Continuing Education Activity

Ozone normally occurs in a gas state as three atoms of oxygen (O) linked in a cyclic structure and is a by-product of water purification, bleaching, and any process generating a spark or electric arc in the presence of oxygen. It is also found in the atmosphere, with higher altitudes containing higher levels of ozone. Ozone is also an environmental air pollutant, along with others, such as sulfur dioxide and particulate matter. In spite of this, ozone can be generated by medical devices for therapeutic purposes. Outside of medicine, ozone has been proposed for use in various settings, such as in the pretreatment of textile wastewater. While ozone itself can cause health troubles, it can also react with chemicals found in a multitude of products to lead to other potentially toxic substances, such as formaldehyde. Despite proponents for its use and its potential applications, toxicity can occur even at environmental levels and may be related to cardiac, respiratory, and neurologic events. This activity reviews the etiology, presentation, evaluation, and management/prevention of ozone toxicity and reviews the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Review the basic pathophysiology and toxicokinetics of ozone exposure toxicity.
• Identify the common presenting features of ozone toxicity on an examination/evaluation.
• Summarize the treatment and management strategies available for patients with ozone toxicity.
• Outline interprofessional team strategies for improving care coordination and communication regarding the management of patients with ozone toxicity.

Introduction

Ozone normally occurs in a gas state as three atoms of oxygen (O) linked in a cyclic structure and is a by-product of water purification, bleaching, and any process generating a spark or electric arc in the presence of oxygen.[1] It is also found in the atmosphere, with higher altitudes containing higher levels of ozone. It is found in the stratosphere, where it absorbs various ultraviolet radiation.[2] Ozone is also an environmental air pollutant, along with others, such as sulfur dioxide and particulate matter.[3][4][5]

In spite of this, ozone can be generated by medical devices for therapeutic purposes. Potential medical applications of ozone therapy have a wide range, including 1) limiting postoperative pain after dental extraction when used as a gel, 2) repairing inner ear damage caused by acoustic trauma, 3) reducing coronary stent restenosis when applied as an auto-hem-transfusion, and 4) enhancing methicillin-resistant Staphylococcus aureus elimination in mediastinitis when used in conjunction with antibiotics.[6][7][8][9][10][11][12][10][6]

Outside of medicine, ozone has been proposed for use in various settings, such as in the pretreatment of textile wastewater.[13][14][13] While ozone can cause health troubles, it can also react with chemicals found in many products to lead to other potentially toxic substances, such as formaldehyde.[15] Despite proponents for its use and its potential applications, toxicity can occur even at environmental levels and may be related to cardiac, respiratory, and neurologic events.[16][17]

With the wide range of possible applications and toxicity that can occur at environmental levels from within a home, research on ozone use and toxicity is likely to increase in the future.

Etiology

Exposure to ozone is most likely unintended and due to environmental sources, both indoor and outdoor. Indoor exposure is decreased in homes with central air due to the decreased exchange of indoor and outdoor air and filtering performed by the air conditioning unit.[18]  Despite its decreased presence, ozone can react with numerous indoor chemicals, such as those related to wood flooring, carpeting, and perfume, to create potentially harmful compounds.[19][20][21]

One's outside environment is a major determinant of ozone exposure, potential toxicity, and overall cardiovascular and respiratory mortality.  One large study of 95 communities in the United States found a statistically significant association between increases in ozone measured in parts per billion (ppb) and short-term mortality. This study illustrates the widespread national public health concerns about ozone exposure. Countries outside of the United States, such as South Korea and Iceland, have also recognized the health impacts of ozone and the impact on public health. 

The exact level and duration of ozone exposure that creates toxicity are not yet known.  Additionally, humans may have variable sensitivity to ozone exposure. One study found that pediatric asthmatics might be more sensitive to certain air pollutants such as ozone.[22] Another suggested that exposure to ambient levels of ozone may be enough to initiate inflammatory cascades of the respiratory tract.[23] Noting that and the study involving 95 communities, it is plausible to say that ozone toxicity affects everyone to some degree and is dependent on multiple factors within and outside of our control.

Epidemiology

The exact risk of ozone toxicity is difficult to determine due to many factors. One large study suggested that a 10 ppb increase in ozone was associated with a 0.52% risk of non-injury-related daily mortality in that community the following week. Additionally, the same increase in environmental ozone may cause a 0.64% increase in mortality due to cardiovascular or respiratory causes.

Aside from the general ozone toxicity, it has the potential to be iatrogenic and work-related. Despite that potential, little research and no case reports were found.

Toxicokinetics

Ozone is a potent oxidant that has the potential to be helpful or harmful, like most other substances depending on the concentration, location, and duration of exposure. For example, ozone has been shown to be beneficial in treating chronic limb ischemia and several kinds of skin infections.[24][25] Conversely, higher doses or more prolonged exposure to the skin will lead to progressive depletion of antioxidant content in the stratum corneum.

In discussing toxicokinetics, it may be helpful to differentiate the exposure location, as the skin is somewhat tolerant (although chronic contact can be deleterious), while the respiratory system is essentially intolerant and can show harmful effects even at low ambient environmental concentrations. Tissue effects can be considered on the basis of ozone’s specificity to certain compounds in addition to its low aqueous solubility and diffusibility. It is important to note that all possible pathways of injury are not yet known, and some known effects are not yet well understood.

Toxic effects are considered to occur through free radicals and oxidation or through radical-dependent pathways. Aside from the generation of free radicals, ozone can deplete a tissue of specific compounds, such as antioxidants (tocopherols and ascorbate), in separate layers of skin (upper epidermis, lower epidermis, dermis).[26]  Additionally, there is a noted increase in lipid and protein oxidation showing oxidative stress.[27][28] Longer exposure to increased concentrations has shown an increase in cyclooxygenase-2, which is a pro-inflammatory marker.[29]

While effects are still related to oxidation and inflammatory pathways, the respiratory tract has some mediation through interleukin-8 and growth-related oncogene-α.

History and Physical

For most patients with symptoms related to ozone toxicity, history will be non-specific. Findings will likely depend on the bodily system involved, such as worsening respiratory symptoms in a patient with underlying asthma, since this population is particularly susceptible to ozone effects.[21][30] The specific history of present illness events may only be found in patients undergoing unconventional medical asthmatic therapies or individuals exposed in a work environment.

Symptoms themselves are largely related to the delivery method of exposure, concentration, and duration. Ozone has been delivered in many routes including, but not limited to, intravenous, intramuscular, topically, intra-articular, nasal, rectal, and oral.

Evaluation

The evaluation of ozone toxicity is similar to the evaluation of any pulmonary irritant. Oxygen saturation monitoring should be implemented, and also bedside spirometry. Providers should also consider arterial blood gas analysis and chest radiography as potential exposure to other pulmonary irritants should always be considered. An electrocardiogram should be performed as well in patients with or at risk for underlying cardiac disease.

Treatment / Management

No specific treatment is available for individuals exposed to ozone, though some have suggested that oral intake of vitamin E is beneficial to the chronic ambient exposure most experience.[31][32][33] Budesonide has been shown to inhibit the airway neutrophilic inflammatory response, although it does not prevent functional impairment of the airway.[34]

Differential Diagnosis

• Acute lactic acidosis

• Acute respiratory distress syndrome (ARDS)

• Alcohol toxicity

• Depression and suicide

• Diabetic ketoacidosis (DKA)

• Emergent treatment of gastroenteritis

• Encephalitis

• Hypothyroidism and myxedema coma

• Labyrinthitis

• Meningitis

• Methemoglobinemia

• Migraine headache

• Opioid toxicity

• Pediatrics hypoglycemia

• Tension headache

Pearls and Other Issues

Providers should be aware of the use of ozone therapy by holistic practitioners and ozone therapists. Although shown to be safe, there have been instances with inexperienced individuals using ozone improperly, potentially causing harm. As with any drug, there is a therapeutic window depending on the dosage. Unfortunately, there is a lack of financial support for conducting randomized controlled trials, and much remains to be discovered about both the therapeutic and toxic effects of ozone.

Enhancing Healthcare Team Outcomes

The actual incidence of ozone toxicity remains unknown but in any case, healthcare providers, emergency room personnel, and nurse practitioners should be familiar with the presentation and management of ozone toxicity. In most cases, the toxicity occurs because of improper use of ozone. Because there is little known about the management of ozone toxicity one should apply the trauma ABCDE protocol and offer supportive care. Most patients do improve with corticosteroid/oxygen therapy.