GoKawiilAs already stated, HCO 3 − is a critical physiological anion that plays crucial roles in the transport of CO 2 throughout the body and in buffering pH (Sherwood, 2013). The fact that its level in the blood is increasing (at a population scale) in parallel with increasing atmospheric CO 2 is concerning. The question remains, however, whether this is really a problem, or whether human physiology will not be negatively impacted. Indeed, some authors have elegantly argued that blood acid-base compensatory mechanisms will easily be able to handle further increases in atmospheric CO 2 (Malte & Wang, 2024; Saunders & Habgood, 2023). Unfortunately, these arguments ignore the mounting evidence that even small, short-term increases in atmospheric CO 2 do indeed impact physiology in many species ranging from gastropods (Mardones et al., 2022; Navarro et al., 2022), to rodents (Kiray et al., 2014; Larcombe et al., 2021; Martrette et al., 2017; Wyrwoll et al., 2022) and humans (Allen et al., 2016; Lu et al., 2015; Satish et al., 2012; Seppänen et al., 1999). Additionally, they do not consider the impact of longer-term (i.e. life-course) exposure, or exposure during critical windows of development and the potential for such exposures to alter our physiological compensation mechanisms. To the best of our knowledge, currently there are no studies of long-term (approximating lifetime) health effects of exposure to atmospheric CO 2 in the range that is vitally important for the near future (500–800 ppm) (IPCC, 2022). However, two recent publications from our research group explore the effects of “life-time” (in utero to early adulthood) exposure to levels just above this (890 ppm) using a mouse model (Larcombe et al., 2021; Wyrwoll et al., 2022). We measured effects on lung structure and function, behaviour and neural expression of genes in CO 2 exposed groups.
The possible effects of increased HCO 3 − and CO 2 can also potentially be observed from other studies of short-term exposure to slightly higher CO 2 levels, such as those commonly experienced in indoor environments (e.g. 1,000 to 3,000 ppm CO 2 ) (reviewed in (Azuma et al., 2017)). For example, an older study (Eliseeva, 1964) reported marked changes in human respiration, circulation, and cerebral electrical activity at 1,000 ppm CO 2 , while more recent studies of humans and animals have shown harmful effects of CO 2 exposure at these levels, such as changes in heart rate, kidney calcification, oxidative stress, neural damage and inflammation (Kiray et al., 2014; MacNaughton et al., 2016; Schaefer, 1982; Thom et al., 2017; Vehviläinen et al., 2016), reviewed in (Jacobson et al., 2019). This is important due to many human populations spending a significant proportion of their time indoors, where CO 2 levels are typically higher. For example, The National Human Activity Pattern Survey (NHAPS) found that Americans spent an average of 87% of their time in enclosed buildings and ~ 6% of their time in enclosed vehicles in 1992–1994 (Klepeis et al., 2001). This has potentially increased since the COVID-19 pandemic (Young et al., 2024), with many people working-from-home in environments with poor mechanical air-ventilation (Nazaroff, 2021). The proportion of time spent in indoor, CO 2 enriched environments could also contribute to the changes in blood chemistry noted in the NHANES data and is an important consideration in interpreting changes over time, and forecasts for the future.
In animals, CO 2 exposure has been found to play a role in oxidative stress caused by reactive oxygen species (ROS) (Ezraty et al., 2011; Kiray et al., 2014). For example. Ezraty et al. (2011) demonstrated that current, and slightly elevated, atmospheric CO 2 levels play a role in exacerbating oxidative stress in a bacterial model (Ezraty et al., 2011). Kiray et al. (2014) concluded that 1,000 ppm CO 2 is associated with oxidative stress and oxidative damage to brain tissue in mice (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 & Ahsan, 2006). In particular, oxidative damage to cellular DNA can lead to mutations resulting in the initiation and progression of cancer.
As discussed above, increased exposure to CO 2 leads to increased blood acidity, and as part of the body’s compensation mechanisms, the kidneys retain bicarbonate helping to normalise blood pH (Schaefer et al., 1979b). This clearly means that bicarbonate levels are normally intimately tied to processes that rely on acid-base balance. However, with long-term high levels of CO 2 in the blood, compensation mechanisms are no longer sufficient, metabolic acidosis occurs and the kidneys do not respond in producing bicarbonate. Under these conditions it appears that Ca2+ ions are mobilized to replace H+ ions, producing calcification (CaCO 3 ) of the kidneys and other body tissues such as arteries (Schaefer, 1982). Tissue calcification has been observed in the kidneys of guinea pigs and rats exposed to 1,500 ppm CO 2 for ~ 6 to ~ 15 weeks (Schaefer et al., 1979b). The effect may be driven by the over-expression of the carbonic anhydrase (CA) enzyme caused by having more CO 2 to catalyse (Phelan et al., 2021) since high CA activity is associated with calcification (Adeva-Andany et al., 2014). This is a protein malfunction that appears possible at projected future CO 2 levels given lifetime exposure. CA malfunction due to elevated CO 2 and HCO 3 − can also have indirect effects on the development and progression of diseases such as cancer and diabetes (Aspatwar et al., 2021). Similarly, a recent report suggests that exposure to increasing atmospheric CO 2 “is likely to lead to proteome malfunction” – due to “protein misfolding, aggregation, charge distribution, and altered interaction with other molecules” (Duarte et al., 2020). The authors suggest that these changes could help explain the increasing prevalence of certain syndromes including diabetes and neurological disorders. In a similar vein, Kryvenko and Vadász (2021) describe how acute and chronic hypercapnia can impair endoplasmic reticulum (ER) function. The ER is a cellular organelle that serves many roles including protein synthesis and calcium storage (Voeltz et al., 2002). Elevated HCO 3 − and CO 2 levels are thought to cause ER stress, which alters ER protein-folding homeostasis potentially leading to tissue and organ malfunction (Kryvenko & Vadász, 2021). More research is required to understand the potential for slightly elevated atmospheric CO 2 levels to lead to these changes.
Another physiological effect of exposure to slightly elevated atmospheric CO 2 is its potential to detrimentally impact learning, cognitive abilities and mental health in humans (Allen et al., 2019; Allen et al., 2016; Satish et al., 2012; Scully et al., 2019). There is now a considerable body of published data showing impacts at levels < 1,000ppm CO 2 , although the effects of exposure remain controversial. For example, one study found no impact of exposure to levels up to 15,000 ppm (Rodeheffer et al., 2018), however the study population was a group of highly trained US Navy submariners. Conversely, studies in young adults (Satish et al., 2012), office workers (Allen et al., 2016) and university staff/students (Snow et al., 2019) showed negative effects at CO 2 levels as low as 950 ppm. Of potential importance, the study by Snow et al. (2019), found that there were no clear physiological drivers underlying the measured impacts on cognitive performance. Such studies are supported by assessment of CO 2 -induced changes in human brainwaves, measured by electroencephalography (EEG) combined with cognitive tests (reviewed in (Zhang et al., 2024)). Such studies show that exposure to CO 2 between 1,000 and 2,500 ppm results in heightened brain activity. Although the mechanisms underlying these impacts are not clear, Stumm (2023) postulates that CO 2 induced increase in extracellular calcium ions may restrict the movement of sodium ions thereby reducing neuron excitability (Stumm, 2023). Another explanation may be that CO 2 signalling activates the autonomic nervous system causing stress which affects cognitive performance (Azuma et al., 2018). Brain activity holds paramount importance for human functioning, acting as the central regulator that coordinates various bodily functions and cognitive processes (Zhang et al., 2024). Given that CO 2 exposure at moderate levels appears to prove detrimental to brain activity, additional research is urgently required to assess whether life-time exposure to CO 2 levels predicted by climate change modelling will have significant impacts on human cognitive function.
Carbon dioxide is also known to cause anxiety and panic attacks in humans (Battaglia, 2017). CO 2 sensitivity is one of the most basic and general alarm/avoidance systems within the realm of biology. While panic and anxiety attacks generally occur at high levels of CO 2 , the distribution of liability to CO 2 sensitivity is continuous and normally distributed in humans and animals. This means that there are potentially small anxiety increases even at the current and near-future elevated levels of atmospheric CO 2 . To this effect, increased hormones associated with anxiety have been observed in mammals at levels of CO 2 in the range 700–1000 ppm (Kiray et al., 2014; Martrette et al., 2017; Wyrwoll et al., 2022). Even a small permanent increase in global human anxiety could have a dangerous impact on societies being associated with greater fear, mental disturbance, conflicts, etc.
Health effects of long-term decreases in calcium and phosphorus
Both calcium and phosphorus are essential for human health, with insufficient levels (hypocalcemia and hypophosphatemia) being associated with a range of adverse health impacts (Gaasbeek & Meinders, 2005; Pepe et al., 2020).
Calcium is essential to maintaining total body health, with low levels potentially impacting virtually any organ or system (Pepe et al., 2020). For example, calcium is essential in muscle contraction, oocyte activation, building strong bones and teeth, blood clotting, nerve impulse, transmission, regulating heart-beat and fluid balance within cells (Pravina et al., 2013). The requirements are greatest during periods of growth such as childhood. Low blood calcium (hypocalcemia) produces symptoms including muscle cramps, lethargy, numbness and tingling in the fingers, and problems with heart rhythm. Systemic Ca2+ is regarded as a hormone itself, as it can modulate the function of the parathyroid gland, the thyroid gland, the kidney, and other organs and cells via the calcium-sensing receptor (Proudfoot, 2019).
Similarly, phosphorus plays many critical roles in the body (Gaasbeek & Meinders, 2005). These include metabolic processes within the cell such as energy metabolism and protein phosphorylation which are key mechanisms that control many cellular functions, including metabolism, growth, and muscle contraction (Shaker & Deftos, 2023). It is a vital component of adenosine triphosphate (ATP), the body’s primary energy carrying molecule (Bonora et al., 2012), and 2,3-diphosphoglycerate (2,3-DPG), which is found in erythrocytes and is crucial in oxygen transport (Macdonald, 1977). Accordingly, abnormally low levels of phosphate can lead to tissue hypoxia and cellular function disruption (Gaasbeek & Meinders, 2005). Phosphorus also plays a role in nucleotide metabolism which is used to build DNA, RNA and it influences phospholipid metabolism that forms a vital part of cell growth and function (Shaker & Deftos, 2023).