OTOTOXINS

1. OTOTOXINS Presented by Nico Potgieter (ROH at SASOL) SAIOH Mpumalanga Branch Workshop 02 October 2014

2. Introduction

3. Introduction • Ototoxin? vs. NOISE • Historically and even today OH Professionals find it slightly surprising that chemical exposure may also lead to hearing loss • Only since around 1980s that ototoxinsin the workplace were considered a risk, although first accounts of ototoxicity were 1000+ years ago • Definition: Ototoxicity is a selective organ toxicity directed towards the inner ear. An ototoxic agent is defined as a drug or other chemical substance that causes functional impairment or cellular damage in the inner ear, especially upon the end organs and neurons of hearing or balance, or the vestibulo-cochlear nerve • In SA, ototoxins are not always well known or understood and are not specifically covered in legislation / guidelines and, therefore, generally do not feature in • Hazard identifications • Risk assessments • Evaluation of chemical exposures • Hearing loss investigations • Medical surveillance protocols • Hearing conservation programmes

4. Introduction • Effect of Ototoxins on Auditory System Noise exposure is particularly damaging to the cochlea, a part of the peripheral auditory system However, chemicals (ototoxins) tend to affect both the cochlear structures and the central auditory system Ototoxic substances may affect the entire organ, specific cells within the organ, components of specific cells or individual biochemical pathways Substances that act at the level of the brainstem or the central auditory pathways are considered to be neurotoxic and not strictly ototoxic, but the adverse effect is altered hearing

5. Introduction • Effect of Ototoxins on Auditory System Schematic of the auditory system showing the possible site of action of some ototoxic chemicals.

6. Introduction • Common Ototoxins in the Workplace Organic solvents: Styrene, Toluene, Xylene, Ethylbenzene, Chlorobenzene, TCE, White spirits (mixture), n-Hexane, n-Heptane, Carbon disulphide Metals: Lead, Mercury compounds, Germanium dioxide, Organic Tin compounds Asphyxiants: Carbon monoxide, Hydrogen cyanide and its salts Nitriles: 3-Butenenitrile, Cis-2-pentenenitrile, Cis-crotononitrile, 3,3’-iminodipropionitrile, Acrylonitrile Pesticides: Organophosphates, Paraquat, Pyrethroids PCBs and various other halogenated hydrocarbons Tobacco smoke

7. Introduction • Common Ototoxins in the Workplace Diverse chemical structures – several targets in auditory system and multiple underlying mechanisms, i.e. effects not restricted to cochlea Effects relatively poorly studied and exposure history generally poor Use generally poorly controlled and / or monitored Confounded by noise Difficult to obtain a clear dose-response relationship

8. Introduction • Common Ototoxic Drugs Antibiotics: Streptomycin, Dihydrostreptomycin, Neomycin, Amikacin, Gentamicin, Kanamycin, Tobramycin, Nentilmicin, Sisomycin, Erythromycin, Minocycline Chemotherapeutics: Cisplatin, Carboplatin, Mechloroethamine, Vincristine, Bleomycin, Nitrogen mustard, Vinblastine Diuretics: Ethacrynicacid, Furosemid, Bumetanid, Azoseamid, Ozolinone Malaria prophylaxis: Quinine, Chloroquine Anti-inflammatory drugs: Acetyl salicylic acid (Aspirin), Ibuprofen, Indomethacin, Naproxen, Phenylbutazone, Sulindac Antimicrobials: Chloramphenicol, Colistin, Erythromycin, Minocycline, PolymyxinB, Vancomycin

9. Introduction • Common Ototoxic Drugs Effects generally restricted to the cochlea Effects vastly studied Use generally well-controlled and monitored (knowledge of intake)

10. Hearing Loss Risks

11. Hearing Loss Risks • Exposure to Ototoxic Substances only • Generally, ototoxicity appears to be a phenomenon of higher than OEL exposure concentrations • However, exposure to some substances below or near OELs showed auditory effects, e.g. • Mercury • Styrene • Toluene • Lead • Carbon disulphide • Carbon monoxide • Ototoxicity not tested for as a matter of routine when setting OELs, which are based on critical health effects. Critical health effects are health effects detected at lowest exposure level. As such, OELs may not be sufficient to protect against ototoxic effects • If there is no specific research into ototoxicity of a substance, there is no other means currently to capture the fact that it may be an ototoxin. Setting of OELs might have captured this issue, if ototoxicity was considered as part of the criteria for setting an OEL

12. Hearing Loss Risks • Exposure to Ototoxic Substances only • Effects on the auditory system found when exposed to certain single ototoxins • E.g. substances mentioned before (such as Toluene) • Effects on the auditory system found when exposed to certain mixtures of ototoxins • E.g. Toluene, Xylene, MEK

13. Hearing Loss Risks • Exposure to both Noise and Ototoxic Substances • Noise exposure is in general more important than ototoxin exposure, due to NIHL being one of most prevalent occupational diseases • However, exposure to ototoxins definitely play a part in hearing loss in industry, of which the total impact is most likely not determined or even considered yet • Hearing loss due to a combination of noise and ototoxin exposure may occur at noise levels lower than 85 dBA • Exposure to certain ototoxinsand co-exposure to noise resulted in hearing loss due to additive effects, i.e. where the total hearing loss is the sum of the NIHL and the CIHL (1+1=2) • E.g. Certain solvents and noise • Exposure to other ototoxins and co-exposure to noise resulted in hearing loss due to synergistic effects, i.e. where the total hearing loss is more than the sum of the NIHL and the CIHL (1+1=4) • E.g. Toluene and noise • E.g. Carbon disulphide and noise

14. Hearing Loss Risks • Exposure to both Noise and Ototoxic Substances • Exposure to another set of ototoxins and co-exposure to noise resulted in hearing loss due to potentiation effects, i.e. where there is no indication of CIHL due to exposure to the ototoxin alone, but if there is exposure to both the ototoxin and noise, a higher hearing loss occurs than for just noise exposure alone (1+0=2) • Some studies indicate that this may be true for carbon monoxide and noise • Exposure to both noise and jet fuel showed an increase in the risk of hearing loss when compared to exposures to only noise or jet fuel. However, after a significant period of exposure to both stressors (> 10 years), the risk of hearing loss was similar to the risk of noise only exposure. • Indicates a plateau for hearing loss due to jet fuel exposure over time and / or that noise exposure becomes more important over time, when exposure to both stressors occur. • Synergistic effects of toluene and noise was found to occur even if exposures were not exactly at the same time • E.g. exposure to toluene occurred before exposure to noise, but still synergistic hearing loss occurred

15. Legislation and Guidelines

16. Legislation and Guidelines • OHSAct (85 of 1993) Section 8 of Act – implies that employer should address the health risk presented by ototoxins

17. Legislation and Guidelines • HCS and Lead Regulations No specific mention of ototoxins in the Regulations No specific regulation of the interaction between stressors from different classes (i.e. noise and chemicals) Reg 5 of HCSR and Reg. 6 of LR require assessment of exposure to chemicals. Reg. 5 of the HCSR further require identification of the effect of the substance on an employee No substances have OELs based on ototoxic effects and no indication is given as to which substances may be ototoxins Reg. 7 of HCSR requires medical surveillance where exposure of an employee to a chemical substance is such that an identifiable disease or adverse health effect may occur. Reg. 7 of HCSR and Reg. 8 of LR also require medical surveillance if an OMP certifies that an employee should be under medical surveillance

18. Legislation and Guidelines • NIHL Regulations No specific mention of ototoxins in the Regulations No specific regulation of the interaction between stressors from different classes (i.e. noise and chemicals) No specific medical surveillance for ototoxins or a combined exposure to noise and ototoxins

19. Legislation and Guidelines • SANS 10083:2013 • Sections 17.7, 18.4 and 20.5 (Baseline, Periodic Screening and Exit Audiometry) • Obtain and record the medical history of the employee with relevance to previous traumatic incidents, medical treatment, ototoxic medication or other non-auditory events which could have an effect on the hearing of an employee • No specific information on otoxins in the workplace or historic exposure thereto • No information on additional / specific audiometric testing for ototoxins or when to conduct such testing

20. Legislation and Guidelines • Other SA Acts and Guidelines • SANS 8253:2011, Part 1 and Part 2 (Acoustics – Audiometric Test Methods) • An otologicallynormal person is a person in a normal state of health who is free from all signs and symptoms of ear disease and from obstructing wax in the ear canal and who has no history of undue exposure to noise, exposure to potentially ototoxic drugs, or familial hearing loss • No mention of workplace ototoxins or methods specifically for ototoxins • COIDAct (130 of 1993) • List of occupational diseases (compensable) caused by various chemical stressors, which includes several ototoxic substances – implies that chemically induced hearing loss may be compensable • No mention of hearing loss due to a combination of ototoxin and noise exposure

21. Legislation and Guidelines • International Guidelines – Europe • Directive 2003/10/EC, 6 Feb 2003 (European Union) • Instructs an employer carrying out a Risk Assessment to give particular attention to any effect on the worker resulting from interactions between noise and ototoxic substances • Occupational exposure limit values, AFS:2011:18 (Sweden) • Added a “Noise” notation to several of their OELs, which indicates that exposure to these chemical substances approaching existing OELs and simultaneous exposure to noise levels approaching 80 dB can cause damage to hearing • Literature Review on Combined Exposure to Noise and Ototoxic Substances, 2009 (European Risk Observatory; EU-OSHA) • Identified substances of concern and listed confirmed ototoxic substances • Conducted a literature review and evaluated the strength of evidence • Identified gaps in research and regulations

22. Legislation and Guidelines • International Guidelines – Europe • Occupational Exposure to chemicals and hearing impairment, 2010 (Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals) • Conducted an evaluation of the human health risks with regards to ototoxins, as well as the strength of evidence • Identified gaps in research • Classified ototoxins into 3 categories, as a basis for occupational standards • Category 1: Human data indicate auditory effects below or near existing OELs. Robust animal data indicate an effect on auditory system. • Category 2: Human data lacking, but animal data indicate an effect on auditory system below or near existing OELs. • Category 3: Human data lacking, but animal data indicate an effect on auditory system well above existing OELs.

23. Legislation and Guidelines • International Guidelines – Australia and New-Zealand • Code of Practice on Managing Noise and Preventing Hearing Loss at Work, Dec 2011 (Safe Work Australia) • Gives general description of ototoxins, as well as industries in which they may be found • Lists ototoxins and indicate the ones that may be taken up into body through skin absorption • Recommends regular audiometric testing where workers are exposed to: • Any of the listed ototoxic substances above 50% of the exposure standard, irrespective of the noise level • Any of the listed ototoxic substances at any level, with noise exposure greater than an 8hr-TWA of 80 dBA or a peak exposure greater than 135 dBC • Recommends that the daily noise exposure of workers exposed to any of the listed ototoxins be controlled to below 80 dBA • Guidance Note for Management of Noise in Mines, Aug 2014 (Queensland Government) • Indicates fact that certain chemicals and drugs may lead to hearing loss and lists specific substances • Indicates that combined exposure to noise (even below OEL) and ototoxins may lead to hearing loss • Lists specifics with regards to audiometric testing when exposed to ototoxins

24. Legislation and Guidelines • International Guidelines – Australia and New-Zealand • A/NZ Standard 1269.0, Occupational Noise Management, Part 0: Overview and General Requirements, 2005 • Describes specifics with regards to industrial ototoxins and hearing impairment due to these substances and audiometric testing requirements, within a standard mainly addressing noise exposure

25. Legislation and Guidelines • International Guidelines – USA and Canada • TLVs and BEIs Booklet, 2014 (ACGIH) • Under the Noise Section, a note is made on the combined exposure to noise and several listed ototoxic substances and the recommendation made that period audiograms be conducted and carefully reviewed • Report R-747. Effects of Chemical Substances on Hearing: Interactions with Noise, 2012 (IRSST Canada) • Conducted an evaluation of the human health risks with regards to ototoxins and noise exposure in combination, as well as the strength of evidence • Reflect specific details for various compounds

26. Legislation and Guidelines • International Guidelines – USA and Canada • Report R-604. Literature review – Chemical substances and effect on hearing, 2009 (IRSST Canada) • Conducted an evaluation of the human health risks with regards to ototoxins, as well as the strength of evidence • Classified substances into 4 categories, based on research and literature review • Category 1: Substance is ototoxic • Category 2: Substance is possibly ototoxic • Category 3: Ototoxicity of substance not conclusively proven • Category 4: Substance is not ototoxic

27. Recommendations

28. Recommendations • Research Bodies Conduct scientific research into characterising the ototoxic properties of substances, including epidemiological studies, in order to detect any critical health effects that may be caused by ototoxicity Conduct scientific research into otoxic effects of substances in combination with noise exposure, as well as mixtures of substances, for better characterisation of the combined effect Research, develop and refine tools to detect and characterise chemically-induced hearing loss

29. Recommendations • Regulatory Bodies Make specific provision for ototoxins in HCS, Lead and / or NIHL Regulations, as well as relevant SANS COPs (e.g. SANS 10083) – possibly as a “hearing loss” or “noise” notation in HCS Tables Establish OELs based on ototoxic effects, where these are the “critical health effects” / most sensitive health effects of the substance Investigate possibility of classifying chemically induced hearing loss as an occupational disease or list it in in combination with NIHL

30. Recommendations • Occupational Hygiene Professionals and Risk Managers Make employees, managers and SHE Departments aware of the risks due to exposure to ototoxins and provide training in this regard Include ototoxicity on SDSs and other risk communication tools Include ototoxins in HIRAs, HRAs, chemical exposure surveys etc. and consider co-exposure with noise Implement risk management measures to reduce exposure to ototoxins – inhalation and other routes of exposure Consider ototoxin exposures during NIHL investigations as well as when recommending and implementing control measures Make ototoxins part of hearing conservation programmes and manage in conjunction with NIHL prevention programmes, not as a separate item Stay abreast of all new developments and research with regards to ototoxins

31. Recommendations • Occupational Health and Medicine Practitioners Make employees, managers and SHE Departments aware of the risks due to exposure to ototoxins and provide training in this regard Make ototoxins part of hearing conservation programmes and manage in conjunction with NIHL prevention programmes, not as a separate item Implement specific occupational health screening activities for ototoxins, as well as tools to detect chemically-induced hearing loss and / or to discern between NIHL and CIHL Consider noise and chemical co-exposure when evaluating cases of NIHL Stay abreast of all new developments and research with regards to ototoxins

32. Recommendations • Control chemical exposure to protect your hearing!

33. Summary

34. Summary Several chemicals can cause hearing loss, through various mechanisms and targets in the auditory system Hearing loss from chemical exposure can occur with or without exposure to noise, depending on the chemical Generally ototoxins are poorly addressed in South Africa, mainly due to a lack of legislation and guidelines. OELs do not account for ototoxicity We have a legal duty to identify exposures to ototoxins and take appropriate steps Several international guidelines available to assist the OH Professional and OMPs / OHNPs in determining the risk and how to manage the risk Research Bodies and Regulatory Bodies should provide sound research data and use such data to implement specific policies, laws, regulationsand / or standards Risk Managers and OH&H Professionals should start considering ototoxins in their day to day activities, in order to protect the hearing of employees Ototoxins should be managed together with noise and not as a separate topic, in order to maintain focus on noise and to consider the combined exposure to the two stressors

35. Questions / Discussion