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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.

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Out of the Depths: The Story of British Mine Diving

If sumps and solo cave diving are, well, a bit too Brit for you, you may want to consider diving into the perfusion of flooded serpentine chert, copper, limestone, silica, slate, and tin mines that honeycomb the length and breadth of the Kingdom. Fortunately, British tekkie and member of UK Mine/Cave Diving (UKMC) in good standing, Jon Glanfield, takes us for a guided tour.

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By Jon Glanfield
Header image courtesy of Alan Ball.

When many think of the UK’s caves, with wet rocks and their penchant for darkness, often the images conjured are of tight, short, silty sumps, that can only be negotiated by intrepid explorers outfitted with diminutive cylinders, skinny harnesses, wetsuits and typically a beard. These are the domain and natural playground of the well-known, highly-respected, Cave Diving Group (CDG). 

In truth, much of our sceptered isle’s caves are of this ilk, but there is an alternative for the diver who favours a more conventional rig, extra room to manoeuvre, and perhaps a more team-orientated approach—one that is less than optimal in many of the true cave diving environments of the UK.

Holme Bank. Photo by Ian France.

Alongside our natural cave diving venues, we also sport a varied collection of flooded mines across the length and breadth of the Kingdom. In the south and southwest, miners have extracted metals such as tin and  copper, while in South Wales it was the mineral, silica. The Midlands Linley Caverns were a source of limestone before being converted to a subterranean munitions store in WWII. Sadly, access to these is no longer feasible. In the rolling hills of the Derbyshire Dales, flinty, hard chert strays close enough to the surface to be mined. In North Wales, the once-proud slate industry has left its Moria and Mithril redolent halls and tunnels beneath the landscape, while copper and slate underlay parts of Cumbria. Meanwhile, just over the border in Scotland, limestone was the resource that drove us to follow its veins into the earth.

Mike Greathead descending the stairway to heaven. Photo by Ian France.

Undeniably, here in the UK, mine diving has a much shorter documented history than that of its close cousin cave diving, but some of the luminaries of this dark world were, and are, active in both. Some of the initial dives in sites like the Cambrian slate mine were undertaken by the incomparable Martyn Farr, Geoff Ballard, and Helen Rider in 2006. But it wasn’t until 2014 that it was further explored and lined by the likes of Cristian Christea, Ian France, Michael Thomas, and Mark Vaughan amongst others. 

Both Rich Stevenson and Mark Ellyatt, who were part of the vanguard of the technical diving revolution in the UK, had personal dramas on trimix dives in the deep shaft of the Coniston Copper Mines, the depth of which runs to 310 m/1012 ft. Ellyatt made his dive at 170 m/555 ft in the early 2000s in a vertical 2 m/6.5 ft square shaft, dropping away into the 6º C/43º F frigid blackness.

Mines Over Matter

As was alluded to, the differences in cave and mine diving are significant. Conventional, redundant open and closed technical rigs can be employed in mine diving due to the predictably larger tunnels, passages, and chambers. Water movement is negligible, so often regular braided lines can be used, lines which would not endure the flow in many of the UK’s upland cave locations. Small teams can dive in safely. 

No Exit. Photo by Chris Elliot.

In general, it is not common to surface and explore the sumped sections of the mines, due to often dangerously contaminated or hypoxic air quality. Also, in some cases, oils and other contaminants have leached into the water. The ever-present risk of collapse—both in the submerged sections and in the dry access adits or portals—haunt divers’ thoughts and is far more common in mines than in the smooth, carved bore of a naturally-formed cave. Casevac (the evacuation of an injured diver) is complex, long-winded, and often dangerous for those involved, and in the event of an issue involving serious decompression illness (DCI), almost certainly helicopter transportation would be necessary given the remote locations.

Landowner access—or, more commonly, denial of access—is an ubiquitous spectre in the underground realm, dry or wet, and much effort is directed at maintaining relations with landowners to safeguard the resources. Some of the most frequented mines are accessible only via traverse of private property, which could be agricultural, arboreal, and in one case, bizarrely on the grounds of an architectural firm. Careful management of these routes into the mines is critical, as is demonstrating respect for the land owner and complying with their requirements when literally on their turf.

At the more prosaic level though, simply getting into some of the mines is a mission on its own, necessitating divers’ decent levels of fitness, the use of hand lines, and sometimes as much consideration of dry weight to gas volume as the dive planning itself. Careful thought and prior preparation are also required in terms of both accident response and post-dive decompression stress, given the exertion expenditure simply to clear the site.

A passageway in Aber Las. Photo by D’Arcy Foley.

Many of the mines are relatively shallow, mostly no more than 30 m/98 ft with exceptions in the notable and notorious Coniston, and the almost mythic levels in Croesor, extending beneath the current 40 m/130 ft galleries that are known and lined. Though, what the mines lack in depth, they make up for in distance and grandeur. 

Aber Las mine survey. Courtesy of UKMC.

Aber Las, or Lost, is more accurately a forgotten section of Cambrian that extends nearly 600 m/1961 ft from dive base at the 6 m/20 ft level, and a second level 300 m/984 ft long at 18 m/59 ft. The section features no less than 35 sculpted chambers hewn off the haulage ways with varying dimensions and exhibiting differing slate removal techniques. Cambrian’s chambers less than a mile away are larger still, and a lost line incident here could be a very bad day given the chambers’ cavernous aspect.

In The Eye of the Beholder

Beauty is—as they say—in the eye of the beholder, but it would be disingenuous to try to draw comparisons between the UK’s mines and the delicacy of the formations in the Mexican Karst, the light effects through the structures in the Bahamian sea caves, or the sinuous power tunnels of Florida. In mines, the compulsion to dive is due in part to the industrial detritus of man, encapsulated in time and water.

In mines, the compulsion to dive is due in part to the industrial detritus of man, encapsulated in time and water.

Parallels are frequently drawn between wreck diving and mine diving, but often the violence invoked at the demise of a vessel—the massive, hydraulic inrush of fluid and the subsequent impact on the seabed—wreaks untold damage and destruction upon its final resting place. In contrast, nature reclaims her heartlands in the mines by stealth: a slow, incremental and inexorable seep of ground water, no longer repulsed by the engines from the ages of men, gradually rising through the levels to find its table. The result is often preserved tableaus of a former heritage with a rich diversity of artefacts left where last they served.

A leftover crate in the Croesor mine. Photo by Alan Ball.

Spades, picks, lanterns, rail infrastructure, boots, slowly decomposing explosive boxes, battery packs, architectural joinery, scratched tally marks, and, even in some cases, the very footprints of the long-past workers in the paste that was cloying, coiling dust clouding the passages and stairways, can be picked out in the beam of a prying LED.

Spades, picks, lanterns, rail infrastructure, boots, slowly decomposing explosive boxes, battery packs, architectural joinery, scratched tally marks, and, even in some cases, the very footprints of the long-past workers in the paste that was cloying, coiling dust clouding the passages and stairways, can be picked out in the beam of a prying LED.

Underpinning, protecting, preserving, and improving these gems of the realm is the UK Mine and Cave Diving Club (UKMC), which formed as mine diving intensified in the mid 2000s. So it was that Will Smith, D’Arcy Foley, Sasha London, Jon Carter, Mark Vaughan, and Ian France, all of whom are respected and experienced cave divers in their own right, forged the club to foster and engage with a community of like-minded divers. 

Sadly, in 2014, Will Smith fell victim to the insidious risks of contaminated air in the Aber Las mine system, which he had been lucky enough to re-discover and in which he conducted early exploratory dives as the club gained traction and direction.

As new members filter into the ranks, new ideas, new agendas, and new skill sets re-shape the club’s direction. At present, we are rebooting the club with a remastered website, focusing on new objectives and seeking opportunities to improve, catalogue, and document the resources we husband.

Lines laid in the Cambrian slate mine. Photo by Mike Greathead.

Exploration continues: the club is laying new line in some areas. What’s more, through our demonstrable respect and care for existing sites, the club is facilitating exploration in previously inaccessible sites, and lost and forgotten sites will resurface. Meanwhile, we’re improving the locations we frequent weekly for the benefit of trainees, recreational (in the technical sense) divers, and survey divers alike. Archaeological projects are rising from the ennui of lockdown; we’re establishing wider links with mine diving communities elsewhere to share techniques, data, and ultimately hospitality.

In Welsh folklore, a white rabbit sighted by miners en route to their shifts was believed to be a harbinger of ill fortune, but for Alice, following the rabbit into its hole led her to a whimsical and magical place. Be like Alice, and come visit the Wunderland!

Additional Resources:


Jon Glanfield was lucky enough to get his first puff of compressed air at the tender age of five, paddling about on a “tiddler tank,” while his dad was taught how to dive properly somewhere else in the swimming pool. A deep-seated passion for the sport has stayed within him since then, despite a sequence of neurological bends in the late 90s, a subsequent diagnosis of a PFO, and a long lay-off to do other life stuff like kids, starting a business, and missing diving. Thankfully, it was nothing that a bit of titanium and a tube couldn’t fix. He faithfully promised his long-suffering wife (who has, at various anti-social times, taken him to and collected him from recompression facilities) that “this time it would be different” and that he was just in it to look at “pretty fishes.” So far, only one fish has (allegedly) been spotted in the mines. The ones Jon has encountered in the North Sea while wreck diving just obscured the more interesting, twisted metal.

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