Document nmDwMDm5d0jDY19vJwn58NwY2

A CRITICAL REVIEW INCLUDING A COMP PRISON OF TWO SERIES OF CASES OF AcNS from Chlornvphthalem: and pitch fumes. K D. Crow; A review of the subject of chioracne will be followed by a comparison of the mamfactunng processes and cases produced during two factory outbreaks of chioracne and pitch acne both due to fume exposure. My definition of chioracne 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 varving structure. Acne caused bv paraffins, whether chlori nated or not, is clinically distinct from chioracne and ail such cases should be regarded as oil acne. Acne due to pitch and heavy coal tar distillates is also usually distinctive. Chioracne has previously been reviewed only once by Braun in a German mono graph in 19u5T. 1 his was essentiali\ bibliographical apart from its report of the author's own work Moreover, there have since then been some important develop ments m our understanding of this condition. It also seems uuhkelv that we shall e\ er again see the thousands of cases of chior acne which occurred in the 1930'Sand 4iVs, and since there may be someol us today who have never encountered tilts 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, form most casts thechenustrv involved was knotvn only vagtielv if at all, and the great value of the earlv works was their recognition that the acne they were observing was chnicallv distinct from that due to products of coal tar and parafinmc oils. First Von HcttnuanJ m l>97. and then IIerxheimer3' observed tins dis tinctive acne among workers engaged in the manufacture of liydrixJiloric acid by the old method using tar lined ah*wrption towers and the newer clcctrohtic method using anodes of tar, bitumen and charcoal. Only workers c\p<*ed to the tar were affected. Although Herxhcimer at first blamed nascent chlorine- hence the term c hloracne --he soon agreed that chlorinated aromatic hydrocarbons were the most likely cause. For manv years some authors clungtubb<>rnly to the naiccnt chlorine theory and even suggested that the chlorine in chioronaphthafcnes was easily released to do its deadly' workT*-,I T*. whereas in fact it was the very converse winch made them such use ful industrial materials! It was of course suggested that all the cases described as chioracne were in fact tar acne and that chlorination had nothing to do w ith it at all**, but these early observers44 were familiar with coal tar acne, and their descriptions of chioracne. 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 Chlornaphthalenes, Chlordiphenyls and Terphenyls, Chlordiphenyl Ethers, Furanes and Dio.vanes, Chiorophenols and Chlorobenzenes (fig. 1). CHLORNAPHTHAtEXES The production by the chlorination of naphthalene of numerous isomers with wax like qualities was first noted by Laurant in 18S3M. but it was not until 1900 that J. W, Aylaw orth in the U.S.A, took out several patents after noting some of the MOMS 202206 80 Cl Cl Cl Trichlornaph th alene Tet rach lordiphenj. 1 Cl Cl Hexachlorterpheny] Cl Cl Trichlordiphen ylet her Tnchlordiphenyl(ene) oxide or Tnchlordi beniofurane Tetrachlordtbenzodtoxane Tetrachlorbemcnc Tricblorophenol 1 --RtpnuaUtivt formula* o( tome uibitutei dimmed id the text HONS 202207 81 remarkable properties oi these materials, i e climcal inertness, high dielectric constant, low viscosity close to the melting point, low shrinkage, non-mflammabilttt. fungicidal and insecticidal properties and strong adhesion to various surfaces including metal. Their use by the Germans in V orld \\ nr [ as substitutes for natural waxes and rubber led to the hint large outbreaks of chioracne 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 manufacturtrs*,,1, ,,<lJ Large scale usage recommenced and with it great outbreaks of chioracne Their industrial applications rapidly widened to include numerous other uses . as synthetic waxes**and lmpregnants, high pressure additives for lubncants11,l,,wood preserva tives** , flame proofers and many functions now superceded by silicones and plastics41'**. 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 chlomaphthaienes from alpha monochlcr- to octochlor- The commercial products are distilled and graded simply according to their chtonne content and all are there fore mixtures of various isomers with one or two main derivatives predominating. Some typical examples of Halowax1*'* chlomaphthaienes are shown in Fig. 2. The'ability of ail 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 chlomaphthaienes are in fact a sublimate, and become profuse at temperatures far below the boiling point. When acncigcnic this is the property which makes them difficult to use safclv in industry. Their abihtv to con dense on cold surfaces" may cause them 1o accumulate in the ducts of ventilating systems, thus reducing their efficiency. Fnlutions 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 either been exposure to fumes from a nearby process** or a simple failure to appreciate their appearance in the process being considered. Thus Schwartz in HM3** described chioracne from solid particles among shipyard cable stnppcrs 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 exposed**'*1. On the other band 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 tus cheeks and the sides of his arms and legs**. This cleared up when the mattress was destroved. The same authors gate that they had observed chioracne in leather and tent factories, which disappeared frhen a synthetic chlomaphthalene wax was abandoned in favour of a return to the traditional bees-wax. These letter cases, occurring only three vears 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. &eaaionally workers, usually of dirty habits, may produce chioracne in the (R) Trade Mark of Koppera Co Inc , Pitubur* It. USA MOHS 202208 nme way in their children whom they cuddle on return from work and also m their wives1* So much then for the physical state . even more important is the degree of chlonation. DEGREE OF CHLORINATION Until 105t there was general agreement among all authors that as the degree of ljorination increased so did the systemic toxicity and the acneigeruc properties of dilomaphthalenes. As a result of Sliellcv and Kligman's'* experiments on human volunteers, the unexpected fact emerged that whereas tn and tetra, hepta and octachlomaphthalenes were entirely non-acneigemc the penta and hexachlor derivative* produced very severe chloracne indeed. Since Shelley deliberately chose suspensions SQj 5 fifW cF ! < ---- r t & 2 -- 012345674 Chlorine atom* Ha low ax 1000 Chlorine atoms Halowax 1001 Chlorine atoms Halowax 1013 Halowax 1014 F. 1 --Example* ot four Htlowu chlomapthaleaei. 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 acneigemc effect. Hambnck'* in 1957 employing the extremely sensitive experimental technique described in 1041 by Adams et al1 using the inner side of the rabbit ear, had already demonstrated that mono- and di-chJomaphthalenes did not produce chloracne, thus clearly incriminating only the penta- and hexachlor derivatives. This work is strongly confirmed by the massive outbreaks of chloracne HONS 202209 which occurred during the late 1930's and 40's largely in the manufacture and use of electric cables1*1*' **** whose outer covering was a fabric impregnated with pervta and hexachlornaphthalcne it therefore seemed clear that the assumption of stvadily increasing toxicity with increased chlorination had been based on insufficient evi dence. Animal experiments on systemic toxicity had paralleled the xenogenic effects but bepta and octachlomaphthaJene 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 octochJomaphthalcnes are non-acneigcmc but the position with regard to tn and tetrachlomaphthaknes, which invanablv exist as a mixture, is more confusing- Several reports of chloracne from trichlomaphthalene used as a paper capacitor impregnant appeared m the French and Belgian literature m the early 1930's but they do not stand up well to critical analysts. Although the informa tion is incomplete m 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 in certain cases1 V It therefore seems likely that pitch was at fault, a suggestion strongly supported by Duvoir**. It h even possible that pitch may have conferred upon the mixture acneigemc properties not possessed by tii and tctrachlomaphthalencs alone. The presence in some of these cases of a coexistent vesicular dermatitis on the face1*1*, and in others of a photosensitivity** the description of which was identical to that of pitch smarts", 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 tetrachlomaphthalene, 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 Xakauchi'* describing two cases of chloracne in a capacitor plant using a tn tctrachlomaphthalcne wax for impregnation is valueless in the absence of details of the chemistry or process ol impregnation or, more impor tant, of sealing. On the other hand, the same author, although providing no experi mental data at all, exposed rabbit cars to the vapour of trichlomaphthalene for several months and noted the development of comedonc-hkc keratoses and h\perkeratosis. Assuming that the chemistry was correctly reported such gross exposure of the very highly sensitive rabbit car may' represent conditions which are not capable of extrapolation to the human situation. Certainly my own w-ork confirms my opinion that there is no evidence that tri/ tetra chloniaphthalene mixtures arc acncigenic or dematitic 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 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 chlorine atoms per molecule. Extensive enquiries in the United Kingdom lead me to believe that these materials we at present used here for paper capacitor impregnation, only as tri and tetrachloniaphthalene and on an increasing)v 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 possibility of their presence must aiw ays be suspected in chloracne of unknown ongin. When I recently examined capacitor impregnation processes using tri/tetrachlornaphthalene mixtures once again I found no evidence of chloracne. HOMS 202210 83 which occurred during the late 1930's and 40`s largely in the manufacture and use of electric cables1* '7'" 0 whose outer covenngwas a fabric impregnated with pcnta and hexachlomaphthalene. It therefore seemed clear that the assumption of straddv increasing toxicity with increased chlorination had been based on insufficient evi dence. Animal experiments on systemic toxicity had paralleled the acneigemc effects but hepta and octachlomaphthalene 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 octochlomaphthalenes arc non-acneigenic but the position with regard to tn and tetrachlomaphthalenes. which invariably exist as a mixture, is more confusing Several reports of ehloracne from tnchlomaphthalene used as a paper capacitor impregnant appeared in the French and Belgian literature in the early 1030 s but they do not stand up well to critical analysis. Although the infurmation is incomplete in many respects there are various reasons for believing that other factors were probably responsible for the acne tn 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 tnchlomaphthalene itself in certain cases14. It therefore seems likely that pitch was at fault, a suggestion strongly supported by Duvoir*4 It is even possible that pitch may have conferred upon the mixture acneigemc properties not possessed by tri and tetrachlomaphthalenes 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 smarts'7, is probabh 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 tetrachiomaphthalene, although these substances have continued to be used extensively for paper impregnation. Furthermore, ihc subsequent observ ation of vast numbers of workers exposed to various chlomaphthalenes only, has produced no further evidence of Contact dermatitis. A report by Xakauchi44 describing two cases of ehloracne in a capacitor plant using a tn/tetrachlomaphthalenc 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 tnchlomaphthalene for several months and noted the development of comcdonc-likc keratoses and hvperkeratosis. Assuming that the chemistry was correctly reported such gross exposure of the very highly sensitive rabbit car may represent conditions which arc 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 arc acneigemc or dermatitic 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 either ceased production altogether several yean ago and handed over to smaller firms, or make a range of products which does not include chlomaphthalenes with more than four chlorine atoms per molecule. Extensive enquiries In the L'nited Kingdom lead me to believe that these materials are at present used here for paper capacitor impregnation, only as tn and tetrachlomaphthalena and on an increasingly small scale: also in timber preservatives as mono, di. tri and tetrachlor derivatives. Nevertheless, the higher chlorinated pro ducts are stilt manufactured abroad and therefore are available, so that the possibility of their presence must always be suspected in ehloracne of unknown origin. When I recently examined capacitor impregnation processes using tn/tetrachlomaphthaiene mixtures once again I found no evidence of ehloracne. HONS 202211 84 CHLORDIPHENYLS AND TERPHENYLS Whilst the uses of chlornaphthalenes are contracting so the applications of chlordiphenyls in modern technology are constantly expanding They are produced, hhe the chlorinated naphthalenes, by the direct chlorination of molten diphenyl and. like chlornaphthalenes, are mixtures of isomers usually with one material predominating. They weic little used until about 1030 when the Westinghouse Company discotered their great advantage oter 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--octochlordiphenyl The chJorterphenv Is are usually resinous solids and there are also numerous mixtures of chlorinated diphenv Is and terphenyis, most of which again exist as low melting point thermoplastic resinous substances. Chlordiphenyls resemble the chlornaphthalenes in their great chemical inertness and resistencc to oxidation, non-inflammabiiity, flame prooting 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 ate 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 mayor difficulty was to produce strong, thin Kraft papers which were lonically pure. Eventually these problems were solved and large scale manufacture of chlordiphenyl capacitors began in Britain around 1950. pentachlor-dtphenyl was first used for this purpose but it had the serious draw-back of being unusable at temperatures below 0C when it solidified and for low temperature A.C. use paraffins continued to be used. Finally the ionic difficulties of using the greatly superior tnchlordiphenyl as a high voltage capacitor impregnant were overcome and its use is now almost universal. Itecause 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 mcrcaed, their uses have multi plied constantly until todav there arc well over I'W different industrial applications for polychlorinated diphenyls and terpheuv!". A detailed anahsis is thernore 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. \ shall mention one specific use because it has been the cause of the only two outbreaks of chioracnc from these materials published since the 1040's. This is their function as heat transfer agents in chemical engineering41'**. Previous chloracne had resulted from crude and careless manufacture in the early days4* or admixture with chlomaphthalencs. TOXICOLOGY Once again, aa in the case of chlornaphthalenes, their acneigenic potential is similarly dependent upon their physical state and the degree of chlorination. The published work on the toxicology of the chlorinated polypheny Is is small, due largely to the iesser problems posed by thetr industrial uses. Nevertheless their toxicity to experimental animals is greater with an increasing number of chlorine atoms certainly tip to 7. Thus Miller's rats** all survived over 60 days after receiving ten 0 5 ml doses of tnchlordiphenyl on alternate days, whereas Drinker et al.!l killed 50% of their rats with the same dosage of heptachlordiphenyl in less than 14 doses. Unlike the chlornaphthalenes 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 202212 with pentachlordipheny Ls** although this was not to be compared with that Irom penta and hexachloraaphthaJene 5mce the change to tnchlordiphenv I however even this has entirely disappeared1* as I can confirm from my own recent inspection ol tome 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 acneigentc hazard The lesser toxicity ts 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 re hepitotOMC, this eftect also seems to be minimal with onlv lour or less chlorine atoms per molecule as the human ingestion of tetrachlordipheny] in Japan has well illustrated. CHLORDIPHENYL OXIDES Experiments have been made with chlordiphenyl oxides or, more correctly, the dibenzofurancs as possible alternatives to chlordiphenyls. There ts some confusion in ' the literature between these compounds and the true ethers of chlordiphenyls. The distinction is most important for the ethers**, like all such compounds vvhether aromatic or aliphatic, are relatively inert even when chlorinated, whereas the furanes are chemically and biologically much more active. The chemical differences are clearly show n in fig 1 The sv stemic toxicity and acneigenic properties of the chlordibenzofuranes or chlordiplienv t-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 pentachlorophcnoi vuth.of course, various isomers of the lesser chlorinated compounds. They- arc used almost e.xiusively 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 arc prepared by the alkaline hydrolysis of crude chlorobenzene, one chlorine atom of which is replaced bv the hydroxy! group. Because of impurities in the basic chlorobenzenes any single chemical product vvill contain other chlorophcnols and reaction products, the latter varying according to temperature, pressure ami other variations in the chemical processes in use, These variations, as we siiaii 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*1*1, whereas they have little cutaneous effect beyond that of the solvent", but m strong solutions thev 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 respiratory tract, and it is in this state that tbev have produced most of their chloracne, Indeed in large plants manufacturing various chlorinated poly phenyls and chlorophenolt today it is the fine dust of the latter which is the main chloracne producer if it is not most carefully 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 tetrachlorphenatc and ortho (3 chloropbenyl)-phenol sodium into sacks under bad working conditions, again as a timber preservative. Large numbers of very severe cases from sodium tetrachlorophenate solutions used ss timber preservatives were reported by Stingily and Gaines in 19-JO7* 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 typical. Around 1950 the more effective pentachlorophenol replaced the lower chlorinated derivatives as a wood preservative, HONS 202213 ttt Chloracne from pentachlorophcnol solutions has never been recorded despite gross skin contamination Nevertheless one dusts have continued to produce it alwavs in the manufacturing plants. Baader and Bauer in J957* 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 respirator> tract were universal thus impl>mg considerable airborne contamination with finel> powdered matcnal**, Kimmig and Schulz in 19o74i. faced with a severe outbreak of chloracne in a chemical plant manufacturing 2, 4. 5-trich!orophenol and using the technique des cribed by Adams et al in 1941 >, quickly established for the hrst time the vital but elementary fact that whereas the plant's crude tnchlorophenol had an acneigemc effect on the inner side of the rabbit ear painted with 50o solutions in polvglvcols, neither the mtiat reaction product crude 1. 2. 4, S-tctrachiorobenzene nor purified 2, 4, 5-tnchlorophenol. did so even in lh0/0 dilutions ft was therefore assumed that a reaction product of the alkaline hydrolj'sis of the chlorobenzene to tnchlorophenol might be responsible. The residues in the reaction vessels and pipe-work of the plant were so eomple\ 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 Manv interesting facts gradually emerged. Neither true diphciivl ethers nor their chlui mated derivatives were acncigenic or toxic, whereas chlordiphenv t ovidrs or, more correctly chlordj* benzofuranes were potent acncigens cv cn in 'J.U.1% solutions and also highly hepatotoxic, a single dose of 0.5 to 1.0 mgms per kgrn. of tnchlorodibenzofuranc being lethal to rabbits. Finally they found a substance so potent that Oools solutions were stronglv amcigenic4*, This material was the chlorinated dibcnzvl cyclic cthei, tetrachiordibeuzodioxane fts sv stymie hepato-toxicity paralleled its acncigcnicity and O.dfi mums in a single dose was lethal to rabbits Although the position of the chlorine at>ins was not absolutely certain*4, what was thought to be 2. 3, ti, 7-tctrachlor<litxnzodiovaiie was isolated L\ kimmig from the residues resulting from the formation of tnchlorophenol by the alkaline hvdrohsis of tetrachlorobcnzol, and its theoretical formation was postulated as shown in tig 3 '\J Mi M i.i.4.f tstrachlorosemese J.i.S TRlCKLOltOPHE.XOL n "V^cAJ lCZ a1 1 HOLS SODIUM TR1CHL0R0PHEWATE 1.M.7 TEIRACKLOROlINEOOlOXA.VE Fto 3 -Stt| in lomuUon of 2. 34 4, T^ctrkhlortiibciuodioxuf HONS 202214 #7 The presence of erythema and swelling of the face and chronic blepharo-coniunctivitis all suggested exposure to fine chloruphcncf dust, and when this was rectified the chloracne ceased Kimmig suggests that, if not tetrachfordibenzodioxane itself, then substances closely related to it are probably responsible for chloracne, not only from trichforuphenols, but possibly tetra and pentachioruphenuls also, all of which are similarly produced by alkaline hydrolysis and heat from the relevant crude chlorobenzenes The great importance of this classic work lav in its emphasis on the basic necessity of establishing whether or not a suspected substance is still toxic when higlilv purified" At the same time also in a trichloroplwnol plant, Dugois and Colomb in two identi cal articles'* described chloracne of great seventy and with evidence of systemic toxicity in a number ol workers who, without protective clothing, were washing out with hot water the accumulated sodium chloride m the reaction \essels. Twelve years later in the verv same factory Dugois, again m 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 pipework. Explosions suggest increased pressure and possibly heat, factors both increasing the chance of dibenzodioxanc formation. Chloracne in these cases. Just as in Kimmig's, was pro ceeded by ery them a and oedema of the face. Although Dugois' paper was short and without detail or explanation it mentions the isolation of a tetuchlor.ucd 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 matenal is so unusual that one cannot exclude systemic absorption as Dugois sug gested. cspeciaih as malaise, anorexia, loss ol weight and mdkv serum with raised cholesterol and fat were also mentioned briefl',, Nevertheless one cannot possibly agree with Dugois in ruling out external contact, since Lmn-Joncs and Knzek*' produced acne on the labbit ear with onlv three paintings of a <mhj(u solution of telrachlorditM.nnnlir.xjnx. In IOM Blciberg* linked for the first time chloracne and hepatic pur pin ria. again in a plant manufacturing dirhloru and tricldorupheitols for conversant to the relevant phenow acetic acid weed killers In my opinion it is of the greatest significance that there was no direct relation ship between the chloracne and the porphyria, some cases having one condition with out the other. This unique occurrence required an investigation of the same calibre as Kimmig's but unfortunatelv the industrial and chemical information was incom plete and sometimes incorrect. Nevertheless vvlulst prophyria from chlnrophcnols clinically or experimentally has never been recorded** there is abundant evidence of its production both clinicalh and experimentally from chlorobenzene isomers of many' different kinds*', Therefore there seems little reason to doubt that the chlor acne was probably produced bv chlorodibenzodioxanes or similar substances as Kimmig and Schulz had already demonstrated, whilst the porphvna was most likely induced by the crude chlorobenzenes used to produce the chlorophenols. CHLOROBENZENES "What evidence is there that chlorobenzenes themselves cause chloracne ? In fact, very little. Exposure to various chlorobenzene isomers has occurred on a vast scale over the yean both externally and Internally in human subjects*' and experimental animals without causing chloracne. The only cases reported in human subjects were in men who vvere grossly' exposed to the fine dust and vapour of crude tnchlor and hexachiorobenzenes. 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 202215 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 ZeigJer*', feeding rats numerous chlorobenzene isomers, found that onlv !, 2, 3, 4-tetrachIorobcnzenc produced p,itchy hair loss, kcratotic plugging of the follicles and disappearance of sebaceous glands, these changes resembling those of chloracne The other chloroben7encs tested includ ing 1, 2, 4, 5-tetrachlorobenrene Mere without effect. \JS tins rather suggests that chloracne may be produced only bv certain chlorobenzenes, and indeed even b> one isomer and not another. Further research is clearlv indicated There hate been reports, mostly ver/ old', of chloracne from other materials, but none of these stand up to critical analy sis 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 majontv 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*i0 11 ", There was always a doubt there fore whether internal administration could cause chloracne at alt, and if so what part it played in any particular case The first concrete evidence appeared in 1948, when a fat-like substance found in the bomb ruins of Berlin was used to fry vegetables and six people we 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 nock in three cases, the chest and back also in three other;, 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 probablv ingested hexachlomaphthalcne, but the identity of the poison has always been the subject of some doubt- Further support was prov ided by the eventual discovery that the mysterious chsensn *'. a fatal wasting sick ness with hyperkeratosis and dilatation of follicles which had decimated cattle lit the U-S.A. and Germane from 1941-1954, was due to the accidental ingestion by them of penta and hexnchlornaphthaicnes in lubricating oils and greases** and timber preservatives'*. So sensitive were cattle that a single oral dose of 1.0 gram of hexachiomaplithalencwouidkilla'lcwt. cajf 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 1900 This was the report of an outbreak of poisoning due to tetrachlordiphenyiwhich, for three days only, leaked from the heat exchange system in a factory manufactur ing cooking oil. The edible oil contained an average of 3.000 p.p.m. of tetraehlordiphenyl and most patients probably took something Jike 1.0 gram per month for 4-5 months. Apart from fatigue, malaise, and nausea the earliest visible firtUThgs were ophthalmic with swelling of the eyelids and discharge, due to increased activity and #cy*tic swelling of meibomian glands. 113 of 138 cases developed chloracne, which began slowly two months later and developed relentlessly for several months more. A* in Hertzberg's cases the chloracne was most severe on the face and neck but also the genitalia, though leu so on the trunk and-scarcely at all on the Jimbs. In the more severe cases there was often a widespread follicular hy-perkeratosis also observed by Duverne*1 from trichiorophenol deriv atives and from cnlomaphthalenes by Hois** 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 202216 89 most interesting of nil were some non-dermatological findings such as oedema nf all four limbs, peripheral neuropath*. anil bursitis--also repot ted bj Hander and Hauer from pcntaclilorophenol poisoning--whilst tiie newborn tnfants of affected mother* had generalised hyperpigmontatinn and In pcrkcratosis. Persistent hj pcrhpaemia affeetine the triglvceride fraction of the srrum was how ever the most consistent finding It had mill been reported twice before from trichlorophenol by Dugois5* and by Goto who report*d even more severe elevation of serum triglvcerides in 10 cases of pentachlorophenol poisonmg,J CLINICAL FEATURES In almost even report, whatever the causative chemical, the clinical features have been most consistent". ' .:rV*::WP W ;te fer, rr* * ` E w w>. S&;>- FWr 8 --T>p*cjtJ cue uf pitch Acne. The most distinctive and almost invariable cutaneous lesion, usually absent in oil acne and rarely seen tn pitch or tar-acne (Fig, 8) both of which are also more inflam matory, is the chloracne cyst**, skin coloured, v arying from I mm even to 1 cm in diameter, and with the central opening difficult or impossible to detect (Fig. 7 ). II these cysts are absent then chloracne should be diagnosed with great caution, except in early or very mild cases. Comedones and small evsts are therefore the 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 are 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 onlv the more severe cases Acne from paraffinic oils and tar products are both more inflammatory than chloracne. especially the first named. HONS 202217 90 This i* predominant^- facial even when the poison lias been ingcsti-d. tin- nial.ir areas, jaws and behind the cars hemp sites <4 particular prvdilvitimi. In mild i jm-% these areas alone mav lie invoiced. Tlie m"e is irivarulih spared except cchen p.ii<miing is systemic. This distribution is not specific to chlorinated aromatic liveInvarbom but to any acnctgentc fume or dust (>>r, as cce shall see, acne from pm h fumes btliavi s in cxactlv the same ccav, Witli increasing severity the rest of the face and neck S'>nn follow, whilst the outer upper arms, chest, back, abdomen, outer thighs and genitalia may be involved in curving 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, hav e 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 divi ded ** '*". 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 uniformiv negative replv 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 anv substance other than chloinaphthalenes, including the numerous and meticulously investigated Japanese cases of systemic tetrachlordiphenyl poisoning, has itching once been mentioned. Pruritus mav therefore be specific to chlornaphthalenes but without more evidence this must remain speculative. HONS 202218 01 DURATION OF EXPOSURE 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 degree of scarring is naturally dependent upon the seieritj 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 chlorJibenzodio.xanes probably involved. HISTOLOGY Findings in the experimental human subject have been confirmed by those in the rabbit ear canal**, in both cases he.xacliiomaphthaiene being the acneigemc 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 disappearancc of the sebaceous glands, until eventually a keratin filled syst-like dilatation is formed. In some cases the exit is tinv whilst others are little more than a shallow trough. Shelley*' suggested that the disappearance o] the sebaceous gland was due to back pressure but accepted that squamous metaplasia occurred as previously shown by Etsen et al. in 1955". Hambrich" with serial biopsies showed that the disappearance of the sebaceous glands had already begun fixe dajs after the first acneigemc applications long bclore am 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 kcraun lilted pilosebaceous follicle was formed There is of course general agreement that, us in acne vujgans. rupture or 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 be mj self. Dugois'1 claimed success from the intravenous infusion of calcium ethylcnediamine tetracetic acid in very severe cases of chloracne and poisoning from tnchlorophenol 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. GHLORACNE IN A PAPER CAPACITOR PLANT USING TRI/TETRA AND PENTA/HEXA CHLORNAPHTHALEXES 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 tolled up like la\ atory 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 m metal clamps used over and over again by four women seated very close to the drying oiens and impregnating vessels, After drying for 2-1 hours at 115C to remove every trace of HONS E022*-9 92 moisture from the paper, racks of capacitors were heated in a vacuum vessel for 24 hours at I10C and then impregnated with molten tn/letraclilomaplithalene run in from a reservoir. After pumping out the molten wax the impregnated units were removed b> hand, cooled and passed to the dipping section If supply exceeded demand impregnated capacitors were stored by embedding them in the impregnating wax in mei.s! travs to prevent ingress of moisture. When reads for dipping this wax was melted in the ovens and the racks of units removed. Exposure to tn/tetrachlornaphthalene fumes was very gross indeed in this section for the following reasons -- 1, Fuming of molten wax residues at 1I0C 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 unvenniated ovens. 3, Welting out in the ovens, trays of stored capacitors. Nevertheless, during its existence from 1956 to 1863 no single case of chioracne occurred among workers in this section, thus indicating most dearly the nonacneigenic nature of tri and tctrachlomaphthalene fumes. After impregnation the unit was dipped into a tougher wax melting at 1304C and consisting of roughly equal parts of pent a- and hexadilomaphtlialene with 5% pentaehloidiphenyi as a plastiuzer This dipping section was a long narrow area inside the main workshop enclosed bv partitions T 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 m 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 chiomapluhalcne. 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. Thisuasdue to -- 1. Ineffective extraction which in anv case only partially covered the fume produc* tion from the dipping vessels and their electncaJIv 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. Tlw molten wax at 16U;C was ladled out by hand fnto trays, the residue removed by a drain cock under the vessels and triehlorethyiene added, the lid screwed down, the mixture boiled and then dtawn off, The stop cock was closed and fresh solid wax added. Other sources of penta/hexachlomaphthalcne fumes were the evaporation by molten solder of ail 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 chioracne only on the fume exposed side of their faces proves the external nature of the chioracne stimulus in this process. , In 1958 extraction was increased but was still inadequate and no further change Mas 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 chioracne continued to occur, though much less severe!v, 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 chlomaphthaltne. Furthermore wire solderers on piece vvork 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 chioracne producing potency of even the HONS 202220 03 smallest regular fume exposure to pcnta and hexachlomaphthalenes, an important observation not true of the equivalent chlorinated ifiplitnj Is, Alternative materials had been uiged for a long time and finally a mixture of three parts of tri/tctrachiomaphthalcne and one part of polyst) rene provided a satisfactory alternative From the time of its adoption ehloraenc ceased, again confirming the non acne-producing nature of chjomaphthalene with less than five chlonne atoms per molecule. because of the constant variations from hour to hour and day to day, any attempt to relate fume level m milligrams per litre to the degree of chluraene would have been too inaccurate to have had an> practical value and was not attempted. For the same reason tt 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. Fie, 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 nsk would be highly inaccurate and will not be presented. When the labour force had been static for a long tune, however, at my first inspection In 1937 almost even- worker in the dipping section had chloracne. Fig, -4 clearly shows the progressive improvement following the institution of preventive measures at the end of 1937 and again after almost total enclosure of the process late in 10GO. The increased percentage of moderate and severe cases after 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. HONS 202221 M Fig. 5 emphasises the concentration of lesions 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 chloracnc, very mild cases may present a few comedones only. It can be seen that inflammatory lesions e X 8 5 s CQMCDOMt* ONLY CAttt COMECOvES AMO CYST* *0 CASES COMCOOMES CYSTS WlbWHMUMr 11 CASES Fig. 6.--Distribution And type ot lesions in 40 cases ot chtoricne 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. 6 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 Jess than 45% of patients, up to ten ttars 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-appeared. There was scarring of seventy in 10^. ail of them being set ere 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 abote data refer only to penta and hexachlomaphthalene and cannot therefore necessarily be assumed to be true for other cldoracne producing materials. HONS 202222 06 MALL NUMtfftl MiOU*L if 310*9 MitaTAMT TO CONSTANT tCUCC2lt*S WMCN ptSlASC HAD MCN CL*A fQ* $ <' i - Flo 4 -- Duration of cMortcne 9* IS S a PREVENTIVE MEASURES The main preventive measures adopted were based on those proposed by Cranch(l6) -- 1. Complete extraction of fumes (which was never achieved). 2, Neck and unit fitting white overalls changed dad) and cleaned in trichlorethylene, 0. 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. FITCH ACNE I 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 ' virtuallv identical in each senes 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, rmn a mechanical mixer it was removed in large masses like baker's dough on to metal trolleys. They were then removed to thermostatically controlled o\ens 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 weighed on a work bench on kitchen type scales and then beaten with an iron bar. It fumed most MONS 202223 99 strongly during all these operations and the extraction, which u ot poor quality, was high up and onh o'er the work bench. Its effects therefore was to draw the fumes from the beaten dough up into the worker s face, Tume exposure was gross and continuous. The cooling mass was then removed to a hydraulic press for moulding. Despite the wearing of asbestos glov es. wiping dirtv 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 pure!) comedomc 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 comedomc eruptions in some of the older accounts of so-called chloracne from trichlomaphthalenc again points to pitch as the probable hazard in these cases, mentioned earlier in this paper14-**. 0 n COMEDONES 40 fl FAMULCS AND FUtTUCS w 0 VMAIAM ANiAS CAMS 11 n CHECKS CHIN COMEDONES ONLV FOLLICULITIS ONLV COMtOCS ANO FOLLICULITIS H n jj FOMHEAD NECK FOHEAMMS rHiiiHi 11CASES Jl - FlO. I.--Pitch sent. Distribution and type of lesion in M cases The inflammatory lesions although again, as in chloracne confined to areas of clothing friction were, in great contrast, almost uniformly devoid of blackheads, Amin, unlike chloracne, folliculitis was seen in six cases without any comedones at tS 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 202224 07 The main differences from chloracne were therefore as follows -- 1. The cysts so typical of chloracne were rarely ob$er\ed. 2. There was an eruption of pure comedones on areas exposed to fumes without friction. 3 Papules and pustules i,c, folliculitis, on the thighs and forearms were rarely accompanied by comedones but were relatn cly common. 4. In general pitch acne clears much more rapidly than chloracne and scars lc<s but, as with the latter, many men had a few persistant comedones which, despite regular squeezing, were still reappearing even ten tears later. CONCLUSION And now I hope jou will forgive me if I conclude with the obvious. Despite the problems posed by difficult management and industrial relations as I 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 bv far the most important is accurate information on the chemitrv concerned, which includes not only information from the users' engineers and chemists but, much more important, the chemical manufacturer of the basic materials In tins connection the role of contaminants or unwanted reaction products rmi-t never be forgotten, may indeed be critical, ami must alvvavs be investigated** * 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, hut it is astonishing how ofttn in the literature these simple facts have been omnicd"''1. Finally, much experimental work remains to be done. Although the usual warning is necessary when interpolating between the experimental and the human amnia!, a good correlation appears to exist between eenuform lesions proiU.ml by cxtvrn.il contact on the rabbit ear and chloracne m man. Furthermore. a< far as it govs, m the only two recorded outbreaks of chloracne in man from mgetion of chlorinated aroma tic hydrocarbons both compounds have also been capahlc of producing chloracne on the skin of man and the rabbit car bv external contact" 4i. This correlation is important because of the much greater difficult!1 of producing in experimental animals chloracne-like lesions front 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 welt as further investigation into the fascumim; hyper- lipaemia with a vanetv 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. Dubilier's and Plessev in the Capacitor Industry ; I.C.I.. Monsanto and B I.C C Research for chemical information . to innumerable colleagues all o\~er 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 . Inah, D D. Spencer, H C and Rone. V K (1941) The response of rabbiUkin to compound* reported to hav * causer! acneform dermatitis />(:<,,> !// _v. -rg 8 I t. Baader. H, C E X' and Bauer, H J (19511 Industrial in toxica cion due to Pcntachlorophenol Induelr Med Surf 80. i SS 3. Bettmann. S (1901) Chlorakne. erne bcaondere Form von ptofcwlonelier Hauterkrankung . Oluk. mid. Itdcfcr 8T. <37 HONS 202225 t B*B. 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(1956) Acne rhlnrique du 2-4-5 trichlorophenol Bun Sot franc. Derm.Sypk <3. 262 and Lyon Mti 1057 38 909 21. Dufois, P-, Colomb, L and Favolle G 11957) Vote sur l'actiriti dtt treatment cbtlateur darts I'acnOchlonque Lyon M/i 188 174 22. Dussart. L. (1946) Aenf ehlonque, dermatnse profrssionr.elle Arck beigei Dtrm 3. 216 23. Duverne. j , Thivolct J and Dfrarri J (I964i .tend chkmque profuse tu\ epanchvmcnt pleural rdcidivant chee un sujet A reactions tubcrculiniques ad|atives. Bull Soc franc Derm Sypk 71 649 24. Duvotr, M (1934) A propot des dermatoses pmfestionnellet par le tnchkironaphtaline Ann.MiiUt 14.539 25. Eiaen, A K. Holyoke. J B and Lobstt \V c 11915) Responses of the superficial pr>rtm ol the human pilosebareous apparatus tn controlled injury J iu. ft Derm 28. 145 28. 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Aencfonn deroiatergori* .ink Derm U, toil 44. Kelley, E F (1043) Arne from sjnt'n.tic '.'.it (Ualoi'ac (Hi) L rot e Man Rtf 47. 238 48 Kimoitg. J and bcliult K H (I9r>*( lleru (In. he \kno (*og Chlorakne) tluich chtonerte aroiaetuche t) Unche Athyr Dtm uln/ecira, 116 '>40 44 Ubnint, W (1803, t bcr Chlorakne -tfli Derm 5i/>A 77 2C."> and 373 47 Linn Jone*. E. and Kruek, H (1062) A technic (or testing aenegtnic potency in fahbiti Applied to the potent acncgcn 2, 3. 7. d-tctrachlorodibenio-p-dioxin J inter/ Derm IP.811 48 He Mattel* F Pin romm united on 40. M*jer M R end 5d' erberg, M G (1538) Skin conditions resulting from exposure to certain chlorinated hi drocirbon* J ri\t 20 244 80 Metg*. J \V, Albotti J J and Kartin, I) L (J904| Chloracnt Irom an unu*ual etp^rure to ATOdoHRl J Amtr ird All 184,1417 81. itenon. I. A. UPSS) Tropica! hazard* as Jucjated with the u*e o( pentachlorophenol Be>` mti J. i, 1188 62, Miller, j \V (1944! Pathologic change* m trnmtli expoicd to a commercial chlorinated diphenyl U S P r61 Henitn Pep 89 I hS '> S3. Uonnanto Techn Bull O-FF I on arocior >B'* polvchlonnated pnlvphcnyl*. 84. Kakauchi, Y. (10401 Hie sog I'ernakrankAcit und ihre Lnitchungiu me jap J Derm I'rol, 44,87. 88 New|ioue, M (1007. Cldoracnc Tram ir Jckn's Hasp Derm Sac 63.108. 38. Newman. M Pets ('einwiiinra/iaii 87 OSa!*on. P (1947. U\ oerkcrato-'W (X disease) ol cattle Cornell Or 43, 135 88 Patty. F. A (1903. Imlutirtal Wigirne and JeueolOfv \ol 2 2nd Edition. Neiv York. tnterjcience Publ p 1401 ` 89. Prouer White R (1034) The Drtn.atirgoses ttr Oanpahonal Affettitnis of Ike Skin, 4th Ed London. H K Lewi*, p 222. 40. Puecinnelli. V (1004> Dell acne chlnnca Verf rf / tore. 48 131 41- Quinone*. A. (1981) Do* case* de acne profcnonel por < ioronakaleno Aft itrtuo-nfihefr 44, 830. 62 Rltnington, C and Ziegler. G 1198J1 Experimental porphyria in rat* induced by chlorinated benrene* Bier*r> Pknrmaeel 12 !3h7 63. Schmid K (I960! Cuiancou* porphyria in Turkev Nett Fuel / ,1/rrf 243 39J 64 Schult. K. H 119S*i Klnutche un<! expcnmcnteilc Lntenuchungen rur Atiolosic dcr Cblor* akne jerk ktm eip Deem 204 '.CO 66 Schwartz. 1. (1043. Outbreak ol (lainwax ini ..ne (cable rath) among electrician* J Amtr m*rf..4ir 122.134 66 Sehwartt, L. and Terk S M (1943) Occupational acne V l1 Nr /.1/erf 43. 1711 67 Schwartz. L 11030 Drrmatitu from xvnthrtie rem* anti im ,4mer f pobt lllik 28 688 66 Schuartr L and Barlow F A (194-'i A blnm. ne fr..m cutting oil* f'6 l(toi:k Pep 57 1 747 69 ASrllei. tv u and hhgman. A M , lS7 1.iptrimcntnl production ol acne b; I'enta and Hetachlorcir'ithalee.ci Art* (nn 78 0*9 70 Sosatle. K O l'J4-' 4 c*ir !-_st-i*K!:eir:r3:dert8at:';.x S'/A jwerf / 33,1264 T1 A_"err"." 1-7 ? '. IV = lisrwc -t ' -ro aid Aider: ,4*re1'mm 33 I'i-'J 7* M r vas r.-nre'-err A yt* * --'stirs, caro~s.< t t't 34 i'i 73 T*lekt* L IVJ7 Lne Peraaiffankheiv / ,-t. il nt 4. r-4' ' 74 Teleky. L. (1637 the Pemakrankheit itu 4. e97 75 Telelrt-, L (19JM Die Pernakraalcheu A7m H si At 7. 214 M. Teller. K (I447i Tmubodermie nach Genn*i ^ot wahrtchemlich cblonertem MictraHeti Artk Derm S\pk 144. 44? 77. ThetwmU-J dm*. A (1841) The aettnlog y (acne with apecial rclerence to acne of occupational origin. J.inistttr H\f 23. M0 74 Thymion, N. (19491 Caaee ol occupational acne. Act* derm vtntetol. 34. 611 79. \Vapener. K. (19511 H> perkemww of cattle in Germany J Amtrvttmti An 119 133 40. Ward, A H. /I956) ItU CAemtMrjr surf Ttckncleiy of It'am. New 2nd Ed, Remold Publ. p 433. 3], , 63 43 Waiter, V. (1916) Gewerbliche Erkrartkun|en durch gechlorte Koh)enuai*erttofie ZU Gewirbekyf. 6.100. tVUkineoei. D, S. (1964) Chloracne from pretenativn in timber Contact DttmaltHs \tusUntr No. 4, London. St. John1* Hotpital lor Dumei ol the Skin p 74. Stk. D , \Viee, J C. and Bridget, At E |19S2) The experimental production ol "N ii*ea*e'' (hyperkeratout) in cattle with chlorinated naphthalene* and petroleum product* J-Amet.sit.mfd.Ais 141, 337. * (B) Trad* Mark of Monaato HONS 202227