2018 EffectsOfLowLevel
2018 EffectsOfLowLevel
Environment International
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A R T I C LE I N FO A B S T R A C T
Keywords: Scientific literature and documents pertaining to the effects of inhalation exposure to carbon dioxide (CO2) on
Carbon dioxide human health and psychomotor performance were reviewed. Linear physiological changes in circulatory, car-
Indoor air diovascular, and autonomic systems on exposure to CO2 at concentrations ranging from 500 to 5000 ppm were
Low-level exposure evident. Human experimental studies have suggested that short-term CO2 exposure beginning at 1000 ppm af-
Physiological change
fects cognitive performances including decision making and problem resolution. Changes in autonomic systems
Psychomotor performance
due to low-level exposure to CO2 may involve these effects. Further research on the long-term effects of low-level
CO2 exposure on the autonomic system is required. Numerous epidemiological studies indicate an association
between low-level exposure to CO2 beginning at 700 ppm and building-related symptoms. Respiratory symptoms
have been indicated in children exposed to indoor CO2 concentrations higher than 1000 ppm. However, other
indoor comorbid pollutants are possibly involved in such effects. In the context of significant linear increase of
globally ambient CO2 concentration caused by anthropogenic activities and sources, reducing indoor CO2 levels
by ventilation with ambient air represents an increase in energy consumption in an air-conditioned building. For
the efficient energy control of CO2 intruding a building from ambient air, the rise of atmospheric CO2 con-
centration needs to be urgently suppressed.
1. Introduction symbolic and significant milestone of 400 ppm for the first time in 2015
(WMO, 2016) and has risen to 403.3 ppm in 2016 (WMO, 2017). The
Carbon dioxide (CO2) is a colorless, tasteless, odorless, and non- mean annual absolute increase during the last 10 years was 2.2 ppm per
flammable gas that is heavier than air and may accumulate at lower year (WMO, 2017). Simulated multi-models project the atmospheric
spaces, causing a deficiency of oxygen (IPCS, 2006). It is naturally average CO2 concentrations to range between 794 and 1142 ppm by
present in the earth's atmosphere as a trace gas and a product of cellular 2100 (IPCC, 2013).
respiration or fossil fuel burning (van Groenigen et al., 2011). The ty- The main source of CO2 in the non-industrial indoor environment is
pical outdoor CO2 concentrations are approximately 380 ppm, although human metabolism, although an increase in the ambient CO2 con-
in urban areas these have been reported to be as high as 500 ppm be- centration will also contribute to an increase in the indoor CO2 con-
cause of the increased anthropogenic sources (Persily, 1997). The in- centration (Alberts, 1994). In addition, the need to reduce energy
creasing CO2 concentration contributes to the greenhouse effect and consumption provides an incentive for low rates of ventilation, leading
accelerates global warming (Bertoni et al., 2004; Cox et al., 2000). to higher indoor CO2 concentrations. The indoor CO2 concentration
According to the World Meteorological Organization, the globally represents an indicator of indoor air quality acceptability, air flow ex-
averaged CO2 concentration in the atmosphere has reached the change suitability, and whether there is sufficient fresh air within
⁎
Corresponding author at: Department of Environmental Medicine and Behavioral Science, Kindai University Faculty of Medicine, 377-2 Ohnohigashi,
Osakasayama, Osaka 589-8511, Japan.
E-mail addresses: kenazuma@[Link] (K. Azuma), [Link]@[Link] (N. Kagi), yanagi@[Link] (U. Yanagi),
osawa@[Link] (H. Osawa).
[Link]
Received 25 June 2018; Received in revised form 25 August 2018; Accepted 25 August 2018
Available online 30 August 2018
0160-4120/ © 2018 Elsevier Ltd.
K. Azuma et al. Environment International 121 (2018) 51–56
indoor spaces in buildings (Emmerich and Persily, 2001). The typical (lower blood pH) results in an acute or chronic respiratory acidosis
average indoor CO2 concentration ranges from 800 to 1000 ppm (NRC, caused by the acid–base imbalance in the blood (Guais et al., 2011).
2008). National indoor air quality guidelines have established an upper Respiratory acidosis corresponds to CO2 accumulation. Acute or
limit of 1000 ppm for CO2 concentrations in non-industrial buildings in acutely worsening chronic respiratory acidosis causes headache, con-
Japan (NRC, 1981); Canada (Health Canada, 1995); Singapore (MOE, fusion, anxiety, drowsiness, and stupor (CO2 narcosis). Slowly devel-
1996); Norway (Becher et al., 1999); China (Peng et al., 2017); South oping, stable respiratory acidosis may be well tolerated, but could result
Korea (Oh et al., 2012); Germany (Lahrz et al., 2008); and Taiwan in memory loss, sleep disturbances, excessive daytime sleepiness, and
(Chen et al., 2016). personality changes. CO2 rapidly diffuses into the brain across the
Ventilation with ambient air is frequently used for reducing indoor blood–brain barrier. Symptoms and signs are the result of high CO2
CO2 concentration. However, when low-level inhalation of CO2 affects concentrations (low central nervous system pH) in the central nervous
human health, the outdoor air flow rate by ventilation must be further system and any accompanying hypoxemia (Porter et al., 2011).
increased to both maintain an acceptable indoor CO2 concentration and Respiratory acidosis appears by definition from exposure to a CO2
to adapt to the increasing outdoor atmospheric CO2 concentration, and concentration of 10,000 ppm for at least 30 min in a healthy adult with
a further step would involve the installation of an indoor CO2 pur- a moderate physical load (DFG, 2012). An increase in the inhaled CO2
ification system within the ventilation system, leading to a tremendous concentration can result in increased respiratory rate, metabolic stress,
increase in the energy load of buildings. increased brain blood flow, and increased minute ventilation (above
Lastly, the effects of low-level CO2 exposure on human health 10,000 ppm); decreased exercise tolerance in workers when breathing
should be re-examined in light of the current trend of increasing out- against inspiratory and expiratory resistance (above 30,000 ppm);
door atmospheric CO2 concentration. Herein we report a review of headache, dizziness, confusion, and dyspnea (above 50,000 ppm);
current literature pertaining to the association of low-level CO2 ex- sweating, dim vision, vomiting, disorientation, hypertension, and loss
posure in non-industrial buildings with human health and related of consciousness (above 100,000 ppm) (ACGIH, 2017; HSDB, 2015;
human responses. Rice, 2003).
An online literature search was conducted across major electronic According to traditional knowledge, although physiological studies
databases, including PubMed, Google Scholar, CiNii, and J-Dream III, showed that CO2 raises the respiration rate increases above the level
between 1950 and June 11, 2018. PubMed was primarily used to required for gas exchange, imposing an additional load on the re-
identify potential articles that qualified the search criteria, and others spiratory system at concentrations higher than 5000 ppm, Pettenkofer
were used as complementary databases. The following key words were and Flügge had proposed in 1881 that 700–1000 ppm should be re-
used as search criteria: “carbon dioxide” AND health AND effect; garded as the permissible indoor CO2 concentration, indicating an in-
“carbon dioxide” AND sick AND building; indoor AND “carbon dioxide” direct index of the contamination of air in buildings, which criteria had
AND health. A total of 1475 articles were retrieved. After exclusion of no physiological basis (Goromosov, 1968). A study in human subjects
duplicate publications, the retrieved articles were reviewed by a re- reported that inhalation exposure to 1000 ppm CO2 for a short term
viewer (KA) in two stages: screening of titles and abstracts, followed by caused marked changes in respiratory movement amplitude, peripheral
full-text review. Additional articles were identified based on prior blood flow increases, and the cerebral cortex functional state. While
knowledge (e.g., documents or reports of international or national or- 1000 ppm CO2 in the air reportedly has a directly harmful effect on
ganizations) and by manual screening of the bibliographies of the re- humans, no detailed experimental methods and analyses were provided
trieved articles. A total of 99 full-text articles were reviewed. Only peer- (Eliseeva, 1964). Thus, the association of CO2 exposures at concentra-
reviewed articles pertaining to original research or review of experi- tions lower than 5000 ppm and human health remained very limited in
mental or human studies directly associated with health and related the 1960s.
response to exposure to CO2, which clearly identified the air con-
centration of CO2, were considered. Useful comprehensive review ar- 4.1. Building-related symptoms
ticles in conference proceedings were carefully considered along with
the cited references. Studies focusing on poor ventilation, medical Building-related symptoms (BRSs), commonly called sick building
treatment, and physical exercise were excluded. The search was up- syndrome, are defined as symptoms that are experienced within the
dated on August 19, 2018. building but improve when away from the building (Redlich et al.,
1997). Symptoms assessed are related to the upper and lower re-
3. Biological effects spiratory tract, eyes, and skin and include headache, fatigue, and dif-
ficulty concentrating (Finnegan et al., 1984). A comprehensive review
CO2 is produced by intracellular metabolism in the mitochondria. of 21 studies reported that around half suggest that the risk of BRSs
The amount produced depends on the metabolism rate and the relative continues to diminish significantly with CO2 concentrations decreasing
amounts of carbohydrates, fats, and proteins metabolized. As CO2 ac- to lower than 800 ppm (Seppänen et al., 1999). According to the
cumulates in the blood, the blood pH decreases (acidity increases). Building Assessment Survey and Evaluation (BASE) study conducted in
Therefore, CO2 is discharged from the human body for maintaining the the U.S.A., significant associations of mucous membrane and lower
acid–base balance in the blood (Geers and Gros, 2000). The CO2 pro- respiratory symptoms with increasing indoor minus average outdoor
duced within the cells is transported into the blood (internal respira- CO2 (dCO2)(100 ppm increase) and maximum indoor 1 h moving
tion) and is carried by the blood through the venous system to the lungs average CO2 minus outdoor CO2 concentrations (250 ppm increase)
where CO2 passes from the blood into the lung alveoli to be exhaled were observed when workday average CO2 concentrations remained
into ambient air (external respiration) (Lifson et al., 1949). lower than 800 ppm (1579 participants of 33 U.S. Office buildings)
Lowering the pH or raising the partial pressure of CO2 (pCO2) re- (Apte et al., 2000; Erdmann and Apte, 2004). In a longitudinal study
leases of oxygen (O2) from oxyhemoglobin (Arthurs and Sudhakar, conducted following the BASE study, upper respiratory symptoms were
2005). An increase of pCO2 delivered to the lungs, that is, hypercapnia, significantly associated with increased indoor CO2 levels (98 partici-
induces an increase of pCO2 in the alveoli. CO2 freely diffuses through pants of 21 Offices). However, the relationship between CO2 con-
the alveolar membrane and into the blood, resulting in an increase of centrations and upper respiratory symptoms in this study was no longer
CO2 tension in arterial blood (PaCO2). In turn, this increase in PaCO2 statistically significant after adjusting for the number of people in the
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K. Azuma et al. Environment International 121 (2018) 51–56
office because people are the main source of CO2 in office buildings relationship between low-level exposure to CO2 and the reported
(Chao et al., 2003). symptoms remain inconsistent between studies (MacNaughton et al.,
A crossover experimental study conducted on 355 university stu- 2016; Zhang et al., 2016; Zhang et al., 2017a). A relationship between
dents of four classrooms suggested that a 100 ppm increase in indoor low-level exposure to CO2 and BRSs is therefore very complicated to
CO2 concentration (range, 674–1450 ppm) was significantly associated prove and strength of the evidence is very limited.
with headache and this association was independent from other related
indoor environmental factors, including temperature, relative hu- 4.2. Autonomic function or psychomotor performance
midity, and air exchange rate (Norbäck and Nordström, 2008). Office
workers exposed to indoor CO2 concentrations higher than 800 ppm Historically, CO2 exposures at concentrations lower than 5000 ppm
reported a significant increase in eye irritation and upper respiratory were not anticipated to affect blood CO2 levels. However, recent studies
symptoms (111 participants from an office on August and November have reported linear increases of pCO2 in the blood at CO2 exposures in
2003) (Tsai et al., 2012). A 100 ppm increase in dCO2 in the range from the range from 500 to 4000 ppm. These studies report other physiolo-
467 to 2800 ppm in indoor CO2 was significantly associated with dry gical responses consistent with increased sympathetic stimulation, in-
throat, tiredness, and dizziness (417 participants from 87 offices) (Lu cluding changes in heart rate variability and peripheral blood circula-
et al., 2015). A 100 ppm increase in CO2 concentration (range, tion increases at CO2 exposures in the range from 500 to 4000 ppm
549–1318 ppm) was positively correlated with non-specific symptoms (MacNaughton et al., 2016; Vehviläinen et al., 2016). These effects
including headache and dizziness (107 participants from 11 offices) were previously observed at CO2 exposures at concentrations from 600
although the correlation was not significant (Azuma et al., 2018). to 5000 ppm (Kajtár and Herczeg, 2012). Groups exposed for a couple
A study in schoolchildren exposed to indoor CO2 concentrations of hours to levels higher than 1500 ppm CO2 showed an increase in
higher than 1000 ppm showed significantly higher risk for dry cough their blood pressure and heart rate compared with that of the 600 ppm
and rhinitis (654 children of 46 classrooms) but outdoor air flow rate exposure group. Autonomic dysfunction impacts a wide array of human
per person was inversely correlated with indoor CO2 concentrations functions including cognitive, urinary, sexual, and digestive systems.
(Simoni et al., 2010). A 200 ppm increase in indoor CO2 concentration The activation of the autonomic system through stress reduces strategic
(range, 1000–2000 ppm) in 45 day care centers (DCCs) was sig- ability and working memory (Starcke and Brand, 2012), which supports
nificantly associated with reported wheezing in the 3186 attending a recent finding that showed a decrease in decision-making perfor-
children, and a positive trend was observed between CO2 concentration mance between 600 and 2500 ppm CO2.
and the prevalence of asthma. However, a positive association was Twenty-two participants were exposed to CO2 at 600, 1000, and
found between indoor CO2 concentration and the increasing number of 2500 ppm (three 2.5-h sessions, one day; artificially elevated CO2
children per room. In addition, indoor CO2 concentration was nega- concentrations) in an office-like chamber. Statistically significant de-
tively associated with increased outdoor wind velocity and open crements occurred in cognitive performance (decision making, problem
window practice. Therefore, poor ventilation in DCCs appears to en- resolution) starting at 1000 ppm (Satish et al., 2012). Twenty-four
hance respiratory symptoms in children (Carreiro-Martins et al., 2014). participants spent six full work days (from 9 AM to 5 PM) during two
The following phase II study conducted in DCCs confirmed that a weeks in an environmentally controlled office space, blinded to dif-
200 ppm increase in CO2 concentration is significantly associated with ferent test conditions: concentrations of VOCs, outdoor air ventilation
asthma diagnoses (1191 children from 19 centers) (Carreiro-Martins rate, and artificially elevated CO2 concentrations independent of ven-
et al., 2016). tilation. VOCs and CO2 were independently associated with decreased
Several epidemiological studies indicate a relationship between cognitive scores (basic activity level, applied activity level, focused
low-level exposure to CO2 and BRSs. However, BRS is possibly influ- activity level, crisis response, information usage, breadth of approach,
enced by other comorbid indoor pollutants, including artificial volatile strategy) in the groups exposed to CO2 at 945 and 1410 ppm compared
organic compounds (VOCs) brought into buildings or occupant-gener- with controls (537 ppm) (Allen et al., 2016). The same research group
ated pollutants (Apte et al., 2000; Chao et al., 2003; Engvall et al., reported additional results from the above experimental study, in which
2005; Erdmann and Apte, 2004). In usual indoor environments, indoor a 1000 ppm increase in CO2 was associated with an increase in heart
CO2 concentration is used as an approximate surrogate for the con- rate and in the number of symptoms (respiratory, eyes and skin,
centrations of occupant-generated pollutants, particularly bioeffluents, headache, cognitive, and sensory) per participant per day
and for estimating a proper ventilation rate per occupant (Apte et al., (MacNaughton et al., 2016). Furthermore, this group reported a study
2000). Bioeffluent is an organic contaminant, especially an atmospheric of the in-flight performance of airplane pilots during advanced man-
pollutant, that emanates from the bodies of humans or animals. Occu- euvers in a flight simulator under varying concentrations of CO2. Thirty
pants of a room contribute to air bioeffluent emissions including VOCs, male active commercial airline pilots performed three 3-h flight simu-
water vapor, particulate matter, CO2 and bioaerosols. Bioeffluent lations on the flight deck at 700, 1500, 2500 ppm CO2. The con-
sometimes causes unpleasant odors in an enclosed space (Engvall et al., centration of CO2 was modified by introducing ultra-pure CO2 into the
2005). In addition, there are many artificial hazardous pollutants simulator, and the ventilation rates remained the same for each test.
brought into buildings and their concentration ranges depend on the The in-flight performance at 2500 ppm CO2 was significantly lower
indoor environment of buildings and building characteristics (Azuma than that at 1500 ppm and 700 ppm. The difference in flight perfor-
et al., 2016; Azuma et al., 2018). However, those pollutants were not mance at 700 ppm and 1500 ppm was not statistically significant;
sufficiently taken into account in the above-described studies because however, the pilots were more likely to successfully perform five of the
indoor CO2 concentration is often correlated with other indoor pollu- seven most difficult maneuvers at the lower CO2 concentration (Allen
tants that may cause BRSs (Apte et al., 2000; Azuma et al., 2018; et al., 2018). These findings suggest that there is a direct effect of low-
Erdmann and Apte, 2004). One human experimental study indicated an level exposure to CO2 on performance, which is independent of venti-
independent effect of CO2 from air exchange rate between low-level lation.
exposure to CO2 and headache (Norbäck and Nordström, 2008). How- In another study, 10 healthy participants were exposed to CO2 at
ever, numerous indoor environmental factors including indoor air 500 ppm and 5000 ppm (artificially elevated CO2 concentrations) for
quality, work environment, and especially psychosocial factors 2.5 h in a low-emission stainless steel climate chamber. End-tidal CO2
(Marmot et al., 2006) contribute to BRSs including headache (Azuma (ETCO2) was higher at 5000 ppm than at 500 ppm. CO2 concentration
et al., 2015). As described in the following section, in recent human at 5000 ppm had no effect on acute health symptoms (respiratory, vi-
experimental studies primarily conducted for evaluating the psycho- sual and skin-related, headache, and sensory) and performance in
motor performance under controlled ventilation conditions, the cognitive tests (Zhang et al., 2016). Twenty-five participants were
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K. Azuma et al. Environment International 121 (2018) 51–56
Table 1
Effects of exposure to CO2 in indoor air.
CO2 concentration Physiological change Psychomotor performance Health symptoms
Above 500 ppm Increased pCO2, increased heart rate, change in Building-related symptoms above 700 ppma
heart rate variability, increased blood pressure, (Norbäck and Nordström, 2008 and supporting
increased peripheral blood circulation (Kajtár and studies; Apte et al., 2000; Erdmann and Apte,
Herczeg, 2012; MacNaughton et al., 2016; 2004; Lu et al., 2015; MacNaughton et al., 2016;
Vehviläinen et al., 2016; Zhang et al., 2017b) Seppänen et al., 1999; Tsai et al., 2012)
Above 1000 ppm Cognitive performance (decision making, Respiratory symptoms in school childrena
problem resolution, speed of addition, number of (Carreiro-Martins et al., 2014; Carreiro-Martins
correct link) (Satish et al., 2012; Allen et al., et al., 2016; Simoni et al., 2010)
2016; Allen et al., 2018; Zhang et al., 2017a)
Above 10,000 ppm Increased respiratory rate, respiratory acidosis,
metabolic stress (decreased blood calcium or
urine phosphorus), increased brain blood flow,
increased minute ventilation (ACGIH, 2017; DFG,
2012; HSDB, 2015; Rice, 2003)
Above 30,000 ppm Decreased exercise tolerance in workers when
breathing against inspiratory and expiratory
resistance (ACGIH, 2017; Rice, 2003)
Above 50,000 ppm Dizziness, headache, confusion, dyspnea (ACGIH,
2017; HSDB, 2015; Rice, 2003)
80,000–100,000 ppm Severe headache, dizziness, confusion, dyspnea,
sweating, dim vision (ACGIH, 2017; HSDB, 2015;
Rice, 2003)
Above 100,000 ppm Unbearable dyspnea, followed by vomiting,
disorientation, hypertension, and loss of
consciousness (HSDB, 2015; Rice, 2003)
a
These symptoms are likely to be caused by comorbid indoor pollutants.
exposed to CO2 at 500, 1000, and 3000 ppm (artificially elevated CO2 5. Effects of low-level CO2 exposure in mice
concentrations, outdoor air supply rate high enough to remove human
bioeffluents) for 255 min in a low-emission stainless steel climate Recent experimental studies using mice showed that microparticles
chamber. In two more conditions, the outdoor air supply rate was re- (MPs) produced by neutrophils exposed to elevations of CO2 in the
duced to allow metabolically generated CO2 by occupants to reach CO2 range of 1000 to 4000 ppm for 2 h have increased the interleukin-1β
concentrations of 1000 and 3000 ppm (bioeffluents were also in- (IL-1β) content, but these effects were biphasic and did not further
creased). Exposures to CO2 at concentrations of 3000 ppm, including increase at 10,000 and 20,000 ppm (Thom et al., 2017a). Mice exposed
bioeffluents, significantly increased the intensity of reported headache, for 2 h to 2000 or 4000 ppm CO2 also exhibited increases in IL-1β,
fatigue, and sleepiness. In cognitive performance tests, the speed of neutrophil and platelet activation, and diffuse inflammatory vascular
addition was significantly reduced in CO2 concentration at 3000 ppm injury, including vascular leaks in brain, muscle, and distal colon
including bioeffluents; the number of correct links made in the cue- (Thom et al., 2017b). The authors suggest a novel mechanism for ad-
utilization test was significantly reduced at 1000 ppm including bioef- verse effects associated with low-level exposure to CO2 in which MPs
fluents. Both parameters tested were linearly correlated with increased would cause vascular injuries and neuropathological effects.
CO2 concentrations (500, 1000, and 3000 ppm) excluding bioeffluents
(Zhang et al., 2017a). Exposures to CO2 at 3000 ppm, including bioef-
fluents, significantly increased diastolic blood pressure and reduced 6. Concluding remarks and future perspectives
nasal peak flow. Salivary α-amylase activity significantly increased
during exposure to CO2 at 1000 ppm including bioeffluents. ETCO2 and Effects of indoor exposure to CO2 are summarized in Table 1. While
heart rate significantly increased during exposure to CO2 under all epidemiological studies suggest a relationship between low-level ex-
conditions both including and removing bioeffluents (Zhang et al., posure to CO2 and BRSs, the observed effects are likely influenced by
2017b). other comorbid indoor pollutants. However, recent studies show clear
Thirty-six participants were exposed to condition A (outdoor air linear physiological changes in circulatory, cardiovascular, and auto-
flow rate of 28.2 l/s person, CO2 concentration 540 ppm) and condition nomic systems, including an increase of pCO2 in the blood, elevated
B (outdoor air flow rate of 2.3 l/s person, CO2 concentration 2260 ppm) blood pressure, increased heart rate, increased peripheral blood circu-
during 4 h. Condition B had a weak negative effect on performance in lation, and increased sympathetic stimulation at CO2 exposures in the
the information retrieval tasks. Condition B slightly increased the range of 500 to 5000 ppm.
workload and fatigue. No effects on health symptoms were noted Regarding the intrinsic effects of CO2 on autonomic function, sev-
(Maula et al., 2017). A crossover experimental study in primary school eral experimental studies on humans suggest that CO2 may affect cog-
students suggested that the increase of outdoor air supply from an nitive performance (decision making, problem resolution, speed of
average of 1.7 to 6.6 l/s per person, which corresponds to decrease from addition, number of correct links) starting at concentrations of ap-
1500 to 900 ppm CO2 concentrations, significantly improves the per- proximately 1000 ppm for short-term exposure to CO2. The research
formance of children, including addition, number comparison, gram- group of Zhang et al. argues that bioeffluents emitted from humans may
matical reasoning, and reading and comprehension (Petersen et al., be associated with these effects. However, in their study, the speed of
2016). In these studies, ventilation rates with outdoor air were reduced addition and the number of correct links in cognitive performance tests
for increasing CO2 levels. Thus, both CO2 and other indoor air pollu- were linearly decreased with the CO2 concentration increase in the
tants including bioeffluents may contribute to the negative effects on range of 500 to 3000 ppm removing bioeffluents. These changes could
performance. be considered to be physiologically significance. A study on humans
conducted under artificially elevated CO2 concentrations at a constant
outdoor air ventilation rate (corresponds to same conditions for
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K. Azuma et al. Environment International 121 (2018) 51–56
bioeffluents) suggests that the performances of decision making and dioxide concentrations using passive diffusion sampling. Atmos. Environ. 38,
problem resolution are affected starting at 1000 ppm CO2. Further re- 1625–1630.
Carreiro-Martins, P., Viegas, J., Papoila, A.L., Aelenei, D., Caires, I., Araújo-Martins, J.,
search on the effect of cognitive performance, especially long-term ef- Gaspar-Marques, J., Cano, M.M., Mendes, A.S., Virella, D., Rosado-Pinto, J., Leiria-
fects on the autonomic system under increased pCO2 of low-level CO2 Pinto, P., Annesi-Maesano, I., Neuparth, N., 2014. CO2 concentration in day care
exposure from 500 to 3000 ppm is required. Animal studies may pro- centres is related to wheezing in attending children. Eur. J. Pediatr. 173, 1041–1049.
Carreiro-Martins, P., Papoila, A.L., Caires, I., Azevedo, S., Cano, M.M., Virella, D., Leiria-
vide further insights into the mechanism of neurobehavioral effects Pinto, P., Teixeira, J.P., Rosado-Pinto, J., Annesi-Maesano, I., Neuparth, N., 2016.
related to low-level exposure to CO2 in future research. In particular, Effect of indoor air quality of day care centers in children with different predis-
susceptible populations, such as children and elderly, may be more position for asthma. Pediatr. Allergy Immunol. 27, 299–306.
Chao, H.J., Schwartz, J., Milton, D.K., Burge, H.A., 2003. The work environment and
sensitive to the effects. Further research on susceptible population workers' health in four large office buildings. Environ. Health Perspect. 111,
groups is also requited. No study on elderly subjects was found in this 1242–1248.
review. Chen, Y.Y., Sung, F.C., Chen, M.L., Mao, I.F., Lu, C.Y., 2016. Indoor air quality in the
metro system in North Taiwan. Int. J. Environ. Res. Public Health 13 (pii: E1200).
Although the effects of low-level exposure to CO2 on cognitive
Cox, P.M., Betts, R.A., Jones, C.D., Spall, S.A., Totterdell, I.J., 2000. Acceleration of global
performance may be sub-clinical and reversible, a reduced performance warming due to carbon-cycle feedbacks in a coupled climate model. Nature 408,
associated with labor productivity or learning may profoundly affect 184–187.
job competence and learning ability, which may have negative socio- DFG, 2012. Kohlendioxid [MAK value documentation, 2002]. In: Documentations and
Methods. MAK Collection for Occupational Health and Safety. Wiley-VCH Verlag
economic repercussions. Therefore, precaution is warranted, particu- GmbH.
larly in the context of significant linear increase in the global ambient Eliseeva, O.V., 1964. Data to substantiate the maximum permissible concentration of
CO2 concentration caused by anthropogenic activities and sources. carbon dioxide in the air of apartments and public buildings. Gig. Sanit. 10–15.
Emmerich, S.J., Persily, A.K., 2001. State-of-the-art review of CO2 demand controlled
Although the ambient CO2 concentration will not be likely to exceed ventilation technology and application. In: NISTIR 6729. National Institute of
1000 ppm owing to global efforts, the increase in ambient CO2 makes it Standards and Technology, U.S. Department of Commerce, Gaithersburg, MD.
difficult to curb CO2 levels in indoor environments as it necessarily Engvall, K., Wickman, P., Norbäck, D., 2005. Sick building syndrome and perceived in-
door environment in relation to energy saving by reduced ventilation flow during
entails ventilation with ambient air, which involves further energy heating season: a 1 year intervention study in dwellings. Indoor Air 15, 120–126.
consumption (e.g., air-conditioning). Therefore, suppressing the in- Erdmann, C.A., Apte, M.G., 2004. Mucous membrane and lower respiratory building
crease in atmospheric CO2 concentration is a key imperative to prevent related symptoms in relation to indoor carbon dioxide concentrations in the 100-
building BASE dataset. Indoor Air 14 (Suppl. 8), 127–134.
influx of CO2 from ambient air to indoor environment. Finnegan, M.J., Pickering, C.A.C., Burge, P.S., 1984. The sick building syndrome: pre-
valence studies. BMJ 289, 1573–1575.
Acknowledgments Geers, C., Gros, G., 2000. Carbon dioxide transport and carbonic anhydrase in blood and
muscle. Physiol. Rev. 80, 681–715.
Goromosov, M.S., 1968. The physiological basis of health standards for dwellings. In:
This study was financially supported by a Health and Labour Public Health Papers No. 33. World Health Organization, Geneva.
Sciences Research Grant-in-Aid (H26-health/crisis-007) provided by van Groenigen, K.J., Osenberg, C.W., Hungate, B.A., 2011. Increased soil emissions of
the Ministry of Health, Labour and Welfare, Japan. potent greenhouse gases under increased atmospheric CO2. Nature 475, 214–216.
Guais, A., Brand, G., Jacquot, L., Karrer, M., Dukan, S., Grévillot, G., Molina, T.J., Bonte,
J., Regnier, M., Schwartz, L., 2011. Toxicity of carbon dioxide: a review. Chem. Res.
Conflict of interest Toxicol. 24, 2061–2070.
Health Canada, 1995. Indoor air quality in office buildings: A technical guide. In: A
Report of the Federal-Provincial Advisory Committee on Environmental and
The authors declare that there is no conflict of interest. Occupational Health. Health Canada, Ottawa.
HSDB. Bethesda (MD): U.S. National Library of Medicine, 2015. Carbon dioxide. In:
References Hazardous Substances Data bank Number: 516, Available from. [Link]
[Link]/cgi-bin/sis/htmlgen?HSDB.
IPCC, 2013. Climate change 2013: the physical science basis. In: Contribution of Working
ACGIH, 2017. Carbon dioxide. In: Threshold Limit Values for Chemical Substances and Group I to the Fifth Assessment Report of the Intergovernmental Panel on Climate
Physical Agents and Biological Exposure Indices with 7th Edition Documentation. Change. Cambridge University Press, Cambridge, United Kingdom and New York.
American Conference of Governmental Industrial Hygienists, Cincinnati, OH. IPCS, 2006. Carbon Dioxide. In: International Chemical Safety Cards 0021, International
Alberts, W.M., 1994. Indoor air pollution: NO, NO2, CO, and CO2. J. Allergy Clin. Programme on Chemical Safety. World Health Organization, Geneva.
Immunol. 94 (2 Pt 2), 289–295. Kajtár, L., Herczeg, L., 2012. Influence of carbon-dioxide concentration on human well-
Allen, J.G., MacNaughton, P., Satish, U., Santanam, S., Vallarino, J., Spengler, J.D., 2016. being and intensity of mental work. IDŐJÁRÁS 116, 145–169.
Associations of cognitive function scores with carbon dioxide, ventilation, and vo- Lahrz, T., Bischof, W., Sagunski, H., Baudisch, C., Fromme, H., Grams, H., Gabrio, T.,
latile organic compound exposures in office workers: a controlled exposure study of Heinzow, B., Müller, L., 2008. Gesundheitliche Bewertung von Kohlendioxid in der
green and conventional office environments. Environ. Health Perspect. 124, Innenraumluft [Health assessment of carbon dioxide in indoor air].
805–812. Bundesgesundheitsbl. Gesundheitsforsch. Gesundheitsschutz 11, 1358–1369 (in
Allen, J.G., MacNaughton, P., Cedeno-Laurent, J.G., Cao, X., Flanigan, S., Vallarino, J., German).
Rueda, F., Donnelly-McLay, D., Spengler, J.D., 2018. Airplane pilot flight perfor- Lifson, N., Gordon, G.B., Visscher, M.B., Nier, A.O., 1949. The fate of utilized molecular
mance on 21 maneuvers in a flight simulator under varying carbon dioxide con- oxygen and the source of the oxygen of respiratory carbon dioxide, studied with the
centrations. J. Expo. Sci. Environ. Epidemiol. [Link] aid of heavy oxygen. J. Biol. Chem. 180, 803–811.
0055-8. Lu, C.Y., Lin, J.M., Chen, Y.Y., Chen, Y.C., 2015. Building-related symptoms among office
Apte, M.G., Fisk, W.J., Daisey, J.M., 2000. Associations between indoor CO2 concentra- employees associated with indoor carbon dioxide and total volatile organic com-
tions and sick building syndrome symptoms in U.S. office buildings: an analysis of the pounds. Int. J. Environ. Res. Public Health 12, 5833–5845.
1994-1996 BASE study data. Indoor Air 10, 246–257. MacNaughton, P., Spengler, J., Vallarino, J., Santanam, S., Satish, U., Allen, J., 2016.
Arthurs, G.J., Sudhakar, M., 2005. Carbon dioxide transport. Contin. Educ. Anaesth. Crit. Environmental perceptions and health before and after relocation to a green building.
Care Pain 5, 207–210. Build. Environ. 104, 138–144.
Azuma, K., Ikeda, K., Kagi, N., Yanagi, U., Osawa, H., 2015. Prevalence and risk factors Marmot, A.F., Stafford, J.M., Stansfeld, S.A., Warwick, E., Marmot, M.G., 2006. Building
associated with nonspecific building-related symptoms in office employees in Japan: health: an epidemiological study of “sick building syndrome” in the Whitehall II
relationships between work environment, indoor air quality, and occupational stress. study. Occup. Environ. Med. 63, 283–289.
Indoor Air 25, 499–511. Maula, H., Hongisto, V., Naatula, V., 2017. The effect of low ventilation rate with ele-
Azuma, K., Uchiyama, I., Uchiyama, S., Kunugita, N., 2016. Assessment of inhalation vated bioeffluent concentration on work performance, perceived indoor air quality,
exposure to indoor air pollutants: screening for health risks of multiple pollutants in and health symptoms. Indoor Air 27, 1141–1153.
Japanese dwellings. Environ. Res. 145, 39–49. MOE, 1996. Guidelines for good indoor air quality in office premises. In: Institute of
Azuma, K., Ikeda, K., Kagi, N., Yanagi, U., Osawa, H., 2018. Physicochemical risk factors Environmental Epidemiology. Ministry of the Environment, Singapore.
for building-related symptoms in air-conditioned office buildings: ambient particles National Research Council (NRC), 1981. Indoor pollutants. In: National Academies Press.
and combined exposure to indoor air pollutants. Sci. Total Environ. 616-617, D.C, Washington.
1649–1655. National Research Council (NRC), 2008. Carbon Dioxide, in Spacecraft Maximum
Becher, R., Hongslo, J.K., Bakke, J.V., Kvendba, J.F., Sanner, T., Schwarze, P.E., Dybkg, Allowable Concentrations for Selected Airborne Contaminants. vol. 5. National
E., 1999. Revised guidelines for indoor air quality in Norway. In: Proceedings of the Academies Press, Washington, DC, pp. 112–124.
8th International Conference on Indoor Air Quality and Climate, Edinburgh, Norbäck, D., Nordström, K., 2008. Sick building syndrome in relation to air exchange
Scotland. vol. 1. pp. 171–176. rate, CO2, room temperature and relative air humidity in university computer
Bertoni, G., Ciuchini, C., Tappa, R., 2004. Measurement of long-term average carbon classrooms: an experimental study. Int. Arch. Occup. Environ. Health 82, 21–30.
55
K. Azuma et al. Environment International 121 (2018) 51–56
Oh, T., Kim, M., Lim, J., Kang, O., Shetty, K.V., Sankararao, B., Yoo, C., Park, J.H., Kim, rhinitis and nasal patency in children. Eur. Respir. J. 35, 742–749.
J.T., 2012. A real-time monitoring and assessment method for calculation of total Starcke, K., Brand, M., 2012. Decision making under stress: a selective review. Neurosci.
amounts of indoor air pollutants emitted in subway stations. J. Air Waste Manage. Biobehav. Rev. 36, 1228–1248.
Assoc. 62, 517–526. Thom, S.R., Bhopale, V.M., Hu, J., Yang, M., 2017a. Increased carbon dioxide levels
Peng, Z., Deng, W., Tenorio, R., 2017. Investigation of indoor air quality and the iden- stimulate neutrophils to produce microparticles and activate the nucleotide-binding
tification of influential factors at primary schools in the north of China. Sustain. For. domain-like receptor 3 inflammasome. Free Radic. Biol. Med. 106, 406–416.
9, 1180. Thom, S.R., Bhopale, V.M., Hu, J., Yang, M., 2017b. Inflammatory responses to acute
Persily, A.K., 1997. Evaluating building IAQ and ventilation with carbon dioxide. elevations of carbon dioxide in mice. J. Appl. Physiol. 123, 297–302.
ASHRAE Trans. 103, 193–204. Tsai, D.H., Lin, J.S., Chan, C.C., 2012. Office workers' sick building syndrome and indoor
Petersen, S., Jensen, K.L., Pedersen, A.L., Rasmussen, H.S., 2016. The effect of increased carbon dioxide concentrations. J. Occup. Environ. Hyg. 9, 345–351.
classroom ventilation rate indicated by reduced CO2 concentration on the perfor- Vehviläinen, T., Lindholm, H., Rintamäki, H., Pääkkönen, R., Hirvonen, A., Niemi, O.,
mance of schoolwork by children. Indoor Air 26, 366–379. Vinha, J., 2016. High indoor CO2 concentrations in an office environment increases
Porter, R.S., et al., 2011. The MERCK MANUAL for Health Care Professionals, 19th ed. the transcutaneous CO2 level and sleepiness during cognitive work. J. Occup.
Merck & Co., Inc., Whitehouse Station, NJ. Environ. Hyg. 13, 19–29.
Redlich, C.A., Sparer, J., Cullen, M.R., 1997. Sick-building syndrome. Lancet 349, World Meteorological Organization (WMO), 2016. The state of greenhouse gases in the
1013–1016. atmosphere based on global observations through 2015. WMO Bull. 12, 1–8.
Rice, S.A., 2003. Health effects of acute and prolonged CO2 exposure in normal and World Meteorological Organization (WMO), 2017. The state of greenhouse gases in the
sensitive populations. In: Second Annual Conference on Carbon Sequestration, NETL atmosphere based on global observations through 2016. WMO Bull. 13, 1–8.
Proceeding, Alexandria, VA Pittsburgh. Zhang, X., Wargocki, P., Lian, Z., 2016. Human responses to carbon dioxide, a follow-up
Satish, U., Mendell, M.J., Shekhar, K., Hotchi, T., Sullivan, D., Streufert, S., Fisk, W.J., study at recommended exposure limits in non-industrial environments. Build.
2012. Is CO2 an indoor pollutant? Direct effects of low-to-moderate CO2 concentra- Environ. 100, 162–171.
tions on human decision-making performance. Environ. Health Perspect. 120, Zhang, X., Wargocki, P., Lian, Z., Thyregod, C., 2017a. Effects of exposure to carbon
1671–1677. dioxide and bioeffluents on perceived air quality, self-assessed acute health symp-
Seppänen, O.A., Fisk, W.J., Mendell, M.J., 1999. Association of ventilation rates and CO2 toms, and cognitive performance. Indoor Air 27, 47–64.
concentrations with health and other responses in commercial and institutional Zhang, X., Wargocki, P., Lian, Z., 2017b. Physiological responses during exposure to
buildings. Indoor Air 9, 226–252. carbon dioxide and bioeffluents at levels typically occurring indoors. Indoor Air 27,
Simoni, M., Annesi-Maesano, I., Sigsgaard, T., Norback, D., Wieslander, G., Nystad, W., 65–77.
Canciani, M., Sestini, P., Viegi, G., 2010. School air quality related to dry cough,
56