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Suggested Citation:"9 Ozone." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

9 Ozone This chapter summarizes relevant epidemiologic and toxicologic studies of ozone. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from the National Research Council (NRC) and other agencies are also presented. The committee considered all that infor- mation in its evaluation of the Navy’s current and proposed 1-h, 24-h, and 90- day exposure guidance levels for ozone. The committee’s recommendations for ozone exposure guidance levels are provided at the conclusion of the chapter with a discussion of the adequacy of the data for defining them and the research needed to fill remaining data gaps. PHYSICAL AND CHEMICAL PROPERTIES Ozone is a highly reactive atmospheric gas whose molecule consists of three atoms of oxygen. At ambient temperatures, it is a pale blue gas that is a powerful oxidizer (Wojtowicz 1996). It is very reactive, and all phases (gas, liquid, and solid) are combustible and explosive. Some describe ozone as having a pungent odor that is detectable at 0.01 ppm (Wojtowicz 1996). Others describe it as having a “pleasant, characteristic” odor at concentrations below 0.2 ppm but as “irritating” at concentrations above 0.2 ppm (Budavari et al. 1989). Se- lected physical and chemical properties are summarized in Table 9-1. OCCURRENCE AND USE Ozone is widely used in water treatment because of its ability to disinfect; to eliminate taste, odor, and color; to lower turbidity; to remove iron and man- ganese; and to degrade a variety of organics, including detergents, pesticides, 184

Ozone 185 TABLE 9-1 Physical and Chemical Data on Ozone Synonyms Triatomic oxygen CAS registry number 7782-44-7 Molecular formula O3 Molecular weight 48.00 Boiling point −111.9˚C Melting point −193˚C Flash point NA Explosive limits NA Specific gravity 2.144 g/L at 0˚C Vapor pressure NA Solubility 49 mL/100 mL water at 0˚C; soluble in alkaline solvents and oils Conversion factors 1 ppm = 1.96 mg/m3; 1 mg/m3 = 0.51 ppm Abbreviations: NA, not available or not applicable. Sources: Solubility data from HSDB 2005; all other data from Budavari et al. 1989. and proteins (Wojtowicz 1996). It is used to treat drinking water, industrial process streams, and municipal wastewater effluents and to treat water in cool- ing towers, swimming pools, and spas. It is also used for pulp delignification and bleaching and in the production of specialty organic chemicals and intermediates. Ozone occurs naturally in the stratosphere at concentrations of 1-10 ppm and shields Earth from biologically damaging ultraviolet (UV) radiation (Wo- jtowicz 1996). In the stratosphere, short-wave UV radiation directly splits mo- lecular oxygen (O2) into atomic oxygen (O⋅) that rapidly combines with O2 to form ozone. In the troposphere, “ground-level” ozone is generated predomi- nantly by a series of complex reactions involving nitrogen oxides, oxygen, and sunlight. Nitrogen dioxide (NO2) absorbs longer-wavelength UV radiation, and this results in the generation of O⋅ and nitric oxide (NO). O⋅ then combines with O2 to form ground-level ozone. NO2 is regenerated by the reaction of NO with the newly formed ozone. In the absence of volatile organic compounds (VOCs), that reaction would approach a steady state with no buildup of ozone. However, atmospheric VOCs react with O⋅ to produce oxidized compounds and free radi- cals that react with NO to form more NO2. Consequently, the NO scavenging of ozone is upset, and this results in increased ozone concentrations. In urban areas—such as Los Angeles, California—with high motor- vehicle traffic that emits large amounts of VOC-containing exhaust and with intense midday sunlight, complex atmospheric reactions are common place and result in what is termed photochemical smog. Ozone, the principal oxidant pol- lutant in photochemical smog, is considered both an environmental and a public-

186 Exposure Guidance Levels for Selected Submarine Contaminants health concern and is classified by the U.S. Environmental Protection Agency (EPA) as a criteria pollutant. EPA has established an 8-h national ambient air quality standard (NAAQS) concentration of 0.08 ppm for ozone (EPA 1996). In 1999, an estimated 90 million residents of the United States lived in areas where ambient ozone concentrations exceeded the NAAQS. Average background con- centrations in the United States, in the absence of local anthropogenic emissions, are estimated to range from 0.02 to 0.04 ppm in the afternoon and are highest during spring (Fiore et al. 2003). Ozone concentrations in airliner cabins on some flights may exceed the Federal Airline Administration and EPA NAAQS. Increased concentrations of ozone are expected primarily on aircraft without ozone converters or with mal- functioning converters that fly at high altitudes (NRC 2002). According to fed- eral airline regulations, ozone in the cabin may not exceed 0.25 ppm at any time during a flight and may not exceed an average of 0.1 ppm during a 3-h flight above 27,000 feet. Mean ozone concentrations on aircraft have been reported to range from 0.022 ppm (Nagda et al. 1989) to 0.20 ppm (Waters 2001). Potential sources of ozone in a submarine include motors, vent-fog pre- cipitators, copying machines, and laser printers (Crawl 2003). No measurements of ozone concentrations onboard submarines have been reported in the literature. SUMMARY OF TOXICITY The toxicity of inhaled ozone has been extensively reviewed (EPA 1996). Numerous studies of controlled acute exposure have been conducted in human and laboratory animals. Study results have demonstrated that ozone is a potent irritant to the upper and lower airways that, when inhaled, results in impairments in pulmonary function and increased airway hyperresponsiveness with concur- rent airway tissue injury and inflammation. The following is a brief review of important toxicologic studies in the scientific literature that were relevant to the committee’s discussion and determination of appropriate guidance levels for ozone. Effects in Humans Accidental and Occupational Exposure In an occupational setting, pulmonary congestion was reported in welders who used an inert-gas shielded-arc process that generated ozone at concentra- tions as high as 9 ppm (Kleinfeld and Giel 1956). Similar effects have been re- ported in welders exposed to ozone concentrations below 2 ppm (Challen et al. 1958). The effects were not observed when exposure concentrations were near 0.2 ppm. An accidental human exposure for 2 h to a high concentration of ozone (1.5 ppm) caused a 20% reduction in timed vital capacity of the lung and other effects (Chambers et al. 1957).

Ozone 187 Experimental Studies The harmful effects of inhaled ozone have been studied extensively in healthy and high-risk human subjects and in laboratory animals (EPA 1996); however, only the studies that are most relevant to the safety of submarine crew members (healthy men) are discussed in this report. Several well-designed stud- ies have been conducted to investigate the pulmonary responses of healthy, non- smoking human subjects acutely exposed to near ambient concentrations of ozone in environmentally controlled inhalation chambers. Those acute ozone exposures have resulted in pulmonary-function alterations, such as a decrease in inspiratory capacity; mild bronchoconstriction; rapid, shallow breathing during exercise; and symptoms of cough or pain on inspiration. Ozone exposure has been shown to result in airway hyperresponsiveness (as demonstrated by in- creased physiologic response to a nonspecific bronchoconstrictor, such as meth- acholine) and airway injury and inflammation (as assessed with bronchoalveolar lavage [BAL] or bronchial biopsy). An ozone-induced decrease in inspiratory capacity results in a decrease in forced vital capacity (FVC) and total lung ca- pacity (TLC) and, in combination with mild bronchoconstriction, contributes to a decrease in the forced expiratory volume in 1 sec (FEV1). The response of healthy adults to inhalation of ozone occurs in three phases: a delay phase in which no response to ozone is detected, an onset phase during which breathing frequency begins to increase, and a response phase during which breathing fre- quency stabilizes at a new higher level (Schelegle et al. 2007). Table 9-2 pro- vides a summary of controlled ozone-exposure studies in humans that are dis- cussed further below. DeLucia and Adams (1977) exposed subjects to ozone at 0, 0.15, and 0.30 ppm for 1 h, while they were at rest and exercising continuously at three work- loads, from light to heavy, with minute ventilation (VE) of 28-66 L/min. Sig- nificant time-dependent increases in breathing frequency and decreases in FEV1 and forced midexpiratory flow (FEF25-75%) were observed in subjects after exposure at 0.30 ppm but only during heavy exercise. In another study, Folins- bee et al. (1978) exposed four groups of subjects (10 per group) to ozone at 0, 0.3, and 0.5 ppm for 2 h. One group was exposed at rest, and the other groups were exposed during intermittent exercise at levels requiring VE of 30, 50, or 70 L/min. They found that there were decrements in pulmonary function, such as FEV1, even in resting subjects at 0.5 ppm and at 0.3 ppm with exercise. Horvath et al. (1979) also examined changes in pulmonary function during resting expo- sure to ozone at 0, 0.25, 0.50, and 0.75 ppm. In this study, resting 2-h exposure at 0.75 and 0.50 ppm caused significant mean decrements in FVC of 10% and 5%, respectively. However, ozone at 0 and 0.25 ppm induced no pulmonary decrements. On the basis of the studies of Folinsbee et al. (1978) and Horvath et al. (1979), which investigated the effects of ozone exposure on sedentary, healthy, young adults, the lowest concentration of ozone causing significant

TABLE 9-2 Controlled Exposure of Healthy Human Subjects to Ozone and Observed Effects on Pulmonary Function 188 Concentration Exposure Duration (ppm) and Activity Subjects and Effects Reference 0.15, 0.30 1 h at rest and light to 6 men, 22-42 years old DeLucia and heavy workloads Mean FEV1 decrements of 14% and 6.1% at 0.30 ppm with moderate and Adams 1977 heavy exercise, respectively 0.5 2 h at rest 40 men, 18-28 years old Folinsbee et al. Decrease in mean FEV1 (7%) and FVC (6%) 1978 0.25, 0.50, 0.75 2 h at rest 8 men and 5 women, 21-22 years old Horvath et al. Mean FVC decrements of 5% and 10% at 0.50 and 0.75 ppm, respectively 1979 0.20, 0.30, 0.40 30-80 min with light 8 men, 22-46 years old Adams et al. to heavy exercise Decrease in FEF with heavy exercise with an effective dose of 0.2-0.3 1981 0.12, 0.18, 0.24, 2.5 h, IE 20-29 men per group, 18-30 years old McDonnell et 0.30, 0.40 Decrease in FVC, FEV1 and FEF at 0.12 ppm al. 1983 0.10, 0.15, 0.20, 2 h, IE 20 men, 21-29 years old Kulle et al. 1985 0.25 Decrease in FEV1 (>5%) and specific airway conductance (>15%) at 0.15 ppm 0.12, 0.18, 0.24 1 h, heavy workload 10 men, 19-29 years old Schelegle and (competitive exercise) Decrease in FVC and FEV1 at 0.18 ppm Adams 1986 0.12 6.6 h, IE 10 men, 18-33 years old Folinsbee et al. Mean FEV1 decrements of 13% after 6.6 h and FVC of 8.3%; cough and 1988 discomfort increased with exposure; airway responsiveness to methacholine doubled after ozone exposure 0.08, 0.10 6.6 h, IE 38 men, mean age 25 years McDonnell et Mean FEV1 decrements of 8.4% at 0.08 ppm and 11.4% at 0.10 ppm; cough al. 1991 and discomfort increased with exposure

0.08, 0.10, 0.12 6.6 h, IE 22 men, 18-33 years old Horstman et Decreased FVC and FEV1 throughout exposure; mean FEV1 decrements of al 1990 7.0%, 7.0%, and 12.3%, respectively 0.12 6.6 h/day, IE 17 men, mean age 25.4 years Folinsbee et 5 consecutive days Mean FEV1 decrements of 12.8%, 8.7%, 2.5%, 0.6%, and improvement of al. 1994 0.2% on days 1-5, respectively; methacholine airway responsiveness increased by 100% on all exposure days; symptoms increased on first ozone day but were absent on last 3 exposure days 0.30 1 h, CE 12 men, 18-34 years old McKittrick Mean decrements of FEV1 17.0-17.9% and Adams 1995 0.25 1 h, CE 32 men and 28 women, 22 ± 0.6 years old Ultman et al. Mean FEV1 decrements of 15.9% in men and 9.4% in women; FEV1 2004 decrements -0.4 to 56% 0.1, 0.4 1 h, IE 12 men and 3 women, healthy, nonsmoking adults Morrison et Neutrophils increased in BAL 6 h after exposure at 0.4 ppm. al. 2006 0.04, 0.06, 0.08 6.6 h, IE 15 men and 15 women, 22.8 ± 1.2 and 23.5 ± 3.0 years old, respectively Adams 2006 Exposures included square-wave and triangular concentration profiles; at 0.08 ppm average, responses were observed earlier with the triangular profile (when ozone concentration was 0.15 ppm) than with the square-wave profile; no significant effects at 0.04 or 0.06 ppm Abbreviations: BAL, bronchoalveolar lavage; CE, continuous exercise; FEF, forced expiratory flow; FEV1, forced expiratory volume at 1 sec; FVC, forced vital capacity; IE, intermittent exercise. 189

190 Exposure Guidance Levels for Selected Submarine Contaminants pulmonary function decrements has been determined to be 0.5 ppm for 2 h with average decrements of about 4% and 7% in FVC and FEV1, respectively (EPA 1986). Adams et al. (1981) exposed subjects to ozone at 0, 0.2, 0.3, or 0.4 ppm during continuous exercise at one of two workloads for 30-80 min. Eight trained male subjects (22-46 years old) completed 18 protocols, including exposure via mouthpiece to filtered air and to ozone at three concentrations, while exercising continuously for 30-80 min. The ozone effective dose was significantly related to pulmonary-function impairment and exercise ventilatory-pattern alteration. Multiple regression analysis, however, substantiated the predominant impor- tance of ozone concentration, with the threshold for ozone toxicity during exercise at a moderately heavy workload—about 65% maximal O2 uptake (VO2 max)—shown to be between 0.20 and 0.30 ppm. McKittrick and Adams (1995) conducted a study designed to determine further what effect exercise pattern has on ozone-induced pulmonary responses when the total inhaled dose of ozone at a given concentration is kept the same. They exposed 12 aerobically trained men to ozone at 0.3 ppm for 1 h during continuous exercise and 2 h during intermittent exercise with equivalent esti- mated total doses of ozone. The two exposure regimens led to similar pulmo- nary-function alterations, but symptoms were slightly less during the last rest period of the intermittent-exercise exposure than at the end of the continuous exposure. After brief exposure to ozone at concentrations over a few tenths of a part per million, exposed people have reported discomfort in the form of headache and dryness of the throat, nasal passages, and eyes. McDonnell et al. (1983) conducted a study designed to determine the lowest ozone concentration at which group mean decrements in pulmonary function occur in heavily exercis- ing healthy young men. Subjects (20-29 per group) were exposed at 0, 0.12, 0.18, 0.24, 0.30, or 0.40 ppm at a VE of 67 L/min for 2.5 h (15-min rest, 15-min exercise). Significant decrements in FVC, FEV1, and FEF25-75% and an in- crease in cough were observed at 0.12 ppm, and there were concentration- dependent responses in all variables measured at concentrations greater than 0.24 ppm. Similar studies have also demonstrated significant decrements in pulmonary function with ozone exposures as low as 0.12 ppm (Kulle et al. 1985; Seal et al. 1993). In a more recent study, Ultman et al. (2004) reported pulmonary responses in 60 healthy nonsmoking adults (32 men, 28 women) exposed to ozone at 0.24 ppm for 1 h with controlled exercise at a target VE of 30 L/min. They found considerable intersubject variability in FEV1, with responses ranging from a 4% improvement to a 56% decrement. One-third of the subjects had decrements of more than 40%. In a study directed at investigating possible mechanisms of pulmonary epithelial damage, Morrison et al. (2006) exposed six healthy nonsmoking adults to ozone at 0.1 ppm and seven similar subjects at 0.4 ppm with 99mtechnetium-

Ozone 191 labeled diethylene-triamine-penta-acetate (99mTc-DTPA) and performed BAL 1 or 6 h after exposure on different occasions. Five control subjects were exposed to filtered air. All study participants were exposed during intermittent exercise. Decreases in FEV1 were observed immediately and at 1 h after exposure at 0.4 ppm. Ozone exposure did not affect 99mTc-DTPA lung clearance, but neutrophils increased in BAL fluid 6 h after exposure at 0.4 ppm. Superoxide anion release from BAL leukocytes decreased after 1 h of exposure at 0.1 ppm and after 6 h of exposure at 0.4 ppm. At 0.4 ppm, products of lipid peroxidation in BAL fluid decreased at 1 and 6 h. There was no change in antioxidant capacity of the lung epithelium or glutathione concentrations as measured after BAL at either con- centration of ozone. Controlled environmental exposure-chamber studies of longer duration have been reported (Folinsbee et al. 1988; Horstman et al. 1990; McDonnell et al. 1991). Adult volunteers were exposed for 6.6 h to ozone at 0.08, 0.10, or 0.12 ppm in whole-body chambers. Moderate exercise was performed for 50 min each hour for 3 h in the morning and afternoon. Folisbee and co-workers found that pulmonary-function decrements became greater after each hour of exposure at 0.12 ppm, with FVC declining by 8.3% and FEV1 declining by 13% at the end of the sixth hour of exposure. Ozone exposure also caused increasing symptoms of cough and chest discomfort and increases in airway responsiveness to meth- acholine challenge. Similar studies were conducted to investigate the effects of ozone at 0.08 ppm on pulmonary function in exercising people (Horstman et al. 1990; McDonnell et al. 1991). Both studies found significant changes in spi- rometric measurements and significant increases in airway reactivity, specific airway resistance, and respiratory symptoms. At exposure concentrations of 0.08 ppm and 0.1 ppm, Horstman et al. (1990) found mean FEV1 decreases of 7% and 8%, respectively. Likewise, McDonnell et al. (1991) found FEV1 decreases at 0.08 and 0.1 ppm ozone of 8.4% and 11.4%, respectively. The FEV1 response data in that study were best fitted to a three-parameter logistic model, suggesting that the ozone pulmonary-function response relationship has a sigmoid shape. That suggests that the induced response has a plateau, which indicates that at the given ozone concentration, workload, and length of exposure, no further in- crease in response is predicted with increasing exposure duration. Folinsbee et al. (1994) extended their controlled-exposure studies by ex- posing healthy, nonsmoking men subjects to ozone at 0.12 ppm for 6.6 h while they exercised for 50 min of every hour at a ventilation rate of 39 L/min (mod- erate exercise) each day for 5 consecutive days. Although spirometric perform- ance decreased with ozone exposure on the first day, the decrease was less on the second day and returned to control values on the third day. However, airway responsiveness to methacholine challenge (a measure of airway reactivity) in- creased progressively from day 1 through day 5. In reviewing data from the literature, McDonnell et al. (1997) found that acute ozone exposure-response models of changes in lung function in humans should be consistent with the following observations: (1) for exposures of less

192 Exposure Guidance Levels for Selected Submarine Contaminants than 8 h, the response increases with increasing concentration (C), VE, and du- ration of exposure (T); (2) the response is nonlinear in each of the three expo- sure variables, and the exposure-response curve is concave upward at low values of the three variables; (3) with increasing T, the response reaches a plateau whose magnitude is a function of the rate of exposure; (4) with increasing C, the response appears to approach a plateau; (5) people vary in their response to ozone, and this variability becomes more pronounced at higher concentrations; and (6) older adults tend to be less responsive than younger adults. Using previ- ously published data on 485 healthy young adult men exposed for 2 h to ozone at one of six concentrations while exercising at one of three levels, McDonnell et al. (1997) identified a sigmoid model that was consistent with previous obser- vations of ozone pulmonary-response characteristics and was found to predict the mean response accurately with independent data. They did not find that the response was more sensitive to changes in C than in VE. They found that the response to ozone decreases with age. Adams (2006) found that chamber exposure to ozone at an average of 0.08 ppm that more closely simulated the summertime ambient pollution exposure profile, which has a triangular shape, compared with the typical chamber expo- sure, which is a square wave, resulted in significantly greater FEV1 response and total symptom severity response at 4.6 h, whereas responses at 6.6 h were not significantly different. Controlled ozone-exposure studies of subjects with mild to moderate asthma suggest that they are at least as sensitive as nonasthmatic subjects. There was a tendency toward increased ozone-induced pulmonary-function decrements in asthmatic subjects relative to nonasthmatic subjects exposed to ozone at up to 0.2 ppm for 4-8 h (Scannell et al. 1996). Similarly, Alexis et al. (2000) reported that statistically significant ozone-induced decreases in FEV1 in mildly atopic asthmatics tended to be greater than those in healthy subjects when both were exposed at 0.4 ppm for 2 h. Horstman et al. (1995) found that people with mild to moderate asthma exposed at 0.16 ppm for a longer duration (7.6 h) had reduc- tions in FEV1 that were significantly greater those in healthy subjects (19% vs 10%, respectively). Information derived from ozone exposure of tobacco- smokers is more limited. The general trend is that smokers are less responsive to ozone under controlled exposure conditions (Framptom et al. 1997; Torres et al. 1997). Lippman (1993) reviewed the relevant literature that addresses pulmonary inflammatory responses to ozone in humans under controlled exposure condi- tions. He reported that ozone-induced pulmonary inflammation is detectable at concentrations as low as 0.1 ppm. He did not find an apparent threshold for ozone-induced pulmonary inflammation as measured with BAL. Devlin et al. (1991) exposed nonsmoking men randomly to filtered air (no ozone) and air with ozone at 0.10 or 0.08 ppm for 6.6 h with moderate exercise (VE, about 40 L/min). BAL was performed 18 h after each exposure, and cells and fluid were

Ozone 193 analyzed. The BAL fluid of volunteers exposed to ozone at 0.10 ppm had sig- nificantly more neutrophils (PMNs), protein, prostaglandin E2 (PGE2), fi- bronectin, interleukin-6 (IL-6), and lactate dehydrogenase (LDH) than BAL fluid from the same volunteers exposed to filtered air. Moreoever, there was a decrease in the ability of alveolar macrophages to phagocytize yeast via the complement receptor; this suggested an ozone-induced impairment of lung de- fense mechanisms. Exposure at 0.08 ppm while exercising also resulted in sig- nificant increases in PMNs, PGE2, LDH, IL-6, alpha 1-antitrypsin and de- creased phagocytosis via the complement receptor. The investigators concluded that exposure of humans to ozone at a concentration as low as 0.08 ppm for 6.6 h is sufficient to initiate an inflammatory reaction in the lung. Epidemiologic Studies There have been no reported epidemiologic studies of health effects in submariners exposed to onboard ozone. Numerous epidemiologic studies have examined the relationship of high ambient outdoor ozone concentrations to hos- pital admissions and daily morbidity and mortality. Some studies have examined the effects of sensitive populations, such as asthmatic children and the elderly; however, these groups are not relevant to the healthy male submariner popula- tion and are not further considered here. EPA (1996) has thoroughly reviewed the epidemiologic dataset. Several studies have reported associations of adverse human health effects with expo- sure to increased ambient ozone (EPA 1996; Medina-Ramon et al. 2006). In one study, healthy adults had significant decrements in lung function when exercis- ing outdoors and exposed to ambient ozone at 0.021-0.124 ppm (Spektor et al. 1988b). Similarly, healthy children attending a summer camp and exposed to ozone at the ambient concentration of 0.12 ppm had significant decrements in average FVC, FEV1, peak expiratory flow rate, and FEF (Spektor et al. 1988a). A study of Taiwanese mail carriers indicated a reduction in peak expiratory flow rates that occurred sometime after exposure to ambient ozone at 0.006-0.096 ppm (Chan and Wu 2005). A study of adult hikers exposed to ambient ozone at 0.028-0.079 ppm while undergoing moderate exercise did not identify signifi- cant effects on lung function (Giradot et al. 2006). Several recent hospital ad- mission and emergency-department visit studies in the United States (Peel et al. 2005), Canada (Burnett et al. 1997), and England (Anderson et al. 1998) have reported associations between an increase in ozone and an increase in risk of emergency-department visits and hospital admissions. In France, a short-term (1-2 days) increase in ozone exposure has been correlated with acute coronary events in middle-aged adults without heart disease (Ruidavets et al. 2005). Sta- tistical modeling of exposure-response curves for ozone concentration and mor- tality indicate that even low concentrations of ozone, in the range of 0.01-0.25 ppm, are associated with an increased risk of premature death in the general U.S. population (Bell et al. 2006).

194 Exposure Guidance Levels for Selected Submarine Contaminants Effects in Animals Acute Toxicity Numerous toxicologic studies of inhaled ozone have demonstrated that the respiratory tract is the principal target for toxicity in laboratory animals. Acute exposures (3-4 h) to ozone at high concentrations (greater than 2 ppm) have been shown to cause death in laboratory rodents because of severe lung injury that results in alveolar edema, congestion, and hemorrhage. Four-hour exposures of rats, mice, and hamsters resulted in LC50s of 2.1-9.9 ppm for rats, 2.1-9.9 ppm for mice, and 15.8 ppm for hamsters (Saltzman and Svirbely 1957). Acute exposures of laboratory animals to ozone at much lower, nonlethal concentrations (less than 1 ppm), some of which are near ambient concentrations commonly in urban atmospheres with photochemical smog (≤ 0.5 ppm), have been reported to cause airway epithelial injury particularly in the nasal passages and the distal conducting airways, especially in the centriacinar regions of the lung where terminal conducting airways have interfaces with the most proximal gas-exhange regions of the lung (the alveolar parenchyma). The more distal pulmonary alveoli in the deep lung of laboratory animals, including nonhuman primates, do not appear to be adversely affected by acute or chronic exposures to ozone at the low concentrations. Most of the reported morphologic studies of ozone-induced injury in laboratory animals exposed at near ambient concentra- tions have focused on the airway lesions in the pulmonary centriacinus. Fewer studies have been specifically designed to examine ozone-induced lesions in the upper respiratory tract, such as in the nose. In general, the character of the airway epithelial changes induced by ozone is similar among laboratory animal species, including rodents and nonhuman primates. Some cell types in the surface epithelium lining affected airway sites are particularly susceptible to acute exposures at low concentrations and may undergo cellular degeneration or cell death. The epithelial cells most sensitive to ozone injury are ciliated cells and nonciliated cuboidal cells in the surface epi- thelium lining the proximal nasal airways, ciliated cells in the distal bronchiolar airways, and the alveolar type II cells lining the alveoli in the walls of respira- tory bronchioles and proximal alveolar ducts. Loss of those sensitive epithelial cells due to death and exfoliation is quickly followed by reparative cellular pro- liferation and an abnormal increase in the numbers (hyperplasia) or size (hyper- trophy) of more resistant nonciliated cells that include mucous goblet cells in the nasal passages, Clara cells in the terminal and respiratory bronchioles, and al- veolar type II cells in the proximal alveolar ducts. Several studies have investigated the time course of pulmonary inflamma- tion after acute ozone exposure in laboratory rodents and rabbits. Maximal in- creases in total protein, albumin, and the number of PMNs in BAL fluid occur 8- 18 h after the end of an acute exposure. Ozone-induced increases in total protein and albumin (indicators of increased permeability) and PMNs (cellular indica- tors of acute inflammation) depend on several factors, including species, strain,

Ozone 195 concentration, exposure duration, and exercise during exposure. Hatch et al. (1986) investigated the acute inflammatory responses of five species (mice, guinea pigs, rats, hamsters, and rabbits) exposed to ozone at several concentra- tions, ranging from 0.2 to 2.0 ppm for 4 h. They found that guinea pigs were the most responsive (increased BAL fluid protein at 0.2 ppm or higher), rabbits were the least responsive (affected only at 2.0 ppm), and rats and mice were intermediate in their measured responses (effects only at 1.0 ppm or higher). Bhalla and Hoffman (1997) reported that rats exposed for 3 h at 0.5 ppm, but not 0.3 or 0.15 ppm, had increased permeability and inflammation in the lung. Dye et al. (1999) investigated strain-related differences in rats acutely exposed at 0.5 ppm and found that Wistar rats had significantly greater lung injury and inflam- mation than Sprague Dawley or F344 rats. The rat strain least sensitive to acute ozone injury was the F344 rat. Several studies have indicated that as ozone ex- posures continue for 3-7 days, the increases in BAL fluid PMNs and protein peak in the first few days and then attenuate, returning to near pre-exposure numbers. Van Bree et al. (2002) and colleagues have shown that rats exposed to ozone for 5 consecutive days had lower levels of protein, fibronectin, IL-6, and inflammatory cells than rats exposed for 1 day. Exercise-induced enhancement of ozone-induced lung injury has been demonstrated in rats acutely exposed at 0.3 ppm (Mautz et al. 1985). The abun- dance and severity of pulmonary lesions increased as exercise and exposure du- ration were increased. Preliminary results also indicate that bacterial endotoxin, a common contaminant of indoor air, can enhance ozone-induced metaplasia in the nonciliated epithelium of the proximal nasal airway of the rat (Harkema and Wagner 2005). Repeated Exposure and Subchronic Toxicity Toxicologic studies of the nasal airways in laboratory rodents and nonhu- man primates exposed to ozone has been reviewed recently (Nikasinovic et al. 2003). Macaques exposed to ozone at 0.15 ppm for 6 days (8 h/day) had acute neutrophilic rhinitis with alterations to the nasal transitional and respiratory epi- thelium in the anterior regions of the nasal passages. The nasal epithelial lesions in the exposed monkeys consisted of ciliated-cell necrosis, degeneration of cili- ated cells with few or shortened cilia, and mucous-cell hyperplasia or metaplasia (Harkema et al. 1987). Exposures of laboratory rats at 0.8 ppm, but not 0.12 ppm, for 3 or 7 days (8 h/day) caused nasal epithelial injury with increased cel- lular proliferation, which resulted in epithelial hyperplasia and mucous-cell metaplasia in the nasal transitional (nonciliated cuboidal) epithelium lining the proximal nasal airways (Harkema et al. 1989; Johnson et al. 1990). Those data and data from several later toxicity studies in rats suggest that the rat nasal epi- thelium is less sensitive to ozone injury than that of nonhuman primates (Hyde et al. 1994).

196 Exposure Guidance Levels for Selected Submarine Contaminants Dungworth et al. (1975) reported that macaque monkeys exposed to ozone at 0.2-0.8 ppm 8 h/day for 7 days had hyperplasia and hypertrophy of the epithe- lium lining respiratory bronchioles in the centriacinar regions of the lung. The ozone-induced epithelial alterations were accompanied by accumulations of cel- lular debris and numerous alveolar macrophages in the affected airway lumina. The investigators stated that the threshold for the histologically detectable changes in the monkeys was below 0.2 ppm and most likely closer to 0.1 ppm. However, the ozone-induced alterations during the first 3-4 days of exposure did not increase in severity after 7 days of exposure, and they suggested cellular adaptation and apparent resistance to any further ozone-induced injury. In later studies in the same laboratory (Harkema et al. 1987), macaques were exposed to ozone at 0.15 or 0.30 ppm for 90 days (8 h/day). After 90 days of exposure, there was ciliated cell necrosis, degenerated ciliated cells with few or attenuated cilia, and mucous-cell hyperplasia in the surface epithelium lining the proximal nasal airways. A neutrophilic inflammatory cell influx (acute rhini- tis) was also present at 6 days, but not 90 days. The same ozone-exposed mon- keys had moderate to marked hyperplasia of bronchiolar epithelium in the pul- monary centriacinar regions with increases in luminal macrophages (Harkema et al. 1993). There were no morphometrically determined differences in the sever- ity of the bronchiolar epithelial lesions among the different ozone-exposed groups. The airway epithelial alterations did not appear to be concentration- or time-dependent. In contrast with the acute response to ozone in the nose, there was no evidence of epithelial-cell necrosis or inflammatory-cell influx (other than an increase in macrophages) accompanying the epithelial hyperplasia in the respiratory bronchioles of monkeys exposed for 6 or 90 days. A small amount of work has been completed in studying the effects of ozone on the central nervous system. Groups of 10 male Wistar rats were ex- posed to air or ozone at 0.25 ppm 4 h/day for 15 or 30 days (Pereyra-Munoz et al. 2006). Motor activity measured over a 5-min period for both ozone-exposed groups was significantly decreased, to comparable degrees, after 15 and 30 days of exposure. Lipid peroxidation measured in the striatum of six rats per group was increased in a time-dependent manner in both ozone-exposed groups. The remaining four rats per group were used in histochemical preparations and for morphologic study. Increases were observed in the expression of dopamine and adenosine 3’,5’-monophosphate-regulated phosphoprotein of 32 KD in the stria- tum after 30 days of exposure and in the expression of inducible nitric oxide synthase and copper-zinc superoxide dismutase in both the striatum and substan- tia nigra after 15 and 30 days of exposure. The number of neurons in the sub- stantia nigra (stained with the Klüver-Barrera technique or histochemically for tyrosine hydroxylase) was reduced in a time-dependent manner in the ozone- exposed groups. There are no reports in the scientific literature demonstrating that exposure of humans to ozone results in neurotoxicity.

Ozone 197 Chronic Toxicity Long-term exposures (more than 90 days) to ozone have been conducted in laboratory rodents and macaques (Catalano et al. 1995; Chang et al. 1992; Tyler et al. 1988). Chang et al. (1992) exposed rats to a background concentra- tion of 0.06 ppm 13 h/day, 7 days/week for 1, 3, 13, and 78 weeks with a sole daily 9-h spike (5 days/week) that rose to 0.25 ppm. The integrated concentra- tion of the daily exposure with the spike was 0.19 ppm. The investigators found that in the terminal bronchioles, cilia were lost (at 78 weeks) and the surface area of Clara cells was decreased (at 1, 3, 13 and 78 weeks). There was also a progressive increase in epithelial hyperplasia, fibroblast proliferation, and thick- ening of the interstitial matrix from 13 to 78 weeks. There was a general postex- posure recovery from the pulmonary lesions except the fibrotic interstitial changes, which were still apparent 17 weeks after the end of the chronic expo- sure. Pulmonary-function alterations consistent with restrictive lung disease and fibrotic lesions were also found in similarly exposed rats (Costa et al. 1995). Tyler et al. (1988) exposed young monkeys (7 months) and rats to ozone at 0.25 ppm 8 h/day, 5 days/week over an 18-month period. Some animals were exposed throughout the entire 18-month period, and others were exposed only during alternate months (total of 9 months of exposure). At the end of the expo- sure, monkeys in both groups had developed respiratory bronchiolitis, increased volume density of respiratory bronchioles, and alterations in lung growth. The monkeys that received ozone exposures only during alternate months had for the most part pulmonary alterations equivalent to those in the group receiving ozone exposures throughout the entire 18-month period and in some cases greater al- terations, such as greater collagen deposition. In the rat study, there were no significant differences between the two exposure groups; both groups had more bronchiole-alveolar duct junctions as determined by morphometric analyses. A comprehensive study of F344 rats exposed at 0.12, 0.5, or 1.0 ppm 6 h/day, 5 days/week for 3 or 20 months has been summarized by Catalano et al. (1995). Detailed morphometric examinations of the noses and lungs of the ani- mals were conducted by a team of investigators in several institutions (Chang et al. 1995; Harkema et al. 1994; Pinkerton et al. 1995; Stockstill et al. 1995). Ad- verse effects were found in the nasal, tracheobronchial, and pulmonary centria- cinar airways. Rats chronically exposed at 0.5 and 1.0 ppm, but not 0.12 ppm, had marked alterations in the nasal airways consisting of chronic rhinitis, turbin- ate atrophy, epithelial hyperplasia, and mucous-cell metaplasia or hyperplasia. Chronic exposure to ozone at all concentrations caused epithelial alterations in the centriacinar regions of the lung. Similar nasal and pulmonary lesions have been reported in mice exposed at 0.5 or 1.0 ppm for 2 years (Herbert et al. 1996). The lesions were shown to persist with an additional 6 months of expo- sure. Although it is well documented that the nasal and pulmonary alterations in all laboratory animals are similar, the concentrations at which ozone-induced

198 Exposure Guidance Levels for Selected Submarine Contaminants lesions are observed differ among rodents and nonhuman primates. After re- viewing comparable acute and chronic ozone-exposure studies in rodents (rats and mice) and in macaques, Hyde et al. (1994) estimated that monkeys are about 10 times more sensitive to the development of ozone-induced nasal and pulmo- nary lesions. In a more recent study, infant monkeys (30 days old) were episodically exposed to ozone at 0.5 ppm alone or with house-dust mite allergen (HDMA) 8 h/day, 5 days/week every 14 days for a total of 11 ozone episodes (Schelegle et al. 2003). The 6-month episodic exposure to ozone alone or with HDMA caused profound remodeling of the distal airways and centriacinar region and loss of bronchiolar airways. Reproductive Toxicity in Males There are few reports in the scientific literature on the effects of ozone on the male reproductive system. Exposure of male and female mice to ozone at 0.05-0.09 ppm before breeding did not affect pregnancy rate, the weight of live fetuses, or skeletal or soft-tissue malformations in offspring (Zhou et al. 2006). In a second study, male rats were exposed to ozone at 0.5 ppm or control air 5 h/day for 50 days (Jedlinska-Krakowska et al. 2006). The number of successful matings and the survival of pups were equivalent in the two groups. The testes of the ozone-exposed and control rats were not different with regard to mor- phology or motility of sperm, but sperm concentration was 17% lower in the ozone-exposed rats. Sokol et al. (2006) retrospectively studied the relationship between air pol- lution and human sperm quality over a 2-year period in Los Angeles, California. A linear mixed-effects model was used to study average sperm concentration and total motile sperm count for each donation (more than 5,000 semen sam- ples) from each study participant (48 donors). The model indicated a statistically significant negative correlation between ozone concentration 0-9, 10-14, and 70- 90 days before sperm donation and average sperm concentration. Other pollu- tion measures did not correlate with differences in sperm quality. The average daily ozone concentration during the study was 0.022 " 0.009 ppm. Bonde (2007) indicated that welders who have an occupational exposure to ozone have been reported not to have lower sperm counts. Immunotoxicity The immune system is a sensitive target for ozone-induced toxicity (Gilmour et al. 1993a; Gilmour et al. 1993b; Gilmour and Selgrade 1993; Ryan et al. 2002; Selgrade et al. 1988). Ozone exposures at high ambient concentra- tions (0.08-0.22 ppm) have been shown to induce adverse effects on the local airway mucosal and systemic immune systems in laboratory animals and in hu-

Ozone 199 mans. The most sensitive effects include inhibition of bacterial phagocytosis by alveolar macrophages (Devlin et al. 1991; Driscoll et al. 1987; Van Loveren et al. 1988), production of proinflammatory cytokines and mediators (Balmes et al. 1996; Becker et al. 1991; Devlin et al. 1991; Driscoll et al. 1993; Driscoll et al. 1987; Jaspers et al. 1997; Scannell et al. 1996; Torres et al. 1997), and recruit- ment of inflammatory cells into the lung (Devlin et al. 1991; Koren et al. 1989) and the nasal airways (Graham et al. 1988; Graham and Koren 1990; Harkema et al. 1987). The ozone-induced effects could influence the development of CD4+ TH2 lymphocytic cytokine responses in allergic airway diseases, such as asthma and allergic rhinitis. Mice exposed to ozone at 0.13 ppm had enhanced allergic sensitization (Osebold et al. 1988), and atopic asthmatic human subjects exposed at 0.12 ppm had increased bronchial responsiveness to allergens (Molfino et al. 1991). In that regard, epidemiologic studies support the experi- mental findings (Bascom 1996). Asthmatic children living in the inner city of Atlanta had more emergency-room visits on days when ozone concentrations were greater than 0.11 ppm (White et al. 1994). Genotoxicity Several in vitro and in vivo studies have been conducted to investigate the genotoxicity and mutagenicity of ozone (Victorin 1996). The research includes in vitro mutagenicity tests in a variety of cell types (bacteria, yeast, plants, hu- man cell lines, and other mammalian cells) and in vitro assays for chromosomal alterations in cells from laboratory animals exposed to ozone at higher than am- bient concentrations. Some of the studies have shown that ozone is genotoxic and mutagenic. Collectively, the data from the genotoxicity studies suggest that ozone is at most a weak mutagen, but more data are needed to draw definitive conclusions. However, the reactive, gaseous, and toxic nature of ozone makes it difficult to conduct interpretable studies in those test systems. Carcinogenicity In a National Toxicology Program chronic bioassay study, male and fe- male rats and mice were exposed to filtered air or ozone at 0.12, 0.5, or 1.0 ppm 6 h/day, 5 days/week for 2 years or a lifetime (Boorman et al. 1994; Herbert et al. 1996). The results in male and female F344/N rats showed no evidence of carcinogenic activity. In male B6C3F1 mice, there was equivocal evidence of carcinogenic activity. There was some evidence of carcinogenic activity in fe- male B6C3F1 mice only at the highest concentration (1.0 ppm). Other lung- tumor development studies that exposed rats, hamsters, or mice chronically to ozone at up to 0.8 ppm for less than their lifetime were either negative or am- biguous for ozone-induced carcinogenicity (Hassett et al. 1985; Ichinose and Sagai 1992; Last and Warren 1987; Witschi et al. 1993). Thus, ozone has been

200 Exposure Guidance Levels for Selected Submarine Contaminants shown to be a weak pulmonary carcinogen only in female mice at one concen- tration and in only one long-term inhalation study. EPA and the International Agency for Research on Cancer have not provided any classification regarding ozone’s carcinogenic potential. TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS Because ozone is a highly reactive gas, it has a negligible half-life, and its uptake is limited to the air-liquid interface lining the mucosal membranes of the respiratory tract. In resting subjects, 40-50% of inhaled ozone is absorbed in the nasopharyngeal airways with nasal breathing or in the mouth and pharynx with oral breathing. The conducting airways remove 90% of the remainder of the inhaled ozone that reaches the lower respiratory tract. Therefore, about 95% of the total inhaled ozone is removed in the respiratory tract (Asplund et al. 1996; Gerrity et al. 1995; Gerrity et al. 1988; Hu et al. 1992a; Hu et al. 1992b). The efficiency of ozone uptake varies directly with concentration and inversely with breathing rate (Gerrity et al. 1988). With increased ventilation rates, there is a decrease in both upper and lower airway absorption that results in more penetra- tion of ozone into the lung (Hu et al. 1992a; Hu et al. 1992b). Mathematical models of ozone dosimetry in the respiratory tract have es- timated that the rate or amount of ozone uptake in the lung would be greatest in the centriacinar regions. The mathematical predictions for the primary intrapul- monary site of ozone-induced toxicity (Miller et al. 1985; Overton et al. 1987) support the numerous experimental-animal studies that have identified site- specific, ozone-induced lesions in this distal region of the respiratory tract. Ex- perimental dosimetry studies with 18O-labeled ozone have also shown that exer- cising humans had 18O concentrations in their BAL fluid 4-5 times greater than those in the BAL fluid of similarly exposed resting laboratory rats (Hatch et al. 1994). The results of that comparative dosimetry study are consistent with pul- monary physiology studies that suggest that ozone has greater detrimental ef- fects on the lung function of humans than in animals (Costa et al. 1989; Overton et al. 1987). Acute responses to controlled exposures to ozone cause alterations in lung function, airway caliber, breathing pattern, respiratory symptoms, and airway inflammation. More than one biologic mechanism appears to mediate the re- sponses to ozone exposure. Broadly categorized, the ozone-induced alteration mechanisms are due to neural or inflammatory mechanisms. Several experimen- tal studies in animals and humans have shown that the reduction in pulmonary function with acute ozone exposure is mediated through the parasympathetic system. Ozone stimulates vagal afferents, including C fibers and rapidly adapt- ing receptors, and this results in vagal reflexes that cause increases in airway resistance and frequency of respiration, symptoms of respiratory irritation, and a decrease in tidal volume (Beckett et al. 1985; Gertner et al. 1983a; Gertner et al.

Ozone 201 1983b; Gertner et al. 1983c; Lee et al. 1979; Passannante et al. 1998; Schelegle et al. 2001; Schelegle et al. 1993). Airway inflammation caused by inhaled ozone is a secondary response to toxicant-induced damage to the epithelial cells lining the luminal surface of the respiratory tract. The extreme reactive nature of ozone with the fluid lining the respiratory tract (epithelial lining fluid, or ELF) makes it unlikely that it passes unreacted into the airway lining cells and causes direct cytotoxicity (Pryor 1992). Ozone is more likely to react with lipids high in unsaturated fatty acids in the ELF or in the outer epithelial cell membranes (lipid peroxidation). Ozonation in the airway lumen, which also has high water content, produces aldehydes, hydroperoxides, and small amounts of ozonides (Driscoll et al. 1993; Frampton et al. 1999a; Frampton et al. 1999b; Leikauf et al. 1993; Pryor et al. 1995a; Pryor et al. 1995b). The ozonation products stimulate airway epithelial cells to release a variety of proinflammatory agents, including eicosanoids, platelet- activating factor, reactive oxygen species, and inflammatory cytokines (Leikauf et al. 1995a; Leikauf et al. 1995b; Pryor et al. 1995a; Schelegle et al. 1989). Ozone-exposed epithelial cells release inflammatory mediators, such as IL-6, IL-8, and fibronectin (Devlin et al. 1994). Cytokines and chemokines released from the injured epithelium recruit neutrophils and monocytes and macrophages into the airways. The activated inflammatory cells release additional mediators that may amplify the inflammatory response and promote later airway structural and functional alterations. Ozone-induced inflammation may directly amplify oxidative damage to the airway tissues due to ozone. It takes several hours for the inflammatory cascade to develop after the start of acute exposure when ini- tial pulmonary function and respiratory symptoms may have abated (Blomberg et al. 1999; Foster et al. 2000; Schelegle et al. 1991). The presence of inflam- matory cells, such as PMNs, and inflammatory mediators in the BAL fluid of exposed subjects are important indicators of acute airway injury (Balmes et al. 1996; Foster and Stetkiewicz 1996; Koren et al. 1989). INHALATION EXPOSURE LEVELS FROM THE NATIONAL RESEARCH COUNCIL AND OTHER ORGANIZATIONS A few organizations have established or proposed acceptable inhalation exposure limits or guidelines for ozone. Selected values are summarized in Ta- ble 9-3. COMMITTEE RECOMMENDATIONS The committee’s recommendations for EEGL and CEGL values for ozone are summarized in Table 9-4. The current and proposed U.S. Navy values are provided for comparison.

202 Exposure Guidance Levels for Selected Submarine Contaminants TABLE 9-3 Selected Inhalation Exposure Levels from the NRC and Other Agenciesa Organization Type of Level Exposure Level Reference Occupational ACGIH TLV-TWA (heavy work) 0.05 ppm ACGIH 2001 TLV-TWA (moderate 0.08 ppm work) TLV-TWA (light 0.10 ppm work) TLV-TWA (2-h, all work 0.2 ppm types) NIOSH REL-Ceiling 0.1 ppm NIOSH 1997 OSHA PEL-TWA 0.1 ppm 29 CFR 1910.1000 Submarine NRC EEGL NRC 1984 1-h 1 ppm 24-h 0.1 ppm CEGL 90-day 0.02 ppm a The comparability of EEGLs and CEGLs with occupational-exposure and public-health standards or guidance levels is discussed in Chapter 1 (“Comparison with Other Regula- tory Standards or Guidance Levels”). Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible expo- sure limit; REL, recommended exposure limit; TLV, Threshold Limit Value; TWA, time- weighted average. TABLE 9-4 Emergency and Continuous Exposure Guidance Levels for Ozone Exposure U.S. Navy Values (ppm) Committee Recommended Level Current Values Proposed Values Values (ppm) EEGL 1-h 1 0.3 0.5 24-h 0.1 0.1 0.1 CEGL 90-day 0.02 0.02 0.02 Abbreviations: CEGL, continuous exposure guidance levels; EEGL, emergency exposure guidance level.

Ozone 203 1-Hour EEGL There is a preponderance of strong dose-response data in the scientific lit- erature on short-duration ozone exposure (hours) in human populations of simi- lar age and sex as submariners, and the committee derived the 1-h EEGL from the weight of evidence from the controlled human studies. Clinical research has demonstrated that healthy young men (18-34 years old) at rest (Folinsbee et al. 1978; Horvath et al. 1979) or performing moderate to heavy intermittent exer- cise (DeLucia and Adams 1977; Folinsbee et al. 1978; McDonnell et al. 1983) or continuous exercise (Adams et al. 1981; Adams and Schelegle 1983; Folins- bee and Horvath 1986) will develop marked decrements in pulmonary function and symptoms of breathing discomfort, such as chest tightness and cough, when exposed to ozone at less than 1 ppm for 1-2.5 h. Collectively, the studies of ex- ercising healthy men have clearly demonstrated that 1 h of continuous exercise or 2-2.5 h of intermittent exercise increases the deleterious pulmonary-function responses to acute ozone exposure. However, in determining the 1-h EEGL for ozone, the committee assumed that most submariners would have VE equiva- lents closer to “rest” than to the “moderate-to-heavy” exercise paradigms used in the experimental studies and protocols reviewed here because of the confined conditions on the submarine. The lowest ozone concentration at which modest reductions in FVC and FEV1 have been reported in nonexercising young men after 2 h of controlled exposures is 0.5 ppm (Folinsbee et al. 1978; Horvath et al. 1979). A concentration of 0.5 ppm was used by the committee as the starting point for the derivation of the 1-h EEGL. Because the controlled human studies used short exposure durations and age classes of interest, no further adjustments to the 1-h EEGL were needed for these specific areas. Variability in sensitivity to low ozone concentrations for that short exposure in low to moderate activity was assumed to be minimal, and an intraspecies adjustment was not considered to be warranted. Therefore, the committee determined that a 1-h exposure to ozone at 0.5 ppm would not impair a submariner’s ability to conduct normal or emergency activities. 24-Hour EEGL There have been no human studies of controlled ozone exposures for 24 h. The committee’s determination of a recommended 24-h EEGL was based on the weight of evidence from the controlled human studies at low ozone concentra- tions (0.08-0.12 ppm) for durations of 4-8 h with a range of exercise loads (Folinsbee et al. 1988; Horstman et al. 1990; McDonnell et al. 1991). In those studies, ozone exposures caused dose-dependent symptoms of cough and chest discomfort, increases in airway responsiveness to methacholine challenge, and consistent but transient decrements in pulmonary function, such as FEV1 and FVC. Further analysis of the data suggests that the ozone-pulmonary response

204 Exposure Guidance Levels for Selected Submarine Contaminants relationship plateaus after a 6.6-h exposure protocol. Therefore, further decre- ments in respiratory function of functional and operational significance with an extended exposure up to 24 h are not expected, and the committee did not con- sider that a time adjustment factor was warranted. The committee acknowledged that the response database exhibits population variability in ozone-induced changes in respiratory function. However, it concluded that the observed degree of change would be clinically or operationally insignificant for low to moderate activity in a submariner population. Therefore, response variability in sensitivity to the low ozone concentrations in submariners in low to moderate exercise for a 24-h exposure was assumed to be low, and no intraspecies adjustment was ap- plied. The committee concluded that exposure to ozone at 0.1 ppm during a 24-h period should not impair a healthy submariner from conducting normal or emer- gency activities. 90-Day CEGL There have been no 90-day controlled human exposures to ozone. How- ever, the 90-day exposure study of macaques conducted by Harkema and col- leagues (Harkema et al. 1987; Harkema et al. 1993) demonstrated that exposures at 0.15 and 0.30 ppm (6 h/day, 5 days/week) resulted in conspicuous morphol- ogic but subclinical airway injury and remodeling in the nose and lung. Al- though the reversibility of the airway lesions in monkeys has not been deter- mined, similar nasal airway lesions induced by ozone in laboratory rats have been shown to persist, although markedly attenuated, at least 3 months after the end of a 90-day exposure (Harkema et al. 1999). Therefore, the committee used a concentration of 0.15 ppm as a starting point for deriving the recommended 90-day CEGL. Because the morphology of the upper and lower respiratory tract of the macaque closely resembles that of humans (Tyler 1983), an interspecies uncertainty factor of 1 was used in the committee’s determination. An uncer- tainty factor of 10 was used to adjust from a lowest observed-adverse-effect level to a no-observed-adverse-effect level. That resulted in a recommended 90- day CEGL for ozone of 0.02 ppm, which is well below the EPA NAAQS con- centration of 0.08 ppm and within estimated background concentrations of out- door ozone in the United States. DATA ADEQUACY AND RESEARCH NEEDS There is a lack of data on personal exposure of submariners to ozone and other oxidant gases. The committee suggests that the Navy consider conducting exposure studies designed to determine the personal exposure of submariners to ozone during their short- and long-term tours of duty.

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U.S. Navy personnel who work on submarines are in an enclosed and isolated environment for days or weeks at a time when at sea. To protect workers from potential adverse health effects due to those conditions, the U.S. Navy has established exposure guidance levels for a number of contaminants. In this latest report in a series, the Navy asked the National Research Council (NRC) to review, and develop when necessary, exposure guidance levels for 11 contaminants. The report recommends exposure levels for hydrogen that are lower than current Navy guidelines. For all other contaminants (except for two for which there are insufficient data), recommended levels are similar to or slightly higher than those proposed by the Navy. The report finds that, overall, there is very little exposure data available on the submarine environment and echoes recommendations from earlier NRC reports to expand exposure monitoring in submarines.

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