1. 1 Chemical Exposure as a Risk Factor for Hearing Loss: Implications for Occupational Health Thais C. Morata, Ph.D. Hearing Loss Prevention Team tmorata@cdc.gov The findings and conclusions in this presentation are those of the author and do not necessarily represent the views of the National Institute for Occupational Safety and Health.

2. 2 No systematic research effort on auditory effects of chemicals, but isolated reports: - Poisoning: accidents or abuse - Occupational exposures (painters, printers, metal, chemical, leather industry workers, etc.) - Environmental exposures (air and water contamination) Before the 1980’s

3. 3 Schacht J, Hawkins JE. 2006 Sketches of otohistory. Part 11: Ototoxicity: drug-induced hearing loss. Audiol Neurootol. 2006;11(1):1-6.

4. 4 Bergstrom & Nystrom, 1986 Scand Audiol. 1986;15(4):227-34.

5. 5 Features of NIHL/Ototoxicity Bilateral, symmetrical, and irreversible Onset in the high-frequency range, progress rate determined by risk factors Cochlear, or with a cochlear component History of exposure General descriptors

6. 6 Ototoxicity of therapeutic drugs Antimalarial Non-steroidal anti- inflammatory Aminoglycosides Antimicrobial Loop diuretics Antineoplastic Chelating agents Mostly: Vastly studied Effects restricted to cochlea Use monitored, i.e., knowledge of intake Approaches: Substitution Antioxidants

7. 7 Ototoxicity of environmental chemical exposures Mostly: Relatively few studies Effects not restricted to the cochlea Use poorly monitored, i.e., poor knowledge of exposure history Confounded by noise Approaches: Substitution/control of exposure Antioxidants Metals Solvents Asphyxiants Pesticides

8. 8 Metals –Trimethyltin (Fechter et al, Crofton et al.) –Methyl mercury (Konshi et al., Ison et al., Rice et al.) –Lead (Discalzi et al) –Pesticides Perry & May J Agromedicine. 2005;10(2):49- 55. Selected key publications reporting effects

9. 9 Chemical asphyxiants –Carbon Monoxide (CO) + noise (Fechter et al) –Hydrogen Cyanide + noise (Fechter et al) –Potassium Cyanide (Konishi et al., Evans & Klinke, Fechter et al. ) Acrylonitrile (Fechter et al., Pouyatos et al.) Selected key publications reporting effects

10. 10 Organic solvents –Toluene (Pryor et al., Sullivan et al., Johnson et al., Crofton et al, Campo et al., Morata et al., Fechter et al.) –Ethyl benzene (Cappaert et al.) –Styrene (Campo et al., Crofton et al., Pryor et al., Morata et al, Sliwinska-Kowalska et al ) –Xylene (Pryor et al., Crofton et al, 1994) –Trichloroethylene (Crofton et al., Fechter et al., Muijser et al.) –N- Hexane (Rebert et al., Nylen et al.,) –Carbon disulfide (Sulkowski, Morata, Chang et al.) –Solvent mixtures ( Rebert et al., Crofton et al., Morata et al., Jacobsen et al., Kim et al., Sliwinska-Kowalska et al) Selected key publications reporting effects

11. 11 ICOH Milano Special Session (June 14 th ) Mini-Symposium (June 15 th ) Other presentations dispersed in noise or chemical sessions 2006

12. 12 In the 1990’s

13. 13 1998-2006 TLVs® and BEIs®: Notes, Noise “Exposure to certain chemicals may also result in hearing loss. In settings in which there may be exposure to noise as well as toluene, lead,… ….periodic audiograms are advised and should be carefully reviewed.”

14. 14 ACOEM Noise-induced Hearing Loss EVIDENCE-BASED STATEMENT, JOEM 45(6) 2003 “Clinicians evaluating cases of possible noise-induced hearing loss should keep in mind the following clinical concerns:… …Coexposure to ototoxic agents, such as solvents, heavy metals and tobacco smoke, may act in synergy with noise to cause hearing loss”.

15. 15 Australia-New Zealand AS/NZS 1269:2005 Occupational Noise Management/Informative Appendix on Ototoxic Agents requiring hearing tests for those exposed to ototoxic agents http://www.standards.com.au/catalogue/ script/search.asp Standards

16. 16 US Army Regulation 1998-2004 Dept. of the Army Pamphlet 40-501 Hearing Conservation Program : Requires consideration of ototoxic chemical exposures (including toluene) for program inclusion, particularly when in combination with marginal noise (¶ 3-3). https://134.11.61.26/CD4/Publications/DA/DA%20Pam/DA%20Pam%2040 -501%2019981210.pdf Fact Sheet 51-002-0903 suggests Action Level for chemicals for inclusion in Hearing Conservation Program. http://chppm-www.apgea.army.mil/documents/FACT/51-002-0903.pdf

17. 17 Legislation The European Community directive on noise (2003/10 EC noise) requires that the interaction between noise and work- related ototoxic substances, and noise and vibration be taken into account in the risk assessment of exposed populations (Article 4 of Section II). http://europa.eu.int/eur-lex/pri/en/oj/dat/2003/l_042/l_04220030215en00380044.pdf

18. 18 Countries (Australia, New Zealand, Brazil) started to accept link between chemical exposure and hearing loss in compensation cases Brazil Decree no. 3048/ May 6, 1999 Australia http://www.workcover.nsw.gov.au/Publicatio ns/WorkersComp/InjuryManagement/Permi mpair.htm Legislation

19. 19 Remaining challenges Lab studies Damage Mechanism Administration Route Field Studies Priority List & Rationale Identify Risk Populations Data over Exposure Range Rationale: Magnitude of exposed populations, chemical’s ototoxicity, general toxicity, as well as nephro- or neurotoxicity. 1- Number of chemicals and combinations Morata et al., 2003

20. 20 Remaining challenges 2- Dose-response, NOEL, LOEL, Action Level, Response Level Chronic effect/ role of peak exposures Biomarkers

21. 21 Groups: Distribution of hearing loss to be compared from groups with different exposure conditions Comparing mean thresholds between groups does not always allow distinction between the effect of each agent (noise or chemical); risk ratios are needed. Remaining challenges 2- Analysis strategies

22. 22 Pure tone audiometry –Requires large population, or –Requires complaint of speech difficulty or other difficulty inconsistent w/ thresholds Need to consistently define hearing loss and change from baseline Need good reference data from unexposed populations Criteria for excluding age/confounders Consideration of non-occupational exposures 2- Analysis strategies

23. 23 Individual cases: Ototoxicity or neurotoxicity/Cochlear vs. retrocochlear? Tests to complement pure- tone audiometry are needed Complaints of hearing difficulties not compatible with audiometric result Other complaints associated with neurotoxicity (balance, vision, etc). 3. Appropriate metrics Remaining challenges

24. 24 Length of test Administration time Ease of analysis Sensitivity/specificity (validity) Utility for retrospective vs. prospective or longitudinal studies Availability of gold standard or screening tests? Not yet (Morata and Little, 2002) 3. Appropriate metrics

25. 25 Impact on Preventive Practices & Research Recommended limits have not taken ototoxic properties or combined exposures into consideration Controlling noise and hearing protectors insufficient for preventing hearing loss Eligibility to Hearing Loss Prevention Programs

26. 26 Remediation Reduce hazardous exposures –Engineering controls –Protective equipment (e.g. respirators, gloves) Education of the potentially affected population

27. 27 NIOSH, Publication Dissemination http://www.cdc.gov/niosh/homepage.html pubstaft@cdc.gov http://www2a.cdc.gov/niosh-comments/nora-comments/input.asp