The aim of this study was to determine in an empirical manner whether the phenomenon of hearing loss due to the exposure to volatile organic solvents was present in the gasification plants of a petrochemical factory. The experimental groups included unexposed (N=20) workers, workers (N=20) exposed to noise and workers (N=19) exposed to noise and volatile organic solvents. The following assessments were made: diagnostic audiometry for the assessment of hearing thresholds; biological monitoring of ortho-cresol and hippuric acid for the biological markers of toluene; passive air sampling and noise measurements. Questionnaires were completed by the three groups to collect information about age, ethnicity, smoking habits, alcohol consumption and work history regarding the exposure to ototoxic substances as well as the period of employment. There were no statistically significant differences between the average ages of the three groups, but more of the workers in the noise group were from a higher age group. This age composition and the work history of the noise group were considered as possible influences on the results of this hearing study. The results of the passive air sampling show that the levels of volatile organic solvents were lower than the occupational exposure limits on the day of sampling. The biological monitoring shows that the markers, namely hippuric acid and o-cresol, were lower than the biological exposure indices. The noise group was exposed to sound pressure levels of 79-90 dB(A) and the noise + hydrocarbon group to levels of 85-88 dB(A). The average hearing thresholds of the noise group were at most of the frequencies (0.5-8 kHz) significantly higher (p≤0,05) than that of the noise + hydrocarbon group. The average hearing thresholds of the control group were overall lower than the noise group's hearing thresholds, but on average a little higher than the noise + hydrocarbon group's hearing thresholds. No relationship was found in this study between the exposure to volatile organic solvents (for example toluene that was used as marker in this study) and the elevation of hearing thresholds of workers at the gasification plants of the petrochemical factory. / Thesis (M.Sc.)--North-West University, Potchefstroom Campus, 2004.

Background: Many well-known pharmacologic agents have been shown to have toxic effects to the cochleo-vestibular system. Examples of such ototoxic agents include cisplatin and aminoglycoside antibiotics. Ototoxicity monitoring consists of a comprehensive pattern of audiological assessments designed to detect the onset of any hearing loss. Three main methods have emerged over the past decade, and include the basic audiological assessment, extended high frequency (EHF) audiometry, and otoacoustic emission (OAE) measurement. These measures can be used separately or in combination, depending on clinical purpose and patient considerations. It is suggested by the American Academy of Audiology Position Statement and Clinical Practice Guidelines: Ototoxicity Monitoring, that baseline testing be done in a fairly comprehensive manner, including pure-tone thresholds in both the conventional- and extended high frequency ranges, tympanometry, speech audiometry, and the testing of OAEs (AAA, 2009). Anecdotal evidence suggests that New Zealand Audiologists do not currently follow a national ototoxicity monitoring protocol. Therefore the main aim of this study was to explore the current status of ototoxicity monitoring within New Zealand. Hypothesis: It was hypothesized that hospital based Audiology departments across New Zealand each followed their own internal ototoxicity monitoring protocol based, to a large extent, on the guidelines proposed by the American Academy of Audiology and by the American Speech-Language-Hearing Association. Method: Through the use of a Telephone Interview Questionnaire, 16 charge Audiologists were interviewed to establish their current state of knowledge regarding ototoxicity monitoring at 16 out of 20 district health boards in New Zealand. Enquiries about the current systems and procedures in place at their departments together with any suggestions and recommendations to improve on these systems were made. Results: This study found that only 9 of the 16 DHBs interviewed currently follow an ototoxicity monitoring protocol. Furthermore, other than initially hypothesized the origin of the protocols followed by the remaining 7 departments were reported to have ranged from independently developed protocols to historically adopted protocols. One department implemented an adapted version of a protocol by Fausti et al. (Ear and Hearing 1999; 20(6):497-505). This diversity in origin however, does confirm our initial suspicion that no universal and standardized monitoring protocol is currently being followed by Audiologists working in the public health sector of New Zealand.

The aim of this study was to determine in an empirical manner whether the phenomenon of hearing loss due to the exposure to volatile organic solvents was present in the gasification plants of a petrochemical factory. The experimental groups included unexposed (N=20) workers, workers (N=20) exposed to noise and workers (N=19) exposed to noise and volatile organic solvents. The following assessments were made: diagnostic audiometry for the assessment of hearing thresholds; biological monitoring of ortho-cresol and hippuric acid for the biological markers of toluene; passive air sampling and noise measurements. Questionnaires were completed by the three groups to collect information about age, ethnicity, smoking habits, alcohol consumption and work history regarding the exposure to ototoxic substances as well as the period of employment. There were no statistically significant differences between the average ages of the three groups, but more of the workers in the noise group were from a higher age group. This age composition and the work history of the noise group were considered as possible influences on the results of this hearing study. The results of the passive air sampling show that the levels of volatile organic solvents were lower than the occupational exposure limits on the day of sampling. The biological monitoring shows that the markers, namely hippuric acid and o-cresol, were lower than the biological exposure indices. The noise group was exposed to sound pressure levels of 79-90 dB(A) and the noise + hydrocarbon group to levels of 85-88 dB(A). The average hearing thresholds of the noise group were at most of the frequencies (0.5-8 kHz) significantly higher (p≤0,05) than that of the noise + hydrocarbon group. The average hearing thresholds of the control group were overall lower than the noise group's hearing thresholds, but on average a little higher than the noise + hydrocarbon group's hearing thresholds. No relationship was found in this study between the exposure to volatile organic solvents (for example toluene that was used as marker in this study) and the elevation of hearing thresholds of workers at the gasification plants of the petrochemical factory. / Thesis (M.Sc.)--North-West University, Potchefstroom Campus, 2004.

Hearing loss or deafness, in its most serious form, affects an estimated 28 million people in America. One of the forms of hearing loss, known as ototoxicity, refers to damage to the ear (-oto) due to xenobiotics. Cisplatin is the most widely used antineoplastic agent in the treatment of various solid tumors. Cisplatin toxicity can lead to severe effects on the kidneys, nervous system and auditory system which significantly reduce the quality of life of cancer patients. While nephrotoxicity could be alleviated by hydration and diuresis, cisplatin-induced ototoxicity is permanent and there is currently no approved treatment for this condition. Previous studies have shown that the generation of reactive oxygen species (ROS) is a critical event that initiates damage to the outer hair cells (OHCs), stria vascularis (SVA) and spiral ganglion cells (SG) of the cochlea, leading to hearing loss after cisplatin treatment. However, the mechanism(s) underlying the transition from ROS generation to the manifestation of ototoxicity is (are) not clearly defined. Recent studies have also implicated inflammatory pathways in cisplatin-induced cell death. Various transcription factors have been linked to the induction of inflammation mediated by cisplatin in the cochlea. Recent study demonstrate that cisplatin activates signal transducer and activator of transcription 1 (STAT1) a transcription factor implicated in inflammation, which mediates damage to utricular hair cell and could also confer cisplatin-induced hearing loss. The aim of this study is to further define a role of STAT1 in cochlear inflammation and in cisplatin-mediated ototoxicity. Based on preliminary data, we hypothesize that STAT1 plays an integral role in cisplatin-mediated inflammation and hearing loss. Our data show that STAT1 couples ROS to the inflammatory process in the cochlea. The major source of ROS appears to be the NOX3 NADPH oxidase system, knockdown of which by short interfering (si)RNA reduces STAT1 activation by cisplatin and alleviates hearing loss. Activation of STAT1 by cisplatin involves phosphorylation of Serine 727 by mitogen activated protein kinases such as extracellular signal regulated kinase (ERK) 1/2 and p38. Knockdown of STAT1 by trans-tympanic administration of siRNA reduces damage to OHCs and protects against cisplatin-induced hearing loss in rats. STAT1 siRNA attenuates the production of inflammatory mediators, such as tumor necrosis factor- α (TNF-α), and reduces the recruitment of inflammatory cells to the cochlea. Furthermore, inhibition of TNF-α by trans-tympanic administration of etanercept, a clinically used TNF-α antagonist, protects against OHC damage and cisplatin-induced hearing loss. These data suggest that targeting STAT1 or the inflammatory genes it regulates could serve as useful strategies for preventing cisplatin-induced hearing loss and improve the overall quality of life of cancer patients.

Cisplatin is a widely used chemotherapeutic drug for the treatment of solid tumors. However, the drug accumulates in the cochlea, and damages inner ear structures, resulting in bilateral andpermanent hearing loss. Previous data from our laboratory indicate that activation of the transient receptor potential vanilloid 1 (TRPV1) receptor (by capsaicin) increases the NOX3 isoform of NADPH oxidase, leading to the generation of reactive oxygen species (ROS) in the cochlea, transient cochlear inflammation and transient hearing loss. We also demonstrated that the transient inflammation was produced by ROS-mediated activation of signal transducer and activator of transcription 1 (STAT1). Surprisingly, over time, this response desensitizes and capsaicin was subsequently able to protect against cisplatin ototoxicity. The goal of this study was to determine the mechanism of otoprotection against cisplatin ototoxicity following the administration of capsaicin. For this study we utilize both an immortalized organ of Corti outer hair cells and rat cochlea. Capsaicin (2.5 µM) increased both Ser727 p-STAT1 and Tyr705 p-STAT3 implicating its role in inflammation. Expression of cannabinoid receptors were observed in UB/OC-1 cells as well as rat outer hair cells (OHCs). However, inhibition of CB2 receptors (by AM630) reduced capsaicin-mediated Tyr705 p-STAT3, but had little effect on Ser727 STAT1. Capsaicin protected UB/OC-1 cells against cisplatin-induced apoptosis. This protection was reversed by CB2 antagonist but potentiated by TRPV1 inhibition. Significant cell death was observed following treatment of UB/OC-1 cells with AM630 alone, underscoring the importance of CB2 receptors in survival of these cells. CB2 agonist, JWH, significantly increased the protective signal, STAT3. Furthermore, capsaicin-mediated protection was reversed by the inhibition of STAT3, implicating STAT3 in otoprotection. In animal studies, oral administration of capsaicin (0.5% solution) induced transient inflammation but led to a long term recovery. Animals pre-treated with oral capsaicin were protected against cisplatin-induced hearing loss as compared to vehicle-treated animals, suggesting protection against hearing loss. Capsaicin increased the expression of both CB1 and CB2 receptors in the organ of Corti, which might confer the long term protective actions of this agent against hearing loss. In rats pretreated with AM630, the protective action of capsaicin was abolished. We conclude that otoprotection mediated by capsaicin is produced by activation of CB receptors in the cochlea which are coupled to both STAT1 and STAT3 activation. However, our data support the conclusion that activation of STAT3 confers the otoprotective action of capsaicin. In contrast, activation of STAT1 by capsaicin could contribute to the transient inflammatory response previously observed in vivo. The net protective action of capsaicin could result from an increase in the STAT3/STAT1 ratio of cells in the cochlea, which antagonizes the ability of cisplatin lower this ratio and promote cell death.

Cisplatin is a commonly used chemotherapeutic agent for multiple solid tumors. However, cisplatin-induced neurotoxicity, nephrotoxicity and hearing loss hamper its use in clinical setting. Although, neurotoxicity and nephrotoxicity can be prevented, there is no cure for cisplatin-induced hearing loss. Cisplatin-induced hearing loss results from damage to outer hair cells (OHCs) in basal turn of the cochlea, to spiral ganglion neurons (SGN), stria vascularis (SV) and fibrocytes of spiral ligament (SL). At the cellular level, cisplatin produces profound increases in reactive oxygen species (ROS) that stimulate cell signaling pathways leading to cochlear inflammation, apoptosis and permanent hearing loss. Thus, potential otoprotective drugs should target oxidative stress and inflammatory mechanisms without interfering with cisplatin chemotherapeutic efficacy. In this study, I characterized the otoprotective actions of the green tea extract, epigallocatechin 3-gallate (EGCG), which possesses anti-oxidant, anti-inflammatory and anti-tumor properties. Oral administration of EGCG to male Wistar rats reduced cisplatin-induced hearing loss, assessed by auditory brainstem responses. These changes were associated with a reduction in cisplatin-induced loss of OHCs primarily in the basal region of the cochlea, along with reduced oxidative stress, inflammatory and apoptotic markers. In addition, EGCG protected against cisplatin-induced decrease in inner hair cell (IHCs) ribbon synapses, labeled with CtBP2. EGCG also protected against cisplatin-induced loss of Na+/K+ ATPase α1 immunoreactivity in the stria vascularis and spiral ligament. In vitro studies using University Bristol/Organ of Corti-1 (UB/OC-1) cells showed that EGCG reduced cisplatin-induced ROS generation and the activation of ERK and STAT1, while it preserved the activity of STAT3 and levels of Bcl-xL. Moreover, EGCG suppressed oxidative stress, inflammatory and apoptotic markers in cisplatin-treated UB/OC-1 cells. Co-administration of EGCG did not alter cisplatin-induced apoptosis of human-derived head and neck cancer cells, ovarian cancer cells or colon cancer cells. In studies using a xenograft model of head and neck cancer in severe combined immunodeficient (SCID) mice, I showed that EGCG did not interfere with cisplatin chemotherapeutic efficacy. These data suggest that EGCG is a potential otoprotective agent for treating cisplatin-induced hearing loss without compromising its chemotherapeutic efficacy.

Background: Fourteen thousand (14, 000) people fell ill with Multi-Drug Resistant (MDR) or Rifampicin-Resistant (RR) Tuberculosis (TB) in South Africa (SA) in 2019. Aminoglycosides, which are commonly used anti-tuberculosis drugs in the treatment for RR/MDR-TB patients, are associated with ototoxicity (cochlear or vestibular). Aminoglycoside-induced cochleotoxicity is characterised by permanent, bilateral, highfrequency (HF) sensorineural hearing loss (SNHL). The impact of hearing loss (HL) due to aminoglycoside-induced cochleotoxicity can influence a patient's communication, psychological, physical functioning and overall well-being negatively and lead to a reduced quality of life (QoL). To reduce the risk of aminoglycoside-induced cochleotoxicity, patients' hearing thresholds are monitored (i.e., cochleotoxicity monitoring) when they are being treated with cochleotoxic aminoglycosides. Cochleotoxicity monitoring is performed to detect a significant threshold shift (STS) early and prevent further deterioration of hearing thresholds and avoid hearing loss which may end up affecting frequencies that are important for speech perception. When a STS or hearing loss is detected during cochleotoxicity monitoring, there are various intervention strategies that can be implemented by the treating medical personnel to avoid further deterioration of patient's hearing thresholds. These strategies may include discontinuing the aminoglycoside, changing the aminoglycoside to a less cochleotoxic alternative in the regimen or changing the frequency of administration of the aminoglycoside. This study, therefore, aimed to determine the effectiveness of different strategies used when a STS in hearing occurred during cochleotoxicity monitoring to prevent further deterioration in hearing thresholds. Methodology: A descriptive prospective repeated-measures design was used in this study. Patients who underwent RR/MDR-TB treatment with Kanamycin, a cochleotoxic aminoglycoside, at Brooklyn Chest Tuberculosis Hospital (BCH) between June to December 2016 were recruited to participate in the study. Only patients (n= 69) with normal hearing thresholds (i.e., pure tone average (PTA) at 500 Hz, 1 kHz and 2 kHz ≤ 25 dB HL) at baseline and age 18 – 55 years were included. Patients who were receiving two aminoglycosides, were retreatment patients or had active middle ear (ME) pathology were excluded from this study. Participants were sampled via a purposive sampling strategy. All audiological testing was performed in a sound-treated booth and participants underwent the following types of assessment; baseline, periodic monitoring, and diagnostic assessment (when indicated). The following tests were performed at baseline: case history, otoscopy (OT), tympanometry (TYMP), conventional pure tone audiometry (cPTA) including air conduction (AC) and bone conduction (BC), and ultra-high frequency audiometry (UHFA). Follow-up monitoring assessment occurred monthly if there was no significant change in hearing thresholds, and biweekly if an STS was detected. The ASHA criteria were used to determine STS. The degree of hearing loss was described as mild, moderate, moderately-severe, severe or profound and the type of hearing loss was either conductive, sensorineural, or mixed. Both descriptive and inferential (Chi-squared, Mann-Whitney U and Kruskal-Wallis) statistical tests were used for data analysis. Results: A total of sixty-nine (69) patients who were undergoing treatment for RR/MDR-TB were recruited to participate in this study. Five participants dropped out of the study due to various reasons, therefore, leaving 64 participants in the study. There was 38 males and 26 females. The median age was 31 [range; 18 - 55] years old. An aminoglycoside-induced cochleotoxicity incidence of 90.6% (58/64) was found in this study. There were no statistically significant associations between the occurrence of STS and age (p = 0.487), sex (p = 0.329) and HIV status (p = 0.764). Three types of intervention strategies were used when a participant experienced an STS: (i) discontinue Kanamycin (Strategy A), (ii) modify the frequency of Kanamycin administration (Strategy B), (iii) and leave the regimen unchanged, i.e., no intervention (Strategy C). A smaller proportion of participants, 12 out of 33, experienced further deterioration of hearing thresholds after intervention strategy A (discontinue Kanamycin) was used, when compared to participants who underwent intervention strategies B and C, but the difference was not statistically significant (p = 0.056). Conclusion: This study found a high incidence of cochleotoxicity among patients receiving Kanamycin treatment for RR/MDR-TB. The results showed that discontinuing Kanamycin led to fewer participants developing further deterioration of hearing thresholds, although not statistically significant. There were no statistically significant associations between the occurrence of STS and age, sex, and HIV status. This study had some limitations; only cochlear hearing loss was investigated, participants were not followed up beyond six months, and genetic testing was not performed. Nonetheless, this study revealed that fewer participants had further significant threshold shifts after discontinuing Kanamycin, and for those patients who still receive regimens containing aminoglycosides, these findings are relevant.

Magister Public Health - MPH / Ototoxic induced hearing loss is a common adverse event related to aminoglycosides used in Multi Drug Resistant -Tuberculosis treatment. Exposure to ototoxic drugs damages the structures of the inner ear. Symptomatic hearing loss presents as tinnitus, decreased hearing, a blocked sensation, difficulty understanding speech, and perception of fluctuating hearing, dizziness and hyperacusis/recruitment. The World Health Organization (1995) indicated that most cases of ototoxic hearing loss globally could be attributed to treatment with aminoglycosides. The aim of the study was to determine the proportion of DR-TB patients initiated on treatment at three decentralized sites during a defined period (1st October to 31st December 2015) who developed ototoxic induced hearing loss and the corresponding risk factors, whilst receiving audiological monitoring with an extended high frequency audiometer (KUDUwave). A retrospective cross-sectional study was conducted. Cumulatively across the three decentralized sites, 69 patient records were reviewed that met the inclusion criteria of the study. The mean age of the patients was 36.1, with a standard deviation (SD) of 10.7 years; more than half (37) were female. Ototoxicity , a threshold shift, placing patients at risk of developing a hearing loss was detected in 56.5% (n=39)of patients and not detected in 30.4%(n=21).The remaining 13,1% (n=9)is missing data. As a result, the regimen was adjusted in 36.2% of patients. . From the 53 patients who were tested for hearing loss post completion of the injectable phase of treatment, 22.6% (n=12) had normal hearing, 17.0 % (n=9) had unilateral hearing loss, and 60.4% (n=32) had bilateral hearing loss. Therefore, a total of 41 patients had a degree of hearing loss: over 30% (n=22)had mild to moderate hearing loss, and only about 15% (n=11)had severe to profound hearing loss. Analysis of risk factors showed that having ototoxicity detected and not adjusting regimen significantly increases the risk of patients developing a hearing loss. The key findings of the study have shown that a significant proportion of DR-TB patients receiving an aminoglycoside based regimen are at risk of developing ototoxic induced hearing loss, despite receiving audiological monitoring with an extended high frequency audiometer that allows for early detection of ototoxicity (threshold shift).

Cisplatin is a potent chemotherapeutic agent that is commonly used to treat a wide variety of tumours. Although highly effective, its administration is complicated by its ototoxic effect, a well known side effect that occurs in a significant number of patients. The hearing loss observed is typically irreversible, progressive, bilateral, high-frequency sensorineural hearing loss associated with tinnitus. At present there is no approved method for protecting or remedying against deterioration of hearing status, therefore, the detection and appropriate management of cisplatin-induced ototoxicity is reliant on effective audiological monitoring. The present study aimed to investigate the prevalence of ototoxicity in head and neck oncology patients who received cisplatin in combination with cranial irradiation. In addition, the study also aimed to examine the current state of audiological monitoring for this population at Christchurch Hospital. Post-treatment diagnostic audiological assessments were performed for 23 participants. The post-treatment assessment battery included case history, standard pure-tone audiometry (0.25 – 8 kHz), extended high-frequency audiometry (9 – 16 kHz), speech audiometry, tympanometry, acoustic reflexes and distortion product otoacoustic emissions. Prior to the assessments, a search of the Christchurch Audiology and Ear, Nose and Throat (ENT) Department oncology audiogram files was undertaken to match any previous audiograms to participating individuals. The results showed that pre-treatment assessment had been performed for 16 of the 23 participants. Of those 16, 15 participants experienced a significant cochleotoxic change in their hearing thresholds according to the ASHA criteria. One participant only received one dose of cisplatin due to deteriorating hearing, while one other participant elected to stop cisplatin treatment after the first dose due to a significant increase in tinnitus severity. Ototoxicity resulting from cisplatin chemotherapy constitutes a significant clinical problem that may have serious vocational, educational, and social consequences. Findings from this study highlight the importance of effective audiological monitoring for the timely detection and appropriate management of cisplatin-induced ototoxicity.

Clinical ototoxicity - permanent hearing loss caused by medications - is estimated to affect millions of patients annually. Two classes of drug are largely to blame: platinum-based chemotherapeutics, primarily cisplatin, and aminoglycoside antibiotics. Development of methods to prevent ototoxicity depends upon an understanding of its mechanisms and may benefit from an understanding of native protective pathways of the inner ear. As the mechanisms behind cisplatin ototoxicity remain unclear, I first sought, and herein report, a refined mouse model of cisplatin ototoxicity which will allow for further in vivo investigation of cisplatin ototoxicity and potential methods for its prevention. This low-dose, multi-cycle model was found to accurately reproduce cisplatin ototoxicity as it has been described clinically and histopathologically. I then used this mouse model of cisplatin ototoxicity to investigate cisplatin pharmacokinetics in the cochlea and their role in driving cisplatin ototoxicity. Cisplatin was found to be retained within the cochlea for months following its administration. This initial finding in mice was extended to cochlear tissue samples from deceased human patients. Analysis of intra-cochlear cisplatin distribution in murine and human tissue identified the stria vascularis region of the cochlea as a promising target for intervention. With the nature of aminoglycoside ototoxicity better understood, I investigated a native inner ear protective pathway which could be leveraged to promote sensory hair cell survival. The improved hair cell survival that has previously been demonstrated as a result of heat stress was found to be mediated by cell-cell communication via extracellular vesicles. Further, hair cell protection against aminoglycosides could be reproduced through the application of exogenous, non-inner ear-derived extracellular vesicles. In sum, these data provide new insight into mechanisms of ototoxicity and details of cellular pathways which can help protect against it.