GUIDANCE FROM OCCUPATIONAL HYGIENE ORGANIZATIONS Several occupational hygiene-associated organizations have released guidance applicable to practitioners regarding ototoxicants. OSHA and NIOSH released a joint safety and health bulletin in 2018 to raise awareness of ototoxicants. The bulletin summarizes the hazards, including effects on hearing, and provides a list of ototoxicants, identifies industries commonly affected by ototoxicants, and discusses methods of controlling exposure to prevent adverse health effects.  While there are no compulsory regulations targeted toward ototoxicants, OSHA has recognized the risk associated with combined exposures to noise and ototoxic substances. An appendix in the chapter on noise in the OSHA Technical Manual summarizes the epidemiological literature and concludes that physiological interactions with some mixed exposures to chemical and physical factors can increase the severity of harmful effects on the auditory system. OSHA recognizes there is “good evidence” of adverse effects from solvents such as toluene, ethylbenzene, xylene, and styrene, among others, and from chemicals that demonstrate interactive effects with noise including lead, carbon monoxide, and other solvents.  Guidance from the Department of the United States Army identifies 21 chemicals classified as ototoxicants, including metals such as arsenic, lead, mercury, and manganese, and solvents such as carbon disulfide, ethylbenzene, toluene, and xylene, among others. Any exposure to these ototoxicants, either in combination with noise or alone, that is greater than 50 percent of each chemical’s respective occupational exposure limit would trigger enrollment in a hearing conservation program.  With its 2019 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices, ACGIH adopted a new “OTO” notation to highlight a chemical’s ability to cause hearing impairment either alone or in combination with noise. The OTO notation is intended to focus attention on exposure reduction using engineering, administrative, and PPE controls and to highlight the need to consider placing affected employees in hearing conservation and medical surveillance programs to monitor auditory capacity. Specifically, ACGIH recommends periodic audiograms in settings with combined exposures to noise and carbon monoxide, hydrogen cyanide, lead, and solvent mixtures and recommends audiograms when ethylbenzene, styrene, toluene, or xylene exposures occur in the absence of noise.  Australian safety regulations, recognizing that exposure standards do not take ototoxicants into account, recommend reduction of noise exposure to 80 dBA and audiometric testing when there are exposures to solvents such as toluene, xylene, styrene, and fuel mixtures; metals such as arsenic, lead, and manganese; and other ototoxicants such as hydrogen cyanide and carbon monoxide in combination with noise exposure.  As detailed by the European Agency for Safety and Health at Work, scientists from France’s Institut national de la recherche scientifique (INRS) recommended lowering the exposure limit for styrene from 50 to 30 ppm and adopting an eight-hour noise OEL of 80 dBA. The European Union’s noise directive (2003/10/EC) requires the employer to assess the occupational risk not only from exposure to noise at work but also from the combined exposure to noise and occupational ototoxic compounds. CONCENTRATIONS ELICITING ADVERSE AUDIOLOGICAL EFFECTS Researchers have sought to identify which industrial chemicals demonstrate ototoxicant potential. While not exhaustive, this discussion will focus on the individual chemicals, chemical combinations, and chemicals combined with noise that exhibit the most evidence for ototoxicity.  Metals A suggestive association between lead exposure and hearing loss is not new. A 2013 feature in The Laryngoscope reported high levels of lead in Beethoven’s bones at the time of his death. His autopsy identified shrunken cochlear nerves consistent with axonal degeneration. While Beethoven’s physicians believed he had alcohol dependence, lead exposure was suspected to have been a result of consuming lead-contaminated wine. A 2009 paper in Science of the Total Environment investigated the effects of manganese, copper, zinc, arsenic, cadmium, lead, and noise exposure for steelworkers. Analysis showed lead levels greater than 7 µg/dL of blood were significantly associated with hearing loss at 3,000-8,000 Hz. The biological monitoring requirements in OSHA’s lead standard (29 CFR 1910.1025) begin with semiannual evaluations at an action level of 30 µg/dL, evaluations every two months at 40–100 µg/dL, and removal of workers from the lead environment when blood lead levels reach 60 µg/dL. The Nordic Expert Group’s review of human research in a variety of industries found central auditory effects associated with current and lifetime blood lead concentrations of approximately 28–57 µg/dl. Researchers publishing in Archives of Environmental Health: An International Journal investigated the effect of blood lead levels and noise exposures on hearing ability in two lead acid battery manufacturing facilities and found an average airborne lead concentration of 0.19 mg/m3, blood lead level of 56.9 µg/dL, and average noise exposure of 86 dBA were correlated with decreased hearing ability. An investigation published in Environmental Health Perspectives examined associations between blood cadmium and blood lead levels with hearing loss in the general U.S. population via the National Health and Nutrition Examination Survey. Personnel with cadmium blood concentrations of at least 8.5 µg/dL had a 13.8 percent decrease in hearing while people with blood lead levels of at least 54 µg/dL had an 18.6 percent decrease at 500–4,000 Hz compared to a reference group.  Solvents The Nordic Expert Group’s review of occupational studies for styrene reported that exposures among workers exhibiting significant hearing loss when compared to non-exposed controls ranged from 3.5 to 22 ppm and involved noise exposures less than 85 dBA. Long-term exposure of 30–50 ppm for at least 10 years has been shown to lead to auditory effects.  A 2008 paper in Critical Reviews in Toxicology summarized the literature regarding styrene concentrations leading to adverse audiological outcomes. A study at a plastic button and fiber-reinforced plastic bath factory revealed mean styrene concentrations of 8 ppm combined with mean exposures of toluene at 7.3 ppm, methanol at 14.5 ppm, and acetone at 5.7 ppm were correlated with decreases in hearing from 500 to 8,000 Hz. A study at a yacht yard and plastic factory revealed that mean styrene concentrations up to 46.5 ppm (14.5 ppm averaged over a working lifetime), combined with toluene and noise in excess of 85 dBA, led to over 78 percent of the population having abnormal audiograms.