We have found in this study that traveling to a country with a high prevalence of smoking results not only in increased exposures to passive smoking but also in the induction of significant health effects, long after the exposures have concluded. This is the first study focusing on the risk of passive smoking among a ubiquitous but underappreciated population – international travelers, of whom the exposure duration is likely to be different from local residents.
We followed 27 travelers between Los Angeles and Beijing and found significantly higher exposures to passive smoking in Beijing, in association with elevated exposures to PAHs, and increased lipid peroxidation in the urine. These results indicate that cross-boundary traveling could change the degree of passive smoking exposures, which may contribute to elevated exposures to toxic chemicals and subsequently, the development of adverse health effects that could promote cardiovascular diseases. In addition, our findings may also inform on potential risks associated to passive smoking exposures among local residences in Beijing, China.
Nicotine is metabolized by cytochromes P450 into cotinine and excreted from human bodies by the kidney (19), reasoning why the urinary concentration of cotinine has been widely employed as a biomarker of exposure to passive smoking in population studies (17, 20). In the current study, we collected multiple urine samples for each participant with intervals of at least one week, which is much longer than cotinine’s half-time of several hours (17). We observed elevated cotinine levels in urine samples collected at different time points in Beijing as compared with Los Angeles (Figure S5), indicating ubiquitous exposures to passive smoking in Beijing among participants. We initially hypothesized that increased passive smoking exposures in Beijing were mostly attributable to SHS since none of the participants were active smokers and they reported longer time near smokers when in Beijing as compared to when in Los Angeles (Table S3). However, we observed that participants who did not report to be near a smoker before the sample collection in Beijing also exhibited elevated cotinine levels in the urine (Figure S2), which might suggest a significant contribution from THS as well. Nevertheless, we cannot exclude the possibility of recall bias or that participants were exposed to SHS unconsciously.
It has been well documented that tobacco smoke is rich in PAHs (21). Passive smoking is potentially a marked contributor to PAHs exposures (22) since smoking mostly occurs near the general population. In this study, we found that urinary cotinine concentrations were associated with ƩOH-PHEs and 1-OH-PYR concentrations (p < 0.001, Table 2), indicating that passive smoking was likely an important determinant of PAHs exposures among the study participants. On the other hand, the levels of 2-OH-DBF, ƩOH-FLUs and ƩOH-PHEs were not only significantly higher in Beijing as compared with LA-before but also, they remained as such after adjusting for urinary cotinine concentrations (Table 2), suggesting that other factors contribute to the increase in PAHs exposure in Beijing such as air pollution (12). Indeed, previous studies have reported a 32.7-fold difference in the annual average concentration of airborne non-naphthalene PAHs between Los Angeles (6.67 ng/m3) (23) and Beijing (218 ng/m3) (24). Albeit diet ingestion has been suggested as the major exposure route of PAHs with < = four rings (e.g. 1-OH-PYR) (25–27), we don’t believe diet played a major role in our study. This is because (i) dietary habits were similar in each study participant while in both cities (Table S3); (ii) samples were collected after 8-h fasting which decreased the influence of diet; and (iii) the PAHs concentration in food has been comparable between China and the U.S. (26, 28).
We have previously shown that traveling from Los Angeles to Beijing led to significant increases in circulating levels of oxidized polyunsaturated fatty acids via enzymatic pathways (e.g. lipoxygenases) 6 to 8 weeks after initiating the travel, while the increase in circulating 8-isoprostane concentrations was only borderline significant (12). Likewise, we have observed significant increases in urinary concentrations of MDA, a lipid peroxidation product from both enzymatic and non-enzymatic pathways, after traveling, which remained elevated throughout the whole stay in Beijing and after returning to Los Angeles (Fig. 2A). On the other hand, there were no significant changes in the concentration of 8-isoprostane, which primarily originates from non-enzymatic oxidation of arachidonic acid, in Beijing as compared with LA-before (Fig. 2B). In particular, we observed a progressive decrease in urinary 8-isoprostane levels after participants arriving at Beijing (Fig. 2D) even though there were no decreases in urinary concentrations of cotinine (Fig. 1C) or OH-PAHs (Figure S2) during the stay in Beijing. Indeed, we have observed higher circulating levels of uric acid, pyroglutamic acid, and taurine in Beijing (data not shown) which might reflect participants’ enhanced capacity to scavenge free radicals in the circulation.
Surprisingly, however, 8-isoprostane concentrations increased after returning to Los Angeles and remained elevated > 70 days after (Fig. 2B), which was consistent across different years and different time points (Figure S5). These results are also consistent with the study of Wu et al who observed in nine volunteers traveling from Germany to China for 8–42 days that they exhibited elevated urinary 8-isoprostane levels, at least four weeks after returning to Germany (29). In addition, urinary MDA concentrations in LA-after remained higher than the baseline level as well (Fig. 2A) in contrast to our previous observation among the same participants that oxidized lipids in the circulating blood, returned to baseline after coming back to Los Angeles (12). The discrepancy between urinary and circulating oxidative biomarkers suggested that elevated urinary levels of MDA and 8-isoprostane in LA-after may reflect oxidation at the organ level (e.g. kidney) instead of the systemic circulation. Remarkably, we observed positive associations between average cotinine levels in Beijing and the increase in 8-isoprostane levels from LA-before to LA-after (Fig. 3C), suggesting that the pro-oxidative effects of passive smoking exposures in Beijing may persist 4–10 weeks after returning to Los Angeles.
The prolonged detection of increased oxidized lipids in the urine is very important since lipid peroxidation has been shown to play a critical role in the pathogenesis of SHS-induced diseases, including those of cardiovascular nature (30). Thus, previous animal studies have shown that tobacco smoke exposure may induce kidney oxidative damages (31). Of interest, we have noted in our study that the pro-oxidative effects of passive smoking could occur at different time scales likely due to the wide range of biological half-lives from different chemicals in the tobacco smoke mixtures. On one hand, urinary cotinine levels, an indicator of recent exposures, were associated with MDA and 8-isoprostane levels, suggesting marked acute pro-oxidative effects of passive smoking, which has been shown to contain redox-active chemicals with short biological half-lives, such as free radicals, aldehydes, peroxides, and epoxides (32). On the other hand, the average cotinine concentrations in Beijing were correlated with the difference in average 8-isoprostane levels between LA-after and LA-before (Fig. 3C). The persistent effects might be attributed to tobacco smoke components with long half-lives such as cadmium, which has been shown to accumulate in the kidney with a clearance half-life of 25 years (15). Additionally, the slow translocation of cadmium from circulation to organs (half-life = 75–128 days) (15) may also explain why urinary 8-isoprostane was not increased until participants returned to Los Angeles.
The concentrations of urinary cotinine in Los Angeles and Beijing in this study were in the same magnitude of other non-smoking population studies from 20 countries (Table S4) (20, 33–36). Thus, the level of urinary cotinine in Los Angeles (LA-before + LA-after) was at lower levels compared with that in studies from other countries (Table S4) (20). In contrast, urinary cotinine in Beijing was at a relatively higher levels, and it was comparable with levels in studies from Korea and several Europe countries (e.g. Portugal and Hungry) (20, 35) but markedly lower that the levels in an Italian Study (36). It is likely that the higher urinary cotinine concentration observed in Beijing was due to a higher prevalence of smoking (30.2%) (37) as compared with Los Angeles (14.3%) (38), together with the markedly higher population density in Beijing (4,700 persons km− 2) as compared to that in Los Angeles (2,300 persons km− 2) (39). Indeed, we have noted a significant association between the smoking prevalence of different countries in 2012 (40) and the urinary cotinine level in people participating in studies from 22 countries (20 from other studies and two from the current study) (r = 0.44, p < 0.05, Figure S6), supporting the logical assumption that increased prevalence of smoking leads to increased exposures to passive smoking. Although previous studies have documented large variabilities in the level of passive smoking exposures among local residents, the latter depended on whether there were active smokers in their families or working places (41, 42). The travelers in our study, however, were more likely exposed to passive smoking outside home and in their workplaces, given positive associations between urinary cotinine levels and self-reported driving time (Table S2). Indeed, nicotine has been detected in the air of 44 public places tested in a previous study (e.g. hospitals, secondary schools and restaurants) with a median concentration of 3.0 µg/m3 (43). This level is comparable to that of smoking-permitted workplaces in the U.S. and might cause notable passive smoking exposures among visitors to those places (44).
Importantly, exposures to passive smoking can be decreased by regulatory policies targeting active smoking. Thus, effective June 2015, the Beijing government banned smoking in all the indoor areas of public places, including workplaces and public transportation as well as outdoor areas of schools and hospitals (45). Our data obtained in Beijing, in the summers of 2014 and 2015 reflect passive smoking exposures before and after the ban policy, respectively. Although urinary cotinine concentrations and self-reported time near smokers were higher in Beijing than in Los Angeles in both 2014 and 2015, we observed trends towards decreased exposures in Beijing from 2014 to 2015 as evidenced by decreased urinary cotinine concentrations (geometric mean in a unit of µg/g creatine: 1.68 in 2014 and 1.21 in 2015, respectively), and decreased self-reported time near smokers (Table S3). These data suggest positive effects, likely derived from the implementation of the regulatory policy; however, we cannot exclude the possibility that the trend was dominated by differences in study participants between 2014 and 2015, given significant associations of urinary cotinine concentrations with year (p < 0.05), but not with the interaction between year and city (Table S2).