Sleep disturbances and occupational exposure to solvents

Sleep Medicine Reviews 13 (2009) 235–243

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Sleep Medicine Reviews journal homepage: www.elsevier.com/locate/smrv

CLINICAL REVIEW

Sleep disturbances and occupational exposure to solvents Mineke Viaene a, b, *, Griet Vermeir b, Lode Godderis a a b

Department of Occupational, Environmental and Insurance Medicine, Catholic University of Leuven, UZ St. Rafae¨l, Kapucijnenvoer 35d5th floor, 3000 Leuven, Belgium Expertise Centre of Neurotoxicology and Neuropsychology, Governmental Psychiatric Hospital, Dr. Sanodreef 4, 2440 Geel, Belgium

s u m m a r y Keywords: Fatigue Chronic solvent encephalopathy Insomnia Sleep apnoea syndrome Organic solvents Occupational exposure

A solvent can be defined as ‘‘a liquid that has the ability to dissolve, suspend or extract other materials, without chemical change to the material or solvent’’. Numerous chemical or technical processes rely on these specific properties of organic solvents in industry. Occupational exposure to solvents is not rare and some activities may cause substantial exposure to these substances in the workforce. Short-term or acute exposures cause a prenarcotic syndrome, and long lasting exposure conditions have been associated with various neurological and neuropsychiatric disorders, e.g., anosmia, hearing loss, colour vision dysfunctions, peripheral polyneuropathy and depression, but most significantly with the gradual development of an irreversible toxic encephalopathy. For the last 3 decades reports and epidemiological studies have been published reporting sleep disturbances among other complaints, related to long-term exposure to these compounds. In addition, the question has been posed if solvents can be the cause of a sleep apnoea syndrome in exposed workers, or on the contrary, if these workers are misdiagnosed and ‘common’ sleep apnoea syndromes are the cause of their chronic symptoms of fatigue and memory and attentional disturbances. Ó 2008 Elsevier Ltd. All rights reserved.

Introduction We frequently meet patients with complaints of sleep disturbances, combined with complaints of fatigue, fatigability, attentional problems and inadequate memory, the latter presumably as a result of this unrefreshing sleep. Personal history, clinical examination, laboratory findings and radiological examination are uneventful. As a subsequence, no aetiological clues are found on polysomnography, although it shows a diminished sleep efficiency, an increased arousal index and sometimes a slightly increased apnoea-hypopnoea index. These are surely insufficient to explain clinical picture. You will find an increased score on many depression questionnaires because fatigue, sleep disturbance, feelings of diminished well being, etc., are part of most of these questionnaires. Maybe one can regard this as a stress or mood related disorder, but the question may have been put to you if it could be

that the patient’s work is responsible for these complaints. Shift work, for example, is a well known factor in sleep disturbances and fatigue, but what about working with organic solvents? For the last three decades reports and epidemiological studies have been published reporting sleep disturbances among other complaints, related to long-term exposure to these compounds. In addition, the question has been posed if solvents can be the cause of a sleep apnoea syndrome in exposed workers, or on the contrary, if these workers are misdiagnosed and ‘common’ sleep apnoea syndromes (SAS) are the cause of their chronic symptomatology of fatigue and memory and attentional disturbances.1–6 This paper gives a short introduction on solvents and their neurotoxicity, and is an attempt to review the vast literature of solvent neurotoxicity concerning those aspects of sleep disturbances and sleep disordered breathing possibly related to occupational exposure. Occupational exposure to organic solvents and their effects

Abbreviations: AI, apnoea index; CI, confidence ratio; CSE, chronic solvent encephalopathy; CTLV, calculated threshold limit value for exposures to mixtures; MEK, methyl ethyl ketone; OSAS, obstructive sleep apnoea syndrome; PR, prevalence ratio; SAS, sleep apnoea syndrome; TLV, threshold limit value, i.e., permissible concentrations for exposed workers during 8 working hours; TST, total sleep time. * Corresponding author. Expertise Centre of Neurotoxicology and Neuropsychology, Governmental Psychiatric Hospital, Dr. Sanodreef 4, 2440 Geel, Belgium. Tel.: þ32 14 57 91 11; fax: þ32 14 58 04 48. E-mail addresses: [email protected] (M. Viaene), [email protected] (G. Vermeir), [email protected] (L. Godderis). 1087-0792/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2008.07.003

Organic solvents represent a group of aliphatic and aromatic organic compounds which are lipophilic and more or less volatile. A solvent can be defined as ‘‘a liquid that has the ability to dissolve, suspend or extract other materials, without chemical change to the material or solvent.’’7 Numerous chemical or technical processes rely on specific properties of organic solvents in industry, e.g., extraction processes in chemical and pharmaceutical industry, degreasing activities, printing, dry cleaning, laminating techniques,

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and production and application of paints, lacquers, varnishes, glues, and wood preservatives. Such activities may cause substantial exposure of these substances to the work force. Although skin contact may contribute to the intensity of exposure, inhalation is the major route in most instances.7 Occupational exposure to solvents is not rare. In 1998 the United Kingdom’s Health and Safety Executive estimated that 8% of the working population regularly used organic solvents,8 while in 1987 the National Institute of Occupational Safety and Health estimated that 3.7% of the general population of the United States was exposed to organic solvents.9 Luckily, during the last decade environmental legislation has led to the use of fewer solvents in industry in Europe and North America.7 Organic solvents have narcotic properties and some are used as anaesthetics, e.g., Propofol (2,6-diisopropylphenol). As a result, the neurological effects of solvents can present as a reversible depression of the central nervous function from short-term exposures (prenarcotic syndrome: headache, dizziness, and light-headedness), often in combination with irritation of mucous membranes (eyes, nose, throat).7,10 This may progress to unconsciousness, seizures, and death in poor working practices that create the conditions for intense exposure in confined spaces.7 In addition to the effects of these short-term or acute exposures, some long-lasting exposure conditions (>5 years in high-exposure conditions, >10 years in lower exposure conditions with recurrent higher peak exposures of short duration) have been associated with various neurological and neuropsychiatric disorders, e.g., anosmia, hearing loss, colour vision dysfunctions, peripheral polyneuropathy and depression, but most significantly with the gradual development of an irreversible toxic encephalopathy.7,10,11 Chronic solvent encephalopathy (CSE) is predominantly characterized by mild and sometimes severe cognitive impairment, affecting memory, attention and psychomotor functions and leading to decreased mental flexibility, mood changes, changes in personality, diffuse pain, and sleeping difficulties. The disabilities generally persist after the exposure to solvents has ceased, compromising daily functioning, social and occupational participation, and quality of life.7,10 History of acute solvent intoxication, for example episodes of prenarcotic symptoms or worse, indicates poor workplace controls and suggests heavy exposure, creating the risk of developing CSE; although compliance with legal occupational exposure limits for solvents [e.g., threshold limit values (TLV) or permissible exposure limits (PEL)] may not be sufficient to protect all workers from long-term adverse effects.7,10 Long-term exposures to solvents do not cause any gross structural damage in animals or in humans.12,13 Therefore diagnosis relies on careful estimation of exposure conditions, differential diagnostic procedures and neuropsychological examinations proving sometimes small, but objective, deteriorations in certain neurocognitive domains, predominantly in attention/executive function/mental flexibility, memory and learning, motor functioning, and visuoconstructive abilities.10,14 Although there is a vast literature on the neurotoxic effects of solvents, the numerous types of solvents (aromatic: e.g., toluene, xylene, styrene; alcohols: e.g., isopropyl alcohol, methanol, ethanol; aliphatic: e.g., n-hexane; chlorinated: e.g., perchloroethylene, methylene chloride, trichloroethylene; ketones: e.g., acetone, methyl ethyl ketone; glycols: e.g., ethylene glycol; etc.) and hydrocarbon mixtures (e.g., white spirits), the different exposures over time in the individual worker and the changing content of these mixtures over time used in occupational settings seemed to make it difficult to generalise conclusions, and made it sometimes a controversial entity with a wide variation of medical and social recognition. In this context it is important that animal research showed almost no overt differences in neurostructural,

neurochemical, and neurobehavioral effects of different kinds of solvents or mixtures.12,15 The neurotransmitter systems that have been studied describe in particular dopaminergic, serotonergic and noradrenergic pathways and concentrations.12,15 In addition, new neuroradiological techniques are showing dose-related underlying neuropathology in CSE patients who have worked in different occupational situations; for example, recently dose–effect related loss of striatal [123I]IBZM (123 I-iodobenzamide) binding ratios were reported in CSE patients and sub-clinically in exposed control subjects, correlating with the clinical toxic effects on performance of attention and psychomotor speed.14 Consequently, most solvents and solvent mixtures are now regarded as one group with respect to most of their health effects in humans,7,10,12 though we have to keep in mind that interaction and differences in effects are surely possible.16

Practice points  Numerous chemical or technical processes rely on specific properties of organic solvents in industry, e.g., extraction processes, degreasing activities, printing, dry cleaning, production and application of paints, lacquers, varnishes, glues and wood preservatives. Such activities may cause substantial exposure of these substances to the work force, mainly by inhalation of solvent vapours.

Complaints of sleep disruption and occupational exposure of solvents All but one study17 concerning the health effects of solvents did not incorporate validated questionnaires regarding sleep or sleep quality, nor objective measurements of daytime hypersomnolence or sleep. Lundberg et al.17 included the Swedish Selfassessment Form. Laire et al.,5 Viaene et al.,18 and Godderis et al.19 included the Neurotoxicity Symptom Checklist-60, which is a well validated Dutch questionnaire with 10 category scores of which one consists of sleep related questions. Mindus et al.,20 Elofsson et al.,21 Knave et al.,22 and Ørbæk et al.23,24 used the Comprehensive Psychopathological Rating Scale (CPRS) including sleep related symptoms. Kaukiainen et al.25 used a modified Euroquest Questionnaire, which has a category Tiredness and a category Sleep Disturbances. One study focused only on sleep disturbances,26 but most reports included some questions about sleep complaints as part of their neurological and neuropsychological questionnaires or (semi-)structured interviews.16,27–37 Table 1 summarizes the findings. Mitran et al.35 showed a 3-fold increase in sleep disturbance complaints in the methyl ethyl ketone (MEK) and cyclohexanone exposure groups, and a 6-fold increase in the acetone exposed group, together with diminished nerve conduction velocities and an excess of memory difficulties, headaches, mood disorders and irritability in these groups. Chen et al.34 mentioned a twofold increase of sleep related difficulties in toluene and xylene exposed workers. Unfortunately, none of the two studies provided a description of the questions and no adequate dose–effect relation was described. In a well-designed retrospective population cohort of still or previously exposed housepainters and controls born in 1925–1945 and residing in Stockholm county, Lundberg et al.17 reported increased prevalence ratios (corrected for age, alcohol use and smoking) regarding diminished sleep quality (prevalence ratio

Table 1 Sleep disturbances and Solvent exposure. Exposure Study design

n exposed n controls

Mean age (range or SD)

Kraut et al., 198831 Aaserund et al., 199032 Linz et al., 198630

Mixture case-study CS2 case-study Mixtures case-control

22

43 (24–62)

8.1 (0.9–37)

Peaks: >4  CTLV

16

56 (43–56)

20 (10–35)

3–30 ppm, peaks: 150–300 ppm

24–56 ?

Lindelof and Alkvist, 199226 Lundberg et al., 1995a,17

Mixtures case-control

15 possible CSE 30 112 99

Ørbæk and Lindgren, 1988a,24 Ha¨nninen et al., 197627 Knave et al., 197822 Mindus et al., 197820 Elofsson et al., 198021 Husman, 198028 Struwe and Weenberg, 198316 De Grosbois and Mergler, 198529 Ørbæk et al., 198523 Ukai et al., 199333 Chen et al., 199434 Daniell et al., 1999a,36 Laire et al., 19975

Mitran et al., 199735

Mean exp. years Mean dose (range or SD)

0.3–24

Covariates mentioned

þ 10/16 6/16 10/16 8/16 8/16 Age, alcohol, education, sex, shift work, social factors, smoking, work conditions

46 (10.7) 58 (5.9) Median 50 Median 50 55 (33–69)

 or >10 years

Mixture cross-sectional Mixture cross-sectional Mixtures cross-sectional Mixtures cross-sectional

100 101 30 30 30 30 80 80

35 (11)

14.8 (1–40)

46.4 (27–66) 46.4 (27–66)

17.1 (2–32)

Mixtures cross-sectional Toluene Mixture cross-sectional

102 102 37 80 80

35 (11) ? (age-matched) <25–65

Alcohols

68 74 50 50 452 5179 233 241

31.4 (8.9) 34.0 (8.8) 42 (27–64) matched 16–60

Exposure index <0.1–>0.6  CTLV Age, alcohol, drugs, education, height, interfering diseases, smoking, weight ? 24.7 ppm Age

?

?

67þ22 126 21 21

(62–74) (62–74) 38.1 (22–58) 38.0 (26–53)

35.5 (9–49)

Acetone 71/86 contr 36 (11.6)/36 (9.4) MEK 41/63 contr 36 (9.2)/36 (12.3) Cyclohexanone 75/85 contr 36 (8.8)/36 (9.5) cross-sectional



þ

Mem Sleep NeuroDose-effect Neuropsy

þ

þ

6/16 þ

10/16 þ

NA

þ

þ

NA

Age

Mixtures 135 retrospective 71 cohort Mixtures 32 follow-up study

Mixtures cross-sectional Toluene cross-sectional Toluene and xylenes cross-sectional Mixtures cross-sectional Mixture cross-sectional

Pers Conc Fatig Equil Auton HA and Mood

14.8 (8.5) ?

2.7 (2.6)

þ



þ

þ

Interfering diseases

þ

þ

þ

þ

Age, alcohol, shift work

þ

þ

þ

Age, alcohol, education, interfering diseases, smoking, social factors Matching factors not mentioned

þ 





Age, education, shift work, sex, work conditions

þ

þ

þ

Age, alcohol, drugs, education, interfering  diseases, smoking, shift work Age, alcohol, education, interfering diseases, social factors

þ

þ

Age

þ þ

0.31  TLV (0.04–2.12) 1  TLV 0.3  TLV selected heavily exposed TLV

<10–203 ppm

15 (2–35)

0.15–0.97  CTLV

14 (3.8) 14 (7.5) 14 (6.2)

0.98–21.1  TLV 0.75–1.71  TLV 1.6–3.7  TLV

þ

þ

þ

þ

 þ þ

þ

þ

þ



þ

þ

þ



þ

Age, alcohol, coffee, education, ethnicity,  Pb exposure Age, alcohol, BMI, coffee, education, shift work, smoking

þ

þ

þ

þ

þ

(þ)

þ

þ

þ

þ

NA

þ



þ

?



þ

þ

?

þ



þ

? þ

?

?

  þ

(þ) þ

þ

þ

þ

þ

þ

(þ)

þ

þ

þ

 No increase over last 3 months ?

þ

þ

þ

þ

þ

þ







þ

(þ)b

þ

þ







þ

þ

þ

þ

NA

þ

 þ

þ



þ

 þ

Age, sex

Age, physical effort, shift work, social factors

þ

þ

Low– Age, alcohol, drugs, interfering diseases, intermediate–high premorbid IQ, smoking

CTLV ¼ 0.32 (4–212) 110–630 mg/m3

þ

þ

þ

?

þ þ

þ

M. Viaene et al. / Sleep Medicine Reviews 13 (2009) 235–243

Study

(þ)



þ

?

(continued on next page) 237





þ þ þ

Age, alcohol, BMI, education, ethnicity, shift work, motivation, smoking

þ Age, alcohol, education, shift work, social class, smoking

6 levels from short/low to long/high <31 mg/m3 and>31 mg/m3

17.4  11.2 ppm 18.9  10.9 ppm

85 66

Mixtures cross-sectional

CS2 cross-sectional

Kaukiainen et al., 200425

Godderis et al., 2006a,19

Viaene et al., 2001a,18

(þ): effect of borderline significance; : no effect; ?: not reported; þ: significant effect, p  0.05; Auton: autonomic dysfunction ¼ excessive sweating, heart palpitations, nausea; Blank: not studied; Conc: concentration difficulties; CSE: chronic solvent encephalopathy; CTLV: calculated threshold limit value for exposures to mixtures CS2: carbon disulfide; Dose-effect: related to the complaints of sleep disturbances; Equil: equilibrium complaints; Exp. years: years of exposure; Fatig: fatigue, hypersomnolence; HA: headache; MEK: methyl ethyl ketone; Mem: memory complaints; NA: not available; Neuro-Neuropsy: results of neurological (e.g., electromyography, nerve conduction studies, electroencephalography, tremor registrations) or neuropsychological tests; Pers and mood: personality and emotional changes, e.g., irritability, aggression, mood changes, emotional lability; ppm: parts per million (measure of air concentration); Sleep: sleep complaints; TLV: threshold limit value. a Including retired workers. b Only in one of the exposed groups (painters, n ¼ 67).

þ 

þ

þ

þ



þ

þ þ þ þ  þ þ þ

þ þ þ þ þ þ þ þ

Age, alcohol, education, ethnicity, height, þ Mn exposure, sex, smoking, social status Age, alcohol, education, motivation, smoking, 9–50  CTLV

154 112 27 exp 90 ex-exp 64 4100 14000 Mixtures cross-sectional Styrene cross-sectional Kilburn, 199937

42.7 (8.2) ? 41.9 (8.8) 37.1  7.9 7.6 (6.5–8.5) 38.1  10.3 5 (0.3–6) 40.3  11.3 Split up over 6 levels from exposure groups short/low to long/high 41.3 (7.3) 10.5 (7.1) 37.2 (7.7)

Pers Conc Fatig Equil Auton HA and Mood Covariates mentioned Mean exp. years Mean dose (range or SD) Mean age (range or SD) n exposed n controls Exposure Study design Study

Table 1 (continued )

?

M. Viaene et al. / Sleep Medicine Reviews 13 (2009) 235–243

Mem Sleep NeuroDose-effect Neuropsy

238

(PR) 3.0, 95% confidence intervel (CI) 1.6–5.7), frequent awakenings and trouble falling asleep again (PR 1.5, 95% CI 1.1–2.2), feeling tired when waking up (PR 2.4, 95% CI 1.5–4.1), and awakening too early (PR 2.5, 95% CI 1.3–4.9) in the highest exposed group, and a slightly, but significantly, longer total sleep time in intermediate and highexposed painters. They also reported a trend to have complaints of disturbed, uneasy sleep (PR 1.4, 95% CI 1.0–2.1). Especially those painters who had been often experiencing prenarcotic symptoms during their work reported trouble waking up (PR 2.2, 95% CI 1.2– 4.2) and a trend for involuntary dozing of during leisure time (PR 1.6, 95% CI 1.0–2.7). The authors concluded that sleep quality appeared to decline with increasing exposure. No differentiation in still exposed, previously exposed or retired subjects were made in the analyses of this study, but similar Odds Ratios for difficulties falling asleep (2.30, 95% CI 1.07–4.96), broken sleep (2.36, 95% CI 1.33–4.19), and waking up too early (2.74, 95%CI 1.54–4.88), were reported in a large Finish cross-sectional study studying neurobehavioural effects in still exposed workers with decreasing exposures due to regulatory legislation.25 Cumulative high past exposures (pre-1990) seemed to be mostly responsible for these results. In comparison, styrene-exposed workers exposed less than 10 years reported no further sleep disturbances after cessation of their exposure, while workers who continued working in the exposed situation still had an excess of sleeping difficulties.18 In these intermediate duration exposure conditions, complaints were only related to the individual mean airborne styrene concentrations and not to the cumulative exposure index (level of exposure  years of exposure), suggesting that in these exposure conditions the acute and reversible ‘alcohol-like’ effects of solvents are still the most important factor in having an increasing number of complaints, while the cumulative exposure index was already significantly related to the existence of subclinical neuropsychological deficits.18 De Grosbois and Mergler29 reported the same dose effect of the number of complaints and the level of airborne solvent concentrations in even more short-term exposed workers, and reported that difficulties falling asleep increased significantly from 31% in exposure conditions lower than TLV to 51% in mixed conditions and 57% in exposure conditions above TLV, also suggesting the existence of an acute ‘alcohol-like’ effect related to the level of exposure, unrelated to the duration of the exposure. In a mixture of workers with short- to long-term exposure to mainly toluene, Ukai et al.33 still showed a dose-dependent increase of many symptoms (nausea, concentration inability, dry mouth, reduced sense of smell, decreased force etc.), but failed to show any dose-dependent relation of the toluene air concentrations with sleeping difficulties and memory complaints. Unfortunately, no cumulative dose effect was reported in this study. Complaints of reduced sleep, and not increased sleep, were also reported in workers exposed to jet fuel,20 but using the same scale, only an increase in nightmares was seen in spray painters21 and only increased sleep was reported by Ørbæk et al.23 in an exposed population with different professions. As Mindus et al.20 and Elofsson et al.21 did not describe some essentials of their population and exposure characteristics; it is difficult to comment on these conflicting results. The study group of Ørbæk et al.23 consisted of 50% rather short-term exposed individuals (cumulative exposure <10 years) and all actual exposures were well below the TLV (with 50% of the study population not exceeding 40% of the permissible dose), although higher historical exposures were present. While no excess of sleep disturbances was found, (borderline) dose-dependent changes on attentional performance, EEG spectra, regional cerebral blood flow and peripheral nervous function were found. In a group of retired painters and a group of retired printers (both exposed to mixtures), only the painters reported sleeping more and being tired easily, although both groups showed a decline in

M. Viaene et al. / Sleep Medicine Reviews 13 (2009) 235–243

neuropsychological functions, and no differences in average number of years of retirement and mean estimated exposure level were present.36 It might be that therefore toxic effects on sleep or the reversibility of these effects may differ according to the exposure conditions. In a prospective follow-up study of CSE patients (follow-up 2–19 years), Ørbæk and Lindgren24 mentioned that 56% had sleep disturbances at the time of the initial diagnosis, which is comparable with the numbers reported in highly but short-term exposed workers29 and with the number of workers who had been referred to a physician for tiredness or sleeplessness before they were referred to the Department of Occupational Medicine as solvent-related health effects were suspected (50% compared to 18% of the controls).26 Linz et al.30 reported that 67% of a group of painters consulting at the Occupational Health Clinic suffered from sleep disturbances compared to 30% of the controls. In Ørbæk and Lindgren’s follow-up study,24 sleep disturbances remained unchanged in 69%, worsened in 18% and improved in 13%. The follow-up results of other complaints were comparable, e.g., mood, memory and concentration difficulties.24 High and long-term exposure to CS2 results in CSE, but more typical for this solvent are the clinical signs of Parkinsonism and peripheral neuropathy. Sixtythree percent of these CS2 patients also mentioned sleep disturbances.32 In much lower CS2 exposed workers an odds ratio of 2.1 (1.0–4.3) was found for sleeping difficulties, together with an increase of sensorimotor complaints (43% in the highest exposed group, 35.7% in the intermediate group vs. 22% in the control workers).19 Most authors did not describe the kind of sleep disturbances encountered, but in the study focusing on sleep disturbances and solvent exposure, Lindelof et al.26 found that the time one needs to fall asleep was doubled in the exposed group (30 vs. 15 min), 37.7% (vs. 13% in controls) reported a very bad or bad sleep quality, and 19.1% needed hypnotics at least several times a week (vs. 0% in controls). This may be an underestimation as the reference group was on average 12 years older and were referred for chronic respiratory disease, both factors in an increased prevalence of sleep disturbances. In healthy long-term solvent exposed workers, Viaene et al.53 found borderline increased scores on the sleep-related questions (20 items). The significant complaints were falling asleep more easily while watching TV and after meals, excessive sweating at night, while increased daytime fatigue was (borderline) significant. In conclusion, the way of questioning sleep disturbances and the differences in exposure conditions (duration, level, solvent) may explain the differences between the previously mentioned studies. In addition, it may be possible that sleeping difficulties associated with occupational solvent exposure are a result of acute (daily concentrations) as well as chronic (lifetime cumulative) exposure, as these have been reported for the other neurotoxic effects18 as well as for alcohol.38 Lindelof et al.26 suggested that sleep disturbances might be responsible for the increased fatigability and emotional lability, but in the available literature complaints of sleep disturbances seem to be present with or without other complaints and objective neurological or psychological deficits and vice versa, which makes it very unlikely that sleep pathology is the only explaining factor for the neuropsychological deficits reported in exposed workers or CSE patients (Table 1). It is important to notice that all but one26 of those reports were primarily focused on neurological and neuropsychological outcomes, meaning that covariates frequently used in sleep research related to occupational conditions39 were ignored (e.g., body mass index or neck circumference), some were sometimes taken into account (coffee intake, shift work, smoking, personality factors, work stress), and others were mostly included (age, alcohol use and abuse, estimations of pre-morbid intelligence, psychoactive drugs) or excluded (interfering diseases like diabetes

239

or cerebrovascular disorders). Depressed mood was even always used as an outcome variable instead of covariate or confounder. It is a fact that it is not always certain that SAS has been excluded in earlier cohorts of CSE patients.24 In addition, some of these studies had other possible biases, e.g., two studies were the result of disputes within the companies concerning the very high or unusual exposure levels, which could have influenced the reporting of symptoms,31,37 and only some authors reported dose– effect relations regarding the results of the questionnaires (see Table 1). Shift work systems may have been a major problem in some studies, although these systems are probably not necessary in all job functions, e.g., housepainters17 or retired workers.36 In addition, the effects of exposure on sleep seem to depend on the time of the day of the exposure.40 This can result in over-reporting, but probably also in under-reporting of sleeping difficulties. Although some authors compared shift work and work stress between groups (e.g., Linz et al.30), only Mitran et al.35, Elofsson et al.,21 and Kaukiainen et al.25 matched groups for occupational factors (shift work, physical effort) and socio-economic factors. Regarding personality factors, there are several indications that pathological results on personality factors are insufficient to explain the neurotoxic health effects in solvent exposed workers.41 Depression as a possible cause of neurotoxic effects such as sleep disturbances in solvent exposed workers is a much more difficult question, troubling many clinicians and neuropsychologists. Mood problems are considered as part of the CSE and they have been reported to be dose-dependent, related to exposure indices in exposed workers and CSE patients, but major depression is also part of the differential diagnosis.7,10,42 In addition, there are conflicting results concerning the regression of mood complaints in CSE patients.24,43,44 They may respond to behavioural therapy, suggesting they are at least partially caused by psychological reactions secondary to the loss of function.44 In longterm follow-up studies of previously solvent exposed workers, Nordling Nilson et al.43 even reported an increase of mood problems, fatigue and neuropsychological dysfunctions, most probably as a result of the interaction of the deleterious effects of high past exposures and ageing. It therefore seems likely that mood changes, neuropsychological deficits, and probably also sleep disturbances are caused by the interaction of primary neurotoxic effects, ageing processes, and psychological reactions secondary to the loss of quality of life. As alcohol is a solvent, a comparison with the literature concerning alcohol use and abuse can be made. As is suspected for solvents, sleep disruption can occur with acute or chronic alcohol consumption, but the pattern and severity of symptoms depend on the amount and timing of alcohol use. As a central nervous system depressant, alcohol can reduce sleep latency through its sedative effects. However, alcohol consumption tends to disrupt the first half of the sleep period with increases in slow wave sleep (SWS) and decreases in rapid eye movement (REM) sleep. In the second half of the sleep period, even relatively low alcohol doses tend to result in increased REM sleep, more frequent episodes of wakefulness, and more frequent shifts between sleep stages. Over a number of days of consistent alcohol use near bedtime, the initial sleep onset effects tend to diminish, but the later sleep disruption persists.38 In a cross-sectional study of long-term exposed workers, sleep architecture differed slightly but significantly between exposed subjects and controls.53 Rapid eye movement and movement time were lower in the solvent exposed workers compared to the referents [rapid eye movement time exposed vs. controls, mean SD (range): 17.7  5.2% (8.8)27.3) vs. 20.9  5%.8 (9.131.5)] [movement time exposed vs. controls, mean  SD(range): 1.9  0.9% (0.33.8) vs. 2.6  1.1% (0.25.3)]. More evidence to support the relation between sleep disruption

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and solvent exposure originates from experimental animal studies, although very few are available. Long-term but not short-term exposures to low levels of trichloroethylene may increase total sleep time (TST)45 (only abstract available). In addition, single exposure to high concentration of toluene increased TST, whilst short-term repeated exposure to higher concentrations of toluene caused a short-lasting, but significant, reduction of TST in rats (545  17 min post-exposure; 569  13 min pre-exposure).46 This was comparable with the degree of effect on TST reported in humans.26 The partial insomnia was associated with evidence of altered serotonergic function in the frontal cortex, hippocampus, midbrain and hypothalamus.46 Single exposure to very high toluene concentrations first affected sleep architecture and then diminished TST dose-dependently.47 In conclusion, it may be said that: (1) a decrease in sleep quality is frequently reported in solvent exposed workers and CSE patients, (2) difficulties falling asleep and awakening early might be related to the acute toxic exposure itself, indicating poor workplace control of exposure, and (3) sleeping disturbance may be one of the many symptoms of an irreversible chronic encephalopathy due to a long-term high exposure. Due to the many shortcomings in the studies, it is very difficult to make definitive conclusions regarding the nature of the relation between sleep disturbances and solvent exposure. However, it may be recommended to question occupational exposure to solvents in patients complaining of an unrefreshing, disturbed sleep and fatigue; also because if a diagnosis of solvent neurotoxicity is established, then withdrawal from exposure can prevent further harm to the individual worker and such a diagnosis can alert the employer to the need for improved workplace hygiene measures and so protect other workers.7

Practice points  It may be recommended to question occupational exposure to solvents in patients complaining of an unrefreshing, disturbed sleep and fatigue, because if a diagnosis of solvent neurotoxicity is established, then withdrawal from exposure can prevent further harm to the individual worker and his/her co-workers.

Research agenda  Studies focusing on the nature of the sleep disturbances in solvent exposed workers and their relation to other influencing factors are lacking.

Occupational solvent exposure and sleep-disordered breathing It is known from literature that alcohol use can induce or augment central and obstructive sleep apnoeas, probably also depending on interactive factors such as time of dose, sex, general health, age, the pre-existence of SAS, chronic obstructive lung disease or snoring.48–50 It has been pointed out that solvent-related complaints, such as fatigue, forgetfulness, and concentration difficulties, are strikingly similar to those reported by patients with obstructive sleep apnoea.3 Edling et al. suggested that some people with SAS could be

misdiagnosed as cases of solvent encephalopathy, while others suggest that solvents might be a cause of SAS. Table 2 summarizes the findings. In 1983, Wise et al.1 described a young, non-obese patient with a severe central SAS, who had a significant exposure to trichloroethane over a period of two years. These authors suggested that the risk of sudden death described some hours after trichloroethane inhalation could be due to respiratory dysregulation. This conclusion was supported by the results of Monstad et al.,51 who studied 17 workers (8 solvent exposed and 9 controls) exposed to trichloroethane, and/or toluene, white spirit, acetone and xylol. The exposed workers had more than a tenfold increase of central and obstructive apnoeas (mean AI ¼ 4.2) compared to the control workers (mean AI ¼ 0.3), who only experienced obstructive apnoeas. But one outlier (AI >20) seemed to have a major influence on these results. Recalculating the results of the other 7 workers resulted in a mean AI of 1.5, which was still elevated compared to the control group (mean AI ¼ 0.3), and which is comparable to the results reported by Laire et al.5 in workers exposed to solvent mixtures [apnoea index (AI) of 1.7 vs. 0.6]. Unfortunately, no biometric data concerning the individual workers were given by Monstad et al..51 In addition, these authors51 described polysomnographic data of 15 patients referred for evaluation of possible CSE. Half (n ¼ 7) of these were found to have an increased AI (>5), mostly obstructive in nature, of which two may have been of clinical importance (AI ¼ 11 and 21; mean AI CSE patients ¼ 6.2). In a Swedish study, Edling et al.3 compared the prevalence of sleep apnoeas in a group of men occupationally exposed to organic solvents to the prevalence in the same age group in the general population. They defined a ‘classical SAS’ as >5% oxygen desaturation combined with >45% periodic respiratory movements during sleep (measured on a static charge sensitive bed). A higher prevalence of SAS was found in the exposed group (RR ¼ 14.1, 95% CI 7.5–24.2), maybe still slightly (but not significantly) increasing if exposure duration exceeded 20 years. Edling et al.3 remarked that none of the SAS cases had been exposed less than 10 years, though it must be kept in mind that life-time exposure is always highly correlated with age and age is a confounder in this regard. Most apnoeas were of the obstructive type, but Edling et al.3 recruited participants from medical centres to which they had been referred based on a clinical suspicion of solvent related neurological problems. As had been mentioned before, these symptoms much resemble those of SAS and thus possibly invite bias by their selection procedures. De Haro et al.4 examined ten workers with high exposures to various solvents thought to have CSE. Eight workers had an Al >10, 2 were predominantly of the obstructive type and 6 had a central SAS. Remarkably, two of these patients recovered after exposure cessation, but four still needed CPAP 10 months later. Similar results were reported by Monstad et al.,2 who combined a case-control study, a cross-sectional study and a prospective study. They showed that CSE patients and a crosssection of still exposed painters were comparable regarding AI increase and severity (AI >5 and AI >10: CSE ¼ 24% and 16%, Painters ¼ 19% and 12%, Controls ¼ 1% and 0%) (both vs. control group: p < 0.05). The CSE patients who had been exposed in the week previous to examination had a significantly higher AI than those whose exposure ceased at least 1 week before [median AI 6.51 (0–23.4) vs. 1.54 (0.26–10.11)]. The follow-up of 12 of these CSE suspected patients with AI >10 showed a significant decrease of AI over the next two exposure-free weeks in 11/12, and when 4 of these workers resumed their exposed work again their AI went up to their original level. Three of the four workers who had AI >20 a short time after exposure ceased, were shown to have AI <15 after at least 2 weeks absence of work. The AI of one worker

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241

Table 2 Sleep apnoea syndrome and solvent exposure. Study

Exposure

n

Mean age (range or SD)

Mean exp. years/Mean dose (range or SD)

1

20 years

2 years

15 CSE suspected patients 10 CSE suspected patients 8 exposed 9 controls

28–63

66 patients population data 21 exposed 21 controls

53

24

Age, BMI, blood pressure

AI >5: RR ¼ 14.1 (7.5–24.2)

38.1 (22–58) 38.0 (26–53)

15 (2–35) 0.10–0.97  CTLV

47.4 (25–67) 47.8 (31–63) 45.2 (25–68)

Exp/14d cessation of exp/re-exp (n ¼ 4)

Age, alcohol, coffee, BMI, education, interfering diseases, motivation, neck circumference, personality, smoking Age

Exposed: AI ¼ 1.7 Controls: AI ¼ 0.6 No correlation neuropsych. test results CSE: 40% AI >5; 16% AI >10 Exposed: 31% AI >5, 12% AI >10 Controls 1% AI >5, 0% AI >10 SAS susp. 79% AI >5, 61% AI >10 Decrease AI after exposure cessation, increase after re-exposition

Age, alcohol, coffee, BMI, hypertension, cardiac problems, drugs, smoking

Male OSAS: OR 1.94 (95% CI 1.11–3.37) to have current whole day exposure Male snorers: OR 1.74 (95% CI 1.10–2.73) to have current whole day exposure Women:  (no women exposed whole days)

Study design Wise et al., 19831 Monstad et al., 198751 De Haro et al., 19944 Monstad et al., 198751 Edling et al., 19933 Laire et al., 19975

Trichloroethane case-report Mixtures case-study

Monstad et al., 19922

Mixtures case-control cross-sectional Prospective

Ulfberg et al., 19976

Mixtures case-control

Mixture case-study Trichloroethane cross-sectional Mixtures cross-sectional Mixtures cross-sectional

51 CSE 16 painters 18 controls 28 SAS suspected patients 12/51 320 OSAS 443 snorers 558 controls

Covariates

Results

Central SAS 7/15 had an AI >5

(27–57)

(4–30)

(22–51) (22–45)

Age

30–64 30–64 30–64

8/10 had an AI >10 5/10 pathological neuropsych. test results Mean AI exposed ¼ 4.2 Mean AI controls ¼ 0.3

AI: apnoea index; CSE: chronic solvent encephalopathy; exp: exposure; neuropsych: neuropsychological; OR: odds ratio; OSAS: obstructive sleep apnoea syndrome; RR: risk ratio; SAS: sleep apnoea syndrome.

diminished from >35 to an AI of <5 after 1 year of exposure cessation. Again, most of the reported apnoeas were obstructive in nature. Although age is taken into account, no other factors such as alcohol use or obesity are described in the previous studies.2,4,51 This is a serious drawback, but Ulfberg et al.6 still found an increased risk of whole-day solvents exposure in male OSAS patients controlling for sex, smoking, BMI, alcohol, age, blood pressure, cardiac disease and psychotropic medication [OR of 1.94 (95% CI 1.11–3.37)]. Snorers moreover had a similar risk to exposure. However, as in the study by Edling et al.,3 a limited sleep apnoea investigation was used. This may be partly explain why a German study could not replicate these results.52 These authors found a relation between OSAS and shift work, but not with solvents-exposed work. They indicated that the results of Ulfberg et al.6 and Monstad et al.2 may also be explained by shift work. Another explanation might be that groups were different regarding the proportion of smokers to non-smokers, alcohol use and age distribution. Both studies are not easily comparable as data are reported differently, but it seems that the Germans’ age distribution is different, and alcohol use and proportion of smokers may be higher in the OSAS group compared to the Swedish population.6 In this respect, Laire et al.5 and Viaene et al.53 suggested that an interaction between solvent exposure and other factors may be important in solvent induced sleepdisordered breathing. Using oximetry in a cross-sectional study design, Laire et al.6 reported a small but significant increase in AI (median 1.7 vs. 0.6 in controls) unrelated to the cumulative exposure index, whilst Viaene et al.53 using polysomnography in an almost identical group (only the mean level of exposure being somewhat higher) and controlling for the same factors, showed an increase in central apnoeas/hypopnoeas correlating with the

cumulative exposure index. However, in both studies it was remarkable that the effects on oxygen desaturation were restricted to the non-smoker group. Whether this is caused by the central stimulant properties of nicotine or to the induction of detoxification mechanisms is not known.5 In addition to the exposure index, alcohol use was a significant factor in the results. In conclusion, available results suggest 1) some SAS patients may be wrongly diagnosed as CSEdtherefore, each CSE suspected patient must undergo a polysomnography; 2) current solvent exposure may aggravate or induce sleep-disordered breathing in some exposure conditions; 3) hence, it may be useful to repeat the polysomnography after some weeks cessation of exposure in highly exposed SAS patients; 4) current exposure might be more important than cumulative exposure; and 5) analogous to findings in alcohol research, it is important to design new studies with advanced polysomnographic methods in which interacting factors such as smoking, obesity, ageing, shift work, level of exposure and duration of exposure-free intervals are taken into account.

Practice points  Some SAS patients may be wrongly diagnosed as CSE and each CSE suspected patient must undergo a polysomnography.  As SAS may be aggravated by the exposure itself, before starting CPAP therapy it is useful to repeat polysomnography after some weeks of exposure cessation in highly exposed SAS patients.

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Research agenda  Studies applying advanced polysomnographic methods and in which interacting factors, such as smoking, obesity, ageing, shift work, level of exposure and duration of exposure-free intervals are taken into account, are needed.

General conclusions It may be said that a decrease in sleep quality is frequently reported in solvent exposed workers and CSE patients, that difficulties falling asleep and awakening early might be related to the acute toxic exposure itself, and finally, that sleeping disturbance may be one of the many symptoms of an irreversible chronic encephalopathy due to a long-term high solvent exposure. On the other hand, SAS may also explain the complaints of a worker exposed to solvents and therefore polysomnography should be performed before the diagnosis of CSE is made. However,one should be careful as in some exposure conditions SAS, central as well as obstructive, may be aggravated by the exposure itself. Conflict of interest None declared. References 1. Wise M, Fisher J, de la Pane A. Trichlorethane and central sleep apnea: a case study. J Toxicol Environ Health 1983;11:101–4. *2. Monstad P, Mellgren S, Sulg I. The clinical significance of sleep apnoea in workers exposed to organic solvents: implications for the diagnosis of organic solvent encephalopathy. J Neurol 1992;239:195–8. *3. Edling C, Lindberg A, Ultberg J. Occupational exposure to organic solvents as a cause of sleep apnoea. Br J Ind Med 1993;50:276–9. 4. De Haro L, Jouglard J, Jahjah F, Sainty JM, Chave B, Cura B. Psychosyndrome aux solvants et recherche du syndrome d’apne´es du sommeil. Arch Mal Prof 1994;2:145–7. *5. Laire G, Viaene MK, Veulemans H, Masschelein R, Nemery B. Nocturnal desaturations, as assessed by home-oxymetry, in long-term solvent exposed workers. Am J Ind Health 1997;32:656–64. *6. Ulfberg J, Carter N, Talba¨ck M, Edling C. Occupational exposure to organic solvents and sleep-disordered breathing. Neuroepidemiology 1997;16: 317–26. *7. Dick FD. Solvent neurotoxicity. Occup Environ Med 2006;63:221–6. 8. HSE. Health risks management: a guide to working with solvents HSG188. Sudburry, United Kingdom: Health and Safety Executive; 1998. 9. NIOSH. Current Intelligence Bulletin 48. Organic solvent neurotoxicity (DHHS Publ No. 87-104). Cincinnati, OH: USDHHS/PHS/CDC/NIOSH; 1987. *10. Viaene MK. Overview of the neurotoxic effects in solvent-exposed workers. Arch Public Health 2002;60:217–32. 11. WHO. White spirits (Stoddard solvent). Environmental Health Criteria 187. Geneva: WHO; 1996. 12. Nielsen GD, Lund SP, Ladefoged O. Neurological effects of White spirits: contribution of animal research during a 30-year period. Basic Clinl Pharmacol Toxicol 2006;98:115–23. 13. Klinken L, Arlien-Søborg P. Brain autopsy in organic solvent syndrome. Acta Neurol Scand 1993;87:371–5. 14. Visser I, Lavini C, Booij J, Reneman L, Majoie C, de Boer AGEM, et al. Cerebral impairment in chronic solvent-induced encephalopathy. Ann Neurol 2008; in press. *15. Kanada M, Miyagawa M, Sato M, Hasegawa H, Honma T. Neurochemical profile of effects of 28 neurotoxic chemicals on the central nervous system in rats. (1) effects of oral administration on brain contents of biogenic amines and metabolites. Ind Health 1994;32:145–64. 16. Struwe G, Wennberg A. Psychiatric and neurological symptoms in workers occupationally exposed to organic solvents-results of a differential epidemiological study. Acta Psychiatr Scand 1983;67(Suppl 303):68–80. 17. Lundberg I, Miche´lsen H, Nise G, Hogstedt C, Ho¨gberg M, Alfredsson L, et al. Neuropsychiatric function of housepainters with previous long-term heavy exposure to organic solvents. Scand J Work Environ Health 1995;21(Suppl 1):1–44.

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