Ozone

Endpoint summary

Additional information

Health surveillance data

There are three available studies focussing on cardiovascular effects and one study on respiratory effects of ozone. In some of these studies, the association between ozone exposure and health effects of interest is quite weak, or sometimes it is even unclear whether reported effects might be associated with other air pollutants. Furthermore, some of the reported findings have only been observed in one study, and/or the effects are so small that they could be seen as a response within normal physiological bounderies (of homeostasis).

 

Cardiovascular/myocardial effects

Ruidavets et al. (2005) studied the association between documented short-term atmospheric ozone exposure in an urban environment and acute myocardial infarction (via registry) within the general population in the south of France. The main finding of this study is a positive relationship between acute heart disease occurrence and ozone exposure. Moreover, analyses performed for a period of 3 days preceding the infarction suggest occurrence of an acute heart disease event during the first 24 hours after ozone exposure. The attributable risk for the population with the age between 35-64 years was around 4-5% according to the definition of acute mycardial infarction used. The attributable risk reached 12% when the oldest population (aged 55-64 years) without history of ischemic heart disease was considered. In this study no associations were found between NO₂ or SO₂ atmospheric exposure and acute myocardial infarction. It should be noted that exposure to particulate matter was not included in the analysis; thus, the contribution of ozone exposure to the relative risk for acute myocardial infarction could be overestimated.

 

A study by Devlin et al. (2012) involving 23 young healthy individuals provides supporting information that exposure to 0.3 ppm ozone for 2 hours airway inflammation and injury as manifested by changes in cellular markers of inflammation and changes in lung function in healthy subjects. Furthermore, this study shows that exposure of healthy young adults to 300 ppb ozone causes an increase in vascular markers of inflammation, changes in fibrinolytic markers that could potentially impair fibrinolysis and changes in autonomic control of heart rate. However, although some of these changes appeared to be statistically significant with the data analysis performed, the magnitude of the changes were small and the clinical significance was not discussed. The biomarkers measured may be on the causal pathway to cardiovascular effects; the extent of the changes is at such a small magnitude that they are more likely indicative of homeostatic processes and thus do not provide sufficient information on the potential of ozone to trigger adverse cardiovascular effects.

A study by Arjomandi et al. (2015) in 26 subjects provides supporting information that exposure for 4 hours to 100 or 200 ppb ozone causes dose-dependent airway inflammation and injury as manifested by changes in molecular and cellular markers of inflammation and increased total protein in bronchoalveolar lavage fluid and transient changes in lung function in healthy and mild asthmatic subjects. Peripheral blood examinations suggested that inhalation of ambient levels of ozone results in an increase in C-reactive protein, perceived by the authors as a systemic inflammatory response, occurring 1 day after the exposure. Measurements of heart rate and heart rate variability (HRV) suggests that ozone exposure (at levels as low as 100 ppb) leads to cardiac autonomic effects as indicated by frequency-domain variables of HRV. The authors state that these effects may contribute to the cardiovascular morbidity associated with short-term exposure to ambient ozone. However, the effect size observed in this study is small and could also be interpreted as a response within normal physiological bounderies without any adverse impact.

Respiratory effects

In a descriptive study by Adam-Poupart et al. (2015), the association between respiratory disease-related work compensations and atmospheric ozone levels during the summer months in Quebec, Canada was investigated. The estimated ozone levels ranged from 7 to 61 ppb. Data analysis revealed no relationship between such compensations and ozone for all industrial sectors. For outdoor workers, associations between the compensations and ozone levels were positive; however, a large statistical variability was noted, and, after adjusting for temperature, the association between compensations and ozone levels was reduced to null. The authors listed a number of limitations of their study for outdoor workers and stated that it is unclear if the observed trends for outdoor workers are due to ozone levels, to high temperatures or to other unmeasured parameters that are associated with them. It was concluded from this study that the atmospheric ozone levels up to 61 ppb are not associated with respiratory disease-related compensations at an "all industry" level in the Quebec region. 

Epidemiological data

The US Environmental Protection Agency (US EPA) performed and published an integrated science assessment (ISA) for ozone (US EPA, 2013). In this assessment, the collective information of a large number of epidemiological human studies was reviewed and summarised. Since this is the most current and comprehensive integrated analysis of the human exposure to ozone, the conclusions from the US EPA ISA report on the epidemiological studies of ozone provide sufficient information for the dossier. The main conclusions for the epidemiological studies, as sorted by either short-term (e.g. within hours, days or weeks up to 30 days) or long-term (more than 30 days) ozone exposure, are provided in the tables below.

Short term:

Health Outcome	Conclusion from epidemiological studies or controlled human exposure studies
Lung function	Controlled human exposure studies demonstrate group mean decreases in FEV1 of 2 -3% with 6.6 -hour exposures to as low as 60 ppb (= 0.12 mg/m^3) O3. The collective body of epidemiologic evidence demonstrates associations between short-term ambient O3 exposure and decrements in lung function, particularly in children with asthma, children, and adults who work or exercise outdoors.
Airway hyperresponsiveness	Increased airway responsiveness has been demonstrated at 80 ppb (= 0.16 mg/m^3) in young, healthy adults.
Pulmonary inflammation, injury and oxidative stress	Epidemiological studies provided evidence for associations of ambient ozone with mediators of airway inflammation and oxidative stress and indicate that higher antioxidant levels may reduce pulmonary inflammation associated with ozone exposure. Generally, these studies had mean 8-h max ozone concentrations less than 73 ppb (= 0.146 mg/m^3). Controlled human exposure studies show O3-induced inflammatory responses at 60 ppb, the lowest concentration evaluated.
Respiratory symptoms and medication use	The collective body of epidemiologic evidence demonstrates positive associations between short-term exposure to ambient O3 and respiratory symptoms (e.g. cough, wheeze, and shortness of breath) in children with asthma. Generally, these studies had mean 8-h max O3 concentrations less than 69 ppb (= 0.138 mg/m^3).
Lung host defenses	Studies demonstrating altered immune responses and natural killer cell function provide further evidence that O3 can affect multiple aspects of innate and acquired immunity with short-term O3 exposures as low as 80 ppb (= 0.16 mg/m^3). Controlled human exposure studies demonstrate the increased expression of cell surface markers and alterations in sputum leukocyte markers related to innate adaptive immunity with short-term O3 exposures of 80-400 ppb (= 0.16-0.8 mg/m^3).
Allergic and asthma related responses	Controlled human exposure studies demonstrate enhanced allergic cytokine production in atopic individuals and asthmatics, increased IgE receptors in atopic asthmatics and enhanced markers of innate immunity and antigen presentation in health subjects or atopic asthmatics with short-term exposure to 80-400 ppb (=-0.16-0.8 mg/m^3) O3, all of which may enhance allergy and/or asthma.
Respiratory Hospital admissions, ED visits, and physician visits	Consistent, positive associations of ambient ozone with respiratory hospital admissions and emergency department visits in the US, Europe, and Canada with supporting evidence from single city studies. Generally, these studies had mean 8-h max O3 concentrations less than 60 ppb (= 0.120 mg/m3).
Respiratory Mortality	Several multicity time-series studies and a multicontinent study consistently demonstrated associations between ambient ozone and respiratory-related mortality across the US, Canada and Europe along with supporting evidence from single city studies. Generally, these studies had mean 8-h max ozone concentrations less than 63 ppb (= 0.126 mg/m^3).
Cardiovascular effects	The overall body of evidence across disciplines indicates that there is likely to be a causal relationship for short-term exposures to O3 and cardiovascular effects.
Central nervous system effects	The collective evidence from studies of short-term exposure to O3 is suggestive of a causal relationship between O3 exposure and CNS effects.
Total mortality	The collective evidence indicates that it is likely that there is a causal relationship between short-term exposures to O3 and total mortality.

  

Long term:

Health Outcome	Conclusion from epidemiological studies or controlled human exposure studies
New onset asthma	There is evidence to indicated that different genetic variants (HMOX, GST, ARG), in combination with ozone exposure, are related to new onset asthma. These associations were observed when subjects living in areas where the mean annual 8-h max ozone concentration was 55.2 ppb (= 0.110 mg/m^3) compared to those who lived in areas where ozone concentration was 38.4 ppb (= 0.0768 mg/m^3).
Asthma hospital admissions	Chronic ozone exposure was related to first childhood asthma hospital admissions in a positive concentration-response relationship. Generally, these studies had mean annual 8-h max ozone concentrations less than 41 ppb (= 0.082 mg/m^3).
Pulmonary structure and function	Evidence for ozone-mediated effects on pulmonary function is inconclusive. However, some epidemiological studies observed positive associations between ozone (mean annual 8-h max O3 concentrations of less than 65 ppb (=0.130 mg/m^3) and altered pulmonary function.
Pulmonary inflammation, injury and oxidative stress	Several epidemiological studies (with mean 8-h max O3 concentrations of less than 69 ppb= 0.138 mg/m^3) provide some observations of O3-induced inflammation and pulmonary injury.
Allergic responses	Evidence shows positive correlation between allergic response and O3 exposure but with variable strength for the effect estimates; exposure to O3 may increase total IgE in adult asthmatics.
Respiratory mortality	A single study demonstrated that exposure to O3 (long-term mean O3 of less than 104 ppb) elevated the risk of death from respiratory causes, and this effect was robust with the inclusion of PM2.5.
Cardiovascular Effects	The overall body of evidence across disciplines is suggestive of a causal relationship between long-term exposures to O3 and cardiovascular effects.
Reproductive and developmental effects	The overall evidence is suggestive of a causal relationship between long-term exposures to O3 and reproductive and developmental effects.
Central nervous system effects	The overall evidence from studies of long-term exposure to O3 is suggestive of a causal relationship between O3 exposure and CNS effects.
Cancer	The overall evidence is inadequate to determine if a causal relationship exists between ambient O3 exposures and cancer.

Findings on mortality

Jerrett et al. (2009) examined the association between mortality due to either cardiovascular or respiratory causes and pollutants (e.g. particulate matter and ozone) in a cohort of nearly 500,000 subjects from the American Cancer Society Cancer Prevention Study II, studying 118,777 deaths in an 18-year follow-up period. The study provides important evidence that associations between health effects and pollutant exposure should not be studied in isolation (single-pollutant-models). In single-pollutant models, increased concentrations of either particulate matter or ozone were significantly associated with an increased risk of mortality from cardiovascular causes. However, in two-pollutants models, ozone was associated with the risk of mortality from respiratory causes while fine particulate matter was associated with a risk of mortality from cardiovascular causes. In summary, the two-pollutants model estimates an increase in the risk of mortality due to respiratory causes of 4% for every 10 -ppb increase in ozone exposure with no additional risk of mortality due to cardiovascular causes.

Populations at increased risk for ozone-related health effects

The populations identified to have increased risk of O₃-related health effects are individuals (especially children) with asthma, younger and older age groups, individuals with certain dietary deficiencies, and outdoor workers (US EPA, 2013; Mortimer et al., 2002).

Findings on fertility

Few epidemiological studies have been published that have evaluated potential effects on fertility in humans in relation to ozone concentrations. Four studies measured sperm parameters

but overall

reported inconsistent decreases in average sperm concentration and/or average sperm count in relation to ozone concentrations measured during the 90 days before semen collection (the period of spermatogenesis).

One other study reported the probability of pregnancy (via intercourse) in relation to ambient ozone. Sokol et al. (2006) conducted a repeated-measures study in Los Angeles, California. The investigators studied 5,134 sperm donations from 48 study subjects during 1996-1998. The investigators reported statistically significant decreases in average sperm concentration during ozone concentrations measured during the 90 days before semen collection and within specific exposure windows (0-9 days, 10-14 days, and 70-90 days before semen collection). The results were adjusted for donor’s age at time of donation, birth date, temperature and seasonality. Study subjects’ ozone concentrations were estimated based on zip code of residence from fixed site monitors. Daily 24-hour ozone concentrations averaged 21.68 ppb (43.36 µg/m³).

Tian et al. (2017) studied semen quality measures in 1,780 men aged 20 to 40 years in relation to daily 8 hour average concentrations of O₃ in Wuhan, China. The investigators reported statistically significant decreased sperm concentration and count with every 1 µg/m³ (=0.001 mg/m³) increase of O₃ during various exposure windows (0-9 days,

day 10

and 10-14 days). [Note: This information was based on the review of an English language abstract of a Chinese language article. Study subjects were reported in the English language abstract as attending a reproductive medicine center. Consequently, it is not clear from the abstract if the study subjects were being evaluated for fertility issues or were considered healthy sperm donors. The abstract does not specify if the study was based on repeated measures of semen or a single semen sample.]

Hansen et al. (2010) investigated the effect of exposure to O₃ and PM_2.5 on sperm quality in 228 men located in three southeastern counties in the US (Wake County, NC; Shelby County, TN; Galveston County, TX). The average concentrations for the three counties were approximately 30-32 ppb (=60-70 µg/m³). The investigators reported decreases in sperm concentration with O₃ concentration although the decreased in sperm concentration and counts were not statistically significant after controlling for temperature and season. Farhat et al. (2016) conducted a repeated-measures analysis of semen donated by 28 men with systemic lupus erythematosus in Sao Paolo, Brazil. Daily concentrations of ozone were evaluated 90 days before each semen collection date. Statistically significant decreases in sperm concentration and count were observed between exposure to ozone as well as intravenous cyclophosphamide (IVCYC) use during an exposure window of 80 to 88 days before semen collection. The association between ozone and decreased sperm concentration and count persisted in 17 patients who had never used IVCYC. The 8-hr average ozone concentrations were 83.3 µg/m³ during the study period. Slama et al. (2013) reported no relation between ozone exposure (and other pollutants) and probability of pregnancy. In a cohort of 2,675 births occurring during 1994-1999 in Teplice, Czech Republic, the investigators studied 1,916 couples, which 486 of them conceived during the first month of intercourse. The investigators did not observe decreases in the probability of pregnancy during the first month of intercourse in relation to ozone concentrations (as measured in a central monitoring station). The analysis was adjusted for maternal age at start of period of intercourse, maternal smoking, maternal education, marital status, maternal body mass index and parity.

Overall, the epidemiologic evidence for an association between O₃ and effects on fertility is limited. The results of the published studies are suggestive of potential decreases in sperm concentration and counts in relation to ozone.

Human volunteer studies

A total of 15 human volunteer studies have been reviewed regarding effects of ozone exposure in healthy subjects (Schelgele et al., 2009; Hernandez et al., 2010a, 2010b; Kim et al., 2011; Adams et al., 2002, 2006; Folinsbee and Hazucha, 2000; Tank et al., 2011; Jorres et al., 2000; Que et al., 2011; Stenfors et al., 2002; Ratto et al., 2006; Holz et al., 2001; DFG, 1998; Alexis et al., 2010). Primarily, the effects of short-term ozone exposures (e.g. single exposure up to 8 hours or repeated exposure of 4 h/day for up to 4 days) on pulmonary function have been studied in detail in controlled chamber studies. Most of these studies have focused on the functional and inflammatory responses of healthy, young and intermittently exercising adults, who are exposed to environmental concentrations of ozone at constant temperature and humidity. These studies have revealed a spectrum of responses, including cough, throat irritation, shortness of breath and pain upon deep inspiration with measurable reductions in lung volume parameters (FEV1 and FVC) during spirometry, the development of airway inflammation as well as tissue injury with altered airway permeability. Generally, the responses are dependent on ozone concentration, minute volume and exposure duration and resolve completely within a few days after the end of exposure. There is a large variation in ozone-induced responses between subjects. Adverse lung function decrements have consistently been observed with controlled human exposures for 6.6 h to ozone of at least 0.08 ppm, but the evidence for adverse effects at lower exposures to 0.06 ppm ozone is less clear. While some studies reported statistically significant effects at 0.06 ppm, others reported no significant effects at this level. Ozone-induced functional and inflammatory changes in the lung were evident in healthy subjects performing mediate exercise, when exposed to either 0.2 ppm ozone or higher for a short (< 2 h) time or to 0.06 ppm ozone or higher for a pro-longed time (6.6 h). Exposure of healthy subjects for 6.6 hours to 0.04 ppm appeared to be without an effect on lung function.

Air quality standards

Based on the overall assessment of epidemiological studies, human controlled exposure studies and toxicity studies, the EPA has recently proposed updates of the air quality standards (US EPA, 2013). The current primary (health) Standard to protect the general population is an 8-hour standard of 75 ppb (= 0.15 mg/m³), and the EPA is proposing to strengthen the health standard to a level within the range of 65 (= 0.13 mg/m³) to 70 ppb (= 0.14 mg/m³). In addition, the EPA is proposing to adjust the Standard to protect the Public Welfare (environment) to a level in the same range proposed to the primary standard.

Summary/conclusion

There is sufficient evidence from both epidemiological and controlled-exposure (of healthy volunteers) studies to indicate that ozone exposure (short-term and long-term) results in various respiratory effects such as decreased lung function, increased airway hyperresponsiveness, allergy-related immune responses, etc.. On the other hand, there is limited information available on other health outcomes (e.g. cardiovascular, reproductive). There is some evidence suggesting effects of ozone on sperm parameters as well as increased risk of mortality with exposure to increasing concentrations of ozone. The populations identified to have increased risk of O₃-related health effects are individuals (especially children) with asthma, younger and older age groups, individuals with certain dietary deficiencies, and outdoor workers.

The current primary (health) standard set by the US EPA to protect the general population is an 8-hour standard of 75 ppb (= 0.15 mg/m³), and the EPA is proposing to strengthen the health standard to a level within the range of 65 (= 0.13 mg/m³) to 70 ppb (= 0.14 mg/m³).