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Ethical considerations in noise-induced hearing loss research
Comment
Ethical considerations in noise-induced hearing loss research federal agencies in the USA, including the National Institute for Occupational Safety and Health and the Occupational Safety and Health Administration.8 Animal studies have shown that noise exposure can lead to synaptic degeneration between the primary cochlear neurons and the sensory cells even when hair cells remain functional and hearing thresholds recover.9 This cochlear synaptopathy has remained hidden for so many years for three reasons: (1) it is not visible in routine histological material, (2) the eventual loss of spiral ganglion cells is extremely slow,10 and (3) measures of hearing thresholds (audiograms) are not sensitive to the loss of those cochlear neurons most vulnerable to noise. Indeed, these vulnerable cochlear neurons do not contribute to threshold detection in quiet settings,11 but are key to the coding of transient stimuli in the presence of continuous background noise.12 To date, there are no established criteria for diagnosis of cochlear synaptopathy in human beings. However, cochlear synaptopathy—resulting from intense noise exposure and causing a temporary auditory threshold shift—has been found in all mammalian species studied so far. Similarly, a massive degeneration of cochlear nerve peripheral axons was found in post-mortem tissues from human temporal bones,13 despite nearnormal hair cell populations and no known history of noise exposure. Finally, in a study of college students with normal audiograms, electrophysiological changes interpreted as signs of neural damage were found in
www.thelancet.com Published online July 14, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31875-5
Published Online July 14, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)31875-5 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(17)31791-9
Steve Gschmeissner/Science Photo Library
Animal studies have shown that glutathione peroxidase 1 (GPx1) is highly expressed in the sensory epithelium of the inner ear, and a targeted mutation of the gene for Gpx1 was found to increase noise-induced hearing loss in mice.1 Based on these observations and given the overlapping role of oxidative stress and cellular injury in noise-induced hearing loss, Jonathan Kil and colleagues2 examined the prophylactic benefits of the administration of ebselen, a GPx1 mimic, in a randomised trial of 83 participants who were exposed to 4 h of standardised sound calibrated to cause a temporary elevation of hearing thresholds, the results of which are published in The Lancet. Each participant was randomly assigned to placebo or one of three different doses of the active drug (200 mg, 400 mg, and 600 mg). The primary outcome was loss of hearing sensitivity at 4 kHz, measured 15 min after the calibrated sound challenge. Hearing thresholds returned to normal within 24 h in all but six participants, five of whom had returned to baseline within 1 week. Significant protective effects of ebselen were reported in participants who received ebselen 400 mg compared with participants who received a matching placebo (difference –2·75 dB, 95% CI –4·54 to –0·97; p=0·0025). Ebselen did not produce a significant protective effect at either of the other doses (200 mg and 600 mg). Decades of research on noise-exposed human beings and animals have shown that acoustic overexposure leads to hair cell damage, threshold elevation, and degraded frequency tuning.3,4 Until 2009, the general agreement was that hair cells were the primary targets of noise, and that death of cochlear neurons was secondary to hair cell degeneration.5 Indeed, hair cell loss can be detected within hours of acoustic exposure, whereas loss of spiral ganglion neurons is not detectable for years.6,7 Hence, the loss of primary auditory neurons was thought to be a delayed downstream consequence of hair cell loss. In Kil and colleagues’ study,2 the acoustic exposure causing temporary threshold elevation was deemed to be benign. Permanent inner ear damage was not suspected because hearing thresholds returned to pre-exposure levels in all but one participant at the time of their final test. This assumption underlies current damage-risk criteria for workplace noise set by several
1
Comment
those most exposed to music, and correlated with students’ difficulty repeating words in challenging acoustic environments.14 Now seen through the lens of cochlear synaptopathy, research protocols with regard to noise exposure that causes a temporary threshold shift will have to be reviewed with increased scrutiny. This study highlights an emerging ethical dilemma, in which a choice has to be made between doing research that could lead to hearing protection from acoustic trauma for millions of people, and accepting the possibility that permanent neural damage might result from noise exposure even if changes in hearing thresholds are temporary. Human research is never risk free, especially in drug development. Scientists, clinicians, and institutional review board members work together to identify and inform participants of any risks of harm that are reasonably foreseeable, even if unlikely, and evaluate the probability and magnitude of harm or discomfort anticipated as a result of participating in a study. Kil and colleagues should be commended for considering the potential impact of cochlear synaptopathy in the design of their protocol. Although norms that define the risk limits of noise exposure in animal models are not directly transposable to human beings, exposure levels were set at levels known to be inefficient in producing cochlear synaptopathy. More importantly, specific disclosures about the risk involved in producing a temporary change in hearing thresholds were provided to each participant. Establishing diagnostic indicators for cochlear synaptopathy in human beings is crucial if we are to understand the prevalence of primary neural degeneration in human populations, identify those with so-called tender ears who are at increased risk, and
2
clarify the true risks of noise for patients, public policy, and research. Stéphane F Maison, *Steven D Rauch Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA [email protected] SDR is a consultant on hearing and balance clinical matters and clinical trial design for Alkermes, Auris Medical, Decibel, Otonomy, and Roche, and serves on the medical or scientific advisory boards of Frequency Therapeutics, Sensorion, and Strekin AG; consultancy was not for ebselen or other GPx1 modulators. SFM declares no competing interests. 1 2
3 4 5 6 7 8 9 10 11 12 13 14
Ohlemiller KK, McFadden SL, Ding DL, Lear PM, Ho YS. Targeted mutation of the gene for cellular glutathione peroxidase (Gpx1) increases noise-induced hearing loss in mice. J Assoc Res Otolaryngol 2000; 1: 243–54. Kil J, Lobarinas E, Spankovich C, et al. Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2017; published online July 14. http://dx.doi.org/10.1016/S0140-6736(17)31791-9. Schmiedt RA. Acoustic injury and the physiology of hearing. J Acoust Soc Am 1984; 76: 1293–317. Liberman MC, Dodds LW. Single-neuron labeling and chronic cochlear pathology. III. Stereocilia damage and alterations of threshold tuning curves. Hear Res 1984; 16: 55–74. Bohne BA, Harding GW. Degeneration in the cochlea after noise damage: primary versus secondary events. Am J Otol 2000; 21: 505–09. Johnsson LG, Hawkins JE Jr. Degeneration patterns in human ears exposed to noise. Ann Otol Rhinol Laryngol 1976; 85: 725–39. Johnsson LG. Sequence of degeneration of Corti’s organ and its first-order neurons. Ann Otol Rhinol Laryngol 1974; 83: 294–303. Arenas JP, Suter AH. Comparison of occupational noise legislation in the Americas: an overview and analysis. Noise Health 2014; 16: 306–19. Kujawa SG, Liberman MC. Adding insult to injury: cochlear nerve degeneration after “temporary” noise-induced hearing loss. J Neurosci 2009; 29: 14077–85. Liberman MC, Kiang NY. Acoustic trauma in cats. Cochlear pathology and auditory-nerve activity. Acta Otolaryngol Suppl 1978; 358: 1–63. Schmiedt RA, Mills JH, Boettcher FA. Age-related loss of activity of auditory-nerve fibers. J Neurophysiol 1996; 76: 2799–803. Costalupes JA, Young ED, Gibson DJ. Effects of continuous noise backgrounds on rate response of auditory nerve fibers in cat. J Neurophysiol 1984; 51: 1326–44. Viana LM, O’Malley JT, Burgess BJ, et al. Cochlear neuropathy in human presbycusis: confocal analysis of hidden hearing loss in post-mortem tissue. Hear Res 2015; 327: 78–88. Liberman MC, Epstein MJ, Cleveland SS, Wang H, Maison SF. Toward a differential diagnosis of hidden hearing loss in humans. PLoS One 2016; 11: e0162726.
www.thelancet.com Published online July 14, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31875-5
Ethical considerations in noise-induced hearing loss research federal agencies in the USA, including the National Institute for Occupational Safety and Health and the Occupational Safety and Health Administration.8 Animal studies have shown that noise exposure can lead to synaptic degeneration between the primary cochlear neurons and the sensory cells even when hair cells remain functional and hearing thresholds recover.9 This cochlear synaptopathy has remained hidden for so many years for three reasons: (1) it is not visible in routine histological material, (2) the eventual loss of spiral ganglion cells is extremely slow,10 and (3) measures of hearing thresholds (audiograms) are not sensitive to the loss of those cochlear neurons most vulnerable to noise. Indeed, these vulnerable cochlear neurons do not contribute to threshold detection in quiet settings,11 but are key to the coding of transient stimuli in the presence of continuous background noise.12 To date, there are no established criteria for diagnosis of cochlear synaptopathy in human beings. However, cochlear synaptopathy—resulting from intense noise exposure and causing a temporary auditory threshold shift—has been found in all mammalian species studied so far. Similarly, a massive degeneration of cochlear nerve peripheral axons was found in post-mortem tissues from human temporal bones,13 despite nearnormal hair cell populations and no known history of noise exposure. Finally, in a study of college students with normal audiograms, electrophysiological changes interpreted as signs of neural damage were found in
www.thelancet.com Published online July 14, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31875-5
Published Online July 14, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)31875-5 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(17)31791-9
Steve Gschmeissner/Science Photo Library
Animal studies have shown that glutathione peroxidase 1 (GPx1) is highly expressed in the sensory epithelium of the inner ear, and a targeted mutation of the gene for Gpx1 was found to increase noise-induced hearing loss in mice.1 Based on these observations and given the overlapping role of oxidative stress and cellular injury in noise-induced hearing loss, Jonathan Kil and colleagues2 examined the prophylactic benefits of the administration of ebselen, a GPx1 mimic, in a randomised trial of 83 participants who were exposed to 4 h of standardised sound calibrated to cause a temporary elevation of hearing thresholds, the results of which are published in The Lancet. Each participant was randomly assigned to placebo or one of three different doses of the active drug (200 mg, 400 mg, and 600 mg). The primary outcome was loss of hearing sensitivity at 4 kHz, measured 15 min after the calibrated sound challenge. Hearing thresholds returned to normal within 24 h in all but six participants, five of whom had returned to baseline within 1 week. Significant protective effects of ebselen were reported in participants who received ebselen 400 mg compared with participants who received a matching placebo (difference –2·75 dB, 95% CI –4·54 to –0·97; p=0·0025). Ebselen did not produce a significant protective effect at either of the other doses (200 mg and 600 mg). Decades of research on noise-exposed human beings and animals have shown that acoustic overexposure leads to hair cell damage, threshold elevation, and degraded frequency tuning.3,4 Until 2009, the general agreement was that hair cells were the primary targets of noise, and that death of cochlear neurons was secondary to hair cell degeneration.5 Indeed, hair cell loss can be detected within hours of acoustic exposure, whereas loss of spiral ganglion neurons is not detectable for years.6,7 Hence, the loss of primary auditory neurons was thought to be a delayed downstream consequence of hair cell loss. In Kil and colleagues’ study,2 the acoustic exposure causing temporary threshold elevation was deemed to be benign. Permanent inner ear damage was not suspected because hearing thresholds returned to pre-exposure levels in all but one participant at the time of their final test. This assumption underlies current damage-risk criteria for workplace noise set by several
1
Comment
those most exposed to music, and correlated with students’ difficulty repeating words in challenging acoustic environments.14 Now seen through the lens of cochlear synaptopathy, research protocols with regard to noise exposure that causes a temporary threshold shift will have to be reviewed with increased scrutiny. This study highlights an emerging ethical dilemma, in which a choice has to be made between doing research that could lead to hearing protection from acoustic trauma for millions of people, and accepting the possibility that permanent neural damage might result from noise exposure even if changes in hearing thresholds are temporary. Human research is never risk free, especially in drug development. Scientists, clinicians, and institutional review board members work together to identify and inform participants of any risks of harm that are reasonably foreseeable, even if unlikely, and evaluate the probability and magnitude of harm or discomfort anticipated as a result of participating in a study. Kil and colleagues should be commended for considering the potential impact of cochlear synaptopathy in the design of their protocol. Although norms that define the risk limits of noise exposure in animal models are not directly transposable to human beings, exposure levels were set at levels known to be inefficient in producing cochlear synaptopathy. More importantly, specific disclosures about the risk involved in producing a temporary change in hearing thresholds were provided to each participant. Establishing diagnostic indicators for cochlear synaptopathy in human beings is crucial if we are to understand the prevalence of primary neural degeneration in human populations, identify those with so-called tender ears who are at increased risk, and
2
clarify the true risks of noise for patients, public policy, and research. Stéphane F Maison, *Steven D Rauch Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA [email protected] SDR is a consultant on hearing and balance clinical matters and clinical trial design for Alkermes, Auris Medical, Decibel, Otonomy, and Roche, and serves on the medical or scientific advisory boards of Frequency Therapeutics, Sensorion, and Strekin AG; consultancy was not for ebselen or other GPx1 modulators. SFM declares no competing interests. 1 2
3 4 5 6 7 8 9 10 11 12 13 14
Ohlemiller KK, McFadden SL, Ding DL, Lear PM, Ho YS. Targeted mutation of the gene for cellular glutathione peroxidase (Gpx1) increases noise-induced hearing loss in mice. J Assoc Res Otolaryngol 2000; 1: 243–54. Kil J, Lobarinas E, Spankovich C, et al. Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2017; published online July 14. http://dx.doi.org/10.1016/S0140-6736(17)31791-9. Schmiedt RA. Acoustic injury and the physiology of hearing. J Acoust Soc Am 1984; 76: 1293–317. Liberman MC, Dodds LW. Single-neuron labeling and chronic cochlear pathology. III. Stereocilia damage and alterations of threshold tuning curves. Hear Res 1984; 16: 55–74. Bohne BA, Harding GW. Degeneration in the cochlea after noise damage: primary versus secondary events. Am J Otol 2000; 21: 505–09. Johnsson LG, Hawkins JE Jr. Degeneration patterns in human ears exposed to noise. Ann Otol Rhinol Laryngol 1976; 85: 725–39. Johnsson LG. Sequence of degeneration of Corti’s organ and its first-order neurons. Ann Otol Rhinol Laryngol 1974; 83: 294–303. Arenas JP, Suter AH. Comparison of occupational noise legislation in the Americas: an overview and analysis. Noise Health 2014; 16: 306–19. Kujawa SG, Liberman MC. Adding insult to injury: cochlear nerve degeneration after “temporary” noise-induced hearing loss. J Neurosci 2009; 29: 14077–85. Liberman MC, Kiang NY. Acoustic trauma in cats. Cochlear pathology and auditory-nerve activity. Acta Otolaryngol Suppl 1978; 358: 1–63. Schmiedt RA, Mills JH, Boettcher FA. Age-related loss of activity of auditory-nerve fibers. J Neurophysiol 1996; 76: 2799–803. Costalupes JA, Young ED, Gibson DJ. Effects of continuous noise backgrounds on rate response of auditory nerve fibers in cat. J Neurophysiol 1984; 51: 1326–44. Viana LM, O’Malley JT, Burgess BJ, et al. Cochlear neuropathy in human presbycusis: confocal analysis of hidden hearing loss in post-mortem tissue. Hear Res 2015; 327: 78–88. Liberman MC, Epstein MJ, Cleveland SS, Wang H, Maison SF. Toward a differential diagnosis of hidden hearing loss in humans. PLoS One 2016; 11: e0162726.
www.thelancet.com Published online July 14, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31875-5