Document NG4DbY0Zkpqw7zgL3p0eq1J5g

Rtpnntri from Th* Transaeliont St. Jekn't Hptpiial Dtrmatolegieal Socuty, Vet. 88. S*. 2. 1970 CHLORACNEt A CRITICAL REVIEW INCLUDING A COMPARISON OF TWO SERIES OF CASES OF ACNC FROM ChLORNAPHTUALEKE AND PITCH FUMES. K. D. Crow; A review of the subject of chloracne will be followed by a comparison of the mani lacturing processes and cases produced during two factory outbreaks of chloracne and pitch acne both due to fume exposure. My definition of chloracne is the production in the human subject of a type of acne with characteristic clinical features, so far produced only by aromatic chlori nated hydrocarbons of varying structure. Acne caused by paraffins, whether chlori nated or not, is clinically distinct from chloracne and all such cases should be regarded as oil acne. Acne due to pitch and heavy coal tar distillates is also usually distinctive. Chloracne has previously been reviewed only once by Braun in a German mono* graph in 1950\ This was essentially bibliographical apart from its report of the author's own work. Moreover, there have since then been some important develop ments in our understanding of this condition. It also seems unlikely that we shall ever again see the thousands of cases of chlor acne which occurred in the 193M`s and 40's, and since there may be some of us today who have never encountered this now uncommon industrial disease a reminder of its characteristics may be of value. It is unnecessary to make more than the briefest mention of the early history of this condition, for in most cases the chemistry involved was known onlv vaguely if at all, and the great value of the varlv works was their recognition that the acne they were observing was clinically distinct from that due to products of coal tar and parafinnic oils. First Von Iranian1 in I>97, and tlicn Ilcrxhcimer31 observed this dis tinctive acne among workers engaged in the manufacture uf hydrochloric acid by the old method using tar lined absorption towers and the newer electrolytic method using anodes of tar, bitumen and charcoal. Only workers exposed to the tar were' affected. Although Herxhcimrr at first blamed nascent chlorine--hence the term chloracne --he soon agreed that chlorinated aromatic hydrocarbons were the most likely cause. For many years some authors clung stubbornly to the nascent chh rine theory and even suggested that the chlorine in chlorouaphtliafcues was easily released to do its deadly workT,,,| ,\ whereas in fact it was the very converse which made thtm such use ful industrial materials! It was of course suggested that all the cases described as chloracne were in fact tar acne and that chlorination had nothing to do with it at allM. but these early observers4' were familiar with coal tar acnq, and their descriptions of chloracne, in particular the emphasis on the peculiar cyst-like lesions" leaves little doubt that they had correctly distinguished between the two conditions. The substances which I shall now consider in detail are Chlomaphthalenes, Chlordiphenyfs and Terphenvls. Chlordiphenyl Ethers. Furanes and Dioxanes, ChJoropnenols and Chlorobcncencs (fig. I). " CHLORNAPHTHALEXES The production by the chlorination of naphthalene of numerous isomers with wax like qualities was first noted by Laurant in 1S&)3'0, but it was not until 1900 that J. \V. Avlaworth in the U.5.A. took out several patents after noting some of the fTbe Dowling Oration, delivered at St. Thomas' Hospital on Friday, 17th April, 1970. {Princess ^larparnt Hniniu). Swindon Willi. MOMS QB2929 Cl c,CQ Trichlomaphthalcne so Cl Cl oo Cl ------- Cl Tetrachlordipheny] Cl_____ ._____ Cl a____ , COO1 Cl'------- 'ci'------- Cl'--------- Cl Cl CrOCl V/ Hexachlorterphenyl Trichlordiplicnylethcr Cl Cl CwC ciOO'o^OC Trichlordiphenyl(enc) oxide or TrichJordibenzofaranc O o ciOAoAOi Tetrachiordibenzodioxanc Cl - rr ciOJ Cl OH .U Cl Tetrachlorbenzcne Trichlorophenol Fif. 1.--Representative formulae of some substances discussed ia Uie text. : MQNS 082925 ei remarkable properties of these materials, i.e. clinical inertness, high dielectric constant, low viscosity close to the melting point, low shrinkage, non-inflammability, fungicidal and insecticidal properties and strong adhesion to various surfaces including metal. Thtir use by the Germans in World War 1 as substitutes for natural waxes and rubber led to the first Urge outbreaks of chioracne. Partly ior this reason and due also to the post-war reappearance of traditional materials there was a great decline in their use until the mia 1030's, when their great superiority to paraffin wax brought them to the notice of capacitor (electrical condenser) and cable manufacturers"'1*-**'1*. Large scale usage recommenced and with it great outbreaks of chioracne. Their industrial applications rapidly widened to include numerous other uses ; as synthetic waxes4* and unpregnants; high pressure additives (or lubricants**-4*; wood preserva tives14 ; flame proofers and many functions now superceded by silicones and plas tics41_ MANUFACTURE '' The method of manufacture is simple; it is achieved by the direct, continuous chlorination of molten naphthalene under high pressure which results in a mixture of chlomaphthalenes from alpha monochlor- to octochlor-. The commercial products are distilled and graded simply according to their chlorine content and all are there fore mixtures of various isomers with one or two main derivatives predominating. Some typical examples of Halowax'*'* chlomaphthalenes are shown in Fig. 2. The ability of all chioracne producing substances to induce chioracne depends upon two things ; their physical state and the degree of chlorination. PHYSICAL STATE From the physical standpoint chlomaphthalene fumes are far the most potent; solutions less so, and contact with the solid substance of little importance except under special conditions. The fumes from molten chlomaphthalenes arc in fact a sublimate, and become profuse at temperatures far below the boiling point. When acncigcnic tlus is the properly which makes them difficult to use safely in industry. Their ability to condenv on cuM surfaces41 may cause them to accumulate in the ducts of ventilating systems, thus reducing their efficiency. Solutions may well be less troublesome because It is easier to avoid skin contact but again chioracne is frequent**. Although it has often been stated that the solid wax in macroscopic particles causes severe chioracne. in every' such publication there has cither been exposure to fumes from a nearby process44 or a simple failure to appreciate their appearance in the process being considered. Thus Schwartz in 104344 described chioracne from solid particles among shipyard cable strippers but in the very same article he mentions their exposure to fumes, and it is known that these workers habitually melted the waxes to seal the cable ends and joints and were indeed fume exposed47-41. On the other hand pro longed contact plus friction may be significant, and a German child whose feather mattress was annually rubbed all over with a chlomaphthalene cobblers wax to prevent escape of feathers, produced chioracne on his cheeks and the sides of his arms and legs*4. This cleared up when the mattress was destroyed. The same authors sjate that they had observed chioracne in leather and tent factories, which disappeared fehen a synthetic chlomaphthalene wax was abandoned in favour of a return to the traditional bees-wax. These latter cases, occurring only three years ago. serve as a warning that, although the higher chlorinated naphthalenes are Little used in industry today we may still come across them from time to time under certain circumstances. Occasionally workers, usually of dirty habits, may produce chioracne in the *(R) Trade Mark of Hoppers Co. loc., Pituburg 19, U S. A. MQN5 082926 tune way in their children whom they cuddle on return from work and also in their wive***'*'. So much then for the physical state : even more important is the degree of chlorietion. DEGREE OF CHLORINATION Until 1057 there was general agreement among all authors that~as the degree of Ijorination increased so did the systemic toxicity and the acneigenic properties of ^ldomaphthalenes. As a result of Shelley and Kligman's*' experiments on human volunteers, the unexpected fact emerged that whereas tri and tetra, hepta and octachlomaphthalenes were entirely non-acneigtnic, the penta and hexachlor derivatives produced very severe chioracne indeed. Since Shelley deliberately chose suspensions 0 12 3 4 5678 Chlorine atoms Halowax 1000 Chlorine atoms Halowax 1001 Halowax 1013 Halowax 1014 Flo. f.--Example* oi four Halowax chlomaptbalenes. of fine particles rather than solutions, varying solvents %nd solubilities cannot have .accounted for the surprising failure oi the two most highly chlorinated derivatives to have any acneigenic effect. Hambrick" in 1957 Employing the extremely sensitive experimental technique described in 1941 by Adams et all using the inner side of the rabbit ear, had already demonstrated that mono- and di-chlornaphthalenes did not produce chioracne, thus clearly incriminating only the penta- and hcxachior derivatives. This work is strongly confirmed by the massive outbreaks of chioracne HONS 082927  which occurred during the late 1030's and 40's largely in the manufacture and use of electric cablcs1*,,T*#'49 whose outer covering was a fabric impregnated with penta and hexachlomaphthalcne. It therefore seemed clear that the assumption of steadily increasing toxicity with increased chlorination had been based on insufficient evi dence. Animal experiments oo systemic toxicity had paralleled the acncigcnic effects but bepta and octachlomaphthalcne had never been tested in this respect, a fact now most difficult to understand. There is no reason to dispute the fact that mono and dichlor, hepta and octochlomaphthalcncs are non-acncigenic~but the position with regard to tri and tetrachlomaplithalcncs. which invariably exist as a mixture, is more confusing. Several reports of chloracne from trichlomaphthalene used as a paper capacitor impregnant appeared in the French and Belgian literature in the early lOIIO's but they do not stand up well to critical analysis. Although the informa tion is incomplete in many respects there are various reasons for believing that other factors were probably responsible for the acne in these cases. It is, for instance, well known that molten pitch was extensively used at that time to seal capacitors after impregnation71, and was also mixed with the trichiornaphthalenc itself in certain cases14. It therefore seems likely that pitch was at fault, a suggestion strongly supported by Duvoir:*. It is even possible that pitch may have conferred upon the mixture acneigcnic properties not possessed by tri and tetrachlomaphtha- lencs alone. The presence in some of these cases of a co-existent vesicular dermatitis on the face14-4*, and in others of a photosensitivity**, the description of which was identical to that of pitch smarts17, is probably relevant. This is further con firmed by the fact that, since pitch has disappeared from capacitor manufacture, so have reports of acne, dermatitis, and photosensitivity from tri and tetrachlomaph- thalcne, although these substances have continued to be used extensively for paper impregnation. Furthermore, the subsequent observation of vast numbers of workers exposed to various chlomaphthalenes only, has produced no further evidence of contact dermatitis. A report by Nakauchi-4 describing two cases of chloracne in a capacitor plant using a tri/tctrachlomaphlhalenc wax for impregnation is valueless in the absence of details of the chemistry or process of impregnation or, more impor tant, of scaling. On the other band, the same author, although providing no experi mental data at all. exposed rabbit cars to the vapour of trirhiomaphthulenc for several months and noted the development of comcdonc-likc keratoses and hyper keratosis. Assuming that the chemistry was correctly reported such gross exposure of the very highly sensitiv e rabbit car may represent conditions which are not capable of extrapolation to the human situation. Certainly my own work confirms my opinion that there is no evidence that tri/ tetra chJorriaptithalcnc mixtures arc acncigenic or dcrmatitic under industrial con ditions. ' PRESENT USES ' I think it is important to know the present uses of chlomaphthalenes in Great Britain. ' All major manufacturers of these products cither ceased production altogether several years ago and handed over to smaller firms, or make a range of products which doe's not include chlomaphthalenes with more than four chlorine atoms per molecule. Extensive enquiries in the United Kingdom lead me to believe that these materials are at present used here for paper capacitor impregnation, only as tri and tetracblomaphthalcne and on an increasingly small scale; also in timber preservatives os mono, di, tri and tetrachlor derivatives. Nevertheless, the higher chlorinated pro ducts arc still manufactured abroad and therefore are available, so that the possibility of their presence must always be suspected in chloracne oi unknown origin. When I recently examined capacitor impregnation processes using tri/tctrachlornaphthalene mixtures once again I found no evidence of cldoracne. MONS 002926 84 CHLORDIPHENYLS AND TERPHEXYLS Whilst the uses of chlomaphthalenes are contracting so the applications of chlordiphenyls in modem technology are constantly expanding. They are produced, like the chlorinated naphthalenes, by the direct chlorination of molten diphenyl and, like chlomaphthalenes, are mixtures of isomers usually with one material predominating. They were little used until about 1930 when the Westinghouse Company discovered their great advantage over mineral oils in the manufacture of high voltage paper capacitors and as transformer oils. They vary from colourless mobile liquids (the monochlor) through ever thicker oily fluids to an off white powder--octochlordiphenvl. The chlorterphenyls are usually resinous solids and there are also numerous mixtures of chlorinated diphenyls and terphenyls, most of which again exist as low melting point thermoplastic resinous substances. Chlordiphenyls resemble the chlomaphthalenes in their great chemical inertness and resistencc to oxidation, non-inflammability, flame proofing qualities and a very high dielectric constant i.e. insulating ability. These qualities, together with the fact that liquids, unlike waxes, do not form voids or spaces when impregnating paper, made them seem ideal materials for paper capacitor impregnation especially for voltages over 250 A.C. but they are great ionic solvents, unfortunately the more so as their chlorine content decreases and the dielectric value correspondingly rises. The great problem here lies in the fact that not only traces of moisture but also the minutest ionic contamination is fata) to capacitor functioning. The major difficulty was to produce strong, thin Kraft papers which were ionically pure. Eventually these problems were solved and large scale manufacture of chlordiphenyl capacitors began m Britain around 1950. Pentachior-diphenvl was first used for this purpose but it had the serious draw-back of being unusable at temperatures below 0C whi*n it solidified and for low* temperature A.C. use paraffins continued to be used. Finally the ionic difficulties of using the greatly superior trichlordiphcnvl as a high voltage capacitor impregnant were overcome and its use is now almost universal. Because the capacitor industry is the country's largest user of chlordiphenyls I have disucusscd it at some length. As the number of available compounds has increased, their uses have multi plied constantly until today there arc well over loo different industrial applications for polychlorinated diphenyls and terphenyls2'3. A detailed analysis is therefore quite beyond the scope of this article but their uses stem essentially from their three major properties; resistance to oxidation, non-inflammability, and high dielectric value. I shall mention one specific use because it has been the cause of the only two outbreaks of chloracnc from these materials published since the 1940 s. This is their function as heat transfer agents in chemical engineering42'39. Previous chloracne had resulted from crude and careless manufacture in the early days42 or admixture with chlomaph thalenes. TOXICOLOGY Once again, as in the case o! chlomaphthalenes, their acneigenic potential is similarly dependent upon their physical state and the degree of chlorination. The published work on the toxicology of the chlorinated polyphenyls is small, due largely to the lesser problems posed by their industrial uses. Nevertheless their toxicity to experimental animals is greater with an increasing number of chlorine atoms certainly up to 7, Thus Miller's rats42 all survived over 60 days after receiving ten 0.5 ml doses of trichlordiphenyl on alternate days, whereas Drinker et al.l> killed 50% of their rats with the same dosage of heptachlordiphcnyl in less than 14 doses. Unlike the chlomaphthalenes they do not sublime at low temperatures whilst at moderate working temperatures fuming is slight and when cold entire!)' absent. Relatively mild fume exposure in the capacitor industry caused occasional chloracnc MONS QQZ9Z9 85 with pentachlordiphenyls** although this was not to be compared with that from penta and hexachlomaphthalene. Since the change to triehlordiphcnyl however even this has entirely disappeared", as I can confirm from my own recent inspection of some two thirds of the British capacitor industry which was using this material extensively. Contact with the cold liquid chlordiplienyls, although undesirable because of skin absorption, appears to pose no aencigenic hazard. The lesser toxicity is confirmed by the entire absence in the literature of any reports-of chloracne from chlordiphenyls containing less than four chlorine atoms. Furthermore, as will be seen in a later section of this paper, although these substances ]| art hepatotoxic, this effect also seems to be minimal with only four or less chlorine jl atoms per molecule as the human ingestion of tetrachlordiphcnyi in Japan has well I illustrated. CHLORDIPHENYL OXIDES Experiments have been made with chlordiphcnyl oxides or, more correctly, the dibenzofuranes as possible alternatives to chlordiphenyls. There is some confusion in the literature between these compounds and the true ethers of chlordiphenyls. The distinction is most important for the ethers*4, like all such compounds whether aromatic or aliphatic, arc relatively inert even when chlorinated, whereas the furanes are chemical!)' and biologically much more active. The chemical differences are clearly shown in fig. 1. The systemic toxicilv and Qf th rhlnrHt. benzofurancs or chlordiphenyl-oxides caused industry to abandon them and the question is now largely academic. CHLOROPHENOLS The study of the chlorinated phenols is probably the most fascinating aspect of the entire subject of chloracnc because of its complexity. They range from mono to pentachlorophcnol with, of course, various isomers oi the lesser chlorinated compounds. They arc used almost exlusivcly as insecticides, fungicides and herbicides, or as chemical intermediates. Consequently they may contact the human subject cither during their use or their chemical manufacture. They arc prepared by the alkaline hydrolysis of crude chlorobenzene, one chlorine atom of which is replaced by the hydroxyl group. Because of impurities in the basic chlorobenzenes any single chemical product will contain other chlorophenols and reaction products. tin? latter varying according to temperature, pressure and other variations in the chemical processes in use. These variations, as we shall see later, may be of significance as far as acneigenic potential and systemic toxicity are concerned. Their direct irritant effects upon the skin and mucosa are variable for each compound and also depend upon their physical state. In very dilute solutions their systemic toxicity is severe3* 41, whereas they have little cutaneous effect beyond that of the solvent; but in strong solutions they can be not only toxic but also powerful skin irritants. In finely powdered form, especially when highly chlorinated, they are extremely irritating especially to the eyes and upper respirator)' tract, and it is in this state that they have produced most of their chloracne. Indeed in large plants manufacturing various chlorinated poly phenyls and chlorophenols today it is the fine dust of the latter w hich is the main chloracne producer if it is not most carefully controlled4*. It is therefore not sur prising that in 1937 Butler1* reported extremely severe and generalised chloracne in men shovelling a fine powder of sodium tctrachlorphenate and ortho (2 chlorophenyl)-*phcnol sodium into sacks under bad working conditions, again as a timber preservative. Large numbers of very severe cases from sodium tetrachlorophenate solutions used as timber preservatives were reported by Stingily and Gaines in 1940' but no details of strengths or solvents were given. Curious features of this and similar outbreaks were the grossly irritant nature of the solutions with the production of bullae and ulcers but the chloracne was apparently tv-pical. Around 19ul> the more effective pcntachlorophenol replaced the lower chlorinated derivatives as a wood preservative. MONS 082930 Chloracne from pontachlorophenol solutions has never been recorded despite gross skin contamination. Nevertheless line dusts have continued to produce it always in the manufacturing plants. Baadcr and Bauer in 1957* reported an outbreak of particular interest because of the association with .peripheral neuropathy and ole cranon bursitis. Plant conditions were evidently bad. for severe irritation of the eyes, nose and respiratory tract were universal thus implying considerable airborne contamination with Andy powdered material**. Kimmig and Schulz in 1957", faced with a severe outbreak of chloracne in a chemical plant manufacturing 2, 4, 5-trichlorophenol and using the technique des cribed by Adams et a). in 1941'. quickly established for the first time the vital but elementary fact that whereas the plant's crude trichlorophenol had an acneigenic effect on the inner side of the rabbit car painted with 5% solutions in polyglycols. neither the intial reaction product crude 1, 2, 4, o-tctrachlorobenzene nor purified 2, 4, 0-trichlorophenol, did so even in 10% dilutions. it was therefore assumed that a reaction product of the alkaline hydrolysis of the chlorobenzene to trichlorophenol might be responsible. The residues in the reaction vessels and pipe-work of the plant were so complex as to defy analysis, and so for two years they proceeded tu test on the rabbit ear over 100 substances which might theoretically form under the conditions of manufacture. Many interesting facts gradually emerged. Neither true diphenyl ethers nor their chlorinated derivatives were acneigenic or toxic, whereas clilordiphenyl oxides or. more correctly, chlurdibenzofurancs were potent acneigcns even in O.UG% solutions, and also highly hepatotoxic, a single dose of 0.5 to 1.0 mgms per kgm. of trichlorodibenzofuranc being lethal to rabbits. Finally they found a substance so potent that 0.<K*l% solutions were strongly acneigenic*7. This material was the chlorinated dtbenzyl cyclic ether, tetrachlordibeiizodioxane. Its systemic hepato-toxicity paralleled its acncigcnicity and O.ho mgms in a single dose was lethal to rabbits. Although the position ot the chlorine atoms was not absolutely certain*4, what was thought to be 2, 5, *>, T-telrachlnrdibvnzodmxam' was isolated by Kimmig hum (lie residues resulting from the formation of trichlorophenol hv the alkaline hydrolysis of tctrachlurobenzol, and its theoretical formation was postulated as shown in tig. 3. et 0 a 1,3.4,1 TSTKACHL0R08ENZENE o M.S TRICHLOKOrHENOL net 3 HOLS SODIUM TRICHLOROPHENATB 3.9,4.7 TETR.SC1ILOROOENZODIOX.OXC Fig. 3.--Stages in formation of 2, 3, 6, 7-tctrachlor<JibR2odioxan t MONS 082931 , * * ' . * . . * * , .. - '* . .. . 87 . The presence of erythema and swelling of the face anil chronic blepharo-cnnjuncti- vitis all suggested exposure to fine chlorophoncl dust, and when this was rectified the chloracne ceased. Kimmig suggests that, if not tetrachlordibenzodioxane itself, then substances closely related to it are probably responsible for chloracne, not only from (richloro- phenols, but 'possibly tetra and pentachlorophcnols also, all of which are similarlv produced by alkaline hydrolysis and heat from the relevant crude chlorobenzenes. The great importance of this classic work lay in its emphasis on the basic necessity of establishing whether or not a suspected substance is still toxic when highly purified. At the same time also in a Irichloroplienol plant, Dugois and Colomb in tw o idem i- cal articles*0 described chloracne of great severity and with evidence of systemic toxicity in a number of workers who. without protective clothing, were washing out with hot water the accumulated sodium chloride in the reaction vessels. Twelve years later in the very same factory Dugois, again in two identical articles* des cribed an apparently unique outbreak of chloracne from a single exposure, of only a few hours duration, to residues released by an explosion of the pipe work. Explosions suggest increased pressure and possibly heat, factors both increasing the chance ul dibcnzodioxanc formation. Chloracne in these cases, just as in Kimmig s, was pre- cecded by' erythema and oedema of the face. Although Dugois' paper was short and without detail or explanation it mentions the isolation of a tetrachlorated ether oxide, a chemically meaningless term, but one is left wondering whether they had in fact isolated the tvtrachlurdibeiuodioxaue described by Kimmig eleven years before. Chloracne from a single exposure to any material is so unusual that one cannot exclude sy stemic absorption as Dugois sug gested, especially as malaise, anorexia, loss of weight and milky serum with raised cholesterol and fat were also mentioned briefly. Nevertheless one cannot pussiblv agree with Dugois in ruling out external contact, since Linn-joncs and Krizek*' produced acne on the rabbit car with only three paintings of a solution of tetrachlordibenzodioxane. in 1904 Blcibcrg1 linked for the first time chloracne and hepatic porphyria. again in a plant manufacturing dichlom and trichlorophenols (or conversion to the relevant phcnoxvacctic acid weed killers. Jn my opinion it is of the greatest significance that there was no direct n latuxi- ship between the chloracne and the porphyria, some cases liasing one condition with out the other. This unique occurrence required an investigation <>( the same calibre as Kimmig's but unfortunatelv the industrial and chemical information was incom plete and sometimes incorrect. Nevertheless wliilst prophyria from chlorophenols clinically or experimentally has never been recorded** there is abundant evidence of its production both clinically and experimentally from chlorobenzene isomers of many different kinds*8. Therefore there seems little reason to doubt that the chlor- M acne was probably produced by chlorodibenzodioxanes or similar substances as [f| Kimmig and Schulz had already demonstrated, whilst the porphyria was most V \ likely induced by the crude chlorobenzenes used to produce the chlorophenols. CHLOROBENZENES What evidence is there that chlorobenzenes themselves cause chloracne ? fn fact, very little. Exposure to various chlorobenzene isomers has occurred on a vast scale over the years both externally and internarily in human subjects*3 and experimental animals without causing chloracne. The only cases reported in human subjects were in men who were grossly exposed to the fine dust and vapour of crude trichlor and hexachlorobenzenes. producing a few rather atypical looking cases of chloracne which ceased when the process was extracted. This report by Bowen and Moursund* was lacking in chemical and engineering HONS 00293^ M detail and in view of the complexity of the reaction products in such chemical manu facturing plants this interesting report requires further confirmation. On the experimental side Rimington and Zeigler**, feeding rats numerous chlorobenzene isomers, found that only l, 2, 3. 4-tetrachlorobcnzcnc produced patchy hair loss, keratotic plugging of the follicles and disappearance of sebaceous glands, these changes resembling those of chloracne. The other chlorobenzenes tested includ ing 1. 1, 4, 5-tetrachlorobcnzene were without effect. All this-rather suggests that chloracne may be produced only by certain chlorobenzenes, and indeed even by one isomer and not another. Further research is clearly indicated. There have been reports, mostly very old*, of chloracne from other materials, but none of these stand up to critical analysis. RATE OF ABSORPTION' AND SYSTEMIC TOXICITY Now we accept that chloracne is caused by exposure to certain chemicals but a vital question remains ; are the effects purely external, secondary only to systemic absorption, or a mixture of both ? ' There can be little doubt that the vast majority of cases produced by industry have been due to external contact alone, especially when only one side of the body has been involved1*. Furthermore where undoubted systemic effects have occurred there has been gross external contact also8*s*,M,,#. There was always a doubt there fore whether internal administration could cause chloracne at all, and ii so what part it played in any particular case. The first concrete evidence appeared in 1045, when a fat-like substance found in the bomb ruins of Berlin was used to fry vegetables and six people were poisoned9"'". There were no deaths and apart from general symptoms, mainly gastrointestinal, first redness and oedema, and then severe chloracne appeared, involving only the face and neck in three cases, the chest and back also in three others, an interesting observation indicating that distribution in itself does not allow one to distinguish between external and internal causation. Such analytical data as were available suggest that they had probably ingested hcxachlomaphthalcne. but the identity of the poison has always been the subject of some doubt. Further support was provided by the eventual discovery that the mysterious "X disease"47, a fatal wasting sick ness with hyperkeratosis and dilatation of loliiclcs which had decimated cattle in the U.S.A. and Germany from 1941-1U34, was due to the accidental ingestion by them of penta and hexachlumaphthalcncs in lubricating oils and greases"9 and timber preservatives7*. So sensitive were cattle that a single oral dose of 1.0 gram oi hvxa- chlomaphthaleno would kill a 2 cwt. calf in 14 days". The final conclusive proof that chloracne can result from systemic intoxication of the human subject with no external contact at all came from Japan in June 1909 (*), This was the report of an outbreak of poisoning due to tetrachlordiphenylwhich, for three days only, leaked from the heat exchange system in a factory manufactur ing cooking oil. The edible oil contained an average of 2,t*H) p.p.m. of tetrachlordi- phenyfana most patients probably took something like l.u gram per month (or 4-3 months. Apart from fatigue, malaise, and nausea the earliest visible findings were ophthalmic with swelling of the eyelids and discharge, due to increased activity and #cystic swelling of meibomian glands. 113 of 136 cases developed chloracne, which 'began slowly two months later and developed relentlessly for several months moTe. As in Hertzberg's cases the chloracne was most severe on the face and neck but also the genitalia, though less so on the trunk and^carcely at all on the limbs. In the more severe cases there was often a widespread follicular hyperkeratosis also observed by Duvernc19 from trichlorophenol derivatives and from chlomaphthalcnes by Hofs11 and Braun*. The other most distinctive feature of the Japanese cases was a generalised pig mentation of the skin affecting also the lips, gums and nails. Also observed was enlargement of Montgomery's glands, and hyperkeratosis of palms and soles. Perhaps MQNS 082933 most interesting of .ill were sonic nmr-dermatolngical findings such as oedema of all /our limbs, peripheral neuropathy ami bursitis--also reported by Hander ami Hauer from pcntachloropherml poisoning--whilst the newborn infants of affected mothers had generalised hyperpigmentution and hyperkeratosis. Persistent hyporlipnemia affecting the triglyceride fraction of the serum was how ever the most consistent finding. It had only been reported twice before from trichlorophenol by Dugois*0 and by Goto who reported even more severe elevation of scrum triglycerides in 10 cases of pcntachlurophenol poisoning42. CLINICAL FEATURES In almost every report, whatever the causative chemical, the clinical features have been most consistent?*. ` FiC. 8.--Typical case of pitch acne The most distinctive and almost invariable cutaneous lesion, usually absent in oil aenc and raicly seen in pitch or tar-acne (Fig. K) both of which are also more inflam matory. is the chloracne cyst*4; skin coloured, varying from l mm even to l cm in diameter, and with the central opening difficult or impossible to detect (Fig. T ), If these cysts are absent then chloracne should be diagnosed with great caution, except in early or very mild cases. Comedones and small cysts arc therefore the basic lesions and may be very few or so numerous as to present confluent sheets. Inflam matory papules and pustules arc not so common, much less so than in nil acnc. and arc almost invariably associated with friction from clothing, being commonest there fore on the back of the neck, shoulders, chest, genitalia, buttocks and thighs, and affecting only the more severe cases. Acne from paraffinic vds ami tar products arc both more inflammatory than chloracne, especially the first named. MGNS 082934 90 DISTRIBUTION This is predominantly facial even when the poison has been ingestrd. the malar areas, jaws and behind the cars being sites of particular pn.*liJc tion. fn ntiM tax-> tlicsc areas alone may l>c involved. The nose is invariably spared except when p..w fil ing is systemic. This distribution is not specific to chlorinated aromatic hydrocarbons but to any acncigenic fume or dust for. as we shall set, acne from pin h fumes bvlums in exactly the same wav. With increasing severity the rest of the face ami neck soon follow, whilst the outer upper arms, chest, back, abdomen, outer thighs and genitalia may be involved in varying degrees in the worst cases. The flexures, hands, legs and feet escape in almost every case. ADOLESCENT ACNE ' The predisposing effects of adolescent acne, so often quoted, have no sound statis tical backing so that the question must remain unanswered. PRURITUS .* This is more difficult to assess, reports of its occurrence being fairly evenly divided,7il4,,T. Although no-one volunteered it, in response to a direct question a little under half of my own cases admitted itching, Of a series of clinic patients with acne vulgaris the same question met with an almost uniformly negative reply. It is there fore possible that where itching is not mentioned in the literature it was neither asked about nor volunteered. In no single report of chloracne from any substance other than chlornaphthulcnes, including the numerous and meticulously investigated Japanese cases of systemic totrachlorJiphenyl poisoning, has itching once been mentioned. Pruritus may theieforc be specific to chlornaphthalencs but without more evidence this must remain speculative. MGNS GQ2935 91 DURATION OF EXPOSURF. BEFORE ONSET This is usually irrelevant because the degree of exposure is so variable. One can only say that even with external contact of the grossest kind most authors agree that four weeks or more are needed for lesions to appear. PROGNOSIS ' The prognosis both as regards the duration of the lesions and degTee of scarring is naturally dependent upon the severity of the disease. This will be seen in greater detail when considering my own cases. Some of the worst recorded instances of scar ring have followed exposure to various chlorophenols, possibly due to the intense toxicity of the chlordibenzodioxanes probably involved. HISTOLOGY Findings in the experimental human subject have been confirmed by those in the rabbit ear canal94, in both cases hexachlornaphthalene being the acneigenic agent used. First of all there is a steady thickening and hyperkeratosis of the epithelium in in the infundibulum of the pilosebaccous follicle. This is accompanied by a slow disap pearance of the sebaceous glands, until eventually a keratin tilled syst-like dilatation is formed. In some cases the exit is tiny whilst others are little more than a shallow trough. Shelley** suggested that the disappearance of the sebaceous gland was due to back pressure but accepted that squamous metaplasia occurred as previously shown by Eisen et al. in 1055s*. Hambrick** with serial biopsies showed that the disappearance of the sebaceous glands had already begun five days after the first acncigcnic applications, long before any back pressure was possible, and thereafter steadily progressed. He therefore suggested that chloracnc producing chemicals initiated squamous metaplasia and that when all sebaceous materia) present had been shed a large, dilated, squamous epithelium lined and keratin tilled piioscbaceous follicle was formed. There is of course general agreement that, as in acne vulgans, rupture ol the follicle produces the inflammatory process. TREATMENT Most authors have accepted it as hopeless but strong exfoliants in the hands of Dussart" cleared 5G mild cases in from one week to five months. Dermabrasion was successfully used by Hubler* and also by myself. Dugois*1 claimed success from the intravenous infusion of calcium ethylcnediamine tctracetic acid in very severe cases of chloracne and poisoning from trichlorophenol residues but no details of his results were given. Otherwise expression of comedones and incision of cysts has been the stand-by of most physicians, but with little success. GHLORACXE IN A PAPER CAPACITOR PLANT USING TRI/TETRA AND PENTA/HEXA CHLORNAPHTHALENES FROM 1956 TO 1963 Very briefly a capacitor or condenser is a means of storing and suddenly discharg ing electrical energy. Basically it consists of an insulator or dielectric between two conductors each with a terminal. The majority'consist of a sheet of paper sandwiched between two sheets of thin metal foil a long length of which is rolled up like lavatory paper to provide a large surface area. In this particular process the rolls of foil and paper with their terminal wires were packed into, and pressed flat in metal clamps used over and over again by four women seated very close to the drying ovens and impregnating vessels. After drying for 24 hours at U5C to remove every trace of MQNS 002936 92 moisture from the paper, racks of capacitors were heated in a vacuum vessel for 24 hours at 110*C and then impregnated with molten tri/tetrachlomaphthalenc run in from a reservoir. After pumping out the molten wax the impregnated units were removed by hand, cooled and passed to the dipping section. If supply exceeded demand impregnated capacitors were stored by embedding them in the impregnating wax in metal trays to prevent ingress of moisture. When ready for dipping this -wax wae melted in the ovens and the racks of units removed. Exposure to tri/tetrachlornaphthalene fumes was very gross indeed in this section for the following reasons :-- 1. Fuming of molten wax residues at 110C when emptying impregnating vessels. 2. Failure to realise that fumes from wax remaining on clamps from pre\ious im pregnation would escape constantly from the non-airtight and unventilated ovens. 3. Melting out in the ovens, trays of stored capacitors. Nevertheless, during its existence from 1956 to 1903 no single case of chloracne occurred among workers in this section, thus indicating most clearly the nonacneigenic nature of tri and tetrachlomaphthalene fumes. After impregnation the unit was dipped into a tougher wax mching at 139*C and consisting of roughly equal parts of penta- and hcxachlomaphthalcne with 5% pcntachlordiphenyl as a plasticizer. This dipping section was a long narrow area inside the main workshop enclosed by partitions 7 It. high. There were two dips, the first in vacuo at high temperature and the second a cooler one at atmospheric pressure. After dipping the wax was removed from the terminal wires by dipping them in molten solder on which floated a metal plate with a hole in it. This both cleaned and returned the wires in one operation at the same time unfortunately vapourising the chlomaphlhalcne. Then the performance data were painted on the capacitor and finally it was coated with an isocyanate resin. The fume escape from dipping was severe. This was due to :-- 1. Ineffective extraction which in any case only partially covered the fume produc tion from the dipping vessels and their electrically heated replenishment tanks. 2. Removal of units from the dipper whilst still wet and fuming strongly. 3. Cleaning out the dipping tanks weekly. This led to gross fume exposure for two to three hours every week. The molten wax at IGuX was ladled out by hand into trays, the residue removed by a drain cock under the v essels and trichlorethylene added, the lid screwed clown, the mixture boiled and then drawn off. The stop cock was closed and fresh solid wax added. Other sources oC penta/hexachlomaphihalcne fumes were the evaporation by molten solder of all the wax on the terminal wires, the extraction being too weak ; and the drawing of a current of fume laden air from the dipper and the wire tinners to the verv powerfully extracted lacquering bench, thus secondarily exposing three further workers to a fume hazard.The first was the printer and the others the lacqucrers especially the two nearest the dipper. The fact that some of the lacqurrcrs developed chloracne only on the fume exposed side of their faces proves the externa) nature of the cliloracne stimulus in this process. In 1953 extraction was increased but was still inadequate and no further change *was made until October 1960 when dipping was totally enclosed, wire tinning very powerfully extracted, and the layout of the process opened by the removal of all partitions. To the Company's despair chloracne continued to occur, though much less severely, among the dippers and wire soldcrers. Careful observation of the process soon revealed that tiny wisps of fume escaped occasionally even from the enclosed dipper, due to exhaust vents becoming choked with sublimed chlomaphthalene. Furthermore wire soldcrcrs on piece work could, if working very fast, remove an occasional unit from the exhaust hood whilst a tiny wisp of fume remained to contaminate the air. This well illustrates the chloracne producing potency of even the 082^37 hqhs smallest regular fume exposure to pcnta and hexachlomaphthalcncs, an important observation not true of the equivalent chlorinated diphenyls. Alternative materials had been urged for a long time and finally a mixture of three parts of tri/tctrachlomaphthalene and one part of polystyrene provided a satisfactory alternative. From the time of its adoption chloracno ceased, again confirming the non acne-producing nature of chlomaphthalene with less, than five chlorine atoms per molecule. - Because of the constant variations from hour to hour and day to day. any attempt to relate fume level in milligrams per litre to the degree of chloracne would have been too inaccurate to have had any practical value and was not attempted. For the same reason it is valueless to record the time taken for chloracne to appear except to say that the grosser the exposure the more rapidly it developed and vice versa. MUD MODERATE SEVERE Fio. 4.--Incidence of chloracne in capacitor plant. ' Similarly, and also because of continuous turnover, any figures relating the number of cases to the total at risk would be highly inaccurate and will not be presented. When the labour force had been static for a long time, however, at my first inspection in 1937 almost every* worker in the dipping section had chloracne. Fig. 4 clearly shows the progressive improvement following the institution of preventive measures at the end of 1957 and again after almost total enclosure of the process late in 19C0. The increased percentage of moderate and severe cases alter the initial precautions was due to the elimination of general fume level which had previously caused many indirectly exposed mild cases, whilst quite severe fume exposure continued at special points. MUNS 082938 w Fig. 6 emphasises the concentration of lesions on the malar areas and this appears to be an essentia) feature of fume exposure as we shall see in the comparison of acne due to pitch fumes. Although cysts are almost always present in chloracne, very mild raw may present a lew comedones only. It can be seen that inflammatory lesions 5 s is a ARCAt CWN i comdoncs only caeca COMCOONCS AND evsm 30 CAStS comcooncs ever* WfFlAMMATOAV 11 CASCS ARIAS Fig. 5.-~DitributiOD and type ol lesions io 40 cases of chJoraeoe. were almost always associated with clothing friction but cysts and comedones were always present in these areas also, again a sharp distinction from pitch acne and I believe an important one. shows the duration of the disease. Whilst the vast majority of cases clear within four years, some of the severest ones still have lesions even at ten years. One unexpected finding was the fact that no less than 45% of patients, up to ten years after they regarded themselves as clear, still had small numbers of residual black beads and occasional small cysts which, despite constant squeezing, had consistently re*appcared. There was scarring of severity in H>'0, all of them being severe cases with inflammation. In 25% there was a very fine pitting of honeycomb atrophy type on the cheeks and in the remainder none at all. It must be remembered that all the above data refer only to penta and hcxachlomaphthalcne and cannot therefore necessarily be assumed to be true for other diioracnc producing materials. MCiNS 082939 96 XtMTANT TO CONSTANT WUUtMQ WMfN QiKUl MAO MtH ClIMI' *0*` JVW* - - - Flo. A.--Duration of chloracne. l( I as PREVENTIVE MEASURES The main preventive mcasuics adopted were based on those proposed by Cranch(ld) 1. Complete extraction of fumes (which was never achieved). 2. Neck and wrist fitting white overalls changed daily and cleaned in trichiorethylenc. 3. Frequent and thorough washing. 4. No eating or drinking in the plant. 6. Rapid turnover of workers until extraction was perfected, in order to minimise the duration of exposure. PITCH ACNE Z now* intend very briefly to compare chloracne with the clinical details and prog* , nosis of a series of 64 cases of acne due to fumes from pitch. Since the exposure was virtually identical in each series of cases any clinical and/or prognostic differences should be significant. The exposure in this case arose in a plant moulding various objects from a thermo* plastic material consisting of a mixture of molten pitch, asbestos, and powdered slate. From a mechanical mixer it was removed in large masses like baker's dough on to metal trolleys. They were then removed to thermostatically controlled ovens set ostensibly at 180*C but often much higher due to malfunctioning thermostats. These were not extracted at all and when opened fume exposure was great. From the oven the specified amount of hot dough was taken out and neighed on a work bench on kitchen type scales and then beaten with an iron bar. It fumed most MONS 082940 06 strongly during all these operations and the extraction, which was o( poor quality, was high up and only over the work bench. Its effects therefore was to draw the fumes from the beaten dough up into the worker's face. Fume exposure was gross and continuous. The cooling mass was then removed to a hydraulic press for moulding. -* Despite the wearing of asbestos gloves, wiping dirty hands on the legs of trousers accounted for the high incidence of folliculitis on the thighs. Fig. 9 shows even more clearly than in chloracnethe great predilection of the malar areas m response to fumes. The purely comedonic nature of the facial lesions is most striking and in marked contrast to the mixture of comedones and cysts present in most cases of chloracne*. The description of similarly profuse comedonic eruptions in some of the older accounts of so-called chloracne from trichlomaphthalene again points to pitch as the probable hazard in these cases, mentioned earlier in this paper1*-49. COMEDONES ONLY I'OIUCUUTIS ONLY COMCOCS ANO FOLLICUUTIS >7CASES 21 ~ FlO. 0.--Pitch acne. Distribution and type of lesions in 54 cases. The inflammatory lesions although again, as in chloracne confined to areas of clothing friction were, in great contrast, almost uniformly devoid of blackheads. Again, unlike chloracne, folliculitis was seen in six cases without any comedones at all even on the face. There were several cases in whom small numbers of residual blackheads remained for many years. These patients, like the chloracne ones, were insistent that these comedones were not present until the industrial acne developed. MONS 082941 97 The main differences from chloracne were therefore as follows :-- i 1. The cysts so typical of chloracne were rarely observed. 2* There was an eruption of pure comedones on areas exposed to fumes without friction. ' ti' Papules and pustules i.e. folliculitis, on the thighs and forearms were rarely accompanied by comedones but were relatively common. 4. In general pitch acne clears much more rapidly than chloracne and scars less but, as with the latter, many men had a few persistant comedones which, despite regular squeezing, were still reappearing even ten years later. CONCLUSION And now I hope you will forgive me if I conclude with the obvious. Despite the problems posed by difficult management and industrial relations as 1 know only too well, in the investigation and reporting of every outbreak of industrial disease the attempt must be made to observe certain minimal criteria. The first and by far the most important is accurate information on the chemistry concerned, which includes not only information from the users' engineers and chemists but. much more important, the chemical manufacturer of the basic materials. In this connection the role of contaminants or unwanted reaction products must never be forgotten, may indeed be critical, and must always be investigated14,**. Now to suggest that no report of industrial disease is complete without a full description of the process concerned and the exact point or point* at which those affected fit into them seems almost absurd, hut it is astonishing how often in the literature these simple facts have been omitted31-73. Finally, much experimental work remains to be done. Although the usual warning Is necessary when interpolating between the experimental and the human animal, a good correlation appears to exist between acnciiorm lesions produced by external contact on the rabbit ear and chloracne in man. Furthermore, as far as it goes, in the only two recorded outbreaks of chloracne in man from ingestion of chlorinated aroma tic hydrocarbons both compounds have also been capable of producing chloracne on the sain of man and the rabbit car by external contact3**4*. This correlation is important because of the much greater difficulty of producing in experimental animals chloracne-likc lesions from ingestion of the suspected toxic substance and the impossibility of doing so in human volunteers. A great extension of work on the rabbit ear as well as further investigation into the fascinating h\-p*r- Upaemia with a variety of commercial and highly purified aromatic chlorinated hydro carbons would therefore seem to be potentially rewarding. Acknowledgements The help I have received in preparing this article is too great to detail but my especial thanks are due to B.I.C.C., Hunts, Dubiiier's and Plessey in the Capacitor Industry; Monsanto and B.I.C.C.Research for chemical information ; to Innumerable colleagues all over the world and in particular Prof. C. D. Calnan. With out the assistance of all those others not specifically mentioned the work would still have been impossible. . REFERENCES I. Adam, E. M., Irish. D D.. Spencer, H. C. and Rowe. V. K. (19411 The response ol rabbit slrfn to compoundi reported to have caused aerteform dermatitis hiut:r. Mtd. S;irg. 2. I. t. Boader. H. C. . XV. and Hauer. H. I. (1951) Industrial intoxication due to Pcntachlorophenol. Indusir. Mtd. Sittg. 20. -SO, 3. Bettpiaan. S. (1901) Cblorakne. ia besontlere Form von pro/essionellcr Hauterkrankunf. Dtuk. mtd. Wukt.Zl, 437. MONS 96 4. Bril. W. B. 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(1950) A mieroanatomical study of the response of the pilose* baeeoutapparatus of the rabbit's ear canal. /.inuesf.Dtrm. 26.183. 36. Hambrick. G. VV. (1037) The effect of substituted naphthalenes on the piloeebaceous appara* tus of rabbit and man. /.iKvcsf.Denn. 28,89. Hettzberg, J. J. (1047) Chlorakne nach Geauss von chloriertem Paraffin. Derm.IPsrAr.H9. 67. Herxbeimer, K. (1901) VVeitere Mitleiluagen iiber Chlorakne. VII. Derma/. Konrr. Breslau, p. 168. 36. Hdfs. VV. (1067) UngewOhnlicbe Eotstehungswdseeiner kindlichen Halogenwachsakne. Derm. (KssAr.186,1. 60. Holden, H. Pert, communication. 40. HuWer, VV. R. (1938) Plastic Planing In chloracne. Arch.Derm. 77, 111. 41. Queries and minor notes. J. Amer. med. Ass. 121. 471. 43. Reports of the study for "Vusho" (chlorobiphcnyls poisoning) June 1969. Study Group for Yusbo, Faculty of Medicine, Kyushu University, Fukuoka, Japan. MGNS 03^943 5$ P tP \ \ 99 > Joans, J. W. and Alden. H. S. (1938) Acneform dermatergosis. ArcK.Dtrm. 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(1927: Die Fareafankbcv- iV:.:kt. 8. A4.8. Teleky. L. (1927. Die Pernakrankheit, W 8. *97. Teieky. L. (1928) Die Pernakrankheit. A7m.ir*r. 7. 214. Teller, H. (1947, Toxikodermic nach Cenuss von wahrscheinlich cbloriertem Mineraifett. Arch.Dtrm.Si ph. 188. 442. 77. TheJwall-Jones, A. (1941) The aetiology ol acne with special reference to acne of occupational origin. J.iniustr. Hyg. 23. 290. Tbyresson. S'. (1949) Cases of occupational acne. Acta dtrm.itnertol:29. oil. Wagener. X. (1951) Hyperkeratoiisof cattle in Cermany. J.Amtr.vtt.rnt4.Ast, lift. 133. Warh. A. H. 11956) Tha Chemistry and Technology of K'esrs. New 2nd Ed.. Reinold PubL p. 463. Wauer, V. (1918) CewerbUche Erkrankungcn durch gechlort# Kohlenwassentofte. Zbl. Gtwurbehyg. 8.100. 9ft. Wilkinson, Z>. S. (1959) Chloracne from preservatives in timber. Contact DtrmtMu S'twsltiter No. 4. London. St. John's Hospital lor Diseases of the Skin. p. 74. 83. SUtes, D., Wise, J. C. and Bridges, M. E. (1952) The experimental production ol"X disease" (hyperkeratosis) in cattle with chlorinated naphthalenes and petroleum products. JsAmor.vtt.mul.Ats, 121. 337. * (R) Trade Mark of Monsanto HONS 062944