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Understanding Oxygen Toxicity Part II: Hypotheses and Hyperoxia

Diver Alert Network’s Reilly Fogarty examines the latest research on the mechanisms behind CNS and pulmonary oxygen toxicity to tease out what we think we know and what it means for your diving. Watch those PO2s!

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by Reilly Fogarty
Header photo by Stephen Frink, Research conducted at the US Navy Experimental Diving Unit.

You can read Part I of this series here.

The history of oxygen toxicity research serves well to set the stage for the complication and nuance of modern research, but it’s important to recognize that what we are currently working with is a series of compounded hypotheses on the effects of oxygen in the body. They’ve been tested to varying degrees and serve as the basis for compounding theories and practices both medical and academic in nature, but the more we learn about the function of oxygen in the human body, the more we realize what we don’t yet know. The specificity of the mechanisms combined with the concurrent reactions required to make those mechanisms possible fills the pages of more than one textbook, but here’s a real-world look at what we think we know, and what it means for divers.

The production of ATP during the breakdown of sugar at normal (normoxic) oxygen partial pressures. Diagram courtesy of aquaCORPS.

Starting Small

Most modern theories of oxygen toxicity focus primarily on the function of oxygen free radicals and lipid peroxidation, in a mechanism that mimics inflammatory processes in the body. Oxygen free radicals, or reactive oxygen species (ROS) are ions (atoms or molecules having an unpaired electron in an outer orbital) that are highly reactive. The pairing or loss of the lone electron results in the generation of an additional free radical, leading to a continuous chain of species production. Their initial creation is primarily the result of an oxi-reductive process in the electron transport chain, the result of which is superoxide, hydrogen peroxides, hydroxyl, and water (Chawla, 2001). These free radicals result in lipid peroxidations (a type of oxidative lipid degradation) in cell membranes, damage to cellular enzymes and interference with nucleic acid and protein synthesis. Exposure to high partial pressures of oxygen increase free radical production and may result in damage to the pulmonary epithelium, intra-alveolar edema, interstitial thickening and several other conditions (Cooper, 2019). 

The production of ATP and reactive oxygen species during the breakdown of sugar at elevated (hyperoxic) oxygen partial pressures.
Diagram courtesy of aquaCORPS.

The general mechanism for central nervous system (CNS) toxicity resulting in tonic-clonic seizures (convulsions involving both muscle stiffening and twitching or jerking) involves hyperoxia-induced free radical production overwhelming specific neural pathways, combined with localized neuron depolarization and hyperexcitability. This theory suggests that exposure to high partial pressures of oxygen results in an increase  in the firing rate of specific neurons, notably those of a part of the brain called the caudal Solitary Complex (cSC), a portion of the dorsal medulla oblongata which is important in cardiorespiratory control and has some neurons that are particularly sensitive to hyperoxia and pro-oxidants (Ciarlone, 2019). The effect of this hypersensitivity combined with increased free radical production is theorized to be the stimulus for the seizure evolution seen in CNS oxygen toxicity, although other mechanisms bring epilepsy models into the fold and propose looping and self-amplifying circuits of neurons that result in seizure evolution. An additional mechanism proposes seizure onset as a result of hyperoxia induced enzyme inhibition, notably of Gama Amino Butyric Acid (GABA). GABA is an inhibitory neurotransmitter, and inhibition of its production is theorized to result in neuronal excitation resulting in seizure (Treiman, 2001). These mechanisms are not exclusionary and in some instances may combine, overlap or catalyze each other. 

Fig. 1.
Fig. 1 courtesy of Divers Alert Network (DAN).

Pulmonary oxygen toxicity is typically proposed to follow a similar inflammatory mechanism caused by free radical production and lipid peroxidation. These mechanisms involve redox and inflammatory damage throughout the body, primarily to the capillary endothelium and alveolar epithelium resulting in impaired gas exchange and neutrophil infiltration leading to respiratory failure (Ciarlone, 2019). The visible effect of this inflammatory reaction is the irritation of the airway, decreased gas exchange and eventual thickening of alveoli and damage to the alveoli and airway tissues. 

There are several additional and notable mechanisms for both CNS and pulmonary toxicity that involve other sources of free radical damage catalyzing neural misfiring, damage to proteins and resulting immune responses, and inappropriate oxidative signals as a result of exposure to hyperbaric oxygen — what’s important to understand in this is not the specifics of the proposed models as much as the applied cause and effect. Exactly why each of these mechanisms functions as it does remains unclear in some instances, but the proposed hypotheses bring us closer to understanding what inputs can be altered to understand and eventually address the resulting symptoms of oxygen toxicity. What’s interesting to note is the significant overlap in many of the proposed mechanisms, many of which provide reactants for or accelerate other similar mechanisms, as well as the recent convergence of many theories on the concept of oxygen toxicities effects being inflammatory or autoimmune in nature. 

Jarrod and Paolo Macciachini during oxygen decompression. Photo courtesy of the GUE archives.

Day-to-Day Variability

The single most significant issue in applying what we know about oxygen toxicity isn’t the unknown nature of specific mechanisms, but the huge variability in the exposures that result in symptom evolution, even in the same individual on two separate days. This variability is partially a function of the many contributing factors in oxygen toxicity, resulting from differences in factors that contribute to, inhibit, or result in the catalysts involved in the mechanisms discussed above. The majority of this variability is proposed to be the result of both the multitude of pathways that result in injury, and factors like antioxidant defense levels, neurotransmitter levels, genetic factors, nitric oxide production rates, and hormone levels — particularly concerning thyroid function, epinephrine production and ACTH levels (Shykoff, 2019). 

This variability is so great that some models propose that CNS toxicity can be affected by inert gases, visual input, and circadian rhythm (Mathieu, 2006). The result of all of this is that the list of variables that contribute to oxygen toxicity risk of all kinds is both incomplete, and so long and variable that they cannot possibly be controlled for in their entirety. In the real world this means that we must apply enormous levels of conservatism to what amounts to an educated guess at the average limits of divers. Comparison of models created by military researchers (using exceptionally fit young males performing difficult work underwater as a model), and academic models (using samples that more closely resemble the diving population) result in significant variability both by model and by acceptable risk. 

NOAA Oxygen Exposure Limits.

For the most part we, as an industry, have found some success in settling for the current NOAA oxygen exposure guidelines, but even these see unexpected injuries in use. The management of some primary diving-related risk factors for oxygen toxicity has resulted in the ability of some divers to far exceed recommended guidelines seemingly without symptoms, but because of this variability we are largely unable to quantify the risk they face — it’s as of yet unclear if the diver performing hours long decompressions in a habitat is taking a gamble with each dive or maintaining a moderate safety margin with the controls they’ve put in place. 

Carbon Dioxide

Carbon dioxide may be the greatest controllable risk factor in CNS oxygen toxicity, and unmitigated CO2 production and retention has been correlated with significantly increased seizure risk. This risk is primarily the result of the combination of CO2 production from exercise, combined with increased retention as a result of increased gas density, hydrostatic compression of the lungs, and dead space ventilation caused by the length of tubing in a breathing apparatus (Carlione, 2019). While breathing a hyperoxic gas may initially inhibit ventilation, continued exposure stimulates ventilation and decreases CO2 retention as long as that CO2 is effectively eliminated. The result of this is increased CO2 production and retention to increase arterial PCO2 and the production of respiratory acidosis. This is exacerbated by the oxygen induced interference with CO2 transport in the body, resulting in a higher dissolved PCO2 and decreased bicarbonate and carbamino concentrations (Carlione, 2019). 

The resulting hypercapnic acidosis increases free radical species formation via a cascade of mechanisms involving an increase in hyperoxic blood delivery to the brain, and an interaction called the Fenton Reaction that in combination results in increased free radical production, which accelerates oxidative stress and increases seizure risk. Like the mechanisms above, this is a broadly accepted but still unproved hypothesis that results in an increase in seizure risk, but while the specifics of the interaction may be variable, the effect of CO2 on convulsion risk have been strongly correlated. 

Hypothermia

Hypothermia presents as a risk factor of its own, and one that compounds the effects of CO2. The specifics of this mechanism remain unclear but the reduction in peripheral blood blow, increased cardiac output and redistribution of blood volume to the core results in increased oxygen delivery to the CNS, which may compound issues with both with CO2 retention and delivery of hyperoxic blood to the brain (Mathieu, 2006). Other factors like circadian rhythm, sleep, inert gases, diet, and gender have been similarly correlated with decreased seizure latency (the time between stimulus and seizure onset), but with varying degrees of study and theorized modeling. 

Diving in cold water might call for a higher level of conservatism. Photo by Nicole Wächter.

The real-world takeaway is that we know a little about a lot of proposed mechanisms, and a lot about very few facets of oxygen toxicity. There’s a growing convergence of theories around the idea of an inflammatory or immune response being central to the mechanisms for both CNS and pulmonary oxygen toxicity, and while these theories are quite good and have withstood significant testing, many have yet to be definitively proven. Academically the outlook is both more obscure and more hopeful — this article is just a brief summary of some of the more common models of oxygen toxicity, but there are numerous other contributory and more detailed models and mechanisms currently being researched to explain the effects of high partial pressures of oxygen on the human body. 

It’s worth noting that as divers we are primarily concerned with just CNS and pulmonary toxicity, but the effects of oxygen in the body are far more reaching and involve numerous other physiological changes. The future of research into the topic yields promise both on academic and applied fronts. Trials with inhibitors of some free radicals, anti-adrenergic and anti-epileptic drugs, ketone metabolic therapy and hyperbaric preconditioning have shown significant promise in the reduction of oxygen toxicity effects. 

Ongoing research into human exposure limits promises to improve our ability to plan real-world dives and extend out limits, and a broad field of researchers are working to overcome the gaps in knowledge that we currently have. There may not be a unique revelation in the currently published research that changes the way that you plan your dives, but the simultaneous progress on so many facets of our understanding indicates that are likely on the cusp of a new understanding of how to manage oxygen exposures and keep ourselves safe in the water. 

Thank you to Dr. Andy Pitkin, Dr. Barbara Shykoff, and Dr. Neal Pollock for their willingness to share their expertise in their respective fields. 

Additional Resources

For more information on the specific mechanisms of oxygen toxicity and the ongoing clinical trials mentioned in this article, please visit the references linked below. 

  1. Chawla, A., & Lavania, A. K. (2001). OXYGEN TOXICITY. Medical journal, Armed Forces India, 57(2), 131–133. doi:10.1016/S0377-1237(01)80133-7
  2. Cooper JS, Shah N. Oxygen Toxicity. [Updated 2019 Mar 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. 
  3. Ciarlone, G. E., Hinojo, C. M., Stavitzski, N. M., & Dean, J. B. (2019, March 9). CNS function and dysfunction during exposure to hyperbaric oxygen in operational and clinical settings
  4. Treiman, D. M. (2001, December 20). GABAergic Mechanisms in Epilepsy
  5. Shykoff, B. (2019). Oxygen Toxicity: Existing models, existing data. Presented during EUBS 2019 proceedings.
  6. Mathieu, D. (2006). Handbook on Hyperbaric Medicine. Dordrecht: Springer.

Reilly Fogarty is a team leader for risk mitigation initiatives at Divers Alert Network (DAN). When not working on safety programs for DAN, he can be found running technical charters and teaching rebreather diving in Gloucester, MA. Reilly is a USCG licensed captain whose professional background includes surgical and wilderness emergency medicine as well as dive shop management.

1 Comment

1 Comment

  1. Dominic Jeanes

    December 3, 2019 at 8:03 pm

    Best piece I have seen published on oxtox, thanks Reilly. If your research pointed you towards any info on the following questions, I’d appreciate it if you could point out further reading sources; or your own views?
    1, If metabolism doesn’t increase due to depth (from my basic understanding of CCR oxygen consumption- perhaps flawed) where does the increased production of free radicals come from? Is it due to the Fenton reaction you mentioned in your article; and if so is it therefore more due to CO2 retention than purely to depth?
    2, In all the studies we see performed, the subjects are obviously wearing full face masks, how much is the facility to nose breath and hence produce more nitrous oxide in inhaled gas effect the outcomes of CNS exposure?
    3, In more basic articles dealing with CNS Oxtox on the diver, the main concern is convulsion and loss of airway; is evidence now pointing towards there being more long term damage to the CNS and this blurring the distinction between CNS and Pulmonary/Whole body oxtox?
    Thanks for any help you can give on this matter. Cheers Dominic.

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Conservation

Preserving Florida’s Springs: The Bottled Spring Water Problem

There’s no doubt that Florida’s Springs are imperiled. Most are flowing 30% to 50% less now than their historical average and are suffering from eutrophication. However, as veteran hydrologist Todd Kincaid explains, the problem is not spring water bottlers like Nestlé, in fact they could be allies in the fight to preserve the springs.

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By Dr. Todd Kincaid
Header photo by Florida DEP of Wakulla Springs in April 2008.

Florida’s Springs are imperiled. Most are flowing 30% to 50% less now than their historical average. Some don’t flow at all except after big storms or abnormally wet periods. Nearly all have become overwhelmed with algae and bacteria (eutrophied) due to excessive nutrient pollution. The causes are straightforward and increasingly hard to ignore: groundwater over pumping, the overuse of fertilizers by agribusiness and homeowners, and insufficiently treated wastewater. Solutions exist, can be widely implemented, and would significantly improve spring water flows and spring water quality, but they require major investments and diversions from status quo: caps on groundwater extractions, tiered fees for groundwater usage applied to all users, tiered taxation on fertilizer usage, advanced wastewater treatment, transition away from septic systems, etc.

Existing policies have failed to even bend the steep downward trajectory of Florida’s springs. “Minimum Flows and Levels” (MFLs) appear to protect spring flows but, in reality, they open the door to continued declines while people argue over the difference between natural and human causes. “Best Management Practices” (BMPs) pretend to reduce nutrient loading, yet are not only unproven and unenforceable, but not even conceptually capable of the needed nutrient reductions. Even as more and more attention and resources are directed at the condition of Florida’s springs, most continue to degrade: less and less flow, more and more nitrate and algae.

In the face of these declines, it’s easy to become disheartened and jaded. It’s even easier to become focused on reactionary measures aimed at what we don’t want and be rooted more in emotion than in facts. This is, I believe, epitomized by the highly publicized reactions to a permit renewal application filed with the Suwannee River Water Management District (SRWMD) by the Nestlé Corporation (Nestlé) for a bottled spring water plant down the road from Ginnie Springs. 

Photos by Todd Kincaid(left) and Jennifer Alder(right) of Gilchrist Blue Springs Park.

The application requests that the SRWMD renew a standing permit that was first issued in the 1980s for the extraction of 5 million gallons per day (MGD) of groundwater from the Floridan aquifer to support spring water bottling. This same permit was voluntarily reduced to 1.1 MGD by the property owners to prevent the possibility that it could be incorporated into one of the many groundwater pipeline schemes that are persistently proposed to transport water from relatively rural north Florida to the substantially more populous cities in central and south Florida. Through the years, several different companies have leased the property and had access to the water, one of which was the Coca-Cola Company, and the most recent being Nestlé.

My perspective on this issue is a product of 30 years of work on karst hydrogeology in Florida, more specifically from my work for Coca-Cola on mapping groundwater flow paths. Specifically, we mapped the pathways to the springs on the western Santa Fe River, including Ginnie Springs, and identified the threats to the quality and quantity of flow to the springs. Even more, my perspective reflects the evolution of my understanding of what it’s going to take to sustainably manage groundwater (synonymous with spring flow) in Florida.

Photo by Jennifer Alder (top) Rich Denmark (bottom of Gilchrist Blue Springs Park).

The problems facing Florida’s springs are not technical and not a consequence of any one particular use or user. The real problems are instead failures of the established policies to take the necessary steps to put concrete limits on groundwater consumption and pollution. If we are to achieve sustainable spring flows, limits on groundwater consumption must be established and enforced and, in reality, must be lower than current levels.

From a quantity perspective, who gets the water is irrelevant. All that matters is how much is taken. At present, not only is too much being taken, but there are no established limits. Conservation measures enacted by one user simply opens the door for new or larger allocations to other users.  This is accomplished when users of the water claim a “beneficial use”. So, while we can and should be proud of those engaged in conservation, the reality is that spring flows will continue to decline.

If we are to restore and preserve spring water quality, nutrient pollution, specifically the input of nitrate and phosphorous into Florida’s groundwater that stimulate the explosive algae growth in Florida’s springs, rivers, lakes, and estuaries that nobody wants, must be dramatically reduced from current levels. Some experts state that nutrient discharge levels will need to be cut across the board by 70% or more in order to meet water quality targets for Florida’s natural waters. That would mean 70% less nutrient loading from agriculture, 70% less nutrient loading from households, and 70% less nutrient loading from wastewater treatment and disposal.  

At present, and for the foreseeable future, there is insufficient political will to achieve any of these needed changes given resistance from corporate and special interests. Year after year, proposed legislation calling for the types of sweeping changes needed fails to receive sufficient public support for passage. While the political efforts that would result in real and positive change continue to fail due to lack of support, the public’s attention focuses on perceived impacts from individual users without regard to the actual impacts those users and uses have on the springs.

Bottled spring water is only one example. Though the entire industry uses only around 1/100th of 1% of the groundwater extracted from the Floridan aquifer and produces absolutely none of the toxic nutrient loading that is killing the springs, it holds a disproportionate grip on the public’s attention to usage, impacts, and solutions.  If tomorrow the entire bottled water industry in Florida were to shut down, there would be effectively zero improvement at the springs in terms of either flows or quality. The little amount of water gained would very likely be quickly and quietly allocated to other users.

If, on the other hand, the roughly 400 bottles of water needed to produce a single bottle of milk were put to better use, say returned to the springs, and the associated nutrient loading to groundwater due the fertilizers used to grow the feed, were thereby eliminated, there would be a near immediate improvement in both flow and quality of water at the springs. Milk production uses far more water and produces drastically more nutrient pollution than the production of water.  The water saved by eliminating milk production would, therefore, take longer to re-allocate to new users and eliminate a huge portion of the nutrient pollution that is killing the springs as well.

Far more water is used for that purpose, and much more nutrient pollution is caused.

Photo courtesy of John Moran / Springs Eternal Project.

Eliminating the production of milk, for example, would also require more time to re-allocate to new users and would eliminate a substantial portion of the nutrient pollution that is killing the springs.

Nearly every drop of water extracted from the Floridan aquifer and not returned reduces spring flows by an equal amount. Certainly from the entirety of the state north of Orlando and Tampa, and regardless of what it’s used for, from water from household taps, watering lawns and golf courses, car washes, crop irrigation, production of milk, soda, energy drinks, and bottled water. Similarly, all the nutrient loading to groundwater west of central Orlando and Gainesville and south of Tallahassee flows to the springs and contributes to the explosive algae infestations, which no one wants to see become normal.

The problems plaguing Florida’s springs stem from these realities, regardless of whether the springs are enshrined as State Parks or privately owned. Florida’s springs need allies not rhetoric—allies who help to build the public support necessary to achieve the only actions that will restore and preserve spring flows and spring water quality: caps on groundwater consumption and dramatic reductions in nutrient loading.

Regardless of corporate culture, spring water bottlers’ economic self-interest is directly aligned with springs protection. Spring water cannot be treated and cannot be captured if there are no more springs. Spring water bottlers, therefore, rely on access to sustainable, high-quality spring water. It then follows that they, along with other like-minded entities, can be strong allies for springs protection. It’s time for Floridians to stop focusing on rhetoric that fails to yield even as little as a diminished rate of springs degradation. It’s time to start working toward real solutions anchored in the realities of water and nutrient budgets. The bottled water industry is not sucking Florida dry, but denial and political inaction are.

As an organization focused on sustaining the environmental quality and required to support healthy underwater ecosystems, our task must be to confront environmental problems from a perspective grounded in the realities of what will be needed to achieve our goal. We must work for what we know we want rather than against what we think we don’t want. And to be successful, we’re going to need as many allies as we can muster.

At Project Baseline, we should and will seek to engage with the people and organizations who share our goals, even if doing so is not palatable to some of our fellow conservationists. We should work with those entities and use our voices, our votes, and our wallets to foster the policies and the actions that are needed to restore and preserve the type of underwater world we want to dive in, be awed by, and pass along to the next generation of underwater explorers.

Additional Resources:

Project Baseline is a nonprofit organization that leverages their unique capacity to see how rapidly the underwater world is changing to advance restoration and protection efforts in the local environments we explore and love. Since 2009, Project Baseline has been systematically documenting changes in the underwater world to facilitate scientific studies and establish protection for these critical underwater environments. 

Learn more about Project Baseline
View their online database
Get involved 


Todd is a groundwater scientist, underwater explorer, and advocate for science-based conservation of water resources and aquatic environments. He holds BS, MS, and Ph.D. degrees in geology and hydrogeology, and is the founder of GeoHydros, a consulting firm specializing in the development of computer models that simulate groundwater flow through complex hydrogeologic environments. He has been an avid scuba diver since 1980, having explored, mapped, and documented caves, reefs, and wrecks across much of the world. Todd was instrumental in the founding of Global Underwater Explorers (GUE) in 1999 and served on its Board of Directors and as its Associate Director from its inception to 2018. Within the scientific and diving communities, Todd advanced the use of volunteer technical divers and the data they can collect in endeavors aimed at understanding, restoring, and protecting underwater environments and water resources. He started Project Baseline with GUE in 2009 and has been the organization’s Executive Director from its beginning. More on Todd at: LinkedIn and ResearchGate

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