NASA/TP-2012-217358

Chronic Exposure to Moderately Elevated CO2

during Long-Duration Space Flight

Patrick D. Cronyn, M.D. 

LCDR MC USN

Emergency Medicine Department 

Naval Medical Center Portsmouth, Virginia

Wyle Integrated Science and Engineering Aerospace Medicine Research Rotation

Sharmi Watkins, M.D., M.P.H.

Element Scientist, Exploration Medical Capability

The University of Texas Medical Branch

NASA/Johnson Space Center Bioastronautics Contract

David J. Alexander, M.D. 

Flight Surgeon

NASA/Johnson Space Center

March 2012
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NASA/TP-2012-217358

Chronic Exposure to Moderately Elevated CO2

during Long-Duration Space Flight

Patrick D. Cronyn, M.D. 

LCDR MC USN

Emergency Medicine Department 

Naval Medical Center Portsmouth, Virginia

Wyle Integrated Science and Engineering Aerospace Medicine Research Rotation

Sharmi Watkins, M.D., M.P.H.

Element Scientist, Exploration Medical Capability

The University of Texas Medical Branch

NASA/Johnson Space Center Bioastronautics Contract

David J. Alexander, M.D. 

Flight Surgeon

NASA/Johnson Space Center

March 2012
Available from:

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301-621-0390 703-605-6000

This report is also available in electronic form at http://ston.jsc.nasa.gov/collections/TRS/
i

Table of Contents

Abstract.....................................................................................................................................................iii

1.0 Introduction......................................................................................................................................1

2.0 Carbon Dioxide in Spacecraft ..........................................................................................................2

2.1 Spacecraft removal capability....................................................................................................2

2.2 International Space Station carbon dioxide monitoring capability............................................3

3.0 Pertinent Literature Review .............................................................................................................3

3.1 Research conducted in microgravity .........................................................................................3

3.2 Terrestrial research ....................................................................................................................4

3.2.1 Animal Models and Patrol Studies ..................................................................................4

3.2.2 Dedicated Studies ............................................................................................................4

4.0 Carbon Dioxide-Related Physiology................................................................................................5

4.1 Carbon dioxide acute toxicity....................................................................................................5

4.2 Prolonged effects of carbon dioxide exposure...........................................................................6

4.2.1 Respiratory Acidosis........................................................................................................7

4.2.2 Pulmonary Response........................................................................................................7

4.2.3 Vascular...........................................................................................................................7

4.2.4 Calcium and Bone Changes Secondary to Respiratory Acidosis ....................................8

4.2.5 Renal Calculi....................................................................................................................9

4.3 Microgravity ..............................................................................................................................9

4.3.1 Lack of Air Convection ...................................................................................................9

4.3.2 Cardiovascular and Fluid Shift ......................................................................................10

4.3.3 Pulmonary Function.......................................................................................................11

4.3.4 Renal Calculi..................................................................................................................11

5.0 Operational Implications and Recommendations...........................................................................12

5.1 Renal calculi and bone reabsorption........................................................................................12

5.2 Cerebral blood flow.................................................................................................................12

5.3 Mission performance ...............................................................................................................13

6.0 Conclusion .....................................................................................................................................14

7.0 Acknowledgements........................................................................................................................14

8.0 References......................................................................................................................................15
ii

Acronyms

CBF cerebral blood flow

CDM carbon dioxide monitor

CSF cerebrospinal fluid

EPA Environmental Protection Agency

ICP intracranial pressure

ISS International Space Station

LiOH Lithium-Hydroxide

MCA Major Constituent Analyzer

NRC National Research Council

SMAC Spacecraft Maximum Allowable Concentration
iii

Abstract

Out of operational necessity, space platforms function with ambient carbon dioxide (CO2) concentrations 

in excess of normal atmospheric conditions (0.03% or partial pressure of 0.23 mmHg). NASA‟s longduration Spacecraft Maximum Allowable Concentration for CO2 is 0.7% (pp CO2 of 5.3mmHg). 

Extensive terrestrial studies support this level as safe and unlikely to cause adverse effects; however, 

International Space Station crews routinely report symptoms of acute CO2 toxicity (e.g., headaches, 

lethargy) that correlate with relative elevations of cabin CO2 below the permissible level. It is unclear if 

the unique environment of space results in increased sensitivity to CO2 or if other confounding factors are 

present. Regardless, acute symptom presentation at levels significantly lower than expected prompts the 

need to reevaluate the potential for adverse effects from long-term exposure. NASA‟s continued 

commitment to long-duration space flight makes it imperative to evaluate the impact of chronic exposure 

on the mission and astronaut health. With no definitive research to provide insight into current symptoms, 

potential avenues of action include incorporating quantifiable methods of measuring crew CO2 burden, 

developing a robust study to examine various low-to-moderate CO2 concentrations on human subjects in 

microgravity and/or implementing design requirements for reduced CO2 levels on future space platforms. 
(This page intentionally left blank)
1

1.0 Introduction

It is impractical to reduce carbon dioxide (CO2) concentrations on space platforms to those experienced 

on Earth (0.03% CO2, pp CO2 0.23 mmHg). Determining an acceptable level of CO2 requires 

consideration of spacecraft capability, resource consumption, and the performance and long-term health 

of the crew. Current operations on board the International Space Station (ISS) are maintained within 

permissible levels of CO2 based on time of exposure (See Table 1). Despite careful consideration of these 

limits, flight crews are reporting symptoms below these predefined acceptable limits. This paper will 

examine the current understanding of environmental CO2 exposure as it relates to space flight and 

recommend areas for further investigation. 

Table 1. Spacecraft Maximum Allowable Concentration (SMAC) for CO2

Exposure Time SMAC (%) Equivalent SMAC (mm Hg)

1 hour 2.0% 15

24 hours 1.3% 10

7 to 180 days 0.7% 5

1000 days 0.5% 4

Reference: James 2008.

For the purpose of this paper, CO2 will be presented in percent concentration (%CO2) and partial 

pressures (millimeters of mercury [mmHg]) as referenced to the standard day sea level pressure of 14.7 

psi (also the nominal pressure on the ISS). The terms “crew” and “astronaut” will be used interchangeably 

and may refer to any human in space without intending to imply nationality or level of training. The intent 

of this paper is to briefly identify specific aspects of CO2 exposure as it pertains to space flight and 

suggest areas of further study. An exhaustive literature review or formal recommendations are beyond the 

scope of this paper. 

The original Spacecraft Maximum Allowable Concentration (SMAC) for CO2 were developed by K. 

Wong Ph, D. and reviewed by the National Research Council (NRC) in 1996. A large body of research 

existed on concentrations of CO2 exceeding 1% CO2 (7.5 mmHg); however, much of that research did not 

meet current standards, and measured disparate concentrations, durations, environments, and endpoints. 

Little research focused on levels below 1% CO2 (7.5 mmHg); as such, there was no definitive study 

available to guide standards. After exhaustively reviewing the available literature, Wong set the standards 

of permissible levels that were eventually accepted by the NRC (James 2008).

ISS crews have repeatedly reported symptoms associated with acute CO2 exposure at levels of 0.66% CO2

(5 mmHg), well below the expected symptom threshold of 2.0% CO2 (15 mmHg) (Environmental 

Protection Agency [EPA] 2000). Headache is typically the first symptom reported by crew, although 

ground medical personnel anecdotally note changes in mood at levels as low as 0.5% CO2 (4 mmHg). 

Reported symptoms were successfully correlated to ISS CO2 levels by Christopher Carr, M.Sc (2006) 

(discussed in section 3.1). Thorough reviews of these reports are documented in In-Flight Carbon Dioxide 

Exposures and Related Symptoms: Association, Susceptibility, and Operation Implications (Law et al. 

2009), and Assessments of Crew Reports on ISS Carbon Dioxide Symptoms (Felker 2003). Symptom 
2

presentation at levels nearly a third of what is expected raises the concern that chronic or adverse effects 

also may be occurring at permissible levels. 

The following sections will address CO2 capabilities on spacecraft, a brief review of pertinent literature, 

specific aspects of CO2 metabolism, the role microgravity may play in exacerbating CO2 sensitivity, 

mission impact, and recommendations for future study and design. 

2.0 Carbon Dioxide in Spacecraft

CO2 is a by-product of metabolism, as metabolic loads increase more CO2 is produced. At rest, a person 

generates approximately 200ml of CO2 per minute. Under maximal exercise, CO2 production can exceed 

4.0L/Min (Williams 2009). If expired CO2 is allowed to accumulate, it can have adverse effects on health 

and performance. Although CO2 also can be generated by combustion, fire suppression equipment, or 

organic matter decay, this paper will focus on the nominal CO2 burden experienced by flight crew. 

Terrestrial studies suggest that initial symptoms develop at or above 2% CO2 (15 mmHg), with headache 

and dyspnea upon exertion. Visual disturbances and tremor appear at 6% CO2 (45 mmHg), 

unconsciousness at 7 to 9% CO2 (53-68 mmHg), and eventually death with the lowest published 

concentration at 9% (68 mmHg) in 5 min or 17% CO2 for 1 min (128 mmHg) (EPA 2000). (See Table 2.)

2.1 Spacecraft removal capability

Space platforms have unique challenges in providing habitable environments. They are essentially closed 

systems with significant power, mass, and volume constraints. CO2 must be selectively removed from the 

cabin‟s ambient air, or the air itself must be voided and replaced continuously. The latter method is an 

impractical model for long-duration flights. 

Spacecraft used for short-duration missions, such as those in the Mercury, Gemini, Apollo, and Space 

Shuttle programs, operated with nonregenerable Lithium-Hydroxide (LiOH) canisters to remove CO2. 

Relatively low concentrations of 0.15 to 0.3% CO2 (1 to 2 mmHg) were achieved, with discrete periods of 

up to 1.0 % (7.6 mmHg) during canister change out (Waligora 1994). 

Use of disposable canisters, other than for contingency use, is logistically prohibitive on long-duration 

missions. Regenerable methods typically have lower affinity for CO2 and more extensive power 

requirements. A balance between engineering requirements and ideal environmental conditions must be 

determined. The Skylab Program incorporated a regenerable molecular sieve system. Although this was 

not as efficient as the LiOH canisters, CO2 levels were effectively managed, averaging 0.66% CO2 (5 

mmHg) for the three Skylab missions (Waligora 1994).

Initial requirements for the ISS cabin environment targeted conservative concentrations of 0.4% CO2 (3 

mmHg). Justification for this level included U.S. submarine operational limits, the longer crew rotation 

cycle on the ISS, potential for renal calculi or loss of bone mass exacerbation and to support on-board 

scientific research (Waligora 1994). Engineering requirements and overall design changes eventually led 

to the selection of higher operating CO2 concentrations consistent with the 1996 SMAC limits of 0.7% 

CO2 (5.3 mmHg) (Waligora 1994). 
3

The typical operating CO2 level on the ISS ranges 0.3 to 0.7% O2 (2.3 to 5.3 mmHg) with a mean of 0.5% 

CO2. Fluctuations dependent on location and environmental loads can raise the hourly mean up to 0.7% 

CO2 (James 2008, Carr 2006). The primary CO2 removal system is the Vozdukh in the Russian-built 

Service Module. The Vozdukh system uses regenerable desiccant and sorbent beds that can vent collected 

CO2 when exposed to a vacuum (Carr 2006). Two Carbon Dioxide Removal Assemblies aid the Vozdukh 

system, also incorporating desiccant and sorbent beds. These assemblies may be run at higher levels as 

needed, but power and service life concerns regulate this use. Nonregenerable LiOH canisters are 

available for contingency use. 

2.2 International Space Station carbon dioxide monitoring capability

Two primary systems monitor ppCO2 on the ISS: the Service Module gas analyzer and the Major 

Constituent Analyzer (MCA) in the U.S. modules. The Service Module gas analyzer is biased low by 

approximately 1 mmHg to 2.5 mmHg based on data from air sampling. The MCA, while less rugged, is 

accurate and samples via collection vents from each U.S. module (Felker 2003). A limiting factor in both 

of these systems is their fixed sampling locations. The lack of air convection in microgravity makes 

ventilation and accurate monitoring difficult as the recorded value at fixed sampling sites may not reflect 

the environment immediately surrounding the crew. This topic will be discussed further in section 4.3. 

Additional capability to monitor CO2 is available with two portable carbon dioxide monitors (CDMs) and 

routine air samples that are returned for detailed analysis on the ground. The portable CDMs are 

periodically deployed to sample CO2 levels at fixed locations and have been donned by crew members for 

mobile monitoring (Felker 2003, Law et al. 2009). 

3.0 Pertinent Literature Review

To assess the long-term implications of CO2 exposure during space flight, an ideal study would evaluate 

long-duration (>30 days) exposures to moderately elevated CO2 (<1%) in microgravity. Finding 

appropriate studies is challenging as research in microgravity is limited and terrestrial studies 

predominantly focus on CO2 exposure at much higher concentrations with brief exposure periods. No 

studies were found addressing the specific criteria mentioned above; therefore, this paper focuses on 

terrestrial studies lasting greater than 20 days at less than 2.0% CO2, selected research at higher 

concentrations or shorter durations as applicable, and any research conducted in microgravity that may 

provide insight into CO2 metabolism. 

Of note, although there are partial analogs to microgravity such as head-down tilt and parabolic flight, the 

material reviewed did not provide further insight as to whether the analogs meet stated criteria for CO2

concentration and duration. 

3.1 Research conducted in microgravity

The ability to conduct research in space is limited by multiple factors. No published research was found 

specifically focusing on moderate elevations of CO2; however, two studies in particular provided insight 

into CO2 symptoms experienced by the ISS crew. Christopher Carr, in a 2006 retrospective study, 

correlated astronaut reports of headache and other CO2 symptoms with periods of elevated CO2 on the 

ISS. Based on recorded CO2 levels and symptoms documented in weekly private medical conferences 
4

from ISS Expeditions I-VII, Carr identified symptom complaints with a positive predictive value of 50% 

and negative predictive value of 90% when CO2 concentrations exceeded 0.63% CO2 (4.8 mmHg). G. 

Kim Prisk evaluated the pulmonary function of 10 astronauts on board the ISS at monthly intervals and 

was able to evaluate lung function over a 130- to 196-day period. Although the elevated CO2 environment 

on board the ISS was not addressed in the study, the pulmonary data collected provide insight into 

pulmonary function in microgravity (Prisk et al. 2006). This study will be discussed further in section 4.3. 

3.2 Terrestrial research

Research of long-duration exposure (>20 day) to moderately elevated CO2 levels (<2%) originates from 

three basic sources: animal models, submarine patrol studies, and a limited number of dedicated 

experiments on humans.

3.2.1 Animal Models and Patrol Studies

The closed-circuit environmental conditions on nuclear submarines, with the exception of microgravity, 

are grossly analogous to space cabins. From 1960 to the mid 1980s, multiple studies evaluating 

submariners on extended patrols and in dive chamber simulations were performed. One of the experts in 

this field, Karl Schaefer from the U.S. Naval Medical Research Laboratory and the Naval Submarine 

Research Laboratory, published numerous articles on both animal models and submariners. The 

submarine patrol studies predominantly corroborated earlier animal studies, and Schaefer intended to 

conduct dedicated long-term manned diving chamber studies to evaluate CO2 concentrations up to 1%. 

However, with the advent of new naval technology reducing CO2 levels below 0.5%, the proposed studies 

were deemed too costly and no longer pertinent (Waligora 1994). 

W. A. Tansey, working with Schaefer in 1979, compiled a retrospective epidemiological evaluation of 

submariners analyzing medical records from 7,650,000 man-days. Tansey evaluated two time periods 

from 1965-67 and 1968-73. Between those two time periods, substantial improvements were made in 

atmospheric controls, most notably a decrease in exposure time to CO2 concentrations greater than 1% 

(70 to 90% during 1963-67, <20% during 1968-73). As a retrospective study, no causal relationship could 

be established, although the data demonstrated reductions in genitourinary (renal calculi), respiratory, and 

gastrointestinal illnesses as measured in lost workdays. 

3.2.2 Dedicated Studies

Two notable studies, Radziszewski (Radziszewski et al. 1988) and a joint NASA-ESA-DARA study 

(1998), evaluated exposure to moderately elevated CO2 concentration over multiple days. Radziszewski 

evaluated 56 subjects in 11 experiments ranging from 6- to 46-day exposures at various CO2 levels. He 

noted little impairment at 1% CO2, and described performance at 1.9% CO2 as “without noticeable 

changes of physiological function at rest and during exercise.” Despite this, he eventually concluded that 

the 0.5% CO2 (3.8 mmHg) limit adopted by the U.S. Navy for long-duration exposure “appears justified.” 

The Joint NASA-ESA-DARA study evaluated four university students in a diving chamber over two 23-

day periods of exposure to 0.7% and 1.2% CO2, respectively. The study was limited by a small 

population, a poor control group (students who continued normal activity with periodic testing), and two 

exposure periods repeated 3 months apart on the same subjects. The authors noted an increase in cerebral 
5

blood flow, lactic acid build up under exercise, and mild performance impairment (Sliwka et al. 1998, 

Hoffmann et al. 1998, Manzey et al. 1998). No significant effect on sleep, circadian rhythm, or peak 

oxygen (O2) consumption during exercise was noted (Gundel et al. 1998 #2, Samel et al. 1998, Hoffmann 

et al. 1998). Cardiorespiratory response, as measured by heart and breathing rate, varied over the duration 

of the experiment. The variation was presumed to be due to cycles of mild compensated and 

uncompensated respiratory acidosis. A steady state was never achieved over the 23-day exposure (Gundel

et al. 1998). Specific areas of these studies will be discussed later in section 4.2 Prolonged Effects of CO2

Exposure.

4.0 Carbon Dioxide-Related Physiology

Crew reports of acute CO2 symptoms appear credible; astronauts are trained to recognize these symptoms, 

they correlate with ISS CO2 levels (Carr 2006), and by anecdotal report, symptoms are observable by 

crew surgeons in mission control during communication exchange with the crew. Given that these 

symptoms occur at levels significantly lower than terrestrial studies predict, it can be hypothesized that 

either an environmental or a physiological condition is sensitizing the astronaut. Many factors may play a 

role—factors such as stress, sleep, or diet—but the most impressive physiological stimulus experienced 

by the flight crew is microgravity. This section will identify the known response to elevated CO2 and 

review the physiological aspects of microgravity that may potentiate that response.

4.1 Carbon dioxide acute toxicity

The effects of CO2 toxicity can include dyspnea, increased respiratory and heart rate, headache, decreased 

alertness, anxiety, dizziness, muscle twitching, coma, or death. Symptom severity is related to the 

concentration of CO2 and the length of the exposure. Headache is the symptom most commonly reported 

by ISS flight crew, typically when levels reach 0.7% CO2 (5 mmHg) (Carr 2006). The SMAC for 

Selected Airborne Contaminants Vol. 2 (1996) cites Radziszewski et al. (1988) in setting 3% CO2 (23 

mmHg) as the threshold for headaches, and 2% CO2 (15 mmHG) as rarely producing headache during 

exercise. The Environmental Protection Agency references 2.0% (15 mmHg) as the threshold for 

headache after several hours of exposure. To put this in perspective, the highest level recorded in a 

manned U.S. spacecraft was 14.9 mmHg or 2.0% CO2 on Apollo 13 (Michel et al. 1975). A detailed list 

of acute CO2 toxicity symptoms can be found in Table 2. 
6

Table 2. Physiological Tolerance Time for Various Carbon Dioxide (CO2) Concentrations and Acute Health 

Effects of High Concentrations of CO2 

PHYSIOLOGICAL TOLERANCE ACUTE HEALTH EFFECTS

ppCO2 Maximum Exposure 

mm Hg % Limit (min) Duration of Exposure Effects

3.8 0.5% Indefinite

7.5 1.0% Indefinite

11 1.5% 480

15 2.0% 60 Several hours Headache, dyspnea upon mild exertion

23 3.0% 20 1 hour Headache, sweating, dyspnea at rest

30 4.0% 10 (4-5%) 

Within few minutes Headache, dizziness, increased blood pressure, 

uncomfortable dyspnea

38 5.0% 7

45 6.0% 5 1-2 minutes

≤16 minutes

Several hours

Hearing, visual disturbances

Headache, dyspnea

Tremors

53 7.0% <3 (7-10%) 

Few minutes

1.5 minutes to 2 hours

9% for 5 minutes

Unconsciousness, near unconsciousness

Headache, increased heart rate, shortness of breath, 

dizziness, sweating, rapid breathing

Lowest published lethal concentration

68 9% N/A

75 10% N/A (>10-15%) 

1 minute to several 

minutes

Dizziness, drowsiness, severe muscle twitching, 

unconsciousness

113 15% N/A

128 17% N/A (17-30%) 

Within 1 minute Loss of controlled and purposeful activity, 

unconsciousness, convulsions, coma, death

Adapted from EPA 2000 by Law 2009.

All U.S. astronauts participate in CO2 toxicity recognition training. The trainee inhales from a 15L 100% 

O2 reservoir with expired gases (CO2) recirculated into the reservoir. Pulse oximetry (SpO2), heart rate, 

respiratory rate, % CO2 inspired and % CO2 expired are displayed. The process continues until inspired 

CO2 reaches 8% CO2 (61 mmHg) or the subject experiences significant symptoms and training objectives 

are met. NASA flight surgeons are present during this evaluation to ensure safety. Characteristic 

symptoms, per ISS Environmental Health System instructor David Stanley, begin with air hunger at 

approximately 5.5% CO2, followed by facial flushing, increased respiration and heart rate, sweating and 

tingling in distal extremities. About 40% of the crew report headache and 60% heavy headedness. Smaller 

numbers note visual disturbances and dizziness. While these data are recorded in each astronaut‟s medical 

record, the training is designed to aid symptom recognition, not scientific analysis (D. Stanley, personal 

conversation). 

4.2 Prolonged effects of carbon dioxide exposure

The following section reviews specific physiologic responses to increased CO2 concentrations. While 

potentially pertinent, the impact on immunological depression, cellular response, and cerebral metabolism 

is not well understood. 
7

4.2.1 Respiratory Acidosis

Respiratory acidosis begins within a few minutes of exposure to elevated concentrations of CO2. Despite 

the body‟s compensatory mechanisms, a mild acidosis will persist until the exogenous CO2 is removed 

(Schaefer 1980). Respiratory acidosis ensues when the body is unable to effectively expel CO2 secondary 

to inadequate ventilation or environmental exposure. Excess CO2 in blood plasma and erythrocytes is 

reversibly converted to bicarbonate and H+ by carbonic anhydrase. Therefore CO2 that cannot be expired 

raises the body‟s concentration of H+, lowering the pH. The body has two basic responses to this 

acidosis. It can neutralize the H+ load with bicarbonate from cellular response and renal absorption or it 

can reduce CO2 through increased ventilation. 

The chemical reaction below demonstrates how this mechanism works:

(HYPERCAPNIA) 2 H2O + CO2 ↔ H2CO3 + H2O ↔ H3O

+

+ HCO3

- 

 (ACIDOSIS)

If respiration is inadequate to eliminate CO2, the equation is driven to the right and acidosis ensues. 

PaCO2, PaO2, and pH chemoreceptors, located in the brain stem and aortic arch, stimulate respiration in an 

effort to rid the body of CO2 and drive the equation back to the left. 

4.2.2 Pulmonary Response

As described above, PaCO2 and pH influence respiratory drive. Exposure to concentrations of 0.5 to 1.5% 

CO2 (3.8 to 11 mmHg) result in arterial CO2 (PaCO2) increases of 1 to 4 mmHg and reduction in pH by 

0.02 to 0.05 (Schaefer et al. 1963, Pingree 1977). These values fluctuate during various phases of 

compensation but remain elevated through the exposure. 

The pulmonary response to this acidosis is increased ventilation volume and rate. Specifically Pingree 

(1977) described a 3.5L/min increase in volume and a 1.5 breaths/min rate increase at 1.0% CO2. 

Although respiratory rate and minute volume tend to return to baseline values by the second to third week 

of exposure, PaCO2 and pH do not (Schaefer 1963). This suggests that the pH and CO2 dependent set 

point for respiratory drive may readjust to the chronic exposure. 

4.2.3 Vascular

CO2 is a potent vasodilator of cerebral blood vessels. Cerebral blood flow (CBF) was monitored by 

Silwka (1998) in 0.7% and 1.2% CO2 environments over 23 days. On days 1-3, there was a 35% increase 

in cerebral blood flow as measured at the middle cerebral artery. After day 3, the blood flow steadily 

decreased to about 12 to 15% above pre-exposure levels. Sliwka reasoned that brain extracellular 

bicarbonate (H CO3-) increases in response to the increased [H+], slowly lowering, but not normalizing, 

the stimulus during exposure. Unexpectedly, CBF did not return to baseline after return to ambient CO2

levels remaining elevated through the end of evaluation period, 2 weeks post-exposure. He was unable to 

explain this persistence of increased CBF post-exposure. 

The impact of increased CBF and its persistence post-exposure is not known. A current area of interest in 

space medicine is case reports of persistently elevated cerebrospinal fluid (CSF) pressures and 

papilledema in long-duration flight crew. Increased CBF secondary to CO2 exposure has not been studied 

as a potential contributor, but should be considered for further investigation. 
8

4.2.4 Calcium and Bone Changes Secondary to Respiratory Acidosis

Calcium loss from CO2 exposure and its impact on bone density is controversial. Calcium balance during 

long-duration space flight is concerning for reductions in bone mass and promotion of renal calculi. Wong 

(1996) in the Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Vol. 2, 

concluded that calcium loss secondary to CO2 was either not present or not of significant magnitude. His 

conclusion was based on the inconsistencies of terrestrial studies and measurements of Skylab flight 

crew‟s urinary calcium excretion. Terrestrial studies presented conflicting data on the presence of CO2-

induced urinary excretion of calcium. Measurements of Skylab crews‟ urinary calcium levels were 

equivocal to patients in terrestrial bed rest studies. These findings suggested to Wong that increased 

calcium excretion was due to microgravity and not significantly affected by CO2 levels. In contrast, using 

rat, rabbit, and guinea pig models along with submarine patrol data, Schaefer portrayed a complex process 

of cyclical phases of respiratory and metabolic acidosis resulting in periods of both Ca2+ release and 

deposition in bone. This cyclical process could help explain the conflicting results mentioned above. To 

promote a more thorough understanding of the processes involved, Schaefer‟s 1980 conclusions are 

summarized here.

Schaefer noted that renal regulation of acid base disorders was dependent upon the level of acidosis. 

Renal regulation via bicarbonate reabsorption is fully active when exposed to high levels of CO2 (>3%, 

23 mmHg); however, at lower levels of hypercapnia (experienced at 0.5 to 1.5% CO2), renal regulation 

becomes less effective and paradoxically the time required for compensation increases with decreasing 

CO2 concentrations (Schaefer 1979). At these lower levels, “bone buffering” becomes the primary 

compensatory method, and cyclic periods of respiratory acidosis followed by metabolic acidosis develop 

in roughly 20-day cycles. In contrast, during higher levels of hypercapnia (experienced at >3% CO2, 23 

mmHg), a pattern of respiratory acidosis with cyclical compensated and uncompensated periods 

predominates (Schaefer 1980). 

Bone has a huge capacity to absorb CO2. Five of the six moles of total body CO2 reserves reside in bone. 

The body can use this reserve to regulate H+ and CO2 levels. CO2 is released or deposited in bone as 

either bicarbonate or calcium carbonate. Bicarbonate is the more easily exchanged form and causes no 

breakdown of the bone. Bicarbonate and a positive ion (Ca2+, K+, Na+) are exchanged for H+. Over 

chronic periods of acidosis, carbonate can be released, though it does result in bone breakdown. This 

process is established in chronic metabolic acidosis but is less well understood in chronic respiratory 

acidosis. Schafer, in his studies, explored the process of chronic respiratory acidosis secondary to 

environmental CO2 exposure. 

Schaefer describes a unique variation of the bone buffering process in which excess CO2 is converted to 

H+ or alternatively deposited in or released from bone as bicarbonate and carbonate. Over an 8-week 

period of exposure to 1% CO2, he saw three distinct phases of alternating cycles of fluctuations in bone 

bicarbonate and carbonate. During Phase 1 and 3 (centered around weeks 1 and 6), calcium and 

phosphorus peaks in the plasma and troughs in the bone. Phase 2 (weeks 2 to 4) shows bone deposition of 

calcium and phosphorus with corresponding drops in the plasma. During phase 2, CO2 is released with 

bicarbonate from the bone resulting in increasing PaCO2. The cyclical nature of the calcium balance 

described by Schaefer may explain the range of findings reported in other studies.
9

After investigating this process in animal studies, Schaefer (1979) noted a greater than 25% increase in 

renal tubule and cortex calcification of guinea pigs following an 8-week exposure to 1% and 1.5% CO2

(7.5 and 11.4 mmHg). Likewise, there was a significant decrease in bone calcium compared to control 

animals. These levels remained depressed 8 weeks after removal from the elevated CO2 environment 

(Schaefer 1980, 2). 

4.2.5 Renal Calculi

Many factors are thought to contribute to stone formation in space, among those are reduced urine pH, 

increased urine Ca2+, and decreased urine output (Whitson et al. 1997). In the third phase (peaking at 

week 6) of the process described above by Schaefer (1980), plasma Ca2+ is at its highest during a period 

of metabolic acidosis where renal regulation reabsorbs bicarbonate and acidifies the urine. If Schaefer‟s 

observations are accurate, this process could promote renal calculi. However, in contrast, Wong (1996), in 

the Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Vol 2, 

concluded that there is no consistent evidence for increased Ca2+ excretion and urine acidification 

secondary to carbon dioxide exposure. 

In a 10-year retrospective epidemiological review of submarines exposed to two distinct periods of known 

CO2 concentration, Tansey et al. (1979) observed an overall reduction in workdays lost to illness when 

CO2 concentrations were reduced. In particular, he noted a threefold reduction in workdays lost to renal 

calculi when exposure to >1% CO2 was reduced to <20% of the time on patrol. As a retrospective study, 

causality could not be proven, and potentially confounding factors were present. Of note, the increased 

risk of renal calculi at the higher exposure percentage is only 2.9x10-4. No evidence was found to validate 

or contradict the conclusions of Schaefer or Tansey. 

4.3 Microgravity

“The immediate effects of weightlessness on the human are not known....The absolute effects of 

weightlessness on the human are not known” -Ellen S. Baker 

Barratt’s Principals of Clinical Medicine for Space Flight

Initial adaptation to microgravity impacts nearly every system of the body. Long-duration space flight on 

board the ISS has revealed complex interactions as the body adapts to its new environment. Analysis of 

these processes is complicated by a small population of subjects, poor analogs to prolonged microgravity, 

and a limited ability to collect data in this environment. Microgravity‟s effect on CO2 may include lack of 

air convection, internal fluid shifts, cardiovascular adaptations, and changes in pulmonary function. In 

addition, physiological response to elevated CO2 may potentiate musculoskeletal, renal, and vascular 

responses to microgravity. The following is intended to suggest potential areas of further investigation; it 

is not an exhaustive study of the impact of microgravity as it pertains to CO2. 

4.3.1 Lack of Air Convection

Isolated pockets of CO2 or other gases can form in spacecraft and remain undetected by fixed 

environmental monitors such as the MCA. On Earth, gravity-driven convection allows for effective 

circulation of expired gases. In microgravity, exhaled gases do not readily disperse and may create 

pockets of CO2. In a computational fluid dynamics study, Chang Son concluded that without exogenous 
10

ventilation, a sleeping crew member in the ISS Service Module could experience a localized CO2

concentration of > 9 mmHg or 1.2% CO2 in 10 minutes (Son et al. 2002) (see figure 1). Although this 

phenomenon does not alter CO2 metabolism, an inability to dissipate expired CO2 could contribute to the 

symptoms reported. 

In Station Detailed Test Objective #25007, two ISS crew members donned CDMs to measure CO2 levels 

in the immediate vicinity of the crew members. The CDMs revealed periodic CO2 spikes during exercise. 

These spikes were not observed by the MCA (fixed) sensor, supporting the hypothesis that localized areas 

of elevated CO2 may be generated during periods of increased metabolic activity (James 2008). Anecdotal 

reports also identify mild CO2 toxicity symptoms near the crew dining area and when conducting work in 

confined or poorly ventilated areas. Further investigation into individual CO2 burden through noninvasive 

monitoring may be warranted. 

4.3.2 Cardiovascular and Fluid Shift

When standing in a 1G environment, venous pooling in the lower extremities generates a vascular 

pressure gradient of approximately 200 mmHg from head to heel. Upon entering a microgravity 

environment, the vascular hydrostatic gradient is lost. When this occurs, a cephalad fluid shift 

redistributes blood volume in the lower extremities throughout the body. This redistribution results in 

increased right atrial filling pressure and cardiac output. Mean arterial pressure, however, is preserved, 

presumably through a decrease in peripheral vascular resistance (Buckey 1996). It is not clear whether 

cardiac output returns to preflight levels while under the influence of microgravity (Prisk 2005). 

Eventually, a new hemodynamic homeostasis is achieved via a 1 to 2L loss of intravascular volume 

achieved though extravasations into the intracellular space and a relative diuresis (Leach et al. 1996, 

Fig. 1: Carbon dioxide (CO2) molar concentration 

an partial pressure in the crew quarters 10 

minutes after fa off (x-z plane) (Son et al. 2002).
11

Barrett et al. 2008). By flight day 9 in microgravity, a new euvolemic state develops with a 10 to 15% 

reduction of plasma volume and a 10% reduction in erythrocyte mass (Lane et al. 1996). 

How this reduction and redistribution of plasma volume affects CO2 metabolism is unknown. Blood 

plasma, proteins, and erythrocytes are responsible for CO2 transport from tissues to the lungs and are the 

primary site of action, via carbonic anhydrase, for respiratory acidosis/alkalosis. Providing a glimpse into 

the possible adverse effects of this hypovolemic state, Burnley (Burnley et al. 2006) investigated 

terrestrial peak exercise performance following a 450-ml blood donation. In that study, he found 

significant reductions in O2 carrying capacity, peak rate of O2 uptake, and exercise tolerance. Further 

investigation into CO2 tolerance and performance in this unique hypovolemic state is recommended. 

The effects of long-duration space flight on cerebral blood flow, venous congestion and increased 

cerebral pressure are not well researched. As presented in section 4.2.3, cerebral blood flow is increased 

in the presence of 0.7% CO2 by as much as 35%. How the cephalad fluid shift described above may 

potentiate any adverse effect from this increased cerebral blood flow is unknown.

4.3.3 Pulmonary Function

Recent studies suggest fewer deficits in lung function from long-duration exposure to microgravity than 

previously assumed. Studies examining pulmonary function in flight crew reveal that vital capacity 

returns to near preflight levels by flight day 9 (Prisk 2006 #2). Furthermore, over extended periods of 

microgravity, pulmonary gas exchange, and muscle strength are preserved (Prisk et al. 2006). 

Interestingly, though it had been theorized that ventilation and perfusion gradients (Va/Q) of the lung 

would normalize and improve in microgravity, Va/Q remains effectively unchanged over the normal 

range of tidal volume, thus suggesting that gravity plays a minimal, possibly even beneficial role in 

normalizing the Va/Q gradient (Prisk et al. 2006). 

G. Kim Prisk „s (2006) long-duration study monitored the pulmonary performance of 10 ISS crew 

members at monthly intervals over a 136- to 196-day period. Measured end-tidal pp CO2 (PETCO2) 

revealed an average 2 mmHg elevation above preflight standing values but matched supine preflight 

values (see Table 4). The only notable variation from preflight values was a 12% decrease in metabolic 

rate, as measured by oxygen consumption and CO2 production. This reduced metabolic rate was attributed 

to disuse of antigravity muscles and work load (Prisk et al. 2006). Based on this analysis, it is unlikely 

that pulmonary adaptations to microgravity significantly alter pulmonary function, but it is unclear if the 2 

mmHg PETCO2 elevation and decreased metabolic rate in the ISS environment are significant. 

4.3.4 Renal Calculi

Renal calculi have the potential to seriously impact mission performance and, in one case, nearly resulted 

in mission termination and unscheduled deorbit (Pietrzyk et al. 2007). While stone formation is 

multifactorial, several factors experienced in microgravity can be pro stone forming; including reductions 

in urinary pH, increases in urinary calcium, decreased urinary output, and decreased urinary citrate (stone 

inhibitor) (Whitson et al. 1997). 
12

5.0 Operational Implications and Recommendations

The known physiological responses to CO2 exposure and microgravity were reviewed in the previous 

sections. Based on that review of available literature, three areas with the most potential for mission 

impact or astronaut health are noted: bone demineralization and renal calculi formation; cerebral blood 

flow and its impact on increased intracranial pressures; and mission performance.

5.1 Renal calculi and bone reabsorption

Renal calculi symptoms almost resulted in an unscheduled deorbit of a symptomatic ISS crew member 

(Pietrzyk et al. 2007). An unscheduled deorbit would create a severe impediment to mission success and 

incur considerable financial and safety consequences. The situation would become more complicated if 

the symptomatic crew member were the Soyuz commander, or if the situation occurred when transport to 

definitive care was not possible. 

Schaefer (Schaefer et al. 1980) depicts a complex cycle of acidosis and bone reabsorption/deposition 

leading to varying plasma calcium levels over an 8-week exposure. The SMAC for Selected Airborne

Contaminants Vol 2 (Wong 2006) in its discussion of subchronic and chronic toxicity of CO2 reveals the 

lack of definitive data to determine the impact on electrolyte levels, kidney, and bone. Given the severity 

of the consequences, the potential for CO2 to alter calcium metabolism may need to be reviewed. 

Recommendations for further evaluation:

1. Conduct an extended human study (greater than 8 weeks), preferably in microgravity, with 

multiple levels of CO2 concentrations from control to 1.0% (7.5 mmHg) to evaluate changes in 

bone mass, arterial and urinary pH, and calcium and phosphorous levels in bone, plasma, and 

urine. These studies could be conducted in conjunction with the cerebral blood flow and 

performance studies suggested in 5.2 and 5.3.

2. Continue current renal calculi prophylaxis of potassium citrate supplementation in astronauts. 

Magnesium citrate or potassium citrate supplementation may decrease the risk of renal stone 

formation during and after space flight (Whitson et al. 2009). The potential for increased calciuria 

secondary to CO2 exposure may be mitigated by this practice. 

3. Consider reduction in environmental CO2 concentration in future spacecraft. Without further 

study, however, selection of a practical concentration would only be speculative.

5.2 Cerebral blood flow

Increased intracranial pressure (ICP), increased intraocular pressure and papilledema in space flight are 

emerging areas of concern, and were the subject of summits at the NASA Glenn Research Center in 

February 2010 and at Space Life Sciences at Johnson Space Center in February 2011. During the 

February 2010conference, a case study was presented describing an astronaut with acute visual symptoms 

in space. The astronaut was found on return to have mild intracranial hypertension, optic nerve sheath 

dilation, and posterior scleral flattening (Rubin et al. 2007). Furthermore, detailed analysis demonstrating 
13

near vision changes in 23% of short-duration and 48% of long-duration crew members was later 

published in Ophthalmology Ocotober 2011 (Mader 2011) following those summits.

The etiology of increased ICP and visual impairment is still being evaluated. One theory is that elevated 

venous pressures may disrupt efficient reabsorption of CSF via the arachnoid granulations. As presented 

above, exposure to 0.7% CO2 (5.3 mmHg) results in an immediate (days 1-3) 35% increase in cerebral 

blood flow. This increased flow partially corrects but does not return to baseline while exposed to 

elevated CO2 and it is unknown how long normalization takes once CO2 levels are returned to ambient 

levels (Sliwka et al. 1998). The impact of increased CBF in combination with the cephalad fluid shift 

experience in microgravity should be evaluated in further studies with regard to increased ICP.

Finally, the physiology of increased CO2 concentrations on the brain and its related structures is 

unknown. The blood brain barrier is highly permeable to CO2 and is susceptible to acid/base shifts 

associated with CO2 exposure. J. M. Clark (Clark et al. 1969) evaluated four subjects exposed to 3.9% 

CO2 (30 mmHg) noting a twofold increase in CSF PCO2 (6 mmHg) compared to arterial PCO2 (3 

mmHG). In a 5-day exposure, the CSF pH and PCO2 remained elevated for 2 days longer than arterial 

PCO2 and pH. A more complete understanding of CO2‟s effects on CSF may be beneficial in 

understanding the etiology of increased ICP. 

Recommendations for further evaluation:

1. Conduct an extended human study (greater than 8 weeks), preferably in microgravity, with 

multiple levels of CO2 concentrations from control to 1.0% (7.5mmHg) to evaluate changes in 

arterial and CSF pH, arterial and CSF pp CO2, ICP, cerebral arterial and venous pressures. These 

studies could be conducted in conjunction with calcium and performance studies suggested in 5.1 

and 5.3. 

2. Incorporate CO2 and/or increased CBF in the ongoing evaluation of ICP elevation.

3. Consider reduction in environmental CO2 concentration in future spacecraft. 

5.3 Mission performance

With documented physical symptoms reported by astronauts at one-third the expected level of CO2 (Carr 

2006), it is reasonable to hypothesize that performance impairment may also present at lower 

concentrations. Terrestrial studies suggest that mild performance impairment should begin at elevations of 

1.2% CO2 (Manzey et al. 1998). However, how the relative hypovolemia post-cephalad fluid shift may 

diminish the body‟s ability to handle increased CO2 burdens or acidosis is unknown. Additionally this 

diminished capacity may become more pronounced during increased physical or neural metabolic 

activity. 

Recommendations for further evaluation:

1. Develop methods for noninvasive monitoring of flight crew‟s CO2 burden. It is important to 

understand if symptoms are related to localized “CO2 pockets,” a physiological sensitization of 
14

microgravity or both. Continuous monitoring of astronauts‟ immediate CO2 environment, PaCO2, 

arterial pH and end tidal CO2 would be preferred, although noninvasive methods are limited. 

Two portable monitors are currently available on the ISS. Wearing the CDMs near the level of 

the head may provide more specific environmental data. Continuous monitoring of arterial pH 

and end tidal CO2 is problematic; however, commercially available transcutaneous PaCO2

monitors are available. Both the TOSCA 500 and V-sign Sentec sensor monitor PaCO2 (PcCO2), 

SpO2 and pulse rate. Critical evaluations of these sensors suggest good capability in trend 

analysis with some overall accuracy concerns (Bernet-Buettiker et al. 2005, Baulig et al. 2007, 

Bernet et al. 2008, McVicar 2009). Both systems use heated (42 to 45°C) ear clips that may 

require evaluation for accurate measurements in microgravity. Further investigation of these 

sensors may be warranted if PaCO2 accuracy can be evaluated.

2. Conduct an extended human study (greater than 8 weeks), preferably in microgravity, with 

multiple levels of CO2 concentrations from control to 1.0% (7.5 mmHg) to evaluate performance 

during continuous stressful activity similar in intensity to ISS missions. If a microgravity 

environment is not feasible, a method to simulate fluid shift should be incorporated. These studies 

could be conducted in conjunction with calcium and cerebral blood flow studies suggested in 5.1 

and 5.2. 

3. Consider reduction in environmental CO2 concentration in future spacecraft. 

6.0 Conclusion 

Reliable reports of acute CO2 symptoms on the ISS are occurring at levels lower than terrestrial studies 

predict. It is logical to postulate that either an environmental or physiological condition is sensitizing the 

astronauts. After review of the pertinent literature, three potential areas of operational impact were 

identified: renal calculi and bone reabsorption; cerebral blood flow; and mission performance. With no 

definitive research to provide insight into these areas, further evaluation of the following is 

recommended:

- Incorporating quantifiable methods of measuring crew CO2 burden through noninvasive 

continuous motoring of selected astronauts.

- Developing a robust study (>8 weeks) examining various low-to-moderate CO2 concentrations on 

human subjects, preferably in microgravity. 

- Implementing design requirements for reduced CO2 levels on future space platforms.

7.0 Acknowledgements

Many thanks to David Stanley, Jimmy Wu, Yael Barr, and Corinne Williams for their contributions to 

this work.
15

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Chronic Exposure to Moderately Elevated CO2 during Long-Duration Space Flight

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13. ABSTRACT (Maximum 200 words)

Out of operational necessity, space platforms function with ambient carbon dioxide (CO2) concentrations in excess of normal 

atmospheric conditions (0.03% or partial pressure of 0.23 mmHg). NASA’s long-duration Spacecraft Maximum Allowable 

Concentration for CO2 is 0.7% (pp CO2 of 5.3mmHg). Extensive terrestrial studies support this level as safe and unlikely to cause 

adverse effects; however, International Space Station crews routinely report symptoms of acute CO2 toxicity (e.g., headaches,

lethargy) that correlate with relative elevations of cabin CO2 below the permissible level. It is unclear if the unique environment of 

space results in increased sensitivity to CO2 or if other confounding factors are present. Regardless, acute symptom presentation at 

levels significantly lower than expected prompts the need to reevaluate the potential for adverse effects from long-term exposure. 

NASA’s continued commitment to long-duration space flight makes it imperative to evaluate the impact of chronic exposure on the 

mission and astronaut health. With no definitive research to provide insight into current symptoms, potential avenues of action include 

incorporating quantifiable methods of measuring crew CO2 burden, developing a robust study to examine various low-to-moderate 

CO2 concentrations on human subjects in microgravity and/or implementing design requirements for reduced CO2 levels on future 

space platforms. 

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long duration space flight; astronaut performance; health; carbon dioxide concentration; 

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