Ugo Bardi*a,
Phil Bierwirthb,
Kuo-Wei Huang
c and
John McIntyred
aClub of Rome, Consorzio Interuniversitario per la Scienza e la Tecnologa Dei Materiali (INSTM), Italy. E-mail: ugo.bardi@unifi.it
bEmeritus Faculty, Australian National University, Australia. E-mail: Philip.Bierwirth@anu.edu.au
cClub of Rome, Center for Renewable Energy and Storage Technologies, Division of Physical Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia. E-mail: hkw@kaust.edu.sa
dIndependent Researcher, Ullapool, Scotland, UK. E-mail: johndmcintyre@gmail.com
First published on 2nd July 2025
The consequences of the human-caused increase in carbon dioxide concentration in the atmosphere are normally discussed mainly in terms of its radiative forcing effect and the consequent global warming and climate change. However, CO2 is a chemically active molecule in aqueous environments, and it has multiple effects on the biosphere. Increasing CO2 concentrations in the atmosphere increase the acidity of seawater and harm marine organisms. High CO2 concentrations can make the photosynthetic reaction faster in some plants but also negatively affect the metabolism of aerobic metazoans, with harmful effects on human health. These effects are already important for people living in closed spaces and can only become stronger with the projected future increases in CO2 atmospheric concentration. The present paper is a critical review of a field that is important for the future of humankind. We find that the chemical and biochemical pollution associated with CO2 is a serious problem that may turn out to be no less important than that of radiative forcing in terms of damage to human health and to the whole biosphere. These results also indicate that geoengineering techniques based on Solar Radiation Management (SRM) alone cannot be sufficient to counter the ecosystem disruption caused by anthropogenic CO2 emissions.
Environmental significanceWe are submitting a paper assessing the chemical and biochemical effects of CO2 on the biosphere and human health. Warming is just one of the several effects of the human perturbation of Earth's ecosystem, which also include seawater acidification (“the ugly sister of global warming”), unbalance of the metabolic activity of plants, and all sorts of harmful effects on human health, mainly resulting from the combined effects of acidification and reduced oxygen supply to tissues. These harmful effects are not compensated for by the minor (if any) advantages in agriculture generated by the fertilization effect of higher CO2 levels. Our study highlights an extremely important subject, unfortunately much neglected and ignored so far. It provides a new perspective on the urgent need to reduce CO2 emissions, independent of their climatic effects. In the long run, it may be necessary to find ways to restore the CO2 concentrations to levels compatible to those at which the human species evolved, no more than ca. 300 ppm. Our study also shows that geoengineering technologies involving solar radiation management are not sufficient to solve the ecosystemic problems generated by anthropogenic carbon emissions. |
The biochemical effects of CO2 are potentially its most important non-radiative effects on the ecosystem since they directly affect the metabolic system of living beings. This is the main subject of the present paper, which explores an area where, so far, no comprehensive review had been published.
CO2 is a component of the two main reactions that create and maintain Earth's biosphere: photosynthesis and respiration. Increased CO2 atmospheric concentrations can make the photosynthetic reaction faster, leading, at least in part, to the “global greening” effect observed in recent years.7,8 Up to some limits, CO2 also increases agricultural yields in greenhouses but it does not generate an increase in the nutritional content of the food produced.9–11
In the case of respiration, the present review highlights how CO2 may negatively affect the metabolism of metazoans12 and human health in particular by altering the acidity of the blood, the oxygen transfer rate, and the body's main metabolic processes, including human cognitive performance. These effects are already detectable at CO2 atmospheric concentrations not much higher than the current ones.13 The projected increase in CO2 concentrations in the coming decades can only worsen the problem, especially considering the human habit of living in closed spaces where the CO2 concentration is higher than in open air.
Our results highlight the need to rapidly reduce CO2 emissions and bring them to zero as soon as possible. This exploration is also relevant to the current debate on geoengineering, in particular, Solar Radiation Management (SRM), which is based on placing mirrors in orbit or injecting particles into the upper atmosphere to increase Earth's albedo.14 This technology can only affect atmospheric temperature, but it cannot avoid the biochemical and chemical damage caused by increasing CO2 levels, as discussed in this paper. Carbon removal by geological or biological sequestration, instead, goes in the right direction to relieve the problem, even though it remains expensive and involves considerable uncertainties.15,16 Phasing out fossil fuels and replacing them with low-carbon energy sources remains the most urgent and the most effective option to avoid further increases in atmospheric CO2 concentration.
Some of these processes involve stabilizing feedback. For instance, an inflow of CO2 in the atmosphere generated by intense volcanism will cause temperatures to rise. But higher temperatures will accelerate the silicate weathering reaction, hence drawing down CO2, and restoring the previous conditions. Conversely, some reactions involve enhancing feedback. For instance, higher CO2 concentrations cause an increase in temperature, which may lead the oceans to release some of the dissolved CO2 they contain, causing more warming.19
The early Earth's atmosphere is believed to have been composed mainly of CO2 and CH4. With the evolution of oxygenic photosynthesis, 3.2–3.8 billion years ago, carbon dioxide started to be turned into organic carbon compounds while molecular oxygen was produced from the splitting of water molecules. The “Great Oxygenation Event” (GOE), around 2.3–2.4 billion years ago, marked the start of a phase of Earth's history in which free molecular oxygen was present in the atmosphere. About 55 million years ago, during the Cenozoic Era, a robust trend of decline in atmospheric CO2 started.20 During the last ca. 12 million years, the second half of the Miocene, the decline has been especially rapid.21,22
During the ice ages of the Pleistocene, the epoch that precedes the current Holocene Epoch, CO2 concentrations fell to values as low as 180 ppm, possibly the lowest ever during Earth's history.23 The pre-industrial concentration was higher, ca. 280 ppm, but still very low in comparison with the average levels during the Phanerozoic.24
The first to discuss the biochemical consequences of the declining CO2 concentration during the Miocene were Lovelock and Whitfield in a 1982 paper.25 They proposed that it was the result of the ecosystem compensating for the temperature increase caused by the sun becoming brighter, a phenomenon known to occur at a rate of ca. 9% per billion years.26 They estimated that, if the trend were to continue, the biosphere would go extinct in approximately 100 million years because CO2 concentrations would have to go below 150 ppm and, at such low concentrations, photosynthesis would become impossible. It was a remarkable insight, recently supported by calculations based on GCM climate models.27 However, Lovelock and Whitfield were wrong in their time scale estimates. The decline in solar radiation is much too slow to explain the CO2 decline of the past few million years. In addition, they didn't take into account the “C4” photosynthetic mechanism that allows the plants that adopt it to survive at CO2 concentrations well below 100 ppm. Other authors found that, in principle, the biosphere will be able to survive for several hundred million years in the future.28,29
On a much shorter time scale, the decline in CO2 concentration has been interrupted during the Holocene by human activities which likely prevented the re-glaciation of the planet expected to occur as a continuation of the Pleistocene temperature oscillations.30 Nowadays, the combustion of fossil fuels and other factors are pushing CO2 concentrations to levels over 400 ppm, comparable to those existing at least 12 million years ago. The trend is continuing at a rate of nearly 3 ppm per year.
hν + CO2 + H2O → O2 + CH2O |
In vascular plants, the exchange of oxygen and carbon dioxide occurs through pores called “stomata” that directly connect the chloroplast cells to the atmosphere. The stomata can open and close, controlling the exchange of CO2 and water and preventing the leaf from drying out. This connection is direct in the case of the “C3” photosynthesis mechanism, the ecosystem's oldest and most common one. The mechanism's efficiency is negatively affected by “dark respiration” or “photorespiration”, especially at low CO2 concentrations. Rubisco has an affinity with oxygen, and in the absence of solar light, it may run the reaction in reverse, producing CO2 by oxidizing organic compounds.
The C4 photosynthesis pathway31 became an important element of the biosphere around the start of the rapid fall in the CO2 concentrations in the mid-Miocene, about 10 million years ago. Today, it accounts for only about 3% of plant species but contributes around 25% of global terrestrial photosynthesis. It uses the same molecular machinery as the older C3 mechanism, but the reaction centers are no longer directly connected to the atmosphere. Instead, CO2 is transformed into malic acid by the phosphoenolpyruvate (PEP) carboxylase enzyme and then accumulated in “bundle sheath” cells. It is later converted again into CO2 by specific enzymes and then transferred to the Rubisco reaction centers. Succulent plants (Crassulaceae and cacti) use a third photosynthetic pathway: CAM (crassulacean acid metabolism), which also uses PEP but makes plants even more resistant to arid conditions. For low CO2 concentrations, the C4 reaction path is faster and more efficient than the C3 one. In addition, since the stomata remain closed for longer, C4 plants do not transpire large amounts of water and are more resistant to arid conditions.
The C4 mechanism was never adopted by trees, likely because it is incompatible with the mechanism that pulls water and dissolved minerals from the roots to the leaves through the xylem.32 Because of this factor, forests are poorly adapted to low-CO2 environments. Indeed, during the last glacial maximum, about 20000 years ago, with a CO2 concentration as low as 180 ppm, Earth's forests were reduced to sparse patches surrounded by steppes or savannas.33
At present, the rise in atmospheric CO2 caused by human activity is affecting the biosphere in various ways. Transpiration from C3 trees has substantial effects on the hydrological cycle34 because changes in column water vapor have a non-linear effect on rainfall, amplifying the effects of a reduction in transpiration. On one hand, a reduction in transpiration reduces low cloud cover, causing warming and reducing the strength of the horizontal water transport by means of the biotic pump mechanism.35 It also increases runoff and hence flooding. Retallack and Conde22 reported a 29% reduction in the transpiration of Ginkgo trees since 1829 and showed a direct connection to increased flooding in Southern USA. On the other hand, increasing temperatures (which is an effect of increasing CO2 concentration) causes an increased leaf-to-air vapor pressure deficit and hence increases transpiration across all biomes and most (though not all) species. The results are reduced photosynthesis, carbon starvation, and cavitation, which stop the flow of water and causes hydraulic stress. These effects are likely more significant than commonly believed. They may cause the range of Northern hemisphere conifers to contract and at the same time increase mortality in Amazonian trees.36 However, it is not yet clear which of these effects will have the biggest ecological and climate impact.36–40
The increasing CO2 concentrations during the industrial age has been going in parallel with a global increase in forest cover, called “global greening”.41,42 The data show that while the forest area decreased globally (by around 4.7 million hectares per year from 2010 to 2020), the biomass per unit area has generally increased, particularly in Europe and North America.43 This greening is generally attributed to the increase in the photosynthesis rate of trees (C3 plants), generated by higher levels of CO2. However, the effect of agricultural fertilizers spreading in the biosphere cannot be ruled out as the primary cause of this phenomenon.44
The response of crop plants to increased atmospheric CO2 concentration has been extensively studied, finding that it may vary considerably with light, temperature, and humidity. Species also differ, with some responding to a doubling of CO2 by reducing mean midday conductance (water flow rates) by less than 15%, and in some cases by more than 50%. Simulations and measurements of carbon dioxide enrichment effects in open-air systems indicate that the relatively large reductions in stomatal conductance in crops translate into reductions of <10% in evapotranspiration, partly because of increases in temperature and decreases in humidity in the air around crop leaves. Acker et al.45 reported that transpiration in wheat and tall fescue was unchanged due to CO2-stimulated leaf growth, but increased in rye grass. Bunce46 reported reductions in leaf stomatal conductance with increasing atmospheric carbon dioxide concentrations reducing water use by crops.
The effect of increasing CO2 concentration on food production is a more complex matter, also considering how crop yield has been increasing during the past few decades due to the extensive use of fertilizers, the so-called “green revolution”. One source attributes all the increases to CO2 fertilization,47 which is improbable, to say the least. Other studies are, correctly, more cautious, but they indicate an effect on crop yields. The results of the “Free Air CO2 Enrichment (FACE)” experiments48 found that, apart from fertilizers, the main factors affecting crop yield are irrigation and temperature. Zheng49 found that the increase in productivity tends to taper off and then decline for CO2 concentrations over around 1000 ppm. This is what one should expect considering the well-established “Liebig principle”, which states that plant growth is determined not by the total resources available, but by the scarcest resource. C4 plants (maize, millet, and sugarcane) show little or no increase in productivity for increasing CO2 concentration.50 For all cases, the increased total biomass produced is not accompanied by a corresponding increase in its nutritional content.9,10
O2 + CH2O → CO2 + H2O + ATP |
“ATP” stands for adenosine triphosphate, the “fuel” for most metabolic reactions in living beings. Unicellular organisms can exchange oxygen and carbon dioxide by diffusion through the cell's lipid bilayer membrane. Large multicellular organisms, instead, use a liquid-based transport system to move gases in and out of their bodies. CO2 is soluble in water as bicarbonate ions (HCO3−), and hence it can be directly dissolved in blood. The reaction is helped by a specific enzyme, carbonic anhydrase.51 O2, instead, is a non-polar molecule, not easily dissolved in polar liquids such as water. Hence, it is transported in blood by special molecules contained in cells called “red blood cells” or “erythrocytes”. In mammals and other vertebrates, haemoglobin is the transporting molecule; hemocyanin plays the same role in arthropods. Haemoglobin can bind up to four oxygen molecules and transports approximately 97% of the oxygen in the body. Haemoglobin can also transport carbon dioxide bound to it to form a compound called “carbaminohaemoglobin”. About 10% of the transported CO2 in mammalian blood moves in this form.
For the O2/CO2 exchange mechanism to work, haemoglobin must act as a “truck”. It must load oxygen at the alveoli in the lungs and unload it near the cells that need it. This mechanism is called the “Bohr effect” when referring to oxygen binding/unbinding and the “Haldane effect” when referring to the parallel and opposite binding/unbinding of CO2.52 The regulation mechanism is based on a conformational change of the haemoglobin molecule, which can assume two different “allosteric” states: the “R-state” (relaxed state), which makes it release O2, and the “T-state” (tense state), which causes it to bind O2. The CO2 molecule acts as the allosteric regulator. When it is dissolved in blood as bicarbonate, the resulting acidic environment stabilizes the T-state of haemoglobin, promoting the release of oxygen. It results from the N-terminal amino groups of haemoglobin's α-subunits and the C-terminal histidine of the β-subunits becoming protonated under acidic conditions. This protonation enhances ionic interactions that stabilize the T state, facilitating oxygen unloading. Finally, CO2 can also react with the N-terminal amino groups to form carbamates, further stabilizing the T state and contributing to oxygen release. This reaction generates additional protons, reinforcing the acidic environment and promoting the Bohr effect.
The consequence of this mechanism is that the oxygen transport in blood is not independent of the parallel mechanism of CO2 removal. More CO2 dissolved in blood means that less oxygen is transported and that has harmful consequences on the metabolism of aerobic creatures. This effect may start at the alveoli, where the partial pressure of oxygen can be calculated using the alveolar gas equation:53
paO2 = (patm − pH2O) FiO2 − paCO2/RQ |
The adverse effects of high CO2 concentrations on human health have been known since the 19th century under the name of “hypercapnia” (from the Greek hyper, “above” and kapnos, “smoke”). It is known that exposure to CO2 concentrations over ca. 50000 ppm (5% of the atmospheric pressure) can be immediately lethal. Until recently, values up to 5000 ppm were considered acceptable for limited times, i.e., an 8-hour working day. However, recent studies have shown that short-term exposures to values in the range of 1000–2000 ppm and even lower have measurable negative effects on human cognitive performance.13,55–59
In this range, there are further physiological effects on humans and animals in the biosphere, including marine animals. In the 1960s, Eliseeva60 reported marked changes in the properties of respiration, cardiovascular system, and cerebral cortex for short-term exposures at just 1000 ppm CO2. More recent studies have shown harmful effects such as increased blood pressure, changes in the heart rate, kidney calcification, oxidative stress, neural damage, and inflammation.61–65
High concentrations of CO2 appear to directly affect the oxygen transport into the brain. Studies of the brain activity using electroencephalogram (EEG) techniques and functional magnetic resonance imaging (fMRI)66 detected a reduction in brain metabolic activity, interestingly coupled with increased oxygen content in the plasma, probably as the result of hyperventilation, but not sufficient to compensate for the reduction in metabolic activity due to increased CO2 concentration. A recent review of the EEG results identified changes in brain activity even at concentrations below 1000 ppm, as found inside buildings.67
There are only a few animal studies in this field; the existing ones show evidence of physiological harm from CO2 including increased stress hormones, reduced growth, and impaired lung function. The most relevant studies have been conducted for the entire life cycle of mammals (including gestation) at relatively long-term (4 months) durations and moderate levels of CO2 (890 ppm).68–71 These studies demonstrate impaired lung function and muscle structure, reduced growth, hyperactivity, and reduced attention, together with increased stress hormones associated with anxiety and cognitive impairment.
Excess CO2 in the atmosphere also tends to reduce the blood's pH.72 The body compensates for this effect by excreting acid via the kidneys, as well as mobilizing Ca2+ ions from bone tissue to replace H+ ions. The long-term effect may be the calcification of organs such as kidneys and arterial walls causing cardiovascular disease and affecting neuron activity in the brain. The body's compensation mechanism, however, will eventually fail under chronic elevated CO2 conditions resulting in acidosis,72 although it's unclear how long this would take, possibly many months. Compensation for low pH, however, doesn't prevent CO2 retention in the body which contributes to cellular malfunctions.73
Tissue calcification has been observed at concentrations as low as 2000 ppm CO2 after a number of weeks63 and the effect may be driven by the over-expression of the carbonic anhydrase enzyme caused by having more CO2 to catalyze.58,73 This is a protein malfunction that appears possible at projected future CO2 levels given lifetime exposure, an example of how increased CO2 might affect the proteome. Protein malfunctions linked to oxidative stress can potentially cause diseases like cancers and neurological disorders.74 Other malfunctions may cause respiratory failure, cardiac diseases, cognitive impairment, and more. There exists, however, evidence that pathologies involving hypoxia can benefit from the vasodilatation effect of CO2, as reviewed by Stepanek et al.75
Despite the several studies indicating harmful effects of CO2 on human health, the field is still developing and we are far from having a definitive assessment of the problem. The existing studies have been criticized for internal inconsistencies and reproducibility problems.76 We also note how some studies could not detect any effects of relatively large CO2 concentrations on cognitive performance77 although these data are for young and healthy submarine crew members.
Clearly, we need more and better studies, but the available data are consistent in reporting that CO2 can harm human health in various ways even at concentrations often experienced today in indoor environments and that human beings could continuously experience in the future.
The other main photosynthesis pathway, the C4 one, uses an intermediate step to concentrate CO2 before it reaches the reaction centers. In this case, it is not surprising that more CO2 in air does not significantly affect the process rate. In contrast, it is known that perturbations of climate created by the radiative forcing effects of CO2 have negative effects on agriculture.76
The effects of high CO2 concentration on respiration are more complex. There is no evidence that the current atmospheric concentration of CO2 of ca. 420 ppm causes serious health problems for humans. However, the comparison with the case of photosynthesis shows how sensitive the regulation of the biochemical mechanisms of the biosphere is to the reactant concentrations. Up to now, no human being, and none of our hominin ancestors, ever lived a whole life at CO2 concentrations higher than 300 ppm. But we will now be forced to do exactly that, while our descendants will experience even higher concentrations. The situation is especially worrisome given the modern tendency for humans to live indoors in scarcely ventilated spaces where CO2 concentrations may be at least double that in open air and sometimes 3–4 times higher. Even higher concentrations are breathed when face masks are worn Table 1.78,79
CO2 concentration ppm | Biochemical effects | Notes |
---|---|---|
180–280 | Evolution of large brains during the Pleistocene | Lowest values ever in Earth's history |
280 | Normal value for the current ecosystem | Stable during the Holocene |
420 | Marine acidification, global greening, and metabolic disruption | Current value |
600–1200 | Limits to CO2 plant fertilization | Above these levels the fertilization effect becomes negative |
1000 | Safe indoor limit | Measurable brain slowdown observed above 600 ppm for short-term exposure |
2000 | Upper limit for continuous indoor exposure | Short-term exposure symptoms such as headaches, slight cardiac alterations, and higher blood pressure |
5000 | Upper limit for exposure in workplaces and under special conditions | Inflammation, bone decalcification, headaches, high blood pressure, and others |
10![]() |
Acceptable for occasional short exposures | Unknown safe limits for long-term exposure. Poses an immediate risk |
50![]() |
Life endangering limit | Lethal for human beings |
Human health is not the only entity being affected by increasing CO2 concentrations. Pushing the parameters of the current biosphere back to the conditions that existed before the Pleistocene, and perhaps before the Miocene, may have unexpected consequences on the metabolic processes of an ecosystem that had adapted to the current conditions over several million years. Remarkably, the evolution of large brains with a high neuron density in humans and other species80,81 occurred during the late Miocene Period, under conditions of CO2 concentrations of the order of 180 ppm. This observation raises the question of whether the metabolic requirements of large brains with densely packed neurons can be maintained at the high CO2 atmospheric concentrations expected to develop in the future. It is not unreasonable to propose that some recent trends in declining human cognitive abilities may be attributed to the current increase in CO2 atmospheric concentrations,13 including the “reverse Flynn effect” (aka “global dumbing”),82 attributed to environmental factors,83 and the increasing incidence of senile dementia in the United States.84
The results reported in the present paper show that even slightly higher CO2 concentrations than the current ones may have harmful consequences on human health, including on the performance of human brains. Consider that, at present, CO2 emissions continue to increase, causing its atmospheric concentration to increase at nearly 3 ppm per year. Hence, the potential future damage to the ecosystem and human beings is potentially large and highly worrisome. It is not even remotely compensated by the “greening” effect on some plants, which generates only minor advantages (if any) in terms of food production.
These considerations highlight the urgent need to understand that the current ecosystemic crisis is not just a problem of rising temperatures, but also, and perhaps primarily, of controlling emissions and eventually reducing the CO2 concentration in the atmosphere to avoid biochemical damage to the human metabolic processes and other parts of the biosphere. Accordingly, solar radiation management technologies can only be useful as a last-ditch effort to buy time to avoid a catastrophically rapid warming trend. Technologies to remove CO2 from the atmosphere exist, e.g., CCS and BECCS, but at present, they are too expensive.15,16 Natural methods based on forest34,85 and marine86 productivity management could be a better approach but, in any case, the effort must prioritize reducing emissions by phasing out major fossil sources and transitioning to low-carbon ones.
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