Hearing loss is an extremely common chronic disorder, disrupting quality of life in those affected owing to resultant difficulties with language processing and communication, causing affected individuals to suffer from depression and social isolation(Reference Rutherford, Brewster and Golub1,Reference Jayakody, Almeida and Speelman2) . Multiple aetiological factors, including genetics and noise exposure, have been well established as important risk factors(Reference Wu, Ni and Qi3,Reference Zhang, Liu and Zhang4) . Accumulating evidences suggest that chronic exposure to heavy metals or excessive intake of trace elements from both environment and pollution is risk factor for hearing impairment(Reference Roth and Salvi5).
Pb and Cd are present in many consumer products, such as batteries, solar panels, pigments and plastic stabilisers(Reference Roth and Salvi5). Pb can cause the barrier between the cochlea and the blood becoming more permeable, enabling toxic compounds to enter the inner ear where they can damage hearing functionality(Reference Liu, Zhang and Wu6). Cd may cause ROS generation and cell death, further disrupting cochlear function. To date, certain epidemiological studies have identified a link between hearing loss and exposure to Pb and Cd. No significant associations of blood Pb with speech – frequency hearing loss was found in Korean adults(Reference Choi and Park7), while another research reported that low levels of Pb exposure might be a significant risk factor for hearing loss in USA adults(Reference Choi, Hu and Mukherjee8). Choi et al., for example, found that low level of Cd exposure was a significant risk factor for hearing loss(Reference Choi, Hu and Mukherjee8), whereas Liu et al. found no such significant association between hearing loss and Cd(Reference Liu, Huo and Xu9). Se is an essential micronutrient, leading many individuals to consume Se-containing supplements, especially in the USA where more than half of the population take dietary supplements(Reference Fairweather-Tait, Bao and Broadley10). It is known that the relationship between Se and health is U-shape(Reference Rayman11). The recommended Se intake is 53 μg per day for women and 60 μg per day for men(Reference Rayman12). Excess Se is suggested to be toxic, and thus the benefits of such supplementation remain debatable. To date, however, only one epidemiological study has assessed the relationship between hearing loss and Se exposure(Reference Chuang, Kuo and Chiu13). Therefore, it is important to investigate the relationship between Se and deafness.
Given the inconsistent conclusions and limited evidence produced by previous research efforts, in order to achieve a more complete understanding of the risks associated with exposure to these metals, we chose to assess the link between environmental Pb, Cd and Se exposure and hearing loss using data from the most recently available NHANES 2011–2012 dataset.
Materials and methods
Study population
The 2011–2012 NHANES (https://www.cdc.gov/nchs/nhanes/) was the source of data used for this study. This study was considered to be national representative of USA civilians. All participants underwent in-home interviews and physical exams at mobile examination facilities. We focused on data from participants ≥ 20 years old who had complete audiometric results and blood heavy metal measurements. We excluded any participants missing variables of interest to the present study, yielding 1503 final participants, all of whom had given written informed consent. The survey study protocol had been approved by the National Center for Health Statistics (NCHS) Research Ethics Review Board (ERB), and no further approval was required for this study as these data are public.
Audiometric measurements and definition of hearing loss
All audiometric examinations were performed by a trained examiner in a sound-isolating room. The MEC Health Technicians who performed the Audiometry Examination Component of NHANES were professionally trained by a certified audiologist from the National Institute for Occupational Safety & Health. For each ear, 0·5, 1, 2, 3, 4 and 6 kHz frequencies were used for assessing pure-tone air conduction hearing thresholds over a –10 to 110 dB intensity ranges. The average of four audiometric frequencies (0·5, 1, 2 and 4 kHz) was used to identify speech-frequency hearing loss (SFHL), while the average of three audiometric frequencies (3, 4 and 6 kHz) was used to identify high-frequency hearing loss (HFHL). SFHL or HFHL ≥ 25 dB in either ear was sued to define hearing loss, based on the WHO definition for this condition(Reference Ikeda, Murray and Salomon14).
Measurements of blood lead, cadmium and selenium
All the measurements were detected in the laboratory of the CDC. The subjects’ whole blood samples were stored at −30°C until assessment. Amounts of blood Se, Cd and Pb therein were assessed by inductively coupled plasma mass spectrometry, with lower detection limits of 0·25 µg/dl for Pb, 0·16 µg/l for Cd and 30µg/l for Se, and this method have been reported by Wu et al.(Reference Wu, Jia and Wang15).
Covariates
For analyses in this study, the following covariates were considered: age, sex, marital status, education level, current smoking status, alcohol consumption, BMI, noise exposure, hypertension(Reference O’Shea, Griffin and Fitzgibbon16) and diabetes(Reference Schernthaner-Reiter, Stratakis and Luger17). We obtained information of age, sex, marital status and education from household interview. Possible education levels were as follows: elementary, middle or high school or college and over. Marital status was: married or other. BMI was determined based on weight divided by height squared (kg/m2). History of cigarette smoking was categorised as self-reported current smoker, former smoker or never smoker(Reference Valcke, Ouellet and Dube18). Noise exposure includes occupational, firearm and recreational noise exposure. The definition of hypertension was BP ≥ 140/90 mmHg or using anti-hypertensive medications. The definition of diabetes was fasting glucose ≥ 126 mg/dl, HbAc1 ≥ 6·5 % or using anti-diabetic medication.
Statistical analyses
Continuous variables were described based upon interquartile ranges when non-normally distributed, and categorical variables were showed in percentages. Both t tests and Mann–Whitney U tests were utilised for comparing continuous baseline variables, while χ 2 tests were employed to compare categorical baseline variables. In order to account for the complex sampling design and non-response in NHANES, the mobile examination centre sample weights was used to analyse. OR of hearing loss linked to levels of Se, Pb and Cd in the blood were estimated via multivariate logistic regression model controlling for age, sex, education, marital status, BMI, smoking, noise exposure, hypertension and diabetes. We conducted tests for linear trend by entering the median value of each category of heavy metal concentrations as a continuous variable in the models. The risk analyses were further stratified by sex and age. Age groups were stratified as follows: <35, 35–52 and >52 years. We used SAS survey procedures (version 9.2; SAS Institute Inc.) to analyse the complex sample design and weights in NHANES 2011–2012. In our study, we used 2-years mobile examination centre sample weights for individual probabilities extracted from the blood metals data set and the auditory test data set according to the NHANES analysis tutorial. All of the tests were double sided, with P values < 0·05 as significance threshold.
Results
Basic study subject characteristics
Participant characteristics were shown in Table 1. A total of 1503 adult participants ages 20–69 years had available data for the analysis, 14·17 and 32·27 % had SFHL and HFHL, respectively. In comparison with the controls, patients with hearing impairment were more likely to have diabetes and hypertension. They had significantly higher expose to recreational, occupational and firearm noise. In addition, they were less likely to have a college or above education. Compared with nonsmokers, each level of blood Pb, Cd and Se was seemed to be higher in smokers. No significant differences were found for drinking. Concentrations of Pb and Cd were nearly 1·5–2 folds higher than that of the controls (P < 0·000). Se concentrations were only significantly higher in persons with high-frequency hearing loss (Table 1).
Selected characteristics of study population
(Number and percentages)
The interquartile ranges (IQR) were used to describe continuous variables for their skewed distribution, whereas categorical variables were showed in percentages. BMI: BMI.
* P-values were derived from t tests or Mann–Whitney U tests for continuous variables and χ 2 tests for categorical variables.
Correlation between lead, cadmium and selenium levels and hearing loss risk
Table 2 showed logistic regression results for hearing impairment risk (speech and high frequency) with blood Pb, Cd and Se. We detected a significant positive association between the risk of hearing impairment and elevated Pb and Cd in the covariate-adjusted models. HFHL adjusted OR determined by comparing the highest and lowest blood Pb and Cd quartiles were 1·98 (95 % CI: 1·27, 3·10) and 1·81 (95 % CI: 1·13, 2·90), respectively. SFHL was significant associated with blood Cd with the OR = 2·42 (95 % CI: 1·35, 4·37) for the highest quartiles. There was no significant association between blood Se and hearing loss.
Odds ratio of hearing loss associated with lead, cadmium and selenium levels
(Odd ratios and 95 % confidence intervals)
* Hearing loss was define as pure tone average >25dB.
† SFHL: Speech-frequency hearing loss (0·5, 1, 2 and 4 kHz).
‡ HFHL: High-frequency hearing loss (3, 4 and 6 kHz).
§ Models were adjusted for age, sex, marital status, education, smoking, drinking, BMI, noise exposure, hypertension and diabetes.
|| P for trend were derived using a continuous variable with the median value of each quartile.
Given the evidence that age and sex might be risk factors for hearing loss, we explored the effect modification by age and sex on the relationship between hearing loss and heavy metal concentrations in blood. We detected a significant dose–response relationship between blood lead levels and risk of HFHL in men (HFHL: OR (95 % CI) = 2·53 (1·22, 4·46)), while in females this relationship was not significant (HFHL: OR (95 % CI) = 1·50 (0·55, 4·09)). There was a significant association between blood Cd levels and speech and high frequency hearing loss in women with the OR = 5·30 (95 % CI: 1·42, 19·18) and 4·97 (95 % CI: 1·69, 12·32) for the highest quartiles, respectively (P trend < 0·05). Speech and high-frequency hearing loss were significantly associated with blood Se in men with the OR = 2·94 (95 % CI: 1·27, 6·83) and OR = 2·42 (95 % CI: 1·10, 5·34) for the highest quartile, respectively (Table 3). No significant relationships of blood Se with hearing impairment were detected in women. Table 4 showed the relationships between hearing loss and levels of heavy metals stratified by age. Among middle-aged adults (35 ≤ and ≤ 52), there was a significant relationship between hearing loss risk and blood lead (SFHL: OR (95 % CI) = 4·03 (1·24, 13·07); HFHL: OR (95 % CI) = 2·90 (1·26, 6·68)) and cadmium levels (SFHL: OR (95 % CI) = 7·06 (1·51, 33·01); HFHL: OR (95 % CI) = 4·08 (1·60, 10·38)) concentration. HFHL was marginal and significantly associated with blood Se in young and older adults with the OR = 2·92 (95 % CI: 1·14, 7·52; P trend = 0·061) and OR = 2·00 (95 % CI: 1·00, 4·00; P trend = 0·302) for the highest quartile, respectively.
Odds ratio of hearing loss associated with lead, cadmium and selenium levels stratified by gender
(Odd ratios and 95 % confidence intervals)
* Hearing loss was define as pure tone average >25dB.
† SFHL: Speech-frequency hearing loss (0·5, 1, 2 and 4 kHz).
‡ HFHL: High-frequency hearing loss (3, 4 and 6 kHz).
§ Models were adjusted for age, sex, marital status, education, smoking, drinking, BMI, noise exposure, hypertension and diabetes.
|| P for trend were derived using a continuous variable with the median value of each quartile.
Risk of hearing loss associated with lead, cadmium and selenium levels stratified by age
(Odd ratios and 95 % confidence intervals)
* Hearing loss was define as pure tone average >25dB.
† SFHL: Speech-frequency hearing loss (0·5, 1, 2 and 4 kHz).
‡ HFHL: High-frequency hearing loss (3, 4 and 6 kHz).
§ Models were adjusted for age, sex, marital status, education, smoking, drinking, BMI, noise exposure, hypertension and diabetes.
|| P for trend were derived using a continuous variable with the median value of each quartile.
Discussion
In the general population, Cd exposure is mainly attributed to dietary intake (such as offal, shellfish and vegetables), cigarette smoke and ambient air (especially in urban and industrial areas)(Reference Shargorodsky, Curhan and Henderson19). Although many countries have been greatly reduced the sources of Pb exposure such as gasoline, paint and solder, Pb is still widely used, and its accumulation in the human body can affect the development of chronic diseases(Reference Muntner, Menke and DeSalvo20). There is increasing evidence that Pb and Cd levels in the current environment have adverse effects on various health outcomes, including macular degeneration, renal function and diabetes(Reference Valcke, Ouellet and Dube18,Reference Wu, Schaumberg and Park21,Reference Navas-Acien, Tellez-Plaza and Guallar22) . In a study of 5187 adults in Korea, Choi et al found blood Pb and Cd levels to be linked with hearing loss. Subjects in the highest blood Cd interquartile (1·471–6·422 µg/l) relative to those in the lowest interquartile (0·068–0·689 µg/l) exhibited an OR of 1·47 (95 % CI: 1·05, 2·05) for HFHL with a significant linear trend. Blood Pb levels >2·823 µg/l had a 1·70-fold elevation in their risk of HFHL compared with adults with Pb levels <1·593µg/l(Reference Choi and Park7). Shargorodsky et al. found a similar result(Reference Shargorodsky, Curhan and Henderson19) by investigating 3389 subjects selected from the NHANES 2005–2008 data sets. A blood Pb concentration above or equal to 2 μg/dl significantly increased the risk of high-frequency hearing loss (OR, 2·22; 95 % CI, 1·39, 3·56) compared with a blood Pb concentration below 1 μg/dl. Individuals with the highest quartile of urinary Cd had a significantly higher risk of low-frequency hearing loss than those with the lowest quartile (OR, 3·08; 95 % CI, 1·02, 9·25). However, our present study found no significant relationship between blood Pb levels and hearing loss in women. Additionally, in our research, each level of blood Pb, Cd and Se was seemed to be higher in smokers compared with nonsmokers. The carbon monoxide released from cigarette smoke is considered a potential ototoxin that can shift the hearing threshold. Additionally, cigarette smoke is a resource of Cd pollution, and its ototoxic effect is probably attributed to Cd to some extent, which can be supported by our results.
Food is the main source of Se in the human body; however, the intake of Se in the diet varies widely, depending on the soil on which fodder and crops are grown(Reference Navarro-Alarcon and Cabrera-Vique23). The addition of Se to various dietary supplements is a popular supplement because lack of Se can be harmful to health. The recommended Se intake is 53 μg per day for women and 60 μg per day for men(Reference Rayman11). Studies have shown that both Se excess and deficiency could lead to neurotoxicity. The lack of Se may link to some adverse mood states, such as confusion, anxiety and hostility(Reference Rayman24). In addition, many studies have evaluated the health effects of acute or chronic Se exposure. For instance, a randomised trial of 501 elderly people with low levels of Se found that a low dose of Se supplementation significantly reduced total and non-high-density lipoprotein cholesterol concentrations, whereas the effect was not found to be significant in a high-dose Se supplementation group (300 μg/d)(Reference Rayman, Stranges and Griffin25). Similarly, a large NHANES in USA found that high serum Se concentration contribute to the development of diabetes(Reference Laclaustra, Navas-Acien and Stranges26,Reference Bleys, Navas-Acien and Guallar27) . Taken together, the relationship between the level of Se and health is U-shaped. In a study, Chuang et al. identified an inverse relationship between Se levels and hearing thresholds, suggesting that Se may actually protect hearing(Reference Chuang, Kuo and Chiu13). However, our present study found that blood Se showed a dose-dependent association with speech and high frequency hearing loss in men. These discrepant results may be due to differences in the populations assessed, the study designs, differences in exposure assessments or other possible differences. Further studies with larger sample sizes are therefore needed to confirm our findings.
We found that men, relative to women, were more likely to suffer hearing loss if exposed to high heavy metal levels. One reason for this may be that those middle-aged men are more likely to be exposed to heavy metals because of occupation or smoking(Reference Hecht, Arheart and Lee28,Reference Driscoll, Carey and Peters29) . However, due to factors such as fertility and physiology (menstruation), women are more likely to be deficient in Fe, subsequently Cd absorption is significantly increased under low iron reserves(Reference Berglund, Lindberg and Rahman30). This explains why we only found Cd in women to have a significant impact on hearing.
One major study strength is our large sample size and strong statistical power. Our study examined the relationship between blood Pb, Cd and Se levels and hearing loss in the USA general population, rather than focusing on occupational workers or animals. Importantly, the survey that generated these data was nationally representative, reducing selection bias risks. Trained personnel collected all heavy metal and audiometric data, ensuring no risk of measurement bias. Nevertheless, several limitations in this study should also be considered. First, as this study is cross-sectional, it does not take into consideration time-based relationships between variables, limiting interpretations of causality and warranting further studies to confirm these findings. Second, levels of Pb in participant blood primarily indicate recent exposure and thus may not predict the effect of long-term expose to lead, whereas bone Pb is a superior biomarker of accumulative Pb exposure(Reference Alvarez-Lloret, Lee and Conti31). Third, while we adjusted for as many potential confounding variables as possible, there is still the risk that other factors not considered may have confounded these results. Such possible confounders could include the use of medicines known to be toxic to auditory functions such as aminoglycoside antibiotics, exposure to ototoxic chemicals, genetic variation and use of appropriate hearing protection at work(Reference Morgan, Vuckovic and Krishnamoorthy32–Reference Kros and Steyger34).
In conclusion, our findings are important for public health as they show that decreasing exposure to Pb and Cd in the environment may decrease hearing loss rate. Additionally, our study provides novel evidence suggesting that excessive Se supplement will increase hearing loss risk in men, and further larger cohort studies are warranted to examine this adverse effect.
Acknowledgements
Thanks to Dr. Liegang Liu and Dr. Sijing Chen for modifying our article.
This work was supported by the National Natural Science Foundation of China (Nos. 81771002, 82071057 and 82000988) and Research fund of Wuhan Union hospital (No.02·03·2019–114).
Y. T. and H. X. designed the research; N. W. and H. W. performed the statistical analysis; Y. T. and G. F. wrote the paper; all authors contributed to writing and reviewing the manuscript and read and approved the final manuscript.
The authors declare that they have no competing interests.
