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Long-term carbon dioxide toxicity and climate change: a major
unapprehended risk for human health.
P.N. Bierwirth, PhD
Emeritus Faculty
Australian National University
First draft - Web Posted 25 February, 2014
Current Version – 8 April, 2022
ResearchGate DOI:10.13140/RG.2.2.16787.48168
Abstract
As atmospheric levels of carbon dioxide continue to escalate and drive climate change, the safe level
for breathing is not clear. The toxicity of CO2 has been defined for short-duration exposures at high
concentrations but it is unknown what levels will compromise human health when individuals are
perpetually exposed for their lifetime. There is now substantial evidence that permanent exposure,
to CO2 levels predicted in the future, will have significant effects on humans. Blood CO2 levels in
populations are increasing and unhealthy concentrations have been measured from people in
common indoor environments where reduced thinking ability and health symptoms have been
observed at levels of CO2 above 600 ppm for relatively short-term exposures. Although humans and
animals are able to deal with elevated levels of CO2 in the short-term due to compensation
mechanisms in the body, the eventual failure of these may have severe consequences in a perpetual
environment of elevated CO2. Protein malfunctions in cells due to elevated CO2 and associated low
pH has the potential to cause threats to life including cancer, neurological disorders, lung disease,
diabetes, etc. In particular excess CO2 causes the overexpression of carbonic anhydrase, the enzyme
that catalyses CO2 in the body, causes calcification in the kidneys, arteries and tissues, along with
other diseases and this may be an existential threat. Although there is very low awareness of this
risk and its proximity is yet to be adequately defined, it is likely that human health will be
significantly affected in the near-future with the progressive severity dependant on CO2 emissions.
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1. Introduction
An axiom of modern science, as quoted from TS Huxley, is “do not pretend that conclusions are
certain which are not demonstrated or demonstrable”. Carbon dioxide is one of the most frequently
overlooked of all toxic gases. Even to refer to CO2 as a toxic gas is a surprise to many safety
professionals (Henderson 2006). In indoor environments CO2 concentration is often elevated relative
to ambient outdoor levels due to the fact that the exhaled breath from humans contains high CO2
(about 4%) and ventilation may not be adequate to prevent the resulting increase in CO2. Despite
the possible adverse effects on health where many people occupy buildings or vehicles, there is very
little awareness of this issue in the general community.
The average ambient concentration of CO2 (in fresh air) has been rapidly increasing and is recently
around 410 ppm (Scripps Institution of Oceanography 2020; Schmidt 2020) (Figure 1). This increase
is due to humanity’s activities, largely resulting from the burning of fossil fuels (Eggleton 2013).
Figure 1. The atmospheric carbon dioxide concentrations (in ppm) over the last 2000 years, based on
measurements of air trapped in Antarctic ice, shown in blue-grey diamonds, and the modern Cape
Grim, Tasmania direct air measurements, shown in orange. (From Schmidt 2020).
Very early primate ancestors of humans were evolving around 23 million years ago. Throughout all
of the ensuing period of human evolution it is clear that levels of CO2 in the ambient atmosphere
remained relatively stable at below or close to 300 parts per million (ppm), this being derived from a
combination of studies of relict features including air trapped in ice cores (Schmidt 2020), the
composition of fossil plankton (Zachos et al. 2001) and Carbon-13 (13C) content in fossil plant
material (Cui et al. 2020). Since about 1820, CO2 levels have increased rapidly and are now above
400 ppm (Figure 1). This is a potentially catastrophic problem for many species of animals, including
humans, for a number of reasons. The most well publicised issue is that of climate change. The
mechanisms and history of global warming associated with CO2 increase are well understood and
the increase in atmospheric energy gradients will produce more extreme temperatures and weather
events. To many people, climate change itself may not appear to be catastrophic – for example it
might be possible to escape the effects of even a 5 degree C increase this century by moving to a
cooler and safer geographic location. However, it is possible that humans have overlooked the more
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direct and immediate toxicity aspect of increasing atmospheric CO2. The earth’s atmosphere has
already reached CO2 levels that are outside the range breathed by humans throughout their
evolution. As well, in earlier pre-primate epochs, the effect of elevated atmospheric CO2 causing
physiological stress, has been postulated to be a cause of mass extinction events (Knoll et al. 1996)
We know that breathing CO2 is toxic to humans when levels are high with numerous deaths reported
based on occupational exposure (Scott et al. 2009). Although the CO2 exposure limit for an 8-hour
working day has been set at 5,000 ppm (OSHA 2012), this limit was decided in 1946 and based on
relatively short-term observations of fit and healthy submariners (Scott et al, 2009). The safe level
for lifetime exposure may be significantly lower than this and a number of researchers suggest there
could be toxicity effects at CO2 levels predicted in the near future with ongoing anthropogenic
emissions (Portner et al. 2004; Robertson 2006; Ezraty et al. 2011; Antic 2012; McNeil and Sasse
2016; Karnauskas et al. 2020). So the question is: how long will it take, at present and future rates of
increase, to reach levels that will impact on human health (no matter where you live) over a
lifetime? To answer this question, the safe level of CO2, for continuous breathing in humans, needs
to be determined. This paper is an attempt to evaluate available knowledge and to examine the
likely and possible risks (for the near to medium-term future).
2. The role of carbon dioxide in breathing
Breathing is one part of physiological respiration and is required to sustain life (Raven et al.
2007). Aerobic organisms like birds, mammals, and reptiles, require oxygen to release energy by
cellular respiration, through the metabolism of molecules such as glucose. During aerobic
respiration, glucose is broken down by oxygen to release energy, while carbon dioxide and water are
the by-products of the reaction. Breathing delivers oxygen to where it is needed in the body and
removes carbon dioxide thereby exchanging oxygen and carbon dioxide between the body and the
environment. Carbon dioxide (CO2) is essentially a waste product and needs to be removed from our
body. CO2 from respiring tissues enters the blood plasma and diffuses into the red cells, where it is
rapidly hydrated to H+ and bicarbonate (HCO3-) by the enzyme carbonic anhydrase (CA) (Arlot et al.
1985; Adeva-Andany et al. 2014). This enzyme enables the breakdown of CO2 which returns to the
plasma as bicarbonate and is then transported to the lungs (Adeva-Andany et al. 2014). When the
bicarbonate reaches the lungs, CA in the alveoli catalyses the reverse reaction generating water and
carbon dioxide which is exhaled as a gas. CA thus allows a large pool of otherwise slowly reacting
plasma HCO3- to be utilized in CO2 excretion (Arlot et al. 1985).
There is an optimal range for the concentrations of CO2 in the air we breathe. Too little can mean
that breathing is too slow and not enough oxygen is brought into the body (Patton and Thibodeau
2009). Too much can compromise our ability to remove CO2 (from our bodies) as a waste product. So
what are the effects of too much CO2 and what is the level that can cause health problems (in
humans)?
3. Health effects from short term exposure to high levels of CO2
Breathing too much CO2 results in high levels of CO2 in the blood (hypercapnia) associated with a
decrease in blood pH (increased acidity) resulting in a condition known as acidosis. The decreases in
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blood and tissue pH produce effects on the respiratory, cardiovascular, and central nervous systems
(CNS) (Eckenhoff and Longnecker 1995). Changes in pH act directly and indirectly on those systems
producing effects such as tremor, headache, hyperventilation, visual impairment, and CNS
impairment. In terms of worker safety, the US Occupational Safety and Health Administration has set
a permissible exposure limit (PEL) for CO2 of 5,000 parts per million (ppm) (or 0.5 %) over an 8-hour
work day (OSHA 2012). They report that exposure to levels of CO2 above this can cause problems
with concentration, an increased heart rate, breathing issues, headaches and dizziness.
Exposures to 1-5 % CO2 for short-term periods have been documented to produce symptoms on
humans and animals such as dyspnea (shortness of breath), modified breathing, acidosis, tremor,
intercostal pain, headaches, visual impairment, lung damage, increased blood pressure, bone
degradation, reduced fertlity, alterations to urine and blood chemistry as well as erratic behaviour
(Halperin 2007; Rice 2004; Guais et al. 2011; Schaefer et al. 1963; Yang et al. 1997). These levels of
CO2 also induce panic attacks, interrupt the processes of metabolic enzymes and disrupt normal cell
division processes (Colasanti et al. 2008; Guais et al. 2011; Abolhassani et al. 2009).
Health risks continue to escalate, with progressively higher CO2 concentrations causing more severe
reactions and faster responses. A value of 40,000 ppm is considered immediately dangerous to life
and health given that a 30-minute exposure to 50,000 ppm produces intoxication, and
concentrations around 70,000 ppm produce unconsciousness (NIOSH 1996). Additionally, acute
toxicity data show the lethal concentration for CO2 is 90,000 ppm (9%) for a 5 minute exposure.
There are indoor situations where exhaled human breath and restricted air flow can produce
extreme and dangerous levels of CO2. For example infant deaths have been associated with levels of
up to 8% (80,000 ppm) CO2 for an infant covered by blankets (Campbell et al. 1996).
4. Physiological compensation for elevated CO2
When considering long-term effects of breathing sustained elevated CO2, it is important to consider
compensation mechanisms in the body, that regulate for increased CO2 and acidity in the blood, and
how these change over time with persistent exposure. The lowering of blood pH triggers various
compensatory mechanisms, including pH buffering systems in the blood, increased breathing to
reduce excess CO2 in the bloodstream, increased excretion of acid by the kidneys to restore acid-
base balance, and nervous system stimulation to counteract the direct effects of pH changes on
heart contractility and vasodilation (widening of the blood vessels) (Burton 1978; Eckenhoff and
Longnecker 1995). In respiratory acidosis, for a period the kidneys retain bicarbonate helping to
normalise the pH of the blood as it passes through them. This occurs within 6 to 8 hours of exposure
but achieves full effect only after a few days. With continued high levels of CO2 in the blood,
metabolic acidosis occurs and the kidneys do not respond in producing bicarbonate (Schaefer et al
1979a). After this the body uses the bones to help regulate the acid levels in the blood. Bicarbonate
and a positive ion (Ca2+, K+, Na+) are exchanged for H+. The kidneys are involved in a wider array of
physiological compensation responses to CO2 induced pH imbalance (acidosis). The kidney tubule
recovers filtered bicarbonate or secretes bicarbonate into the urine to help maintain acid-base
balance in the blood and this again involves the CA enzyme (Adeva-Andany 2014).
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5. Health effects at common indoor CO2 concentrations
5.1 Classrooms
There is a large volume of recent literature that has documented the occurrence and levels of CO2 in
classrooms across the world including kindergartens, day-care centres, primary schools, high schools
and universities (Bako-Biro et al 2011; Widory and Javoy 2003; Kukadia et al. 2005; Dijken et al.
2005; Branco et al. 2015; Heudorf et al. 2009; Santamouris et al. 2008; Ferreira and Cardoso 2014;
Gaihre et al. 2014; Jurado, et al. 2014; Lee and Chang 2000; Muscatiello et al 2015; Carreiro-Martins
et al. 2014). There is general agreement that the levels of CO2 in 20-50% of classrooms commonly
exceed 1,000 ppm and are often much higher, sometimes reaching levels as high as 6000 ppm for
extended periods. A number of studies have identified CO2 associated symptoms and respiratory
diseases such as sneezing, rales, wheezing, rhinitis, and asthma (Carreiro-Martins et al. 2014;
Ferreira and Cardoso 2014). Other symptoms; i.e. cough, headache, and irritation of mucous
membranes, were also identified (Ferreira and Cardoso 2014). Lack of concentration was associated
with CO2 levels above 1000 ppm. Gaihre et al. (2014) found that CO2 concentrations exceeding 1000
ppm is associated with reduced school attendance. Teachers also report neuro-physiologic
symptoms (i.e., headache, fatigue, difficulty concentrating) at CO2 levels greater than 1000 ppm
(Muscatiello et al. 2015).
5.2 Offices
Offices have levels of CO2 similar to classrooms depending on the number or density of workers and
the types of ventilation systems (Lu et al. 2015; Tsai et al. 2012, Seppanen et al. 1999). These studies
have found strong evidence of the relationship between CO2 levels in offices and Sick Building
Syndrome (SBS) health effects such as headaches, dizziness, fatigue, respiratory tract symptoms, eye
symptoms, nasal and mucous membrane symptoms (Seppanen et al. 1999; Lu et al. 2015; Tsai et al.
2012; Vehviläinen et al. 2016; MacNaughton et al. 2016). Seppanen et al. (1999) conducted a review
of available literature and were careful to eliminate other confounding airborne building
contaminants. The reviewed studies included over 30,000 human subjects, and they concluded that
the risk of SBS symptoms decreased significantly with carbon dioxide concentrations below 800
ppm. Whether CO2 itself is responsible for the health symptoms is still a subject of debate since
historically it has been assumed, despite lack of direct evidence, that other airborne contaminants
are the cause (Zhang et al. 2017).
More recently a number of studies have demonstrated that CO2 has direct impacts on human
physiology at levels commonly found in indoor environments (Azuma et al . 2018). Symptoms such
as fatigue and drowsiness caused directly by CO2 have been demonstrated by the use of
electroencephalogram (EEG) techniques (Snow et al. 2018; Pang et al. 2020). In a study of office
workers, a 20% increase in blood CO2, to significantly above normal levels, was measured along with
sleepiness, headaches, heart rate variation and poor concentration in air that averaged 2,800 ppm
CO2 (Vehviläinen et al. 2016) while lowered heart rate and arousal level (fatigue) is clear at 4000
ppm (Xia et al. 2020). Measurements of end-tidal PCO2 show a significant increase of CO2 in human
blood during tests conducted on astronauts after 4 months continually exposed to about 5,000 ppm
(Hughson et al. 2016). Increases in blood CO2 were associated with restricted lung function at levels
between 2,000 and 3000 ppm CO2 (Shriram et al. 2019). Zheutlin et al. 2014 used statistical data to
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determine an increasing trend in the average levels of CO2 in the blood for a national sample of
5,000 people from 1999 to 2012. Heart rate variation at 2700 ppm is confirmed by Snow et al. (2019)
for 10 minute exposure. MacNaughton et al. (2016) found that a 1,000 ppm increase in CO2 from
background levels was associated with a 2.3 bpm increase in heart rate after adjusting for potential
confounders. Another older study (Goromosov 1968) reported harmful physiological effects on
humans at only 1,000 ppm CO2 with changes in respiration, circulation, and cerebral electrical
activity. These physiological effects are being observed at much lower levels of CO2 than previously
anticipated (Azuma et al. 2018).
5.3 Vehicles
Although rarely studied for health effects, vehicles can often contain even higher levels of CO2
particularly where there are multiple passengers for relatively long journey times. CO2 levels can
build up to 5,000 ppm after less than an hour of driving with two people in a car with only internal
air (Gładyszewska-Fiedoruk 2011). With five people in a car with recirculated air levels of CO2 can
exceed 10,000 ppm (1%) after only 28 minutes, this being a level that is known to result in
respiratory acidosis (Constantin et al. 2016). Buses with high numbers of passengers consistently
reach average CO2 concentrations of > 2500 ppm (Chiu et al 2015). Airliners can contain levels of
around 2000 ppm for the duration of the flight (Gładyszewska-Fiedoruk 2012). Measurements on an
Italian submarine showed a steady increase to 5000 ppm CO2 after 2 hours of being submerged
(Ferrari et al. 2005). Extremely high CO2 concentrations (10,000-20,000 ppm) are commonly found
inside motorcycle helmets in both stationary and moving situations (Bruhwiler et al. 2005).
5.4 Mental impairment in indoor environments
There is now a significant body of research studies involving the detrimental effect of CO2 on
learning and cognitive abilities in humans at common indoor concentrations (Du et al. 2020). Testing
of students has found that CO2 can negatively affect attention, memory, concentration and learning
ability impacting on academic performance (Bako-Biro et al. 2011; Coley et al. 2007). Several recent
university studies of cognitive effects of CO2 have been notable in their strong research design
(Satish et al 2012; Allen et al 2016; Allen et al 2018; Scully et al 2019) with the testing environments
injected with pure CO2 meaning that the analysis of CO2 effects was not confounded by the presence
of other substances. These studies showed that low level CO2 (between 950 ppm and 2500 ppm CO2)
affected the cognitive abilities of students, information professionals and pilots in the indoor
environment. Satish el al. (2012) tested only variations in CO2 over periods of 2.5 hours of exposure.
For seven of nine scales of decision-making performance (basic activity, applied activity, task
orientation, initiative, information usage, breadth of approach, and basic strategy), performance was
significantly impaired in a dose-response manner with higher CO2 levels. For example, compared
with mean raw scores at 600 ppm CO2, mean raw scores at 1,000 ppm CO2 were 11–23% lower, and
at 2,500 ppm CO2 were 44–94% lower. As part of a larger study that included volatile organic
compounds (VOCs), Allen et al. (2016) found that, after CO2was independently modified (from a
baseline of 480-600 ppm) for individual 8 hour exposures, cognitive function scores were 15% lower
at 950 ppm and 50% lower at 1400 ppm. This study used similar methodology to score cognitive
function and the results largely repeated the findings of the earlier work (Satish et al 2012). However
one difference was that, at 1500 ppm CO2, even focussed activity was found to have declined (Allen
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et al 2016). In a study of pilots’ performance, Allen et al. (2018) found that negative impacts on
cognitive function were observed between 700 ppm and 1500 ppm CO2. Another study found similar
negative effects on human cognitive abilities, in experiments involving 140 minute sessions, as well
as increased fatigue at levels of 3000 ppm CO2 compared with 600 ppm (Kajtar and Herczeg 2012).
This study also measured some physiological parameters with heart rate analysis suggesting
significantly increased mental effort at 3000-4000 ppm.
Cognitive and neurological effects are also observed in animal studies. Mice exposed from birth to
1,000 ppm CO2 for 38 days had decreased Insulin-like Growth Factor-1 (IGF-1) which resulted in
greater anxiety and reduced cognitive function (Kiray 2014). Neurons were reduced in number and
were malformed at this CO2 level for several areas of the brain, with the largest effect for those areas
associated with learning and memory. Mice exposed to only 890 ppm from preconception to 3
months of age showed increased corticosterone levels in the blood and brain (Wyrwoll et al 2022).
Chronic elevation of brain corticoids associates with cognitive impairment and could harm the
developing brain (Stolp 2022).
5.5 Sleep impacts
Sleep quality is reduced at 1900 ppm CO2 when compared to 800 ppm in both subjective indices and
electroencephalogram (EEG) measurements of brain activity (Xu et al. 2020). When CO2 in arterial
blood rises to a certain extent, it will produce carbon dioxide narcosis respiratory inhibition,
weakened respiration, and hypoxia of human cells resulting in poor sleep quality (Xu et al. 2020).
Another example is people affected by sleep disordered breathing (SDB). Brillante et al (2012) found
that the development of nocturnal hypercapnia in normal indoor CO2 air concentration, quantitated
by a large difference in carbon dioxide in the blood between morning and evening, predicted
increased mortality in SDB patients. This is a result of the lack of efficacy of an individual’s
respiratory regulatory system in sleep for maintaining normal blood gas tensions (Brillante et al.
2012). As CO2 levels in the atmosphere increase into the future, the impacts on and number of
affected individuals will logically increase.
6. Health effects from long term exposure to elevated CO2 levels below 1%
Where indoor levels of CO2 are relatively high and affecting health, it is generally possible to obtain
relief by going outdoors. However this may not be the case in a climate change future where
ambient CO2 is persistently high and effects of continuous long-term exposure must be considered.
There have been very few studies related to long-term exposure at lower CO2 levels, elevated above
ambient, perhaps for logistical reasons since it is difficult to arrange an experiment for relevantly
long timeframes. We are looking for information on the effect on humans of CO2 levels at 1,000
ppm or less – noting that this is the level that some feasible models predict could be reached in the
ambient atmosphere in less than 100 years (Smith and Woodward 2014). Given the lack of research
at these CO2 levels, it seems reasonable to examine the research available for medium-term studies
on levels of CO2 less than 10,000 ppm (1%). Table 1 provides a summary of health effects, found in
the published literature and discussed in this paper, resulting from breathing CO2 at levels at or
below 1%.
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Table1. Documented health effects from breathing CO2 at concentrations at or below 1%.
CO2 Level Health effect Exposure Source
10,000 ppm
(1%)
Kidney calcification, decreased bone formation and
increased bone resorption in guinea pigs
6 weeks Schaefer et al., 1979a
10,000 ppm
(1%)
Cognitive impairment, increased diastolic blood
pressure
75 min Tu et al. 2020
8500 ppm Increased lung dead space volume 20 days Rice 2004
7000 ppm
(0.7%)
35% increase in cerebral blood flow (implications for
cognitive effects seen in other studies)
23 days Sliwka et al. 1998
5000-6600
ppm
Headaches, lethargy, moodiness, mental slowness,
emotional irritation, sleep disruption
Short-term Chronin et al. 2012; Law et
al. 2010
5000 ppm Kidney calcification, bone degradation in guinea pigs 8 weeks Schaefer et al 1979b
5000 ppm Elevated blood CO2 levels in astronauts 4 months Hughson et al. 2016
5000 ppm Current allowable levels for continuous exposure in
submarines and spacecraft
Operational
continuous
Halperin et al. 2007; Chronin
et al 2012
5000 ppm Permissible exposure limit (PEL) for a work day 8 hours OSHA 2012
5000 ppm Vascular and neurological changes 1.5 minutes Bright et al. 2020
4000 ppm Increase in heart rate, lowered arousal level/
increased fatigue and sleepiness
17 minutes Xia et al. 2020
3500 ppm Cognitive impairment, reduced human vigilance
(increased sleepiness)
4 hours Pang et al. 2020, Zhang et
al. 2020
3000 ppm Cognitive impairment, anxiety, neural damage,
oxidative stress in mice
38 days Kiray et al. 2014
3000 ppm Systemic inflammation and physiological stress in
rodents
9-13 days Beheshti et al. 2018
2700 ppm Drowsiness measured by EEG 10 min Snow et al. 2018
2700 ppm Increase in heart rate 10 min Snow et al. 2019
2000-4000
ppm
Unhealthy blood CO2 levels - 15% above normal
range, sleepiness, headaches, heart rate variations
4 hours Vehviläinen et al. 2016
2000-4000
ppm
Inflammation and vascular damage in mice 2 hours Thom et al.2017
2000-3000 Restrictive lung behaviour and elevated blood CO2 3 hours Shriram et al. 2019
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ppm
2000 ppm Kidney effects in animals (likely calcification) -
incomplete study
Chronic
studies
Schaefer 1982
1900 ppm Reduced sleep quality, drowsiness 8 hours Xu et al. 2020
1400-3000
ppm
Significant impairment of cognitive function
including fatigue
2.5 to 8
hours
Satish et al 2012; Allen et al
2016; Kajtar & Herczeg 2012
1200 ppm Reduced cognitive function 2.5 hours Scully et al. 2019
1000 ppm Harmful changes in respiration, circulation, and the
cerebral cortex
A short time Goromosov 1968
1000 ppm Oxidative stress and damage to DNA in bacteria
(implications for cancer diseases in humans)
3 hours Ezraty et al. 2011
1000 ppm Cognitive impairment, anxiety, neural damage,
oxidative stress in mice
38 days Kiray et al. 2014
1000 ppm Level associated with respiratory diseases,
headache, fatigue, difficulty concentrating in
classrooms
Short-term Carreiro-Martins et al. 2014;
Ferreira and Cardoso 2014;
Seppanen et al. 1999
950-1400
ppm
Health symptoms (respiratory, skin, eyes, headaches,
cognitive, dizziness, sensory), increase in heart rate
30 min MacNaughton et al. 2016
950-1000
ppm
Moderate impairment of cognitive function 2.5 to 8
hours
Satish et al 2012; Allen et al
2016; Allen et al 2018
890 ppm Impaired lung function in new-born female mice,
slightly lower blood pH. Reduced growth,
hyperactivity, increased stress hormone associated
with cognitive impairment
3 months Larcombe et al. 2021;
Wyrwoll et al. 2022
800 ppm Level associated with Sick Building Syndrome -
headaches, dizziness, fatigue, respiratory tract, eye,
nasal and mucous membrane symptoms
Short-term Seppanen et al. 1999; Lu et
al. 2015; Tsai et al. 2012
700-900 ppm Gastropods: reduced growth, reduced food
absorption and oxygen uptake, reproductive failure
6-10 months Navarro et al. 2022;
Mardones et al. 2022
700 ppm Modification of behaviour, stress hormone and
respiratory muscle structure in rats
15 days,
6hrs/day
Martrette et al. 2017
400 ppm Current average outdoor air concentration - no
known effect
Lifetime Carbon Dioxide Information
Analysis Center 2015
280-300 ppm Pre-industrial outdoor level from about 1820 to at
least 25 million years ago - no effect
Lifetime Beerling and Royer 2011;
Zachos 2001.
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6.1 Spacecraft
A good information source may be the safety guideline documents for activities where humans are
required to remain in enclosed spaces for long periods such as spacecraft and submarines. NASA
sought to determine the safe levels for long-term exposure to CO2, but found little research focused
on levels below 10,000 ppm CO2; as such, there was no definitive study available to guide standards
(Cronyn et al. 2012). They set the maximum allowable CO2 concentration limits, for long term (1,000
day) habitation of submarines and spacecraft, at 5000 ppm (James and Macatangay 2009).
International Space Station (ISS) crew members have repeatedly reported symptoms associated with
acute CO2 exposure at levels of 5,000 to 6,600 ppm CO2 (see Table 1). The most commonly reported
symptom was headache; other symptoms reported included lethargy, mental slowness, emotional
irritation, and sleep disruption (Law et al. 2010). For space flight, Cronyn et al. (2012) identified three
potential areas of operational impact of elevated CO2: renal calculi (kidney calcification) and bone
reabsorption; cerebral blood flow; and mission performance. With no definitive research to provide
insight into these areas, further evaluation was recommended to examine the effects on human
subjects of various low-to-moderate CO2 concentrations (from ambient levels up to 1%).
Consequently flight rules have been employed to reduce CO2 limits in the ISS to about 3 mm Hg
(4,000 ppm) (Ryder et al. 2017).
6.2 Submarines
Studies of CO2 effects on humans in enclosed submarines have been reviewed by the US government
(Halperin 2007) although most of these studies are for high (> 1%) CO2 levels at relatively short
exposure durations. At these levels (>1%), many of the debilitating and acute symptoms described
above were noted. Current safe levels for continuous exposure in submarines were deemed to be
around 5,000 ppm CO2. This level is set arbitrarily at one-third of the level where there were obvious
signs of health problems (James and Macatangay 2009). It was also noted that if problems are
observed, a submarine can surface so that its occupants can be exposed to the ambient atmosphere.
Halperin (2007) reports that exposures to CO2 levels as low as 7,000 ppm can lower blood pH by up
to 0.05 units and induce renal (kidney) compensation in healthy subjects. This compensation occurs
over a variable period of time, but effects of lowered pH on clinical status or performance have not
been reported either experimentally or operationally. Given that kidney compensation cannot occur
indefinitely, there is some doubt about whether submariners could sustain the “safe” level of 5,000
ppm CO2 if they spent years exposed to it.
7. Protein malfunctions caused by elevated CO2 in the body
Carbon dioxide is a fundamental physiological gas known to profoundly influence the behaviour and
health of millions of species within the plant and animal kingdoms (Phelan et al 2021). It is known
that CO2 plays a major role in sensing and signalling on a cellular level although the physiological
response is complex and not well understood. Research has found that increases in CO2 resulting in
reduced pH alters mitochondrial metabolism reducing oxygen consumption and releasing
intracellular calcium stores (Phelan et al 2021).
The endoplasmic reticulum (ER) is a large dynamic structure within cells that serves many roles
including protein synthesis and calcium storage. Elevated CO2 levels cause protein malfunctions by
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altering ER folding machinery. These malfunctions are associated with ER stress triggering
maladaptive responses and effecting all kinds of diseases e.g., chronic lung disease and reduced
immunity, tissue and organ malfunction (Kryvenko and Vadasz 2021)
7.1 Elevated CO2 causes carbonic anhydrase enzyme disfunction and related diseases
Carbonic anhydrase (CA) enzymes are widely expressed in the nervous system and tissues
throughout the body where they play important physiological roles (Aspatwar et al 2021). The
reaction that CA catalyses, the reversible hydration of CO2 to bicarbonate and a proton, lies at the
heart of a wide range of vital physiological processes (Chegwidden and Carter 2021; Aspatwar et al
2021). Abnormal regulation of carbonic anhydrase-related proteins causes a range of diseases
conditions including cancer, Alzheimer’s, cardiovascular disease, diabetes, glaucoma, epilepsy,
stroke, bipolar disorder etc. The use of CA isozyme inhibitor drugs for treating these diseases is now
a major science (Celebioglu et al 2021; Lemon et al 2021). However, CA inhibitors can cause CO2
retention and result in cellular malfunctions (Phelan et al 2021). The progressive increase in CA
disfunction due to increasing atmospheric CO2 will result in worsening outcomes for the diseases
mentioned above.
7.2 CO2 induced deposits of calcium in the body
Carbonic anhydrase (CA) enzymes participate in metabolic reactions that convert CO2 and result in
the precipitation of calcium carbonate (Adeva-Andany et al. 2015; Kim et al. 2012; Tan et al. 2018).
CA is implicated in calcification of human tissues, including bone and soft-tissue calcification (Adeva-
Andany et al. 2015). The enzyme may be also involved in bile and kidney stone formation and
carcinoma-associated micro-calcifications. The molecular mechanisms regulating the development
of calcification in human tissues and arteries are similar to those that regulate physiological
mineralization in bone tissue, being poorly understood (Adeva-Andany et al. 2015). Carbon dioxide
conversion by the CA enzyme provides bicarbonate and hydrogen ions that fuel the uptake of
ionized calcium which is then deposited in the body tissues as calcium carbonate. With elevated CO2
in cells there is increased release of calcium from the ER (Kryvenko and Vadasz 2021).
Kidney calcification is known to occur with longer term exposure to elevated CO2 levels (Rice 2004;
Schaefer et al., 1979a). A similar causal link between the activity of CA enzyme, which is mainly
responsible for the reversible breakdown of CO2, and calcium deposits has also been established for
arteries (Adeva-Andany et al. 2014). As part of a US Navy experimental program in the 1960’s and
1970’s investigating impacts of long-term CO2 exposure, Schaefer et al (1979b) found that, in a study
of guinea pigs in an enclosed environment breathing 5,000 ppm CO2 for 8 weeks, the kidneys started
to calcify along with bone degradation (see Table 1). Schaefer (1982) also indicated that preliminary
experiments had found kidney calcification effects in animal studies for CO2 concentration as low as
2,000 ppm. Although these studies did not identify a mechanism, they established the casual link
between CO2 and kidney calcification. More recent studies have found that tissue calcification is
promoted where CA is overexpressed due to increased CO2 in the body (Song et al 2021; Phelan et al
2021). Increased CA activity is also linked to cancer where the enzyme helps create a hostile, low pH
environment suitable for cancers to flourish in (Hulikova et al. 2014; Logozzi et al. 2019; Di Fiore et
al. 2020).
12
8. Other important physiological CO2 effects on health
8.1 Impaired growth and muscle development
Female mice exposed to 890 ppm CO2 for 3 months from pre-pregnancy showed reduced growth
(Wyrwoll et al 2022) and a range of lung and respiratory impairments including lower lung
compliance (Larcombe et al. 2021). Prolonged exposure to CO2 on behaviour, hormone secretion
and respiratory muscles in young female rats exposed at 700 ppm CO2 during 6 hours per day for 15
days (Martrette et al. 2017) (see Table 1). CO2 exposure, though not continuous, produced
significant disturbances in behaviour and was accompanied by increased plasma levels of
corticosterone, suggesting that prolonged exposure to CO2 was stressful producing anxiety.
Increased corticosterone associated with hyperactivity in mice was also found from long-term
exposure to 890 ppm CO2.
8.2 Increased cerebral blood flow
Cerebral blood flow (CBF) effects from breathing CO2 is a significant issue for humans. As CO2 in the
blood increases, CBF increases to effectively wash out CO2 from brain tissue and helps regulate
central pH (Ainslie and Duffin, 2009). In a 23-day experiment on humans, Sliwka et al. (1998) found
that cerebral blood flow is increased in the presence of 7,000 ppm (0.7%) CO2 by as much as 35%
(see Table 1) and that CBF remained elevated until the end of the evaluation period, 2 weeks after
the exposure. The impacts of persistent increase in CBF are unclear although there may be a risk of
raised intracranial pressure (ICP) which can compress and damage delicate brain tissue. There is also
evidence that the CBF response to increased CO2 is impaired in Alzheimer’s patients and that this is
linked to the decline in cognitive abilities (Glodzik et al 2013) which will worsen as CO2 in the
atmosphere increases.
8.3 Oxidative Stress
In humans, carbon dioxide is also known to play a role in oxidative stress caused by reactive oxygen
species (ROS) (Ezraty et al. 2011; Kiray et al. 2014). ROS are produced by aerobic metabolism of
molecular oxygen and play a major role in various clinical conditions including malignant diseases,
diabetes, atherosclerosis, chronic inflammation and neurological disorders such as Parkinson’s and
Alzheimer’s diseases (Waris and Ahsan 2006). In particular, oxidative damage to cellular DNA can
lead to mutations resulting in the initiation and progression of cancer. Ezraty et al (2011)
demonstrated that current atmospheric CO2 levels play a role in oxidative stress and that increasing
CO2 levels between 400 and 1,000 ppm exacerbated oxidative stress and damage to DNA in bacteria.
Kiray et al. (2014) concluded that oxidative stress and oxidative damage to brain tissue in mice is
associated with low Insulin-like Growth Factor 1 (IGF-1) levels in mice impacting the growth of bones
and tissues. Increased CO2 promotes the production of ROS leading to greater incidence of cancers
and other diseases including the promotion of virus activity (Waris and Ahsan 2006). Ezraty et et al
(2011) concluded that with higher atmospheric CO2 concentrations, this exacerbation might be of
great ecological concern with important implications for life on Earth.
13
8.4 Inflammation
Inflammation is a serious illness that is known to be caused by elevated CO2 exposure in humans and
animals (Thom et al. 2018; Beheshti et al. 2018; Zappulla 2008; Jacobson et al. 2019). CO2 increases
result in higher levels of Interleukin, a protein involved in regulating immune responses, which
causes inflammation and vascular damage in mice (Thom et al. 2017). Rodents exposed to 3,000
ppm CO2 in spacecraft experiments for 9-13 days showed evidence of inflammation and
physiological stress (Beheshti et al. 2018).
8.5 Stroke
Another study has shown that increased CO2 in the blood of patients can increase the severity of
Subarachnoid haemorrhage; a life-threatening form of stroke, due to the dilatation of arterial
cerebral vessels (Reiff et al 2020).
9. Discussion
Evidence reviewed in this paper suggests that there is a direct risk to the human species posed by
the breathing of ambient atmospheric CO2 concentrations that are rapidly increasing. The level of
ambient atmospheric CO2 that provides unacceptable risk and the exact effect on physiology are not
clearly determined. If this level is reached in the near future, the global human society should be
concerned. Some climate models suggest that atmospheric CO2 levels could be as high as 1,000 ppm
in this century. This is completely unknown for the whole primate evolutionary lineage which has
only experienced levels well below and recently up to the current level of around 410 ppm.
Given the seriousness of the risks identified in this paper an important question has to be: why has
there been no societal discussion of this issue uniquely or in relation to climate change? With the
startling rapid rise of CO2; the permanent changing of our breathable air composition, one would
surely expect the question of whether we can physiologically deal with future projected levels of
CO2, to at least be examined. However, it appears that the issue is not even thought of. There is an
assumption even among scientists that if this was a real issue it would have already been
researched, i.e., we would know about it, though this perception is not scientific and precludes novel
investigation. It appears that the issue of long-term CO2 elevated toxicity has never been significantly
investigated since we have never been in this situation before. Our body’s CO2 compensation
system, as discussed earlier, has been perfectly adequate to deal with a stable level of atmospheric
CO2. It is also possible that climate change has become the main focus of rising CO2 levels and there
is a lack of vested interest amongst climate scientists about the potential dangers of long-term
exposure to elevated CO2. The most recent IPCC report on the health impacts of climate change
didn’t discuss the issue at all (IPCC 2022). This is surprising since the previous IPCC report (Smith and
Woodward 2014) described the findings of Satich et al. (2012) as a reported “reduction in mental
performance at 1,000 ppm CO2 and above, within the range that all of humanity would experience in
some extreme climate scenarios by 2100”. Since the earlier report there have been many more
studies of cognitive decline (Du et al. 2020) and the damaging effects of elevated CO2 on physiology
(this paper). It is therefore disturbing and shocking that the latest IPCC report failed to recognise this
serious and fundamental aspect of climate change. CO2 toxicity at elevated levels is a discipline of
14
environmental medicine which has not focussed on the potential problem because chronic impacts
of increasing environmental CO2 have not yet been recognised. This may also help to explain why
there are very few researchers involved at this stage and public awareness is close to non-existent.
There are few long-term physiological studies of human exposure to 1,000 -2,000 ppm CO2
or less.
However, there are short-term exposure studies describing disease symptoms and physiological
effects as well as reduced cognitive ability in humans at levels around 800 - 950 ppm CO2; these are
CO2 levels that are typically present in offices, classrooms and apartments (Gall et al. 2016). It
appears that many of the physiological effects of CO2 are due to the stimulation of the autonomic
nervous system resulting in elevated blood pressure, respiration, and heart rate (MacNaughton et al.
2016) and this is also associated with a decline in cognitive ability due to increased Cerebral Blood
Flow (CBF) with resulting effects on central nervous system and brain cortical function (Satish et al
2012; Glodzik et al 2013; Bright et al. 2020). The effect on cortical function is supported by a study of
infants that showed an inverse relationship between blood CO2 and electrocortical activity (Wikstrom
et al. 2011). Long-term exposure to environmentally relevant levels of CO2 leads to increases in the
levels of CO2 in human blood (Zheutlin et al. 2014; Hughson et al. 2016; Vehviläinen et al. 2016). This
is retention of CO2 in the human body at greater than normal levels and disturbingly the levels of
CO2 in our blood will continue to increase as atmospheric levels rise.
Increased CO2 in the blood also affects protein behaviour causing inflammation (Thom et al. 2018),
calcification (Schaefer 1982) of body tissue and a range of demonstrated pH-related protein
malfunctions (Duarte et al. 2020), both with potentially serious outcomes. Reduced pH due to CO2
has been found to alter mitochondrial metabolism affecting oxygen consumption (Phelan et al.
2021). Elevated CO2 causing protein malfunctions can trigger diseases including cancer, neurological
disorders, lung disease, reduced immunity and organ failure (Duarte et al 2020; Kryvenko and
Vadász 2021). Perhaps the most significant protein malfunction is the overexpression of the CA
enzyme due to increased CO2 in the body. This widely distributed enzyme plays a vital role allowing
for respiration and the processing of CO2 in all animals and plants. New research is showing that CA
malfunction due to elevated CO2 causes a range of health problems including cancer and diabetes
(Aspatwar et al 2021). Perhaps the most serious of these is tissue calcification which can result in
kidney and cardiovascular failure. Furthermore, the incidence and prevalence of human kidney
calcification (i.e. stones) is increasing globally (Romero et al. 2010; Turney et al. 2011;
Kittanamongkolchai et al. 2018) and it is possible that rising indoor CO2 levels (boosted by increasing
ambient CO2) is the contributing cause.
So what level of permanent CO2 will cause significant calcification and other protein malfunction
effects? It has been suggested that blood pH would be reduced to dangerous levels, if there were no
physiological compensation, at CO2 levels as low as about 430 ppm (Robertson 2006) implying that
ongoing compensation would occur at this level. Ambient conditions may already be dangerously
close to CO2 levels that cause human tissue calcification, particularly when considering the additive
effect of increased ambient levels on indoor CO2 concentrations. In the final paper of the US Navy
CO2 research program in the 1960’s and 1970’s, Schaefer (1982) indicated that this issue had
“become the concern of the Department of Energy and other US government agencies” although it
appears to have been largely forgotten since. If allowed to persist, problems such as kidney and
artery calcification could lead to cardiovascular failure. In the extreme case, lifespans could become
15
shorter than the time required to reach reproductive age. Calcification of kidneys and arteries can be
fatal through renal and cardiovascular failure. This could threaten the viability of human and animal
species without interventions such as the creation of artificial living environments.
Cognitive decline due to CO2, evidenced by definitive studies (Satish et al 2012; Allen et al 2016;
Allen et al 2018) of indoor environments, would logically produce lower intelligence scores in IQ
tests. In fact this phenomenon of declining intelligence is now being measured around the world
(Bratsberg and Rogeberg 2018) with the data suggesting an unidentified environmental cause. It is
feasible that rising outdoor CO2 levels are the cause of the measured decline in human intelligence
(Bierwirth 2018). It is possible that such effects occur without recognition in daily life (Satish et al.
2012). The modest reductions in multiple aspects of decision making, seen as low as 950 ppm (Allen
et al. 2016), may not be critical to individuals, but at a societal level or for employers an exposure
that reduces performance even slightly could be economically significant. The impacts on students
including sickness, reduced attendance and reduced learning abilities should also be a concern for
society. Moreover, the relatively high levels of CO2 in vehicles associated with declining
concentration and fatigue has serious implications for the safety of drivers and their passengers. This
is an issue that does not appear to have been raised in research on driver fatigue illustrating the
general lack of awareness about CO2 effects.
The human species is already impaired in indoor environments and this is likely to get worse as rising
outdoor levels of CO2 contribute to increased indoor concentrations (Azuma et al. 2018). It is not
only humans that are at risk. It has been demonstrated that animals have varying degrees of
susceptibility to carbon dioxide (Schaefer et al. 1971). The impacts of elevated CO2 are even greater
for water breathing animals than air breathing animals. In general, land animals have much higher
blood CO2 than aquatic animals and can compensate for hypercapnia by increasing ventilation. In
aquatic animals, compensation by increased ventilation is rare and a small increase in ambient CO2
causes hypercapnic acidosis (Portner et al. 2004; Knoll et al. 1996; McNeil and Sasse 2016). Studies
have shown that hypercapnia in fish produces substantial neurological, behavioural and
physiological effects (Ishimatsu et al. 2005; Heuer and Grosell 2014) for even short-term exposures
at a CO2 concentration predicted to be persistent in the ocean before the year 2100; this level
corresponding with an atmospheric concentration of 650 ppm CO2 (McNeil and Sasse 2016).
Most of the problems associated with elevated indoor CO2 levels greater than about 800 ppm, can
be alleviated by spending time in fresh air. The indoor environments can be restored to acceptable
CO2 levels with effective ventilation although this is often not being achieved. The available resource
of fresh air may be the underlying misguided reason why there is a lack of concern for pollution and
its effects. Significantly this resource may not be available in the future as rising atmospheric CO2
associated with climate change could exceed the 800 ppm level in the current century (Smith and
Woodward, 2014). At that stage, there would be no outdoor escape from the described symptoms.
Under such a condition of permanent exposure, there could be health impacts at levels less than 800
ppm.
10. Conclusions
16
There is now a significant body of research work that demonstrate (1) current health impacts of
rising CO2 levels and (2) more serious CO2 health impacts for humans at some time in the near
future.
Current impacts of elevated and increasing ambient CO2 in indoor environments include
inflammation, respiratory diseases, headaches, fatigue, increased heart rate, increased blood
pressure, and other symptoms at levels above about 800 ppm. This finding together with the
associated impairment of cognitive abilities at CO2 levels just above ambient (between 600 and 950
ppm) is significant in that it has implications at a societal level for human function particularly for
jobs with critical responsibility (e.g., surgery, air-traffic controllers, drivers etc.) together with the
impact on learning, human development and economies. Physiological CO2 effects will be increased
and more permanent in a future with elevated outdoor ambient CO2 concentrations. Ongoing
impacts may include the exacerbation by CO2 of cellular oxidative stress and protein malfunctions
resulting in an increase in cancers, neurological diseases, viruses and many other conditions. Studies
of health effects at higher levels of CO2 at around 2,000-5,000 ppm demonstrate the impact of the
inability of the body to fully compensate for increased CO2 and acidity in the blood. These effects
include human tissue calcification and bone degradation; the former, associated with the
overexpression of the enzyme carbonic anhydrase that is responsible for processing CO2, might
represent the greatest existential threat for many animals. Given there is a lack of studies in humans
at lower but elevated CO2 levels, demonstrated effects in animals and symptoms experienced by
humans indicate that longer-term mechanisms compensating for increased blood CO2 are active
when breathing at around 800-1000 ppm CO2. Long-term exposure to these and potentially lower
levels would likely cause severe illness. These levels are predicted for the ambient atmosphere by
the end of the century in a “business as usual” world. At some stage in the near future humans could
be experiencing persistent physiological effects resulting in serious health problems.
The risk from rising CO2 levels for human and animal population health in the near-future is
extremely high with the health or survival of species under threat. Communication and global
awareness of this issue alongside climate change would further strengthen the need to drastically
reduce CO2 emissions. New research on the health effects of long-term exposure to realistic future
atmospheric CO2 levels is urgently needed to quantify this risk.
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