At the end of the 19th century, NAIs were found in the natural environment for the first time (Krueger AP 1972; Krueger AP et al., 1976). By the beginning of the 20th century, NAIs have been successively showed to have a variety of potential biological functions, including regulating respiratory system function, sedation, hypnosis, hypotension, regulating mood, neurological function, metabolism, and endocrine, among others in human health (Charry JM 1984; Day DB et al., 2018). Negative ion generators (NIAPs) have been widely utilized in various living environments and working places, and with the continuous development of science and technology, it have been gradually optimized including no ozone as a by-product (Jiang SY et al., 2021). Historically, various physiological or health effects related to exposure to charged air ions have been suggested, but the evidence of these effects is still ambiguous, and to the writers, there seems to be a lack of in-depth mechanism research.
4.1 NAIs exposure and cardiovascular events
Previous studies have suggested that NAIs can effectively inhibit the sympathetic nerve and activate the parasympathetic nerve. At the same time, the paraventricular nucleus of the hypothalamus (PVN), locus coeruleus (LC), and nucleus ambiguous (NA) plays a key role in the regulation of sympathetic nervous system activity (Lucini D et al., 2020; Farrell MC et al., 2020). Therefore, it is speculated that NAIs can affect the autonomic regulatory activity of PVN, LC, and Na neurons, thus affecting autonomic nerve function to adjust heart rate and blood pressure. However, the neural mechanism of NAIs-mediated autonomic regulation is unclear. Bailey WH et al. reviewed the literature on animal experimentation and the potential biological effects of NAIs published from 1935 to 2015 (Bailey WH et al., 2018). Suzuki S et al. (Suzuki S et al., 2008) preliminarily explored the mechanism of NAIs regulating the activity of the autonomic nervous system. The laboratory selected adult male Wistar rats and randomly divided them into two groups. One group was exposed to 5000–8000 / cm3 NAIs air, and the other group was exposed to about 400–500 / cm3 normal air to control temperature and humidity, blood pressure (BP), heart rate (HR), and heart rate variability (HRV) was monitored. The expression of c-fos in PVN, LC, Na, and nucleus tractus solitaries (NTS) was detected by immunohistochemistry. The results showed that NAIs significantly reduced blood pressure and heart rate and increased the high-frequency power of the HRV spectrum. The expression of c-fos was significantly down-regulated in PVN and LC regions and up-regulated in NA and NTS regions. After vagotomy, the above physiological changes and neuronal activity were not observed. It is considered that NAIs can regulate autonomic regulation by inhibiting the activity of PVN and LC neurons and activating NA neurons, and the vagal nerve may mediate these effects.
At the same time, some animal studies have not found that positive or negative air ion exposure affects heart rate, respiratory rate, or blood pressure. In 2021, Kim M et al. (Kim M et al., 2021) published an in vitro study to explore the antioxidant and anti-inflammatory pathways of NAIs. After NAIs exposed or unexposed HaCaT cells were treated with particulate matter (PM), the levels of reactive oxygen species (ROS) and inflammatory factor IL-1 were detected. The expression levels of nuclear transcription factor activator protein 1 (AP1) and p38 protein were also detected at the same time. The results showed that NAIs could exert anti-inflammatory and antioxidant effects by inhibiting ROS / p38 MAPKs (mitogen-activated protein kinases) / AP1 pathway in HaCaT cells exposed to PM.
There exist several population investigations about the health effect of NAIs exposure. Dong W et al. published a randomized, double-blind cross-over test in 2019 (Dong W et al., 2019). In the study, 44 students in Beijing were selected to use commercial anion air purifiers for five weeks to monitor the indoor NAIs, PM, black carbon (BC), and ozone concentrations and observe the changes in HRV of volunteers. The results demonstrated that HRV exhibited a negative change, and the alteration of HRV was more significant at a high concentration of NAIs. However, some studies (Liu S et al., 2020; Gui Hanlin et al., 2018) have not found that NAIs exposure can improve cardiopulmonary function in healthy people. It is considered to be associated with the adverse effects of by-product ozone, or the beneficial effect is only related to the decrease of PM2.5 concentration.
4.2 Evidence on the function of NAI on the respiratory system
High concentration NAIs inhalation may improve lung function, regulate metabolism and treat asthma symptoms. Alexander DD et al. (Alexander DD et al., 2013) systematically reviewed 23 studies related to negative ions and respiratory system function published from 1933 to 1993. The research population included in the literature involved infants, adolescents, and adults. The sample size varied from 8 to 123 subjects; most studies focus on 10–30 persons. There are few large sample studies. A double-blind or single-blind cross-over test is mainly used, and the exposure range of negative ions is 1600 / cm3-1500000 / cm3. Among them, two studies believe that NAIs exposure can improve the symptoms of patients with bronchial asthma. Overall, the review concluded that negative ion exposure did not significantly improve respiratory function or asthma symptoms. However, these studies are relatively old, limited to the small sample size, different experimental methods, and inconsistent conclusions. Dong W et al. (Dong W et al., 2019) also observed volunteers’ respiratory function changes and analyzed the correlation with environmental factors. The results showed that after using the air purifier, the PM0.5, PM2.5, PM10, and BC could be reduced by 48%, 44%, 34%, and 50%, respectively. The concentration of negative ions increased from 12 / cm3 to 12997 / cm3. The forced expiratory volume in 1s (FEV1) of volunteers increased by 4.4%, and fractional nitric oxide (FeNO) decreased by 14.7%. Therefore, it could be considered that using a negative ion purifier can significantly improve the function of the respiratory system. Liu S et al. (Liu S et al., 2020) found that the increase in NAIs concentration and the decrease in PM level can improve respiratory system function by accelerating energy metabolism and improving anti-inflammatory and antioxidant capacity.
Other population studies have explored the effect of a high concentration of NAIs exposure on respiratory function during exercise, or evaluated the effect of exercise and NAIs therapy on patients with respiratory diseases, but the research conclusions are also inconsistent (Su Yanfeng et al., 2018; WEN Lanying et al., 2017; A. Nimmerichter A et al., 2014; Mao Qing-gen et al., 2016; Shi Yongbin et al., 2016). Su Yanfeng et al. (Su Yanfeng et al., 2018) evaluated the therapeutic effect of load-breathing training under NAIs synergistic treatment on 50 smokers with moderate and mild chronic obstructive pulmonary disease. The results showed that the volunteers exposed to high levels of NAIs exhibited a more significant improvement in lung function indexes. WEN Lanying found that the level of NAIs positively correlates with the training effect on respiratory function. Training in a high concentration of NAIs is conducive to improving respiratory muscle strength and pulmonary ventilation function (WEN Lanying et al., 2017). However, Nimmerichter A et al. did not find the high concentration of NAIs (220 ± 30 × 103 / cm3) exposure had any effect on oxygen metabolism during exercise (Nimmerichter A et al., 2014).
Several researchers discussed the effects of NAIs exposure on the respiratory system in experimental animals. Bailey WH et al. (Bailey WH et al., 2018) systematically review found that Krueger laboratory studied the effects of air ions on the ciliary flow in the trachea of anesthetized rabbits, rats, guinea pigs, and mice and their potential relationship with the level of neurotransmitter hemolysin. It is considered that negative ions can reduce the ciliary activity and mucus flow in the trachea. However, the lack of sufficient data on the experimental design and results, including the lack of statistical analysis, the failure to control temperature, humidity, possible by-products, and other factors, and the inability to quantitatively evaluate these effects. Other laboratories have reported that their studies have not replicated the above results. Sirota T. V et al. reported that daily exposure of rats to NAIs with a concentration of 100,000-600,000 ions / cm3 produced by Lustre ionizer could lead to tracheal tissue damage and biochemical changes, suggesting that high concentrations of NAIs may cause oxidative stress. At the same time, this phenomenon has not been found in NAIs generators of other brands (Sirota T. V et al., 2006). The laboratory subsequently reported that rats exposed to the same level of NAIs did not produce tissue damage but did change the indicators of reactive oxygen species. This response was also consistent with the lower degree of ozone exposure, which was considered to be the effect caused by the by-product ozone (Sirota TV et al., 2008).
4.3 Impact of NAIs on regulating emotion
It has been proposed that high concentration NAIs exposure may reduce the severity of depression, psychological stress, and anxiety, to improve well-being (Anushree Malik et al., 2010; Flory R et al., 2010), but the conclusion is uncertain, as Perez V et al found no correlations between air ions and emotion related mental health (Perez V et al., 2013). The inconsistent findings may due to confounding effects, such as air temperature, air humidity, air flow, electromagnetic field, and/or other unmeasured factors. Meta-analysis was conducted on five studies on negative ions and depression. The results showed that high concentration NAIs exposure was significantly correlated with lower depression scores. The MD value in the high-level NAIs exposure group was 14.28 (95% CI: 12.93–15.62), and the low-level NAIs exposure group was 7.23 (95% CI: 2.62–11.83). Patients with seasonal or chronic depression can respond to higher levels of NAIs, but the effect of lower levels of NAIs is only observed in patients with seasonal depression.
Flory R et al. published a five-year study to evaluate the efficacy of two active antidepressant therapies, white light, and high-density NAIs, and two placebo therapies, dark red light and low-density NAIs, on seasonal affective disorder (SAD) (Flory R et al., 2010). Seventy-three female patients were included and exposed to one of the treatment methods in a controlled environment for five consecutive years in January each year. A total of 12 consecutive cycles of treatment were carried out. Volunteers completed the seasonal pattern assessment questionnaire (SPAQ) before treatment, and made a retrospective self-evaluation of the seasonal change patterns and degrees of sleep, social activities, mood, weight, appetite, and energy levels. After treatment, the treatment expectation questionnaire (TEQ), Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version - Self Rating (SIGH-SAD-SR), and Beck Depression Inventory (BDI) were completed. The results demonstrated no significant difference in TEQ scores between four groups. However, the SIGH-SAD-SR and BDI scores were positively correlated with NAIs treatment Overall, the effect of white light therapy was higher than that of high-density anion therapy, both of which were higher than that of placebo therapy, but there was no significant difference in the effect of NAIs.
Bowers B et al. evaluated the continuous exposure of 40 SAD subjects to high-density or zero density (placebo condition) NAIs for 18 days, 30 minutes, or 60 minutes a day (Bowers B et al., 2018). The results showed that high-density NAIs exposure was better than placebo in alleviating depression and atypical SAD symptoms. In the high-density anion group, 30 minutes and 60 minutes of daily exposure could relieve depressive symptoms. In the high-density NAIs group, subjects with sleep type of morning were better treated than those with sleep type of night.