National Ambient Air Quality Objectives For Ground-Level Ozone- Summary - Science Assessment Document

8. Human Health Effects - Continued

Acute effects: Emergency Department (ED) visits

Hospital Emergency Department (ED) visit data generally support the findings from the respiratory hospitalization studies, i.e., increases in ambient ozone concentrations are associated with significantly increased visits to the Emergency Department [Table 5 (SAD Table 12.3b)]. The percent increase in ED visits from single-pollutant studies varies from 5.9% per 10 ppb of 1-hour maximum ozone, to 7.2% per 10 ppb of 8-hour average ozone, to 11% per 10 ppb of 24-hour average ozone, usually lagged one or two days. When adjusted for PM, temperature, and other gaseous pollutants, for a 10 ppb increase in 5-hour average ozone, the increase in respiratory ED visits is 5.6-14.2%. The mean summertime ozone levels (1-5 hour metrics) varied between 30 ppb and 90 ppb. The results are considered consistent for these studies, given that two studies looked at children, two were for all ages in general, and two for 3 or 4 individual age groups. Four studies did not show significant increases in ED visits following elevated ozone pollution. Inadequacies in statistical analyses, including lack of treatments for underlying cyclic variation in ozone, temperature, and co-pollutants likely explain these results.

Table 5. Summary of relative risk estimates for Emergency Department Visits due to a 10 ppb increase in ozone concentrations, in univariate and multi-variate models (full references listed in Science Assessment Document).

Location and reference	Ozone mean oncentrations and range	Outcome (population included)	Percent increase (95% CI) per 10 ppb ozone. Ozone only models.	Percent increase (95% CI)_ per 10 ppb ozone. Multi-variate models.
New Jersey, USA Cody et al. 1992	49 ppb (mean of 5 h from 10am-3pm) 34 days >120 ppb (1988) 8 days >120 ppb (1989)	asthma, bronchitis (all ages)	-	5-h avg. ozone: +SO2, temperature, RH, visibility: 1988-1989 (lag 1d): 5.6% (1.7-9.5%); 1988 (lag 1d): 7.4% (2.5-12.3%); 1989 (lag 0d): 9.7% (3.2-16.2%); 1989 (lag 1d): 7.3% (1.4-13.2%)
New Jersey, USA Weisel et al. 1995	53 ppb (mean of 5 h from 10am-3pm)	asthma (all ages)	-	5-h avg. ozone: +temperature, RH, sulphate, NO2, SO2, visibility: 1986: 7.1% (0.04-14.2%) 1987: 7.7% (1.8-13.6%) 1988: 7.0% (1.1-12.9%) 1989: 14.2% (7.9-20.5%) 1990: 6.9% (2-11.8%)
Atlanta, Ga., USA White et al. 1994	78 ppb (mean of 1-h daily max.) (range 10-163 ppb)	asthma (children, ages 1- 16 yr., mostly black, low SES)	1-h max. ozone, when >110 ppb for asthma visits: 33% (-6% to 71%) for other causes of visits: Total: 37% (2-73%) Non-upper respiratory infection: 53% (14-92%).	1-h max. ozone: + temperature, PM10, day of the week: asthma visits at ozone >110 ppb: 42% (-1% to 100%, p=0.057). also corrected for autocorrelation + above factors: 43% (4-97%) + temperature, PM10, day of the week, pollen: 33% (-9% to 92%). +temperature, PM10, day of the week, dose-response relations: 80-90 ppb, 1% (-25% to 36%); 90-99 ppb, 24% (-7% to 65%); 100-109 ppb; 29% (-14% to 93%); 110 ppb, 50% (2-121%).
Mexico City, Mex. Romieu et al. 1995	90 ± 40 ppb (mean 1- h daily max) (range 10-250 ppb 28% of days >110 ppb)	asthma (children, <16 y)	-	1-h max. ozone: 8.60% (4.8-13.2%) +temperature, SO2, day of the week; 8.6% (4.6-13.0%) +temperature, SO2, day of the week, sex, age
Vancouver, BC Bates et al., 1990	1-h max., 30.4 ppb in summer; 18.8 in winter	Asthma, other respiratory and non-respiratory visits. All age, & 0- 14 y, 15-60 y, 61+y	1-h max. ozone: Associated with total ED visits; not with respiratory visits. No values given.	-
Barcelona, Spain Castellsagne et al., 1995	1-h summer: 43 ppb, winter: 29 ppb	Asthma, 14-64 y.	1-h max. ozone: No association Value not given.	1-h max. ozone: +Temperature, RH, month, day of the week, soybean loading: Summer: -0.7% (-4.7% to 3.5%). Winter: 4.3% (-0.16% to 9.1%).
Melbourn, Australia Rennick & Jarman, 1992	For ozone days, average 2.7 (range 1-6) stations recorded ozone levels >120 ppb (1- h) and >50 ppb (8-h avg.).	Asthma, >2 y children	-Smog alert days not significantly related to asthma ED visits. -Ozone days not significantly related to asthma visits. Results not given.	-
Toronto, ON Kesten et al., 1995	Data not shown	Asthma visits for all ages.	-Asthma visits not assoc. with ozone on daily, weekly or monthly basis; -associated with ozone with 7 day lag, but not 1 day lag. No value given	-
Montreal, Quebec Delfino et al. 1997	8-h: 1992: 33 ppb; 1993: 36 ppb; 1-h: 1992: 29 ppb; 1993: 31 ppb	all respiratory, asthma (all ages, separated into ages <2y, 2-34y, 35-64y, 65+y)	-No assoc. in 1992, no value given. -1993, no assoc. in <2y and 2-64y, no value given -1993, significant associations in >64y. 1-h max. ozone: 5.9% (2.4-9.4%); 8-h avg. ozone: 7.2% (2.9-11.5%).	1993 data, 8-h avg. ozone: the Elderly: 5.7% (0.21-11.2%) +PM2.5
Baton Rouge, Louisiana Jones et al., 1995	69.1 ppb (mean of 1- h max) (range 25.3-165 ppb) 4 days >120 ppb. 24-h average 28.2 (9.3-57.9).	all respiratory (all ages, separated into ages 0-17 y, 18-60y, 61+y	24-h avg. ozone: Children: -7.0% ( -15.4% to 1.4%) Adult: 11.1% (3.8-18.4%). Elderly: 4.5% ( -1.9% to 10.9%).	24-h avg. ozone, +temperature, RH, mold, pollen: Children: -6.5% (-17.3% to 4.3%) Adults: 9.9% (0.71-19.1%) Elderly: 13.4% (-3.2% to 30.0%).

Acute effects: The field (camp and panel) studies

Camp studies have the advantage that the subjects, usually children, are active in an environment in which pollutant levels can be closely monitored. In panel studies, a group of subjects (who may be asthmatics) are selected and their medical history and activity patterns and episodes of illness are closely followed. In such studies, pollution exposure can be more accurately gauged than for the general population. Endpoints studied were primarily changes in lung function and increased symptoms.

All eight camp studies reviewed have shown that exposure of healthy or asthmatic children and adolescents to ozone under ambient conditions (daily 1-hr maximum up to 160 ppb) can result in measurable declines in lung function and increases in respiratory symptoms. Most of the 13 panel studies reported significant decrements in pulmonary function and increases in symptoms and asthma medication use in asthmatic and healthy children and adults, in response to ozone episodes. The ozone levels ranged from low (daily 1-hour maximum below 40 ppb) to high (daily 1-hour maximum 390 ppb, in Mexico City). Outdoor workers and individuals who are exercising out of doors in summer experience measurable declines in pulmonary function, and, if exposures are repeated on consecutive days, also a systematic decline in pulmonary function. The decrements of pulmonary function were significantly associated with hourly maximum ozone (often below 80 ppb).

Chronic effects

Chronic effects have been more difficult to demonstrate at least partly because of the technical difficulty in conducting effective long term epidemiological studies and a consequent dearth of data. Most studies are cross-sectional in nature. In areas with chronically high ozone levels, a worsening of asthma symptoms, increased bronchial hyperresponsiveness and altered immunological function in children have been observed in the few studies available. Some studies have demonstrated permanent changes in lung function in the form of faster rates of lung function decline in adults living in more polluted regions, and possible lower than expected FEV₁ in children in higher ozone areas, but the effect of other co-occurring pollutants could not be evaluated. New evidence published in 1997 for persistent decrements of small airway function and new cases of asthma from chronic ozone exposure (lifelong residents of California) suggest that long term exposure to ambient ozone is of great public health and economic concern.

8.2 Controlled Human Exposure Studies

Carefully controlled, quantitative studies of exposed humans in laboratory settings offer a complementary approach to epidemiological investigations. The advantage of this type of study is the use of a highly controlled environment to identify responses to individual pollutant or pollutant mixtures to characterise exposure-response relationships where possible. In addition, such experiments provide an opportunity to examine interactions with other environmental variables, such as exercise, humidity or temperature. Potentially susceptible populations may also be directly studied, although those with more severe pre-existing disease and hence those most likely to be affected by air pollutants are naturally excluded from such studies. Clinical studies also have other limitations: for practical and ethical reasons, studies must be limited to small groups, which may not be representative of general population; exposure must also be limited to a short duration and to concentrations of pollutants that are expected to produce mild and transient responses; and exposures are often limited to a single pollutant, or to a very limited pollutant mix, which never replicates the complex mixture to which populations are actually exposed. Furthermore, transient responses in clinical studies have not been validated as predictors of more chronic and persistent effects.

Results from clinical studies

An important finding of human clinical studies is that at a given ozone concentration, the increase in ventilation results in elevated pulmonary function responses and inflammation. An increase in ventilation rate also lowers the concentration of ozone required for a given pulmonary response. Thus the concept of "effective dose" is introduced, namely, a product of the minute ventilation rate (V__E), the concentration of ozone ([ozone]) and the exposure duration (V__E x [ozone] x duration). This concept provides opportunity to further develop models and to investigate the sensitivity of different ages, genders, and disease status in response to ozone exposure. This also implies that persons doing outdoor exercise during an ozone episode may be at higher risk due to their increased intake of ozone. This assumption has been confirmed by observations that exposure to ozone concentrations as low as 60 ppb for only 16 to 28 min caused a significant decrease in endurance to heavy exercise and a significant increase in respiratory symptoms.

Exposure to ozone under controlled conditions leads to the appearance of symptoms (cough, shortness of breath, etc.), decrements in spirometric values, increases in airway resistance and bronchial responsiveness to stimuli, and airway inflammation. There is a large variability in response to ozone exposure between individuals. The range of response within each individual also varies, albeit not as much as between individuals. Prolonged exposure (6.6 hours) of healthy subjects to ambient levels of ozone (as low as 80 ppb) with intermittent exercise at ventilation rate (V__E) of 35 to 50 L/min has been found to cause increased bronchial responsiveness to methacholine to 33-56%, increased inflammation in deep airway (influx of polymorphonuclear neutrophils and proteins, and elevated inflammatory cytokins), and decreased FEV₁. For shorter exposure duration (1 to 4-hours) to ≤120 ppb ozone, a significant increase in bronchial responsiveness and airway inflammation has been observed, while little or no change in pulmonary function is seen.

A study using varying doses (0 to 240 ppb, back to 0 ppb) as well as a constant dose of 120 ppb over 8 hours has demonstrated that the varying doses produced FEV₁ decrements almost twice as large as the constant dose of ozone, although the total concentration was the same in the two dose regimens. These results suggest that the average dose value calculated as a mean over an 8-hour exposure may underestimate the effect of ozone on pulmonary function induced by a peak exposure.

With respect to the age difference in response to ozone, clinical studies have shown that adolescents appear to be more sensitive to ozone-induced pulmonary function decrements when compared with adults using the same dose regimen. Older adults (60 years or older) have not been shown to be more susceptible to ozone-induced pulmonary function changes than their younger counterparts when given the same dose. Of the hospitalization studies that compared the effects of ozone on different age groups, most of them did not find that elderly people (>65 years) were more at risk than younger populations (<65 years). This suggests that age itself may not be a major determinant of response to ozone exposure, and that young adults may be equally sensitive to ozone as older adults.

People with pre-existing respiratory diseases have been demonstrated to be more sensitive to ozone-induced health effects than are the healthy individuals. Patients with chronic obstructive pulmonary diseases (COPD) had significantly more loss of FEV₁ than their same age healthy counterparts (-19% versus -2%, respectively), when exposed to 240 ppb ozone for 4-hours during intermittent exercise (V__E = 20 L/min). COPD patients also show moderate increases in symptoms and decrease in blood oxygenation, conditions which were not seen in healthy subjects.

For patients with asthma, prolonged exposure (6.6 hours, to 120 to 160 ppb ozone, V__E approximately 30 L/min) has demonstrated more pronounced decrements of FEV₁ in asthmatics than in healthy subjects. Adolescent asthmatic patients appear to be more responsive to ozone-induced pulmonary function decrements. Ozone exposure at 120 - 180 ppb for 40 to 60 minutes caused significant reduction of lung function variables in adolescent asthmatics, but did not affect the lung function of adult asthmatics. Asthmatic subjects are revealed to be more sensitive toward ozone-induced airway inflammation than healthy subjects. At concentrations of 120 to 240 ppb (90 minutes at V__E - 50 L/min, and 6-hours at V__E - 25 L/min), ozone induced higher inflammatory responses in asthmatics than in healthy subjects. For patients with allergic rhinitis, data suggest that they have a greater rise in airway resistance than healthy subjects when exposed to 180 to 250 ppb ozone for 2 to 3-hours with intermittent exercise (V__E - 30 L/min). Allergen treatment exacerbated ozone-induced FEV₁ decrement in these patients.

So far no cardiac patients have been tested for their susceptibility to ozone exposure. No clinical study on tissue injury at ozone concentrations lower than 80 ppb has been conducted.

8.3 Animal Toxicological Studies

Studies on experimental animals (or on tissue samples) have many of the same advantages and disadvantages of controlled human studies. A wide range of pollutants and concentrations can be tested under controlled laboratory conditions for a dose-effect relationship, and autopsies of study animals can be performed to investigate tissue damage from exposure to pollutants. However, experimental studies very often involve well-defined pollutants that do not reflect full range of complex ambient pollutant mixtures to which humans are exposed, a problem noted above with respect to controlled human exposure studies. There is considerable uncertainty also in extrapolating results from animal inhalation studies and applying these results to humans for the purpose of risk assessment. Therefore, such studies are most appropriately used to explore mechanistic aspects of the toxicity of ozone.

Results from Animal Studies

Collectively, in the animal studies the deposition modelling of inhaled ozone indicates the terminal bronchiolar and centriacinar regions as sites of maximal tissue deposition of the gas.

For acute and short-term (<2 weeks) exposures for which adverse effects (inflammation) were observed, concentrations were as low as 100 ppb. For long-term (more than 2 weeks) studies, significant morphological changes have been observed at ozone concentrations as low as 120 ppb. The principal effects observed after acute exposures of a variety of species to ozone concentrations less than 1000 ppb are:

• effects on host defence (damaged mucociliary clearance cells, impaired alveolar macrophage phagocytotic ability, impaired bactericidal activity, reduced numbers of T- and B-lymphocytes), following acute or short-term exposures;
• lung inflammation and changes in lung permeability (increased influx of proteins and polymorphonuclear neutrophils in alveoli, airway epidelial cell necrosis, especially in centriacinar regions), after acute or long-term exposures;
• increased airway responsiveness to bronchoconstrictors (mostly acute exposures);
• impaired pulmonary function (which requires long term exposure, or acute exposure at high ozone concentrations >1000 ppb ozone), following acute or long-term exposures;
• reduction of heart rate, arterial blood pressure and core temperature, and increase in frequency of arrhythmia in rats (acute and short term exposures);
• increased mortality, at ozone concentrations as low as 300 ppb for 3 weeks, or 400 ppb for 3 hours in animals that were also challenged with Streptococcus zooepidemicus bacteria.

Ozone is, at most, a weak mutagen. There is not enough evidence to demonstrate that ozone is carcinogenic.

With respect to ozone interactions with other pollutants, most animal toxicological studies have been conducted with binary mixtures (predominantly with nitrogen dioxide or sulphuric acid). The effects of ozone interactions can be antagonistic, additive or synergistic, depending on the animal species, exposure regimen and endpoint studied. Therefore, the animal studies clearly demonstrate the complexities and potential importance of interactions, but do not provide a scientific basis for predicting the results of interactions under ambient exposure scenarios.

In most of the animal studies, the doses used are higher than those used for human clinical studies, as well as those seen in ambient air. However, a recent comparative dosimetric study using ¹⁸O-labelled ozone on humans and rats, was able to demonstrate that the exercising humans had 4- to 5-fold higher ¹⁸O concentrations in all of their bronchioalveolar lavage constituents than did the resting rats, when they were acutely exposed to the same dose of ozone (400 ppb). The humans also had significant increases in all of the airway inflammatory markers after 400 ppb ozone, whereas the rats did not. Thus, it is conceivable that the doses used in rats (as low as 100 ppb) that produced pathological changes are relevant to the concentrations encountered by human population during ozone episodes.

Mechanisms of effects

The ozone molecule is very reactive and is not likely to penetrate through cell membranes or even the surfactant layer of the lung. Thus it has been hypothesized that a "reactive cascade", starting from interaction of ozone with the lining of the lung, forms reactive oxygen intermediates that penetrate into the cells and cause the biological effects observed. Free radicals generated from the cascade and oxygenated biomolecules that result from reaction with ozone may mediate the effects of ozone. With respect to target molecules, most of the attention has been centred on polyunsaturated fatty acids and carbon-carbon double bonds as the prime targets of ozone. Reactions with sulfhydryl, amino, and some electron-rich compounds may be equally important.

8.4 Exposure Assessment

Exposure is defined as any contact at a boundary between a person and a specific ozone concentration for a specified time interval. Exposure assessment involves estimating the intensity, frequency, and duration of human contact with ozone.

Direct personal monitoring studies have been conducted in an attempt to delineate the ozone exposure levels in the immediate microenvironment (breathing zone) of the person, as opposed to using data from a fixed ambient monitor (FAM). Personal monitoring studies in Canada and the US reveal a temporal pattern of ozone exposure levels similar to that of FAM data, although ozone levels from personal monitoring are approximately 50% lower than the concentrations from FAM. These results suggest that ozone data from FAM, often used in epidemiological studies, can be a good indicator for population exposure, especially during summer in Canada. On average, ozone concentrations obtained from personal monitoring studies are 70% higher than those in indoor air, and 50% lower than those in outdoor air. The drawback of most personal monitoring data is that they are collected over relatively long averaging times (12 hours, 24 hours or weekly). Data from health effect studies have demonstrated that acute increases in mortality and morbidity are significantly associated with daily 1-hour maximum ozone concentrations. Averaging concentrations over longer times cannot adequately assess these acute responses.

Predictive exposure assessment studies using probabilistic National (Ambient Air Quality Standard) Exposure Model (pNEM) provide estimates of the distribution of ozone exposures within a defined population for a specified exposure period. This model uses detailed information on human activity patterns, indoor-outdoor ozone concentration ratios, and air exchange rates to predict how many days a "typical person" in a sub-population cohort will be exposed above any given level during a specified exposure period.

Results from pNEM modelling using populations from Toronto, Montreal and Vancouver for 1988, 1990 and 1991 demonstrate that an average of 42% (Vancouver) to 91% (Toronto) of the population were exposed to ozone above 82 ppb (1-hour maximum; the existing Canadian National Ambient Air Quality Objective) for at least once a year. Almost 92% to 100% of the population were exposed to 50 ppb or higher level of ozone at least once a year. During the worst pollution year (1988), almost half of the Toronto population were exposed to 82 ppb ozone for more than 5 days, whereas in Vancouver only 6.4% of the population were exposed to 82 ppb ozone for more than 2 days. The pNEM data are in agreement with the results from FAM indicating that the ambient ozone concentrations and the number of episode days are significantly higher in Toronto than in Vancouver, with Montreal in the middle of the range. The pNEM data also are in line with Canadian hospitalization studies that have consistently shown a lower hospitalization risk associated with ozone in Vancouver and Montreal than in other parts of the country.