br Results from our study
Results from our study support previous reports that tooth loss was significantly associated with increased lung cancer risk. In the Health Professionals Follow-Up Study, among European American male po-pulations with high educational attainment, having fewer teeth was associated with an increased risk of lung cancer . A Japanese hos-pital-based case-control study also reported a 1.5-fold increased lung cancer risk for those who had lost all teeth compared to those with at least 21 teeth remaining . Hujoel et al.’s study, based on the NHANES I Epidemiologic Follow-up Study, found that individuals who had lost all teeth had a ∼2-fold increased risk for lung cancer in an age-and gender-adjusted model, but the association became non-significant after adjusting for confounding factors such as race, socioeconomic status, smoking duration, and pack-years . A very recent study from the Atherosclerosis Risk in Communities study (ARIC) reported that having lost all teeth was significantly associated with increased lung and bronchus cancer risk among the European American population, but not among the African American Linezolid .
In the present study, periodontal disease was positively associated
with lung cancer risk. Results from previous studies are inconsistent. Results from the Health Professionals Follow-Up Study (5) and Women’s Health Initiative Observational Study  reported a positive association bwtween periodontal disease and lung cancer with an HR of 1.36 and 1.25, respectively. However, results from the Swedish Twin Registry found that periodontal disease did not significantly increase the risk of lung cancer . The results of a Taiwanese study using National Health Insurance data revealed that patients with periodontitis did not have a significantly higher risk of lung cancer . The NHANES I Epidemiologic Follow-up Study reported that lung cancer risk was associated with periodontitis (HR = 1.73, 95% CI: 1.01, 2.97) only, not gingivitis (HR = 1.31, 95% CI: 0.68, 2.53) . We did not collect information for periodontitis and gingivitis separately, and thus, are not able to evaluate the specific eﬀects of periodontitis and gingi-vitis separately. In a very recent study conducted within ARIC , severe periodontitis was significantly associated with increased lung cancer risk among the European American population. The association among African Americans was not significant, perhaps due to the small sample size .
We found evidence that the associations between oral health and lung cancer risk may diﬀer by smoking intensity. When stratified by intensity of cumulative smoking exposure, the association of poor oral health with lung cancer risk was more evident among smokers who have higher pack-year histories than smokers who have lower pack-year histories, and the interaction was significant. Previous studies have proven the harmful eﬀects of smoking on oral health [14,22]. Rad and colleagues demonstrated that long-term smoking significantly reduces the whole-mouth salivary flow rate that helps maintain healthy oral conditions, thus aggravating oral health resulting from dry mouth . In addition, results from The Veterans Administration Dental Long-itudinal Study suggested that smoking cessation could help prevent tooth loss, and suggested that long-term smoking cessation could re-duce the risk to the level of never smokers .
Although the underlying mechanisms of oral health and lung cancer risk are not clear, several biologically plausible hypotheses support our findings. First, recent research has suggested that periodontal patho-gens induce an inflammatory response that is characterized by in-creased levels of C-reactive protein, IL-1β, IL-6, TNF-α, and matrix metalloproteinases [25–28]. Also, patients with periodontitis have
higher levels of C-reactive protein compared to patients without peri-odontitis . Thus, exposure to the chronic inflammation that is caused by poor oral health may initiate and promote lung cancer de-velopment, and smoking can aggravate inflammation and carcinogen-esis. Second, poor oral health could generate a potent carcinogen, ni-trosamine . It has been reported that people with poor oral health have higher nitrosamine levels, which are driven by nitrate-reducing bacteria, in their oral cavities [11,31]. Third, oral bacteria could themselves produce adverse eﬀects on human health, e.g., toxin-pro-ducing bacteria could disturb the normal cell cycle and growth . The oral microbiome is the primary source of lung bacteria, and our ongoing study has found that several oral bacteria are associated with lung cancer risk . Interestingly, Yan et al. have reported that pa-tients with lung cancer have high levels of salivary microbiota, such as Capnocytophaga and Veillonella . Also, Meyer et al. have speculated that bacteria may play a more direct carcinogenic role in lung or oral cancer, rather than an inflammatory role .