Hearing loss associated with organic solvent exposure: a systematic review

Mont'Alverne, Lucienne Rezende; Corona, Ana Paula; Rêgo, Marco Antônio Vasconcelos

doi:10.1590/2317-6369000113615

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Review • Rev. bras. saúde ocup. 41 • Oct 2016 • https://doi.org/10.1590/2317-6369000113615 linkcopy

Hearing loss associated with organic solvent exposure: a systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Introduction: evidences indicate chemicals as potentially otoneurotoxic agents; however, there is no consensus as to the associations between exposure characteristics and the ototoxicity of different chemicals present in industrial environments.

Objective: to review the available scientific literature in order to identify studies that point to evidence of association, or non-association, between hearing impairment and occupational exposure to organic solvents.

Method: systematic review of the literature, through query on electronic databases, considering only original articles, published from January 1987 to February 2013.

Results: thirty-one studies were included in the systematic review.

Discussion: studies have confirmed exposure to certain solvents as a risk factor for occupational hearing loss, especially in the presence of noise. Various assessment and classification methods were used regarding cochlear and/or central hearing impairment, contributing to the understanding of the extent of chemical-induced hearing loss as well as to the identification of populations at risk. However, data on appropriate diagnostic procedures, safe levels of chemical exposure and dose-response effect have not yet been fully elucidated.

Keywords:
hearing loss; organic solvents; occupational exposure; systematic review

Reference	Exposure	Study place/design	Population/Selection/Activity	Characteristics of groups	Audiological procedures	Outcomes
^{Morata et al. (1993)}	Noise/Toluene/Solvent mixture:	Brazil/Cross-sectional	190 men/random sampling/printing and paint manufacturing	(1) 50 non-exposed	PTA (0.5-8 kHz)	HL/RR prevalence:
	- toluene (main component);			(2) 50 exp. noise	Immitanciometry:	(1) 8%
	- xylene;			(3) 50 exp. noise + toluene	Decay	(2) 26%/4.1 (95%CI 1.4-12.2)
	- MEK (methyl ethyl ketone);			(4) 39 exp. solvent mixture		(3) 53%/10.9 (95%CI 4.1-28.9)
	- methyl isobutyl ketone.					(4) 18%/5.0 (95%CI 1.5-7.5)
						HL classification I: majority (3) (p<0,001)
						HL classification I-IV - predictive probability (adjusted for length of service): (3)>(4)>(2)>(1)
						Recruiting (% bigger): (2) p<0,005
						Decay (% bigger contralateral and 2 kHz): (3) p<0.001
^{Sass-Kortsak, Corey e Robertson (1995)}	Noise/Styrene	Canada/Cross-sectional	- 299 men (36.6 years ±10,7)/Convenience/Exposed: Fiber-reinforced plastic products plant Non-exposed: local offices.	(age: 36.6±10.7 years)	PTA (0.125-8 kHz) (beginning and end of work shift)	HL - overall
				(1) "directly"		- 10% compensation (0.5; 1; 2 and 3 kHz ≥ 25 dBNA);
				(2) "indirectly"		- 1/3 PA > 25 dBNA in 6 and 8 kHz.
				(3) "non-exposed"		Association between age and HL development (subjects < 50 years and HL<50 dBNA):
				Length 7.6±6.4 years		- Age: significant
						- InTSty: non-significant
						- Cigarette (P=0.001 p=0.01)
						- Extra-occupational noise: signif. ((P=0.01 β= - 0.02))
						- Extra-occupational: signif. em 4 kHz
						Correlation
						- Age and InNoise (r=0.55) - high
						- InTSty and InNoise (r=0.52) - high
						- Age and InTSty (r=0.16) - low
						Regression - InTSty/InNoise:
						- Significant association between noise and HL (3 and 4 kHz)
						- Age and InNoise: signif. interaction
						Regression - InTWA/InTWAN:
						- Association between noise and HL in 3 and 4 kHz stronger (4 kHZ - OE: P=0.006 β= 3.55)
^{Morata et al. (1997a)}	Noise/Solvent mixture:	Brazil/Cross-sectional	124 men/not informed/Rotogravure printing plant	Age average: 33.8 years (21-58)	PTA (0.5-8 kHz)	HL (3-6kHz) - 49% (overall total)
	- toluene			Study group (several combinations of solvents and noise )	Immitanciometry:	HL - age and biological marker (toluene):
	- ethyl alcohol (ethanol)			Average length of employment - years:	Decay	OR: 1.07/year of age (95%CI 1.03-1.11)
	- ethyl acetate			07 (1-25)		OR for 2.5 g/g of creatinine (100 ppm in the air): 4.4 (95%CI 2.50-7.45); 1.76/gram of hippuric acid (IC 95% 1.00-2.98)
						No significant interaction: between solvents, solvent mixture and noise, or individual solvent and noise.
^{Morata et al. (1997b)}	Noise/Solvent mixture:	South America/Cross-sectional	438 workers/Convenience/Oil refinary	(1) 41 non-exposed	PTA (0.5-8 kHz)	HL (3-6kHz) bigger number (p<0.005)/OR adjusted:
	- benzene;			(2) 89 (monitoring)	Acoustic reflex	(2) 49%/2.4 (95%CI 1.0-5.7)
	- toluene;			(3) 40 (dispatch)	Immitanciometry decay	(3) 42%/1.8 (95%CI 0.6-4.9)
	- xylene;			(4) 180 (maintenance)		(4) 50%/3 (95%CI 1.3-6.9)
	- ethylbenzene;			(5) 19 (sole previous exp. to aromatics)		(5) 42%
	- cyclohexane.			(6) 69 (quality control lab)		HL (3-6 kHz):
						(6) 15%
						Reflex decay: (2) (4) (p<0.005)
^{Sliwinska-Kowalska et al. (2001)}	Noise/Solvent mixture:	Poland/Cross-sectional	517 workers (311 men; 206 women)/Not informed/Paint and varnish companies	(1) 214 non-exposed (113 men, 101 women; 38.5±10.6 years)	PTA (1-8 kHz)	HL/RR incidence - HL in 2-8 kHz:
	- Mixed xylene isomers (ortho, meta and para);			(1a) 174		(1) 36%
	- Ethyl acetate;			(1b) 40		(2) 57,5%
	- White spirit (Detectable concentrations of toluene, butyl acetate and ethyl benzene).			(2) 207 exp. solvents (121 men, 86 women; 39.3±9.5 years)		(2a) 4.4 (95%CI 2.3-8.1)
				(2a) 104		(2b) 2.8 (95%CI 1.8-4.3)
				(2b) 103		(3) 61.5%/2.8 (95%CI 1.6-4.9)
				(3) 96 exposed noise + solvent (77 men, 19 women; 38.4±9.1 years)		OR: HL risk slightly higher in (3) than (2) (all freqs.)
				Length of employment		Higher hearing thresholds in 1-8 kHz: (2) (3)
				(2) 12.8±8.2 years		Higher hearing thresholds averages in 2-8 kHz: (3)
				(3) 12.2±8.5 years		Linear correlation:
						HL risk and solvent exposure index: not observed
						Isolated frequencies and solvent exposure index - observed (3, 4 and 6 kHz for toluene, and 2 and 3 kHz for xylene)
^{Morata et al. (2002)}	Noise/Styrene	Sweden/Cross-sectional	313 workers (278 men; 35 women)/Convenience/Fiberglass and metal products industry	(1)	PTA (0,1-8 kHz)	PTA
				(1a) 65 exp. to styrene (43 years (21-62))		(1) > thresholds in 2, 3, 4 and 6 kHz (p<0.05), being worse than the median in 4, 6 and 8 kHz (p<0.01).
				(1b) 89 exp. to styrene and noise (43 years (21-65))		(2) thresholds worse than the median in 6 and 8 kHz (p<0.01; p<0.05)
				(2) 78 exp. to noise (42 years (20-64))		HL
				(3) 81 non-exposed (45 years (26-62))		(1a) 47%
				Length of employment - years:		(1b) 48%
				(1)		(2) 42%
				(1a) 17 (01−39)		(3) 33% (no statistically significant difference between the groups)
				(1b) 15 (02−37)		2-6kHz thresholds:
				(2) 12 (01−35)		Worse for (1) compared to (2) and (3)
				(3) 18 (2−38)		OR (for each year of age)
						1.19 (95%CI 1.11-1.28)
						OR (for each 1 mmol of mandelic acid per gram of urinary creatinine)
						2.44 (95%CI 1.01-5.89).
						OR (for each 1dB of noise > 85 dB)
						1.18 (95%CI 1.01-1.34)
^{Sulkowski et al. (2002)}	Solvent mixture:	Poland/Cross-sectional	101 men/Not informed/Paint and varnish company	(1) 61 exp. solvents (39.8±11.2 years)	PTA	HL (above 1 kHz)
	- ethylbenzene;			(2) 40 non-exposed (39.2±10.5 years)	TEOAE, DPOAE	(1) 42%
	- xylene;			(1a) 20	Acoustic reflexes	(2) 5%
	- trimethylbenzene isomers;			(1b) 23	ENG	DPOAE amplitude - dBNPS
	- toluene;			(1c) 18		(1a) 1,99±6,14
	- ethyl toluene;			Length of employment		(1b) -0,31±10,90
	- styrene;			(1) 15.8±9.1 years		(1c) -2,87±9,06
	- n-propylbenzene.					(2) 7,48±4,67
^{Sliwinska-Kowalska et al. (2003)}	Noise/Styrene/Solvent mixture:	Poland/Cross-sectional	513 (men and women)/Not informed/	(1) 157 non-exposed	PTA (1-8 kHz)	HL (1 - 8kHz)/OR - HL:
	- styrene (main compound);		Exposed to solvents: plastic factory and yacht yard. Non-exposed:	(2) 356 exposed		(1) 93 (41.7%)
	- toluene;		- subgroup 1: blue-collar workers;	(2a) 194 exp. styrene		(2) 183 (63.1%)/3.9 (95%CI 2.4-6.2)
	- acetone;		- subgroup 2: metals.	(2b) 66 exp. noise		(2a) 56.2%/5.2 (95%CI 2.9-8.9)
	- dichloromethane.			(2c) 26 exp. styrene + toluene		(2b) 63.3%/3.4 (95%CI 1.7-6.4)
				(2d) 56 exp. styrene + noise		(2c) 76.8%/13.1 (95%CI 4.5-37.7)
				(2e) 14 exp.styrene + toluene + noise		(2d) 76.9%/10.9 (95%CI 4.9-24.2)
						(2e) 78.6%/21.5 (95%CI 5.1-90.1)
						Styrene and noise
						OR: 3
						Auditory threshold average in all frequencies:
						Exposed to solvents was significantly higher
						No dose-response relation for HL and solvent concentrations.
						Positive linear relation between lifetime exposure average (styrene) and auditory thresholds at 6 and 8kHz
						Difference between groups
						- Previous exposure to occupational noise (p< 0.001):
						(1) 6%
						(2) 28%
^{Chang et al. (2003)}	Noise/Carbon dissulfide	Taiwan/Cross-sectional	346 men/Sudy group: census. Control groups: (3) random and (2) census/	(1) 131 exp. noise + carbon dissulfide	PTA (0.5-8 kHz)	HL /OR - HL
			Viscose manufacturing plant (1) (3). electronics and adhesive tape industries (2)	(48.3±8.7 years)		(1) 67.9 %/6.8 (95%CI 3.9-12.1)
				(1a) 41: <14.6 ppm + ≤85 dB(A)		(1a) 1.7 (95%CI 0.8-3.7)
				(1b) 5: <14.6 ppm + >85 dB(A)		(1b) 0.8 (95%CI 0.1-7.5)
				(1c) 24: ≥14.6 ppm + ≤85 dB(A)		(1c) 35.5 (95%CI 7.8-161.3)
				(1d) 61: ≥14.6 ppm + >85 dB(A)		(1d) 18.7 (95%CI 8.1-42.9)
				(2) 105 exp. noise		(2) 32.4%
				(42.2±5.8 years)		(3) 23.6%
				(3) 110 non-exposed		HL - 40-54 dBNA
				(42.0±6.2 years)		(1) 18% (noise≤85 dB(A))
				Length of employment:		(2) 4%
				(1) 20.8±10.5 years		HL 0.5. 1 e 2 kHz: (1)
				(2) 21±5.7 years		HL 4 kHz: (2)
				(3) 11.3±6.4 years		HL 6 kHz: (1) e (2)
^{Sliwinska-Kowalska et al. (2004)}	Noise/Solvent mixture:	Poland/Cross-sectional	906 (men and women)/Not informed/	Controls of the same company	PTA (1-8 kHz)	HL/OR - HL:
	- xylene isomers;		Exposed: dockyard.	(1) 517 exp. noise + solvent (37.4±9.2 years)		(1) 67.5 %/4.8 (IC 95% 3.9-7.6)
	- ethylbenzene;		Not exposed: white-collar workers.	(2) 184 exp. noise (42.2±9.3 years)		(2) 64.7 %/3.3 (IC 95% 2.0-5.4)
	- ethyl acetate;			(3) non-exposed (39.8±.3 years)		(3) 39.5 %
	- butyl acetate;					OR for each year of age: 1.12
	- n-butanol;					OR for for each dB(A) average of total exposure time to noise: 1.07
	- white spirit.					OR for each increase in lifetime exposure index to solvents: 1.00
						Lower thresholds for (1) and (2), especially at 8 kHz (worst at (1) - positive linear correlation with exposure time to solvents)

^{Kim et al. (2005)}	Noise/Solvent mixture:	Korea/Cross-sectional	328 men/Convenience/ Aircraft industry	According to "Cumulative exposure index":	PTA (0.5 - 8 kHz)	HL/OR (adjusted) for HL:
	- toluene;			(1) 151 non-exposed (31.1±6.3 years)		(1) 6.0%
	- xylene;			(2) 146 exp. noise (31.2±6.1 years)		(2) 17.1%/4.8 (IC 95% 1.71-10.75)
	- methyl ethyl ketone			(3) 18 exp. solvent (38.6±6.0 years)		(3) 27.8%/2.57 (IC 95% 0.64-10.31)
	(all samples).			(4) 13 exp. noise + solvent (39.6±4.7 years)		(4) 54.6%/8.12 (IC 95% 2.03-32.53)
^{Kaufman et al. (2005)}	Noise/Solvent mixture:	USA/Cross-sectional	138 workers/Not informed/Military facility (aircraft maintenance and other workers)	(1) 90 exposed	Automatic PTA (0.5-6 kHz)	OR for HL by combined "noise and solvent" exp.:
	- benzene;			(42.8±6.0 years)		03 years - 1.70 (95%CI 1.14-2.3)
	- toluene;			(2) 48 non-exposed		12 years - 8.25 (95%CI 1.67-55.6)
	- xylene;			(40.8±9.9 years)		OR for regular intake of alcoholic beverage: 3.03 (IC95% 1.42-6.45)
	- hexane;			Years of employment:
	- heptane;			(1) 15.8±5.4
	- kerosene (aviation).			(2) 15.6±7.2
^{Seeber et al. (2005)}	Toluene	Germany/ Retrospective cohort (5 years of follow-up)	216 workers (initially: 333 workers)/ Convenience/Printing plant	(1) 106 high exp.	PTA (0.125; 0.25; 0.5; 0.75; 1; 1.5; 2 - 12 kHz)	"Cases"
				(2) 86 low exp.		(1) 29
				(a) short exp.		(2) 28
				(b) long exp.		OR: 0.791 (95%CI 0.42-1.50)
				Exposure time - average:
				(a) 6 years
				(b) 21 years
^{Sliwinska-Kowalska et al. (2005)}	Noise/Solvent mixture:	Poland/Cross-sectional	1117 workers/Not informed/	(1) 731 exp. solvent mixture (xylene)	PTA (1; 1.5-8 kHz)	HL/OR/ PTA freqs.:
	- xylene as main component;		(1) (2) (3): lacquers and paints, footwear, plastics, ship and yacht. (4a): metal factory. (4b): white-collar workers	(38.0±9.4 years)		(1) 63.1%/2.4 (p<0.001)/4; 6 e 8 kHz
	- mainly to styrene;			(2) 290 exp. styrene		(2) 63.1%/3.9 (p<0.001)/1-8 kHz
	- n-hexane and toluene.			(34.5±7.9 years)		(3) 73%/5.3 (p<0.001)/6 e 8 kHz
				(3) 96 exp. n-hexane and toluene		(4) 41.7%
				(39.0±8.7 years)		Only exp. to solvents
				(4) 223 non-exposed to solvents		OR: 4.1-5.2 times greater than controls
				(40.0±9.4 years)		Only exp. to noise
				(4a) 66 exp. noise		OR: 3.8 times greater than controls
				(4b) 157 non-exp. noise		Co-exp. to "noise e solvent"
						OR: 6.7-21.5
						Co-exp. to "noise and two solvents"
						OR: 20
^{Chang et al. (2006)}	Noise/Toluen	Taiwan/Cross-sectional	174 men/Census/Adhesive material manufacturing	(1) 58 exp. toluene + noise	PTA (0.5-6 kHz)	HL - including 0.5 kHz/excluding 0.5 kHz
				(1a)		(1) 86.2%/67.2%
				(1b)		(2a) 44.8%/32.8%
				(1c)		(2b) 5.0%/8.3%
				(2) 118 reference		OR - including 0.5 kHz/excluding 0.5 kHz
				(2a) 58 exp. noise		(1) 10.9 times higher than (2a)/5.8 times higher than (2a)
				(2b) 60 management		Poor thresholds in all frequencies, markedly at 4 and 6 kHz, for (1) e (2a), with 1 kHz worse in (1).
				Average age:		Adjusted OR - including 0.5 kHz/excluding 0.5 kHz (1) 140 (95%CI 32.1-608)/29.1 (95%CI 9.3-91.4)
				(1) 40.0±9.7
				(2a) 41.5±3.1
				(2b) 40.9±3.4
				Length of employment:
				(1) 12.3±8.81
				(2a) 11.5±5.73
				(2b) 9.52±5.26
^{Johnson et al. (2006)}	Noise/Styrene	Sweden/Cross-sectional	313 (278 men; 35 women)/ (1) convenience; (2) equal selection to (1); (3) random/	(1)	PTA (0,1-8 kHz)	PTA
			(1) fiberglass products manufacturing; (2) metal products manufacturing; (3) mail terminal	(1a) 89 exp. to styrene (43 years (21-62))	DPOAE	(1) > thresholds at 2, 3, 4 and 6 kHz (p<0.05), being worse than median at 4. 6 and 8 kHz (p<0.01).
				(1b) 81 exp. to styrene and noise (43 years (21-65))	MTF	(2) thresholds worse than median at 6 and 8 kHz (p<0.01; p< 0.05)
				(2) 65 exp. to noise (42 years (20-64))	ACR	PTA after 03 years: 20% of individuals with worse auditory thresholds at one frequency at least
				(3) 78 non-exposed (45 years (26-62))	IS	MTF - threshold average
				Length of employment - years:	Speech in noise	Significant difference between (1b) and (3) and between (1b) and (2), with reduced peak values for (2)
				(1)		DPOAE - "input-output"
				(1a) 17 (01-39)		Interaction between exposed groups and signal level (p<0.006)
				(1b) 15 (02-37)		- signal up to 50 dB: (2) and (3) DPOAE higher than (1)
				(2) 12 (01-35)		- signal > 50 dB: (3) DPOAE level stabilized, (1) and (2) fell
				(3) 18 (2-38)		ACR
						(1) and (2) difference over latency score (p<0.05) compared to (3)
						Interrupted speech
						No difference in score average between groups
						Compared to reference values: (1) below 93% or 78% of corrects answers (p<0.05)
						Speech in noise
						Difference between groups (p<0.001)
						Compared to reference values: (1) and (2) below - 7.8 S/N (p<0.05)
^{Schäper, Seeber e Van Thriel (2008)}	Noise/Toluene	Germany/Cohort (5 years)	Men	Follow-ups:	PTA (0.125-0.5; 0.75; 1; 1.5; 2-8; 12 kHz)	PA: 36%
			Initial total: 333 (100%)	- initial: 333 (100%)		Effect of noise intensity on threshold average was almost twice the effect of toluene intensity.
			Final total: 216 (64,9%)	- 2: 278 (83.5%)		Differences between exposure level or length in cases and noncases were not significant (p = 0.49; p = 0.51 respectively).
			(complete data for 192 participants)/Convenience/ Rotogravure printing	- 3: 241 (72.4%)		HL high frequencies (subsample with biomarkers): 36%
				- 4: 216 (64.9%)		No exposure variable found any significance in the statistical model.
				Complete data for 192 participants
				Stratification by intensity of exp. to toluene:
				(1) 106 high exp.
				(2) 86 low exp.
				Stratification by length of exp. to toluene:
				(3) long exp.
				(4) short exp.
				Stratification by intensity of exp. to noise:
				(5) high exp.
				(6) low exp.
				Exposure time to toluene and noise - years:
				(3) 21.3±6.5
				(4) 5.9±2.2
^{Rabinowitz et al. (2008)}	Noise/Carbon Monoxide/Solvent mixture:	USA/Retrospective cohort (5 years)	1319 (men and women)/ Census/Aluminium industry	1319 subjects	PTA	OR (HL dichotomous outcome/exp.>5 years)
	- toluene;			(30.4±3.7 years): 1167 men		(1) 1.87 (95%CI 1.22-2.89; p=0.04)
	- xylene;			(1) 116 (8.8%) solv. exp.
	- methyl ethyl ketone.			(solv. exp. index >1)
				(2) 140 (10.6%) carbon monoxide exp.
				(solv. exp. index >1)
^{Triebig, Bruckner e Seeber et al. (2008)}	Styrene	Germany/Cross-sectional - with repetition measures	155 men/Census/Boat building	- 128 more exp. styrene	PTA PTA high freqs. (9-16 kHz) TOAE	HL: 105 "cases"/132 "non-cases"
				- 127 less exp. (5-25 ppm (below 200mg/g creat.))		High exp.: 55%/45%
				According to biomarkers - all participants:		Low exp.: 41%/59%
				(1a) 99 low exp. (37.8±8.9 years)		(2a) 35%/65%
				(1b) 118 medium exp. (38.5±8.9 years)		(2b) 60%/40%
				(1c) 31 high exp. (37.9± 11years)		Auditory thresholds (dB) between 8 e 12.5 kHz slightly different between the high and low exposure groups, with no dose-response effect.
				According to exposure length - " extreme groups":		Change in chronic exposure from (2a) to (2b): OR 7.46 (IC>1) for HL
				(2a) 34 "low-short" exp. (42.6±8.4 years)		TEOAE
				(2b) 17 "high-long" exp. (43.5±11.1 years)		No direct association between the groups and S/N relation or amplitude.
				Length of employment - years:
				(1a) 6.2±4.3 (1-26)
				(1b) 5.7±3.6 (1-23)
				(1c) 6.3±4.8 (1-26)
				(2a) 6.4±3.4 (2-16)
				(2b) 14.6±6.7 (10-26)
^{Fuente et al. (2009)}	Solvent mixture:	New Haven - USA/ Cross-sectional	110 participants/Census/ Coating factory	(1) 20 minimum exp. (38.1±11.6 years; 12 women. 08 men)	PTA (0,5-8 kHz)	Altered PTA in 69 subjects/Altered PTA high freqs. in 22 subjects
	- toluene;			(2) 18 moderate exp. (41.0±12.4 years; 01 woman. 17 men)	PTA high freqs. (12 and 16 kHz)	(1) 25%
	- methyl ethyl ketone.			(3) 72 maximum exp. (39.5±11.4 years. 04 women . 68 men)	DD	(2) 61%/16.6%
	Less quantity:			(categorized by a hygeniest)		(3) 73.6%/26.4%
	- trichlorethylene;					(1) thresholds better than (3) (PTA p=0.004; PTA high freqs. p=0.034)
	- acetone;					DD
	- n-methyl-pyrrolidone;					(1) better responses than (2) (p=0.001) and (3) (p=0.000)
	- dimethylformamide;					Estimate for subjects with normal PTA: (2) -0.382(3) - 0.471
	-clorobenzeno;					Estimate for all subjects: (2) -0.274(3) - 0.386
	- isopropyl alcohol.
^{Zamyslowska-Szmytke et al. (2009)}	Styrene	Poland/Cross-sectional	109 workers/Not informed/ Fiberglass for manufacturing	(1) 59 exp. styrene (40±09 years; 6 women, 53 men)	PTA (0.125-8 kHz)	PTA
				(2) 50 non-exposed (37±11 years; 16 women, 34 men)	GIN	(1) worse thresholds (0.25-8kHz)
					FPT	(1) 86.4%
					DPT	(2) 34%
						GIN/FPT /DPT
						(1) worse averages
						(1) 24%/59%/85%
						(2) 12%/20%/26%
						(1) Chi-square/ANCOVA adjusted for age and HL
						FPT: 11.7 (p<0.01) /6.8 (p<0.01)
						DPT: 26.4 (p<0.01) /19.3 (p<0.001)
						GIN: 1.2 (p>0.05)
^{Guest et al. (2010)}	Noise/Aircraft fuel (F-111)	Australia/Cross-sectional (with serial measurements)	1530 workers/(1) convenience; (2) (3) random/Royal Australian Air Force	(1) 605 exposed (98% men; 87%<55years)	PTA (0.5; 1; 1.5-8 kHz)	Overall HL: 25% of clinically significant difference (compensation).
				(2) 510 technical comparison - different base, same function (99% men; 91%<55years)		PTA
				(3) 398 no technical comparison - same base, different function (99% men; 90%<55years )		(0.5; 1; 1.5-8 kHz) worse than normalcy standard (presence of a noise notch at 6 kHz)
						OR for HL: similar among the three groups
						(2) 1.1 (CI95% 0.2-2.0)
						(3) 0.9 (CI95% 0.6-1.3)
^{Mohammadi, Labbafinejad e Attarchi et al. (2010)}	Noise/Solvent mixture:	Iran/Cross-sectional	441 men/Census/ Automobile plant	Average age: (33.07 years; 20-58 years)	PTA (0.5-8 kHz)	HL (average 3-8kHz)/adjusted OR
	- benzene;			(1) 173 exp. noise (33.36±6.95 years)		(1) 24.08±11.89/1
	- toluene;			(2) 104 exp. solvents - within limits (31.87±5.49)		(2) 25.71±7.01/1.8 (95%CI 1.08-3.03)
	- xylene;			(3) 164 exp. noise + solvents - above limits (33.53±6.22)		(3) 32.77±16.04/4.13 (95%CI 2.59-6.58)
	- tetrachlorethylene;			Length of employment:		(3) more common (p<0.001))
	- acetone.			8.06 years (0.5 a 30 years)
^{Beshir, Elserougy e Amer (2011)}	Noise/Solvent mixture:	Sadat - Egypt/ Cross-sectional	204 men/(1) census; (2) (3) not informed/Ceramics plant	(1) 44 exp. solvent mixture (36±2 years)	PTA (0.25-2; 4; 8 kHz)	HL - 0.5; 1 and 4 kHz
	- acetone;			(2) 73 exp. noise (38.1±7.3 years)		(1) 72.7%; 45.5%; 45.5%
	- butanol;			(3) 87 non-exposed (37±3.5 years)		(2) 94.5%; 69.9%; 67.1%
	- ethanol;			Length of exposure:		(p<0.05)
	- ethyl acetate;			(1) 16±6		(1) more common at 8 kHz than 4 kHz
	- isopropanol;			(2) 15±9		(2) more common at 4 kHz than 8 kHz
	- toluene;					v-notched
	- xylene.					(1) 63.3%
						(2) 31.5%
						(p<0.01)
						Correlation between exp. length and freqs. of 4 and 8 kHz (adjusted)
						(1) 0.795 (p=0.000) and 0.869 (p=0.000)
^{Fuente, Mcpherson e Hickson (2011)}	Solvent mixture:	Chile/Cross-sectional	92 workers/(1) not informed; (2) convenience/ (1) paint factories; (2) University of Chile/Chilean police officers	(1) 46 exp. solvent mixture (37.3±8.2 years; 41 men and 05 women)	PTA (0.5-8 kHz)	Normal auditory thresholds (inclusion criterion), but worse for (1) at freqs. of 1, 2 and 3 kHz.
	- toluene;			(2) 46 non-exposed (36.1±6.1 years; 41 men and 5 women)	RGD	Score differences between groups (adjusted)
	- xylene;			Length of exposure:	MLD	DD (F=4.77; p=0.032)
	- methyl ethyl ketone;			(1) 02 to 30 years (13.3±8.2 years)	PPS	PPS (F=2.87; p=0.014)
	- varsol.				DD	FS (F=5.85; p<0.0001)
					FS	RGD (1; 2; 4 kHz) (F=3.22; 2.83; 4.20 p<0.02, respectively)
					HINT	HINT SRT (F= 13.3 p<0.0001)
						No statistically significant difference was observed for MLD and HINT (speech-in-noise subtests)
^{Morata et al. (2011)}	Noise/Styrene	Finland, Sweden and Poland/Cross-sectional	Initial totall:	(1) 423 exp. solvents	PTA (0.125-8 kHz)	(1) and (2) worse thresholds than reference standard at all frequencies.
			1620 workers (1276 men; 312 women; 32 gender not informed). Final total: 1404 workers/Not informed/ Fiberglass products plants; industries: metal, wood products, yacht yard and office work.	(2) 268 exp. noise + solvents		(1) p=0.0001
				(3) 359 exp. noise		(2) p=0.0192
				(4) 354 non-exposed		OR for HL (for each year of age and each increase of 1 mg/m³ of styrene):
				Age - years: 18-63		(1) 1.0188 (95%CI 1.0140-1.0236)
						(2) 1.0055 (95%CI 1.0009-1.0102)
						(3) 1.01 (95%CI 0.99-1.03)
^{Kaewboonchoo et al. (2013)}	Noise/Solvent mixture:	Thailand/Cross-sectional	149 men/Census/ Thailand Navy officers	Age: (20-56 years)	PTA (0.5;1; 2; 4; 8 kHz)	HL in 40 % of workers
	- toluene;			Exposed to solvents: 103 (69.1%)		Inclination at 4 kHz: 22.8%
	- xylene;			Length of employment: 0		High frequencies: 14.8%
	- ethyl acetate;			1 a 36 years (31.5%>08 years; 6.9±8.5 years)		Adjusted OR
	- butyl acetate;					Age: 15.83 (IC 95% 3.39-73.92)
	- cyclohexane.					Length of service: 2.19 (95%CI 1.01-4.97)
						Correlation coefficient adjusted for age
						Length of service - frequency of 4 kHz: 0.108 (p<0.05)
^{Fuente, Mcpherson e Cardemil et al.(2013)}	Misture of xylene isomers	Santiago - Chile/ Cross-sectional	60 workers/Convenience/ (1) public hospital histology lab; (2) University of Chile	(1) 30 exp. xylene (15 men. 15 women; 37.1±10.7 years)	PTA (0.25-8 kHz) BAEP DPOAE PPS ATTR DD MLD HINT	HL - 0.5 - 8 kHz
				- cumulative dose of methyl hippuric acid:		(1) thresholds worse than (2)
				(1a) 10		DPOAE adjusted for age
				(1b) 10		No statistically significant difference between (1) and (2)
				(1c) 10		(associated age p≤0.001)
				(2) 30 non-exposed (15 men. 15 women. 35.9 ±11.7 years)		BAEP adjusted for age
				- comared to study subgroups:		(1) greater latencies I, III e V) and inter-peak intervals (I-III, III-V e I-V) (p=0.001)
				(2a) 10		(age not statistically associated)
				(2b) 10		Score difference between groups (adjusted for age)
				(2c) 10		PPS (F=8.04 p<0.01)
				Length of exposure (self-reported):		DD (F=9.03 p<0.01)
				11.8±10.5 years (02-29 years)		HINT (final score) (F=13.77; p<0.0001)
						No statistically significant difference was observed for MLD, ATTR e HINT SRT (p>0.05)
						(age associated with HINT (final score) and PPS (p<0.01 and p<0.0001, respectively))
						BEI in (1)
						Moderate positive correlation between BEI (p=0.42) and binaural average of hearing levels at 2-8kHz (p=0.02). BEI concentrations predicted the binaural average of hearing levels (β=0.59. p<0.01): for each 1g/g of creatinine, increase of 0.034 dBNA.
						No correlation with the remaining procedures (p>0.05)
						Dose-response effect and PTA - average
						(1a) 8.1±6.7
						(1b) 9.0±3.9
						(1c) 20.7±9.1
						((1a) e (1b) significantly different from (1c))
						(1c) different from (2) (p<0.01)
						Dose-response effect and DPOAE - average
						(1a) 4.15±8.78
						(1c) -4.04±6.03
						((1a) e (1c) significantly different)
						(1b) -0.57±5.39
						There was no significant difference between the subgroups
						"Dose-response effect" subgroups and the remaining procedures.
^{Fuente, Mcpherson e Hickson (2013)}	Solvent mixture:	Santiago - Chile/ Cross-sectional	144 workers/convenience/ Paint factory	(1) 72 exp. solvents (66 men. 6 women; 39.9±8.5 years)	PTA (0.25-8 kHz)	PTA
	- methyl ethyl ketone;			(2) 72 non-exposed (58 men. 14 women; 37.5±7.1years)	BAEP	(1) worse thresholds (1, 2, 3 and 8 kHz) than (2) (p<0.003)
	- tolueno;			Length of employment - exp. to solvents:	TEOAE	TEOAE
	- xylene;			(1) 15.8±8.1 years	RGD	(1) worse S/R ration than (2) (p<0.01)
	- thinner (Stoddard solvent -mineral spirit);				HINT	CAP testing
	less quantity:					Worse scores (1) for RGD, HINT SRT, HINT1, HINT 2 and HINT (final score) - (p<0.05)
	- benzol;					No statistically significant difference between was observed for HINT3 (p>0.05)
	- esters;
	- alcohol.
^{Fuente, Mcpherson e Hormazabal et al. (2013)}	Solvent mixture:	Santiago - Chile/ Cross-sectional	96 workers/census/Paint factory	(1) 48 exp. solvents (38.6±7.1 years)	PTA (0.5-8 kHz) RGD AIADH	PTA - threshold average (dBNA) OD/OE
	- methyl ethyl ketone;			(2) 48 non-exposed (36.8±4.8years)		(1) 9.2±5.6/10.1±5.6 (worse thresholds at 0.5-4 kHz)
	- toluene;			Length of exp. to solvents:		(2) 7.1±4.3/8.4±4.1
	- xylene;			(1) 13.5 years		None of the subjects showed HL according to WHO
	- Stoddard solvent.					RGD
						(1) worse results
						(difference between (1) and (2) (p<0.05))
^{Hughes e Hunting (2013)}	Noise/JP -8 (aircraft kerosene)/Solvent mixture:	USA/Retrospective cohort (3.2 years)	503 workers (94,6% male)/ Not informed/US Air Force Reserve	(1) 148 exp. noise	PTA 0.25-8 kHz shift threshold standard (STS):	Shift threshold standard (STS) - average of worse ear not informed:
	- toluene;			(2) 65 exp. solvents	≥ 10dB, in either ear, between 2 and 4 kHz, based on reference exam.	(1) 11±7.4
	- styrene;			(3) 220 exp. noise + solvents	Categories:	(2) 3±4.6
	- xylene;			(4) 70 non-exposed (94.6% men)	- STS (≥10 dB)	(3) 12±5.5
	- benzene.			Age (years) at date of first audiogram - median:	- hearing loss (>0 a <10 dB)	(4) 6±8.6
				(1) 28.5±8.5	- no hearing loss (≤0 dB)	RR for HL - worse ear:
				(2) 34.0±8.7		(1) 1.1 (CI95% 0.9-1.4)
				(3) 30.5±8.4		(2) 0.8 (CI95% 0.6-1.2)
				(4) 30.0±10.0		(3) 1.2 (CI95% 0.9-1.5)
				Length of follow-up - years:		(4) 1.1 (CI95% 0.7-1.5)
				(1) 3.5±2.4		Study follow-up length associated with increased HL chance (OR=1.23.CI95% 1.12 - 1.35) for each follow-up year.
				(2) 1.8±1.7
				(3) 3.3±2.0
				(4) 3.4±1.7

Substance	Below OEL and absence/noise <85 dB(A)	Above OEL and absence/noise <85 dB(A)	Below OEL and noise ≥85 dB(A)	Above OEL and/ noise ≥85 dB(A)	Association	Hearing impairment	References
Styrene				X	-	P	^{Sass-Kortsak, Corey and Robert- son (1995)}
			X		+	P	^{Morata et al. (2002)}
				X	+	P	^{Sliwinska-Kowalska et al. (2003)}
			X		+	P	^{Johnson et al. (2006)}
	X				+	P	^{Triebig, Bruckner and Seeber (2008)}
	X	X			+	P and HS	^{Zamyslowska-Szmytke et al. (2009)}
					+	P	^{Morata et al. (2011)}
Toluene				X	+	P and C	^{Morata et al. (1993)}
	X				-	P	^{Seeber et al. (2005)}
		X			+	P	^{Chang et al. (2006)}
	X	X			-	P	^{Schäper, Seeber and Van Thriel (2008)}
Carbon dissulfide			X	X	+	P	^{Chang et al. (2003)}
Xylene	X				+	P, C and HS	^{Fuente et al. (2013)}
Solvent Mixture				X	+	P	^{Morata et al. (1997a)}
	X				+	P and C	^{Morata et al. (1997b)}
	X				+	P	^{Sliwinska-Kowalska et al. (2001)}
	X	X			+	P	^{Sulkowski et al. (2002)}
				X	+	P	^{Sliwinska-Kowalska et al. (2004)}
			X		+	P	^{Kaufman et al. (2005)}
			X		+	P	^{Kim et al. (2005)}
			X	X	+	P	^{Sliwinska-Kowalska et al. (2005)}
					+	P	^{Rabinowitz et al. (2008)}
	X				+	P and HS	^{Fuente et al. (2009)}
				*X	-	P	^{Guest et al. (2010)}
				X	+	P	^{Mohammadi, Labbafinejad and Attarchi (2010)}
	X				-	P	^{Beshir, Elserougy and Amer (2011)}
	X				+	P and HS	^{Fuente et al. (2011)}
	X				+	P and HS	^{Fuente et al. (2013)}
	X				+	P and HS	^{Fuente et al. (2013)}
			X		-	P	^{Hughes and Hunting (2013)}
	X				+	P	^{Kaewboonchoo et al. (2014)}

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[TFN7] * MEK: methyl ethyl ketone. POS: Psycho-Organic Syndrome. PTA: Pure Tone Audiometry. SRT: Speech Reception Threshold. SRPI: Speech Recognition Percentage Index. IS: Interrupted Speech. DS: Distorted Speech. BAEP: Brainstem Auditory Evoked Potential. CRA: Auditory Cortical Response. ENG: Electronystagmography. CTE: Solvent-Induced Chronic Toxic Encephalopathy. TEOAE: Transient Otoacoustic Emissions. DPOAE: Distortion Product Otoacoustic Emissions. S/R: Signal to Noise Ratio. RGD: Random Gap Detection. MLD: Masking Level Difference. PPS: Pitch Pattern Sequence. DD: Dichotic Digit. FS: Filtered Speech. HINT: Hearing-In-Noise Test. MTF: Psychoacoustic Modulation Transfer Function. AIADH: Amsterdam Inventory for Auditory Disability and Handicap. GIN: Gaps-in-noise. FPT: Frequency Pattern Test. DPT: Duration Pattern Test. FS: Filtered Speech. ATTR: Adaptive Test of Temporal Resolution. STS: Shift Threshold Standard.