4. Discussion
The above data including Table 1, Table 2 and Table 3 indicate that mandatory daily long-term use of masks, especially for pregnant women, children, adolescents and younger people can be expected to have negative effects.
For example, the requirement that pupils wear masks throughout the entire school day is problematic. So does the extended N95 mask-wearing by pregnant women. With reliable measurements the experimentally determined CO
2 concentrations in the inhaled air under masks can reach – depending on exposure time – values of 0.42 up to 3.52 Vol% (Table 1) [18-20,23-25,27]. One has to remember, that in those experiments the time measured wearing a mask ranged from 1 minute to several minutes with a maximum of 60 minutes in a few studies, which is not always representative for real-world settings.
For pregnant women there is a metabolic need for a fetal-maternal CO2 gradient. The mother's blood carbon dioxide level should always be lower than that of the unborn child. This is necessary to ensure the diffusion of CO2 from the fetal blood into the maternal circulation via the placenta. Therefore, the hypercapnic gas shifts promoted by masks could, even with subliminal carbon dioxide increases, act as an interference variable of the fetal-maternal CO2 gradient and increasing over time of exposure [11]. Thus, even if compensatory mechanisms are active, an additional risk for pregnant women and their unborn children must be considered. A study in 22 pregnant women shows that wearing N95-masks during 20 min of exercise leads to significantly higher percutaneous CO2 values with average PtcCO2 values of 33.3 mmHg compared to 31.3 mmHg without masks (p = 0.04) [37]. Another comparative study on pregnant women wearing N95 mask shows increased levels of CO2 in expired air [38]. These results measuring the accumulation of CO2 in the mother´s blood give evidence that a mask can lead to significant changes in the blood gas hemostasis of pregnant women (Table 2) despite the compensatory mechanisms [28,50] caused by the increased inhaled carbon dioxide. It is well-known from many disciplines that the toxicity of a pollutant depends on the one hand on the concentration and on the other on the duration of exposure. The frequency of exposure and time are of toxicological importance and there is the notion, that time is a variable equivalent to dose in toxicology [52,53]. According to Rozman, risk projecting should include time as a variable (including toxicokinetic, toxicodynamic, exposure frequency/duration). Adding time to dose as an independent variable in toxicology allows a risk assessment in which a single acute dose would represent the liminal case when the dose rate equals the dose. Consequently, a single high dose exposure will not be much different from exposure to proportionally smaller daily dose rates [52,53].
Additionally, one has to consider the special susceptibility of early life conceptual tissues with less well developed protective/conjugative pathways [14].
However, taking into account the above facts of increased carbon dioxide rebreathing under masks with values ranging from 0.22 to 3.52 vol% CO2 and in the majority of studies with values above 1% [18,19,21-25,27] including Table 1, it is clear even to laymen that carbon dioxide rebreathing, especially when using N95 masks, is above the 0. 8% CO2 limit set by the US Navy to reduce the risk of stillbirths and birth defects on submarines with female personnel who may be pregnant [58,59,60] (Table 3). One has to keep in mind that US Navy female submarine officers are of very high mental and physical fitness, incomparable to the level of physical health of pregnant women in the broad population. Nowadays all over the world masked pregnant women (especially those using N95 masks) are potentially exposed to carbon dioxide re-breathing levels that are prohibited by US Navy for female submarine officers because of the risk of stillbirth and birth defects. Analysis of online available data on mask mandates [98] show, according to our calculations, that most countries (150 out of 194) worldwide had a masking requirement (77.3%) roughly corresponding to 4 496 149 755 people worldwide accounting for 58% of the world population.
So one has to ask: May there be a link between an increased mask-related (pandemic) global carbon dioxide re-breathing since 2020 and the current reported rise in stillbirths worldwide [99] of disturbing 28%? In a prospective registry of 263 infants of 179 infected mothers the authors found no evidence that a SARS-CoV-2 infection is associated with significant higher risk of damage to unborn life [100]. However, current data on the new Delta variant, imply a possible slightly higher risk of stillbirths (prepandemic stillbirth rate of 0.59% versus 0.98% in COVID-19–affected deliveries and 2.70% during the Delta period), but the evaluation was not able to separate SARS-CoV2 exposure from higher mask exposure in those women [101]. Interestingly, recent data from Australia shows that lockdown restrictions and other measures (including masks that have been mandatory in Australia), in the absence of high rates of COVID-19 disease, were associated with
a significant increase in preterm stillbirths [102]. May there be also a link between the pandemic driven excessive mask-use and the fact that 42% of female USA surgeons surveyed between November 2020 and February 2021 [103] lost a pregnancy according to a recent study? During a pandemic, surgeons are likely to have the heaviest mask exposure compared to the general population. Data from Italy show with statistical significance three-fold increase in stillbirths in the general population during lockdown period (March-April-May) 2020 compared to the same period in 2019 [104]. A recent rapid review and meta-analysis gives clues about the severity of the indirect influence of COVID-19 lockdown implementations [105]. The authors found that lockdown measures were associated with a significant risk of stillbirth with RR=1.33 (95% CI 1.04, 1.69) when compared to before lockdown period [105]. It is well known that lockdown measures include mask mandates as well [2].
Among the few countries that do not require the wearing of masks in public is Sweden. Interestingly, despite similar pandemic measures and SARS-CoV2 presence in the media and in the real world, no increased risk of stillbirths was observed in Sweden. A Swedish nationwide study „did not find any associations between being born during a period when many public health interventions aimed at mitigating the spread of COVID-19 were enforced and the risk for any of the preterm birth categories or stillbirth (adjusted OR 0.78, CI 0.57 to 1.06)“[106]. Although society was not completely closed, Swedish authorities enforced many policies to mitigate the spread of COVID-19, such as promotion of general hygiene measures and social distancing (including remote working), ban of nonessential travel, prohibition of gatherings of more than 50 people and the closure of upper secondary schools and universities [106].
A look at Table 3 shows that the results of the FDA (1979) [58] and Howard experiments (2012) [59,60] on toxic CO2 levels may explain the increase in the incidence of stillbirths found in the above studies. Moreover, wearing N95 masks that are linked to a higher carbon dioxide re-breathing (Table 2) [31,32,41] is significantly more associated with higher gestational age than surgical masks [107].
Interestingly, a recent publication realised a large on-going longitudinal study of child neurodevelopment in Rhode Island, an USA state with mask mandates, examining general childhood cognitive scores in 2020 and 2021 vs. the preceding decade, 2011-2019 [108]. The scientists found that children born during the pandemic have significantly reduced verbal, motor, and overall cognitive performance compared to children born pre-pandemic with consistent and significant reductions (p<0.001) showing lower cognitive skills [108]. Could there be a connection between the increased use of N95 masks by pregnant women [107], higher carbon dioxide re-breathing levels (Tables 1&2) [18-25,27,31,32,41] and the results [108] of this recent study? Fresh outdoor air has around 0.04% carbon dioxide [15,16] and the level of re-breathed CO2 under masks can rise to levels far higher than 1% as mentioned above [18,19,21-25,27], especially when masks are worn in closed buildings additionally worsening the sick building syndrome [15,16]. A look at Tables 1 and 3 shows that the results of the Kiray 2014 [77] experiments could be an explanation of these findings due to the fact that most human studies prove CO2 exposition of higher than 0.3% while using a face mask. After low-level exposure of 0.3% CO2 to the pregnant dams, Kiray was able to detect neuron destruction in prefrontal cortex and hippocampus, decreased IGF-1 levels, increased anxiety and impaired memory and learning after birth [77] of the offspring.
The problem of prolonged mask use in children and in schools needs to be discussed as well. One has to consider that children are not just small adults. This means that exposure criteria should be based on information relevant to predicting risks to children and should account for such toxicokinetic differences occurring with development [14]. It is necessary to evaluate the psychological and neurological effects when masks are compulsory at school [15,16, 18-25,27,76]. A statement was made in a recent scoping review on masks that “the long-term sociological, psychological and educational consequences of a comprehensive masking requirement extended to schools are unpredictable with regard to the psychological and physical development of healthy children “[11]. In this psychological, neurological and pediatric context it is crucial to discuss the toxicological impact of prolonged mask wearing and the concomitant elevation in re-breathed carbon dioxide (Tables 1, 2 and 3). Regarding the experimentally measured CO2 concentrations in the inhaled air under masks from Table 1 with values ranging from 0.22% to 3.52% being mostly above 0.3% [18-27], the results from Table 3 [81,95] are remarkable. In 2014 Uysal could demonstrate with his experiments that a mere 0.3 % CO2 exposure to adolescent brain neurons can cause destruction in the gyrus dentatus and the prefrontal cortex with decreased IGF-1 levels resulting in less activity, increased anxiety and impaired learning and memory [81]. Already in 1972 Vandemark revealed – only after a 4-hour low level CO2 exposure – a carbon dioxide dependent destruction of spermatid and Sertoli cells in testes, streaking & vacuolization of the tubular components with no maturation of spermatids [95]. Calculated with a human safety factor [59,60,96], the carbon dioxide content of the inhaled air should be at least below 0.5% CO2 for a 4-h exposure to avoid these adverse effects on testicular tissue. According to data from Table 1, when wearing masks – for example in schools– this seems difficult to achieve in many cases [18-25,27] especially when room air (in crowded classrooms) already has an increased CO2 content [15,16,76].
Altogether, there is disturbing experimental evidence for a possible negative impact risk on the mental and reproductive health of children, adolescents and pregnant women due to chronic carbon dioxide re-breathing since the introduction of mask mandates (Table 1 and Table 3). Indeed, masks (being a medical device) for general and long term use in the populace should be evaluated more thoroughly according to the German Medical Devices Act (Medizin-Produkte-Gesetz), the European MDR (Medical Device Regulation) and the FDA [17,109,110].
In summary, benefits and risks of masks have to be assessed according to the WHO especially for children, pregnant women, the elderly and the ill [11,111]. Therefore, the justification of the mask mandate for the general public must be critically and scientifically questioned.
On the one hand there is no clear high-quality empirical data providing moderate or strong evidence that mask use in the general population could have a relevant impact on SARS-CoV2 virus transmission rates [3-8,10]. An overview of systematic reviews on mask use against airborne virus diseases [8] did find only one high quality study [7]. Moreover, they concluded that „wearing a mask may make little to no difference”.
On the other hand, empirically, the assumption that asymptomatic persons are significant virus spreaders cannot be supported [112,113] and systematic reviews do not provide moderate or strong evidence for the asymptomatic as significant spreaders [114-116]. Thus, if asymptomatic people are not the focus of infection according to these findings a mask for the asymptomatic must be questioned. Even if the mask were to work its widespread use should be questioned because of the lack of literature clearly demonstrating the infectiousness of symptomless SARS-CoV2 infected individuals [113]. Therefore, the argumentation to make a mask mandatory in places where symptomatic individuals are excluded (tests, admission control, restrictions etc.) in order to contain SARS-CoV2 spreading cannot be substantiated [112,113].
In addition, the infectivity [117] and average lethality risk of SARS-CoV-2 ranging from 0.1 to 0.14% must be considered when recommending universal mask use [118,119]. This figure is far lower for children and fertile young women [120]. In a recent study, no healthy children between 5 and 18 years of age were found to have died from COVID [121].
Indeed, if the potential adverse effects and possible long-term consequences of masks [11] are taken into account (Table 3) even greater doubts arise regarding masks as a defensible, effective and harmless means of combating SARS-CoV2 in widespread use, especially regarding our referenced data with possible deleterious effects for children, adolescents and pregnant women [18-25,27,58-60,77,81,95]. The background of the political decisions on far-reaching mandatory mask use is difficult to understand scientifically [120]. According to the medical principle of "primum nihil nocere" (at first do not harm) and in view of the presented findings, the mask would have to be scientifically re-evaluated as a SARS-CoV2 pandemic control. The credo of all those involved in the containment of the crisis, including politicians, should be to prevent the damage caused by precautionary or therapeutic measures at all costs so as not to exceed the damage caused by the disease. When it comes to medical decision-making in a sick person, the assessment of therapeutic measures for the benefit of the patient against the side effects of the therapy is to be evaluated differently than a prophylactic procedure in healthy people. If wrong decisions are made in the selection of preventive measures in healthy people or if they are improperly applied, the consequences are usually much more severe and liability claims are often unavoidable. In view of the possible toxicological mask effects of re-breathed carbon dioxide in pregnant women, children and adolescents, and in view of the limited scientific evidence for masks as an effective pandemic measure, there is need to re-evaluate and rethink mask mandates especially for these vulnerable subgroups.
5. Conclusions
It is widely believed that the use of masks - including in the general population - could be an important measure to combat SARS-CoV2 [2] and a huge number of publications on this topic cannot be overlooked. However, elevated blood carbon dioxide levels are an important cornerstone of the so called Mask-Induced Exhaustion Syndrome (MIES) (Table 2) [11]. A significant rise in carbon dioxide occurring while wearing a mask is scientifically proven in many studies [11,18-25,27,30-44], especially for N95-masks (Table 2) [20,23-25,27,30-33,35,37-39,41,43,44], due to their higher deadspace and breathing resistance [11].
Fresh air has around 0.04% CO2 while masks bear a possible chronic exposure to low level carbon dioxide of 0.42 to 3.52% in laboratory test suites [20,23], of 1% to 3.05% in modeling studies [21,22] and reliable human measurements even yield values of 1.41 to 3.2% CO2 of the inhaled air (Table 1) [18,19,24,25,27].
Animal experimental data shows deleterious proven effects of elevated CO
2 of inhaled air in the long term with threshold values of above 0.3%, 0.5% and 0.8% (Table 3) [58-60,68,77,81,95]. The risk for children's mental development starts at levels of above 0.3% [77,81], to adolescent male sexual development at levels of above 0.5% [95], as well as to unborn life at levels of above 0.8 % [58-60] resulting in reduced cognitive performance, reduced fertility and stillbirths (Table 3).
There is circumstantial evidence that popular mask use may be related to current observations of a significant rise of 28% to 33% in stillbirths worldwide and a reduced verbal, motor and overall cognitive performance of two full standard deviations in scores in children born during the pandemic [99,102-105,108]. Assuming that time is a toxicological variable equivalent to dose [52,53] long term everyday mask use cannot be claimed as harmless, as exposure to smaller daily doses will not be much different from exposure to a single high dose. Instead of worrying only about the potential risks of a future harmful long-term CO2 increase in the atmosphere with impact on human health [76,122,123], the focus of research should also be on the current mask-related CO2 increase in breathing air (Table 1) with its numerous effects. In this article we only focused on CO2, however, other noxious agents in the masks contribute to toxicological long term effects like the inhalation of synthetic microfibers, carcinogenic compounds and volatile organic compounds could also play a role [124,125].
It must be remembered that the increased carbon dioxide content of the breathing air behind the mask may also lead to a displacement of oxygen. In this case, in addition to hypercapnia, hypoxia could also have an effect, which would certainly be very important for the teratogenetic aspects (e.g. spinal malformations due to hypoxia) [126]. The fact that in this context (toxic effect of carbon dioxide versus hypoxia) no sharp distinction is made it can lead up to the mixing of sequelae, which was mentioned by Hubert Meesen [127].
The general extended masking requirement, especially for children and pregnant women [14], is a measure that has not been thoroughly tested and studied. According to the literature found, masks bear some toxicological unpredictable risks with respect to carbon dioxide [11,18-25,27]. Unfortunately, wearing of N95 masks, that are linked to a higher carbon dioxide re-breathing (Table 1&2) [32,32,41] has a considerable association with an advanced gestational week than surgical masks [107].
Consequently, it should be the task of governments in conjunction with their responsible health authorities to perform an appropriate benefit risk assessment of the mandatory use of masks in each country. This is the fundamental basis of all approvals for chemicals, medical devices and drugs aimed to protect humans, animals and the environment.
Reliable studies on possible carbon dioxide re-breathing while wearing a mask in real-world scenarios are necessary to exclude possible damaging effects [99,102-105,108]. Therefore, health authorities should organise and perform further toxicological studies focusing on masks in specific user groups according to Good-Clinical-Practice and Good-Laboratory-Practice.
So far, such mandatory activities by governments and health authorities are not visible globally. Regarding the referenced literature, low level CO2 exposure can be related to mask use. Keeping in mind the weak antiviral mask efficacy, the current behavior of the media, science and politics vehemently forcing mask mandate even for the vulnerable subgroups appears highly unethical and not in line with the obligation in particular to protect born or unborn children from potential harmful influences [14]. The actual – so called „ preventive “– proceeding concerning mask obligations in many countries around the world and especially in schools is not in line with the Helsinki Declaration [128], the Lisbon Declaration [129] and the Nuremberg Code [130].
Acknowledgements: We thank Bonita Blankart and Markus Veit for proofreading the manuscript.
Author Contributions: Conceptualization, K.K., S.W., O.H., B.K.; A.P.; methodology, K.K., S.W., O.H., B.K. and A.P.; software, K.K., O.H.; formal analysis, K.K., S.W. O.H., B.K., A.P.; investigation, K.K., S.W., O.H.,B.K. A.P.; writing—original draft preparation, K.K., S.W., O.H., B.K.,A.P.; writing—review and editing K.K., S.W., O.H., B.K. and A.P. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflict of Interest: The authors declare no conflict of interest.
Institutional ethics board committee approval: not applicable.
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