Francois Lemay

A weight of evidence approach for the assessment of the ototoxic potential of industrial chemicals

There is accumulating epidemiological evidence that exposure to some solvents, metals, asphyxiants and other substances in humans is associated with an increased risk of acquiring hearing loss. Furthermore, simultaneous and successive exposure to certain chemicals along with noise can increase the susceptibility to noise-induced hearing loss. There are no regulations that require hearing monitoring of workers who are employed at locations in which occupational exposure to potentially ototoxic chemicals occurs in the absence of noise exposure. This project was undertaken to develop a toxicological database allowing the identification of possible ototoxic substances present in the work environment alone or in combination with noise exposure. Critical toxicological data were compiled for chemical substances included in the Quebec occupational health regulation. The data were evaluated only for noise exposure levels that can be encountered in the workplace and for realistic exposure concentrations up to the short-term exposure limit or ceiling value (CV) or 5 times the 8-h time-weighted average occupational exposure limit (TWA OEL) for human data and up to 100 times the 8-h TWA OEL or CV for animal studies. In total, 224 studies (in 150 articles of which 44 evaluated the combined exposure to noise and a chemical) covering 29 substances were evaluated using a weight of evidence approach. For the majority of cases where potential ototoxicity was previously proposed, there is a paucity of toxicological data in the primary literature. Human and animal studies indicate that lead, styrene, toluene and trichloroethylene are ototoxic and ethyl benzene, n-hexane and p-xylene are possibly ototoxic at concentrations that are relevant to the occupational setting. Carbon monoxide appears to exacerbate noise-induced hearing dysfunction. Toluene interacts with noise to induce more severe hearing losses than the noise alone.

A Web Tool for the Identification of Potential Interactive Effects of Chemical Mixtures

This project was undertaken to develop a toxicological database allowing the identification of possible additive or other interactive effects of mixtures present in the work environment. In the first phase of the project, whose findings have already been published, critical toxicological data were compiled for each of the 695 chemical substances in the Quebec Occupational Health Regulation, allowing the prediction of potential additivity among components of a mixture. In the second phase of this project, the types of interactions for mixtures most likely to be found in workplaces and for which primary literature data are available were specified. The toxicological data were evaluated only for realistic exposure concentrations up to the short-term exposure limit or ceiling value or five times the 8-hr time-weighted average (TWA) permissible exposure limit (PEL) for human data and up to 100 times the 8-hr TWA PEL or ceiling value for animal studies. In total, 675 studies were evaluated covering 209 binary mixtures of substances. For the majority of cases where potential additivity was identified in Phase 1, there is a lack of toxicological data in the primary literature. In these cases, the results of the first phase will be useful as the default hypothesis. The resulting database integrates the results from both phases of the project. A web-based computer tool allows the user to determine whether there is potential additivity or interaction among components of a mixture.

Ototoxicity of trichloroethylene in concentrations relevant for the working environment

Organic solvents can cause hearing loss themselves or promote noise-induced hearing loss. The objective of this study was to review the literature on the effects of low-level exposure to trichloroethylene on the auditory system and consider its relevance for the occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the Quebec permissible exposure limits: 50 ppm 8-h time-weighed average exposure value (TWAEV) and 200 ppm short-term exposure value (STEV). In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at the STEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. There is no convincing evidence of trichloroethylene-induced hearing losses in workers. In rats, trichloroethylene affects the auditory function mainly in the cochlear mid- to high-frequency range with a lowest observed adverse effect level (LOAEL) of 2000 ppm. No studies on ototoxic interaction after combined exposure to noise and trichloroethylene were identified in humans. In rats, supra-additive interaction was reported. Further studies with sufficient data on the trichloroethylene exposure of workers are necessary to make a definitive conclusion. In the interim, we recommend considering trichloroethylene as an ototoxic agent.

Ethyl benzene should be considered ototoxic at occupationally relevant exposure concentrations.

Organic solvents can produce ototoxic effects in both man and experimental animals. The objective of this study was to review the literature on the effects of low-level exposure to ethyl benzene on the auditory system and consider its relevance for the occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the permissible exposure limits. In Quebec, the Time-Weighed Average Exposure Value for 8 h (TWAEV) is 100 ppm (434 mg/m3) and the Short-Term Exposure Value for 15 min (STEV) is 125 ppm (543 mg/m3). In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at STEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. In workers, there is no evidence of either ethyl benzene-induced hearing losses or ototoxic interaction after combined exposure to ethyl benzene and noise. In rats, ethyl benzene affects the auditory function mainly in the cochlear mid-frequency range and ototoxic interaction was observed after combined exposure to noise and ethyl benzene. Further studies with sufficient data on the ethyl benzene exposure of workers are necessary to make a definitive conclusion. Given the current evidence from animal studies, we recommend considering ethyl benzene as an ototoxic agent.