Incidental Evidences Suggest that High CO₂ Concentrations Could Inhibit Cancer

At low (400), but not at high (> 930), ppm CO₂ the entropy produced per glucose mole is lower in fermentation than in respiration. Then, applied to the proliferation of the fermentative cancer cells within vertebrate body, the Prigogine theorem of the trend to minimize the rate of entropy production would predict that cancer must growth faster than normal tissues at low but not at high CO₂ concentrations. Accordingly, re-examination of epidemiologic data shows link between low cancer incidence or death and jobs or habits likely exposed to high CO₂ concentrations. Further experiments should confirm the suggested inhibition of cancer by CO₂.

Under usual environmental and cellular conditions, the entropy production per mole of glucose consumed is some 10% lower in fermentation to lactate (359.4 JK^-1 mol^-1) than in respiration (403.9 JK^-1 mol^-1). Therefore, for the open steady state systems of body tissues, the trend to produce entropy at the lowest rate (Prigogine theorem) [1] favours the proliferation of predominantly fermentative cancer cells (Warburg effect) over normal respiratory cells [2,3].

Although the concentration of CO₂ does not affect to the production of entropy per mole of glucose in the fermentative reaction, the production of entropy in the respiratory reaction strongly diminishes when the concentration of CO₂ increases as show by the formula:

∆S = 700.2 - 6 x R x ln[CO₂] (ppm) JK^-1 mol^-1 = 700.2 - 49.9 x ln[CO₂] (ppm) JK^-1 mol^-1

Accordingly, for concentrations of CO₂ higher than 930 ppm the production of entropy per mole of glucose consumed in respiration is lower than the 359.4 JK-1mol-1 produced by fermentation. Therefore, if the competition between cancer and normal cells for the consume of glucose obeys the Prigogine theorem, theory predicts that fermentative cancer cells should not proliferate at higher rate than respiratory normal and stem cells when the concentration of CO₂ is higher than 930 ppm. The consequence is that the multiplication of cancer cells should be arrested under atmospheric CO₂ concentrations above 930 ppm. Under this optimistic scenario, to avoid adverse effects of very high CO₂ concentrations (as drowsiness), moderately high CO₂ concentrations, between 1,000 and 1,200 ppm, would stop the growth of cancer without significant bothersome side effects.

Considering the actual atmospheric 400 ppm CO₂, humans are not usually exposed to CO₂ concentrations around 1,000 ppm, but short expositions to moderate high CO₂ concentrations are frequent and could be one factor to ponder when explaining the associated cancer incidence in several jobs and life habits. To get insight on this hypothesis, reports on low cancer incidences in certain jobs and habit behaviors are revised for the possibility that they are associated to moderately high concentrations of CO₂.

Estimation of transitory high CO₂ concentrations

Human respiration is the most frequent cause of the high CO₂ concentration at room. The rates of respiratory CO₂ emission by adult peoples strongly vary with human activity from 0.013 m³ h^-1 person^-1 sleeping to 0.35 m³ h^-1 person^-1 at hard work [4]. Some 0.022 m³ h^-1 person^-1 may be a reference value at sit-work office or attending/resting at home. Thus, sedentary human respiration increases by 2.2x10⁴/V ppm h^-1 person^-1 in a V m³ hall volume without ventilation. Then, the concentration of CO₂ in a poor-ventilated 120 m² home (V = 300 m³) with a four-members family would increase up to a rate of 300 ppm h^-1 above base line 400 ppm. Accordingly, in typical, moderately ventilated office buildings, steady-state CO₂ concentrations is around 700 ppm above outdoor air levels [5].

Correlations of cancer incidence and CO₂ concentrations

Sedentary indoor jobs could show relative lower incidence of cancer due to temporal but recurrent exposition to high CO₂ concentrations. Similarly, workers frequently confined in small compartments (where human respiration rapidly increases the concentration of CO₂), could be benefited by low cancer incidence. Some epidemiological investigations focus on sedentary influence on cancer but no one points to possible consequences of high CO₂ concentrations associated with indoor sedentarism. Usually, the values of cancer incidence and mortality are supposed to be influenced by the presence or the absence of cancer-promoting factors concurrent with high CO₂, which make difficult to discern an effect specific of CO₂. In fact, epidemiological studies focus on cancer promoting factors and seldom take in consideration factors that, like high CO₂ concentration, could inhibit cancer. In a novel approach, reported epidemiological investigations are re-examined looking for indications of the possible protection of high CO₂ concentrations against cancer.

Data collected showed that truck and lorry drivers in London [6] and in Reykjavik [7] had excess deaths from malignant neoplasms, SMR (standardised mortality ratio) 1.25 to 1.36 and 1.8, respectively, that were commonly attributed to the exposition to street contaminants produced by the combustion of gases in cities. Surprisingly, taxi drivers, similarly exposed to combustion products, did not show the cancer excess (SMR approximately 1). It must be speculated that, in cold cities, the almost closed small volume of the driver compartment in the cab rapidly reaches around 1,000 ppm CO₂ due to the respiration of the same taxi driver. Under this condition, the trend of tissue cells of the taxi driver to produce entropy at the lowest rate would decrease the growth rate of cancer fermentative cells bellow the growth rate of normal respiratory cells. Thus, compensating the carcinogenic effects of contaminants common to all city drivers.

In a similar way, the presumable high CO₂ concentrations within submarine during long travels could explain the surprising low cancer incidence and death (SMR 0.69) of submariners, as one study [8], extended between 1979 and 1989, showed on 15,138 submariners who had conducted their first submarine training between 1960 and 1979.

Biases toward accepted cancer promoting factors impair the relevance of the influence of CO₂ concentration in many epidemiological studies. In addition, the potential protecting effects of indoor stay at home or in public building is masked by the frequent room ventilation or by the in-house radon radiation. Nevertheless, slight decreases of cancer incidence and death associated to some habits suggest the protective effect of frequent expositions to high CO₂ that could be unmasked with specific questionnaires able to discriminate among different factors potentially affecting cancer growth.

An extensive study in Nordic countries [9] showed that, of 54 occupational categories, frequent indoor jobs (with a minimum of 82 observations each) as teachers, administrators, clerical workers, sale agents and shop workers have low cancer standard incidence rate (SIRs 0.42, 0.44, 0.52, 0.54 and 0.54, respectively). In contrast, high cancer incidence is typical in open air jobs (with a minimum of 384 observations each) as farmers, gardeners, fishermen and forestry workers (SIRs 1.57, 1.58, 2.27 and 1.40, respectively). Obviously, several factors are responsible of the observed cancer incidence, but the potential influence of the habitual concentration of CO₂ in the job place is hardly escapable.

More specific studies point significant lower cancer incidence in peoples regularly attending cultural events as cinemas, theatre, art galleries, live music shows, museums or religious services. Thus, a study [10] on 9,011 random selected Swedish adults reported that rare and moderate attendees to cinemas, theatres, art galleries, live music shows and museums were 3.23 and 2.92 times, respectively, more likely to die of cancer during the follow-up (1991 to 2003) period than frequent attendees. A similar study [11] on self-reported questionnaires about religious attendance carried out between 1992 and 2012 and extended on 74,534 women, showed that cancer mortality among women regularly attending more than once per week religious services has a 0.79 ratio with those who never attend. Psychology, social support, nutrition habit and no smoking may be mediators of the reduced cancer incidence in some cases, but probably are not the only. Attention should be paid to the fact that peoples attending cultural and/or religious events frequently joint in reduced spaces where the concentration of CO₂ increases up to around 1,000 ppm. In a roughly estimation, the frequency of cancer incidence would decrease in percentage like the percentage of the current life time they are exposed to high CO₂.

Crowding habit of some vertebrates can increase the concentration of CO₂ in the immediate atmosphere and thus affect cancer incidence. This may explain the very low cancer incidence in mole rat [12], rodents usually crowded in colonies underground, presumably accumulating high concentrations of CO₂.

Elevated CO₂ were reported to cause mitochondrial dysfunction in human cell lines and cultures and impairs cell proliferation [13]; inhibition of the key enzyme (lactate dehydrogenase) deviating glucose metabolism from respiration to fermentation is a therapeutic strategy for treatment of cancer [14] and inhibition of the Warburg effect suppresses tumor growth in vivo [15]. However additional experimental approaches are required to confirm the inhibition of cancer by elevated CO₂ concentrations.

Entropy production provides a new perspective to understand the transitions between fermentative and respiratory metabolisms in cancer based on the theorem of Prigogine of the trend to decrease the rate of entropy production per mole of glucose consumed [2,15]. In this framework, possibilities that fermentation favours proliferation of cancer cells over respiratory normal cells and that the preferred proliferation of cancer cells is reverted at high concentration of CO₂ are appealing. However, theory does not provide indication on the rapidity at which one of the two proliferation rates reaches dominance. In a first approach, it may be assumed that the time required to detect cancer inhibition by high CO₂ is within the same magnitude order than that of cancer induction after exposition to cancerogenic agents, or after spontaneous oncogene activation at normal 400 ppm CO₂ concentration. This time is highly variable depending on the target tissue and may be in the range of one year.

So, within the range of a few years assumed for effects depending on the entropy production rate, epidemiological investigations should provide valuable proofs for the hypothesised inhibition of cancer by high concentration of CO₂. From published results, evidences suggesting a link between high CO₂ and low cancer incidence and mortality are revised in the Results section for jobs, human habits and mole rat. A common feature of all reports of low cancer incidence or mortality is the probable exposition to high CO₂ concentrations. However, from the investigations published, statistical results, though suggestive, do not conclusively discriminate potential effects of high CO₂ concentrations of other concurrent factors. In addition, exposition time, volume and human density in gathering sites for job activities and cultural and religious events surely are highly variable and only in a few of them the concentration of CO₂ increases up to 1,000 ppm. Possibly, re-examination of raw data will identify populations where frequent exposition to high CO₂ would be specifically distinguished. Otherwise, the theoretical background justifies the distinction of populations specifically exposed to high CO₂ to address the relations between health and environment in further investigations. At that point, records of CO₂ concentration should be commended.

The author acknowledges to Mercedes Martín and María D. Marín for helpful discussion and commentaries to the manuscript.

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