Document MM6O4R94rmX7B2vNmQ9vRaB2x

Edward L. Baker, Jr., md , mph , Thomas J. Smith, PhD, and Philip J. Landrigan, md . ms c Organic solvents, particularly stryrene, are Used widely in boatbuilding. They may be absorbed by workers either through the respiratory tract or the skin. Uptake is influenced by level and duration of exposure, work load, and specific physicochemical features of each solvent, as well as by work practices and use of protective equipment. Kinetics of -X metabolism and excretion kinetics are highly variable among compounds. Metabolites can be measured in blood, urine, or exhaled breath and may Serve as indirect indices of absorption. Acute high-dose exposure to organic solvents can produce a transient narcotic effect on the central nervous system. This effect occurs in proportion to brain dose, which in turn is determined by intensity and duration of exposure. Additionally, chronic exposures to organic solvents have been reported to produce an increased frequency of neurologic signs and symptoms. These findings include peripheral neuropathies and toxic encepha lopathies. The latter are characterized by alterations in affect, memory loss, and impaired cognition. Concern exists dial prolonged excessive exposure to organic solvents may lead to premature and persistent dementia in certain workers. Key words: organic solvents, styrene, boatbuilding, neurotoxicity, occupational disease I INTRODUCTION ' The construction and repair of modern boats Involves the use of large volumes of organic solvents, particularly styrene. As is detailed in the work of Crandall and Hartle 11985], presented elsewhere in this issue of the journal, workers engaged in the manufacture of fiberglass-reinforced plastic (FRP) boats may be heavily exposed to styrene vapors, as the result of inadequate ventilation coupled with the frequent necessity to work in confined spaces. The acute neurotoxic effects of heavy exposure to the vapors of organic solvents have been recognized since the 19th century and are described in detail by Browning Occupational Health Program, Harvard School of Public Health, Boston, MA (E.L.B., T.J.S.). Division of Surveillance, Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health, 4676 Columbia Parkway, Cincinnati, OH (P.J.L.). Dr. Philip J. Landrigan is now at the Environmental Sciences Laboratory, Mt. Sinai School of Medicine of the City University of New York, 10 East 102nd Street, New York, NY 10029. Address reprint requests to Dr. Baker, Occupational Health Program. Harvard School of public Health, 677 Huntington Avenue, Boston, MA 02115. < Accepted for publication May 16, 1985. & 1985 Alan K. Liss, Inc. j 208 Baker, Smith, and Landrigan 11965]. Axelson et al ] 1980] have noted that by virtue of their acute narcotic effects, several of the solvents, including trichloroethylene, vinyl chloride, and even gasoline, found at least brief use as general anesthetics. The concept that chronic exposure to organic solvent vapors might have delete rious effects on the central nervous system, even in the absence of acute narcosis, has arisen more recently. Although there had been scattered early references to impaired neurologic function in relation to chronic solvent exposure {Browning, 1965]. the modern recognition of this association appears to have resulted from the ciinical observation in the early 1970s by a Swedish psychologist of memory loss in two workers who had heavy styrene exposure in the manufacture of sport boats and swimming pools (L. Sundell, personal communication, 1984), These observations led to a cross-sectional study in Sweden among house painters exposed to solvents [Sundell, 1975]. That investigation found decreases in reasoning capacity and in psychometric test results among exposed painters as compared witih unexposed controls. That seminal observation led to a series of further studies, conducted first in Scandinavia [Hane et al, 1977; Seppalainen et al, 1980; Struwe et al, 1980] and then elsewhere [Baker and Smith, 1984]. These reports confirmed and extended the notion that chronic solvent exposure causes both subjective and objective impairment of central neurological function in chronically exposed workers. A major unanswered question in this work is to determine the level of exposure at which this impairment first becomes evident. In this report, we shall present a detailed summary of the literature relating to acute and chronic neurologic effects of solvent exposure, including that described by other investigators as the psychoorganic syndrome [Flodin et al, 1984]. UPTAKE Uptake of solvent into the peripheral blood occurs within minutes of the onset of exposure by either the inhalation route or through percutaneous absorption [Engstrom et al, 1978, Riihimaki et al, 1979; Laiiwerys et al, 1978]. Alveolar ventilation rate is an important determinant of solvent uptake through inhalation, and increased levels of physical exercise (associated with increased pulmonary capillary blood flow) have been associated with increasing uptake by a factor of two to three times the baseline level [Monster et til, 1979; Riihimaki et al, 1979]. Respiratory uptake varies between individual solvents in relation to their specific air/blood partition coefficients, which are determined by alveolocapiliary membrane permeability and blood solubil ity. A general review of the factors affecting solvent uptake from inhalation exposure is contained within the report of Astrand [1975], Although skin absorption is recog nized as a possible major route of entry for some solvents, it has been studied for only a few, Engslrom and Bjurstrom [1977] found that brief (10-15 minute) immer sion of a subject's hands in xylene produced blood concentrations of xylene compa rable to those following an 8-hour inhalation exposure at 100 ppm (the threshold limit value [TLV]). The rate of solvent uptake through the skin varies substantially among workers owing to variations in skin thickness, skin perfusion, and the presence of cuts or abrasions of the skin [Riihimaki and Pfaffli, 1978; Bird, 1981], Occlusion of skin surfaces such that solvent is trapped between clothing and the skin may also enhance solvent absorption. A review of percutaneous absorption kinetics for five imp trad MET of a' r.ecc by c sho\ com for lowi inch sinvi tarn solv 197: In a met dep inte dur: will into indt the tor indmb EX DUP050067922 e narcotic effects, md even gasoline, night have deletecute narcosis, has ences to impaired wing. 1965], the from the clinical Tiory loss in two ` sport boats and : observations led >osed to solvents capacity and in witib unexposed conducted first et al, 1980] and and extended die ctive impairment lajor unanswered t this impairment nature relating to that described by 4]. utes of the onset bsorption [Engseolar ventilation n, and increased Hary blood flow) three times the try uptake Varies lion coefficients, id blood solubilalation exposure irption is recogbeen studied for minute) immerf xylene coropae threshold limit stantially among the presence of 1], Occlusion of ; skin may also icinetics for five Solvent Neurotoxicity 209 important organic solvents (xylene, styrene, toluene, 1,1,1 trichloroethane, and teimchloroethylene) is contained within the report of Riihimaki and Pfaffli 11978]). me t a b o l is m A detailed description of the biotransfprmation reactions that influence the fate of absorbed solvents is beyond the scope of this discussion but is contained in the recent review of Toftgard and Gustafsson [1980]. Modification of metabolism rates by other exogenous substances will be briefly reviewed. Waldron et al 11983] have shown that blood toluene levels increased acutely in individuals who received ethanol concomitantly, presumably secondary to reduced metabolism because of competition for alcohol dehydrogenase. In contrast, workers chronically ingesting ethanol had lower blood toluene levels than nondrinking fellow workers, an effect attributed to induction of hepatic microsomal enzymes responsible for toluene metabolism. In a similar study, increased blood xylene concentrations were noted following concomi tant ethanol exposure [Savolainen elal, 1980]. A reduced rate of metabolism of one solvent in the presence of other solvents has been reported in two studies [VanRees, 1972; Ikeda et al, 1972] involving trichloroethylene, styrene, benzene, and toluene. In a recent study [Riihimaki et al, 1982], ethanol ingestion appeared to decrease the metabolic clearance rate of xylene by about one half. Since xylene metabolism depends upon reactions catalyzed by alcohol and aldehyde dehydrogenase, metabolic interaction with ethanol is to be expected. Several volunteers experience nausea during the simultaneous exposure condition. In one individual, nausea was associated with an elevated blood acetaldehyde concentration consistent with a form of ethanol intolerance. In addition to causing higher levels of solvent in blood, the ethanolinduced metabolic inhibition may also be associated with adverse reactions caused by the accumulation of ethanol metabolites such as acetaldehyde. In summary, acute ethanol ingestion raises blood solvent levels by competition for metabolism; chronic ethanol ingestion lowers blood solvent concentrations by inducing solvent-metabolizing enzymes. Simultaneous exposure to organic solvent mixtures may have similar synergistic effects. EXCRETION Solvents are eliminated primarily either through exhalation of unchanged sol vent or through urinary excretion of unchanged solvent or solvent metabolites. The relative importance of each path of excretion and the excretion kinetics vary signifi cantly between compounds and, therefore, influence the strategy for biological mon itoring in which concentrations of these eliminated substances are measured as an index of solvent uptake. General discussions of the theoretical basis for alveolar air sampling have been recently presented IFiserova-Bergerova et al, 1980; Kellman, 1982]. In general, rapid decreases are observed in concentrations of all Organic solvents in expired air with increasing time from the end of exposure [Nomiyama and Nomiyama, 1974; Engstrom et al, 1978; Jakobson et al, 1982; Sedivec and Flek, 1976]. Thus, the timing of sample collection relative to the termination of exposure, is critical for reliable estimates of uptake. DUP050067923 210 Baker, Smith, and Landrigan NERVOUS SYSTEM TOXICITY General In the evaluation of individuals exposed to organic solvents, assessment of nervous system function is central to any form of medical evaluation. Solvents exert both transient and persistent effects on the nervous system. Transient effects appear to be mediated directly by the pharmacologic action of solvents within the central nervous system and these transient changes in function are proportional to the measured concentrations of solvent within the brain. Persistent neurological effects have been associated with histopathological changes in neural tissue. Experimental Human Studies A variety of detailed experimental studies performed primarily by Gamberale and colleagues in Sweden and Savolainen and colleagues in Finland have elucidated the time course and nature of the changes in psychophysiological functions that occur following solvent exposure [Gamberale, 1976]. These reports show impairment in simple and choice reaction time and selected tests of psychomotor function as the level and duration of exposure to solvents increase over brief (usually 2-6 hours) exposure periods. In an evaluation of exposure to m-xylene at concentrations of 100400 ppm [Riihimaki and Savolainen, 1980], acute central nervous system effects were correlated with blood xylene concentrations, and the occurrence of adverse effects also seemed to depend on a rapid rise of blood xylene concentration. Physical exercise was also noted in this study to increase the uptake rate and enhance the central nervous system effects of xylene absorption. The most pronounced effects noted in this report were a disruption of body balance and impairment of simple and choice reaction time. Some development of tolerance to the effects on reaction time were noted over extended exposures to xylene. In two other studies of short-term xylene exposure, exercise potentiated the effects on psychological function such as reaction time, manual coordination, and body balance [Savolainen et al, 1980; Gamberale et al, 1978]. Further studies have indicated that disruptions in equilibrium are a partic ularly sensitive neurologic effect of Short-term exposure to xylene [Savolainen and Linnavuo, 1979]. Experimental exposure to toluene and methyl chloroform have shown similar patterns of dose-related performance decrement [Gamberale, 1976]. Clinical Case Reports Several clinical case reports exist that relate neurological syndromes to prior exposure to organic solvents. Cerebellar syndromes have been reported following exposure to toluene by several authors [Boor and Hurtig, 1977; Grabski, 1961; Takeuchi et al, 1981]. Isolated reports of polyneuropathy among methyl ethyl ketoneexposed shoe factory workers has also appeared [Dyro, 1978], Other neurological syndromes reported following solvent exposure include loss of smell [Eramat, 1976] and Joss of visual acuity and other symptoms associated with toxic optic neuropathy (particularly recognized following exposure to methanol and ethanol, but also other organic solvents including trichloroethylene, carbon tetrachlo ride, and methylchloride) [Grant, 1974]. A loss of sensation and muscular function in the face as well as double vision has been described in several case reports following exposure to trichloroethylene and similar compounds [Feldman, 1979; Swedish Work Environment Fund, 1981]. One report indicated an increased rate of multiple sclerosis among jx (Amuduct aliphatic 1 Epidemii Ofi evaluate ; nervous s system is of periph ketone [! exposure to solven exposure etal, 19' ation bet of chron of develi twice th; A exposed behavio by Sepp exposed solvents the ner sensory with ur grams populat althoug popula1 descrit al, 19: sunun: using ' electro in .soh expos', the nt. time t< before a gre, anals; react i 1981] have DUP050067924 its, assessment of on. Solvents exert ent effects appear within the central oportional to the urological effects ily by Gamberale d have elucidated actions that occur w impairment in r function as the ually 2-6 hours) mtrations of 100stem effects were f adverse effects Physical exercise lance the central 1 effects noted in mple and choice action time were hort-term xylene such as reaction 10; Gamberale et ium are a partic[Savolainen and :hloroform have berale, 1976]. dromes to prior >orted following Grabski, 1961; lyl ethyl ketone- .ure include loss associated with o methanol and arbor, teirachlo:ular function in -ports following ; Swedish Work ultiple sclerosis Solvent Neurotoxicity 211 among persons exposed to organic solvents in the shoe manufacturing industry [Amaducci et al, 1982]. Shoe manufacturing involves exposure to a variety of aliphatic hydrocarbons including pentane, hexane, and heptane derivatives. Epidemiologic Investigations Of greater significance than isolated cases reports are epidemiologic studies that evaluate acute and chronic effects of solvent exposure on the central and peripheral neryotts systems. The principal neurologic syndrome affecting the peripheral nervous system is the occurrence of axonal degeneration with attendant symptoms and signs of peripheral neuropathy seen among workers exposed to hexane and methyl n-butyl ketone [Spencer and Schaumberg, 1980]. Chronic toxic encephalopathy following exposure to a variety of organic solvents constitutes the major concern with respect to solvent effects on the central nervous system (CMS) that persist after the immediate . L-j exposure period. Two epidemiologic studies, a case-referent investigation [Axelson * et al, 1976] and a follow-up study [Mikkelsen, 1980], have demonstrated the associ 3 ation between employment in solvent-exposed jobs and the occurrence of excess rates 1 of chronic neuropsychiatric conditions including dementia. In these studies, the risk i of developing chronic CNS impairment in solvent-exposed groups was approximately 1 twice that of the reference populations. '? A much larger number of studies have been performed in which various solvent- exposed groups have been evaluated with a variety of neurophysiological and neuroj behavioral tests. The two most important neurophysiological studies were performed by Seppalainen et al [1978] and by Elofsson et al [ 1980], Both groups studied workers ? exposed as industrial painters, a group recognized to have heavy exposure to organic solvents. Standard motor and sensory nerve conduction velocities were measured in the nerves of the upper and lower extremities, and modest slowing of motor and sensory conduction was noted in exposed populations in both studies in comparison with unexposed groups. Seppalainen et al [1978] also performed electroencephalo - grams (EEGs) and found significant differences betwen exposed and unexposed populations with respect to EEG abnormalities. In the study of Elofsson et al [1980], although no significant differences were noted between exposed and unexposed populations with respect to the visual evaluation of EEGs, subtle abnormalities were described. In another similar investigation of workers exposed to jet fuel [Knave et al, 1978], a reduced amount of alpha activity was noted in exposed workers. In summary, the electrophysiqlogic evaluations of workers exposed to solvent mixtures Using both standard techniques for evaluating peripheral nerve function as well as electroencephalography, have noted mild changes in neurophysiologic parameters. A large number of evaluations of neurobehavioral function have been performed in solvent-exposed groups to assess both short-term and persistent effects of solvent exposure on behavior. To evaluate acute effects of styrene on workers employed in the manufacture of fiberglass boats. Cherry and colleagues [1980] performed reaction time testing, vigilance testing, and other measures of psychomotor function and mood before and after the work day. Mood changes and increased fatigability were noted to a greater extent in exposed workers than a reference group and, in subsequent analyses, individuals from the same population who cleared styrene slowly had slower reaction times than their co-workers with average rates of metabolism [Cherry et al, 1981]. A variety of behavioral studies that have evaluated solvent-exposed groups have noted an excess of subjective symptoms, abnormalities of psychomotor perfor- DUP050067925 212 Baker, Smith, and Landrij>an mance, memory deficits, impairment in verbal concept formation, and disturbances of mood when compared with reference groups (Table 1). The most extensive series of these investigations has been performed by Hanninen, Lindstrom, and colleagues at the Institute of Occupational Health in Helsinki, In addition to cross-sectional evaluations, Lindstrom [1980] evaluated a group of 56 male workers diagnosed between 1971 and 1973 as having an occupational illness caused by exposure to organic solvents. Follow-up testing performed five or more years after cessation of solvent exposure noted a decline in visual/motor performance and attentional deficits that correlated with the duration of solvent exposure that had occurred in these individuals prior to their time of diagnosis. A similar follow-up evaluation performed by Bruhn et al [1981] indicated that the neurological status, degree of neuropsycho logical impairment, and the degree of cortical atrophy, was unchanged two years after the initial diagnosis of chronic toxic encephalopathy among a group of 26 house painters. Neurological features of the toxic encephalopathy diagnosed primarily by neurobehavioral testing included cortical atrophy [Juntunen et al, 1980] and reduced cerebral blood flow [Arlieii-Soborg et al, 1982]. Impaired vestibular function was also noted in one study of house and car painters who demonstrated reduced vestibular reactions following auditory canal irrigation with cold water [Arlien Soborg et al, 1981]. In a recent report [Maizlish et al, in press], 104 spray painters and lOl unexposed matched controls received a battery of behavioral and neurologial tests, a physical examination, and a medical questionnaire. Industrial hygiene sampling was performed to evaluate exposure levels. Despite the large number of tests performed, only two showed a dose-response relationship between exposure and performance: two-point discrimination on the dorsum of the foot and mean color-word time from the Siroop test. The authors conclude that the study did not show evidence that workers chronically exposed to hydrocarbon solvents at levels below the current TLV perform poorer on behavioral tests than unexposed individuals. TABLE 1. Summary of Epidemiologic Studies on Chronic Neurotoxic Effects of Solvents Exposed group Visual/ Verbal Subjective motor concept symptoms performance Memory formation Mood Reference Car painters Lacquerers Car painters House painters Spray painters House painters Solvent-poisoned workers Laminators Jet fuel-exposed workers Primers Steel workers Dry cleaners +* + + + + + + + Hanninen 11979J + Struwe 11980] Husman 11980] + + + Arlien-Soborg 11979] + _b Elofsson [1980] +-- Hane 11977) + +- Lindstrom 11980] + -- Harkonen [1977J Knave [1978] - + *** Hanninen [1979] + - Anshelm Olson 11981] - Tuttle 11977) " + = adverse effect was observed. b - = effect was tested for but not observed. Summary c In smv peripheral r. exposed to; individuals nervous sys degeneratioi methyl n-bu on electrop attention: ft toxicity in j The accunn lopathy can and boatbui psychomou of such beh and persist toxicity ha primarily 1 obviously frequently pronounce' Fund, 198 have sbov. exposure. PREVENT Redt systems a solvents u toring of concentra Control ( In a glove ma creams. T etal, 197 in prever study, bl comparal or even ; styrene-c al, 19801 [Dutkiev of percu efficacy DUP050067926 nd disturbances extensive series and colleagues cross-sectional kers diagnosed by exposure to iter cessation of entional deficits curred in these ition performed >f neuropsychoi two years after jp of 26 bouse ;d primarily by 50] and reduced ir function was iuced vestibular n Soborg et al, iinters and 101 rologial tests, a e sampling was ests performed, d performance: word time from v evidence that die current TLV Solvents Reference len [1979] : 11980] m11980] -Soborg f 1979] an (1980] 1977J rom 11980] nen [1977] 11978J icn 11979] Im Olson 11981] 119771_________ Solvcnl Neurotoxicity 213 Summary of Neurological Effects In summary, existing studies indicate the occurrence of defined syndromes of peripheral neuropathy and toxic encephalopathy that occur in individuals heavily exposed to solvents over a period of months to years. An important recent study of individuals chronically exposed below the TLV failed to demonstrate significant nervous system impairment. Peripheral neuropathy occurs as a result of axonal degeneration caused by exposure primarily to the hexacarbon solvents n-hexane and methyl n-butyl ketone. Studies that indicate peripheral nervous system abnormalities on electrophysiologic testing in populations exposed to solvent mixtures deserve attention; further research is necessary to evaluate the potential for peripheral neuro toxicity in groups exposed to solvents other than n-hexane or methyl n-butyl ketone. The accumulated evidence supports the occurrence of a syndrome of toxic encepha lopathy caused by excessive exposure to organic solvents in trades such as painting and boatbuilding. This syndrome is characterized by memory disturbances, impaired psychomotor function, impaired verbal abilities, and disturbances of mood. The onset of such behavioral complaints occurs during periods of excessive exposure to solvents and persists after exposure has ceased. A nonspecific manifestation of early solvent toxicity has been referred to as "the neurasthenic syndrome," which manifests primarily as fatigability, irritability, depression, and episodes of anxiety. Although obviously caused by many other etiologies, this constellation of symptoms occurs frequently in individuals with excessive exposure to solvents in the absence of more pronounced disruptions of neurobehavioral function [Swedish Work Environment Fund, 1981], Follow-up studies of patients with solvent-induced toxic encephalopathy have shown persistence of functional impairment years after removal from solvent exposure. PREVENTION OF DISEASE Reduction of airborne exposure levels through the use of proper ventilation systems and process design is essential to prevent excessive exposure to organic solvents used in boatbuilding. Reduction of skin uptake and periodic medical moni toring of exposed workers can be used along with measurement of airborne solvent concentrations to provide additional steps to prevent significant illness. Control of Skin Uptake In addition to the previously known problem of penetration of solvents through glove materials, there aTe also significant questions about the efficacy of barrier creams. Two recent reports of the evaluation of barrier creams in humans [Lauwerys et al, 1978] and in animals [Boman et al, 1982] indicate little evidence of their efficacy in preventing percutaneous absorption of xylene, toluene, or benzene. In the animal study, blood solvent concentrations two to three hours after exposure onset were comparable between animals with unprotected skin and those where barrier creams or even glove materials were used to protect the animals' skin surface. A study of styrene-exposed workers showed a similar lack of barrier-cream efficacy [Brooks el al, 1980]. Previous studies have demonstrated that styrene is absorbed percutaneously [Dutkiewicz and Tyras, 1968]. Therefore, although skin protection to reduce the risk of percutaneous solvent absorption seems appropriate, a clear demonstration of its efficacy is lacking in the recent literature. DUP050067927 214 Baker, Smith, and Landrigan Biological Monitoring of Exposed Populations In recent years, a variety of assays have been developed for monitoring the concentration of solvents and their metabolites in blood, urine, and exhaled air. These tests are useful because they measure uptake resulting from both inhalation and percutaneous absorption and, therefore, serve as an integrated index of the dose to the individual. An excellent recent publication summarizes the available information on biological monitoring for specific agents and should be referred to for a more detailed treatment of these issues [Lauwerys, 1983] . In general, urinary determinations reflect cumulative exposure to a greater extent than do blood or exhaled air analyses. The value of a specific urine determi nation varies with the pharmacokinetics of metabolism and the excretion route of the specific solvent. In most instances, blood concentrations and exhaled air concentra tions show a similar concentration profde over time and the choice of test usually is determined by the availability of sampling procedures and analytical techniques. Blood and air determinations are usually only of value during the immediate exposure period in view of the short half-life of these compounds in the blood. In some situations, such as the measurement of hippuric acid concentrations as an index of toluene uptake, dietary constituents interfere with test analyses owing to the presence of substances (eg, benzoic acid) that are metabolized to a common pathway. Drugs may also interfere in a similar fashion (eg, chloral hydrate, a common sedative, is converted to trichloroethanol and trichloroacetic acid). Therefore, a detailed dietary and drug history should be taken of individuals participating in biological monitoring programs. Interpretation of test results is further limited by the large variability in uptake occurring even at fixed exposure levels as a result of changing workload and variations in individual metabolic responses. Increasing phys ical exertion can increase the metabolite concentration by 3-5 times the level seen in sedentary individuals. Finally, the absence of normal population reference values, standard collection and analysis techniques, and a system of laboratory quality control for these assays limits their usefulness. Nevertheless, biological testing is of value in assessing individuals and groups exposed to solvents and as a means of quantifying total solvent uptake. Comparison of pre- and post-shift urinary solvent metabolite concentration is a useful way of assessing time-weighted exposure over the eight-hour work period. If the concerns mentioned above are adequately addressed, such testing can prove useful in assessing individual exposures. Reliance on an experienced laboratory with careful quality control procedures cannot be overemphasized in the analysis of solvent metabolites in biological materials. ACKNOWLEDGMENTS This work was supported in part by a Center Grant 0ESOOOO2-21 from the National Institute for Environmental Health Sciences (NIEHS) and a Special Empha sis Career Award (#K01QH00043) from the National Institute for Occupational Safety and Health. AnsheUn O 'long Arlicn-tn't* Seal Arlien-Sob chn H>~ Arlien-Si'b occi Astrand 1 i Hca Axelson 0 wor Axelson C D, Baker EL . Ad- Bird MC> l Oc. Boman Apre Boor JW. 4^: Brooks S! e* He Browning CV Bruhn P. Nt Chcrn !* c\ Chcrr> N a. Crand/i rr. Dutkic" Dyro > v ElofsM'r H Emm;:.: t Engst"'* Engsn FcMrn.:- FisCr* >. FIo Um'. or monitoring the . . ' exhaled air. These - . - - -"S* <h inhalation and * lex of the dose to - liable information --*! ed to for a more , sure to a greater fic urine determi- etion route of the ed Sir concentraof test usually is -tical techniques. mediate exposure . .. ~Z~ .4 r ^ ,^ 4 concentrations as nalyses owing to sd to a common drate, a common 1). Therefore, a participating in er limited by the s as a result of Increasing physthe level seen in iferenee values, y quality control ng is of value in s of quantifying mcentration is a work period. If :an prove useful ary with careful ysis of solvent 32-2.1 from the Special Etnphaipalional Safety shoe and leather 3. Solvent Neurotoxicity 215 /Vnshclm Olson, B, Gamberalc F, Gronqvist )B <1981): Reaction time changes among steel workers. A longitudinal study. J.nl Arch Occup Environ Health 48:211-218. Arlien-Soborg j>, Bruhn P, Gyldcnslcd C, Mclgaard B (1979): Chronic painter's syndrome. Acta Neurol Sound 60:149-156. Arlien-Soborg P, Hcnriksen L, Cade A, Gyldcnsted C, Paulson OB (1982): Cerebral blood flow in chronic toxic encephalopathy in house painters exposed to organic solvents. Acta Neurol Scand 66:34-41. Arlien-Soborg P, Zilslorff K, Grandjean B, Milting Pedersen L (1981): Vestibular dysfunction ip occupational chronic solvent intoxication. Clin Otolaryngol 6:285-290. Astrand :1 (1975): Uptake of solvents In the blood and tissues of man. A review. Scand J Work Environ Health 1:199-218. Axclsnn O, Hanc M, Hogsiedt C (1976): A case-referent study on ncuropsychiatric disorders among workers exposed to solvents. Scand J Wprk Environ Health 2:14-20. Axclson O, Hane M, Hogstedt C (1980): Current aspects of solvent-related disorders. In Zenz C (ed): Developments in Occupational Medicine." Chicago: Year Book Medicat publishers. Baker EE. Smith TJ (1984): Evaluation of exposure to organic solvents. In Harrington JM (ed): "Recent Advances in Occupational Health," Vol 2. London: Churchill Livingstone. Bird MG (1981): Industrial solvents: Some factors affecting their passage into and through the skin. Ann Occup Hyg 24:235-244. Boman A, Wahlberg IE, Johansson G (1982): A method for the study of the effect of barrier creams and protective gloves on the percutaneous absorption of solvents, permatoiogica 164:157-160. Boor JW, Hurtig HI (1977): Persistent cerebellar ataxia after exposure to toluene. Ann Neurol 2:440- 442. Brooks :SM, Anderson L, Emmett E, Carson A, Tsay J, Elia V, et al (1980): The effects of protective equipment on styrene exposure in workers in the reinforced plastics industry. Arch Environ Health 35(5):287-294. Browning E (1965): "Toxicity and Metabolism of Industrial Solvents." Amsterdam: Elsevier Publishing Company. Bruhn P, Arlien-Soborg P, Gyldensted C, Christensen EL (1981): Prognosis in chronic toxic encephalo pathy. A two-year follow-up study in 26 house painters with occupational encephalopathy. Acta Neurol Scand 6:259-272. Cherry N, Rodgers B, Venables H, Waldron HA, Wells GG (1981): Acute behavioural effects of styrene exposure; A further analysis. Br J Ind Med 38:346-350. Cherry N, Waldron HA, Wells GG, Wilkinson RT, Wilson HK, Jones S (1980): An investigation of the acute behavioural effects of styrene on factory workers. Br J Ind Med 37:234-240. Crandall MS, Hartle RW (1985): An analysis of exposure to styrene in the reinforced plastic boat making industry. Am J Ind. Med (in press). Dutkiewicz I, Tyras H (1968); Skin absorption of toluene, styrene, and xylene in man. Br J Ind Med 25:243-249. Dyro FM (1978): Methyl ethyl ketone polyneuropathy in shoe factory workers. Clin Toxicol I3(3):371- 376. Elofsson S, Gamberalc F, Hindmarsh T, Iregren A, Isaksson A, Johnsson I, et al (1980): Exposure to organic solvents. A cross-sectional epidemiologic Investigation on occupationally exposed car and industrial spray painters with special reference to the nervous system. Scand J Work Environ Health 6:239-273. Emmat EA (1976); Parosmia and hyposmia induced by solvent exposure. Br J Ind Med 33; 196-198. Engstrom K, Bjurstrom R (1977); Exposure to methylene chloride. Content in subcutaneous adipose tissue. Scand J Work Environ Health 3:215-224. Engstrom K, Husnian K, Pfaffli P, Riihimaki V (1978): Evaluation of occupational exposure to xylene by blood, exhaled air and urine analysis. Scand,} Work Environ Health 4:114-121, Feldman RG (1979): Trichloroethylene. In Vinken PJ, Bruyn GW (eds): "Handbook of the Nervous System." Amsterdam; North-Holiand Publishing Co., pp 457-464. Fiserova-Bergcrova V, Vlach J, Cassady JC (1980): Predictable "individual differences" in uptake and excretion of gases and lipid soluble vapors simulation study. Br J Ind Med 37:42-49. Flodin U, Edling C, Axelson O (1984): Clinical studies of psychoorganic syndrome among workers with exposure to solvents. Am J Ind Med 5:287-295. Gamberalc F (1976): Behavioral effects of exposure to solvent vapors. Experimental and field studies. In Horvath M (ed): "Adverse Effects of Environmental Chemicals and Psychotropic Drugs," Vol 2. pp 111-113. DUP050067929 1 216 Baker, Smith, and Landrigan Gambcrulc F, Annual! G, Hultengrcn M ([1978): Exposure to xylene and ethylbenzene. 111. Effects on central nervous functions. Scand J Work Environ Health 4:204-211. Grubski DA (1961): Toluene sniffing producing cerebellar degeneration. Am 3 Psychiatry 118:461-462. Grant WM (1974): "Toxicology of the Eye." Springfield, IL: Thomas Publishers. Hanc M. Axelson O, Blumc J, Hogstedt C, Sundell L, Ydreborg B (1977): Psychological function changes among house painters. Scand 3 Work Environ Health 3:91-99. Hanninen H, Eskelinen L, Husman K, Nurminen M (1979): Behavioral effects of long-term exposure to a mixture of organic solvents. Scand J Work Environ Health 4:240-255. Harkonen. H (1977) Relationship of symptoms to occupational styrene exposure and to the findings of electrocncephalographic and psychological examinations..Int Arch Oeeup Environ Health 40:231239. Husrnan K (1980) Symptoms of car painters with long-term exposure to a mixture of organic solvents. Scand J Work Environ Health 6:19-32. Ikeda M, Ohtsuji H. Imamura 1 (1972): In vivo suppression of benzene and styrene oxidation by coadministered toluene in rats and effects ofphenobarbetal, Xenobiotica 2:101-106. Jakobson I, Wahlberg JE, Holmberg B, Johansson Q (1982): Uptake via the blood and elimination of 10 organic solvents following epicutaneous exposure of anesthetized guinea pigs, Toxicol Appl Pharmacol 63:181-187. Juntunen J, [Hupli V, Hernberg S, Luisto M (1980): Neurological picture of organic solvent poisoning in industry. Int Arch Occup Environ Health 46:2)9-231. Ketman OR (1982): Theoretical basis ofalveolar sampling. Br J lnd Med 39:259-264. Knave ;B, Anshetm-Olson B, Elofsson S, Gamberale F, Isaksson A, Mindus P, Persson HE, Struwe G, Wennberg A, Westerholm P (1978): Long term exposure to jet fuel. II. A cross-sectional epidemiologic investigation on occupationally exposed industrial workers with special reference to the nervous system. Scand J Work Environ Health 4:19-45. Lauwerys RR (1983): "Industrial Chemical Exposure: Guidelines for Biological Monitoring.'' Davis, CA: Biomedical Publications. Lauwerys RR, Dath T, Lachapelle J-M, Buchet J-P, Reels H (19.78): The influence of two barrier creams on the percutaneous absolution of m-xylene in man. 3 Occup Med 20:17-20. Lindstrom K (1980): Changes in psychological performances of solvent-poisoned and solvent-exposed workers. Am 3 lnd Med 1:69-84. Maizlish N A, Fine L3, Alberts JA, Whitehead LW, Langolf GO. A neurological evaluation of workers exposed (o mixtures of organic solvents. Brit 3 lnd Med (in press). Mikkelscn S (1980): A cohort study of disability pension and death among painters with special regard to disabling presence dementia as occupational disease. Scand 3 Soc Med [Suppl]16:34-43. Monster AC, Boersma G, SteenwegH (1979): Kinetics of 1,1,1-trichlotoethane in volunteers; influence of exposure concentration and work load. Int Arch Occup Environ health 42:293-301. Nomiyama K, Nomiyama H (1974): Respiratory elimination of organic solvents in man; benzene, toluene, n-hexane, trichloroethylene, acetone, ethyl acetate and ethyl alcohol. Int Arch Arbeitsmed 32:85-91. Riihimaki V, Pfaffli P (1978): Percutaneous absorption of solvent vapors in man. Scand 3 Work Environ Health 4:73-85. Riihimaki V, Pfaffli P, Savolainen ,K (1979): Kinetics of m-xylene in man. Influence of intermittent physical exercise and changing environmental concentrations on kinetics. Scand 3 Work Environ Health 5:232-248. Riihimaki V, Savolainen K (1980): Human exposure to m-xylene, kinetics and acute effects on the central nervous system. Ann Occup Hyg 23:411-422. Riihimaki V, Savolainen K, Pfaffli P, Pekari K, Sippel HW, Laine A (1982): Metabolic interaction between m-xylene and ethanol. Arch Toxicol 49:253-263. Savolainen K, Linnavuo M (1979): Effects of m-xylene on human equilibrium measured with a quantitative method. Acta Pharmacol Toxicol 44:315-318. Savolainen K, Riihimaki V, Seppalainen AM, Linnoila M (1980): Effects of short-term m-xylene exposure and physical exercise on the central nervous system. 1m Arch Occup Environ Health 45:105-121. Sedivec V, Flek J (1976); The absorption, metabolism, and excretion of xylenes in man, Int Arch Occup Environ Health 37:205-217. Seppalainen AM, Husman K, Martenson C (1978): Neurophysiological effects of long-term exposure to a mixture of organic solvents. Scand I Work Environ Health 4:304-314. ' . V-v. - - : ' ; .i 'i \ ' j * i I : ! ` ; j !I Scpp Spec Strut Sum! Sv.cc Take Toftg TuttU VanR Wald: lylbenzene. 111. Effects on I psychiatry 118.461-462, >ers. '); Psychological function i oflong-term exposure to we and Jo the findings of p Environ Health 40:231- tture of organic solvents. styrene oxidation by co101-106. >od and elimination of 10 ittea pigs. Toxicol Appl ,.J . :-.aai i ,i .j anic solvent poisoning in 9-264. PersSon HE, Struwe C, II. A cross-sectional s with special reference -i .J al Monitoring.'' Davis, | e oftwo barrier creams 10. :d and solvent-exposed | j 1 evaluation of workers ?rs with special regard Sup{B116:34-43, i volunteers; influence ,2:293-301. nts in man; benzene. lcohol. Int Arch Ar- Jeand J Work Environ luencc of intermittent cand J Work Environ acute effects on the Metabolic interaction m measured with a short-term m-xyfene cup Environ Health nan, Int Arch Occup n&-tcrm exposure lo Seppalainen AM, Ltndstrom K, Martelin T (19.80): Neurophysiological and psychological picture of solvent poisoning. Am J lnd Med 1:31-42. Spencer PS and Schaumbcrg HH (1980): "Experimental and Clinical Neurotoxicology." Baltimore: Williams and Wilkins. Struwe G, Mindus P, Jonsson B (1980): Psychiatric ratings in occupational health research: A study of mental symptoms jn lacquercrs. Am J lnd Med 1:23-30. Sundell L (1975): Mental fonctian changes among house painters. Lakartidningen 72:702-706. Swedish Work Environment Fund (1981): ``Solvents in die work environment--survey and analysis of needs for research." Stockholm. Takeuchi Y, Hisanaga N, Ono Y.Ogawa T, Hamaguchi Y, Okamolo S (1981): Cerebellar dysfunction caused by sniffing of toluene-containing thinner, lnd Health 19.: 163-169. Toftgard R, Gustafsson J (1980): Biotransformation of organic solvents. A review. Scand J Work Environ Health 6:1-18. Tuttle TC, Wood GD, GretberCB. A behavioral and neurological evaluation of dry cleaners exposed to perchlorethylene. Cincinnati, NIOSH, 1977. VanRees H (1972): Mutual influence on the metabolism of some industrial solvents in rats. In "Proceed ings of ibe European Society for the Study of Drug Toxicity, XIII. Toxicological Problems of Drug Toxicity." Amsterdam: Excerpta Mediea Foundation, pp 69-74. Waldron BA, Cherry N, Johnston ID (1983): The effects of ethanoi on blood toluene concentrations. Inf Arch Occup Environ Health 51:365-369.