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Health Effects of Ozone in the General Population

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Introduction

Inhaling ground-level ozone can result in a number of health effects that are observed in broad segments of the population. Some of these effects include:

Respiratory symptoms can include:

This section addresses exposure and health effects issues common to all people. The following section addresses those issues specific to people with asthma and possibly other people with existing lung diseases.

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How are people exposed to ozone?

Exposure occurs when people inhale ambient air containing ozone. The rate of exposure for a given individual is related to the concentration of ozone in the surrounding air and the amount of air the individual is breathing per minute (minute ventilation).

Although ozone concentrations in the outside (ambient) air are generally similar across many locations in a particular airshed, a number of factors can affect ozone concentration in "microenvironments" within the larger airshed (e.g., inside a residence, inside a vehicle, along a roadway). Ozone concentrations indoors typically vary between 20% and 80% of outdoor levels depending upon whether windows are open or closed, air conditioning is used, or other factors. People with the least exposure in a particular location are those resting in an air-conditioned building with little air turnover.

People with the greatest exposure are those heavily exercising outdoors for long periods of time when ozone concentrations are high. This is because heavily exercising people tend to breathe more rapidly and deeply (increased tidal volume). In addition, when people breathe more deeply, ozone uptake may shift from the upper airways to deeper areas of the respiratory tract, increasing the possibility of adverse health effects, as explained below.

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How does ozone react in the respiratory tract?

Because ozone has limited solubility in water, the upper respiratory tract is not as effective in scrubbing ozone from inhaled air as it is for more water soluble pollutants such as sulfur dioxide (SO2) or chlorine gas (Cl2). Consequently, the majority of inhaled ozone reaches the lower respiratory tract and dissolves in the thin layer of epithelial lining fluid (ELF) throughout the conducting airways of the lung.

In the lungs, ozone reacts rapidly with a number of biomolecules, particularly those containing thiol or amine groups or unsaturated carbon-carbon bonds. These reactions and their products are poorly characterized, but it is thought that the ultimate effects of ozone exposure are mediated by free radicals and other oxidant species in the ELF that then react with underlying epithelial cells, with immune cells, and with neural receptors in the airway wall. In some cases, ozone itself may react directly with these structures. Several effects with distinct mechanisms occur simultaneously following a short-term ozone exposure and will be described below.

Schematic illustration showing how ozone injures the lining of the respiratory tract. Figure 2: Ozone is highly reactive in the respiratory tract. When breathed into the airways, ozone interacts with proteins and lipids on the surface of cells or present in the lung lining fluid, which decreases in depth from 10 µm in the large airways to 0.2 µm in the alveolar region. Epithelial cells lining the respiratory tract are the main target of ozone and its products. These cells become injured and leak intracellular enzymes such as lactate dehydrogenase into the airway lumen, as well as plasma components. Epithelial cells also release a variety of inflammatory mediators that can attract PMNs into the lung, activate alveolar macrophages, and initiate a train of events leading to lung inflammation. Antioxidants present in cells and lining fluid may protect the epithelial barrier against damage by ozone or its reaction products.
Source: Devlin et al., (1997)

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What are ozone's acute effects?

Short-term ozone exposure - up to 8 hours - induces lung function decrements such as reductions in forced expiratory volume in one second (FEV1) and some or all of the following respiratory symptoms:

These effects are reversible, with improvement and recovery to baseline varying from a few hours to 24 to 48 hours after an elevated ozone exposure.

Current thinking is that both symptom and lung function changes are due to stimulation of airway neural receptors (probably airway C-fibers) and transmission to the central nervous system via afferent vagal nerve pathways. Although ozone exposure results in some airway narrowing, neural inhibition of inspiratory effort at high lung volumes is believed to be the primary cause of the predominant physiological effect, being unable to inhale to total lung capacity (TLC).

Schematic illustration showing how ozone stimulation of bronchial nerve fibers induces respiratory responses. Figure 3: Ozone induces neurally mediated responses in the bronchial airways. Stimulation of nociceptive interepithelial nerve fibers by ozone leads to reflex cough and a decrease in maximal inspiration that is relieved by opioid agonists, which block sensory pathways. Two possible mechanisms are involved: (1) stimulation of irritant receptors contributes to cough and induces a vagally mediated reflex that increases airway resistance, probably via airway smooth muscle contraction that is blocked by atropine; (2) C fiber stimulation releases neurokinins such as substance P that dilate nearby capillaries, activate mucous glands, and contract airway smooth muscle via neurokinin receptors. Prostaglandin E2 released by epithelial cells exposed to ozone or to ozone reaction products also sensitizes C fibers.   Source: Devlin et al. (1997)

The major effect is thus restrictive rather than obstructive in nature and reflects itself in decreases in forced vital capacity (FVC), FEV1 and other spirometric measures that require a full inspiration. Observed changes in breathing pattern to one with more rapid shallow breathing may also be a manifestation of C-fiber stimulation and may be a protective response to limit penetration of ozone deep into the respiratory tract. It is likely that these lung function changes and respiratory symptoms are responsible for observations that short-term ozone exposure limits maximal exercise capability.

Graph depicting the effects of ozone on lung function. Ozone reduces the maximum inspiratory position and may slightly reduce the maximum expiratory position. Figure 4: Effects of ozone on lung function. Ozone reduces the maximal inspiratory position (at the left of the curves) and may slightly increase the residual volume (at the right). Reduction in maximum inspiration reduces forced vital capacity (FVC), and this causes a reduction in expiratory flow measurements, such as flow at 50% of FVC expired (FEF50%). Because ozone causes only a small change in resistance, the relationship between flow and volume is not changed to a large extent.
Source: Devlin et al. (1997)

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What effects does ozone have at the cellular level?

As a result of short-term exposure, ozone and/or its reactive intermediates cause injury to airway epithelial cells followed by a cascade of other effects. These effects can be measured by a technique known as bronchoalveolar lavage (BAL), in which samples of ELF are collected during bronchoscopy on volunteers experimentally exposed to ozone. Cells and biochemical markers in the lavage fluid can be analyzed to provide insight into the effects of exposure.

Cellular injury is suggested by an increase in the concentration of lactate dehydrogenase (LDH), an enzyme released from the cytoplasm of injured epithelial cells, in the ELF. Mediators (e.g., cytokines, prostaglandins, leukotrienes) that are released by injured cells include a number that attract inflammatory cells resulting in a neutrophilic inflammatory response in the airway.

Other effects that may be related to the underlying injury and inflammatory response are:

The decrease in barrier function is measured by an increase in the concentration of plasma proteins appearing in the ELF following exposure and by more rapid clearance of inhaled radio-labeled markers from the lung to the blood. This has the potential for allowing increased movement of inhaled substances (e.g. allergens) from the airway to the interstitium.

Although the significance of increased nonspecific airway reactivity to substances such as methacholine or histamine is not understood in healthy individuals, it is clearly of concern for people with asthma, as increased airway reactivity is a predictor for asthma exacerbations. (See section entitled How does ozone affect people with asthma?).

Over a period of several days following a single short-term exposure, inflammation, small airway obstruction, and increased epithelial permeability resolve; damaged ciliated airway epithelial cells are replaced by underlying cells; and damaged type I alveolar epithelial cells are replaced by more ozone-resistant type II cells. Over a period of weeks, the type II cells differentiate into type I cells, and following this single exposure, the airway appears to return to the pre-exposure state.

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What are the other potential effects of short-term ozone exposure?

Some epidemiological studies have associated daily ozone levels with several other effects, the mechanisms of which are not known. On days with high ozone concentration, for example, respiratory symptoms, illness, or disease lead more people to be absent from school, visit doctors or emergency rooms, and be admitted to hospitals. Newly reported observations suggest that daily ozone concentrations may also be associated with increased mortality, but it is not clear what populations are at increased risk. Distinguishing effects due to ozone, other pollutants, or pollutant combinations is an ongoing research focus.

Causality for the effects observed in epidemiological studies has not been clearly established, and these relationships have not been as well characterized as the observations resulting from controlled human exposure studies, as mentioned above. Studies of laboratory animals and of immune cells in vitro also indicate that ozone exposure can modulate immune response, although the significance of this for humans is not known at this time.

Graph showing how the number of adjusted respiratory hospital admissions rose as the daily maximum 1-hour level (ppm), lagged 1-day increased. Figure 5: The number of emergency or urgent daily respiratory admissions to acute care hospitals is related to estimated ozone exposure. Respiratory admission rates to 168 hospitals in Ontario, Canada during the period 1983 through 1988 are plotted against deciles of the daily 1-hour maximum ozone concentration, lagged by 1 day. Admission rates were adjusted for seasonal patterns, day-of-week effects, and hospital effects. Ozone displayed a positive and statistically significant association with respiratory admissions for 91% of the hospitals during the Spring through Fall seasons, but not during the Winter months of December to March when ozone levels were low.   Source: Burnett et al., 1994; U.S. EPA, 1996

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Hoes does response vary among individuals?

One striking characteristic of the acute responses to short-term ozone exposure is the large amount of variability which exists among individuals. For a 2-hour exposure to 0.4 parts per million (ppm) ozone that includes 1 hour of heavy exercise, the least responsive individual may experience no symptom or lung function changes while the most responsive individual may experience a 50% decrement in FEV1 and have severe coughing, shortness of breath, or pain on deep inspiration. Other individual responses fall into what appears to be a unimodal distribution between these two extremes. Differences in responsiveness seem to be stable over periods of at least one year as evidenced by similar responses within individuals following re-exposure. The only factor found to explain any of this variability is age, with young adults (teens to thirties) being much more responsive than older adults (fifties to eighties).

Graph plotting decrements in FEV1 (liters) during exposure to different levels of ozone. The mean response to exposure is represented by the yellow line with the red and blue shaded areas representing individuals with greater and lesser responsiveness to ozone. Figure 6: Variability of response to ozone exposure.
Source: Devlin et al. (1997) 		Graph plotting mean FEV1 decrements (liters) as a function of concentration for three different age groups. Figure 7: Sensitivity to ozone exposure is age related.
Source: Devlin et al. (1997)

The majority of the variability in response is unexplained, however. Although variability in other responses such as cell injury and inflammation has been observed, it has not been determined whether this represents stable individual differences in these responses or day-to-day variability in response or measurement. It does appear, however, that the magnitude of the neurally-mediated lung function response is not related to the degree of cell injury and inflammation for a given individual.

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At what exposure levels are effects observed?

The lowest concentration at which effects are observed depends upon the level of activity, the duration of exposure, and the sensitivity of each individual to ozone. Although this is almost certainly true for all effects of ozone, levels that cause effects have been best characterized for symptom and lung function changes. For example, an adult of average sensitivity exposed for 2 hours while alternating heavy exercise and rest would be expected to experience small lung function and symptom effects following exposure to 120 parts per billion (ppb) ozone. An average adult undergoing moderate exercise might experience similar effects as well as lung injury and inflammation following an 8-hour exposure to 80 ppb ozone. More sensitive individuals may experience such effects at lower concentrations while less sensitive or less heavily exercising individuals may not experience effects at these levels. Children without asthma experience lung function decrements similar to those of adults, but do not report respiratory symptoms at the lowest ozone concentrations. It is not clear whether this is the result of reduced sensitivity with regard to symptoms or whether children are less likely to recognize and report mild symptoms.

Emergency room data from one study indicate that asthma attacks in the most sensitive population (e.g., children with asthma or reactive airway disease) increase following days on which the 1-hour maximum ozone concentrations exceeded 110 ppb. (White et al., 1994) Another study observed increased emergency room visits for asthma on days following those when 7-hour averages exceeded 60 ppb compared to those with lower ozone concentrations. (Weisel et. al., 1995) Based on results from several field studies, the lung function of highly active asthmatic and ozone sensitive children in open-air summer camps and the exercise performance of endurance athletes may be affected on days when the 8-hour maximum ozone concentration exceeds 80 ppb ozone. (U.S. EPA, 1996, Air quality criteria for ozone related photochemical oxidants.)

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What are the effects of recurrent or long-term exposure to ozone?

One of the major unanswered questions about the health effects of ozone is whether repeated episodes of damage, inflammation, and repair induced by years of recurrent short-term ozone exposures result in adverse health effects beyond the acute effects themselves.

Daily ozone exposure for a period of 4 days results in an attenuation of some of the acute, neurally-mediated effects (e.g., lung function changes and symptoms) for subsequent exposures occurring within 1 to 2 weeks. Some health experts have, therefore, suggested that individuals living in high ozone areas may be protected from any harmful effects of long-term ozone exposure. Others suggest, however, that the attenuation of the ozone-induced tendency to take rapid and shallow breaths may blunt a protective mechanism, resulting in greater delivery and deposition of ozone deeper in the respiratory tract.

Studies including bronchoalveolar lavage and bronchial mucosal biopsies indicate that, unlike the neurally-mediated lung function changes, the processes of airway injury, inflammation, and repair continue to occur during repeated exposure. After either 4 or 5 days of exposure, markers of cell injury and increased epithelial permeability remain elevated, and an increase in airway mucosal PMNs, which was not present following a single exposure, has been noted. Also, unlike the neurally-mediated effects, small airway function has been observed to remain depressed over the course of exposures and is thought to be related to the ongoing inflammation.

Part of the difficulty in determining whether long-term exposure to ozone results in adverse chronic respiratory effects has been the paucity of good, longitudinal air pollution epidemiologic studies in general. Studies have to contend with assessment of exposure over a period of many years, confounding co-exposures, subject migration, and even an interpretation of what, if any, adverse effects may be caused by such exposures.

Despite limitations, there is some preliminary epidemiologic evidence that long-term ozone exposure may result in the induction of new asthma. This is supported by animal toxicological evidence that co-exposure to ozone can enhance sensitization to known allergens. New data in nonhuman primates also indicate that exposure very early in life during respiratory tract maturation may have profound effects upon the distribution and function of various cell types in the airway, suggesting that young children may be especially susceptible to effects of ozone on lung development.

How such developmental effects may manifest themselves in later life is not clear. Consistent with the ongoing process of damage, inflammation, and repair noted above, long-term laboratory animal exposures result in chronic inflammation in the terminal bronchioles, an increase in interstitial fibrous material, and some change in cell types in the distal airway without, however, any evidence of physiological dysfunction. More research to determine whether these changes are precursors to development of chronic respiratory disease is needed. These findings all suggest that it would be prudent to avoid repeated short-term exposures, particularly in young children, until more is known about the effects of long-term ozone exposure.

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