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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 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 information 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). Selected 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 manganese; and to degrade a variety of organics, including detergents, pesticides,
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 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 cooling 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 (Wojtowicz 1996). In the stratosphere, short-wave UV radiation directly splits molecular oxygen (O2) into atomic oxygen (O·) that rapidly combines with O2 to form ozone. In the troposphere, “ground-level” ozone is generated predominantly 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 radicals 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 pollutant in photochemical smog, is considered both an environmental and a public-
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 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 concentrations 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 malfunctioning converters that fly at high altitudes (NRC 2002). According to federal 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 precipitators, 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 concurrent 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 concentrations as high as 9 ppm (Kleinfeld and Giel 1956). Similar effects have been reported 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).
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 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 studies 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 increased physiologic response to a nonspecific bronchoconstrictor, such as methacholine) 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 capacity (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 frequency stabilizes at a new higher level (Schelegle et al. 2007). Table 9-2 provides a summary of controlled ozone-exposure studies in humans that are discussed 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 workloads, from light to heavy, with minute ventilation (VE) of 28-66 L/min. Significant 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, Folinsbee 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 exposure 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
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 TABLE 9-2 Controlled Exposure of Healthy Human Subjects to Ozone and Observed Effects on Pulmonary Function Concentration (ppm) Exposure Duration and Activity Subjects and Effects Reference 0.15, 0.30 1 h at rest and light to heavy workloads 6 men, 22-42 years old Mean FEV1 decrements of 14% and 6.1% at 0.30 ppm with moderate and heavy exercise, respectively DeLucia and Adams 1977 0.5 2 h at rest 40 men, 18-28 years old Decrease in mean FEV1 (7%) and FVC (6%) Folinsbee et al. 1978 0.25, 0.50, 0.75 2 h at rest 8 men and 5 women, 21-22 years old Mean FVC decrements of 5% and 10% at 0.50 and 0.75 ppm, respectively Horvath et al. 1979 0.20, 0.30, 0.40 30-80 min with light to heavy exercise 8 men, 22-46 years old Decrease in FEF with heavy exercise with an effective dose of 0.2-0.3 Adams et al. 1981 0.12, 0.18, 0.24, 0.30, 0.40 2.5 h, IE 20-29 men per group, 18-30 years old Decrease in FVC, FEV1 and FEF at 0.12 ppm McDonnell et al. 1983 0.10, 0.15, 0.20, 0.25 2 h, IE 20 men, 21-29 years old Decrease in FEV1 (>5%) and specific airway conductance (>15%) at 0.15 ppm Kulle et al. 1985 0.12, 0.18, 0.24 1 h, heavy workload (competitive exercise) 10 men, 19-29 years old Decrease in FVC and FEV1 at 0.18 ppm Schelegle and Adams 1986 0.12 6.6 h, IE 10 men, 18-33 years old Mean FEV1 decrements of 13% after 6.6 h and FVC of 8.3%; cough and discomfort increased with exposure; airway responsiveness to methacholine doubled after ozone exposure Folinsbee et al. 1988 0.08, 0.10 6.6 h, IE 38 men, mean age 25 years Mean FEV1 decrements of 8.4% at 0.08 ppm and 11.4% at 0.10 ppm; cough and discomfort increased with exposure McDonnell et al. 1991
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 0.08, 0.10, 0.12 6.6 h, IE 22 men, 18-33 years old Decreased FVC and FEV1 throughout exposure; mean FEV1 decrements of 7.0%, 7.0%, and 12.3%, respectively Horstman et al 1990 0.12 6.6 h/day, IE 5 consecutive days 17 men, mean age 25.4 years Mean FEV1 decrements of 12.8%, 8.7%, 2.5%, 0.6%, and improvement of 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 Folinsbee et al. 1994 0.30 1 h, CE 12 men, 18-34 years old Mean decrements of FEV1 17.0-17.9% McKittrick and Adams 1995 0.25 1 h, CE 32 men and 28 women, 22 ± 0.6 years old Mean FEV1 decrements of 15.9% in men and 9.4% in women; FEV1 decrements −0.4 to 56% Ultman et al. 2004 0.1, 0.4 1 h, IE 12 men and 3 women, healthy, nonsmoking adults Neutrophils increased in BAL 6 h after exposure at 0.4 ppm. Morrison et 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 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 Adams 2006 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.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 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 importance 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 estimated total doses of ozone. The two exposure regimens led to similar pulmonary-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 exercising 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 increase 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-
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 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 concentration 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 methacholine 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 spirometric 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 increase in response is predicted with increasing exposure duration. Folinsbee et al. (1994) extended their controlled-exposure studies by exposing 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 (moderate exercise) each day for 5 consecutive days. Although spirometric performance 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) increased 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
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 than 8 h, the response increases with increasing concentration (C), VE, and duration of exposure (T); (2) the response is nonlinear in each of the three exposure 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 previously 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 observations 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 exposure, 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 reductions 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 conditions. 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
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 analyzed. The BAL fluid of volunteers exposed to ozone at 0.10 ppm had significantly more neutrophils (PMNs), protein, prostaglandin E2 (PGE2), fibronectin, 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 defense mechanisms. Exposure at 0.08 ppm while exercising also resulted in significant increases in PMNs, PGE2, LDH, IL-6, alpha 1-antitrypsin and decreased 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 hospital 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 population 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 exposure to increased ambient ozone (EPA 1996; Medina-Ramon et al. 2006). In one study, healthy adults had significant decrements in lung function when exercising 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 significant effects on lung function (Giradot et al. 2006). Several recent hospital admission 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). Statistical modeling of exposure-response curves for ozone concentration and mortality 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).
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 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 concentrations 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 epithelium 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 respiratory bronchioles and proximal alveolar ducts. Loss of those sensitive epithelial cells due to death and exfoliation is quickly followed by reparative cellular proliferation and an abnormal increase in the numbers (hyperplasia) or size (hypertrophy) of more resistant nonciliated cells that include mucous goblet cells in the nasal passages, Clara cells in the terminal and respiratory bronchioles, and alveolar type II cells in the proximal alveolar ducts. Several studies have investigated the time course of pulmonary inflammation after acute ozone exposure in laboratory rodents and rabbits. Maximal increases 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 indicators of acute inflammation) depend on several factors, including species, strain,
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 1-Hour EEGL There is a preponderance of strong dose-response data in the scientific literature on short-duration ozone exposure (hours) in human populations of similar 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 exercise (DeLucia and Adams 1977; Folinsbee et al. 1978; McDonnell et al. 1983) or continuous exercise (Adams et al. 1981; Adams and Schelegle 1983; Folinsbee 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 exercising 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 equivalents 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 concentrations (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
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 relationship plateaus after a 6.6-h exposure protocol. Therefore, further decrements in respiratory function of functional and operational significance with an extended exposure up to 24 h are not expected, and the committee did not consider 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 applied. 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 emergency activities. 90-Day CEGL There have been no 90-day controlled human exposures to ozone. However, the 90-day exposure study of macaques conducted by Harkema and colleagues (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 morphologic but subclinical airway injury and remodeling in the nose and lung. Although the reversibility of the airway lesions in monkeys has not been determined, 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 uncertainty 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 concentration of 0.08 ppm and within estimated background concentrations of outdoor 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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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 Driscoll, K.E., L. Simpson, J. Carter, D. Hassenbein, and G.D. Leikauf. 1993. Ozone inhalation stimulates expression of a neutrophil chemotactic protein, macrophage inflammatory protein 2. Toxicol. Appl. Pharmacol. 119(2):306-309. Dungworth, D.L., W.L. Castleman, C.K. Chow, P.W. Mellick, M.G. Mustafa, B. Tarkington, and W.S. Tyler. 1975. Effect of ambient levels of ozone on monkeys. Fed. Proc. 34(8):1670-1674. Dye, J.A., M.C. Madden, J.H. Richards, J.R. Lehmann, R.B. Devlin, and D.L. Costa. 1999. Ozone effects on airway responsiveness, lung injury, and inflammation. Comparative rat strain and in vivo/in vitro investigations. Inhal. Toxicol. 11(11):1015-1040. EPA (U.S. Environmental Protection Agency). 1986. Air Quality Criteria for Ozone and Other Photochemical Oxidants, Vols. I-V. EPA-600/8-84-020aF-eF. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, U.S. Environmental Protection Agency, Research Triangle Park, NC. EPA (U.S. Environmental Protection Agency). 1996. Air Quality Criteria for Ozone and Related Photochemical Oxidants, Vol. I-III. EPA/600/P-93/004aF, EPA/600/P-93/004bF, EPA/600/P-93/004cF. National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC [online]. Available: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=2831#Download [accessed June 20, 2007]. Fiore, A., D.J. Jacob, H. Liu, R.M. Yantosca, T.D. Fairlie, and Q. Li. 2003. Variability in surface ozone background over the United States: Implications for air quality policy. J. Geophys. Res. 108(D24):4787. doi:10.1029/2003JD003855 Folinsbee, L.J., and S.M. Horvath. 1986. Persistence of the acute effects of ozone exposure. Aviat. Space Environ. Med. 57(12 Pt.1):1136-1143. Folinsbee, L.J., B.L. Drinkwater, J.F. Bedi, and S.M. Horvath. 1978. The influence of exercise on the pulmonary function changes due to exposure to low concentrations of ozone. Pp. 125-145 in Environmental Stress: Individual Human Adaptations, L.J. Folinsbee, J.A. Wagner, J.F. Borgia, B.L. Drinkwater, J.A. Gliner, and J.F. Bedi, eds. New York: Academic Press. Folinsbee, L.J., W.F. McDonnell, and D.H. Horstman. 1988. Pulmonary function and symptom responses after 6.6-hour exposure to 0.12 ppm ozone with moderate exercise. JAPCA 38(1):28-35. Folinsbee, L.J., D.H. Horstman, H.R. Kehrl, S. Harder, S. Abdul-Salaam, and P.J. Ives. 1994. Respiratory responses to repeated prolonged exposure to 0.12 ppm ozone. Am. J. Respir. Crit. Care Med. 149(1):98-105. Foster, W.M., and P.T. Stetkiewicz. 1996. Regional clearance of solute from the respiratory epithelia: 18-20 h postexposure to ozone. J. Appl. Physiol. 81(3):1143-1149. Foster, W.M., R.H. Brown, K. Macri, and C.S. Mitchell. 2000. Bronchial reactivity of healthy subjects: 18-20 h postexposure to ozone. J. Appl. Physiol. 89(5):1804-1810. Frampton, M.W., P.E. Morrow, A. Torres, K.Z. Voter, J.C. Whitin, C. Cox, D.M. Speers, Y. Tsai, and M.J. Utell. 1997. Effects of Ozone on Normal and Potentially Sensitive Human Subjects. Part II. Airway Inflammation and Responsiveness to Ozone in Nonsmokers and Smokers. Reseach Report No. 78. Health Effects Institute, Boston, MA. Frampton, M.W., W.A. Pryor, R. Cueto, C. Cox, P.E. Morrow, and M.J. Utell. 1999a. Aldehydes (Nonanal and Hexanal) in Rat and Human Bronchoalveolar Lavage Fluid After Ozone Exposure. Reseach Report No. 90. Health Effects Institute, Boston, MA.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 Frampton, M.W., W.A. Pryor, R. Cueto, C. Cox, P.E. Morrow, and M.J. Utell. 1999b. Ozone exposure increases aldehydes in epithelial lining fluid in human lung. Am. J. Respir. Crit. Care Med. 159(4 Pt. 1):1134-1137. Gerrity, T.R., R.A. Weaver, J. Berntsen, D.E. House, and J.J. O'Neil. 1988. Extrathoracic and intrathoracic removal of O3 in tidal-breathing humans. J. Appl. Physiol. 65(1):393-400. Gerrity, T.R., F. Biscardi, A. Strong, A.R. Garlington, J.S. Brown, and P.A. Bromberg. 1995. Bronchoscopic determination of ozone uptake in humans. J. Appl. Physiol. 79(3):852-860. Gertner, A., B. Bromberger-Barnea, A.M. Dannenberg, Jr., R. Traystman, and H. Menkes. 1983a. Responses of the lung periphery to 1.0 ppm ozone. J. Appl. Physiol. 55(3):770-776. Gertner, A., B. Bromberger-Barnea, R. Traystman, D. Berzon, and H. Menkes. 1983b. Responses of the lung periphery to ozone and histamine. J. Appl. Physiol. 54(3):640-646. Gertner, A., B. Bromberger-Barnea, R. Traystman, and H. Menkes. 1983c. Effects of ozone on peripheral lung reactivity. J. Appl. Physiol. 55(3):777-784. Gilmour, M.I., and M.K. Selgrade. 1993. A comparison of the pulmonary defenses against streptococcal infection in rats and mice following O3 exposure: Differences in disease susceptibility and neutrophil recruitment. Toxicol. Appl. Pharmacol. 123(2):211-218. Gilmour, M.I., P. Park, D. Doerfler, and M.K. Selgrade. 1993a. Factors that influence the suppression of pulmonary antibacterial defenses in mice exposed to ozone. Exp Lung Res. 19(3):299-314. Gilmour, M.I., P. Park, and M.K. Selgrade. 1993b. Ozone-enhanced pulmonary infection with Streptococcus zooepidemicus in mice. The role of alveolar macrophage function and capsular virulence factors. Am. Rev. Respir. Dis. 147(3):753-760. Girardot, S.P., P.B. Ryan, S.M. Smith, W.T. Davis, C.B. Hamilton, R.A. Obenour, J.R. Renfro, K.A. Tromatore, and G.D. Reed. 2006. Ozone and PM2.5 exposure and acute pulmonary health effects: A study of hikers in the Great Smoky Mountains National Park. Environ. Health Perspect. 114(7):1044-1052. Graham, D.E., and H.S. Koren. 1990. Biomarkers of inflammation in ozone-exposed humans. Comparison of the nasal and bronchoalveolar lavage. Am. Rev. Respir. Dis. 142(1):152-156. Graham, D., F. Henderson, and D. House. 1988. Neutrophil influx measured in nasal lavages of humans exposed to ozone. Arch. Environ. Health 43(3):228-233. Harkema, J.R., and J.G. Wagner. 2005. Epithelial and inflammatory responses in the airways of laboratory rats coexposed to ozone and biogenic substances: Enhancement of toxicant-induced airway injury. Exp Toxicol. Pathol. 57(Suppl. 1):129-141. Harkema, J.R., C.G. Plopper, D.M. Hyde, J.A. St George, D.W. Wilson, and D.L. Dungworth. 1987. Response of the macaque nasal epithelium to ambient levels of ozone. A morphologic and morphometric study of the transitional and respiratory epithelium. Am. J. Pathol. 128(1):29-44. Harkema, J.R., J.A. Hotchkiss, and R.F. Henderson. 1989. Effects of 0.12 and 0.80 ppm ozone on rat nasal and nasopharyngeal epithelial mucosubstances: Quantitative histochemistry. Toxicol. Pathol. 17(3):525-535. Harkema, J.R., C.G. Plopper, D.M. Hyde, J.A. St George, D.W. Wilson, and D.L. Dungworth. 1993. Response of macaque bronchiolar epithelium to ambient concentrations of ozone. Am. J. Pathol. 143(3):857-866.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 Harkema, J.R., K.T. Morgan, E.A. Gross, P.J. Catalano, and W.C. Griffith. 1994. Consequences of Prolonged Inhalation of Ozone on F344/N Rats: Collaborative Studies. Part VII. Effects on the Nasal Mucociliary Apparatus. Research Report No. 65. Health Effects Institute, Boston, MA. Harkema, J.R., J.A. Hotchkiss, E.B. Barr, C.B. Bennett, M. Gallup, J.K. Lee, and C. Basbaum. 1999. Long-lasting effects of chronic ozone exposure on rat nasal epithelium. Am. J. Respir. Cell. Mol. Biol. 20(3):517-529. Hassett, C., M.G. Mustafa, W.F. Coulson, and R.M. Elashoff. 1985. Murine lung carcinogenesis following exposure to ambient ozone concentrations. J. Natl. Cancer Inst. 75(4):771-777. Hatch, G.E., R. Slade, A.G. Stead, and J.A. Graham. 1986. Species comparison of acute inhalation toxicity of ozone and phosgene. J. Toxicol. Environ. Health 19(1):43-53. Hatch, G.E., R. Slade, L.P. Harris, W.F. McDonnell, R.B. Devlin, H.S. Koren, D.L. Costa, and J. McKee. 1994. Ozone dose and effect in humans and rats. A comparison using oxygen-18 labeling and bronchoalveolar lavage. Am. J. Respir. Crit. Care Med. 150(3):676-683. Herbert, R.A., J.R. Hailey, S. Grumbein, B.J. Chou, R.C. Sills, J.K. Haseman, T. Goehl, R.A. Miller, J.H. Roycroft, and G.A. Boorman. 1996. Two-year and lifetime toxicity and carcinogenicity studies of ozone in B6C3F1 mice. Toxicol. Pathol. 24(5):539-548. Horstman, D.H., L.J. Folinsbee, P.J. Ives, S. Abdul-Salaam, and W.F. McDonnell. 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(5):1158-1163. Horstman, D.H., B.A. Ball, J. Brown, T. Gerrity, and L.J. Folinsbee. 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):369-385. Horvath, S.M., J.A. Gliner, and J.A. Matsen-Twisdale. 1979. Pulmonary function and maximum exercise responses following acute ozone exposure. Aviat. Space Environ. Med. 50(9):901-905. HSDB (Hazardous Substances Data Bank). 2005. Ozone (CASRN: 10028-15-6). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed March 14, 2007]. Hu, S.C., A. Ben-Jebria, and J.S. Ultman. 1992a. Longitudinal distribution of ozone absorption in the lung: Quiet respiration in healthy subjects. J. Appl. Physiol. 73(4):1655-1661. Hu, S.C., A. Ben-Jebria, and J.S. Ultman. 1992b. Simulation of ozone uptake distribution in the human airways by orthogonal collocation on finite elements. Comput. Biomed. Res. 25(3):264-278. Hyde, D.M., R.P. Bolender, J.R. Harkema, and C.G. Plopper. 1994. Morphometric approaches for evaluating pulmonary toxicity in mammals: Implications for risk assessment. Risk Anal. 14(3): 293-302. Ichinose, T., and M. Sagai. 1992. Combined exposure to NO2, O3 and H2SO4-aerosol and lung tumor formation in rats. Toxicology 74(2-3):173-184. Jaspers, I., E. Flescher, and L.C. Chen. 1997. Ozone-induced IL-8 expression and transcription factor binding in respiratory epithelial cells. Am. J. Physiol. 272(3 Pt. 1):L504-L511.
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