Abstract

Background

This study evaluates the risk of benign brain tumors (BBTs) and malignant brain tumors (MBTs) associated with dental diagnostic X-ray, using a large population-based case–control study.

Materials and methods

We identified 4123 BBT cases and 16 492 controls without BBT (study 1) and 197 MBT cases and 788 controls without MBT (study 2) from Taiwan National Health Insurance claim data. The risks of both types of tumor were estimated in association with the frequency of received dental diagnostic X-ray.

Results

The mean ages were ∼44.2 years in study 1 and 40.6 years in study 2. Multivariable unconditional logistic regression analysis showed that the risk of BBT increases as the frequency of received dental diagnostic X-ray increases. The BBT odds ratio increased from 1.33 [95% confidence interval (CI) 1.22–1.44] for those with annual mean X-ray examination of less than one to 1.65 (95% CI 1.37–1.98) for those with three or more X-ray examinations, after controlling for comorbidities. No significant association was found between MBTs and dental diagnostic X-ray exposure.

Conclusions

Exposure to dental diagnostic X-rays in oral and maxillofacial care increases the risk of BBTs, but not MBTs.

introduction

The biological hazards of ionizing radiation have been well documented since the atomic bomb explosion in Hiroshima and Nagasaki [1, 2], which caused a high incidence of atomic bomb-induced health issues, including various types of cancer. The molecular mechanism of ionizing radiation-induced cancer is a consequence of DNA damage. Ionization radiation is a confirmed environmental risk factor for human brain tumors. It produces several types of DNA damage, including oxidative damage to nucleotide bases, single- and double-strand DNA chains, and DNA–DNA or DNA–protein covalent bonds [3]. Many studies have recently shown that high-dose ionizing radiation is a well-established risk factor for brain tumors, including meningoma, a mostly benign brain tumor (BBT), and glioma, a malignant brain tumor (MBT) [4–6]. However, there are fewer low- to medium-dose ionizing radiation exposure studies than high-dose exposure studies.

Intracranial meningiomas are solid tumors arising from the meninges (which protects the central nervous system). They contribute to most part of BBTs. Typically, they result in benign histological findings. Their incidence increases with age and are more common in women. They account for ∼20% of intracranial tumors. Depending on the size and location of intracranial tumors, patients may show neurological symptoms of increased intracranial pressure, including headaches, nausea, vomiting, lethargy, and papilloedema; or focal brain dysfunction, including limb weakness or numbness and seizures [7]. Compared with meningiomas, gliomas are relatively malignant and severe. Gliomas are mainly named by their specific cell types, such as ependymonas, astrocytomas, and oligodendrogliomas. Several studies have suggested that glioma risk is based on quantitative X-ray exposure, especially moderate- and high-dose ionizing radiation, and atomic explosion exposure [2, 8, 9]. The most common sources of low- to medium-dose ionizing radiation are medical diagnostic and environmental exposure. In Taiwan, people are most frequently exposed to X-rays during routine dental examinations. Four types of X-ray procedures are commonly used during dental examinations: periapical, panoramic, TMJ (lateral skull or cephalometric) film, and dental CT. The exposure doses of dental X-ray types are periapical film, 0.018–1.2 mSv; panoramic film, 0.135–0.9 mSv; and diagnostic X-ray film including head and neck, skull, and spine film, 0.03–0.2 mSv [6, 10–12]. However, the risk of BBTs and MBTs after low- to medium-dose ionizing radiation from dental X-ray exposure is unclear and no large-scale population-based studies describe the risk of these brain tumors. This study uses representative Taiwan National Health Insurance (TNHI) claim data to compare patients with and without brain tumors and their dental X-ray exposure (low- to medium-dose IR exposure) to separately evaluate benign and malignant tumors.

materials and methods

data sources

The TNHI program integrated all public insurance systems in 1995 as a single-pay program to serve all residents of Taiwan with 96% of 23.74 million residents covered in 1996. The coverage rate has reached >99% since 1999 [13]. The system has contracted >90% hospitals and clinics. The insured individuals are free to choose services, including dental cares. The Taiwan Department of Health authorized the National Health Research Institute (NHRI) to manage the claims data. The NHRI cooperated with the Bureau of National Health Insurance to establish several datasets for public use. This study used a claims dataset of 1 000 000 individuals randomly selected from all insured with claims data abstracted from 1996 to 2010. Claims data contain basic demographic information on insured residents (sex, birth date, income used for estimating the premium, occupation, and residential area) and medical care received for inpatient and ambulatory visits. The International Classification of Disease, Ninth Revision of Clinical Modification (ICD-9-CM), is available in the claims data to define disease status.

study samples

Figure 1 shows the process for identifying relevant cases for the two case-controlled studies. For study 1, we identified from the same claims data patients with BBTs diagnosed between 1997 and 2010 (ICD-9-CM codes 225) and control individuals without brain tumors. Patients with MBTs diagnosed between 1997 and 2010 (ICD-9-CM codes 191, 192, 194.3, and 194.4) and control individuals without brain tumors were also identified from the claims data. Patients suffering from cancer, strokes, or head injuries at the baseline were excluded from the case and control groups. For each case identified, four controls were selected and frequency matched by age, sex, and year of diagnosis. Claims data were used to quantify the X-ray radiography each person received for dental care and to identify baseline comorbidities of dementia and epilepsy. We used treatment procedure codes destined by the health insurance system to identified X-rays prescribed only for dental care, including periapical radiography, bite-wing radiography, occlusal radiography, panoramic radiography, cephalometric radiography, and TMJ radiography unilateral.

Figure 1.

Process for selecting study subjects.

Figure 1.

Process for selecting study subjects.

Study 1 included 4123 BBT patients and 16 492 non-BBT controls. Study 2 included 197 MBT patients and 788 non-MBT controls.

statistical analysis

For study 1, data analysis first compared cases with controls on the proportional distributions of demographic status, comorbidity, and X-rays received. Unconditional logistic regression analysis was used to estimate the odds ratio (OR) of the brain tumor for cases by annual mean number of dental care X-rays received, compared with those who had received none. Multivariable unconditional logistic regression analysis was used to assess the adjusted tumor risk, controlling for age, sex, and comorbidities. The Cochran–Armitage trend test was used to examine dose–response relationship between the frequency of dental diagnostic X-ray and the risk of brain tumor. The same data analysis procedures were used for study 2. Analyses were carried out using SAS 9.1 (SAS Institute, Inc., Carey, NC), with P < 0.05 considered as statistically significant.

results

study 1

Table 1 shows that the BBT cases and controls were dominated by female (58.3%) and 40- to 60-year-old groups (∼40%). Mean ages for the BBT cases and controls groups were 44.2 (SD = 17.6) and 43.9 (SD = 17.7) years (P = 0.28), respectively. Dementia, epilepsy, and X-ray examinations were more prevalent in BBT patients (P < 0.0001). The association between X-ray frequency and BBT was measured using annual mean X-ray frequency (Table 2). The OR increased with an increase in X-ray examination frequency. Compared with patients without X-rays, the adjusted OR increased with X-ray frequency, from 1.33 [95% confidence interval (CI) = 1.22–1.44] for those received one or less examination to 1.65 (95% CI = 1.37–1.98) for those with three or more X-ray examinations (P-value for trend <0.001). Table 2 also shows that the brain tumor was strongly associated with dementia (OR = 2.97, 95% CI = 1.72–5.14) and epilepsy (OR = 16.5, 95% CI = 11.4–23.9).

Table 1.

Comparison between baseline demographic status and comorbidities between benign brain tumor cases and controls

 Benign brain tumor
 
P-value 
Cases (N = 4123)
 
Controls (N = 16 492)
 
n n 
Age, year 
 ≤20 375 9.10 1500 9.10 0.99 
 20–40 1299 31.5 5197 31.5 
 40–60 1649 40.0 6596 40.0 
 >60 800 19.4 3199 19.4 
Mean (SD) 44.2 17.6 43.9 17.7 0.28a 
Sex 
 Female 2403 58.3 9612 58.3 0.99 
 Male 1720 41.7 6880 41.7 
Comorbidity 
 Dementia 26 0.63 31 0.19 <0.0001 
 Epilepsy 142 3.44 36 0.22 <0.0001 
Ever X-ray examined 1494 36.2 4815 29.2 <0.0001 
 Benign brain tumor
 
P-value 
Cases (N = 4123)
 
Controls (N = 16 492)
 
n n 
Age, year 
 ≤20 375 9.10 1500 9.10 0.99 
 20–40 1299 31.5 5197 31.5 
 40–60 1649 40.0 6596 40.0 
 >60 800 19.4 3199 19.4 
Mean (SD) 44.2 17.6 43.9 17.7 0.28a 
Sex 
 Female 2403 58.3 9612 58.3 0.99 
 Male 1720 41.7 6880 41.7 
Comorbidity 
 Dementia 26 0.63 31 0.19 <0.0001 
 Epilepsy 142 3.44 36 0.22 <0.0001 
Ever X-ray examined 1494 36.2 4815 29.2 <0.0001 

Chi-square test for categorical variables.

at-Test for comparing means.

Table 2.

Logistic regression analysis-estimated odds ratios of benign brain tumor by annual mean dental X-ray frequency

 Case Control OR (95% CI)
 
N = 4123 N = 16 492 Crude Adjusted 
Comorbidity (yes versus no) 
 Dementia 26 31 3.37 (2.00–5.68)*** 2.97 (1.72–5.14)*** 
 Epilepsy 142 36 16.3 (11.3–23.5)*** 16.5 (11.4–23.9)*** 
X-ray frequency 
 0 2629 11 677 1 (reference) 1 (reference) 
 ≤1 995 3356 1.32 (1.21–1.43)*** 1.33 (1.22–1.44)*** 
 1–2 236 731 1.43 (1.23–1.67)*** 1.47 (1.26–1.71)*** 
 2–3 96 278 1.53 (1.21–1.94)*** 1.57 (1.24–1.99)*** 
 >3 167 450 1.65 (1.37–1.98)*** 1.65 (1.37–1.98)*** 
 All 1494 4815 1.38 (1.28–1.48)*** 1.39 (1.30–1.50)*** 
P-value for trend <0.001***   
 Case Control OR (95% CI)
 
N = 4123 N = 16 492 Crude Adjusted 
Comorbidity (yes versus no) 
 Dementia 26 31 3.37 (2.00–5.68)*** 2.97 (1.72–5.14)*** 
 Epilepsy 142 36 16.3 (11.3–23.5)*** 16.5 (11.4–23.9)*** 
X-ray frequency 
 0 2629 11 677 1 (reference) 1 (reference) 
 ≤1 995 3356 1.32 (1.21–1.43)*** 1.33 (1.22–1.44)*** 
 1–2 236 731 1.43 (1.23–1.67)*** 1.47 (1.26–1.71)*** 
 2–3 96 278 1.53 (1.21–1.94)*** 1.57 (1.24–1.99)*** 
 >3 167 450 1.65 (1.37–1.98)*** 1.65 (1.37–1.98)*** 
 All 1494 4815 1.38 (1.28–1.48)*** 1.39 (1.30–1.50)*** 
P-value for trend <0.001***   

OR (95% CI), odds ratio and 95% confidence interval adjusted for age, sex, dementia, and epilepsy.

***P < 0.001.

study 2

Table 3 shows that the average ages of MBT and control patients were ∼4 years younger than those of BBT and control patients. MBT patients were more prevalent with epilepsy than control patients (P < 0.001). No significant association was found between X-ray examinations and MBT (Table 4). Approximately 9.14% of cases had the history of epilepsy (OR = 20.6, 95% CI = 6.85–61.8).

Table 3.

Comparison between baseline demographic status and comorbidities between malignant brain tumor cases and controls

 Malignant brain tumor
 
P-value 
 Cases (N = 197)
 
Controls (N = 788)
 
 
 n n  
Age, year 
 ≤20 44 22.3 176 22.3 0.99 
 20–40 51 25.9 200 25.4 
 40–60 64 32.5 260 33.0 
 >60 38 19.3 152 19.3 
Mean (SD) 40.6 21.2 40.4 21.4 0.92a 
Sex 
 Female 94 47.7 376 47.7 0.99 
 Male 103 52.3 412 52.3  
Comorbidity 
 Dementia 0.00 0.13 0.62 
 Epilepsy 18 9.14 0.51 <0.0001 
Ever X-ray examined 47 23.9 188 23.9 0.99 
 Malignant brain tumor
 
P-value 
 Cases (N = 197)
 
Controls (N = 788)
 
 
 n n  
Age, year 
 ≤20 44 22.3 176 22.3 0.99 
 20–40 51 25.9 200 25.4 
 40–60 64 32.5 260 33.0 
 >60 38 19.3 152 19.3 
Mean (SD) 40.6 21.2 40.4 21.4 0.92a 
Sex 
 Female 94 47.7 376 47.7 0.99 
 Male 103 52.3 412 52.3  
Comorbidity 
 Dementia 0.00 0.13 0.62 
 Epilepsy 18 9.14 0.51 <0.0001 
Ever X-ray examined 47 23.9 188 23.9 0.99 

Chi-square test for categorical variables.

at-Test for comparing means.

Table 4.

Logistic regression analysis-estimated odds ratios of malignant brain tumor by mean annual dental X-ray frequency

 Cases Controls OR (95% CI)
 
N = 197 N = 788 Crude Adjusted 
Comorbidity (yes versus no) 
 Dementia – – 
 Epilepsy 18 19.7 (6.59–58.9)*** 20.6 (6.85–61.8)*** 
X-ray frequency 
 0 150 600 1 (reference) 1 (reference) 
 ≤1 37 129 1.15 (0.76–1.72) 1.16 (0.76–1.77) 
 1–2 35 0.69 (0.28–1.66) 0.65 (0.26–1.63) 
 >2 24 0.67 (0.23–1.95) 0.60 (0.19–1.87) 
 All 47 188 1.00 (0.69–1.44) 0.99 (0.68–1.45) 
 Cases Controls OR (95% CI)
 
N = 197 N = 788 Crude Adjusted 
Comorbidity (yes versus no) 
 Dementia – – 
 Epilepsy 18 19.7 (6.59–58.9)*** 20.6 (6.85–61.8)*** 
X-ray frequency 
 0 150 600 1 (reference) 1 (reference) 
 ≤1 37 129 1.15 (0.76–1.72) 1.16 (0.76–1.77) 
 1–2 35 0.69 (0.28–1.66) 0.65 (0.26–1.63) 
 >2 24 0.67 (0.23–1.95) 0.60 (0.19–1.87) 
 All 47 188 1.00 (0.69–1.44) 0.99 (0.68–1.45) 

OR (95% CI), odds ratio and 95% confidence interval adjusted for age, sex, and epilepsy.

***P < 0.001.

discussion

Studies have shown that ionizing radiation is a hazard to human health and causes cancer-related diseases. With medical progress, medical diagnostic X-ray instruments are more commonly used. In Taiwan, most people are exposed to ionizing radiation during routine dental X-ray examinations. This study shows that an association exists between dental X-ray exposure (low- to medium-dose IR exposure) and BBTs, but not MBTs. These results are consistent with recent population-controlled studies on the relationship between dental X-ray exposure and meningioma risk [10, 11]. Dental X-rays have been used since 1919 [14]. Although the exposure dose of dental X-ray equipment is low, the IR biological hazard from this equipment is strictly and carefully regulated. Protective procedures during dental X-ray exposure include wearing a lead apron. Even though X-rays are regulated and require protection, they still expose the brain to radiation from lower and upper jaw apex film, bitewing film, panoramic film, and cephalometric film. This study indicates that the BBT risk increases with dental X-ray exposure (Table 2). This implies that repeated dental X-ray exposure carries a high risk of BBTs. Our further data analysis showed that cases received more frequent scaling services for the removal of plaque (1.02 versus 0.68 times/year in average). It is not clear whether more frequent health services increase the detection of cases of BBT.

The results also show that women are at higher risk than men, and people between 20 and 60 years old account for most patients (∼71.5%). This is consistent with findings by Wiemels et al. [15]. This study confirms recent studies [11, 16–18] which have suggested that regular, full-mouth dental X-ray film, and panoramic film are associated with a high risk for intracranial benign tumors. Reports have stated that these BBTs (such as meningomas) progress slowly. The data show that no significant statistic correlation exists between MBTs and dental X-ray exposure. MBT risk may be correlated with quantitative exposure. Some reports have suggested that high-dose IR is an established risk factor for gliomas [6,8,19]. The comorbidity of epilepsy between X-ray exposure and BBTs and MBTs indicates that both stratified patients experience these conditions more than those in the control group. But, in the dementia group, BBT is more prevalent.

A limitation to this study is the difficulty of defining the actual exposure of dental X-ray equipment because equipment is designed differently. Exposure frequency may also be underestimated because the dental X-ray database was collected by contracted TNHI practitioners and excludes non-TNHI data (including self-paying patents). Only 2% of dental clinics do not have contract with the insurance system. However, dental X-ray received before 1996 is unavailable in the NHRI datasets. Misclassification of the X-ray exposure status is possible and some patients are thus included in the non-exposure group. The risk of brain tumor could be thus underestimated.

This is the largest population-based study to investigate the correlation between dental X-ray exposure and risk of BBTs and MBTs. The results are important, because routine dental X-rays are the most commonly used medical imaging equipment in Taiwan. X-rays are useful and powerful diagnostic tools used for dental care, periodontal disease, endodontic treatment, and extractions. Patients are exposed to dental IR at least once during dental treatment and BBT risk may increase with exposure frequency. Therefore, protection from IR is as important as the diagnostic benefit to patients. This study indicates that medical providers should reduce the iatrogenic IR exposure risk factors of such therapeutic and diagnostic equipment.

funding

This work was supported in parts by China Medical University Hospital (DMR-100-076 and DMR-100-077); Taiwan Department of Health Clinical Trial and Research Center for Excellence (DOH102-TD-B-111-004); Taiwan Department of Health Cancer Research Center for Excellence (DOH102-TD-C-111-005); International Research-Intensive Centers of Excellence in Taiwan (I-RiCE) and National Science Council (NSC101-2911-I-002-303).

disclosure

The authors individually or collectively have no significant conflicts of interest or financial disclosures.

references

1
Sadamori
N
Shibata
S
Mine
M
, et al.  . 
Incidence of intracranial meningiomas in Nagasaki atomic-bomb survivors
Int J Cancer
 , 
1996
, vol. 
67
 (pg. 
318
-
322
)
2
Shintani
T
Hayakawa
N
Hoshi
M
, et al.  . 
High incidence of meningioma among Hiroshima atomic bomb survivors
J Radiat Res
 , 
1999
, vol. 
40
 (pg. 
49
-
57
)
3
US National Research Council
Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2
 , 
2006
Washington, DC
National Research Council, National Academies of Science
4
Anderson
JR
Treip
CS
Radiation-induced intracranial neoplasms. A report of three possible cases
Cancer
 , 
1984
, vol. 
53
 (pg. 
426
-
429
)
5
Bondy
M
Ligon
BL
Epidemiology and etiology of intracranial meningiomas: a review
J Neurooncol
 , 
1996
, vol. 
29
 (pg. 
197
-
205
)
6
Davis
F
Il'yasova
D
Rankin
K
, et al.  . 
Medical diagnostic radiation exposures and risk of gliomas
Radiat Res
 , 
2011
, vol. 
175
 (pg. 
790
-
796
)
7
Longstreth
WT
Jr
Dennis
LK
McGuire
VM
, et al.  . 
Epidemiology of intracranial meningioma
Cancer
 , 
1993
, vol. 
72
 (pg. 
639
-
648
)
8
Hall
EJ
Brenner
DJ
Cancer risks from diagnostic radiology
Br J Radiol
 , 
2008
, vol. 
81
 (pg. 
362
-
378
)
9
Ron
E
Modan
B
Boice
JD
Jr
, et al.  . 
Tumors of the brain and nervous system after radiotherapy in childhood
N Engl J Med
 , 
1988
, vol. 
319
 (pg. 
1033
-
1039
)
10
Claus
EB
Calvocoressi
L
Bondy
ML
, et al.  . 
Dental x-rays and risk of meningioma
Cancer
 , 
2012
, vol. 
118
 (pg. 
4530
-
4537
)
11
Longstreth
WT
Jr
Phillips
LE
Drangsholt
M
, et al.  . 
Dental X-rays and the risk of intracranial meningioma: a population-based case-control study
Cancer
 , 
2004
, vol. 
100
 (pg. 
1026
-
1034
)
12
2000
Lyon, France
IARC, WHO International Agency for Research on Cancer
 
IARC Monographs on the Evaluation of Carcinogenic Risks of Humans Volume 75: part 1
13
Cheng
TM
Okma
KGH
Crivelli
L
Taiwan's national health insurance system: high value for the dollar
Six Countries, Six Reform Models: Their Healthcare Reform, Experience of Israel, The Netherlands, New Zealand, Singapore, Switzerland and Taiwan
 , 
2009
Hackensack, NJ
World Scientific
(pg. 
171
-
204
)
14
Richards
AG
Colquitt
WN
Reduction in dental X-ray exposures during the past 60 years
J Am Dent Assoc
 , 
1981
, vol. 
103
 (pg. 
713
-
718
)
15
Wiemels
J
Wrensch
M
Claus
EB
Epidemiology and etiology of meningioma
J Neurooncol
 , 
2010
, vol. 
99
 (pg. 
307
-
314
)
16
Preston-Martin
S
Paganini-Hill
A
Henderson
BE
, et al.  . 
Case-control study of intracranial meningiomas in women in Los Angeles County, California
J Natl Cancer Inst
 , 
1980
, vol. 
65
 (pg. 
67
-
73
)
17
Preston-Martin
S
Paganini-Hill
A
Henderson
BE
, et al.  . 
Risk factors for meningiomas in men in Los Angeles County
J Natl Cancer Inst
 , 
1983
, vol. 
70
 (pg. 
863
-
866
)
18
Ryan
P
Lee
MW
North
B
, et al.  . 
Amalgam fillings, diagnostic dental x-rays and tumours of the brain and meninges
Eur J Cancer B Oral Oncol
 , 
1992
, vol. 
28B
 (pg. 
91
-
95
)
19
Sadetzki
S
Chetrit
A
Freedman
L
, et al.  . 
Long-term follow-up for brain tumor development after childhood exposure to ionizing radiation for tinea capitis
Radiat Res
 , 
2005
, vol. 
163
 (pg. 
424
-
432
)

Author notes

These authors contributed equally to this work.