A systematic review of mercury ototoxicity

Mercury is neurotoxic, and numerous studies have confirmed its ototoxic effect. However, the diagnosis and follow-up of mercury exposure require understanding the pathophysiology of the chemical substance. Based on a systematic literature review, this study aimed to demonstrate whether mercury is ototoxic and to analyze its mechanism of action on the peripheral and central auditory system, in order to contribute to the diagnosis and follow-up of exposure. This was a systematic review of studies published on the effects of mercury exposure on the auditory system. The full text of the studies and their methodological quality were analyzed. The review identified 108 studies published on the theme, of which 28 met the inclusion criteria. All the articles in the analysis showed that mercury exposure is ototoxic and produces peripheral and/or central damage. Acute and long-term exposure produces irreversible damage to the central auditory system. Biomarkers were unable to predict the relationship between degree of mercury poisoning and degree of lesion in the auditory system. Mercury; Toxicity; Hearing; Dizziness Introduction Environmental contamination with persistent pollutants showing toxic and cumulative effects on organisms, as in the case of mercury (Hg), has reached global proportions due to the persistence and mobility of these substances 1. Various studies 2,3,4,5 have corroborated the Minamata findings, indicating that mercury exposure results in a series of neurotological alterations 6,7,8,9,10. The principal complaints by patients are dizziness and hearing loss. Each ototoxic agent has its own mode of action on the various organ systems, and diagnosis of the lesion site can vary according to time and degree of exposure. Independently, the consequences of hearing loss can be irreversible, with clinical alterations that often go undetected by neurological examination and biological markers, thus jeopardizing the quality of life of these individuals. Since mercury is known to be neurotoxic, many studies have focused only on the central auditory system. However, other studies have shown that acute or chronic exposure to mercury generates alterations in both the peripheral and/ or central auditory systems 11,12,13,14. Follow-up of ototoxicity is important for detecting hearing changes involving chemical substances, thereby suggesting new treatment strategies for the patient and phonoaudiological intervention when a disabling hearing impairREVISÃO REVIEW Hoshino ACH et al. 1240 Cad. Saúde Pública, Rio de Janeiro, 28(7):1239-1247, jul, 2012 ment occurs 15. Murata et al. 16 demonstrated that the persistence of prolonged I-III inter-peak latencies during childhood, indicating that intrauterine mercury exposure causes irreversible neurotoxic lesions. Interdisciplinary studies as in the case of Audiology and Clinical Toxicology are extremely rich and complex, thus justifying the current study as an important tool for organizing and summarizing similar primary studies for decision-making on therapeutic and preventive measures in the environmental and health field for populations exposed to mercury. Based on a systematic review, the study aimed to show whether mercury is ototoxic, and if so, to elucidate its action on the peripheral and central auditory system.


Introduction
Environmental contamination with persistent pollutants showing toxic and cumulative effects on organisms, as in the case of mercury (Hg), has reached global proportions due to the persistence and mobility of these substances 1 .Various studies 2,3,4,5 have corroborated the Minamata findings, indicating that mercury exposure results in a series of neurotological alterations 6,7,8,9,10 .The principal complaints by patients are dizziness and hearing loss.
Each ototoxic agent has its own mode of action on the various organ systems, and diagnosis of the lesion site can vary according to time and degree of exposure.Independently, the consequences of hearing loss can be irreversible, with clinical alterations that often go undetected by neurological examination and biological markers, thus jeopardizing the quality of life of these individuals.Since mercury is known to be neurotoxic, many studies have focused only on the central auditory system.However, other studies have shown that acute or chronic exposure to mercury generates alterations in both the peripheral and/ or central auditory systems 11,12,13,14 .
Follow-up of ototoxicity is important for detecting hearing changes involving chemical substances, thereby suggesting new treatment strategies for the patient and phonoaudiological intervention when a disabling hearing impair-REVISÃO REVIEW ment occurs 15 .Murata et al. 16 demonstrated that the persistence of prolonged I-III inter-peak latencies during childhood, indicating that intrauterine mercury exposure causes irreversible neurotoxic lesions.
Interdisciplinary studies as in the case of Audiology and Clinical Toxicology are extremely rich and complex, thus justifying the current study as an important tool for organizing and summarizing similar primary studies for decision-making on therapeutic and preventive measures in the environmental and health field for populations exposed to mercury.
Based on a systematic review, the study aimed to show whether mercury is ototoxic, and if so, to elucidate its action on the peripheral and central auditory system.

Methodology
A systematic review was performed, including studies on the effects of mercury exposure on the peripheral and/or central auditory system, published from January 1966 to April 2011, the period covered by the set of selected databases.
The review of the studies focused on the following questions: "Did the studies demonstrate that mercury is ototoxic?","In the case of confirmed ototoxicity, which area was injured?", and "Is it possible to relate the degree of mercury poisoning or exposure time to the results of the hearing tests?"

Inclusion and exclusion criteria
The inclusion criteria were: original articles and Master's and Doctoral theses published from 1966 to 2011 in Portuguese, English, French, or Spanish, on the acute or chronic effects of mercury on the peripheral and/or central auditory pathways in humans or laboratory animals.The study excluded review articles, editorials, case reports, and articles that related auditory alterations to noise rather than mercury exposure or auditory alterations to mercury exposure and other chemical substances concurrently.

Research strategy
The study covered the following databases: MEDLINE, from January 1966 to March 2011; LILACS, from January 1982 to March 2011; SciELO, from January 1997 to March 2011; Web of Science; and Science Direct.Electronic and manual searches were also performed for the references cited in the selected articles; in websites related to the theme, like Excerpta Medica online (EMBASE), Grey Literature, ATSDR, and SINITOX, and in thesis/dissertation databases at the University of São Paulo (USP), Oswaldo Cruz Institute/Fiocruz, and Institute of Studies in Collective Health (IESC/UFRJ).The descriptors, combined with the descriptor "mercury", were: "hearing", "hearing loss", "hearing disorders", "dizziness", and "postural balance".The search for the descriptors covered the full text and title.
All the studies selected in the database using the descriptors were classified according to the inclusion criteria through their abstracts.The full texts of the studies were analyzed and their data were keyed in to a previously established protocol containing data on the variables corresponding to the eligibility criteria for the individuals involved in the studies (age, sex, occupation), type of study (cross-sectional, cohort, case-control), exposure (chronic or acute), number of individuals in the study, presence of control groups, use of biomarkers, type of evaluation performed in the study (questionnaires, audiometry, evoked potential, cognitive tests, and others), and the conclusions' consistency with the findings.The studies were analyzed by two independent reviewers.
The studies' methodological quality was classified in a table adapted from the Cochrane Collaboration quality assessment 17 concerning the risk of bias.Eight items were analyzed: specification of inclusion criteria, presence of justification for the sample size, presence of a control group, absence of bias (selection, measurement, and loss-to-follow-up), quality of the evaluation performed to investigate the auditory pathways, exposure only to mercury, presence of biomarker, and conclusions consistent with the findings.Each of these questions was answered with Yes, No, and Not Informed.

Results and discussion
The electronic database searches identified 108 articles published on the theme.Initially, based on reading the article abstracts, 85 articles were excluded because they were literature reviews, articles in foreign languages that failed to meet the inclusion criteria, case reports, and articles that were not associated with the research topic.The other 23 articles were analyzed using the full text.The manual search for references cited in the articles identified five additional articles that met the inclusion criteria (Figure 1).
The search of thesis/dissertation databases at USP, Oswaldo Cruz Institute/Fiocruz, and IESC/ UFRJ identified only two Master's theses, which were not included because one investigated both mercury and factory noise, while the other had already been identified in the electronic search, in the form of an original article.
Twenty-eight studies met the inclusion criteria, of which 16 had been conducted in humans (Table 1), ten in animals (Table 2), and two in in vitro cells (Table 3).Table 4 describes the methodological quality of the selected articles.
Among the 16 studies in humans, only two were case-controls, while the others were descriptive.Ten conducted some type of audiologic evaluation, of which five also performed the biomarker test and the other five confirmed the relationship between exposure and auditory alteration using questionnaires and/or databases.Two studies did not perform audiologic evaluations, presented data on biomarkers, and confirmed the relationship between exposure and altered hearing by means of questionnaires and/ or databases.Four did not perform audiologic evaluations or biomarker tests, confirming the relationship between exposure and symptoms by means of questionnaires and/or databases.All the articles stated that mercury is ototoxic.Only one reported a relationship between exposure time or the degree of mercury poisoning and auditory alterations found in the study.Six reported that the lesion occurred in the central auditory system (five based on brainstem auditory evoked potential, or BAEP, and one on central auditory processing, or CAP), three in both the central and peripheral regions (tone audiometry with BAEP/ CAP/otoneurological evaluation), one in the peripheral region (high-frequency audiometry), and six failed to report the lesion site.
In Brazil, the industrialization process generates growing amounts of waste that can lead to environmental problems if not adequately disposed of or stored.Lacerda & Marin (1997, apud Azevedo & Chasin 18 ) estimate mercury emissions in Brazil at 116 tons/year, with various industrial sectors contributing to the emissions: chlor-alkali (10.1%), paint, electric-electronic appliances, and energy (petroleum) (< 5%), zinc, lead, and cadmium metallurgy (3.9%), iron and steel (10.4%), burning of natural plant material (7.5%), and gold mining (67.3%).Technological innovation has helped decrease the burden of contamination for workers, but it has created new risks, not only for workers but for the overall population as well.In this systematic review, only three studies assessed the conditions involved in occupational exposure.
Only two studies specified the age bracket, evaluating vulnerable populations in greater detail, such as pregnant women, newborns, children, and elderly.Importantly, mercury crosses the placenta and methyl-mercury is actively transferred to the fetus 19,20,21 .The consumption of fish contaminated with mercury leads to a series of neurotoxic effects observed in the pregnant woman, fetus, and newborn, especially when the latter is exposed during development of the central nervous system 19,22,23 .
Early childhood years are critical for the development of auditory and language skills and mark the maturation of the central auditory system.No study described the consequences of hearing loss for the quality of life of these individuals.Even the two articles that reported alterations in central auditory processing did not elaborate a questionnaire or tool to assess the impact of hearing loss.
All ten studies in animals were descriptive and performed audiologic evaluations or autopsies.All reported that mercury is ototoxic.Six related time of exposure or degree of mercury poisoning to auditory alterations.Four reported that the lesion occurred in the central auditory system (BAEP), one in the peripheral and central regions (audiometry and BAEP), four in the peripheral region (high-frequency audiometry), and only one found a result within normalcy, since the study's objective was to demonstrate that 4mg/m3Hg 0 was not toxic to rats, although the authors reported that mercury is ototoxic at other doses.The first studies in animals were performed to determine the pathophysiology of mercury poisoning, while the more recent studies approach issues such as the effects of mercury on animals exposed during gestation and in early life, comparing the experimental doses with those from chronic exposure in humans in contaminated areas or doses received by children, as in the case of cinnabar (a pediatric anesthetic).
It would certainly be difficult to conduct a study in pregnant women, newborns, or children to evaluate the time and degree of exposure and the consequences, but excluding the fact that it is difficult to systematize a sample of this population for the factors age, time of exposure, and degree of poisoning, studies have already shown the effects of mercury in humans at these ages, and there are still occupationally and environmentally exposed populations that could help elucidate this entire picture.Such studies provide important information, for example, about the ages at which mercury exposure is more or Cad. Saúde Pública, Rio de Janeiro, 28 (7):1239-1247, jul, 2012 less aggressive to the central auditory system and the relationship between this factor and time of exposure or the exposure dose.
A study using in vitro cells concluded that chronic (as compared to acute) exposure presents a more toxic effect on the auditory nervous system, and that the doses used in the study were within the range of doses for human exposure.The second article analyzed the effect of mercury on the potassium currents in the external ciliated cells of the cochlea, demonstrating metabolic alterations in this system that can lead to hearing loss.Such studies are important for understanding mercury's pathophysiology in the peripheral and central auditory system, allowing therapeutic and/or preventive management.
The toxic effects of mercury on hearing have been studied for years and are still the object of investigation.This clearly demonstrates that mercury exposure is still a current problem and that its environmental liability will have consequences for many future generations.It has also been shown that the lesion occurs in both the central and peripheral auditory system, thus highlighting the need for further research in this area, assessing the consequences for the quality of life in the exposed population.The great majority of studies focused on only one type of test.In this case, the conclusions focused only on the type of procedure used for the peripheral or central evaluation of the auditory system.The use of combined procedures can increase the diagnostic precision of the lesion site, as in the case of two articles on humans 7,24,25 and one on animals 26 which performed audiometry together with BAEP or otoneurological evaluation, identifying peripheral and central alterations as the outcome.
Acute and long-term mercury exposure produces alterations in the peripheral and/or central auditory system 11,12,13,14 .Huang et al. 11,12,13 and Chuu et al. 14 suggest that the metabolic alterations in the central auditory system (Na(+)/K(+) -ATPase) may be responsible for the mechanism of the lesion.With current technological advances, new diagnostic equipment has been developed, thereby creating new fields of research and providing a better understanding of hearing.One can thus suggest further research focusing on the effect of activation of the efferent auditory system on otoacoustic emissions (suppression) that evaluate the central auditory system, together with cochlear function 27 .
In all, 26 articles were published in English and two in Portuguese, while 19 investigated the biomarker.

Conclusion
All the articles analyzed here showed that mercury exposure is ototoxic, inducing peripheral and/or central hearing loss.It is a consensus in the literature that acute and long-term exposure produces irreversible damage to the central auditory system.Measuring mercury levels with biomarkers was unable to predict the relationship between the degree of mercury poisoning and the degree of damage to the auditory system.
With technological development, new fields of research have been created, but they have scarcely been explored by Clinical Toxicology.It is important to raise awareness in the overall population and define the control of exposure to chemical agents as a public health priority.

Figure 1 Description
Figure 1Description of studies found in the databases.
Table1Description of 16 articles on the relationship between mercury exposure and hearing in humans, selected for the systematic review.

Table 2
Description of 10 articles on the relationship between mercury exposure and hearing in animals, selected for the systematic review.

Table 3
Description of two articles on the relationship between mercury exposure and hearing in experimental studies, selected for the systematic review.

Table 4
Qualitative description of studies on mercury exposure and hearing, selected for the systematic review.