection Agency. ( 2005 ) . Supplemental guidance for assessing susceptibility from early - life exposure to carcinogens. Washington, DC: Risk Assessment Forum. EPA/630/ R - 03 /003F. http://www.epa.gov/raf/publications/pdfs/childrens_supplement_final.pdf . 2 Regulatory definitions of PM size fractions, and information on reference and equivalent methods for measuring PM in ambient air, are provided in 40 CFR Parts 50, 53, and 58 . With regard to national ambient air quality standards (NAAQS) which provide protection against health and welfare effects, the 24 - hour PM 10 standard provides protection against effects associated with short - term exposure to thoracic coarse particles (i. e., PM 10 - 2.5 ). 3 U.S. EPA (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/139F, 2009. 4 U.S. EPA. (2009). Integrated Science Assessment for Particulate Matter ( Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/139F. 5 The causal framework draws upon the assessment and integration of evidence from across epidemiological, controlled human exposure, and toxicological studies, and the related uncertainties that ultimately influence our understanding of the evidence. This framework employs a five - level hierarchy that classifies the overall weight of evidence and causality using the following categorizations: causal relationship, like ly to be causal relationship, suggestive of a causal relationship, inadequate to infer a causal relationship, and not likely to be a causal relationship ( U.S. EPA. (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environme ntal Protection Agency, Wa shington, DC, EPA/600/R - 08/139F, Table 1

– 3). 6 78 FR 3086 ( January 15, 201 3) pages 3103 - 3104. 7 77 FR 38890 ( June 29, 2012 ) pages 38906 - 38911. 8 These causal inferences are based not only on the more expansive epidemiolog ical evidence available in this review but also reflect considerat ion of important progress that has been made to advance our understanding of a number of potential biologic modes of action or pathways for PM - related cardiovascular and respiratory effects ( U.S. EPA. (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Wa shington, DC, EPA/600/R - 08/139F, chapter 5). 9 78 FR 3086 (January 15, 2013) pages 3103 - 3104 . 10 U.S. EPA. (2009). Integrated Sc ience Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Wa shington, DC, EPA/600/R - 08/139F, chapter 6 (section 6.5) and chapter 7 (Section 7.6). 11 78 FR 3103 ( January 15, 201 3). 12 78 FR 3103 ( January 15, 201 3). 13 78 FR 3103 - 3104 ( January 15, 201 3). 14 78 FR 3104 ( January 15, 201 3). 15 U.S. EPA. (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Wa shington, DC, EPA/600/R - 08/139F. pg 2 - 13 . 16 U.S. EPA. (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/139F. Chapter 8 and Chapter 2. 17 77 FR 38890, ( June 29, 2012 ) page 38910. 18 78 FR 3086 ( January 15, 201 3) page 3104. 19 U.S. EPA. (2011) . Policy Assessment for the Review of the PM NAAQS. U.S. Environmental Protection Agency, Wa shington, DC, EPA/452/R - 11 - 003. section 2.2.1.***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 29 22 U.S. EPA. (200 9). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/139F. Chapter 8 and Chapter 2 (Section 2.4.1). 23 U.S. EPA. (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/139F. Section 2.3.4 and Table 2 - 6. 24 78 FR 3167 - 8 (January 15, 2013) . 25 77 FR 38947 - 51 (June 29, 2012) . 26 U.S. EPA. (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/139F. Section 2.3.5 and Table 2 - 6. 27 78 FR 3121 (January 15, 2013) . 28 Human exposure to ozone varies over time due to changes in ambient ozone concentration and because people mo ve between locations which have notable different ozone concentrations. Also, the amount of ozone delivered to the lung is not only influenced by the ambient concentrations but also by the individuals breathing route and rate. 29 U.S. EP A. Integrated Science Assessment of Ozone and Related Photochemical Oxidants (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 10/076F, 2013. The ISA is available at http://cfpub.epa.gov/ncea/isa/recordisplay.cfm?deid=247492#Dow nload . 30 The ISA evaluates evidence and draw s conclusions on the causal relationship betw een relevant pollutant exposures and health effects, assigning one of five “wei ght of evidence” determinations: causal relationship, likely to be a causal relationship, suggestive of a causal relationship, inadequate to infer a causal relationship, and not likely to be a causal relationship. For more information on these levels of evidence, please refer to Table II in the Preamble of the ISA. 31 U.S. EPA (2008). Integrated Science Assessment (ISA) for Sulfur Oxides

– Health Criteria (Final Report). EPA/600/R - 08/047F. Washington, DC,: U.S.EPA. Retrieved on March 19, 2009 from http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=198843 . 32 U.S. EPA (2008). Integrated Science Assessment for Oxides of Nitrogen

– Health Criteria (Final Report). EPA/600/R - 08/071. Washi ngton, DC,: U.S.EPA. Retrieved on March 19, 2009 from http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=194645 . 33 U.S. EPA (2008). Integrated Science Assessment for Oxides of Nitrogen – Health Criteria (Final Report). EPA/600/R - 08/071. Washington, DC: U.S.EPA. 34 U.S. EPA, (2010). Integrated Science Assessment for Carbon Monoxide (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 09/019F, 2010. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=218686 . 35 The ISA evaluates the health evidence associated with different health effects, assigning one of five “weight of evidence” determi nation s : causal relationship, likely to be a causal relationship, suggestive of a causal relationship, inadequate to infer a causal relationship, and not likely to be a causal relationship. For definitions of these levels of evidence, please refer to Sec tion 1.6 of the ISA. 36 Personal exposure includes contributions from many sources, and in many different environments. Total personal exposure to CO includes both ambient and nonambient components; and both components may contribute to adverse health e ffects. 37 U.S. EPA. (2000). Integrated Risk Information System File for Benzene. This material is available electronically at: http://www.epa.gov/iris/subst/0276.htm . 38 International Agency for Researc h on Cancer. (1982). IARC monographs on the evaluation of carcinogenic risk of chemicals to humans, Volume 29, Some industrial chemicals and dyestuffs, International Agency for Research on Cancer, World Health Organization, Lyon, France 1982.***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 30 39 Irons, R.D. ; Stillman, W.S.; Colagiovanni, D.B.; Henry, V.A. (1992). Synergistic action of the benzene metabolite hydroquinone on myelopoietic stimulating activity of granulocyte/macrophage colony - stimulating factor in vitro, Proc. Natl. Acad. Sci. 89:3691 - 3695. 40 A unit risk estimate is defined as the increase in the lifetime risk of an individual who is exposed for a lifetime to 1 μg/m3 benzene in air. 41 U.S. EPA. (2000). Integrated Risk Information System File for Benzene. This material is available electronicall y at: http://www.epa.gov/iris/subst/0276.htm . 42 International Agency for Research on Cancer (IARC). 1987. Monographs on the evaluation of carcinogenic risk of chemicals to humans, Volume 29, Supplement 7, Som e industrial chemicals and dyestuffs, World Health Organization, Lyon, France. 43 U.S. Department of Health and Human Services National Toxicology Program. (2011). 12th Report on Carcinogens available at: http://ntp.niehs.nih.gov/?objectid=03C9AF75 - E1 BF - FF40 - DBA9EC0928DF8B15. 44 Aksoy, M. (1989). Hematotoxicity and carcinogenicity of benzene. Environ. Health Perspect. 82: 193 - 197. EPA - HQ - OAR - 2011 - 0135 . 45 Goldstein, B.D. (1988). Benzene toxicity. Occupational medicine. State of the Art Reviews. 3: 541 - 554. 46 Rothman, N., G.L. Li, M. Dosemeci, W.E. Bechtold, G.E. Marti, Y.Z. Wang, M. Linet, L.Q. Xi, W. Lu, M.T. Smith, N. Titenko - Holland, L.P. Zhang, W. Blot, S.N. Yin, and R.B. Hayes. (1996). Hematotoxicity among Chinese workers heavily exposed to benzene. Am. J. Ind. Med. 29: 236 - 246. 47 U.S . EPA (2002). Toxicological Revie w of Benzene (Noncancer Effects). Environmental Protection Agency , Integrated Risk Information System (IRIS), Research and Development, National Center for Environmental Assessm ent, Washington DC. This material is available electronically at http://www.epa.gov/iris/subst/0276.htm . 48 Qu, O.; Shore, R.; Li, G.; Jin, X.; Chen, C.L.; Cohen, B.; Melikian, A.; Eastmond, D.; Rappaport , S.; Li, H.; Rupa, D.; Suramaya, R.; Songnian, W.; Huifant, Y.; Meng, M.; Winnik, M.; Kwok, E.; Li, Y.; Mu, R.; Xu, B.; Zhang, X.; Li, K. (2003). HEI Report 115, Validation & Evaluation of Biomarkers in Workers Exposed to Benzene in China. 49 Qu, Q. , R. Shore, G. Li, X. Jin, L.C. Chen, B. Cohen, et al. (2002). Hematological changes among Chinese workers with a broad range of benzene exposures. Am. J. Industr. Med. 42: 275 - 285. 50 Lan, Qing, Zhang, L., Li, G., Vermeulen, R., et al. (2004). Hematotoxi cally in Workers Exposed to Low Levels of Benzene. Science 306: 1774 - 1776. 51 Turtletaub, K.W. and Mani, C. (2003). Benzene metabolism in rodents at doses relevant to human exposure from Urban Air. Research Reports Health Effect Inst. Report No.113. 52 U. S. Agency for Toxic Substances and Disease Registry (ATSDR). (2007). Toxicological profile for benzene. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service. http://www.a tsdr.cdc.gov/ToxProfiles/tp3.pdf . 53 A minimal risk level (MRL) is defined as an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure. 54 U.S. EPA. (2002). Health Assessment of 1,3 - Butadiene. Office of Research and Development, National Center for Environmental Assessment, Washington Office, Washington, DC. Report No. EPA600 - P - 98 - 001F. This document is available electronically at http://www.epa.gov/iris/supdocs/buta - sup.pdf . 55 U.S. EPA. (2002) “Full IRIS Summary for 1,3 - butadiene (CASRN 106 - 99 - 0)” Environmental Protection Agency, Integrated Risk Information System (IRIS), Research and Development, National Center for Environmental Assessment, Washington, DC http://www.epa.gov/iris/subst/0139.htm .***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 31 56 International Agency for Research on Cancer (IARC). (1999). Monographs on the evaluation of carcinogenic risk of chemicals to humans, Volume 71, Re - evaluation of some organic chemicals, hydrazine and hydrogen peroxide and Volume 97 (in preparation), World Health Organization, Lyon, France. 57 International Agency for Research on Cancer (IARC). (2008). Monographs on the evaluation of carcinogenic risk of chemicals to humans, 1,3 - Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide) Volume 97, World Health Organization, Lyon, France. 58 NTP. ( 2011). Report on Carcinogens, T we lfth Edition. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. 499 pp. 59 U.S. EPA. (2002). “Full IRIS Summary for 1,3 - butadiene (CASRN 106 - 99 - 0)” Environmental Protection Agency, Integrated Risk Information System (IRIS), Research and Development, National Center for Environmental Assessment, Washington, DC http://www.epa.gov/iris/subst/0139.htm . 60 Bevan, C.; Stadler, J.C.; Elliot, G.S.; et al. (1996). Subchronic toxicity of 4 - vinylcyclohexene in rats and mice by inhalation. Fundam. Appl. Toxicol. 32:1 - 10. 61 EPA. Integrated Risk Information System. Formaldehyde (CASRN 50 - 00 - 0) http://www.epa.gov/ir is/subst/0419/htm . 62 National Toxicology Program, U.S. Department of Health and Human Services (HHS), 12th Report on Carcinogens, June 10, 2011 . 63 IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Volume 88 (2006): Formaldehyde, 2 - Butoxyeth anol and 1 - tert - Butoxypropan - 2 - ol . 64 IARC Mongraphs on the Evaluation of Carcinogenic Risks to Humans Volume 100F (2012): Formaldehyde . 65 Hauptmann, M..; Lubin, J. H.; Stewart, P. A.; Hayes, R. B.; Blair, A. 2003. Mortality from lymphohematopoetic malign ancies among workers in formaldehyde industries. Journal of the National Cancer Institute 95: 1615 - 1623. 66 Hauptmann, M..; Lubin, J. H.; Stewart, P. A.; Hayes, R. B.; Blair, A. 2004. Mortality from solid cancers among workers in formaldehyde industries . Am erican Journal of Epidemiology 159: 1117 - 1130. 67 Beane Freeman, L. E.; Blair, A.; Lubin, J. H.; Stewart, P. A.; Hayes, R. B.; Hoover, R. N.; Hauptmann, M. 2009. Mortality from lymphohematopoietic malignancies among workers in formaldehyde industries: The National Cancer Institute cohort. J. National Cancer Inst. 101: 751 - 761. 68 Pinkerton, L. E. 2004. Mortality among a cohort of garment workers exposed to formaldehyde: an update. Occup. Environ. Med. 61: 193 - 200. 69 Coggon, D, EC Harris, J Poole, K T Palmer. 2003. Extended follow - up of a cohort of British chemical workers exposed to formaldehyde. J National Cancer Inst. 95:1608 - 1615. 70 Hauptmann, M,; Stewart P. A.; Lubin J. H.; Beane Freeman, L. E.; Hornung, R. W.; Herrick, R. F.; Hoover, R. N.; Fraumeni, J. F.; Hayes, R. B. 2009. Mortality from lymphohematopoietic malignancies and brain cancer among em balm ers exposed to formaldehyde. Journal of the National Cancer Institute 101:1696 - 1708. 71 AT SDR. 1999. Toxicological Profile for Formaldehyde, U.S. D epartment of Health and Human Services (HHS), July 1999. 72 AT SDR. 2010. Addendum to theToxicological Profile for Formaldehyde. U.S. Department of Health and Human Services (HHS), October 2010. 73 IPCS. 2002. Concise International Chemical Assessment Document 40. Formaldehyde. World Health Organization. 74 EPA (U.S. Environmental Protection Agency). 2010. Toxicological Review of Formaldehyde (CAS No. 50 - 00 - 0)

– Inhalation Assessment: In Support of Summary Information on the Integrated Risk Information System (IRIS).***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 32 External Review Draft. EPA/635/R - 10/002A. U.S. Environmental Protection Agency, Washington DC [online]. Available: http://cfpub.epa.gov/ncea/irs_drats/recordisplay.cfm? deid=223614 . 75 NRC (National Research Council). 2011. Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde. Washington DC: National Academies Press. http://books.nap.edu/openbook.php?record_id=13142 . 76 U.S. EPA (1991). I ntegrated Risk Information System File of Acetaldehyde. Research and Development, National Center for Environmental Assessment, Washington, DC. This material is available electronically at http://www.epa. gov/iris/subst/0290.htm . 77 U.S. EPA (1991). Integrated Risk Information System File of Acetaldehyde. This material is available electronically at http://www.epa.gov/iris/subst/0290.htm . 78 NTP. (2011). Report on Carcinogens, T we lfth Edition. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. 499 pp. 79 International Agency for Research on Cancer (IARC). (1999). Re - evaluation of so me organic chemicals, hydrazine, and hydrogen peroxide. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemical to Humans, Vol 71. Lyon, France. 80 U.S. EPA (1991). Integrated Risk Information System File of Acetaldehyde. This material is avai lable electronically at http://www.epa.gov/iris/subst/0290.htm . 81 U.S. EPA. (2003). Integrated Risk Information System File of Acrolein. Research and Development, National Center for Environmental Asses sment, Washington, DC. This material is available electronically at http://www.epa.gov/iris/subst/0364.htm . 82 Appleman, L.M., R.A. Woutersen, and V.J. Feron. (1982). Inhalation toxicity of acetaldehyde i n rats. I. Acute and subacute studies. Toxicology. 23: 293 - 297. 83 My ou, S.; Fujimura, M.; Nishi K.; Ohka, T.; and Matsuda, T. (1993). Aerosolized acetaldehyde induces histamine - mediated bronchoconstriction in asthmatics. Am. Rev. Respir.Dis.148(4 Pt 1): 940 - 943. 84 U.S. EPA. (2003). Integrated Risk Information System File of Acrolein. Research and Development, National Center for Environmental Assessment, Washington, DC. This material is available at http://www.epa.gov/iris/subst/0364.htm . 85 International Agency for Research on Cancer (IARC). (1995). Monographs on the evaluation of carcinogenic risk of chemicals to humans, Volume 63. Dry cleaning, some chlorinated solvents and other industrial chemicals , World Health Organization, Lyon, France. 86 U.S. EPA. (2003). Integrated Risk Information System File of Acrolein. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. This material is available at http://www .epa.gov/iris/subst/0364.htm. 87 U.S. EPA. (2003). Integrated Risk Information System File of Acrolein. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. This material is available at http://www.epa.gov/iris /subst/0364.htm. 88 U.S. EPA. (2003). Toxicological review of acrolein in support of summary information on Integrated Risk Information System (IRIS) National Center for Environmental Assessment, Washington, DC. EPA/635/R - 03/003. p. 10. Available online at: http://www.epa.gov/ncea/iris/toxreviews/0364tr.pdf . 89 U.S. EPA. (2003). Toxicological review of acrolein in support of summary information on Integrated Risk Information System (IRIS) National Center for Environmental Assessment, Washington, DC. EPA/635/R - 03/003. Available online at: http://www.epa.gov/ncea/iris/toxreviews/0364tr.pdf . 90 Morris JB, Symanowicz PT, Olsen JE, et al. (2003). Immediate sensory nerve - mediated respiratory responses to irritants in healthy and allergic airw ay - diseased mice. J Appl Phy siol 94(4):1563 - 1571.***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 33 91 U.S. EPA. (2009). Graphical Arrays of Chemical - Specific Health Effect Reference Values for Inhalation Exposures (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 09/061, 2009. http://cfpub.epa.gov/nc ea/cfm/recordisplay.cfm?deid=211003 . 92 U.S. EPA. (2006). Air quality criteria for ozone and related photochemical oxidants (Ozone CD). Research Triangle Park, NC: National Center for Environmental Assessment; report no. EPA/600/R - 05/004aF - cF.3v. page 5 - 78 Available at http://cfpub.epa.gov/ncea/. 93 U.S. EPA Air Quality Criteria for Ozone and Related Photochemical Oxidants (Final). U.S. Environmental Protection Agency, Washington, D.C., EPA 600/R - 05/004aF - cF, 2006. page 5 - 63. This document is available in . This document may be accessed electronically at: http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_cr_cd.html . 94 U.S. EPA Air Quality Criteria for Ozone and Related Photochemical Oxidants (Final). U.S. Environmental Protection Agency, Washington, D.C., EPA 600/R - 05/004aF - cF, 2006. page 5 - 78. This document is available in . This document may be accessed electronically at: http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_cr_cd.html . 95 Agency for Toxic Substances and Disease Registry (ATSDR). (1995). Tox icological profile for Polycyclic Aromatic Hydrocarbons (PAHs). Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service. Available electronically at http://www.atsdr.cdc.gov/ToxProfiles/TP.asp?id=122&tid=25. 96 U.S. EPA (2002). Heal th Assessment Document for Diesel Engine Exhaust . EPA/600/8 - 90/057F Office of Research and Development, Washington DC. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=29060 . 97 International Agency for Research on Cancer (IARC). (2012). Monographs on the Evaluation of the Carcinogenic Risk of Chemicals for Humans, Chemical Agents and Related Occupations. Vol. 100F. Lyon, France. 98 U.S. EPA (1997). Integrated Risk Information Sy stem File of indeno(1,2,3 - cd)pyrene. Research and Development, National Center for Environmental Assessment, Washington, DC. This material is available electronically at http://www.epa.gov/ncea/iris/subst/0457.htm. 99 Perera , F.P.; Rauh, V.; Tsai, W - Y.; et al. (2002). Effect of transplacental exposure to environmental pollutants on birth outcomes in a multiethnic population. Environ Health Perspect. 111: 201 - 205. 100 Perera, F.P.; Rauh, V.; Whyatt, R.M.; Tsai, W.Y.; Tang, D.; Diaz, D.; Hoepner, L.; Barr, D.; T u, Y.H.; Camann, D.; Kinney, P. (2006). Effect of prenatal exposure to airborne polycyclic aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner - city children. Environ Health Perspect 114: 1287 - 1292. 101 U. S. EPA. 1998. Toxico logical Review of Naphthalene (Reassessment of the Inhalation Cancer Risk), Environmental Protection Agency, Integrated Risk Information System, Research and Development, National Center for Environmental Assessment, Washington, DC. This material is avail able electronically at http://www.epa.gov/iris/subst/0436.htm . 102 U. S. EPA. 1998. Toxicological Review of Naphthalene (Reassessment of the Inhalation Cancer Risk), Environmental Protection Agency, Inte grated Risk Information System, Research and Development, National Center for Environmental Assessment, Washington, DC. This material is available electronically at http://www.epa.gov/iris/subst/0436.htm . 103 U. S. EPA. (1998). Toxicological Review of Naphthalene (Reassessment of the Inhalation Cancer Risk), Environmental Protection Agency, Integrated Risk Information System, Research and Development, National Center for Environmental Assessment, Washingt on, DC. This material is available electronically at http://www.epa.gov/iris/subst/0436.htm . 104 Oak Ridge Institute for Science and Education. (2004). External Peer Review for the IRIS Reassessment of the Inhalation Carcinogenicity of Naphthalene. August 2004. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=84403 . 105 NT P. (2011). Report on Carcinogens, T we lfth Edition. Resear ch Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. 499 pp.***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 34 106 International Agency for Research on Cancer (IARC). (2002). Monographs on the Evaluation of the Carcinogenic Risk of Chemica ls for Humans. Vol. 82. Lyon, France. 107 U. S. EPA. (1998). Toxicological Review of Naphthalene, Environmental Protection Agency, Integrated Risk Information System, Research and Development, National Center for Environmental Assessment, Washington, DC. This material is available electronically at http://www.epa.gov/iris/subst/0436.htm . 108 U.S. EPA. (1998). Toxicological Review of Naphthalene. Environmental Protection Agency, Integrated Risk Information System (IRIS), Research and Development, National C enter for Environmental Assessment, Washington, DC http://www.epa.gov/iris/subst/0436.htm . 109 U.S. EPA Integrated Risk Information System (IRIS) database is available at: www.epa.gov/iris . 110 It should be noted that there are no peer review ed EPA - authored review s of traffic - related health studies. The HEI panel primarily used epidemiology studies for inferring whether there was sufficient evidence of a causal association exists between a particular health effect and traffic - related air pollution, In its weight - of - evidence determinations, the panel also placed “considerable weight” on controlled human exposure studies. However, it restricted consideration of other toxicological studies to whether or not th e studies provided “general mechanistic support” for the inferences of causality made on the basis of epidemiology. 111 Health Effects Institute Panel on the Health Effects of Traffic - Related Air Pollution. (2010). Traffic - related air pollution: a critica l revie w of the literature on emissions, exposure, and health effects. HEI Special Report 17. [Online at http://www.healtheffects.org] . 112 Bureau of Labor Statistics. (2009). American Time Use Survey. [Online at http://www.bls.gov/tus] . 113 Bureau of Trans portation Statistics. (2003). Highlights of the 2001 National Household Travel Survey. Report BTS03 - 05. [Online at http://www.bts.gov] . 114 The autonomic nervous system (ANS) consists of sympathetic and parasympathetic components. The sympathetic ANS sig nals body systems to “fight or flight.” The parasympathetic ANS signals the body to “rest and digest.” In general, HRV is indicative of parasympathetic control of the heart. 115 Baja, E.S.; Schw artz, J.D.; Wellenius, G.A.; Coull, B.A.; Zanobetti, A.; Vokon as, P.S.; Suh, H.H. (2010). Traffic - related air pollution and QT interval: modification by diabetes, obesity, and oxidate stress gene polymorphisms in the Normative Aging Study. Environ Health Perspect 118: 840 - 846. doi:10.1289/ehp.0901396 . 116 Zanobetti a, A.; Stone, P.H.; Speizer, F.E.; Schw arz, J.D.; Coull, B.A.; Suh, H.H.; Nearing, B.D.; Mittleman, M.A.; Verrier, R.L.; Gold, D.R. (2009). T - wa ve alterans, air pollution and traffic in high - risk subjects. Am J Cardiol 104: 665 - 670. doi:10.1016/j.amjcar d.2009.04.046 . 117 Brook, R.D.; Rajagopalan, S.; Pope, C.A.; Brook, J.R.; Bhatnagar, A.; Diez - Rouz, A.V.; Holguin, F.; Hong, Y.; Luepker, R.V.; et la. (2010). Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from

the American Heart Association. Circulation 121: 2331 - 2378. doi:10.1161/CIR.0b013e3181dbece1 . 118 Bastain , T.M.; Gilliland, F.D.; Li, Y.; Saxon, A.; Diaz - Sanchez, D. (2003) Intraindividual reproducibility of nazal allergic responses to diesel exhau st particles indicates a susceptible phenotype. Clinical Immunol 109: 130 - 136. 119 Gilliland , F.D.; Li, Y.; Diaz - Sanchez, D. (2004) Effect of glutathione - S - transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomized, placeb o - controlled crossover study. Lancet 363:119 - 125. 120 Svartengren , M., Strand, V.; Bylin, G. J ä rup, L.; Pershagen, G. (2000) Short - term exposure to air pollution in a road tunnel enhances the asthmatic response to allergen. Eur Respir J 15: 716 - 724. 121 Vri jheid, M.; Martinez, D.; Manzanares, S.; Dadvand, P.; Schembari, A.; Rankin, F.; Nieuwenhuijsen, M. (2011). Ambient air pollution and risk of congenital anomalies: a systematic review and meta - analysis. Environ Health Perspect 119: 598 - 606. doi:10.1289 /ehp.1002946 .***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 35 122 Raaschou - Nielson, O.; Reynolds, P. (2006). Air pollution and childhood cancer: a review of the epidemiological literature. Int J Cancer 118: 2920 - 2929. doi: 10.1002/ijc.21787 [Online at http://dx.doi.org] . 123 National Research Council, ( 1993). Protecting Visibility in National Parks and Wilderness Areas. National Academy of Sciences Committee on Haze in National Parks and Wilderness Areas. National Academy Press, Washington, DC. This book can be viewed on the National Academy Press Website at http://www.nap.edu/books/0309048443/html/ . 124 U.S. EPA (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/139F, 2009. 125 U.S. EPA (2009). Integrated Scien ce Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/139F, 2009. pg 9 - 19 through 9 - 23 . 126 U.S. EPA (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environm ental Protection Agency, Washington, DC, EPA/600/R - 08/139F, 2009. 127 U.S. EPA. (2005). Review of the National Ambient Air Quality Standard for Particulate Matter: Policy Assessment of Scientific and Technical Information, OAQPS Staff Paper. EPA - 452/R - 05 - 005. 128 U.S. EPA. (2008). Integrated Science Assessment for Oxides of Nitrogen and Sulfur - Ecological Criteria (Final). U.S. EPA, Washington D.C., EPA/600/R - 08/082F. 129 U.S. EPA. (2008). Integrated Science Assessment for Oxides of Nitrogen and Sulfur - Ecological Criteria (Final). U.S. EPA, Washington D.C., EPA/600/R - 08/082F. 130 Environmental Protection Agency (2003). Response Of Surface Water Chemistry to the Clean Air Act Amendments of 1990. National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency. Research Triangle Park, NC. EPA 620/R

– 03/001. 131 Fenn, M.E. and Blubaugh, T.J. (2005). Winter Deposition of Nitrogen and Sulfur in the Eastern Columbia River Gorge National Sceni c Area, USDA Forest Service. 132 Gallow ay, J. N.; Cowling, E. B. (2002). Reactive nitrogen and the world: 200 years of change. Ambio 31: 64

– 71. 133 Bricker, Suzanne B., et al., (1999). National Estuarine Eutrophication Assessment, Effects of Nutrient Enric hment in the Nation’s Estuaries, National Ocean Service, National Oceanic and Atmospheric Administration, September, 1999. 134 Smith, W.H. (1991). “Air pollution and Forest Damage.” Chemical Engineering News, 69(45): 30 - 43. 135 Gaw el, J.E.; Ahner, B.A.; Fr iedland, A.J.; and Morel, F.M.M. (1996). “Role for heavy metals in forest decline indicated by phytochelatin measurements.” Nature, 381: 64 - 65. 136 Cotrufo, M.F.; DeSanto, A.V.; Alfani, A.; et al. (1995). “Effects of urban heavy metal pollution on organic matter decomposition in Quercus ilix L. woods.” Environmental Pollution, 89: 81 - 87. 137 Niklinska, M.; Laskowski, R.; Maryanski, M. (1998). “Effect of heavy metals and storage time on two types of forest litter: basal respiration rate and exchangeable meta ls .” Ecotoxicological Environmental Safety, 41: 8 - 18. 138 U.S. EPA (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/139F, 2009. Section 9.4.5.2. 139 Mason, R.P. and Sullivan, K.A. (1997). “Mercury in Lake Michigan.” Environmental Science & Technology, 31: 942 - 947. (from Delta Report “Atmospheric deposition of toxics to the Great Lakes”). 140 Landis, M.S. and Keeler, G.J. (2002). “Atmospheric mercury deposition to Lake Michigan during the Lake Michigan Mass Balance Study.” Environmental Science & Technology, 21: 4518 - 24. 141 U.S. EPA. (2000). EPA453/R - 00 - 005, “Deposition of Air Pollutants to the Great Waters: Third Report to Congress,” Office of Air Quality Plannin g and Standards, Research Triangle Park, North Carolina.***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 36 142 National Science and Technology Council (NSTC) (1999). “The Role of Monitoring Networks in the Management of the Nation’s Air Quality.” 143 Callender, E. and Rice, K.C. (2000). “The Urban Environmental Gradient: Anthropogenic Influences on the Spatial and Temporal Distributions of Lead and Zinc in Sediments.” Environmental Science & Technology, 34: 232 - 238. 144 Rice, K.C. (1999). “Trace Element Concentrations in Streambed Sediment Across the Conte rminous United States.” Environmental Science & Technology, 33: 2499 - 2504. 145 U.S. EPA. (2013) Integrated Science Assessment for Lead (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 10/075F, 2013. 146 Ely, JC; Neal, CR; Kulpa , CF; et al. (2001). “ Implications of Platinum - Group Element Accumulation along U.S. Roads from Catalytic - Converter Attrition.” Environ. Sci. Technol. 35: 3816 - 3822. 147 U.S. EPA. (1998). EPA454/R - 98 - 014, “Locating and Estimating Air Emissions from Sources of Polycyclic Organic Matter,” Office of Air Quality Planning and Standards , Research Triangle Park, North Carolina. 148 U.S. EPA. (1998). EPA454/R - 98 - 014, “Locating and Estimating Air Emissions from Sources of Polycyclic Organic Matter,” Office of Air Qu ality Planning and Standards , Research Triangle Park, North Carolina. 149 Simcik, M.F.; Eisenreich, S.J.; Golden, K.A.; et al. (1996). “Atmospheric Loading of Polycyclic Aromatic Hy drocarbons to Lake Michigan as Recorded in the Sediments .” Environmental Sc ience and Technology, 30: 3039 - 3046. 150 Simcik, M.F.; Eisenreich, S.J.; and Lioy, P.J. (1999). “Source apportionment and source/sink relationship of PAHs in the coastal atmosphere of Chicago and Lake Michigan.” Atmospheric Environment, 33: 5071 - 5079. 151 Arzayus, K.M.; Dickhut, R.M.; and Canuel, E.A. (2001). “Fate of Atmospherically Deposited Polycyclic Aromatic Hydrocarbons (PAHs) in Chesapeake Bay.” Environmental Science & Technology, 35, 2178 - 2183. 152 Park, J.S.; Wade, T.L.; and Sweet, S. (2001). “Atmo spheric distribution of polycyclic aromatic hydrocarbons and deposition to Galveston Bay, Texas, USA.” Atmospheric Environment, 35: 3241 - 3249. 153 Poor, N.; Tremblay, R.; Kay, H.; et al. (2002). “Atmospheric concentrations and dry deposition rates of poly cyclic aromatic hydrocarbons (PAHs) for Tampa Bay, Florida, USA.” Atmospheric Environment 38: 6005 - 6015. 154 Arzayus, K.M.; Dickhut, R.M.; and Canuel, E.A. (2001). “Fate of Atmospherically Deposited Polycyclic Aromatic Hydrocarbons (PAHs) in Chesapeake Ba y.” Environmental Science & Technology, 35, 2178 - 2183. 155 U.S. EPA. (2000). EPA453/R - 00 - 005, “Deposition of Air Pollutants to the Great Waters: Third Report to Congress,” Office of Air Quality Planning and Standards , Research Triangle Park, North Carolina . 156 Van Metre, P.C.; Mahler, B.J.; and Furlong, E.T. (2000). “Urban Sprawl Leaves its PAH Signature.” Environmental Science & Technology, 34: 4064 - 4070. 157 Cousins, I.T.; Beck, A.J.; and Jones, K.C. (1999). “A review of the processes involved in the exc hange of semi volatile organic compounds across the air - soil interface.” The Science of the Total Environment, 228: 5 - 24. 158 Tuhackova, J. et al. (2001). Hydrocarbon deposition and soil microflora as affected by highway traffic. Environmental Pollution, 1 13: 255 - 262. 159 O nly a small percentage of all the plant species growing within the U.S. (over 43,000 species have been catalogued in the USDA PLANTS database ) have been studied with respect to ozone sensitivity (U.S. EPA. Review of the National Ambient A ir Quality Standards for Ozone: Policy Assessment of Scientific and Technical Information. OAQPS Staff Paper. U.S. Environmental Protection Agency, Washington, DC, EPA - 452/R - 07 - 007, 2007. p.7 - 7). Thus, ozone impacts could be occurring in areas where pl ant species sensitive to ozone have not yet been studied or identified. In addition, the concentration at which ozone levels overwhelm a plant’s ability to***** EO12866 Review -**  **Draft -**  **Do Not Cite, Quote, or Release During Revi ew ** ***

6 - 37 detoxify or compensate for oxidant exposure varies ( U.S. EPA. Welfare Risk and Exposure Assessment for Ozone. Second External Review Draft. EPA - 452/P - 14 - 003a, 2014. Figure 6 - 2, p. 6 - 5). Thus, whether a plant is classified as sensitive or tolerant depends in part on the exposure levels being considered. 160 U.S. EPA. Integrated Science Assessment of Ozon e and Related Photochemical Oxidants (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 10/076F, 2013. The ISA is available at http://cfpub.epa.gov/ncea/isa/recordisplay.cfm?deid=247492#Dow nload . 161 The Ozone ISA evaluates the evidence associated with different ozone related health and welfare effects, assigning one of five “weight of evidence” determinations: causal relationship, likely to be a causal relationship, suggestive of a causal relationship, inadequate to infer a cau sal relationship, and not likely to be a causal relationship. For more information on these levels of evidence, please refer to Table II of the ISA. 162 U.S. EPA. (1991). Effects of organic chemicals in the atmosphere on terrestrial plants. EPA/600/3 - 91/0 01. 163 C ape JN, ID Leith, J Binnie, J Content, M Donkin, M Skewes, DN Price AR Brown, AD Sharpe. (2003). Effects of VOCs on herbaceous plants in an open - top chamber experiment. Environ. Pollut. 124:341 - 343. 164 Cape JN, ID Leith, J Binnie, J Content, M Donkin , M Skewes, DN Price AR Brown, AD Sharpe . (2003). Effects of VOCs on herbaceous plants in an open - top chamber experiment. Environ. Pollut. 124:341 - 343. 165 Viskari E - L. (2000). Epicuticular wax of Norw ay spruce needles as indicator of traffic pollutant deposition. Water, Air, and Soil Pollut. 121:327 - 337. 166 Ugrekhelidze D, F Korte, G Kvesitadze. (1997). Uptake and transformation of benzene and toluene by plant leaves. Ecotox. Environ. Safety 37:24 - 29. 167 Kammerbauer H, H Selinger, R Rommelt, A Ziegler - Jons, D Knoppik, B Hock. (1987). Toxic components of mo tor vehicle emissions for the spruce Picea abies. Environ. Pollut. 48:235 - 243.