m-xylene

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Human population study, published in peer-reviewed literature, notable limitations in design and/or reporting but contributing to a weight of evidence assessment.

Data source

Reference

Reference Type:

publication

Title:

Xylene-Induced Auditory Dysfunction in Humans

Author:

Fuente A, McPherson B, and Cardemil F

Year:

2013

Bibliographic source:

Ear and Hearing, 34, 651-660

Materials and methods

Study type:

cross sectional study

Endpoint addressed:

neurotoxicity

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The auditory function of 30 medical laboratory workers (15 males and 15 females) who had been exposed to a mixture of xylene isomers was compared to that of 30 non-exposed workers matched for gender, age, and educational level. Xylene-exposed participants were not exposed to noise levels above 85 dBA time-weighted average.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Xylene

EC Number:

215-535-7

EC Name:

Xylene

Cas Number:

1330-20-7

Molecular formula:

C8H10

IUPAC Name:

xylene

Details on test material:

The xylene mixture used contained approximately 21% p-xylene.

Method

Ethical approval:

confirmed and informed consent free of coercion received

Details on study design:

The auditory function of 15 male and 15 female workers exposed to a mixture of xylene isomers and recruited from 9 histology laboratories in public hospitals in Santiago, Chile, was compared to that of 30 non-exposed residents of the same city. Comparison subjects, selected from volunteers who responded to public advertisements, did not have a history of exposure to solvents or excessive noise and were matched for gender, age (± 4 years), and educational level. Xylene-exposed subjects had mean age 37.1 (SD=10.7) years and comparison subjects had mean age 35.9 (SD=11.7) years. Participants were excluded if they reported a history of neurological, metabolic and cardiovascular diseases, repetitive episodes of otitis media, or exposure to high levels of noise in previous jobs, or participated in noisy activities on a regular basis. Participants were also excluded if otoscopy revealed pathological alterations of the external ear canal. Xylene-exposed participants were not exposed to noise levels above 85 dBA time-weighted average. All participants were evaluated in a sound-treated room, using a comprehensive audiological test battery, which included measures of peripheral and central auditory function. Xylene-exposed participants were evaluated before their shift commenced (around 9 A.M.), approximately 16 hours after their last exposure.

Exposure assessment:

estimated

Details on exposure:

Xylene-exposed participants were extensively interviewed regarding solvent and noise exposure in their current and previous jobs. All workers reported direct xylene exposure in their current histology laboratory jobs and some of them reported xylene exposure in previous jobs. The xylene mixture used contained approximately 21% of para-xylene. Subjects reported intermittent xylene exposure which only occurred when they prepared samples of human tissue for further microscopic examination, and the airborne xylene concentration depended on the number of tissue samples requiring examination. The self-reported mean duration of xylene exposure was 11.8 (SD=10.5) years, with a range of 2 to 29 years. Airborne xylene samples were collected at 11 different work stations throughout the 9 histology laboratories studied. The mean airborne xylene concentration was 36.5 (SD=66.6) mg/m3, with a highest recording of 217 mg/m3, below the permissible exposure limit for xylene in Chile of 347 mg/m3 (8-hr time-weighted average). Urine samples from each xylene-exposed worker were collected at the end of the last work shift of a working week, and the methyl hippuric acid concentration was determined. The mean concentration of methyl hippuric acid was 216.3 (SD=44.2) mg per gram of creatinine in urine, with a highest recording of 2237 mg per gram of creatinine in urine. Cumulative exposure to xylene was calculated by multiplying the concentration of methyl hippuric acid by the number of years of xylene exposure, and subjects were categorised into 3 subgroups (low, moderate and high) containing equal number of participants (n = 10) on the basis of their cumulative xylene exposure. Noise dosimetry was also performed on each xylene exposed subject. The mean daily noise exposure level for a nominal 8-hr working day was 72.9 (SD=4.5) dBA, with a maximum of 84.5 dBA.

Statistical methods:

Group comparisons for pure-tone hearing thresholds were made using Student's t test. The mean values of DPOAEs, ABR, MLD, ATTR, DD, PPS, and HINT among xylene-exposed and non-exposed participants were compared using Analysis of Covariance (ANCOVA) adjusted for age (all dependent variables), and binaural average hearing level (MLD, ATTR, DD, PPS, and HINT). Binaural average hearing level was calculated as the average of the right and left ear hearing thresholds for the frequencies 0.25, 0.5, I, 2, 4 6, and 8 kHz. A Wilcoxon test was performed to compare PPS and DD scores for the right and left ear. For xylene-exposed participants, Spearman correlations and simple linear regression models were used to examine the relationship between methyl hippuric acid concentration in urine and selected auditory function test scores (MLD, ATTR, HINT SRT, and HINT composite scores, hearing level, and the binaural averages of DPOAE amplitudes (2 to 8 kHz), ABR wave V, ABR III to V IPL, PPS and DD scores), and one-way analyses of variance (ANOVA) with Tukey's honestly significant difference (HSD) post hoc test were performed to identify possible significant differences in the same auditory function test scores between the 3 xylene cumulative exposure groups. For auditory outcomes displaying significant differences between the cumulative exposure groups, the test results of xylene-exposed subjects in each cumulative exposure subgroup (low, moderate, and high) were compared (Student’s t test) with their respective matched controls in order to control for confounding by age.

Results and discussion

Results:

All participants presented with either normal hearing or sensorineural hearing loss, type A results for tympanometry. Xylene-exposed participants presented with worse pure-tone thresholds for all of the frequencies tested, and audiometric hearing thresholds were statistically significantly worse at 0.5, 1, 2, 3, 4, and 8kHz for the right ear and at 0.5, 1, 3, and 6 kHz for the left ear. The xylene-exposed participants demonstrated significantly worse results than the control group participants for the PPS test, DD test, the ABR test (absolute and interpeak latencies), and the HINT composite score. No significant differences between groups were observed for DPOAEs at the explored frequencies for both ears, the ATTR, MLD and HINT SRT tests. Concentrations of methyl hippuric acid in urine were significantly correlated with binaural average hearing level in xylene-exposed workers, but not with other auditory function test scores. There was a statistically significant difference in the mean binaural average of hearing level for the 3 xylene exposure subgroups (p < 0.0I), and in the binaural average DPOAE amplitude (p=0.04). Post hoc comparisons using Tukey's HSD test indicated that the mean binaural average hearing level for the low-exposure subgroup (8.1 dB) and the moderate-exposure subgroup (9.6 dB) were significantly different from the high-exposure subgroup (20.7 dB). The mean binaural average hearing levels for the high-exposure subgroup and their matched control participants were also significantly different. The mean binaural average DPOAE amplitudes for the high and low exposure subgroups were significantly different, but there was no significant difference between xylene-exposed participants from the cumulative exposure groups and their respective matched control participants.

Confounding factors:

The exposed and non-exposed groups were matched for age and sex. No adjustment was made for noise exposure, although participants stated that they had not been exposed to excessive levels.

Strengths and weaknesses:

Strengths:
-comprehensive assessment of auditory function.

Weaknesses:
-noise and xylene exposure levels were measured in a cross-sectional manner.
- cumulative xylene exposure was based on a single determination of methyl hippuric acid and self-reported duration of exposure.
-the time between all testing in the exposed group and their last exposure was only 16 hr and any observed adverse effects of xylene exposure on the auditory system may be temporary, not permanent

Applicant's summary and conclusion

Conclusions:

The results of the study provide limited evidence that xylene may induce a decrement in pure-tone hearing thresholds as well as in some central auditory nervous system functions such as temporal ordering, binaural integration, and speech perception in noise, but dose-response relationships were not observed between xylene exposure and the outcomes for central auditory nervous system function. It could not be determined whether the adverse effects are acute or permanent. Outer hair cell dysfunction is not indicated by the nonsignificant differences in DPOAE amplitudes between xylene-exposed and non-exposed.

Executive summary:

The auditory function of 30 medical laboratory workers (15 males and 15 females) who had been exposed to a mixture of xylene isomers was compared to that of 30 non-exposed workers matched for gender, age, and educational level. Participants of both groups were not exposed to noise levels above 85 dBA time-weighted average. All participants were evaluated in a sound-treated room, using a comprehensive audiological test battery, which included measures of peripheral and central auditory function. Xylene-exposed participants were evaluated before their shift commenced, approximately 16 hours after their last exposure. Airborne xylene samples were collected at 11 different work stations throughout the 9 histology laboratories studied. The mean airborne xylene concentration was 36.5 mg/m³. Urine samples were collected from each xylene-exposed worker and the methyl hippuric acid concentration was determined. The mean concentration of methyl hippuric acid was 216.3 mg per gram of creatinine in urine. Noise dosimetry was also performed on each xylene exposed subject and the mean daily noise exposure level was 72.9 dBA. The xylene-exposed participants showed significantly worse pure-tone thresholds in comparison with the nonexposed participants. The xylene-exposed participants demonstrated significantly worse results than the control group participants for the pitch pattern sequence test, dichotic digit test, speech recognition in noise test, and the auditory brainstem response (absolute and interpeak latencies). A significant correlation between the concentrations of methyl hippuric acid in urine and binaural average hearing level (2 to 8kHz) was found in xylene-exposed workers. Also, participants with high cumulative dose of xylene exposure presented with poorer test results than participants with low cumulative dose of xylene exposure. The results of the study provide limited evidence that xylene may induce a decrement in pure-tone hearing thresholds as well as in some central auditory nervous system functions such as temporal ordering, binaural integration, and speech perception in noise, but dose-response relationships were not observed between xylene exposure and the outcomes for central auditory nervous system function. It could not be determined whether the adverse effects are acute or permanent. Outer hair cell dysfunction is not indicated by the nonsignificant differences in DPOAE amplitudes between xylene-exposed and nonexposed.