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CHLORACNEf A CRITICAL REVIEW INCLUDING A COMPARISON OF TWO SRRIBS OF CASKS OF AcNH FROM CHLORNAPHTHALENE AND PITCH FUMES. K D Crow} A review of the subject of chloracne will be followed by s comparison of the mam factunng processes and cases produced during two factory outbreaks of chloracne and pitch acne both due to fume exposure. My definition of cliloracne is t!.e 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 it alto usually distinctive Chloracne has previously been reviewed only once by Braun in a German mono graph in 1966'. Tliis 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 1930'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 only vaguely if at all, and the great value of the early works was their recognition that the acne they were observing was clinically distinct from that due to products of coal tar and parafinmc oils. First Von Bettman* in 1897, and then Herxheuner*7 observed this dis tinctive acne among workers engaged in the manufacture of 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 Herxheimer 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 chlorine theory and even suggested that the chlorine in chloronaphthafenes was easily released to do its deadly workT*,*i,,r whereas in fact it was the very converse which made them such use ful industrial materials I 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 all1*, but these early observers** were familiar with coal tar acne, and their descriptions of chloracne, in particular the emphasis on the peculiar cyst-like lesions*7 leaves little doubt that they had correctly distinguished between the two conditions The substances which 1 shall now consider in detail are Chlomaphthalenes, Chlordiphenyls and Terphenyls. Chlordiphenyl F.thers, Furanes and Dioxanes, Chlorophenols and Chlorobenzenes (fig, 1). CHLORNAPHTHALEN ES The production by the cliloriuation of naphthalene of numerous isomers with wax like qualities was first noted by Laurant in 1883', but it was not until 1900 that J. W Aylsworth in the USA took out several patents after noting some of the fTbc Dowling Oration, delivered At St Thotnu' Hojpitil on Fndmy, 17th April, 1970 lPrillcam MirgAret Hcxpit*], Swindon. Wilt* HONS 212441 Cl Cl 60 Trich lomaphthalene Tetrachlordiphenyl Cl Cl Hexachlorterphenyl Cl Cl Tnchlordiphenylether Trichlordiphenyl(ene) oxide or Trichlordibenzofurane Telrachlordtbenaodtoxane Cl /\C1 Cl Cl Tetrachlorbenzene Trichlorophenol Fig 1 --R*prHotitif formulae of come eubetascee ditcuaeed io the text, HONS 212**2 91 remarkable properties of these materials, i.e, clinical inertness, high dielectric constant, low viscosity close to the melting point, low shrinkage, non-inflammabibty, fungicidal and insecticidal properties and strong adhesion to various surfaces including metal. Their use by the Germans in World War I as substitutes for natural waxes and rubber led to the first large outbreaks of chloracne. Partly for this reason and due also to the post-war reappearance of traditional materials there was a great decline in their use until the mid 1930's, when their great superiority to paraffin wax brought them to the notice of capacitor (electrical condenser) and cable manufacturers44'1****'1*. Large scale usage recommenced and with it great outbreaks of chloracne. Their industrial applications rapidly widened to include numerous other uses ; as synthetic waxes*1 and unpregnants, high pressure additives for lubricants****; wood preserva tives 41, flame proofers and many functions now superceded by silicones tad plas tics11'" 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 chloracne producing substances to induce chloracne 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 are in fact a sublimate, and become profuse at temperatures far below the boiling point. When acneigenk this is the property which makes them difficult to use safely m industry. Their ability to con dense on cold 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 chloracne is frequent4*. Although it has often been stated that the solid wax in macroscopic particles causes severe chloracne, in every such publication there has either been expoeure to fumes from a nearby process44 or a simple failure to appreciate their appearance in the process being considered Thus Schwartz m 1943" described chloracne from solid particles among shipyard cable strippers but in the very same article he mentions their expoeure to fumes, and it is known that these workers habitually melted the waxes to seal the cable ends and joints and were indeed fume exposed*4-41. On the other hand pro longed contact plus friction may be significant, and a German child whose feather mattress was annually rubbed alt over with a chlomaphthalene cobblers wax to prevent escape of feathers, produced chloracne on his cheeks and the sides of his arms and legs'*. This cleared up when the mattress was destroyed. The same authors state that they had observed chloracne in leather and tent factories, which disappeared when a synthetk 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 chloracne in the *(R) Trade Mark ol Hopper* Co lac . Pittaburg IS, USA HONS 212*0 82 same way m their children whom they cuddle on return from work and also in their wives,M\ So much then for the physical state even more important is the degree of chlonation. DEGREE OF CHLORINATION Until 1067 there was general agreement among alt authors that as the degree of 1 .formation increased so did the systemic toxicity and the acneigentc properties of clitomaphthalenes. As a result of Shelley and Ragman's** experiments on human volunteers, the unexpected fact emerged that whereas tn and tetra, hepta and octachlomaphthalenes were entirely non-acneigenic, the penta and hexachlor derivatives produced very severe chloracne indeed Since Shelley deliberately chose suspensions 0 1234 6 6 7 8 Chlorine atoms Halowax 1000 80 <4 S 60 Halowax 1001 012345678 Chlorine atoms Chlorine atoms Halowax 1013 Halowax 1014 Fig 1--Examples ol four Halowax cMornapthalene* of fine particles rather than solutions, varying solvents and solubilities cannot have accounted for the surprising failure of the two most highly chlorinated derivatives to have any acneigenic effect. Hambrick** in 1967 employing the extremely sensitive experimental technique described m 1941 by Adams et al1 using the inner side of the rabbit ear, had already demonstrated that mono- and di-cnlomaphthalenes did not produce chloracne. thus clearly incriminating only the penta- and bexachlor derivatives. This work is strongly confirmed by the massive outbreaks of chloracne HONS 2124*4 83 which occurred during the late 1930'e and 40't largely in the manufacture and use of electnc cables1*,"'**,<' whose outer covering was a fabric impregnated with penta and hexachlomaphthalene It therefore leemed clear that the assumption of steadily increasing toxicity with increased chlorination had been based on insufficient evi dence Animal experiments on systemic toxicity had paralleled the acneigenic effects but hepta and octachlomaphthalene had never been tested in this respect, a tact now most difficult to understand There is no reason to dispute the fact that mono and dichlor, hepta and octochlornaphthalenes are non-acneigenic but the position with regard to tri and tetrachlomaphthalenes, which invariably exist as a mixture, is more confusing Several reports of chloracne from tnchlomaphthalene used as a paper capacitor impregnant appeared in the French and Belgian literature in the early 1930'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 m 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 trichlomaphthalene Itself m certain cases1*. 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 acneigenic properties not possessed by tri and tetrachlomaphtha- lenes alone, The presence in some of these cases of a cu-existeut vesicular dermatitis on the face14'*', 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- thalene, 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** describing two cases of chloracne in a capacitor plant using a tri/tetrachlomaphthalene wax for impregnation is valueless in the absence of details of the chemistry or process of impregnation or, more impor tant, of sealing. On the other hand, the same author, although providing no experi mental data at all, exposed rabbit ears to the vapour of trichlomaphthalene for several months and noted the development of comedone-like keratoses and hyper keratosis. Assuming that the chemistry was correctly reported such gross exposure of the very highly sensitive rabbit ear may represent conditions which srt not capable of extrapolation to the human situation . Certainly my own work confirms my opinion that there is no evidence that tri/ tetra chlomaphthalene mixtures are acneigenic or dermatitk under industrial con ditions. PRESENT USES 1 think it is important to know the present uses of chlomaphthalenes in Great Britain. All major manufacturers of these products either ceased production altogether several years ago and handed over to smaller firms, or make a range of products which does not include chlomaphthalenes with more than four chlonne 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 tn and telrachlomaphthalene and on an increasingly small scale, also in timber preservatives as mono, di, tn and tetrachlor derivatives. Nevertheless, the higher chlorinated pro ducts are still manufactured abroad and therefore are available, so that the possibibty of their presence must always be suspected in chloracne of unknown origin. When I recently examined capacitor impregnation processes using tri/tetrachlomaph thalene mixtures once again I found no evidence of chloracne. HONS 212445 1 CHLORDIPHENYLS AND TERPHENYLS Whilst the uses of chiomaphthalenes 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 chiomaphthalenes, 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 m 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 ofl white powder--octochlordiphenyl. The chlorterphenyls are usually resinous solids and there are also numerous mixtures of chlorinated aiphenyb and terphenyls, most of which again exist as low melting point thermoplastic nautous substances. Chlordiphenyls resemble the chiomaphthalenes in their great chemical inertness and resistence 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 260 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 fatal to capacitor functioning. The major difficulty was to produce strong, thin Kraft papers which were kmically pure Eventually these problems were solved and large scale manufacture of chlordiphenyl capacitors began in Britain around 1960. Pentachlor-dlphrny! was first used for this purpose but It had the senous draw-back of being unusable at temperatures below 0*C when it solidified and for low temperature A.C. use paraffins continued to be used. Finally the ionic difficulties of using the greatly superior trichloTdiphenyl 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 1 have disucussed it at some length. As the numher of available compounds us mereased, their uses have multi plied constantly until today there are well over 100 different industrial applications for polychlorinated diphenyls and terphenyls". A detailed analysis is therefore quite beyond the scope of this article but their uses stem essentially from their three major f'roperties; resistance to oxidation, non-inflammability, and high dielectric value hall mention one specific use because it has been the cause of the only two outbreaks of chloracne from these materials published since the lMO't. This is their function as heat transfer agents m chemical engineering**'". Previous chloracne had resulted from crude and careless manufacture in the early days*1 or admixture with chlomaphthaienea. TOXICOLOGY Once again, as in the case of chiomaphthalenes, 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 1. Thus Miller's rats" all survived over 00 days after receiving ten 0 6 ml doses of trichlordiphenyl on alternate days, wbereas Drinker et at.1* killed 60% of their rats with the same dosage of heptachlordiphenyl in less than 14 doses. Unlike the chiomaphthalenes they do not sublime at low temperatures whilst at moderate working temperatures fuming is slight and when cold entirely absent. Relatively mild fume exposure in the capacitor industry caused occasional chloracne HONS 212446 86 with pentachlordiphenyls** although this was not to he compared with that from penta and hexachlomaphthalene Since the change to trichlordiphenyl however even this has entirely disappeared**, as 1 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 chlordiphenyls, although undesirable because of skin absorption, appears to pose no acneigenic hazard The lesser toxicity is confirmed by the entire absence in the literature of any reports of chloracne from chlordiphenyls containing less than four chlonne atoms Furthermore, as will he seen m a later section of this paper, although these substances are hepatotoxic, this effect also seems to he minimal with only four or less chlonne atoms per molecule as the human ingestion of tetrachlordiphenyl in japan has well Illustrated CHLORDIPHENYL OXIDES Experiments have been made with chlordiphenyl 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**, like alt such compounds whether aromatic or aliphatic, are relatively inert even when chlorinated, whereas the furanes are chemically and biologically much more active The chemical differences are clearly shown in fig 1. The systemic toxicity and acneigenic properties of the chlordi* bcnzofuranes 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 chloracne because of its complexity. They range from mono to pentachlorophenol with, of course, various isomers of the lesser chlorinated compounds. They are used almost exlusively as insecticides, fungicides and herbicides, or as chemical intermediates. Consequently they may contact the human subject either during their use or their chemical manufacture. They are prepared by the alkaline hydrolysis of crude chlorobenzene, one chlonne 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, the 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 severe**-*1, 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 lorm, especially when highly chlorinated, they are extremely irritating especially to the eyes and upper respiratory tract, and it is in this state that they have produced most of their chloracne. Indeed in large plants manufacturing various chlorinated pdyphenyls and chlorophenols today it is the fine dust of the latter which is the main chloracne producer if it is not most carelully controlled** It is therefore not sur prising that in 1937 Butler1* reported extremely severe and generalised chloracne in men shovelling a fine powder of sodium tetrachlorphenate and ortho (2 chloropbenyl) phenol sodium into sacks under bad working conditions, again as a timber preservative. Large numbers ol very severe cases Irom sodium tetrachloropbenate solutions used as timber preservatives were reported by Stingily and Gaines in 1940T* but no details ol 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 typical. Around I960 the more effective pentachlorophenol replaced the lower chlorinated derivatives as a wood preservative. HONS 212447 86 Ch] oracne from pcntachlorophenol solutions has never been recorded despite gross skin contamination. Nevertheless fine dusts have continued to produce it always in the manufacturing plants. Baader and Bauer m 1667* 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 finely powdered material** Klmmig and Schulz in 1967", faced with a severe outbreak of chloracne m a chemical plant manufacturing 2. 4, 6-tnchlorophenol and using the technique des cribed by Adams et al. in 1941', quickly established for the first time the vital but elementary fact that whereas the plant's crude tnchloropbenol had an acneigenic efleet on the inner side of the rabbit ear painted with 6% solutions in polyglycols, neither the mtial reaction product crude 1, 2, 4, 6-tetrachlorobentene nor purified 2. 4, 6-tncliloropheiiol, 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 m the reaction vessels and pipe-work of the plant were so complex as to defy analysis, and so for two years they proceeded to 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 chlordiphenyl oxides or, more correctly, chlordibenzofuranes were potent acneigens even m 0,06% solutions, and also highly hepatotoxic, a single dose of 0,6 to 1.0 mgms per kgm of trichiorodibenzofurane being lethal to rabbits. Finally they found a substance so potent that 0.001% solutions were strongly acneigenic*7. This material was the chlorinated dibenzy! cyclic ether, tetrachlordibenzodioxane Its systemic hepato-toxicity paralleled its acneigemcity and 0.06 mgms in a single dose was lethal to rabbits. Although the position of the chlorine atoms was not absolutely certain4*, what was thought to be 2, 3, 6, 7-tetrachlordibenzodioxane was isolated by Kimmig from the residues resulting from the formation of tnchlorophenol by the alkaline hydrolysis of tetrachlorobenzol, and its theoretical formation was postulated as shown in fig. 3. 1 MOLS SODIUM TR1CKLOROPKBNAT* a,S,,7 TMTRACHLOROBRflZODtOXAMB Fla. S --Stage* In formation Df 1, S, t, T-tetrachlordlbaniodioxaDe HONS 212448 67 The presence of erythema and swelling of the face and chronic blepharo-conjunctivjtis all suggested exposure to fine chlorophenol 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 tnchlorophenols, but possibly tetra and pentachlorophenols also, all of which are similarly 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 tune also in a trichloropheiiol plant, Dugois and Colomb in two identi cal articles*11 described chloracne of great seventy and with evidence of systemic toxicity in a number of workers who, without protective clothing, were washing out with hot water the accumulated sodium chlonde in the reaction vessels. Twelve years later in the very same factory Dugois. again in two identical articles1', 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. Expiations suggest increased pressure and possibly heat, factors both increasing the chance of dibenzodioxane formation. Chloracne in these cases, just as in Kimmig's, was preceeded 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 tetrachlordibenzodioxane described by Kimmig eleven years before Chloracne from a single exposure to any material is so unusual that one cannot exclude systemic 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 possibly agree with Dugois in ruling out external contact, since Linn-Jones and Krizek*' produced acne on the rabbit ear with only three paintings of a 0.001% solution of tetrachlordibenzodioxane. In 1004 Bleiberg* linked for the first time chloracne and hepatic porphyna, again in a plant manufacturing dichloro and trichlorophenols for conversion to the relevant phenoxyacetic acid weed killers In my opinion it is of the greatest significance that there was no direct relation ship between the chloracne ana the porphyna, some cases having one condition with out the other This unique occurrence required an investigation of the same calibre as Kimmig's but unfortunately the industrial and chemical information was incom plete and sometimes incorrect. Nevertheless whilst prophyna from chlorophenols clinically or expenmentally has never been recorded** there is abundant evidence of its production both clinically and expenmentally from chlorobenzene isomers of many different kinds". Therefore there seems little reason to doubt that the chlor acne was probably produced by chlorodibenzodioxanes or similar substances as Kimmig and Schulz had already demonstrated, whilst the porphyria was most likely induced by the crude chlorobenzenes used to produce the chlorophenols. CHLOROBENZENES What evidence is there that chlorobenzenes themselves cause chloracne 7 In fact, very little. Exposure to various chlorobenzene isomers has occurred on a vast scale over the years both externally and internally in human subjects" and experimental animals without causing chloracne. The onlv cases reported in human subjects were in men who were grossly exposed to the fine dust and vapour of crude tnchlor and hexachlorobenzenes, producing a few rather atypical looking cases of chloracnewhich ceased when the process was extracted This report by Bowen and Moursund* was lacking in chemical and engineering HONS 21Z449 88 detail and m view of the complexity of the reaction products in auch chemical manu facturing plants this Interesting report requires further confirmation On the experimental side Rimington and Zeigler*1, feeding rats numerous chlorobenzene isomers, found that only l, 2. 3, 4-tetrachlorobenzene 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, 2, 4, 5-tetrachlorobenzene were without effect. AU 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 cldoracne 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 involved11 Furthermore where undoubted systemic effects have occurred there has been gross external contact also*'*'"**'" There was always a doubt there fore whether internal administration could cause chloracne at all, and if so what part It played in any particular case The first concrete evidence appeared m 1945, when a fat-like substance found in the bomb ruins of Berlin was used to fry vegetables and six people were poisoned" ", 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 m three cases, the chest and back also in three others, an interesting observation indicating that distribution m itself does not allow one to distinguish between external and internal causation. Such analytical data as were available suggest that they had probably ingested hexaclilomaphthalene, 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''1', a fatal wasting sick ness with hyperkeratosis and dilatation of follicles which had decimated cattle in the U-S-A. and Germany from 1941-1954, wan due to the accidental ingestion by them of penta and hexachlomaphthaienes in lubricating oils and greases*1 and timber preservatives'*, So sensitive were cattle that a single ora] dose of I 0 gram of hexachlomaphthalene would kill a 2 cwt. calf in 14 days4. 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 1959 (**). This was the report of an outbreak of poisoning due to tetrachlordiphenyl which, for three days only, leaked from the heat exchange system in a factory manufactur ing cooking oil. The edible oil contained an average of 2,000 p.p.m. of tetrachlordi phenyl ana most patients probably took something like 1.0 gram per month for 4-5 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 more. As m Hertzberg's cases the chloracne was most severe on the face and neck but alto the genitalia, though less so on the trunk and scarcely at all on the limbs, In the more severe cases there was often a widespread follicular hyperkeratosis also observed by Duveroe** from trichtorophenol derivatives and from chfomaphthalenes by Hofs14 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 HONS 212450 89 most interesting of all were some non-dermatological findings such as oedema of all four limbs, peripheral neuropathy and bursitis--also reported by Baader and Bauer from pentaclilorophenol poisoning- whilst the newborn infants of affected mothers had generalised tnperpignientation and hyperkeratosis Persistent hvperlipaemia affecting the triglyceride fraction of die serum was howevet the most consistent finding ft had only been reported twice before from tnchloroplunnl bv IJugois'0 and bv Goto who reported even more severe elevation of serum tnglvieiidcs m 10 cases of pentaclilorophenol poisoning*' CLINICAL riiAl UKICS In -almost evciy report, whatever the causative clicmical, the clinical features have been most consistent" l!ir. 8 --Typical case of pitch acne The most distinctive and almost invariable cutaneous lesion, usually absent in ml acnc and rarely seen in pitch or tar-acne (l`ig H) both of which are also more inflam matory. is the chioracne cyst", skin coloured, varying from 1 nmi even to 1 cm in diameter, and with the central opening difficult or impossible to detect (Pig. 7 ) If these cysts are absent then chioracne should be diagnosed with great caution, earept in early or very mild cases Comedones and small cysts are therefore die basic lesions and may be very few or so numerous as to present confluent sheets Inflam matory papules and pustules are not so common, much less so than in oil acne, and arc almost invariably associated with friction from clothing, being commonest there fore on the back of the neck, shoulders, chesl, genitalia, buttocks and thighs, and affecting only the more severe cases Acne from paraffinic oils and tar products are both more inflammatory dun chioracne, especially the first named HONS 212451 90 Vic 7 --Typical case of cliloracnc DISTRIBUTION This is predominantly faciei even when the poison has been ingested, the malar areas, jaws and behind the ears being sites of particular predilection In mild cases these areas alone may be involved The nose is invariably spared except when poison ing is systemic This distribution is not specific to chlorinated aromatic hydrocarbons but to any acneigenic fume or dust for, as we shall see. acne from pitch fumes behaves m exactly the same way, With increasing seventy the rest of the face and neck soon follow, whilst the outer upper amis, 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 11ns is more difficult to assess, reports of its occurrence being fairly evenly divi ded*7'44'" Although no-one volunteered it, in response to a direct question a little under half of my own cases admitted itching, Of a senes 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 chlomaphthalenes, including the numerous and meticulously investigated Japanese cases of systemic tetrachlordiphenyl poisoning, has itching once been mentioned. Pruntus may therefore be specific to chlomaphthalenes but without more evidence this must remain speculative. HONS 212452 91 DURATION OF EXPOSURE BEFORE ONSET This is usually irrelevant because the degree of exposure is to 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 degree of scarring is naturally dependent upon the severity of the disease This will be teen in greater detail when considering my own cases. Some of the worst recorded instances of scar ring have followed exposure to various ^nlorophenols, possibly due to the intense toxicity of the chlordibentodioxanes probably involved. HISTOLOGY Findings in the experimental human subject have been confirmed by those in the rabbit ear canal14, in both cases hexachlomaphthalene being the acneigenic agent used. First of all there is a steady thickening and hyperkeratosis of the epithelium in in the infundibulum of the pilosebaceous follicle This is accompanied by a slow disap pearance of the sebaceous glands, until eventually a keratin filled syst-like dilatation is formed. In some cases the exit is tiny whilst others are little more than a shallow trough. Shelley*1 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 si. in 195611. Hambrick11 with serial biopsies showed that the disappearance of the sebaceous glands had already begun five days after the first acneigenic applications, long before any back pressure was possible, and thereafter steadily progressed. He therefore suggested that chloracne producing chemicals initiated squamous metaplasia and that when all sebaceous material present had been shed a large, dilated, squamous epithelium lined and keratin filled pilosebaceous follicle was formed. There is of course general agreement that, as in acne vulgaris, rupture of the follicle produces the inflammatory process. TREATMENT Most authors have accepted it as hopeless but strong exfoliants in the hands of Dussart11 cleared 66 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 ethylenediamine tetracetic 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. CHLORACNE IN A PAPER CAPACITOR PLANT USING TR1/TETRA AND PENTA/HEXA CHLORNAPHTHALENES FROM 1966 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 tolled up like lavatory paper to provide a large surface area. In this particular process the roils 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 116*0 to remove every trace of HONS 212453 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 tn/tetrachlomaphthalene 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 was melted in the ovens and the Tacks of units removed Exposure to tn/tetrachlomaphthalene fumes was very gross indeed in this section for the following reasons -- 1. Fuming of molten wax residues at 110*C when emptying impregnating vessels. 2. Failure to realise that fumes from wax remaining on clamps from previous 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 1960 to 1963 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 melting at 130C and consisting of roughly equal parts of penta- and hexachlomaphthalene with 6% pentachlordiphenyl as a plasticizer. This dipping section was a long narrow area inside the mam workshop enclosed by partitions 7 ft. 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 retinned the wires in one operation at the same time unfortunately vapourising the chlomaphthalene 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 gToss fume exposure for two to three hours every week, The molten wax at 160"C was ladled out by hand into trays, the residue removed by a drain cock under the vessels and tnchloretbylene added, the lid screwed down, the mixture boiled and then drawn off. The stop cock was closed and fresh solid wax added. Other sources of penta/hexachlomaphthalene 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 very powerfully extracted lacquering bench, thus secondarily exposing three further workers to a fume hazard. The first was the printer and the others the lacquerers especially the two nearest the dipper. The fact that some of the lacquerers developed chloracne only on the fume exposed side of their faces proves the external nature of the chloracne stimulus in this process. In 1968 extraction was increased but was still inadequate and no further change was made until October 1960 when dipping was totally enclosed, win tinning very powerfully extracted, and the layout of the process opened by the removal of all partitiona. To the Company's despair chloracne continued to occur, though much less severely, among the dippers and wire solderers. 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 solderers 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 HONS 212454 63 smallest regular fume exposure to pent* ud hexachlornaphthaienes, 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/tetrachlomaphthalene and one part of polystyrene provided a satisfactory alternative. From the time of its adoption chloracne ceased, again confinning the non acne-producing nature of chlornaphthalene 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 nave been too inaccurate to have had any practice] 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 vena. Fio 4 --Incidence <rf chloracne is capacitor plant Similarly, and alio because of continuous turnover, any figures relating the number of cues 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 1667 almost every worker in the dipping section had chloracne. Fig, 4 dearly show* the progressive improvement following the institution of preventive measures at tbe end of 1667 and again after almost total enclosure of the process late in 1660, The increased percentage of moderate and severe esses after the initial precautions was due to tbe elimination of general fume level which had previously caused many indirectly exposed mild cases, whilst quite severe fume exposure continued at tpetial points. HONS 212455 w Fig. 5 emphasises the concentration of lesion* on the malar areas and this appears to be an essential feature of fume exposure as we shall see in the comparison of acne due to pitch fumes. Although cysts are almost always present in chioracne, very mild cases may present a few comedones only. It can be seen that inflammatory lesions areas CHIN ARIAS Flo 0 --Distribution and type of lesion* is 40 cases oi chioracne 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. Fig. 9 shows the duration of the disease. Whilst the vast majority of cases clear within four yean, some of the severest ones still have lesions even at ten years. One unexpected finding was the fact that no less than 49% of patients, up to ten years after they regarded themselves as clear, still had small numbers of residual black heads and occasional small cyst* which, despite constant squeesing, had consistently re-appeared. There was scarring of severity in 10%. all of than being severe cases with inflammation, In 26% 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 pent* and hexachlomaphthalene and cannot therefore necessarily be assumed to be true for other chioracne producing materials. MONS 212456 OS Fio 6 --Dtmttoi of cUoncu. PREVENTIVE MEASURES The mtin preventive measures adopted were based on those proposed by Cranch(lS) :-- 1. Complete extraction of fumes (which was never achieved). 2. Neck and wrist fitting white overalls changed daily and cleaned in trichlore- thylene. 5. 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 I now intend very briefly to compare chlorecne with the clinical details and prog' noais of a aeries of 64 cases of acne due to fumes from pitch. Since the exposure was virtually identical in each aeries 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 1B0*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 weighed on a work bench on kitchen type scales and then beaten with an iron bar. It fumed most HONS 212457 m strongly during all these operations and the extraction, which was of 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 chloracne the great predilection of the malar areas in response to fumes. The purely comedontc nature of the facia! 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 tnchlomaphthalene again points to pitch as the probable hazard in these cases, mentioned earlier in this paper14'4*. so mpuiis ano eurruitt cljlJICHIN sonewAD NECK COMEDONBA ONLY FOLucuumt only COMEoca AND FOLUCUUTIS OTCAStS *l ' Flo --Pitch Kit Distribution and type of Mon* in 54 cm** 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. HONS 212458 The main differences from chloracne were therefore as follows -- 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. 3. 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 1 hope you will forgive me if 1 conclude with the obvious. Despite the problems posed by difficult management and industrial relations as t 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 investigated1*'**. Now to suggest that no report of industrial disease is complete without a full description of the process concerned and the exact point or points at which those affected fit into them seems almost absurd, but it is astonishing bow often in the literature these simple facts have been omitted*1-**. 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 acneUorm 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 akin of man and the rabbit ear by external contact*1-41. This correlation is important because of the much greater difficulty of producing in experimental animals chioracne-like 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 hyperiipaenua 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 m preparing this article is too neat to detail but my especial thanks are due to B.I.C.C., Hunts, Dubllier's and Plessey in the Capacitor Industry; I.C.I, Monsanto and B.I.C.C.Research for chemical information ; to innumerable colleagues all over the world and in particular Prof. C. D. Cainan. With out the assistance of all those others not specifically mentioned the work would still have been impossible. REFERENCES 1 Aduu. E. M . Irish, D. D , Spnw, H C end Row*. V K (1941) The response of rabbit skin to compounds reported to have caused acnelorm dermatitis Inditlr Mtd S*r/ % : t. Bandar. H. C. E. W and Bauer. K J (]9S1) Industrial intoxication dm to Pentechlorophenol. Indus*. Mtd Surf SO. 1M 1 Bettmasn. S. (1901) CbJorakoe. eins besondere Form von profeasioneller Hauterkmnkung. DUek mtd Wuhr *7. 437 HONS 212459 98 4 B*U, W B [ltS4) The production of hyperkeratosis (X disease) by e tingle administration ol chlorinated niphthalenes J Amtr vtl msi Ass IM. ISt e. Blelb*rg, J,, Wallen, M,, Brodkin, R and AppUbeum, 1 L (1M4) Induttrially acquired porphyria A rck Dtrm St, 7t3 e. Bowen, S 5 and Moursund, M P (1967) Chloracosin the manufacture ol DOT Artk Dtrm 71,74t 7 Braun, W. (ItOC) Cbloiakne A ultniorff W Simmy, Edlho Cantor 8. Braun, W, (1969) Kbmtche Beobaebtungen nr EntstehungderChlorakne Haularrt, 10, lte Broueeole, W (IBlt) Acn4 prolessiocneiW dee Uavaiileur* de la naphtaline Bull SoC /rant Dsrm.Sypk M,CS 10 Butler, M C. (1137) Acneform dermatosis produced by ortho (t chloropbenyljpbenal eodium and tetrechlorphenol sodium Artk Dtrm M, 161 11 Collier, E. (1941) Poieoning by chlorinated naphthalene Lamctt, i, 71, It Connelly, T. P, and Manb, W C (1144) Chloracae (cable raah) V S. not/ matt Bull 41,401. It Contreree, F (IMO) Acne chlorko profeeionaJ enlennedad de la perna o "Halowax". Att itrmo-sifiiep 41. tCt 14 Courtoie-Suffit, Touraine, A and Mendtral, B (1*14) Etude eur l'intoxlcatton profeaskmnehe par le triehloronaphtaline A m MU Uf 14, 411 1C Cranch, A. C. (144) Precautions in handling chlorinated hydrocarbon waxes InimJr Mai Sum It. 110 is Crow, K D , Hannan, R R M and Holden, H (IMS) Amine flux scnaitiration dermatitis in electricity sable Jointer* Bnl I Dtrm SO. 701 17 Crow, K D , Alexander, E., Buok, W H L . Johnson, B E, Magnus, I. A and Porter. A D (1M1) Photosensitivity due to pitch Bnl J.Dtrm 71. ItO. is Drinker, C. K, Warren, M F. and Bennett, & A (ltt7) The problem ol possible systemic effects from certain chlorinated hydrocarbon vapours J mdustr.Hyr It, tl) it Dugois, P , Amblard, P , Aimard, M and Deshort, C. (IMS) Aon4 ehloriane collective et accldentelle d'un type nouveau Bull Sat franc Dtrm.Sypk , 75, t#0 and Lyon MU git, 101 to Dugois, P and Golomb, L (IMS) Acn4 ehloriqoe du 1-4-6 trichlorophenot Bull.Soe front Dtrm Sypk tt. IS! and Lyon MU 1M7. IS, St# tl. Dugois, P,, Colomb, L and Fevolle G (1*67) Note nr I'aetivitt du traitment ch4lateor dans i'acnd chlortqne. Lyon MU. IM, 174 tt. Dinasrt. L. (IMS) Acn4 chloriaue, dermatoee professionnelle, Artk tssifst Dtrm t, HI. tt Duvems. J., Thivolst, J and Bdrard, J (1M4) Acn4 chlortque profuse avec dpancbement pleural rdcidivant chei un eujet 4 inaction* tubercuUniques negatives Bnll Soc.frant J>arm.Sypk 71. t4t, t4 Duvoir, H (19*4) A propos dee dermatoees proieaalonneUea par le tricUoronaphtallne Ann.MU.Ut 14,119. ts, Ellen. A. K. Holyoke, J. B and Lobitr, W C (IMS) Responses of the superficial portion of the human pilosebaceous apparatus to controlled injury, J.tnvtst Dtrm H, 146 IS, Pulton. W, B and Matthew*. J L, (ISM) Dermatologies! and systemic edicts ol bexa- chlornaphthalene and chlordlpbenyl. Comm Pm*.Dipl.Labor and Ini.Sptc Butt No 43 17, Good, C. K and Penalty, N, (1943) Halowax (*> acne (cable rash) Artk.Dtrm , 4S, Ml tt Gordon, D (1S6S) How dangerous It pentaehlorpphenoi Mai J Auxt 1, 416 Greenberg. L, Mayers, M R and Smith. A R (IStt) Systemic effect* resulting from expo sure to certain chlorinated hydrocarbons J tninttr Hyt II, tt. to. Greenberg, L. (1S4S) Chlorinated aspthalenes and dlphenyb lndmtr.Mti Stag It, 510 tl Grimmer, H. (1M4) Uber acne artiBclaJb dutch chkrnerte Naphthaline(ChlorakM) z Haul-u Gttckl -#fr. If, t7 tt Grimmer. H. (IMS) Beruflkh bedingte Acnedurch chloriertearomatieche Kohleowasmrstoffe (Chlorakns Psrnakrankhelt) Zbt ArbtiltmM I, TS tt. Halowax f*> chlorinated naphthalenes techn Bull Koppere Co Inc Tar Products Div Pittsburg It Fa U.S A 14 Hambrkk. G.W and Blank. H (1969) A mtcroanatomical study ol the response ol the pikoe- baoeout apparatus of the rabbit's ear canal J.invtsl.Dtrm. St, IM. M. Hambrtck, G W. (1917) The elect of substituted naphthalene on the pilosebaceous appara tus of rabbit and man J invest Dtrm M, tt It Hertsberg. I, J. (1147) CUorakne each Genurn von chloriertem Paraffin Dtrm Wttkr lit, 4M. 17. Hsnduimer, K. (1901) Walters MitteUungen ober Chlorakne VII Dtrmal Kongr Breslau, p. 1*1 1. H0fa/W.^1M7) UngewShnUche Entstehungswelee steer klndUchen Halogenwachsakne Dtrm tt Holden, H Part communication 40. Hubter, W, R (IMS) Plaatie Planing in chloracna Artk Dtrm 77. Ill 41. Queries and minor notes, I Amer, med. Ase. Ill, 471. 4t Reports of the study for "Ywsho" (chlorobiphenylt poieoning) June IMt Study Group for Yueho. Faculty of Medicine, Kyuabu University, Fukuoka, Japan MONS 212460 43. Jona*. J W. and Aldan. H S (1836) Acseform dermaterroeis Arck.Dtrm 33. 1013 44 Kelhqr. E. F (1043) Acne from synthetic wax (Halowax 7r)), Vroi.cutart Rto 47, 330 40. Kimmig, J and Schult, K H j I *67) Beru (liehe Akne (tog Chlorakne) dumb chlorjarta aromatieche tyklieche Ather Dirmatologtea IIS, MO 40 Lehmann, W (1906) Uber Chlorakne Arch Derm Sypk 77, 366 and 333 47 Linn Jonaa. E and Krik, H (1901) A technic lor testing acnegenlc potency In rabbits, applied to the potent acnegen 3, 3, 7. S-tetrechlorodibenko-p-dioxIn J tnvtit Dtrm 39, *11 48 Da Hattela, F Pert tommnmcaltoH 49 Mayers, M R and Silverbarg,M C (1933) Skin conditions resulting irom exposure to certain chlorinated hydrocarbons j uiduiir Hyf 30, 344 50 Meigs J W , Albom. J. J. and Kartin, B L (1904) Cbloracne from an unusual exposure to aroclori*) JAnurataiAtt 184,1417 61 Manon, J A (1958) Tropical hazard* associated with the use of pentachlorophenol BrU.mtd J 1,1166. 61 Miller, j W. (1944) Pathologic changes In animals exposed to a commercial chlorinated diphenyl V S Pubt Hitllk Rip 19.1086 63 Monsanto Techn Bull. O-FF/1 on aroclor (hi* polychlorinated polyphenyls. 64 Nakauchi, Y (1940) Die aog Psrnakrankhelt und this Enstehungrwalee jap J,Dtrm.Uni 48.97 66 Newhouae, M (1967) Cbloracne Irani St John t Hup Dtrm Sec 13, 106. 66 Newman. M Ptri-Cornmnnicatton 67 Olaleon, P (1947) Hyperkeratoau (X disease) of cattle Comtll Vtt 43. 136 68 Patty, F A (1968) Induttnal Hyfilar and Toticoloty Vol 3. 3nd Edition, New York. Interscience Publ p 1401 69. Prosser White, R (1934) The Dtrmaltrtotts or Occupational Afftcttont of Iks She, 4th Ed London, H K Lewis, p 333 60 Pucclnnelll, V (1964) De)lracne chlorica Mai i Luzon, 46.131 61 Quinones, A (1961) Doe casoe de acne profeeionel por cloronaftaleno Act.dtrme-ttfiliofr 43, 630 63 Rimicgton, C and Ziegler, C (1963) Experimental poiphyria in rets induced by chlorinated benzenes Btockem Pktrmacol 13,1397 63 Schmid. K (1960) Cutaneous porphyria In Turkey. New Rnfl I.Mat 398. 997 64 Schuli. K, H (1967) KUnteche und experimentelle Untenucnungen iur Atioiogie der Chlorakne Arek kite txp Dtrm 306, 699 66 Schwartz, L. (1943) Outbreak of Halowax (R) acne (cable rash) among electrician! j.Amar mti Au 133.153 6. Schwarts, L, and Paok. S U (1943) Occupationa! acne N Y St J.Mti 43. 1711 67 Schwartz, L. (1936) Dermatitis from synthetic resins and waxes Atm I puMNlik 36. 666 69 Schwartz, L. and Bariow, F A (1943) Cbloracne Irom cutting oils Pub.Httllk Rip. 17, 1747 63 Shelley. W. B and Kllgman. A M (1967) Experimental production Of acne by Penta and Hexachlomaphthaianee Arck.Dtrm. 73. 319. 70 Stingily, K O (1940) A nawindustrial cbamical dermatitis. 5tk mti J, 33,1108 7h Sulzberger, M B (1336) In diecumion of Jones and Alden Auk Dtrm 33. 1033 73 Sulibergar. M B and Eontanberg. A, (1934) AeneUofm eruption! NY St.J.Mai 34, 199 73 Teleky. L (1937)Die Peniakraakhett. Klin Wtckr. |. 946 74 Teleky, L (1937)Die PernakrankhsU. ibti. 3. 337 75 Teleky. L (1938)Die Pernakmnkhstt Kht Wtckr 7. 814 76. Teller. H (1947) Toxikodermie nach Gennee von wabncbeitiUch ehkrriertem Minetalfett A rch Dtrm Sypk 136. 443 77 Tbelwall-Jonae. A (1641) The aetiology of acne with special reference to acne of occupational origin J tnduxtr Hyg 33, 390 78 Thyramon. N (1949) Cases of occupational acne. A eta dorm vtnartoi 89.611 76 Wegener. K (1961) Hyperkeratosis of cattle in Germany J.Atur.vtt.mti.Att. 119,133 30. Warh^A H^I063) Tkt Ckamittry mti Tuknotofy of Wtxn New Ind Ed, RetnoM I Wauer, V. (1919) Gewerbliche Erkrankungen durcb gecblorte KohieowaaeerstoSe. 2H Gtwtrbttyr 3,100 1. Wilkinson, D. S. (1968) Cbloracne from preeer* stives in timber Contact DirmatlHt NuatletUr No, 4, London, St. John's Hospital lor Diseases of the Sldn, p 74 ft Sikes, D , Wise, J C. and Bridges, M E (1663) The experimental production of "X disease" (hyperkeratosis) in cattle with chlorinated naphthalenes and petroleum products J.Amtr oat mti Au 131,337 * (R) Trade Mark of Monsanto MONS 212461