Document 0x0wab2YVLGeoJGBQ4wgD92n

ix El^ptation i. 493, Geneva roallpoi eradl nd global cer 3ME/78.21, Ge : Towards the 9 May 1980. /orld Health nd VC JOURNAL OF HYGIENE, EPIDEMIOLOGY, MICROBIOLOGY AND IMMUNOLOGY 25, 1SS1, No. 3, 233-243 I NEUROLOGICAL CHANGES IN VINYL CHLORIDEEXPOSED WORKERS V. STtBLOVA', V. L A M B L >, 0. CHUMCAL'. V. KELLEROVA', v. paskova\ j. viiovcdvA', l. Slab1 *) Department of Neurology, Medical Faculty of Hygiene, Charles University, Prague 2) Outpatient Clinic o! Occupational Health, District Centre ol National Health, MSlnlk, Czechoslovakia Vinyl chloride (VC) toxicity for the human organism Is not still fully clear. The occupational exposure to VC is linked with the development of liver hemanglosarcomas, or with other malignant processes of varying locality. Some authors diagnose changes In terms of scleroderma, universally are described roentgenologically detected lesions of interphalangeal Joints and zonal osteoly sis. They are described in association with Raynaud's syndrome (12, 10, 1, 4, S and others). Lange with his colleagues (12) describes angiologically detect able constriction of digital arteries, stenosis or partial occlusion of phalangeal blood vessels. Described are also various types of dysesthesia in fingers, parti cularly cold and numbness sensations. Also Byczkowska (3) reports frequent occurrence of finger paresthesia, whitening "of fingers, but also of palms and soles, and other symptoms of peripheral vasomotor disorders. Neurological manifestations are described only sporadically. Spirtas and colleagues (16) emphasize particularly the narcotic action of VC at -higher peak exposure concentrations. This manifests itself by vertigo, nausea and hea dache pains. Mentioned are also hand parestheslae (prlnckling, formication). Langauer-Lewowicka (11) analyzes also the clinical symptoms In her group of 200 examinees who showed most frequently signs of cerebellar symptomatol logy. She 'recorded frequent occurrence of headaches and sleep disorders, but also trigeminal neuralgia. | Because of a lack of more detailed neurological studies among the VC-ex- v posed persons, we conducted field investigations among the occupationally ex- i posed workers in a plant where there was six years before put into operation l a workshop with a considerable VC hazard. ,, *- 8SK. MATERIAL AND METHODS The group of examinees consisted of 293 workers (263 males and 30 females), age 18--58 years, mean age 32.8 years. Of these 76 % were below 40. The average time of exposure was 2.8 years (range from 2 months to 6 years). After consultations with plant'physician and plant toxicologist the group was divided into two subgroups ac cording to the level of exposure. The subgroup of high-risk workers, in which the ten tatively established maximum allowable concentration of 10 mg. m~3 had been fre quently and sometimes highly exceeded, involved polymerization worker^,, and some maintenance workers (a total of 109 persons). The subgroup of lower-risk category of workers included those engaged in drying and bagging operations, but even here they were sometimes exposed to high peak exposure concentrations during cleaning and sampling operations, and those from the other plant workshops -- combustion, compres sors, cracking, chlorination, regeneration -- where the exposure risk was relatively low (a total of 184 persons). All the workers were examined neurologically, some of them repeatedly. A more detailed analysis of subjective complaints was performed on the basis of EOD and N5 questionnaire surveys. Electroencephalographic examination with photostimulation was made in 232 persons (255 recordings). The group of controls consisted of 46 persons without exposure to toxic substances. RESULTS An overview of subjective complaints is presented in Table 1. Headaches occur frequently, but they are less frequent than in.the control group. The in cidence of gastrointestinal disorders and other neurovegetative disorders (palpi tations, retrosternal pressure sensations) are significantly higher than in con trols. Psychic disturbances were observed only in those exposed. Table X. Overview of subjective complaints In workers occupational!)' exposed to vi nyl chloride, in a comparison with controls Complaints Headache Sleep disorders GIT disorders Vertigo Psychic disturbation Dysesthesia Palpitations Total number of examinees VC -- exposed ~~ " number 0/ to 46 15.7 16 5.5 20 6.9 3 1.0 23 4.5 9 3.1 14 4.8 293 100.0 Controls number % 9 19.6 2 4.4 1 2.2 1 2.2 0 0.0 1 2.2 0 0.0 46_ 100.0 Significant differences were observed between the two subgroups of ex posed workers divided according to the level of exposure (Table 2). The sub group of more exposed workers showed a higher lncidenc^of headaches and Table 2. Overview Complain Headache Sleep disorder* GIT disorder* Vertigo Psychic disturhatic Dysesthesia Palpitations Total number of ex gastrointestinal was observed a] In persons with ches was doublt more than 4 ye psychic disturbs Table 3. Overvie #- Complain Headache Sleep disorder* GIT disorders Vertigo Psychic distnrbath Dysesthesia Palpitations Total number of d posed workers showed a slgnl cent of more sc Graph 1 pr syndromes dete lesion of peripfa : 8.7 %). Diagnc or loss of tendc ilesj^ge e time of .om with -oups ac- the tenbeen fre:nd some tegory of iere they nlng and comprestvely low A more ) and N5 tlon was : persons adaches The in(palpiin con- d to vl- 9.6 4.4 2.2 2.2 0.0 2.2 0.0 0.0 ol exhe sub.es and Table 2, Overview of subjective complaints in workers occupationally exposed to vi nyl chloride, relation to the level of exposure Complaints Headache Sleep disorders GIT disorders Vertigo Psychic disturbation Dysesthesia Palpitations Total number of examinees Total number % 46 1S.7 16 5.5 20 6.9 3 1.0 13 4.5 9 3.1 14 4.8 293 100.0 More exposed number 0/ fO ' 19 7 11 2 6 7 5 109 17.4 6.4 10.1 1.8 5.5 6.4 4.6 100/0 Less exposed number % 27 14.7 9 4.9 9 4.9 1 0.5 7 3.8 2 1.1 .9 4.9 184 100.0 gastrointestinal disorders, and furthermore, of dysesthesia of extremities. There was observed also a certain correlation with the length of exposure (Table 3). In persons with the exposure time longer than 4 years, the incidence of heada ches was double the incidence in the group with a shorter time of exposed for more than 4 years. Sleep disorders, gastrointestinal complaints, vertigo and psychic disturbances were also more frequent in those with a longer time of ex- Table 3. Overview of subjective complaints in workers occupationally exposed to vinyl chloride, relation to the length of exposure Complaints Headache Sleep disorders GIT disorders * Vertigo Psychic disturbation Dysesthesia Palpitations Total number of examinees Total number 0/o/ 46 15.7 16 5.5 20 6.9 3 1.0 13 4.5 9 3.1 14 4.8 293 100.0 Exposure longer than 4 years number % 24 8 9 3 8 8 ----- -4 101 23.8 7.9 8.9 3.0 7.9 7.9 4.0 100.0 Exposure shorter than 4 years number % 22 11.0 8 4.2 11 5.7 0 0.0 5 2.6 1 0.5 10 5.2 192 100.0 posed workers is characterized in Table 4. The group of more exposed workers showed a significantly lower per cent of normal findings and a higher per cent of more severe findings than the group of less exposed workers. Graph 1 presents incidence of the most frequent, objectively diagnosed syndromes detected in exposed and control groups. The most'frequent was the lesion of peripheral neurons, either motor or sensory, or both of them (16.8 % : x 8.7 %). Diagnosed were Impairments of muscle tonus or trophicity, reduction or loss of tendon and bone reflexes, abnormal sensitivity. Compared to controls. i Krai'S Table 4. Severity of objectively diagnosed changes in workers occupationally exposed to vinyl chloride In relation to the level of exposure Severity of changes Normal light changes Manifest changes Total number of examinees Total number % 165 57.0 112 38.0 16 5.0 293 100.0 More exposed number 0//o 50 46.0 49 4S.0 10 9.0 109 100.0 Less exposed number % 115 62.5 34.2 6 3.3. 184 100.0 the group of exposed workers showed also more frequently the symptomatology of peripheral neurovegetative disorders (12%: 4.4%), specifically acrohypothermy, acrohyperhldrosis or whitening of fingers, associated with dysesthesia* diagnosed In VC-e bined with the dl abnormities. Rela 46.5 % of cases). Graph l: Objectively diagnosed changes In VC-exposed workers in a comparison to controls. X-axis -- objectively diagnosed changes: A -- peripheral neuron lesions, B -- peripheral neurovegetative symptomatology, C -- cerebellar symptomatology, D -- vestibular symptomatology, F -- extrapyramidal symptomatology, G -- disperse central symptomatology. Blank column -- group of controls, hatched column -- group of VC* -exposed. Y-axis -- % of examinees Graph 2 shows objectively diagnosed symptoms In relation to the level of exposure. A marked difference is in the incidence of peripheral neuron lesions: more exposed workers are affected more than twice as often (25.6 % : 11-8 %]. Celebellar and vestibular syndrome Is also more frequent (10%: 7.6% and 6.4 % : 3.3 %, respectively). There are also certain Indications of a correlation with the length of exposure, see Graph 3: those with more than 4 years of ex posure have more frequently peripheral neuron lesions -f 22.8 % : 13.fi %] and cerebellar Impairments (13.9 %: 5.7 %). Frequency of the vestibulocerebellar syndrome is also higher (5 % : 0.5 %) In these persons. The results of EEG examinations of exposed and 81 non-exposed control workers are compared In Table 5. The per cent of abnormal EEG recordings in the group of exposed workers is higher than lq the conta>l group; the EEG abnormities detected in the controls were always least severe. Abnormities 236 < Graph 2: Objective) of exposure. X-axis lower exposure lev a higher degree ferencesj^ve ob pnly in of . wards beta and tf The addition; were used to lm Graph 3: Objective! of exposure. X-ax column -- expost than 4 y R&S 114692 f cposed 62.5 34.2 3.3 100.0 natology crohypoesthesla. diagnosed In VC-exposed workers were predominantly episodic, In 5 cases com bined with the diffuse abnormity. Three EEG recordings revealed only diffuse abnormities. Relatively frequent was also the presence of sleep waves (in 46.5% of cases]. In 16% of workers the sleep activity manifestations were of irlsi i les jgy, D -- e central p ol VC- level of lesions: 11.8%). 1 % and 'relation s of ex%) and ?rebellar control dings In .he EEG ormltles Graph 2: Objectively diagnosed changes in VC-exposed workers in relation to the level of exposure. X-axis abjectively diagnosed changes: A-D see Graph 1. Blank column -- lower exposure levels, hatched column -- higher exposure levels. Y-axis -- % of the total number of exposed subjects. a higher degree of severity (2c to 3, according to Roth (13)). Significant dif ferences were observed also in the photostimulation reaction that was normal only in 40 % of cases. The most frequent was extension of photic driving to- The additionally conducted N5 and EOD (6, 7, 8, 9) questionnaire surveys were used to improve analysis of subjective complaints and to complement Graph 3: Objectively diagnosed changes in VC-exposed workers in relation to the length of exposure. X-axls -- objectively diagnosed changes: A-D see Graph 1. column -- exposure shorter than 4 years, hatched column -- exposure than 4 years. Y-axis -- % of the total number of exposed subjects. i #i ;:|t anamnestic data. The questionnaire N5 examines superficial personal traits as and to onnP^owi n e well as certain clinical symptomatology, particularly neurovegetative syndro naud's syndrome i me, neurasthenic, depressive and anxiety-phobic symptoms, and the so-called toxic syndrome. Data provided by this type of questionnaire were suggestive of in terms of stenos lesions diagnosed ed by a direct n< companylng more ssa Table 5. Severity of EEG changes in workers occupationally exposed to vinyl chloride, in a comparison to controls _ "EEG changes Normal Suspect Abnormal Total slight medium total Exp Med number 0/O/ 148 63.8 48 20.7 . 30 12.9 6 2.6 36 15.5 232 100.0 . Control* number | % 57 70.4 19 23.4 5 6.2 0 0.0 5 6.2 81 100.0 a higher frequency of sleep disorders (36%) than originally revealed hy ana mnestic data, highly frequent (5 /o level of significance] was also somnolence (76 %), which had not been also indicated in personal histories. More frequent were also feelings of bad performance, fear of loosing life or health. Furthermore, the frequency of hyperhidrosis was also very high (73%). The Eyseneck perso nality questionnaire examines neurottcism. It reveals subjective tendencies that are evaluated by the examinee and confronted with the objective reality. In the examined group there were not detected any significant deviations from the norm; increased neuroticism could not be demonstrated. The narcotic changes In the be irreversible chan] ves in EEG recoi firmed in a relat nees as well as solvents (19, 21, 2 more serious ant cortical brain st diffuse abnormal! ment with the c This leads us to i centrations, can structures. VC-induced manifest themsel of changed hype authors on the 1 with oi^faiding: wKo bel exposed worker: damage. Compai in persons expo: DISCUSSION Clinical examination of VC-exposed workerSTevealed significant changes predominantly in neurologic symptomatology. Some of the subjective complaints, such as headaches, vertigo, sleep disorders or increased sleepiness during the 1) Exposure day, as revealed by questionnaire N5, are suggestive of the narcotic action of terature, also tt VC, similarly as the occurrence of the cerebellar and/or vestibulocerebellar these neurologii symptomatology. These changes have been, already described by Spirtas and of exposure. colleagues (16), Langauer-Lewowlcka [XI], but also by Schwartzovfi (15] and 2) Some ol others. This characteristic symptomatology was also described in our previous tion of VC, sue! studies concerned with the occupational exposure to trichloroethylene, benzene locerebellar syi and other organic solvents (17,18, 20]. Here we also observed a high incidence of dysesthesia after exposures to some solvents, particularly to benzene. We 3) Among ascribed It either to peripheral vasomotor changes, or -- at least in some cases tion is, no dou! ii -- to initial phases of polyneuropathy. In case of VC the presence of peripheral binatlon with t vasomotor changes Is evidently very significant: according to literature data motor changes 238 aits yndro^" celled tlve of lloride, A A .2 .0 > y anaolence equent more, persoes that In im hanges plaints, Ing the tion of ebellar as and 5) and revious >enzene sldence ne. We e cases ipheral e data and to our own experience these changes are frequently associated with Ray naud's syndrome and may presumably lead to even more severe consequencies In terms of stenosis or occlusion, as described by Lange (12). Peripheral nerve lesions diagnosed m our group of VC-exposed examinees oould be then explain ed by a direct neurotoxic action of VC, or as a consequence of hypoxia ac companying more severe vasomotor changes In the periphery. The narcotic action of VC can be either transitory, inducing only reversible changes in the brain function, or persistent, causing more permanent, sometime Irreversible changes In the CNS. Slight functional changes manifest themsel ves in EEG recordings by waves typical for various stages of sleep, as con firmed in a relatively high per cent (46.5%) of cases in our group'cJf exami nees as well as in some of the examined subjects exposed to other organic solvents (19, 21, 22). Detection of episodic or diffuse EEG abnormalities Is rather more serious and may be indicative of chronic changes in mediobasal and/or cortical brain structures. In our group of examinees, the joint episodic and diffuse abnormality occurred in 15.6 % of workers. This frequency is in agree ment with the cited literature data as well as with our previous experience. This leads us to a conclusion that even VC, particularly at higher exposure con centrations, can produce neurotic changes in the above described brain structures. VC-induced pathophysiological changes are believed by some authors to manifest themselves by the central neurovegetative dysregulation, as a result of changed hypothalamus functions (2). This localization, presumed by these authors on the basis of their experimental studies, seems to be in agreement with our findings of EEG episodic abnormalities. We also believe that even FS reaction changes, recorded in our group of exposed workers, may be of Importance in the early diagnosis of VC-induced damage. Comparable FS reaction changes were also described by Rouskovd (14) in persons exposed to other toxic agents. CONCLUSIONS 1} Exposure to VC may lead, besides to otheFchanges described in the li terature, also to lesions of the nervous system. The onset and development of these neurologic changes depend on the VC exposure level and on the length of exposure. 2) Some of the neurologic manifestations are caused by the narcotic ac tion of VC, such as certain subjective complaints and cerebellar and/or vestibu locerebellar syndrome. These symptoms can be transitory or persistent. 3} Among the important manifestations that are characteristic for VC ac tion is, no doubt, the peripheral vasomotor symptomatology, sometimes in com bination with the Raynaud's syndrome described In the literature. These vaso motor changes in the periphery may further develop, leading consequently to 239 more severe lesions of peripheral blood vessels. Equally Important are the ge neral neurovegetatlve manifestations (gastrointestinal and cardiovascular dis orders, hyperhldrosis, etc.) that might result from the central neurovegetatlve dysregulation. Important are also symptoms of peripheral neuron lesions caus ed by a direct neurotoxic action of VC or by hypoxia-related mechanisms. 4) Episodic abnormality in EEG recordings seems to agree with the assumed Involvement of hypothalamic structures (Basalajev and colleagues). It occurs even at exposure to the other types of organic solvents (15,19, 21^^!) and may be indicative of a more diffuse affliction of mediobasal and cortical structures of the brain. Less severe manifestations of EEG sleep activity can be ascribed to the nacrotic action of VC, more pronounced sleep manifestations accompa nied with abnormal EEG changes may be suggestive of more persistent changes in the CNS. 5) Neurological changes have not been so far sufficiently accentuated in the professional literature and, therefore, the monitoring of workers at risk is not conducted systematically and by suitable methods. It is necessary to en sure a neurological prevention in these occupationally exposed workers. Of the supplementary methods of examination there are recommendable, both for pre vention and research purposes, to use EEG examination with photostimulation, questionnaires N5 and EOD, and electromyographic examination. SUMMARY Neurological examinations were conducted in 293 workers occupationally exposed to vinyl chloride. Subjective complaints were evaluated on the background of N5 and EOD questionnare survey analysis. EEG examinations. Including photostimulation, were performed in 232 persons. The control group comprised 48 nonexposed subjects. Average time of exposure was 2.8 years, the longest time of exposure was 6 years. Among the most frequent subjective complaints were headache, neurovegetatlve disorders and dysesthesiae, among objective findings dominated cerebellar and/or vestibulocerebellar syndrome, lesions of peripheral neurons and peripheral neurovege tatlve symptomatology. Subjective and objective symptoms were found to depend on the exposure level and the time of exposure. ' EEG examinations confirmed in 15.5 % of cases abnormities, predominantly episo dic, sometlnmes combined with the diffuse abnormality. 4B.5 % of the exposed showed presence of sleep activity as a consequence of VC narcotic action. The episodic EEG activity could be ascribed to lesions of mediobasal structures, or even to changes In brain cortex. Our data have confirmed that vinyl clorlde has a considerable impact on the human nervous system. Most frequent are lesions of vestibulocerebellar system and vlgillty disorders due to VC narcotic action. Frequent occurrence of peripheral sympto matology can be explained by a direct neurotoxic action of VC, or as a consequence of hypoxia caused by peripheral vasomotor changes. As a rule, regular check-ups of VC-exposed workers do not Include systematic neurological examinations. The systematic neurologic prevention, based on the as sessment of clinical, EEG and/or EMG examinations, should become obligatory. Supple mentary use of N5 and EOD questionnaire surveys is highly .pdvlsable. 240 < Stfblovf v4, V., Vftov Chlorure de Yin II a 4t4 At posAs au Chlcr; 4 l'aide des ant ficatif prodult l'exposition sub Les trouble gAtatifs et dysi t&me vestibule pArlphArique vi xlque direct pi ayant lieu lors Des donnAi sujets dAmontr (chez 15,5 %) atteinte des st Les sujets jour, aux exam dans ce cas, i sues de l'EEG Stjblov v 4, V., Vft rid exponiertei Man beobc Vlnylchlorid e; mit Hilfe der I Einwlrkung v< Exposition abh Die hftufig tome und Dys zerebellarsystt ren vegetative wohl als direl / bei peripherec In dem EEC fest, die die Aktlvltat [bei durch Affektl gen erkiaren. Die Vinylgischen Stanr ar^Ae geivasc^rar disirovegetative lesions causanisms. the assumed s). It occurs 22} and may al structures be ascribed ns accompatent changes accentuated kers at risk ssary to enkers. Of the >oth for prejstimulation. 'ally exposed d of N5 and ulatl^^were 3cts^^age urovegetative ellar and/or 1 neurovege3 depend on nantly eplsoosed showed episodic EEG > changes in 'act on the system and eral symptotsequence of : systematic on the as* ory. Supple- RESUME Styblovd, V., L a m b 1, V., Cbumchal, 0., K e 11 e r o v 4, V., P a S k o v a, V., V 11 o v c o v &, 2 1 a b, L.: L'image neurologique chez les snjets exposes an chlornre de vinyle II a 6t6 etudi d'une manure complexe l'image neurologique chez 293 sujets ex poses au chlorure de vinyle. Des troubles ubjectifs ont 6t6 analyses au plan detailie & l'aide des anqufites EOD et N5. II a 6te mis en evidence un effet neurotoxique significatif prodult par chlorure de vinyle qul depend de la qualitfi et de la quantity de l'exposition subie. Les troubles subjectlfs rencontres le plus souvant: maux de tfite^ymptflmes vdgdtatifs et dysesthdsie. Les donnfies objectives tdmoignent pour une affection du syst&me vestlbulocdrdbelleux et pour celle du neurone pdrlphdrique et de l'innervation pdrlphdrlque vdgdtatlve. La symptOmatologie pdriphdrique peut rdsulter de l'effet toxlque direct produit par chlorure de vinyle aussi bien que du mdcanisme d'hypoxie ayant lieu lors des changements vasomoteurs pdrlphdrtques. Des donnds issues de l'EEG tSmoignant une activity de sommeil chez 46,5 % de sujets ddmontrent un effet narcotique du chlorure de vinyle. L'activitd dpisodique (chez 15,5%} associde parfols a l'anomalie de diffusion pourrait s'expliquer par une attelnte des structures mddlobasales, mfime lide aux changements du cortex. Les sujets exposds a 1'influence du chlorure de vinyle ne se soumettent, jusqu'a ce jour, aux examens systdmatiques au plan neurologique. 11 est ndcessaire de poursuivre, dans ce cas, une prophylaxie neurologique dtudiant l'image Clinique, les donndes Is sues de l'EEG ou mfime de l'EMG. 11 est utile d'employer les anquStes EOD et N5. ZUSAMMENFASSUNG Sty bl ovd, V., Lambl. V.. Chumchal. 0,, Keller ova, V,, PaSkov d, V., V11 o v c o v a, V., 21 a b, L.: Neurologisches Bild bei den dem Vlnylchlorid exponierten Arbelteoden Man beobachtete kompiexerweise das neuroioglsche Bild bel 293 Arbeltenden, die Vlnylchlorid exponiert waren. Subjektive Schwierigkelten analysierte man eingebender mit Hilfe der EOD- und N 5-Fragebogen. Dabei hat man eine signifikante neurotoxische Einwirkung von Vlnylchlorid nachgewiesen, die von der Intensitat und Dauer der Exposition abhfingig 1st. ----___ Die h&uflgsten subjektlven Schwierigkelten waren Kopfschmerzen vegetative Symptome und Dysesthfisle. Der objektive Befund zeugt von der Affektion des Vestibularzerebellarsystems, ferner von der Affektion des peripheren Neurons und der peripheren vegetativen Innervation. Die periphere Symptomatologie kann man erklBren sowohl als direkte Einwirkung von Vlnylchlorid, als auch den hypoxiscben Mechanlsmus bei peripheren vasomotorischen Veranderungen. In dem EEG-Befund stellte man bei 46,5 % Tiele der Gesamthelt die Schlafaktiviiat fest, die die narkotiscbe Einwirkung von Vlnylchlorid dokumentiert. Die eplsodische Aktlvitat (bel 15,5%) manchmal in Verbindung mit Dlffus.ionsabnormitat ktinnte man durch Affektion von roediobasalen Strukturen, gegebenenfals" durch Kortexver&nderungen erkiaren. Die Vlnylchlorid exponierten Arbeltenden werden blsher systematlsch vom neurologiscben Standpunkt nicht beobacbtet. Die Verfasser balten die gezielte neurologiscbe R&S 114698 Vorbeugung m Verbindung mit Beobachtung des klinischen Bildes, des EEG- eventuell auch des EMG-Befundes far notwendlg. Sehr geeignet ist die Anwendung der EOD- und N 5-Fragebogen. RESUMEN S t f b 1 o v 4, V,, L a m b 1, V., Cbumcbal, O., Kellerovd, V., P a 5 k o v4, V., Vltovcovfl, V., 2lab, L.: El cuadro nenrolAgico en trabajadnrjs expuestos al vinilcloruro Se ha examinado globalmente el cuadro neuroldgico en 293 traba]adores expuestos al vinilcloruro. Las dlficultades subjetlvos se las analizA detalladamente raedlante los cuestionarios EOD y N 5. Se mostrb el resultado neurotOxlco marcado del vinilcloruro, el que dependla de la altura y duraciAn de la expostcidn. Las dlficultades subjetivas m6s frecuentes eran los dolores de la cabeza, los sintomas vegetativos asi que la disestesia. El hallazgo. objetlvo muestra la afectacidn del slstema vestibulocerebelar, asi que la de la neurona vegetatlva perifdrica y de a InervacIAn vegetatlva perifdrica. La sintomatologla perifdrica la puede explicar tanto por el efecto tdxico directo Bel vinilcloruro, como por el mecanismo hipdxico con los cambios vasomotdricos perifdricos. Se halld en hallazgos electroencefalograficos una actividad del suefio en el 46,5 p. c. del conjunto, lo que prueba el resultado narcdtico del vinilcloruro. La actividad epizOdica (en el 15,5 p. c.], a veces en la combinacidn con la anormidad difusa podrla se explicar por afectaciOn de las estructuras mediobasales, eventualmente por cambios de la epidermis. Los trabajadores expuestos al vinilcloruro no son adn examinados neuroldgicamente de manera sistemdtica. Hace falta que se haya realizado neuroldgica prevencidn encaminada incluso el cuadro clinlco, el hallazgo electroencefalogrdfico, eventualmente el electromiogrdfico. Se recomienda user los cuestionarios EID y N 5. REFERENCES 1. Angulescu, F., Otoiu, m., Dobronescu, E.: Med. Int. 4, 1969, pp. 473--480. -- 2. Basalajer, A. V., Vaztn, A. N., Kocetkov, A. G.: Gig. truda 2, 1972, pp. 24--27. -- 3. Byczkowska, Z., et al.: Pol. tyg. lekar. 29; 1974, 26, pp. 1461--1464. -- 4. Dinman, B. D., Warren, A., Whitehouse, W. M.: Arch. Environ. Hlth. 22, 1971, 1, pp. 61--73. -- 5. Dodson, V. N., Bertram, ., Dinman, B. D., Whitehouse, W. M.: Arch. Environ. Hlth. 22, 1971, 1, pp. 83--91. -- 6. Engelsmann, F.: Cs. psycho). 3, 1960, pp. 322-- 337. -- 7. Engelsmann, F., Drdkovfi, S.: Cs. psycho!. 4, 1964, pp. 340--348. -- 8. Engelsmann, F., Drdkovfi, S.: Actlv. nerv. sup. 2, 1959, pp. 108--118. -- 9. Eysenck, H. J., Eysenck, S. G. B.: Manual of the Eysenck 242 Personality Inventory. Unlv. of London Press, London -24,.1964. -- 10. Harris, D. VL, Adams, W. G. M-: Brit. Med. J. 16, 1967, pp. 712--714. -- 11. Langaner-Lawowicka, H., Kurzbauer, H., Byczkowska, Z., Wocka-Marek, T.: Actlv. nerv. sup. 21, 1974, 4, pp. 290. -- 12. Lange, C. E., Juhe, S., Stein, G., Veltman, C.: Int. Arch. Arbeitsmed'. 32, 1974, pp. 1--32. -- 13, Roth, B.: Narkolepsie a hypersomnle z hlediska fysiologie spSnku. Praha, SZdN, 1957.. -- 14. Raoskovd, V..* Int. Arclr. Arbeitsmed. 34, 1975, pp. 283--299. -- 15. Schwartzovd, K.; Neurologick6 a EEG ndlezy u chronic* kjch prdmyslovych otrav n&kterfml organickymi rozpouStedly. Plzeftsky 16k. sb. Suppl. 26, 1970, pp. 5--88. -- 16. Splrtas, -^ R., Me Michael, A. L., M.: Am. Ind. Hyg. A pp. 779--789. -- 17. 16k. VII, 1955, 5, p; Stfblovi, V.: Acta Unii 12, 1960, pp. 269--274. Cs. neuroL 26, 1963, p. Received Novembe :ven OD- __ a5 k o ores ex- expueslediante vlnlleloles subasl que icerebe/a perldlrecto cos pe el 46,5 dlvldad podrfa ambios iIGglca/enclbn Imente R., Me Michael, A. L., Gamble, Van Ert, M.: Am. Ind. Hyg. Ass. J. 36. 1975, 10, pp. 779--789. -- 17. Stfblovfi, V.: Prac. 16k. VII, 1955, 5, pp. 260--263. -- 18. Stfblovfi, V,: Acta Unlv. Carol. Med. Suppl. 12, 1960, pp. 269--274. -- 19. Stfblovfi, V.: Cs. neurol. 26, 1963, p. 399. -- 20. Stfblo- vfi, V.: Diagnoza a prevence v prdmyslov6 neurologll. Praha, SZdN, 1968. -- 21. StfblovS, V.: Int. Arch. Occup. Environ. Hlth. 38, 1977, pp. 263-- 282. -- 22. Stfblov*, V., Holanovfi, V.: Prac. 16k. 25, 1973, pp. 90-- 96f Recelved November 10, 1980 V, StJblovS, Dept. Neurology, Medical Faculty ol Hygiene, Charles University, Srob4rova*?50, 100 42 Praha 10, Czechoslovakia London *ris, D. is. ier-Le- ovrska, up. 21, , Jube, h.. Ar. Roth, edlska 67. -- d. 34, v, K.: ironic- orgak. sb. pirtax. v^ 243 R&S 114682 1S--~ '* ^ - EXO-MEDICAL. RESEARCH * DOCUMEKT DESCRIPTION POEM TM~ Duplicate .in all cards: 63 ' 68 6976 I 11 year as-1961- File number [Right justify [Numeric only] * Author (s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 1 20 21 40 41 77 78 IZZZ3 Sub-Index Code 60 51 62 11 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. 12 61 62 r------------------------------------- " 21 vc - . isc rvo* ts<? sps isc fs7z> fse/77#s>r~ 22 23 24 V654) vGVtf Source (Journal, Vol., Number, Pages, Date) 12 1 62 31. 32 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 \[C The origin off -human cancers John Cairns'1* Imperial Cancer Research Fund, Buttonhole Lane, London NW7 1 AD, UK ^^ The limited evidence available suggests that most human cancers are not caused by conventional mutagens but are more likely to be the result ofgenetic transpositions. Although the molecular biology of transposition is starting to be understood, the external factors that influence its frequency have not yet been studied in any detail. ..... Different human populations tend to suffer from different for such local changes). However, the processcannot be quite as 33 kinds of cancer: the inhabitants of third world countries have an simple as that. In most cases, repeated doses of the mutagen excess of liver cancer, those of western nations have an excess of have to be administered over an appreciable fraction of the cancer of the breast and colon, the Japanese have an excess of animal's lifespan, and in those few situations where a single dose 114683 stomach cancer, and so on. Most of this variation must be due to of mutagen is carcinogenic the resulting cancer usually does not varied diets, customs and environment rather than to differences appear for a long time4. Thus the creation of a cancer cell is in genetic constitution, because nations have been observed to thought to involve a sequence of events of which perhaps only undergo changes in cancer incidence from one generation to the the early steps bear any direct relation to the interaction next and migrant populations tend to take on the pattern of between mutagen and DNA. This is borne out by the obser cancer that is characteristic of their new homes. Cancer is vation that the later events can be caused by other agents therefore thought to be a preventable disease. (`promoters') that are not themselves mutagenic The con In the western world the twocommonest cancers are cancer of ventional explanation is that `initiation* represents the produc the skin and the lung, and each of these happens to be so strongly tion of mutants and that the subsequent steps of promotion are dependent on a single factor (that is, sunlight and smoking) that required because the relevant mutations either happen to be their cause could be identified without the need for any under recessive (and so will only be detectable following deletion or standing of the underlying mechanism of carcinogenesis. The somatic recombination) or usually involve repressor genes (and preventable causes of the other common cancers are less clear- so are not expressed until the existing stock of repressor mole cut and it may be difficult to identify them until much more is cules has been depleted by further cell multiplication). But this known about mechanism. Eventually the techniques of nucleic type of interpretation is not without difficulties. The'first step in acid chemistry should allow us to itemize all the differences in the sequence seems to be too efficient*"7; in certain situations, nucleotide sequence and gene expression that distinguish a __eyen quite low doses of mutagen are capable of initiating the cancer cell from its normal counterpart, and perhaps at that process in almost every exposed cell. Conversely, the later steps point the steps involved in carcinogenesis will cease to be in seem to be too sluggish*-*; in several instances, more than 10 cell doubt. But until then we have to be content with circumstantial divisions may be needed following initiation to achieve expres evidence. This review discusses the evidence and makes certain sion of the new phenotype in any of the descendent cells. . deductions about the molecular biology of human cancer. Cancers can arise following infection with certain viruses. Here the explanation seems at first sight more straightforward, Experimental carcinogenesis for it is easy to see how novel phenotypes could result from an interaction between the genes of a virus and those of the host. Much of cancer research is based on the reasonable premise that However, the interval between initial infection by the virus and we should be able to learn about human cancer by studying final appearance of the cancer can be a large fraction of the carcinogenesis in animals. During the 65 years since coal tar was animal's lifespan10, and so even here the exact biology of the shown to be carcinogenic for the skin of rabbits, many ways have carcinogenic process may sometimes be quite as obscure as in been found for producing cancer in experimental animals. The most chemical carcinogenesis. problem is to decide which of these very diverse forms of Cancers can also be produced in animals by transplanting carcinogenesis is likely to be the best model for most human certain tissues, such as ovary" or embryo", into special sites cancers. where the cells can multiply without restraint; similarly, cancers The easiest and most widely studied method is to expose the may arise in the tissues next to implanted sheets of plastic, chosen target in the animal to physical or chemical agents that apparently because the cells have lost the restraining influence damage DNA. Because the carcinogenic potency of such agents provided by contact with each other". It seems unlikely that any is fairly well correlated with their ability to cause point muta conventional form of mutation can play a part in these types of tions , these forms of cancer are commonly assumed to arise as carcinogenesis, particularly as the cancer cells produced by the result of local changes in DNA sequence (in the rest of this transplantation can sometimes be restored to a normal, article, the words 'mutation' and `mutagen' are used specifically regulated pattern f growth by transplantation back to more demanding sites*4"14. * Present address: Harvard School of Public Health, 665 Huntington Lastly, a number of cancers have been bserved to arise Avenue, Boston, Massachusetts 02115. spontaneously in animals that are given unlimited food, but not 0028-0836/81/050333--05S01.00 j\//hT0/ee- 0181 Mwnill.n Journal* Lot 3 S3 -3T7ft 1 ?/J in artimajj whose intake of cal ries has been slightly restricted*7. The Mechanism-of carcinogenesis by these few extra calories is . completely obscure. Those seem to be the main ways of causing cancer in animals. It is not obvious what, if anything, they have in common, and in "the absence of any additional source of information we could therefore have no way of knowing which of these experimental cancers are the best models of the common human cancers; and if we do not know that, we cannot guess what class of environ mental agent is likely to be the most important-factor in causing human cancer. The genetics of susceptibility to cancer When the precise chemistry of any biological process is in doubt, it has usually been helpful to determine what kinds of mutation affect the process. This stratagem has been applied successfully in working out various metabolic pathways and in identifying many of the components involved in the synthesis of macromolecules, and it would seem to be the surest way of finding out what classes of biochemical event tend to be ratelimiting for human carcinogenesis. The method is, however, subject to certain logical restraints. (1) When the main effect of a mutation of a multicellular animal is to alter the phenotype of one particular class of cells, the fact that it also raises the incidence of cancer in these cells may not be relevant when we come to consider the cause of other cancers. For example, some forms of inherited immunodeficiency are associated with an increased incidence of certain rare cancers arising in cells of the immune system**; obviously, this tells us little or nothing about the origin of the common cancers in other tissues. (2) In general, mutations that increase the incidence of any cancer should be interpreted with some caution. Going back to the previous example, it is conceivable that the leukaemias and lymphomas of immunodeficient children arise by some special pathway, so that they may not even be a good model for the leukaemias and lymphomas that occur in normal subjects. (3) The most informative mutations are usually those that stop things from happening. For example, mutations that block the induction of aryl hydrocarbon hydroxylase make mice more sensitive to the short-term toxicity and less sensitive to the long-term carcinogenicity of certain polycyclic aromatic hydro carbons19-20. If we could show that similarmutations in humans ' lowered the incidence of any of the common cancers, this would suggest that these compounds are important in human carcino genesis. So far, however, such studies in human populations have been inconclusive21-12. (4) In practice, much of our information may have to come from negative evidence. For instance, if a mutation that completely blocked the metabolism of certain potential carcinogens had no efrect on the incidence of cancer, this would constitute very strong evidence that these chemicals and their metabolic products were probably not important In fact, the first case we shall consider is an example of negative evidence. If the conventional dogma is correct and cancer is usually initiated by localized somatic mutations produced by the chem ical mutagens in our environment, we would expect inherited defects in DNA repair to have a marked effect on the incidence of the common cancers. Yet this turns out not to be true. The test case is the disease called xeroderma pigmentosum (XP). This arises when both copies of any one of the genes involved in the main pathway for excision repair contain an inherited defect2*-2*. The result seems to be equivalent to the effect of the uor mutations of Escherichia coli and Salmonella typhimurium, which make these bacteria into exquisitely sensitive tester strains for most chemical carcinogens. Like such bacteria, the cells of XP patients have a defect in DNA excision that makes them up to 10 times more sensitive to the lethal25'*2 and mutagenic**"** effects of most mutagens (the main exceptions . being X rays and certain simple alkylating agents). As a result of this defect, XP patients are extremely sensitive to UV light. They-suffer an age-specific incidence of skin cancer that is several thousand times higher than normal and they frequently die from malignant melanoma; as these skin cancers arise on the exposed parts of the body, they are presumably the result of mutations induced by UV light in the basal cells of the skin, perhaps coupled with some radiation damage to the local immune system of the skin39. Yet, even though the repair defect of XP patients extends to all the tissues that have been tested and apparently affects the response to all bulky lesions and major distortions of the double helix2*, it does not result in any obvious increase in the common fatal cancers (such as cancer of the lung, alimentary canal and breast). This is a striking anomaly, but it seems to have been pointed out only once before*0. For example, not one death from internal cancer was recorded in any of the published clinical reports on series of XP patients41-50 summarized in Table 1; and a survey of the entire literature on XP for the past 40 years51 (which included a search through 6 years of US death certificates52 and therefore must comprise "many hundreds of cases) has revealed only seven internal neoplasms and only two or three deaths from cancers that could not have been caused by sunlight. Now, it is possible at this point to indulge in some special pleading--byarguing, for example, that XP patients do not live long enough to experience the common internal cancers which, for some as yet unknown reason, cannot be brought forward in time as readily as skin cancers. But the most reasonable conclusion is that the com monly fatal cancers are not caused by the kind of lesions of DNA that XP patients (and bacterial uor mutants) are specifically unable to repair. That conclusion is strengthened when we consider Bloom's syndrome, an inherited disease that apparently does increase the incidence of the common cancers. Its molecular biology is not understood, but the disease is associated with a high frequency of chromosomal aberrations and exchanges5*-54. (Interestingly, the patients' eplls do not show any very marked increase in sensitivity to various mutagens2*.) From a registry of cases it has been possible to calculate very crude estimates of `life-tables' and of relative risk for carcinomas and for leukaemias and lymphomas (Fig. 1, Table 1). We see that the death rate from cancer is raised about 100-fold in each age group (Table 1). This demonstrates that it is possible to observe such increases in risk even when the number of subjects is small and their lifespan very limited; for XP, where the numbers are greater and lifespan is somewhat longer, it should have been even easier; in this sense, . therefore, Bloom'ssyndrome serves as a control. (Two other inherited diseases, Fanconi's anaemia and ataxia telangiectasia, are associated with chromosomal instability, and they too show a high incidence of leukaemia; however, the published reports are not sufficiently detailed for the calculation of life tables.) Comparison of the clinical records for XP and Bloom's syndrome therefore leads to the following conclusions. (1) For most people the main source of mutagenic lesions in DNA is UV light. (2) Chemical mutagens (of the kind detected in the usual tests for mutagenicity) seem unlikely to be the rate-limiting components in most human carcinogenesis. (3) Large-scale changes in the genome (such as rearrangements and deletions) seem to be more hazardous than the local changes produced by conventional mutagens. The karyotype of human cancers If genetic rearrangement or deletion is a critical step in the formation of most human cancers, the change might often be large enough to produce a visible alteration in ebr mosomat anatomy. Unfortunately, it is not easy to obtain good metaphase spreads for the cancer cells in solid tumours, and so most studies of karyotype have been confined to the leukaemias55 and to a few solid tumours, such as meningiomas56 and gliomas57, which contain neoplastic cells that gr w readily in vitro. In these R&S 114684 T diseases, visible chromosomal rearrangements have proved to be more .the rule than the exception, and for many cancers the karyptype has actually been observed to become progressively abnormal with time. It is therefore clear that at least the later stages in development of cancers are usually associated with large-scale changes in the genome. For obvious reasons, much less is known about the earlier. stages of carcinogenesis. About 90% of chronic myeloid leuk- . aemias show a translocation from chromosome 22 to 9, which creates the characteristically shortened 22 known as the Philadelphia chromosome"; in several mstances59"6' the trans location has been observed to be present quite early in the sequence of events leading to the leukaemia, suggesting that it was primarily this alteration that allowed the precancerous stem cell to multiply without restraint and gradually colonize most of the bone marrow. (The exceptional cases of chronic myeloid leukaemia that do not have the translocation run a distinctly less favourable clinical course*2, and so they can probably be classified as a different kind of cancer, brought on by a different sequence of events.) Similarly, patients with ataxia telangiec tasia are often found to be harbouring an expanding clone of lymphocytes with a translocation affecting chromosome 14 (refs 63,64) and the lymphatic leukaemia which commonly occurs in these patients apparently develops within these clones. (Inter estingly, myelomas and one class of lymphomas may also show translocations to chromosome 14 (ref. 65).) Those are the clearest examples where a particular change in karyotype appears to be an essential, early step in carcinogenesis. Of course, it is possible that still earlier in each of those sequences some crucial step occurred that made inevitable the subsequent emergence of cells bearing these particular rearrangements. For example, benign meningiomas have often been observed to be diploid in their early stages**, and it is only later that they tend to be dominated by a characteristic cell that has lost one chromo some 22 (ref. 56); and there are certain kinds of cancer, such as acute myeloid leukaemia, that sometimes maintain an apparently normal karyotype throughout the whole course of the disease**. , These studies of karyotype can therefore be interpreted in one of two ways. The obvious conclusion is that large chromosomal 3) rearrangements are usually the crucial steps in carcinogenesis, fto but that there are exceptions and in certain classes of cell the 03 critical changes either are not rearrangements or are on too small a scale to be detected by chromosomal banding tech niques. .It is,, however, possible to, argue that the cellular 4* O) CO environment within any growing cancer is very abnormal and applies strong selection pressure for very unusual phenotypes, Ol and these are most easily generated by large-scale rearrange ments of the genome; the observed changes in karyotype could therefore be trivial secondary events that occur after all the rate-limiting steps of carcinogenesis have been completed. The evolutionary analogy is worth pursuing a little further. The normal architecture and programmes of cell renewal in multicellular animals seem to be so an-anged that the various multiplying stem cells do not, as a rule, compete with each other for territory*2. For example, it is clear from studies of'X- chromosome mosaicism that adult human tissues are made up of a large number of very small families of cells which therefore cannot be undergoing clonal selection****; similarly, the haematopoietic stem cells that circulate in the blood of mice are capable of establishing themselves in the marrow and forming clones of descendants, but they win only do so if the resident stem cells occupying the available sites in the marrow have been killed20. So one of the crucial steps in the development of a cancer must be the change that allows a stem cell to compete favourably with its neighbours and form an expanding clone vitkin which further natural selection can then take place. We hould therefore consider the possibility that the formation of a cancer proceeds by the same mechanism as the evolution of a new species. In other words, we might expect normal non- cancerous cells to be like species that are not evolving quickly: they will accumulate local alterations in base sequence and Fig. 1 Life tables for patients with Bloom's syndrome. The calculations have been based on a collection of 89 cases (J. German, unpublished). 12 of whom have died of cancer, a. Pro portion who have not yet died of leukaemia or lymphoma; b, proportion who have not yet died of carcinoma. amino acid sequence due to forced or unforced errors in DNA replication, but these will tend to be neutral and have little effect on phenotype71. In contrast, a family of cancer cells should be like a species that is undergoing a rapid evolution in morphology. Such evolution is now thought to be due mainly to pleiotropic changes in the regulation of gene expression that are the result of large-scale alterations in gene arrangement and chromosome constitution72'7*. In short, the analogy with evolu tion would predict that cancer should usually be due to gene rearrangements rather than to the local changes in sequence produced by conventional mutagens. Before considering what is known about the molecular biology of such rearrangements, it is worth examining the other half of the proposition, namely that carcinogenesis by conventional mutagenesis is not making a major contribution to the national incidence of cancer. Mutagenesis and cancer ` t. ' It seems dearly established that localized lesions in DNA can be carcinogenic: for example, pyrimidine dimers must be the cause of the skin cancers produced when animals are irradiated with UV light, because the cancers can be prevented by photo reversal with visible light (a reaction that seems to be spedfic for dimers)7*; similarly, the formation of 0*-alkylguanine in DNA is apparently the basis for carcinogenesis by certain alkylating agents because the cancers tend to be confined to the tissues that are unable to repair that particular lesion75'7*. So the issue is not Simply whether conventional mutagens are capable of causing cancer, but whether they reach our cells in suffident quantity to make a major contribution to our present national incidence of cancer. In short, it is a question of the balance between dose of mutagens and the efficiency of our various pathways for DNA repair. ' Although skin cancer due to UV light is the commonest cancer in western nations, it is seldom fatal and accounts for only 1% of all cancer deaths. But when there is a defect in the relevant DNA repair pathway (as in XP) the age-specific incidence of skin cancer can be raised several thousandfold and life-expectancy drop to about 20; this shows the extent to which an efficient system of repair is protecting us against one of the major hazards of our environment. Similarly, the repair pathway that handles the lesions produced by X-ray irradiation seems to be equally effective, because only about 1% of all cancer deaths are believed to be attributable to the natural sources of ionizing radiation'7. Presumably there has always been strong selection jjressure'for adequate methods of DNA repair, and so it is hardly surprising to,find such low levels { risk from agents like UV light and'X rays, which have not changed in intensity for millions of years. -- There are reasons for thinking that our exposure to the chemical mutagens in our environment is now actually some what less than it used to be. The argument runs as follows78. Experimental animals tend to show a rather limited range of responses when mutagens are added to their diet; a few, very reactive chemicals produce cancer of the oesophagus and stomach, but most mutagens produce cancer of the liver. In humans, however, liver cancer accounts for only 1% of the cancer deaths in countries like the United States and Europe; oesophageal cancer is not very common outside certain parts of Africa, Iran and China; and stomach cancer is on the decline in all industrialized nations. So it seems likely that when affluence brings us the opportunity to choose what we eat, we tend to avoid foods heavily contaminated with mutagens and are there fore able to stay well within the capabilities of our DNA repair pathways. Actually, even in undeveloped countries the level of exposure to chemical carcinogens seems to be within most people's capacity for repair; in Africa, for example, the liver cancer caused by aflatoxin is largely confined to people chronically infected with hepatitis B virus79, which indicates that although aflatoxin is known to be one of the most potent carcinogens for certain experimental animals it is not present in a high enough concentration even in Africa to produce many cancers in normal people. So much for the `natural* mutagens in our environment. Fortunately, the novel unnatural mutagens that we have met in the first half of this century as a result of our industrialization seem to be no more powerful than the natural ones*0. Occupa tional cancers probably account for less than 5% of all cancer deaths*1; and the number attributable to mutagenesis is actually less than this because a large proportion of today's occupational cancers are due to asbestos, which is negligibly mutagenic81 although it is known to produce chromosomal abnormalities83. These numbers are, of course, trivial cbmpared with the effect of tobacco. This has proved to be the outstanding carcinogen of the Table 1 Deaths from internal cancers Age 0-4 5-14 15-24 25-34 35-44 45-54 Totals Bloom's syndrome* ' obs./exp.t Leukaemias Patient and years lymphomas Carcinomas 340 1/0.013 0/0.017 640 3/0.020 0/0.019 327 2/0.011 0/0.016 108 2/0.005 2/0.013 16 1/0.008 3 1/0.005 12/0.127 Xeroderma pigmentosumt obs./exp. Patient AH cancers years (exd. skin) 640 0/0.059 886 0/0.055 450 0/0.036 213 0/0.035 109 0/0.038 54 0/0.107 0/0.330 The observed values were obtained from various clinical reports. For Bloom's syndrome the estimates are probably fairly reliable, because the condition is very rare and so the fate of each case Is usually followed rather closely; of these 89 cases, 17 are known to have died (12 from cancer}. Because XP is much less rare, cases tend to be reported but not followed up, and so the existing literature may be used to give some idea Of their incidence of cancer but will give an underestimate of their death rate. During the limited period when these 140 cases were observed, 71 had had skin cancer (which was fatal in 8 cases), 1 had had a brain tumour and 1 had chronic myeloid leukaemia. *89 cases (J. German, unpublished). tExpected values were calculated from the current age-specific cancer death rates in England and Wales. 1140 cases reported in refs 41-50, twenuem cenimy miu is 4 bj^VtWlVIV SVI v, cancer deaths. But it is not at all clear lhai these cancers can be * classified as due to mutagenesis. Although cigarette smoke condensate contains mutagens81, it is much more powerful as a promoter than an initiator in experimental carcinogenesis*3 8*. Fdrthermore, if tobacco were mainly acting as a mutagen, there should have been some reports of lung cancer in XP patients; after all, strong sunlight (which in normal people is about a^_ carcinogenic as heavy smoking) can produce skin cancer in thes^^fc patients by the time they are 7 years old, and so smoking shoul^^^ have given some of them lung cancer by the time they are 30. * Ail these arguments are indirect, but they do suggest rather strongly that local changes in DNA sequence, produced by conventional mutagens, are probably making only a minor contribution to our national death rates. Genetic transposition as a cause of cancer In the last decade, the routes leading to genetic diversity have become much better understood87 . Diffusion of heritable information is now known to occur not only by `legitimate* recombination between homologous regions of different genomes, but also by 'illegitimate' recombination between largely nonhomologous regions (which can be in different parts of the genome or even in different individuals). The second of these processes is equivalent to a chromosomal rearrangement and allows the shuffling of certain modules of information (`transposons') so that new combinations of genes can be tested for survival advantage. The process depends on the presence of certain short sequences in the DNA that are the substrates for various recombinational enzymes (`transposases'), and it represents a much more drastic form of genetic variation than localized changes in base sequence because it can alter the expression of whole regions of the genome. Transpositions can be site specific (for example,the changes in surface antigens of Salmonella and certain trypanosomes) or nonspecific (such as the spread of antibiotic resistance between `different bacteria); they are usually solitary, but they can occ in clusters; and their frequency can vary from 1 per cell divisi down to 10"?. A transposon can be the substrate for a trans^ posase encoded elsewhere in the genome or it can make its own specific transposase. As the result of moving to a new site, a transposon can start or stop being transcribed; but the main effect can be not on itself so much as on neighbouring genes, which can be turned on or off or made unstable by its presence. ^-Transposition is therefore a very special form of genetic regulation because it can be programmed to occur at any predetermined rate, can be concerned with any desired number of alternative states, and can be made virtually irreversible. For example, the switch in the mating type of yeasts is the result of a transposition which occurs at a rate that is itself under separate genetic control89; but the change has all the characteristics of a step in differentiation because it concerns the function of a large number of genes but normally is confined to one particular branch of the cell lineage (the mother cells, rather than the buds)90. It is not yet clear whether transposition is important in vertebrate development. As the result of certain experiments on nuclear transplantation, there has been a tendency in recent years to regard the nuclei of the somatic cells of vertebrates as totipotential and therefore not fundamentally different from the germ line91. However, the fact remains that although it is easy to produce a norma] animal using the nucleus taken from a fertil ized egg or an early blastula cell, no one has ever succeeded in producing a normal animal using the nucleus taken from a somatic cell of an adult. It is therefore quite conceivable that changes in gene arrangement do occur during vertebrate development, especially as it is now known that antibody diver sity is generated by specific transpositions that occur durinJfe differentiation of B lymphocytes91-93. As pointed out in the earlier sections of this review, there are good reasons for believing that the steps leading to human cancer are more likely to be transpositions than localized noobt l *v .-changejin sequence. It is therefore important to find out what * classes of external agents or features of cellular behaviour raise \ v. - the* frequency of such transpositions. Interestingly, conven tional mutagens often appear to have no effect. Indeed, it was the inability of any mutagen to raise the spontaneous reversion rate of certain forward mutations in E. coli that initially marked out these mutations as beingunusual'4 and eventually led to the discovery that they were due to the movement of insertion sequences; similarly, the movement of certain transposable elements in yeast has been found to occur `spontaneously' but does not appear to be strongly catalysed by any of the common mutagens95. However, rates of transposition can be influenced by external factors. For example, transpositions are only a minor cause of mutation in rapidly multiplying bacteria95, but they are a major source of forward mutations in stationary cultures97; the growth of Drosophila cells in vino leads to the proliferation of certain repetitive sequences9*; the frequency of the trans positions that produce variegation in Drosophila and in Antir rhinum petals is inversely related to temperature99'100; and the integration of a tumour virus can be associated with trans positions in the neighbouring host DNA101. Lastly, many mutagens are known to cause sister chromatid exchanges and other chromosomal interactions in mammalian cells, although it is not always dear to what extent these gross changes ar functionally equivalent to genetic transpositions. The assay of mutagens using bacterial tester strains has been one of the most fruitful practical results of molecular genetics. Its success stems from the fact that the chemistry of DNA is the same for all forms of life and so the chemistry of mutagenesis (and of repair) also tends to be the same. The molecular biology of transposition promises to be more idiosyncratic. The trans posable genetic elements were discovered by McCIintock'01 in 1950 and their possible role in carcinogenesis was first discussed by Temin103 in 1970, but it is still too early for there to have been much systematic molecular biological investigation of the factors that trigger transpositions, either in prokaryotes or in eukaryotes. The rate of movement of most transposons will have been subject to evolutionary pressures and many transposons will therefore have acquired their own individual controls. Thus It may not be a simple matter to devise a general assay for the factors that drive the carcinogenic transpositions. 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In a letter mailed to each employee at Texas City, Plant Manager Damon L. Engle and Plant Physician David H. Glenn said that the excessive occurrence of brain cancer "may represent a chance occurrence" and is not a result of any chemical exposure at the plant The Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health reported last year that they had found 18, and possibly as many as 25, brain cancer cases among employees at the Texas City plant. That was about twice the incidence rate found among the surrounding population, the agencies re ported (Current Report, OcL 30, 1980, p. 573). Union Carbide's study, begun in 1979, found 12 deaths due to primary malignant brain cancer among the 6,588 Texas City employees studied. By comparison with U.S. rates, 7.42 cases would have been expected, the company stated. The overall mortality rate of employees working at Texas City since 1941 is "significantly less" than the national average. 765 observed compared with 923.82 expected, ac cording to the company. Three reasons for labeling the* four or five excess deaths a chance occurrence were given by Engle and Glenn: The company was. unable to associate the deaths with any particular chemical exposures. The types of brain cancer found are present in the same percentages as those seen among the general population. Ordinarily, the company maintained, chemically caused cancer is a specific and often unusual type, different than those seen in the general population. Excessive brain cancer has not been confirmed in any chemical plant similar to the Carbide facility in any other part of the U.S. "There is no cause for alarm," the company officials told the Texas City employees. They added that deaths due to cancer, "however small in number," will "continue to re ceive our attention and concern," and that Carbide will continue its investigations and cooperation with NIOSH in the agency's own on-going study. Union Carbide said it expects that the NIOSH study will reflect conclusions similar to those of the Carbide investiga tion. Both studies used a common data base that includes the health and work histories of 6,588 workers who have been employed at the Texas City plant since 1941, according to the company. Current standards and practices at the Texas City facility "provide more than adequate protection from known health hazards," Union Carbide asserted. The Carbide study was reviewed by Dr. Brian McMahon of Harvard University and and Dr. Philip Enterline of the University of Pittsburgh. A spokeswoman for the National Institute for Occupation al Safety and Health, while stressing that the institute was pleased with the cooperative professional relationship it has experienced with Union Carbide, nonetheless questioned some of the company's interpretations of the data. Spokeswoman Deborah Van Brunt told BNA Nov. 16 that, although NIOSH could corroborate the overall results re ported by the company, an additional finding was made of a threefold increased risk among employees who worked at the plant 20 years or longer. In addition, NIOSH said it was aware of 23 -- not 12 -- brain cancer cases, as reported in its preliminary findings in August 1980. The institute also took issue with the three reasons stated by Carbide for speculating that the excess may have been due to chance. First, the institute acknowledged that (he the failure to find a correlation between particular exposures and the cases was "important evidence" but maintained that such evidence does not rule out an occupational hazard as the cause. Van Brunt added that the cause may be traceable instead to a class of chemicals or certain chemicals in combination with one another. Second, the institute stated that brain cancer in general, as well as the types of brain cancer found at the plant, indeed'represent an unusual and specific cause of de^^ Five such deaths usually are found among 100.000 males in the general population, the institute maintai^ff making it the sort of "unusual" cancer attributed to chemi cal exposures by Carbide. In addition, the institute ques tioned that company assumption, saying that common types of cancer are related to occupational exposures as often as are unusual types. Third, the institute, while acknowledging that no similar ---excess had been confirmed at other locations, contended that unconfirmed higher-than^xpected incidence rates found at several plants "raise a very strong suggestion of brain cancer as an occupational hazard." NIOSH gave as an example a Union Carbide plant at South Charleston. W.Va., which it said used similar chemicals to those at the Texas City facility. A twofold brain cancer excess was found there, it noted. 11-19-81 Occupation 009**3237 R&S 114688