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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**  6.1.1 Particulate Matter

6.1.1.1 Background Particulate matter (PM) is a highl y complex mixture of solid particles and liquid drop lets distributed among numerous atmospheric gases which interact with solid and liquid phases. 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 um in diameter and a grain of salt is about 100 μm). Atmospheric particles 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’ parti cles (< 1 to 3 μm), and coarse particles (>1 to 3 μm). For regulatory

purposes, fine particles 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 and referring to total particle mass under 2.5 and between 2.5 and 10 micrometers, respectivel y. The EPA currently

has standards that measure PM 2.5 and PM 10 . A Particles span man y sizes and shapes and consist of hundreds of different chemicals . Particles are emitte d 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 pollution also varies b y time of year and location and is affect ed b y several weather - related factors, such as temperature, clouds, humidity , and wind. A further lay er of complexity

comes from particles ’ abilit y to shift between solid/liquid and gaseous phases, which is influenced b y concentration and meteorology , esp ecially temperature. Fine particles are produced primaril y b y combustion processes and b y transformations of gaseous emissions (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 carbon and metal compounds. These p articles can remain in the atmosphere for day s to weeks and travel through the atmosphere hundreds to thousands of kilometers. 1

A 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.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 2 6.1.1.2 Health Effects of PM This section provides a summary of the health effects associated with exposure to ambient concentrations of PM. B The information in this section is based on the information and conclusions in the Integrated Science Assessment (I SA) for Particulate Matter (December 2009) prepared b y EPA’s Office of Research and Development (ORD) . C The I SA concludes that ambi ent concentrations of PM are associated with a number of adverse health effects. D The I SA characterizes the weight of evidence for different health effects associated with three PM size ranges: PM 2.5 , PM 10 - 2.5 , and UFPs. The discussion below highlights the IS A’s conclusions pertaining to these three size fractions of PM, considering variations in health effects associated with both short - term and long - term exposure periods.

6.1.1.2.1 Effects Associated with Short- term Exposure to PM 2.5 The I SA concludes that cardi ovascular effects and premature mortality are causall y associated with short - term exposure to PM 2.5 . 2 It also concludes that respiratory effects are likely to be causall y associated with short - term exposure to PM 2.5 , including respiratory emergency

department (ED) visits and hospital admissions for chronic obstructive pulmonary disease (COPD), respiratory infections, and asthma; and exacerbation of respiratory s ymptoms in asthmatic children.

6.1.1.2.2 Effects Associated with Long- term Exposure to PM 2.5 The I SA concl udes that there are causal associations between long - term exposure to PM 2.5 and cardiovascular effects, such as the development/progression of cardiovascular disease (CVD), and premature mortality , particularl y from cardio vascular causes. 3 It also conclud es that long - term exposure to PM 2.5 is likely to be causally

associated with respiratory effects, such as reduced lung function growth, increased respiratory s ymptoms, and asthma development. The ISA characterizes the evidence as suggestive of a causal re lationship for associations between long - term PM 2.5 exposure and reproductive and developmental outcomes, such as low birth weight and infant mortality . It also characterizes the evidence as suggestive of a causal relationship between PM 2.5 and cancer inc idence, mutagenicity , and genotoxicity .

B Personal exposure includes contributions from many different types of particles, from many sources, and in many different environments. T otal personal exposure to PM includes both amb ient and nonambient components and collectively these com

ponents may contribute to adverse health effects. C The ISA is available at http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=216546 D The ISA evaluat es the health evidence associated with different health 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 causal relation ship, and not likely to be a causal relationship. For definitions of these levels of evidence, please refer to Section 1.5 of the ISA.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 3 6.1.1.2.3 Effects Associated with PM 10 - 2.5 The I SA summarizes evidence related to short - term exposure to PM 10 - 2.5 . PM 10 - 2.5 is the fraction of PM 10 particles that is larger than PM 2.5 . 4 The I SA concludes that available evide nce is suggestive of a causal relationship between short - term exposures to PM 10 - 2.5 and cardiovascular effects. It also concludes that the available evidence is suggestive of a causal relationship between short - term exposures to PM 10 - 2.5 and respiratory e ffects, including respiratory - related ED visits and hospitalizations. The I SA also concludes that the available literature suggests a causal relationship between short - term exposures to PM 10 - 2.5 and mortality . Data are inadequate to draw conclusions regarding health effects associated with long - term exposure to PM 10 - 2.5 . 5

6.1.1.2.4 Effects Associated with Ultrafine Particles The I SA concludes that the evidence is suggestive of a causal relationship between short term exposures to UFPs and cardiovascular effects, in cluding changes in heart rh ythm and vasomotor function (the ability of blood vessels to expand and contract). 6 The I SA also concludes that there is suggestive evidence of a causal relationship between short - term UFP exposure and respiratory effects. The ty

pes of respiratory

effects examined in epidemiologic studies include respiratory s ymptoms and asthma hospital admissions, the results of which are not entirel y consistent. There is evidence from toxicological and controlled human exposure studies that exposure to UFPs may increase lung inflammation and produce small asy mptomatic changes in lung function. Data are inadequate to draw conclusions regarding health effects associated with long - term exposure to UFPs. 7 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 pollution sources such as highway and nonroad moto r 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 relativel y stagnant, ozone and its precursor s 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 ozo ne production is quickly limited by removal of the NO X . Under these conditions NO X reductions are highl y effective in reducing***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 4 ozone while VOC reductions have little effect. Such conditions are called “NO X - limited.” Because the contribution of VOC emiss ions 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 also can be lowered by the reaction of nitric oxide (NO) with ozone, forming nitrogen dioxide (NO 2 ); as the air moves downwind and the cycle 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 whic h change with time and location. When NO X levels are relativel y high and VOC levels relatively low, NO X forms inorganic nitrates (i.e., particles) but relatively

little ozone. Such conditions are called “VOC - limited . ” Under these conditions, VOC reducti ons are effective in reducing ozone, but NO X reductions can actually 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 usuall y NO X - limited, due to the relatively 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 exhibit moderate sensitivity to changes in either pollutant.

6.1.2.2 Health Effects of Ozone Exposure to ambient ozone contributes to a wide range of adverse health effects. E These health effects are well documented and are critically assessed in the EPA ozone air quality criteria document (ozone AQCD) and EPA staff paper. 8 , 9 We are rel yi ng on the data and conclusions in the ozone AQCD and staff paper, regarding the health effects associated with ozone exposure. Ozone - related health effects include lung function decrements, respiratory sy mptoms, aggravation of asthma, increased hospital and emergency room visits, increased asthma medication usage, and a variet y of other respiratory effects. Cellular - level effects, such as inflammation of lungs, have been documented as well. In addition, there is suggestive evi dence of a contribution of ozone to cardiovascular - related morbidity and highly

suggestive evidence that short - term ozone exposure directl y or indirectly contributes to non - accidental and cardiopulmonary - related mortality , but additional research is needed to clarify the underl yi ng mechanisms causing these effects. In a recent report on the estimation of ozone - related premature mortality

published by

the National Research Council (NRC), a panel of experts and reviewers concluded that short - term exposure to ambient ozone is likely to contribute to premature deaths and that ozone - related mortalit y should be included in estimates of the health benefits of reducing ozone exposure. 10 People who appear to be more susceptible to effects associated with exposure to ozone include children, asthmatics and the elderly . Those with greater exposures to ozone, for instance due to time spent outdoors (e.g., children and outdoor workers), are also of concern.

E Human exposure to ozone varies over time due to changes in ambient ozone concentration and because people mo ve betw een 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.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 5 Based on a large number of scientific studies, EPA has identifie d several key health effects associated with exposure to levels of ozone found today in many areas of the country . Short - term (1 to 3 hours) and prolonged exposures (6 to 8 hours) to ambient ozone concentrations have been linked to lung function decrement s, respiratory symptoms, increased hospital admissions and emergency room visits for respiratory problems. 11 , 12 , 13 , 14 , 15 , 16 Repeated exposure to ozone can increase susceptibility to respiratory

infection and lung inflammation and can aggravate preexisting respiratory diseases, such as asthma. 17 , 18 , 19 , 20 , 21 Repeated exposure to sufficient concentrations of ozone can also cause inflammation of the lung, impairment of lung defense mechanisms, and possibly irreversible changes in lung structure, which over time could affect premature aging of the lungs and/or the development of chronic respiratory

illnesses, such as emphy sema and chronic bronchitis. 22 , 23 , 24 , 25 Children and outdoor workers tend to have higher ozone exposure because they t ypically are active outside , working, playing and exercising, during times of day and seasons (e.g., the summer) when ozone levels are highest. 26 For example, summer camp studies have reported statistically

significant reductions in lung function in children who are active outdoors. 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 Further, children are more at risk of experiencing health effects from ozone exposure than adults because their respiratory s ys tems are still developing. These individuals (as well as people with respiratory

illnesses, such as asthma, especiall y asthmatic children) can experience reduced lung function and increased respiratory sy mptoms, such as chest pain and cough, when exposed to relatively

low ozone levels during prolonged periods of moderate exertion. 35 , 36 , 37 , 38 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 from ore. Nitrogen dioxide (NO 2 ) i s 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 ammonia to form sulfates and nitrates, both of which are important components of ambient PM. The health effects of ambient PM are discussed in Section 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 overview of the health effects associ ated with SO 2 . Additional information on the health effects of SO 2 can be found in the EPA Integrated Science Assessment for Sulfur Oxides. 39 Following an extensive evaluation of health evidence from epidemiologic 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 lik ely

resulting from preexisting inflammation associated with this disease. In laboratory 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 i n asthmatics engaged***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 6 in moderate to heav y l evels of exercise , with more limited evidence 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 ppm, both in terms of increasing severity of respiratory sy mptoms and decrements in lung function, as well as the percentage of asthmatics adversel y affected. In epidemiolog ic 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 fo und an association between 24 - hour average ambient SO 2 concentrations and respiratory s ymptoms in children, particularly

those with asthma. Generally consistent associations also have been observed between ambient SO 2 concentrations and emergency departme nt 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 regress ion models. These anal ys es indicate that although copollutant adjustment has varying 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 gaseou s and particulate copollutants, suggesting that the observed effects of SO 2 on respiratory endpoints occur independent of the effects of other ambient air pollutants. Consistent associations between short - term exposure to SO 2 and mortality have been obser ved 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 respe ct to the interpretation of these associations due to potential confounding b y various copollutants. The U.S. EPA has therefore concluded that the overall evidence is suggestive of a causal relationship between short - term exposure to SO 2 and mortality. S ignificant 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 In formation on the health effects of NO 2 can be found in the EPA Integrated Science Assessment (I SA) for Nitrogen Oxides. 40 The EPA has concluded that the findings of epidemiologic, controlled human exposure, and animal toxicological studies provide evidence that is sufficient to infer a likely causal relationship between respiratory effects and short - term NO 2 exposure. The I SA con cludes that the strongest evidence for such a relationship comes from epidemiologic studies of respiratory effects including s ymptoms, emergency department visits, and hospital admissions. Based on both short - and long - term studies, the ISA concludes that associations of NO 2 with respiratory health effects are stronger among a number of groups; these include individuals with preexisting pulmonary conditions (e.g., asthma or COPD), children and older adults. The ISA also draws two broad conclusions regardi ng airway responsiveness following NO 2 exposure. First, the ISA concludes that NO 2 exposure may enhance the***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 7 sensitivity

to allergen - induced decrements in lung function and increase the allergen - induced airway inflammatory

response following 30 - minute expo sures of asthmatics to NO 2 concentrations as low as 0.26 ppm . Second, exposure to NO 2 has been found to enhance the inherent responsiveness of the airway to subsequent nonspecific challenges in controlled human exposure s tudies of asthmatic subjects. S ma ll but significant increases in non - specific airway hy perresponsiveness were reported following 1 - hour exposures of asthmatics to 0.1 ppm NO 2 . Enhanced airway

responsiveness could have important clinical implications for asthmatics since transient increas es in airway responsiveness following NO 2 exposure have the potential to increase sy

mptoms and worsen asthma control. Together, the epidemiologic and experimental data sets form a plausible, consistent, and coherent description of a relationship between N O 2 exposures and an array

of adverse health effects that range from the onset of respiratory sy mptoms to hospital admission. Although the weight of evidence supporting a causal relationship is somewhat less certain than that associated with respiratory m orbidit y, NO 2 has also been linked to other health endpoints. These include all - cause (nonaccidental) mortality , hospital admissions or emergency department visits for cardiovascular disease, and decrements in lung function growth associated with chronic exposure. 6.1.4 Health Effects of Carbon Monoxide In formation on the health effects of carbon monoxide (C O ) can be found in the EPA Integrated Science Assessment (I SA) for Carbon Monoxide . 41 The ISA concludes that ambient concentrations of CO are associated with a number of adverse health effects. F This section provides a summary

of the health effects associated with exposure to ambient concentrations of CO . G Human clinical studies of subjects with coronary artery disease show a decrease in the time to onset o f 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 , particularly increased emergency

room visits and hospital admissions for coronary heart disease (including ischemic heart disease, m yocardial infarction, and angina). Some epidemiologic evidence is also available for increased hospital admissions and emergency room visits for congestive heart failure an d cardiovascular disease as a whole. The IS A concludes that a causal relationship is likely to exist between short - term exposures to CO and cardiovascular morbidity . It also concludes that available data are inadequate to conclude that a causal relations hip exists between long - term exposures to CO and cardiovascular morbidit y.

F The ISA evaluates the health evi dence associated with different health effects, assigning one of five “weight of evidence” determination s : causal relationship, likely to be a causal relationship, suggestive of a causal relationship, inadequate to infer a causal relationship, and not lik ely to be a causal relationship. For definitions of these levels of evidence, please refer to Section 1.6 of the ISA. G Personal exposure includes contributions from many sources, and in many different environments. Total personal exposure to CO inclu des both ambient and nonambient components; and both components may contribute to adverse health effects.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 8 Animal studies show various neurological effects with in - utero CO exposure. Controlled human exposure studies report inconsistent neural and behavioral effects following low - leve l CO exposures. The I SA concludes the evidence is suggestive of a causal relationship with both short - and long - term exposure to CO and central nervous s ys tem effects. A number of epidemiologic and animal toxicological studies cited in the ISA have evaluated associations between CO exposure and 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 bir th weight. Animal toxicological studies have found associations between perinatal CO exposure and decrements in birth weight, as well as other developmental outcomes. The ISA concludes these studies are suggestive of a causal relationship between long - te rm exposures to CO and developmental effects and birth outcomes. Epidemiologic studies provide evidence of effects on respiratory morbidit y such as changes in pulmonary

function, respiratory

s ymptoms, and hospital admissions associated with ambient CO conc entrations. 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 evidence makes it difficult to disentangle effec ts 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 evid ence of altered pulmonary vascular remodeling and oxidative injury . The IS A concludes that the evidence is suggestive of a causal relationship between short - term CO exposure and respiratory morbidit y, and inadequate to conclude that a causal relationship exists between long - term exposure and respiratory morbidity . Finally , the I SA concludes that the epidemiologic evidence is suggestive of a causal relationship between short - term exposures to 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 I SA also concludes that there is not likely to be a causal 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 associated with additional health effects, including genetic changes in both humans and animals and increased proliferation of bone marrow cells in mice. 42 , 43 , 44 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 b etween benzene exposure and chronic non - ly mphocy tic leukemia and chronic***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 9 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. H , 45 The International Agency fo r 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. 46 , 47 A number of adverse noncancer health effects includin g blood disorders, such as preleukemia and aplastic anemia, have also been associated with long - term exposure to benzene. 48 , 49 The most sensitive noncancer effect observed in humans, based on current data, is the depression of the absolute ly mphocy te count in blood. 50 , 51 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 conditions. 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. 52 , 53 , 54 , 55 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. 56 , I

6.1.5.2 1,3 - Butadiene EPA has characterized 1,3 - butadiene as carcino genic to humans by inhalation. 57 , 58 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. 59 , 60 , 61 There are numerous studies consistently

demonstrating that 1,3 - butadien e 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 strongly suggests that the carcinogenic effects are mediated b y g enotoxic 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 which to draw conclusions about sensitive subpopulations. The URE for 1,3 - butadiene is 3 × 10 - 5 per μg/m 3

. 62 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 sensitive effect was ovarian atrophy observed in a lifetime bioassay of female mice. 63 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 planning to develop an assessment of the health effects of exp osure 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

H 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. I A m inim al 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.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 10 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 relationships 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. 75 An Inhalation Unit Risk for cancer and a Reference Dose for oral noncancer effects were developed by the Agency

and posted on the Int egrated 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. 76 , 77 , 78 The conclusions b y IAR C and N TP 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 reported an increased risk of nasophary

ngeal cancer and specific ly mphohematopoietic malignancies among workers exposed to formaldeh yde. 79 , 80 , 81 A National Institute of Occupational Safety and Health study

of garment workers also reported increased risk of death due to leukemia among workers exposed to formaldeh yde. 82 Ex tended 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. 83 Finall y, a study of embalmer s reported formaldeh yd e exposures to be associated with an increased risk of my eloid leukemia but not brain cancer. 84 Health effects of formaldehyde in addition to cancer were reviewed b y the Agency for Toxics Substances and Disease Registry in 1999 85 and supplemented in 2010 , 86 and by the World Health Organization. 87 These organizations reviewed the literature concerning effects on the ey es and respiratory

s ys tem, the primary

point of contact for inhaled formaldehyde, including sensory irritation of ey es an d 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. 88 The draft assessment reviewed more recent research from animal and human studies on cancer and other health effects. The NRC released their review report in April 2011 89 (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 Acetaldeh yd e is classified in EPA’s IRI S database as a proba ble human carcinogen, based on nasal tumors in rats, and is considered toxic by the inhalation, oral, and intravenous routes. 90 The URE in IRIS for acetaldeh yd e is 2.2 × 10 - 6 per μg/m 3

. 91 Acetaldehyde is reasonabl y anticipated to be a human carcinogen by the U.S. DHHS in the 12 th Report on***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 11 Carcinogens and is classified as possibly carcinogenic to humans (Group 2B) b y the IARC. 92 , 93 EPA is currentl y conducting a reassessment of cancer risk from inhalation exposure to acetaldeh yde. The primary

noncancer effect s of exposure to acetaldehyde vapors include irritation of the ey es, skin, and respiratory tract. 94 Inshort - term (4 week) rat studies, degeneration of olfactory epithelium was observed at various concentration levels of acetaldehyde exposure. 95 , 96 Data fro m these studies were used by 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. 97 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 concl uded 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 c arcinogenicity . 98 The IARC determined in 1995 that acrolein was not classifiable as to its carcinogenicity

in humans. 99 Lesions to the lungs and upper respiratory tract of rats, rabbits, and hamsters have been observed after subchronic exposure to acrolei n. 100 The Agency has developed an RfC for acrolein of 0.02 μg/m 3 and an RfD of 0.5 μ g/kg - day . 101 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 suffe r intolerable ey e and nasal mucosal sensory reactions within minutes of exposure. 102 These data and additional studies regarding acute effects of human exposure to acrolein are summarized in EPA’s 2003 IR IS Human Health Assessment for acrolein. 103 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 and 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 104 ) and demonstration of similar effects in humans (e.g., reduction in respiratory r ate), 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 acrolein. 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 Califo rnia 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. 105***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 12 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, clastogen (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 atmospheres. 106 Effects of ground - level smog causing intense ey e irri tation have been attributed to photochemical oxidants, including PAN. 107 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 lun g morphology , behavioral modifications, weight loss, and susceptibility

to pulmonary

infections. Human exposure studies indicate minor pulmonary function effects at high PAN concentrations, but large inter - individual variability precludes definitive concl usions. 108

6.1.5.8 Polycyclic Organic Matter The term pol yc yclic organic matter (POM) defines a broad class of compounds that includes the polycyclic aromatic hydrocarbon compounds (PAHs). One of these compounds, 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 exhaus t, coke oven emissions, roofing tar emissions, and cigarette smoke; all of these mixtures contain POM compounds. 109 110 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. 111 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. 112 Sin ce 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 pre school children (3 y ears of age). 113 , 114 These and similar studies are being evaluated as a part of the ongoing IR IS 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 d iesel 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 hum ans 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. 115 Chronic (long term) exposure of workers and rodents to naphthalene has been reported to cause cataracts and retinal damage. 116 EPA released an external review draft of a reassessment of the inhalation carcinogenicity of naphthalene based on a number of recent***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 13 animal carcinogenicit y studies. 117 The draft reassessment completed external peer review. 118 Based on exte rnal 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 not represent official agency opinion and was released sole ly 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 bioassay s reporting clear evidence of carcinogenicity in rats and some evidence of carcinogenicity

in mice. 119 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. 120 Naphthalene also causes a numbe r of chronic non - cancer effects in animals, including abnormal cell changes and growth in respiratory and nasal tissues. 121 The current EPA IRI S assessment includes noncancer data on h yperplasia and metaplasia in nasal tissue that form the basis of the inha lation RfC of 3 μg/m 3

. 122 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 hydrocarbon and PM emissions from vehicles w ill be affected by this proposa l . 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. J 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 frequentl y have emplo ye d 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 summari zed. 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 Health Effects Institute (HEI) Panel on the Health Effects of Traffic - Related Air Pollution, published in 2010 as a review of relevant studies. K , 123 Other sy stematic reviews of relevant literature are cited were appropriate.

J U.S. EPA Integrated Risk Information System (IRIS) database is available at: www.epa.gov/iris K It should be noted that there are no peer reviewed 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 w eight” on controlled human exposure studies. How ever, it restricted consideration of other toxicological studies to whether or not the studies provided “general mechanistic support” for the inferences of causality made on the basis of epidemiology.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 14 6.1.6.1 Populations near major roads Numerous studies have estimated the size and demographics of popu lations 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 the 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 factor in the AHS. The AHS reports are published every two y ears. As such, trends in the AHS can be reported to describe whether a greater or lesser proportion of homes are located near major roads over time. Figure 6 - 1 depicts trends in the number and proportion of homes located near majo r transportation sources, which generally indicate large roadway s. As the figure indicates, 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 clos e proximity to these sources , which may be affected by

near - road air quality

and health concerns, appears to have increased over time .***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 15 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, ac cording to data from the 2008 American Time Use Survey (ATUS), conducted b y the Bureau of Labor Statistics (BTS), Americans spend more than an hour traveling each day , on average. 124 Although the ATUS does not indicate their mode of travel, the majority of trips undertaken nationally is by motor vehicle. 125 As such, daily travel activit y bring s 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 - assoc iated 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 expose d to traffic - associated air pollution . In addition, based on several short - term studies of exposure, the panel concluded that there was evidence that there was “suggestive but not sufficient” evidence to infer a causal relation between traffic related exp osure and cardiovascular mortalit y.

6.1.6.3 Cardiovascular effects 6.1.6.3.1 Cardiac physiology Exposure to traffic - associated pollutants has been associated with changes in cardiac phy siology , including cardiac function. One common measure of cardiac function is heart r ate***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 16 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. L Reduced HRV is associated with adverse cardiovascular events, such as myocardial infarction, in heart disease patients. The HEI panel concluded that available evidence provides evidence 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 evid ence 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. 126 , 127

6.1.6.3.2 Heart attack and atherosclerosis The HEI panel concluded that epidemiologic evidence of the association between traffic related pollutants and heart attacks and atherosclerosis was “suggestive but not sufficient” to infer a causal association. Inaddition, 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 func tion.” The panel noted there are few studies of human volunteers exposed to real - world traffic mixture, which were not entirel y consistent. The panel notes that the studies provide consistent evidence for exposure to PM and impaired cardiovascular respon ses. In addition to the HEI stud y, several other reviews of available evidence conclude that there is evidence supporting a causal association between traffic - related air pollution and cardiovascular disease. 128 A number of mechanisms for cardiovascular dis ease are highlighted in the HEI and AHA report, including modified blood vessel endothelial function (e.g, the ability to dilate), atherosclerosis, and oxidative stress. The HEI review cites “two well executed studies” in which hospitalization for acute myocardial 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.

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 epidemiologic 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 freque ntly

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

L The autonomic nervous system (ANS) consists of sympathetic and parasympathetic components. The sympathetic ANS signals 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.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 17 is sufficient evidence for a causal association between exposure to traffic - related air pollution and exacerbation of asthma sy mptoms in children. While there is general consistency in studies examining asthma incidence in children, the availa ble studies employ

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 on set asthma, are less consistent than for asthma sy mptoms. The HE I 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 ( HE I Panel on the Health Effects of Traffic - Related Air Pollution, 2010). A recent meta - 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 eviden ce that exposures is consistent with a effect of exposure on asthma incidence (Anderson 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 mode ls). 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 incident asthma.

6.1.6.4.2 Chronic obstructive pulmonary di sease (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 is insufficient evidence for traffic - associated a ir 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 commo n allergens. 129 , 130 , 131 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 eviden ce, 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 mech anistic 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 dise ase (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 achievable during exhalation. The forced expiratory volume in the first second of***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 18 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 obstruction in asthma and COPD. Measurements of air fl ow at various times during forced exhalation, such a s 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 populations in areas with high traffic - related air po llutant 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 traffic 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 have reported associations between traffic - relate d 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 an d 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 metrics. 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 pollution and congenital abnormalities has been p ublished, 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 studies 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 overlap 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 published. 133 In that review, onl y one stud y dir ectly 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 studies examining various t ypes of childhood cance r 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 pollution and childhood cancer. An earlier review art icle on the topic noted that studies reporting positive***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 19 effects tended to be small, while those with null effects tended to be larger, suggesting the potential for publication bias in the available literature. 134

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 canc er. 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 o f 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 Pollutants**  6.2.1 Visibility

Degradation Visibility can be defined as the degree to which the atmosphere is transparent to visible light. 135 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 recreational opportunities. Visibility is also highly

va lued in significant natural areas, such as 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. 136 EPA is pursuing a two - part strategy to a ddress visibility

impairment. First, EPA developed the regional haze program (64 FR 35714) which was put in place in July 1999 to protect the visibility

in Mandatory

Class I Federal areas. There are 156 national parks, forests and wilderness areas catego rized 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. Second, EPA has concluded 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 vis ibility impact effectiveness such as dry

chemical composition 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 expec ted to be met through attainment of the existing secondary

standards for PM 2.5 . Figure 6 - 2 shows the location of the 156 Mandatory Class IFederal areas.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 20 **Figure 6**  **- 2**  **Mandatory Cla ss I Federal Areas in the U.S.**  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 and 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 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 , 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 by its empirically - derived scattering and/or absorption eff iciency , 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. Inaddition to this indirect method of assessing light ext inction, there are o ptical measurements which directly 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 absorption, or at a few sites using a transmissometer, which measures total light extinction . Scene characteristics are ty picall y recorded usi ng digital or video photography 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. Directly measured light***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 21 extinction is used under the IMPROVE protocol to cross check that the aerosol - derived light extinction levels 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 aver age 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 impairment 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. 137 6.2.2 Particulate Matter Deposition P articulate 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 pred ominant 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 Integrated Science Assessment for Oxides of Nitrogen and Sulfur - Ecological Criteria . 138 , 139 , 140

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, nutrients needed for growth and pro ductivity . Excesses of nitrogen or sulfur can lead to acidification, nutrient enrichment, and eutrophication of aquatic ecos ys tems. 141 The process of acidification affects both freshwater aquatic and terrestrial ecosy stems. Acid deposition causes acidifi cation 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 and sediments, flows into lakes an d 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 cycling of nutrients within these ecos ys tems. Decreases 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 essential nutrients for plant growth and ph ysiology . Changes i n the relative proportions of these nutrients, especially 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 n itrate 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***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 22 trees to acid precipitation (rain, snow) include accelerated weatheri ng 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 processes

— all which serve to weaken trees so that they are more sus ceptible 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 locations in the eastern U.S. 142 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 s hown to impact ecos ys tems in the western U.S. A study conducted in the Columbia River Gorge National Scenic Area (CRGNSA), located along a portion of the Oregon/Washington border, indicates that lichen communities in the CRGNSA have shifted to a higher proportion of nitrophilous species and the nitrogen content of lichen tissue is elevated. 143 Li chens are sensitive indicators of nitrogen deposition effects to terrestrial ecos ys tems and the lichen studies in the Columbia River Gorge clearl y show that ecologi cal 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 sources exceed the biological requirements of the ecos ys tem. The effects associated with nitrogen saturation include: (1) decreased productivity , increased mortalit y, and/or shifts in plant community

comp osition, often leading to decreased biodiversity in many natural habitats wherever atmospheric reactive nitrogen deposition increases significantly above background and critical thresholds 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 cycles through changes in the functioning and species composition of beneficial soil organisms. 144 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 Mountains of New York; the red spruce forests at Whitetop Mountain, Virgini a, 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 ecos ys tems (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; eutr ophication and algae blooms; altered fish distributions, catches, and phy siological states; loss of biodiversity ; habitat degradation; and increas es in the incidence of disease. Atmospheric deposition of nitrogen is a significant source of total nitrogen t o 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***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 23 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 indicated 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 levels of oxygen in the water column, fish and shellfish kills, outbreaks of to xic 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 impo rtant habitat for man y 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 disso lved ox ygen and toxic blooms. Declines in tourism occur when low dissolved oxygen causes noxious smells and floating mats of algal blooms create unfavorable aesthetic conditions. Risks to human health increase when the toxins from algal blooms accumulate in edible fish and shellfish, and when toxins become airborne, causing respiratory problems due to inhalation. According to a NOAA report, more than half of the nation’s estuaries have moderate to high expressions of at least one of these s ymptoms

– an i ndication that eutrophication is well developed in more than half of U.S. estuaries. 145

6.2.2.2 Deposition of Heav y M etals Heav y metals, including cadmium, copper, lead, chromium, mercury , nickel and zinc, have the greatest potential for impacting forest growth . 146 Investigation of trace metals near roadway s and industrial facilities indicate that a substantial load of heavy metals can accumulate on vegetative surfaces. Copper, zinc, and nickel have been documented to cause direct toxicity to vegetation under fie ld c onditions . L ittle research has been conducted on the effects associated with mixtures of contaminants found in ambient PM. While metals ty pically exhibit low solubility , limiting their bioavailability and direct toxicity , chemical transformations of meta l compounds occur in the environment, particularly 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 underg o 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 metal 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 northeaster

n 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 s ys tematic and significant in crease 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. 147 Contamination of plant leaves b y h eavy 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. 148 , 149 Upon enterin g the soil environment, PM pollutants can alter ecological processes of energy flow and***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 24 nutrient cycling, inhibit nutrient uptake, change ecosy stem structure, and affect ecos ys tem biodiversity . Man y of the most important effects occur in the soil. The so il environment is one of the most dy

namic sites of biological interaction in nature. It is inhabited by microbial communities of bacteria, fungi, and actinom ycet es. These organisms are essential participants in the nutrient cycles that make elements avail able for plant uptake. Changes in the soil environment that influence the role of the bacteria and fungi in nutrient cycling determine plant and ultimately

ecos ys tem response. 150 The environmental sources and cycling 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 l argel y partitions into the gas phase (in elemental form), and therefore has a longer residence time in the atmosphere than a metal found 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 from atmospheric deposition, accounting for approximately

eight y percent of the mercury in Lake Michigan. 151 , 152 Over fifty percent of the mercury in the C hesapeake Bay

has been attributed to atmospheric deposition. 153 Overall, the National Science and Technology Council identifies atmospheric deposition as the primary source of mercury

to aquatic sy stems. 154 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 without a mercury

point source. Elevated levels of zinc and lead have been identified in streambed sediments, and these elevated levels have been correl ated with population density and motor vehicle use. 155 , 156 Zinc and nickel have also been identified in urban water and soils. In addition, platinum, palladium, and rhodium, metals found in the catal ys ts of modern motor vehicles, have been measured at elevat ed levels along roadsides. 157 Plant uptake of platinum has been observed at these locations.

6.2.2.3 Deposition of Polycyclic Organic Matter Polycyclic 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. 158 Polycyclic 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 the 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. 159 Since PAHs are insoluble, the compounds generally are particle reactive and accumulate in sediments. Atmospheric deposition of particles is believ ed to be the major source of PAHs to the sediments of Lake Michigan. 160 , 161 Anal ys es of PAH deposition in Chesapeake and Galveston Bay

indicate that dry

deposition and gas exchange from the atmosphere to the surface water predominate. 162 , 163 Sediment concentrati ons of PAHs are high enough in some segments***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 25 of Tampa Bay

to pose an environmental health threat. EPA funded a study to better characterize the sources and loading rates for PAHs into Tampa Bay . 164 PAHs that enter a water bod y through gas exchange likely p artition 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. 165 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 increased health risk concerns. Trends in PAH deposition levels are difficult to discern because of highly variable ambient air concentrations, lack of cons istency in monitoring methods, and the significant influence of local sources on deposition levels. 166 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 incr eases in automobile use. 167 Cousins et al. estimate that more than ninet y percent of semi - volatile organic compound (SVOC) emissions in the United Kingdom deposit on soil. 168 An analy sis of PAH concentrations near a Czechoslovakian roadway indicated that co ncentrations were thirt y t imes greater than background. 169

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 depo sition of PM (especiall y sulfates and nitrates) can ph ys ically affect materials, adding to the effects of natural weathering processes, by potentiall y promoting or accelerating the corrosion of metals, by degrading paints, and by deteriorating building mat erials such as concrete and limestone. Only chemicall y active fine particles or h ygroscopic coarse particles 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 of 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 There are a number of environmental or public welfare effects associated with the presence of ozone in the ambient air. 170 Inthis section we discuss the impact of ozone on plants, including trees, agronomic crops and urban ornamentals. The Air Qualit y Criteria Document f or Ozone and related Photochemical Oxidants notes that, “ozone affects vegetation throughout the United States, impairing crops, native vegetation, and ecos ys tems more than any other air pollutant . ” 171 Li ke carbon dioxide (CO 2 ) and other gaseous substances, ozone enters plant tissues primarily through apertures (stomata) in leaves in a process called “uptake . ” 172 Once sufficient levels of ozone ( a highly reactive substance ) , or its reaction products , reaches the interior of plant cells, it can inhibit or dama ge essential cellular components and functions, including enzy me activities, lipids, and cellular membranes, disrupting the plant's osmotic (i.e., water) balance and energy utilization patterns. 173 , 174 If enough tissue becomes damaged from these effects, a pl ant’s capacit y to fix carbon to form***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 26 carboh ydrates, which are the primary form of energy used b y plants , is reduced, 175 while plant respiration increases. With fewer resources available, the plant reallocates existing resources away from root growth and sto rage, above ground growth or yi eld, and reproductive processes, toward leaf repair and maintenance, leading to reduced growth and/or reproduction. Studies have shown that plants stressed in these way s may exhibit a general loss of vigor, which can lead to secondary

impacts that modify

plants' responses to other environmental factors. Specifically , plants may

become more sensitive to other air pollutants, more susceptible to disease, insect attack, harsh weather (e.g., drought, frost) and other environment al stresses. Furthermore, there is evidence that ozone can interfere with the formation of mycorrhiza, essential sy mbiotic fungi associated with the roots of most terrestrial plants, by reducing the amount of carbon available for transfer from the host to the sy mbiont. 176 , 177 This ozone damage may

or may not be accompanied by

visible injury

on leaves, and likewise, visible foliar injury may or may not be a sy

mptom of the other t yp es of plant damage described above. When visible injury is present, it is common ly manifested as chlorotic or necrotic spots, and/or increased leaf senescence (accelerated leaf aging). Because ozone damage can consist of visible injury to leaves, it can also reduce the aesthetic value of ornamental vegetation and trees in urban lands capes, and negatively affects scenic vistas in protected natural areas. Ozone can produce both acute and chronic injury in sensitive species depending on the concentration level and the duration of the exposure. Ozone effects also tend to accumulate over the growing season of the plant, so that even lower concentrations experienced for a longer duration have the potential to create chronic stress on sensitive vegetation. Not all plants, however, are equall y sensitive to ozone. Much of the variation in sensitivity between individual plants or whole species is related to the plant’s ability to regulate the extent of gas exchange via leaf stomata (e.g., avoidance of ozone uptake through closure of stomata) 178 , 179 , 180 Other resistance mechanisms may involve the intercellular production of detoxifying substances. Several biochemical substances capable of detoxifying ozone have been reported to occur in plants, including the antioxidants ascorbate and glutathione. After injuries have occurred, plants may be capab le of repairing the damage to a limited extent. 181 Because of the differing sensitivities among plants to ozone, ozone pollution can also exert a selective pressure that leads to changes in plant community composition. Given the range of plant sensitivities and the fact that numerous other environmental factors modify plant uptake and response to ozone, it is not possible to identify threshold values above which ozone is consistently

toxic for all plants. The next few paragraphs present additional informati on on ozone damage to trees, ecosy stems, agronomic crops and urban ornamentals. Assessing the impact of ground - level ozone on forests in the United States involves understanding the risks to sensitive tree species from ambient ozone concentrations and acco unting for the prevalence of those species within the forest. As a way to quantify

the risks to particular plants from ground - level ozone, scientists have developed ozone - exposure/tree response functions by

exposing tree seedlings to different ozone level s and measuring reductions in growth as “biomass loss.” Ty pically , seedlings are used because they are eas y to manipulate and measure their growth loss from ozone pollution. The mechanisms of susceptibility to ozone***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 27 within the leaves of seedlings and mat ure trees are identical, though the magnitude of the effect may be higher or lower depending on the tree species. 182 Some of the common tree species in the United States that are sensitive to ozone are black cherry

( Prunus serotina ), tulip - poplar ( Liriodend ron tulipifera) , and eastern white pine ( Pinus strobus) . Ozone - exposure/tree - response functions have been developed for each of these tree species, as well as for aspen ( Populus tremuliodes ), and ponderosa pine ( Pinus ponderosa ). Other common tree specie s, such as oak ( Quercus spp .) and hickory ( Carya spp.), are not nearl y as sensitive to ozone. Consequently , with knowledge of the distribution of sensitive species and the level of ozone at particular locations, it is possible to estimate a “biomass loss” for each species across their ran ge. Ozone also has been conclusively shown to cause discernible injury to forest trees. 183 , 184 In terms of forest productivity and ecosy stem diversity , ozone may be the pollutant with the greatest potential for regional - sca le forest impacts. Studies have demonstrated repeatedl y that ozone concentrations commonly observed in polluted areas can have substantial impacts on plant function. 185 , 186 Because plants are at the base of the food web in many ecos ys tems, changes to the plant community

can affect associated organisms and ecosy stems (including the suitability of habitats that support threatened or endangered species and below ground organisms living in the root zone). Ozone impacts at the community and ecosy stem level vary wi del y depending upon numerous factors, including concentration and temporal variation of tropospheric ozone, species composition, soil properties and climatic factors. 187 In most instances, responses to chronic or recurrent exposure in forested ecos ys tems ar e subtle and not observable for many y ears. These injuries can cause stand - level forest decline in sensitive ecosy stems. 188 , 189 , 190 Itis not y et possible to predict ecos ystem responses to ozone with much certaint y; however, considerable knowledge of potential ecosy stem responses has been acquired through long - term observations in highly damaged forests in the United States. Air pollution can have noteworthy cumulative impacts on forested ecos ys tems by affecting regeneration, productivity , and species compositi on. 191 Inthe U.S., ozone in the lower atmosphere is one of the pol lutants of primary concern. Ozone injury

to forest plants can be diagnosed b y examination of plant leaves. Foliar injury is usually the first visible sign of injury to plants from ozone e xposure and indicates impaired ph ys iological processes in the leaves. 192 However, not all impaired plants will exhibit visible sy mptoms. Laboratory

and field experiments have also shown reductions in yields for agronomic crops exposed to ozone, including veg etables (e.g., lettuce) and field crops (e.g., cotton and wheat). The most extensive field experiments, conducted under the National Crop L oss Assessment Network (NCLAN) examined 15 species and numerous cultivars. The NCLAN results show that “several eco nomicall y important crop species are sensitive to ozone levels ty pical of those found in the United States.” 193 Inaddition, economic studies have shown reduced economic benefits as a result of predicted reductions in crop yi elds associated with observed oz one levels. 194 , 195 , 196***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 28 Urban ornamentals represent an additional vegetation category likel y to experience some degree of negative effects associated with exposure to ambient ozone levels. It is estimated that more than $20 billion (1990 dollars) are spent annua lly on landscaping using ornamentals, both by private property

owners/tenants and by

governmental units responsible for public areas. 197 This is therefore a potentially costl y environmental effect. However, in the absence of adequate exposure - response func tions and economic damage functions for the potential range of effects relevant to these t yp es of vegetation, no direct quantitative analy sis has been conducted.

6.2.3.1 Recent Ozone Visible Foliar Injury Data for the U.S In the U.S. the national - level visible fol iar injury indicator is based on data from the U.S. Department of Agriculture (USDA) Forest Service Forest Inventory and Analy sis (FIA) program. As part of its Phase 3 program, formerly known as Forest Health Monitoring, FIA examines ozone injury

to ozone - sensitive plant species at ground moni toring sites in forest land across the country . For this indicator, forest land does not include woodlots and urban trees. Sites are selected using a sy stematic sampling grid, based on a global sampling design. 198 , 199 At each site that has at least 30 individual plants of at least three ozone - sensitive species and enough open space to ensure that sensitive plants are not protected from ozone exposure by the forest canop y, F IA looks for damage on the foliage of ozone - se nsitive forest plant species. Because ozone injury

is cumulative over the course of the growing season, examinations are conducted in July and August, when ozone injury is ty pically highest. Monitoring of ozone injury to plants by the USDA Forest Service h as expanded over time from monitoring sites in 10 states in 1994 to nearl y 1,000 monitoring sites in 41 states in 2002. There is considerable regional variation in ozone - related visible foliar injury to sensitive plants in the U.S. The U.S. EPA has dev eloped an environmental indicator based on data from the USDA FIA program which examines ozone injury to ozone - sensitive plant species at ground monitoring sites in forest land across the country . The data underl yi ng the indic ator in Figure 6 - 3 are based on averages of all observations collected in 2002, the latest year for which data are publicly available at the time the study was conducted, and is broken down by U.S. EPA Region. Ozone damage to forest plants is classified usin g a subjective five - category biosite index based on expert opinion, but designed to be equivalent from site to site. Ranges of biosite values translate to no injury , low or moderate foliar injury (visible foliar injury to highl y sensi tive or moderatel y s ensitive plants, respectivel y) , and high or severe foliar injury , which would be expected to result in tree - level or ecos ys tem - level responses, respectivel y. 200 , 201 The highest percentages of observed high and severe foliar injury , those which are most likely to be associated with tree or ecos ys tem - level responses, are primaril y found in the Mid Atlantic and Southeast regions. In EPA Region 3 (which comprises the States of Pennsy lvania, West Virginia, Virginia, Delaware, Maryland and Washington D.C.), 12 perc ent of ozone sensitive plants showed signs of high or severe foliar damage, and in Region 2 (States of New York, New Jersey), and Region 4 (States of North Carolina, South Carolina, Kentucky , Tennessee, Georgia, Florida, Alabama, and Mississippi) the value s were 10 and 7 percent , respectivel y. The sum of high and severe ozone injury ranged from 2 to 4 percent in EPA Region 1 (the six New England States), Region 7 (States of Missouri, I owa, Nebraska and Kansas), and Region 9 (States of California, Nevada, H awaii and Arizona). The percentage of sites showing some ozone damage was about 45 percent in each of these EPA Regions.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 29 **Figure 6**  **- 3**  **Ozone Injury to Fo**  **rest Plants in U.S. by EPA Regions, 2002**  **ab** 6.2.3.2 Indicator L imitations The categories for the biosite index are subjective and may not necessaril y be directl y related to biomass loss or phy siological damage to plants in a particular area. Ozone may have other adverse impacts on plants (e.g., reduced productivity) that do not show signs of visible foliar injury . 202 The presence of diagnostic visible ozone injury on indicator plants does provide evidence that ozone is having an impact in an area. However, absence of ozone injury in an area does not necessarily

mean that there is no impact from ozone exposure. Field and laboratory

studies were reviewed to identify the forest plant species in each region that are sen sitive to ozone air pollution and exhibit diagnostic injury . Other forest plant species, or even geneti c variants of the same species, may not show s ymptoms at ozone levels that cause effects on the selected ozone - sensitive species. Because species distributions vary regionall y, different ozone - sensitive plant species were examined in different parts of th e country . These target species could vary with respect to ozone sensitivity , which might account for some of the apparent differences in ozone injury among regions of the U.S. Ozone damage to foliage may be reduced under conditions of low soil moisture, but most of the vari ability in the index (70 percent ) was explained by ozone concentration. 203***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 30 Though FIA has extensive spatial coverage based on a robust sample design, not all forested areas in the U.S. are monitored for ozone injury . Even though the biosite data have been collected over multiple years, most biosites were not monitored over the entire period, so these data cannot provide more than a baseline for future trends. 6.2.4 Environmental Effects of Air Toxics Emissions from producing, transporting a nd 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. 204 In laboratory experiments, a wide range of tolerance to VOCs has been observed. 205 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 production, leaf water content and photosy nthetic efficiency

were reported for some plant species. 206 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 oxides. 207 , 208 , 209 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.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 31 **References** 1 U.S. EPA (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmenta l Protection Agency, Washington, DC, EPA/600/R - 08/139F, 2009. 2 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 2.3.1.1. 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. Section 2.3.1.2. 4 U.S. EPA (2009). Integrated Science Assessment for Particulate Matter (Final Rep ort). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/139F, 2009. Section 2.3.4. 5 U.S. EPA (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/1 39F, 2009. Table 2 - 6. 6 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 2.3.5.1. 7 U.S. EPA (2009). Integrated Science Assessment f or Particulate Matter (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/139F, 2009. Table 2 - 6. 8 U.S. EPA. (2006

). Air Quality Criteria for Ozone and Related Photochemical Oxidants (Final). EPA/600/R 05/004aF - cF. Washington , DC: U.S. EPA. 9 U.S. EPA. (2007

). Review of the National Ambient Air Quality Standards for Ozone: Policy Assessment of Scientific and Technical Information, OAQPS Staff Paper . EPA - 452/R - 07 - 003. Washington, DC, U.S. EPA. Docket EPA - HQ - OAR - 2011 - 0135 10 National Research Council (NRC), (2008). Estimating Mortality Risk Reduction and Economic Benefits from Controlling Ozone Air Pollution. The National Academies Press: Washington, D.C. 11 Bates, D.V., Baker - Anderson, M., Sizto, R. (1990). Asthma attack per iodicity: a study of hospital emergency visits in Vancouver. Environ. Res., 51 ,51 - 70. 12 Thurston, G.D., Ito, K., Kinney, P.L., Lippmann, M. (1992). A multi - year study of air pollution and respiratory hospital admissions in three New York State metropoli tan areas: results for 1988 and 1989 summers. J. Exposure Anal. Environ. Epidemiol, 2 ,429 - 450. 13 Thurston, G.D., Ito, K., Hayes, C.G., Bates, D.V., Lippmann, M. (1994). Respiratory hospital admissions and summertime haze air pollution in Toronto, Ontari o: consideration of the role of acid aerosols. Environ. Res., 65, 271 - 290. 14 Lipfert, F.W., Hammerstrom, T. (1992). Temporal patterns in air pollution and hospital admissions. Environ. Res., 59 ,374 - 399. 15 Burnett, R.T., Dales, R.E., Raizenne, M.E., Krews ki, D., Summers, P.W., Roberts, G.R., Raad - Young, M., Dann,T., Brook, J. (1994). Effects of low ambient levels of ozone and sulfates on the frequency of respiratory admissions to Ontario hospitals. Environ. Res., 65 , 172 - 194. 16 U.S. EPA. (2006

). Air Quali ty Criteria for Ozone and Related Photochemical Oxidants (Final). EPA/600/R 05/004aF - cF. Washington, DC: U.S. EPA. Docket EPA - HQ - OAR - 2011 - 0135 17 U.S. EPA. (2006). Air Quality Criteria for Ozone and Related Photochemical Oxidants (Final). EPA/600/R 05/004aF - cF. Washington, DC: U.S. EPA. 18 Devlin, R. B., McDonnell, W. F., Mann, R., Becker, S., House, D. E., Schreinemachers, D., Koren, H. S. (1991). Exposure of humans to ambient levels of ozone for 6.6 hours causes cellular and biochemical changes in the lung . Am. J. Respir. Cell Mol. Biol., 4, 72 - 81.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 32 19 Koren, H. S., Devlin, R. B., Becker, S., Perez, R., McDonnell , W. F. (1991). Tim e - dependent changes of markers associated with inflammation in the lungs of humans exposed to ambient levels of ozone. Toxicol. Pathol., 19 , 406 - 411. 20 Koren, H. S., Devlin, R. B., Graham, D. E., Mann, R., McGee, M. P., Horstman, D. H., Kozumbo, W. J., Becker, S., House, D. E., McDonnell, W. F., Bromberg, P. A. (1989). Ozone - induced inflammation in the lower airways of human subj ects. Am. Rev. Respir. Dis., 39, 407 - 415. 21 Schelegle, E.S., Siefkin, A.D., McDonald, R.J. (1991). Time course of ozone - induced neutrophilia in normal humans. Am. Rev. Respir. Dis., 143 ,1353 - 1358. 22 U.S. EPA. (1996). Air Quality Criteria for Ozone and Related Photochemical Oxidants . EPA600 - P - 93 - 004aF. Washington. D.C.: U.S. EPA. 23 Hodgkin, J.E., Abbey, D.E., Euler, G.L., Magie, A.R. (1984). COPD prevalence in nonsmokers in high and low photochemical air pollution areas. Chest, 86 , 830 - 838. 24 Euler, G.L., Abbey, D.E., Hodgkin, J.E., Magie, A.R. (1988). Chronic obstructive pulmonary disease symptom effects of long - term cumulative exposure to ambient levels of total oxidants and nitrogen dioxide in California Seventh - day

A dventist residents. Arch. En viron. Health, 43 , 279 - 285. 25 Abbey, D.E., Petersen, F., Mills, P.K., Beeson, W.L. (1993). Long - term ambient concentrations of total suspended particulates, ozone, and sulfur dioxide and respiratory symptoms in a nonsmoking population . Arch. Environ. He alth, 48 , 33 - 46. 26 U.S. EPA. (2006). Air Quality Criteria for Ozone and Related Photochemical Oxidants (Final). EPA/600/R 05/004aF - cF. Washington, DC: U.S. EPA. 27 U.S. EPA. (2006). Air Quality Criteria for Ozone and Related Photochemical Oxidants (Final) . EPA/600/R 05/004aF - cF. Washington, DC: U.S. EPA. 28 Avol, E.L., Trim, S. C., Little, D.E., Spier, C.E., Smith, M. N., Peng, R. - C., Linn, W.S., Hackney, J.D., Gross, K.B., D'Arcy, J.B., Gibbons, D., Higgins, I.T.T. (1990 June). Ozone exposure and lung fun ction in children attending a southern California summer camp . Paper no. 90 - 150.3. Paper presented at the 83rd annual meeting and exhibition of the Air & Waste Management Association, Pittsburgh, PA. 29 Higgins, I. T.T., D'Arcy, J. B., Gibbons, D. I., Avol , E. L., Gross, K.B. (1990). Effect of exposures to ambient ozone on ventilatory lung function in children. Am. Rev. Respir. Dis., 141 , 1136 - 1146. 30 Raizenne, M.E., Burnett, R.T., Stern, B., Franklin, C.A., Spengler, J.D. (1989). Acute lung function respo nses to am bient acid aerosol exposures in children. Environ. Health Perspect., 79, 179 - 185. 31 Raizenne, M.; Stern, B.; Burnett, R.; Spengler, J. (1987 June). Acute respiratory function and transported air pollutants: observational studies. Paper no. 87 - 32. 6. Paper presented at the 80th annual meeting of the Air Pollution Control Association, New York, NY. 32 Spektor, D. M., Lippmann, M. (1991). Health effects of ambient ozone on healthy children at a summer camp. In: Berglund, R. L.; Lawson, D. R.; McKee, D. J., eds. Tropospheric ozone and the environment: papers from an international conference ; March 1990; Los Angeles, CA. Pittsburgh, PA: Air & Waste Management Association; pp. 83 - 89. (A&WMA transaction series no. TR - 19). 33 Spektor, D. M., Thurston, G.D ., Mao, J., He, D., Hayes, C., Lippmann, M. (1991). Effects of single - and multiday ozone exposures on respiratory function in active normal children. Environ. Res, 55, 107 - 122. 34 Spektor, D. M., Lippman, M., Lioy, P. J., Thurston, G. D., Citak, K., James , D. J., Bock, N., Speizer, F. E., Hayes, C. (1988). Effects of ambient ozone on respiratory function in active, normal children. Am. Rev. Respir. Dis., 137 , 313 - 320. 35 U.S. EPA. (2006). Air Quality Criteria for Ozone and Related Photochemical Oxidants (F inal). EPA/600/R 05/004aF - cF. Washington, DC: U.S. EPA. 36 Hazucha, M. J., Folinsbee, L. J., Seal, E., Jr. (1992). Effects of steady - state and variable ozone concentration profiles on pulmonary function. Am. Rev. Respir. Dis., 146, 1487 - 1493.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 33 37 Horstman, D.H., Ball, B.A., Folinsbee, L.J., Brown, J., Gerrity, T. (1995). Comparison of pulmonary responses of asthmatic and nonasthmatic subjects performing light exercise while exposed to a low level of ozone. Toxicol. Ind. Health., 11(4), 369 - 85. 38 Horstman, D.H.,; Folinsbee, L.J., Ives, P.J., Abdul - Salaam, S., McDonnell, W.F. (1990). Ozone concentration and pulmonary response relationships for 6.6 - hour exposures with five hours of moderate exercise to 0.08, 0.10, and 0.12 ppm. Am. Rev. Respir. Dis., 142 , 1158 - 1163. 39 U.S. EPA (2008). Integrated Science Assessment (ISA) for Sulfur Oxides

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6 - 34 55 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. R eport No.113. 56 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.atsdr.cdc.gov/ToxProfiles/tp3.pdf . 57 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 . 58 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 . 59 International Agency for Rese arch 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, Fr ance. 60 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, Worl d Health Organization, Lyon, France. 61 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. 62 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 . 63 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. 75 EPA. Integrated Risk Information System. Formaldehyde (CASRN 50 - 00 - 0) http://www.epa.gov/iris/subst/0419/htm 76 National Toxicology Program, U.S. Department of Health and Human Services (HHS), 12th Report on Carcinogens, June 10, 2011 77 IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Volume 88 (2006): Formaldehyde, 2 - Butoxyethanol and 1 - tert - Butoxypropan - 2 - ol 78 IARC Mongraphs on the Evaluation of Carcinogenic Risks to Humans Volume 100F (2012): Formaldehyde 79 Hauptmann, M..; Lubin, J. H.; Stewart, P. A.; Hayes, R. B.; Blair, A. 2003. Mortality from lymph ohematopoetic malignancies among workers in formaldehyde industries. Journal of the National Cancer Institute 95: 1615 - 1623. 80 Hauptmann, M..; Lubin, J. H.; Stewart, P. A.; Hayes, R. B.; Blair, A. 2004. Mortality from solid cancers among workers in formaldehyde industries. American Journal of Epidemiology 159: 1117 - 1130. 81 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 form aldehyde industries: The National Cancer Institute cohort. J. National Cancer Inst. 101: 751 - 761. 82 Pinkerton, L. E. 2004. Mortality among a cohort of garment workers exposed to formaldehyde: an update. Occup. Environ. Med. 61: 193 - 200.. 83 Coggon, D, E C Harris, J Poole, KT Palmer. 2003. Extended follow - up of a cohort of British chemical workers exposed to formaldehyde. J National Cancer Inst. 95:1608 - 1615. 84 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.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 35 85 AT SDR. 1999. Toxicological Profile for Formaldehyde, U.S. Department of Health and Human Services (HHS), July 1999. 86 AT SDR. 2010. Addendum to theToxicological Profile for Formaldehyde. U.S. Department of Health and Human Services (HHS), October 2010. 87 IPCS. 2002. Concise International Chemica l Assessment Document 40. Formaldehyde. World Health Organization. 88 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 Inform ation System (IRIS). 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 89 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 90 U .S. EPA (1991). Integrated 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 . 91 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 . 92 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. 93 International Agency for Research on Cancer (IARC). (1999). R e - evaluation of some organic chemicals, hydrazine, and hydrogen peroxide. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemical to Humans, Vol 71. Lyon, France. 94 U.S. EPA (1991). Integrated Risk Information System File of Acetaldehyde. Thi s material is available electronically at http://www.epa.gov/iris/subst/0290.htm . 95 U.S. EPA. (2003). Integrated Risk Information System File of Acrolein. Research and Development, National Center for E nvironmental Assessment, Washington, DC. This material is available electronically at http://www.epa.gov/iris/subst/0364.htm . 96 Appleman, L.M., R.A. Woutersen, and V.J. Feron. (1982). Inhalation toxicity of acetaldehyde in rats. I. Acute and subacute studies. Toxicology. 23: 293 - 297. 97 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. 98 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 . 99 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 in dustrial chemicals, World Health Organization, Lyon, France. 100 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 avail able at http://www.epa.gov/iris/subst/0364.htm. 101 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.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 36 102 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. Av ailable online at: http://www.epa.gov/ncea/iris/toxreviews/0364tr.pdf . 103 U.S. EPA. (2003). Toxicological review of acrolein in support of summary information on Integrated Risk Information System (IRIS) National Center for Environmental Assessment, Washing ton, DC. EPA/635/R - 03/003. Available online at: http://www.epa.gov/ncea/iris/toxreviews/0364tr.pdf . 104 Morris JB, Symanowicz PT, Olsen JE, et al. (2003). Immediate sensory nerve - mediated respiratory responses to irritants in healthy and allergic airway - dise ased mice. J Appl Physiol 94(4):1563 - 1571. 105 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/ncea/cfm/recordisplay.cfm?deid=211003 106 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/. 107 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 108 U.S. EPA Air Quality Criteria for Ozone and Related Photochemical Oxidants (Final). U.S. Environmental Protection Agency, Wa shington, 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 109 Agency for Toxic Substances and Disease Registry (ATSD R). (1995). Toxicological 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. 110 U.S. E PA (2002). Health 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 . 111 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. 112 U.S. EPA (1997). Integrated Risk Information System 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. 113 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. 114 Perera, F.P.; Rauh, V.; Whyatt, R.M.; Tsai, W.Y.; Tang, D.; Diaz, D.; Hoepner, L.; Barr, D.; Tu, 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. 115 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, Washington, DC. This material is available electronically at http://www.epa.gov/iris/subst/0436.htm . 116 U. S. EPA. 1998. Toxicological Review of Naphthalene (Reassessment of the Inhalation Cancer Risk), Environmental Protecti on 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 . 117 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 Asses sment, Washington, DC. This material is available electronically at http://www.epa.gov/iris/subst/0436.htm .***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

6 - 37 118 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 . 119 NT P. (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. 120 International Agency for Research on Cancer (IARC). (2002). Monographs on the Evaluation of the Carcinogenic Risk of Chemicals for Humans. Vol. 82. Lyon, France. 121 U. S. EPA. (1998). Toxicological Review of Naphthalene, Environmental Protection Agency, Integrated Risk Information System, Research and Development, National Center for Environmental Assessment, Wa shington, DC. This material is available electronically at http://www.epa.gov/iris/subst/0436.htm 122 U.S. EPA. (1998). Toxicological Review of Naphthalene. Environmental Protection Agency, Integrated Risk Information System (IRIS), Research and Developme nt, National Center for Environmental Assessment, Washington, DC http://www.epa.gov/iris/subst/0436.htm . 123 Health Effects Institute Panel on the Health Effects of Traffic - Related Air Pollution. (2010). Traffic - related air pollution: a critical revie w of the literature on emissions, exposure, and health effects. HEI Special Report 17. [Online at http://www.healtheffects.org] 124 Bureau of Labor Statistics. (2009). American Time Use Survey. [Online at http://www.bls.gov/tus] 125 Bureau of Transportation Statistics. (2003). Highlights of the 2001 National Household Travel Survey. Report BTS03 - 05. [Online at http://www.bts.gov] 126 Baja, E.S.; Schw artz, J.D.; Wellenius, G.A.; Coull, B.A.; Zanobetti, A.; Vok onas, 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 127 Zanobett ia, 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.amjcard.2009.04.046 128 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 129 Bastain , T.M.; Gilliland, F.D.; Li, Y.; Saxon, A.; Diaz - Sanchez, D. (2003) Intraindividual reproducibility of nazal allergic responses to diesel exhaus t particles indicates a susceptible phenotype. Clinical Immunol 109: 130 - 136. 130 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, placebo - controlled crossover study. Lancet 363:119 - 125. 131 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 Res pir J 15: 716 - 724. 133 Vrijheid, 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 134 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] 135 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 bo ok can be viewed on the National Academy Press Website at http://www.nap.edu/books/0309048443/html/ 136 U.S. EPA (2009). Integrated Science Assessment for Particulate Matter (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R - 08/1 39F, 2009.***** E.O. 12866 Review –**  **Revised Version 3/25/13**  **– Do Not Cite, Quote, or Release During Review ** ***

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