1. Noise-induced cochlear neuropathy: Regulatory implications Robert A Dobie University of Texas HSC, San Antonio Larry E Humes Indiana University, Bloomington

2. Outline of Talk What is noise-induced cochlear “synaptopathy”? – TTS experiments in rodents Pitfalls in extrapolating these data to human noise exposure regulations – Susceptibility differences across species – Exposures that yield synaptopathy exceed OSHA PEL – Exposures that yield synaptopathy produce PTS or “pathological TTS” (which in humans occurs only with exposures above OSHA PEL)

3. Cochlear “Synaptopathy” Kujawa and Liberman 2009 (and later papers) Exposure causing very large TTS at 24 hours – Immediate IHC denervation, with slow loss of SGNs at base of cochlea – Preferentially affecting low-SR, high-threshold SGNs Also seen with very long moderate-level exposures and with aging Studies pose important challenges to conventional wisdom regarding hearing loss, especially NIHL

4. Kujawa & Liberman 2009 Adult mice 8 – 16 kHz, 2 hours, 100 dB Threshold shift, dB 40 dB TTS, 24 hours post-exposure

5. Kujawa & Liberman 2009 After 40 dB TTS @ 24 hr: Immediate permanent partial denervation of IHCs above exposure band “TTS can no longer be considered safe” (at least for mice)

6. Do these rodent data challenge human exposure limits (e.g., OSHA)? “ … noise exposure is more dangerous than has been assumed.” (Kujawa & Liberman 2009) “… noise is much more dangerous than we have previously thought.” (Kujawa & Liberman 2015) “… many common workplace and leisure exposures to noise are likely more dangerous to hearing health than current federal guidelines indicate.” (Maison et al 2013) “ … noise levels that had been considered as ‘harmless’ may actually represent a significant risk to hearing and public health.” (Truong & Cunningham 2011)

7. Pitfall #1 in extrapolating these rodent TTS data to human exposure regulations Different susceptibilities for TTS, HC loss (rank order): 1. Chinchilla, gerbil 2. Mouse (varies by strain) 3. Guinea pig 4. Human 1 > 3 (Drescher 1974, Saunders 1982) 1 > 4 (Mills 1988) 2 > 3 (Burdick 1978, Henry 1982, Duan 2008) 3 > 4 (Liang 1992)

8. Pitfall #2 in extrapolating these rodent TTS data to human exposure regulations Species may also differ in relative susceptibility of cochlear cell types to noise damage (as is true for age-related damage) Rodents might lose neurons before hair cells Primates might lose hair cells before neurons “TTS can no longer be considered safe” might be true for rodents, but not for primates

9. Pitfall #3 in extrapolating these rodent TTS data to human exposure regulations None of the exposures in these rodent students that caused “synaptopathy” would be permissible under OSHA regulations, even ignoring species differences in susceptibility

11. Kujawa & Liberman (2009) mouse exposure: 100 dB SPL, 2 hours -if shifted down two octaves to match human audiogram, would be about 102 dBA, with OSHA TWA about 92 dBA—i.e., “hazardous” -lower levels caused no synaptopathy in adult mice

12. Maison Usubushi & Liberman (2013) mouse exposure: 85 dB SPL, 1 week - synaptopathy minimal in animals with intact efferents - if shifted down two octaves, would be about 87 dBA, with OSHA TWA reaching 97 dBA at 32 hours—i.e., “hazardous” ‒hazardous exposure for humans produced minimal synaptopathy

13. Guinea pig mean audiogram more similar to human (Heffner Heffner Masterton 1971)

14. Lin Furman Kujawa & Liberman (2011) Guinea pig, exposure: 106 dB SPL, 2 hours - caused PTS - OSHA TWA would be about 97 dBA—i.e., “hazardous” ⁻hazardous for humans and guinea pigs

15. Pitfall #4 in extrapolating these rodent TTS data to human exposure regulations In synaptopathy experiments, TTS at 24 hours post-exposure typically exceeded 40 dB TTS lasting 24 hours considered “pathological” in humans, and does not occur with exposures less than OSHA PEL

16. “normal” vs “pathological” human TTS TTS 2 < 30 dB two minutes post-exposure recovers quickly, as log time, complete at 24 hrs TTS 2 > 40 dB recovers slowly, linearly with time, and is on borderline of PTS (“critical” or “pathological” TTS, per Ward 1969, 1973)

17. “Pathological” TTS in humans, persistent at 24 hours, occurs with exposures above OSHA PEL “Super-pathological” TTS in humans, like that required to cause mouse synaptopathy (40 dB after 24 hrs), has been reported at least once (Ward, 1960) (skip next 2 slides unless time allows)

18. RS (the red point in next slide) No synaptopathy in mice MB (one of the green points) human mouse Ward (1960): 105 dB, 2 hours, 2 kHz OBN: subject RS (most susceptible) (did he suffer cochlear neuropathy, like mice that had similar TTS recovery?) “normal” TTS

19. Ward, 1960; 2 kHz OBN, 2 hours Davis, 1950; BBN, 32 minutes Davis, 1950; 2 kHz tone, 16 minutes OSHA PEL NIOSH REL ALL show pathological TTS and ALL “hazardous”

20. MB (typical Subject, per Ward) 91 dB, 120 minutes (mice) and 105 dB, 120 min (human) yield similar 24-hour TTS Suggests about 14 dB average susceptibility difference

21. Evidence for noise-induced cochlear neuropathy in humans? Makary et al 2011: SGN counts below mean for age in 2 of 3 subjects with ± history of noise exposure Stamper and Johnson 2014 (Ear & Hearing) – Students with more self-reported noise exposure had smaller ABR wave I amplitudes – No control for sex (but men have both more noise exposure and smaller wave I amplitudes) Spankovich (pers. Comm., 5/11/15) – Replication with control for sex shows no association between noise and wave I amplitudes

22. Regulatory implications No evidence yet that exposures permissible under OSHA cause: – Neuropathy in animals, considering species audiogram (but not susceptibility differences) – Pathological TTS in humans But effects of impermissible exposures (even isolated) might be worse than previously suspected, at least at base of cochlea (> 20 kHz for mice) Supports more vigorous early enforcement (and education) rather than more stringent limits Agriculture, construction, oil & gas sectors largely unregulated – deserve more attention

23. Unanswered questions Cochlear neuropathy after impulse noise? Growth over days/wks/mos/yrs? Exchange rate? Cochlear neuropathy in primates? (yes, per MCL, but in context of large PTS) Comparing noise-exposed people to audiometrically- matched controls (in progress, per SGK) – ABR wave I (or ASSR) amplitude – Speech in noise ???