Document b5wajnKnXzM998v3XQ5yremm6

OCCURRENCE OF ACNE CHLORINA AND PORPHYRIA CUTANEA TARDA DURING THE PRODUCTION OF HERBICIDES . The a ttiri suVxlt i!ier sa cvslaitia cf dsU .vjwrlej hi i t i l<tcratere m u lta c? th lonx-laa fati.* tip ot 71 (.lucri* wali ca eeeciuiiaeal ditea*r ertaci Ljr ama. a /etere ci t i f i c i Je t --- i-col.isiJiupbf iud and dirir i i ve e! 7.1.5 * *iL; c e l l o : i t u c u t t e r 74n*J=cu teUerdi /re a t i r e < ili-n u tiiA ric d le o l i c u c i y I scip tjr a e ic c e * ed la ( e r e ; c u r i h / U r;c cp ii. cl.cciu.-i ad rulrtiog u n a - v c a Ci tvfcclo to if . I t a t i r i c i die!cal pictero Js decsettratei ea p S ecy rifii. XWair* * va! i t i p s t i c t i - i i i Leparie fole* * l sj-e:picei ci parpbprU esibita, tiri* . t 4 ` f parenti l u i nerveti a i c*U l dt-ordcrc. . # .* | Il v i i talaalei thst th akta c z i (ocarcValfecCocs vere e s c iti 3f5A74tU*> cldnfedftinxadtaxta-vhtcb 11 fonu4 *dcrlnj aikc!tri-Itfdrblfsli`cf tim ellorcbrctaajf late tsdiua txtcHttc?tisUta. Tfcj ru stie t u pertoemei b / i q j c a r i l i i i grocedosV p t 1 l ex penici e t I5J*C ai p m n c i 45 tu. f i c a th Ksrk et S tin lr c a i G a n ti" U li K m i ib i tu* tooc r c d i a t i Ci noi te m e i e tic i i te tor n a tilo U orrleJ o d t i la -rr tca|< ntci ( U V C Kd tip ortica c a ^ d la pradu tira ef t c A i t i s i tvcre sJUxic bei else r u l a t t r a a cestire. rcsearch ero tte i d orber liv e ; ite duucl 1 tir li.-: C :m i3 te tr o <1 u n te *s!*r dcremile, ]a c3 fc* rcsateder tt s tiric i fcy e rio* cr-pLra e/ c e x rte tin aed tfcctr dcvclogosel tata eptet. ta rta n iratl/ra an i c i s i t c j h-crt iz jzd cslp la ih* n o ti severe and estensive aftectteea. I t a sita a n i Clinic! caclfctim sss csrmposdcd bi dau rti-orted U th lucrata*. la 17 pattcnU. fcs-.vsvcr. a s ti ctTcrld rLrrUd t a sneturl wap fcp prpalcprttulocs cnpUacx c a 0 crirea: L o. la 24 p ru n i tha esthsrs cUrsrvcd teceUtitlea la tha alitile v tid i va net reparto! prcrtstiir. 71:5 dlsrase dses t e i elicci tha 1117 part oT Ita l tn 3 and 1 oca pausai 1: i r r e t i r c i even I r t a th a s ite la ita .lite and ea th sctic Etera he j r c e e Vrcid. ubile t b cooditlaa pcrUcd at ber O tti, faucsls xtuk a tcp aln d pary'-rrin sscUislisc s b ir c i tre n T jptiJ fcppsrptpscsiaUsa a n i hr?=trtehco* end cniy esc ci i h to s i b ctiO i s e lla la t i ten t i l iIca. IlrpcnnchoOi c=d hTpcrplcocst- Ocn w i o i::n r:i c b j la 17 svh^ca Uh acne libati izhattiary s= s of p - ^ ; d t la th: perled porr la tlx d iirs a ca O ccu ltiti rrcitopaticc Xaoati r e e nasci. TT.r ! ; t r : : r .'t i l la. u rie InOance teiere de=3latclcti sad t o m i dasapc da* Yclbpcd d i e Oicr: crresare. la e l x r l&Oeaccs a s c i c i ] / ls= end c u c ite c i p s e i e a e c i e r i; rrCl s>=:ptict. U a ;j:e Ibis th a c th c i are esaossed C ti zha inic z iiif ni ite (Licer d tp ccti o : .e co C ip e s v i b i prcdc^etica. Tha psiiccts hrd Ttiicu corspTri^u-ssorth^ r : : r : j eud s e n ti and ncsar t i U*X3 h=d ecasidcsclde-etichi IcsrcJL Tura i t : i I.* tesevi] laicitialicn, lu-a t e a fa r; crrrcr hai sa far C xs u t jp ctiilc 10 rais .*L*:!r'.!p h=:sir 11 a i rclcled ta rLc cm>|i=anarl cjparure. S e c a n m c ^ a ic riicti t i thteritiicS haCicrwbesi peducci la Ha partlrclrr piati ca s=t p e t i s far. lh= e t i t i t i AscraU'fteti t p p u u v i i li* Utiacscd b j U i x d b a s la cresi no^c. All p a tis ti eie t t i r * .#ellaa sj c f 1 catiahnntKa mh xpcstatists ta lato c a l tcctci=c end a r.cvec!r"tv*. Atcx tha peak t e i luca r o t i c i -- ascallp efisr 1--2 pcnea defalca -- tha diserte rserJs veiy sleadp. la ssu e p i t ic a , bs^evc.% th c e r j r t i tp rp tic * c i-c re m i latiite iO ti p e riti alrtcdp ler 1 prcn. U ttira p a tiC c c tir d i p s i c i l;u:a ciicrCve. A cenila trsprercssct a t hp repdar e-iy-'i-*- Oeo of c : e r i r r a ani eleni, la SU priirurt ercczlary prcreciloa as trcah- ^ c c t a r i diuaces la ccruiLacca 10 lepri p m n sim , pAgs 2 part I During the years from 1965 through 1969# a chemical plant producing herbicides - pontachlorophenol and 2,4,5-trichloro-- phcnoxyacctic acid derivatives - reported a mass outbreak of acne chlorine. The number of persons stricken, 78, is one of the largest ever recorded. Furthermore, some of cur patients were also stricken by a complete intoxication manifested by liver* lesions, by a deficiency in porphyrin, fat and protein metabolism and by nervous and physical changes In tvo cases, the i n t o x i cation was fatal. This part of the research will deal primarily with skin symptoms and the internal and neurological changes will be discussed in a subsequent work (23] and in more detail la * another work [32]. The acne forming dermatoses are caused in most cases by crude oil derivatives - known as acne oleosa - and less often by tar and its derivatives - in these cases it is acne picea. In contrast to those acr.es, acne chlorine is relatively very rare because it is only caused by a small number of certain chlorinated hydrocarbons which are produced and used only on a limited scale. Acne chlorine also differs from other acne forming dermatoses by its localization, clinical picture and course. Hass- occurrences of acne chlorina have been recorded during several time periods which are separated by decades, in accord with industrial and chemical development and with the gradual introduction into production of new chlorinated hydrocarbons. The first cases were described by Kerxheimer [18] in 1899 in the electrolytic production of sodium chloride and sodium hydroxide from brine. Herxhe icier assumed that the illness was caused by the inhalation .of chlorine and by its excretion through membranes and he therefore named the disease acne chlorina, i.e., chloracne. The French authors Thibierge 43,44] and Eallopcau (16] were of the sane opinion as to the incidence of this disease. Further more, Ilallopeau thought that the black coloration of the comedones O' - K 5 IS tv Vi tjr-. m w-i .3 h- : r-rX-."! & "<i r " f-; t*` r t 'H L~ 1 i Ml*" Pag 3 was caused by some lead compound that formed on tho chamber*s lead walls as a result of a reaction with chlorine. Renon 135] also connected chloracne with lung tuberculosis in one of his patients and ascribed both diseases to gaseous chlorine. However, Hlrsch (20] concluded in that sane year that the cause must be a solid substance which forned on the anodes during electrolysis because exposure to chlorine gas alone did not cause the disease. This finding was supported by Bettnann (2] who ob served 21 patients who were engaged in the production of hydro chloric acid and who were in contact -with chlorinated tar cocapounds but not with chlorine gas. Lehmann [26], in 1903, 'concluded that the actual causes of the * disease were chlorinated products such as haxachlorobenzene, peats-- chlorobenzoic acid and hexachloroethane which forned on the car bon anode during electrolysis. Because similar cases of acne I chlorine were also observed in the production and processing of pI nitrochlorobenzene, W. Lehmann [27] concluded that acne chlorine i was caused primarily by chlorobenzenes. As soon as carbon anodes | were replaced by magnetite anodes, the incidence of acne during i electrolysis ceased. Before Korld Kar 1, Wahle [46] observed acne chlorine in two chemists which was probably caused by a chlorine compound - phenylene dioxide - not identified or known in more detail at that time. * .. i The next wave of the disease's incidence occurred at the end of Korld War I during the production of chlorinated naphthalenes or pcrchloronaphthalenes. In this-period the disease was given an additional new name - Pernakrankheit (Wauer [42]). Chlorinated naphthalenes and diphenyls with a waxy consistency, also known as halovaxcs, have some very valuable properties such as vaterproofr.css, flame resistance and acid resistance. These properties earmarked these materials for the production of protective gas nasfcs and other military equipment. A new increase in the incidence of the disease occurred in the nineteen-twenties during the use of chlorinated naphthalenes Pag 4 as an insulating material in the raining industry (Telcky (42) ). Acne chlorina also appeared in the electrolytic production of chlorine when insulating coatings of tar vero used. This fact brought about numerous disagreements and questions as to whether % tho disease in those production processes was not actually acne picca. On the other hand, Telcky supported the contention that the tar acne could be caused by chlorinated hydrocarbons contaainating the tar. The excellent dielectric properties of the chlorinated naphthalenes Chaftax", "halowax", nibrene") led to their vide utilization in the production of cables and condensers and another nass occurrence of the disease was produced in the nineteen-thlrti.es when the U.S.A. and other countries recorded hundreds of stricken individuals. Holtzmann [22] also noted the occurrence of acne among the family members of workers employed in the production of. condensers. These family members handled and washed work clothes contaminated with the chlorinated naphthalenes. Based on these observations, Holtzmann corrected his previous original conclusions and stated that the chloracne was actually tar acne and judged the effect of halowaxcs to be that of an external acnegenic cause. Orrasby [31] observed acne chlorina with the use of a fungicide used in the impregnation of lumber (sodium tetrachloro-o-phenylphenolate). Jones and Alden [24], Schwartz [39] and later many others also observed total disorders in their patients and Fllnn and Jarvik [8] noted a death due to yellow liver atrophy. In 1938, Kaycrs and his ccvorkers [28] were unsuccessful in clarifying the mechanism of occurrence of dematitides and acne chlorina in their patients with the aid of epicutaneous tests -- the tests were nega tive. During World War II, chlorinated naphthalenes were used for the impregnation of ships* hulls when it was discovered that these substances could protect ships from damage of magnetic mines. The use of halovaxes increased significantly, especially in the electi on 1 industry. American authors gave acne chlorina another name, Paga 5 xicauca of tha occupation (cable production) of the and coworkers [14], Schwartz [40], Morris [29]) aassive outbreaks of acno and several deaths were 2t World War II, the incidence of acne did not sub- r \a undesirable experiences with the chlorinated Id not prevent their use in the electrical industry An interesting observation was recorded by Herzberg He observed seven cases of acne chlorina in patients id chlorinated paraffins in the form of a food iis prompted Herzberg to conclude that acne chlorina sr the internal ingestion of chlorinated hydroLarly, Fuchs (91 also noted the affliction.of three leir mothers after they had eaten potatoes fried in Hinkler [48] recorded 10 cases of dermatitis and \e chlorina among 23 workers in a condenser factory *ne in the production sequence. From these cases led that "chlorinated hydrocarbons cause the forma ts that in turn cause an Increased secretion from inds". In 1949 Gavrilova [10] warned of the photoaffect of polychloronaphthalenes.' In recent years, replaced chlorinated naphthalenes in industrial use. / the production of sodium hydroxide may be a source 1a. He have observed more cases between 19S0 and i causes of acne chlorina in these cases have been i of chlorine gas with the hydrocarbons in the .tar itings on the electrolytic containers and tubs and il oils which were used to protect the electrode authors noted several cases of acne chlorina among -cers after the use of nibrene in the electrical a 1950*8. re, the acnegenic effects of the mineral oil based -s used in metal working Increase when chlorinated re added. Therefore, some cases of acne oleosa were exhibited a partial acne chlorina character (more rruthe Jos. 5*2 W ` a nong verni da ion di d thors .ge to dlf' i.e. , i9 :ed r ib- acne '*SR? w }; tr phenol to 1 ~ Paga 7 disorder of tho liver, kidney, myocardium and nervous system. The author described the death of a patient from necrosis of the pancreas as a special case. Furthermore, he also obsorved dermatitis in a nurse who had had contact only with experimental animals. Finally, ho diagnosed acne chlorina in the fourteen year old son of an employee whose disease was contracted only from the household environment - by wearing his father's con taminated scarf and by using his father's towel. Actual observations The process called POP (pentachlorophenol) which caused mass damage In Czechoslovakia was, as far. as production is con cerned# identical to the process from which Kirnaig and Schulz drew their patients for observation. The final products of this process were sodium pentachlorophenolate, 2,4,5-tricholorphenoxy -- . acetic acid and the latter's sodium salt and butyl ester. The primary raw material was technical grade trichlorobenzene which was produced in a neighboring building for the production of hcxachlorocyclohexane (HCH) and lindane. .The table shows the entire production scheme (Table I). The chlorination of trlchlorobenzcne produced tetrachlorobenzene and hexachlorobenzene. Sodium pentachlorophenolate was formed by the alkaline hydrolysis of hexachlorobenzene. Sodium trichlorophenolate was produced by the alkaline hydrolysis of tetrachlorobenzene. The hydrolysis of tetrachlorobenzene with sodium hydroxide in the presence of methanol took place in an autoclave at 190*C and at 45 atm of pressure for one hour. After cooling, the methanol was distilled from the hydrolysate, the hydrolysate was diluted with water to a 25% concentration and it was then syphoned into a storage tank. The condensation of sodium trichlorophenolate with monochloroacetic acid produced sodium trichlorophenoxyacetate. Following cooling# centrifugation and flushing with water, the dried sodium trichlorophenoxyacetate was picked out by hand and placed in small barrels. Some of this product was used to produce the butyl ester of Pago 8 -u sm arjT-q *--3 trichlorophcnoxyacetic acid. This production took place in another building. The production of both the primary products took place in a four story building with grated floors (WEKA grates) which was one reason why the entire building was contaminated with the high risk substances. The building was not sufficiently airtight# the local exhausts were in most cases improperly installed and hernctization and mechanization were insufficient. Initially# ihe sodium tctrachlorophenolate [sic] was escaping from the centri fuge into the work space in the fora of a mist. A series of tasks such as the removal of solid substances and the pumping of ' liquids were performed by hand. The workers were dressed in linen work clothes. The thorough cleaning and frequent changing t0 of the work clothing was impossible to guarantee over the entire interval of production. Rubber gloves and respirators were used at some work sites. The conditions surrounding the production of the butyl ester of trichlorophenoxyacetic acid were the same as those described above. Kimnig and Schulz [25] found that the main source of acnegenic hydrocarbons was that segment of the production process in which sodium trichlorophenolate is formed by the alkaline hydro lysis of tetrachlorobenzene in the presence of methanol. A coworker of these authors# Doctor (of Chemistry) Sorge# had de duced on theoretical grounds that if this reaction were conducted at 190 *C and 45 atm of pressure# chlorinated hydrocarbon by-pro ducts such as polychlorodibenzo-p-dioxines, polychlorodibenzo-- furans# polychlorodiphenyl ethers and polychlorodiphenyl oxides may be formed in small amounts (Schulz [36]). Sorge also pre pared seme of these substances by his synthetic process. Animal tests carried out by the authors (Schulz and Kimaig) with tetrachlorodibenzofuran and 2,3# 6#7--tetrachlorodibenzodloxine have proved an extraordinarily high toxicity for these substances. A simple smear of a 0.11 solution of tr i-- and tctrachlorodibenzo-- furan on a small area of a rabbit's auricle caused heavy liver Ivase* * P*ga 9 * damage and death of the test animal within 2 to 3 weeks (Schulz (361). 2,3,6,7-Tctrachlorodlbcnzodioxino, which also has very strong ncncgenic effects, was proved to be far more toxic. Only then was Dr. Sorge successful in the identification of this enormously toxic substance in the production process and in the final product. He proved that this toxic substance is forced only at certain temperatures and pressures. If during the alkaline hydrolysis of tetrachlorobenzene to sodium trichlorophenolate the temperature is reduced below 153*C, the toxic substances do not fora. However/ at this low temperature/ the reaction time is extended from one to five hours and the productivity is ob viously lover. Furthermore/ it was proved that the condensation of two nolecules of trichlorophenolate to give tetrachlorodibenzodioxine is an exothermic reaction. Several explosions of auto claves with injuries and the lethal intoxication of workers were reported to be the result of this reaction in the German Demo cratic Republic (East Germany) (Schulz [38]/ Goldmann [11/12]). Tctrachlorediber.zodioxine was also identified in the Czechoslo vakian production process and in the products as veil. The first two cases of acne chlorin were noted In 1965 in two technicians who operated the production machinery. It was as sumed at that time that these two cases were caused by careless work and an undeveloped production technology under semiproduction conditions. After one year without a reported case and during which production was temporarily halted, a mass outbreak of 78 cases was recorded within the following three years. Finally, after a detailed investigation and study of the entire problem, the process was terminated and production ceased in 1968. KOrkers .from all stages of production were stricken. At that time, it . was impossible to determine which production stage was the most risky because most of the workers were involved in several stages at various locations in the plant within a relatively short tine. Workers directly involved in production as well as maintenance per sonnel and workers digging sewage ditches were stricken. Later, ,,a research scientist working to isolate the ecnegenic ballast js 4 --*3 t- r*' ti * PJ -: f l.:t'- t *1 .-*/-- * Pago 10 substances from the products of the individual production phases was even stricken. His research work was carried out outsida the production plant in a research institute's laboratory. In addi tion to the 78 patients with dangerous symptoms of acna chlorin* or porphyria# other workers in this plant had symptoms of acne whLch were# however# symptoms of juvenile acne or of a similar' character and could not therefore be counted as an occupational disease. With the exception of two female laboratory technicians# the patients consisted of males from 18 to 57 years of age (4 persons below 20# 46 persons from 21 to 30# 11 persons from 31 to 40# 10 persons from 41-50 and 7-persons from 51 to 57). Therefore# the acne chlorina patients, were mostly young people. On the other hand# core than half the patients with porphyria cutanea tarda were older than 40 years. Generally# the disease followed a normal course as described ' by other authors. In only six patients did the diseascT'begia sud %denly as acute solar dermatitis# i.e. # by erythrema and edema in regions exposed to solar radiation and continued by acne sym ptoms (Photographs 1 and 2)# as observed by Goldmann (12]# Grimmer (15]# .Braun (6] and before these authors, also by Touraine and co workers [45]. Therefore# chlorinated phenols in some cases have similar'photodynamic effects as the chloronaphthalenes described by Gavrilova [1C]. Erythema and edema in these patients were obvious cainly on their auricles. Sometimes# small blisters in thick groupings were observed there. In all the other patients the acne developed slowly. Among the less severe cases the disease was limited to single or densely grouped comedones# ccr.ditoned by follicular hyperkeratosis# which were so small and sometimes so numerous that they appeared to be a slate grayish-brown color#, like dirty spots on the skin. These symptoas were noted cainly on the face# with maximum occurrence above the cheek bones (Photograph 3) In the more severe cases# the comedones gradually developed into small white cysts simllax ` > f .r i ""*,f`ll">a11 I-- Pag 11 to nilia# although with black centers# and into largo cysts ranging frost the siza of a pea to that of a nut (Photographs 4# 5 and 6). As opposed to other acne forming dermatoses# th described symptoms and manifestations mainly lacked signs of an infection. Only in the more severe cases and rather in the vici nity of large cysts were some reactive inflammations# infections and abscesses noted. The emptied- cysts and abscesses left behind large atrophied scars with raised edges and with bridges of intact skin under which a probe could be inserted (Photograph 7). This basic clinical picture was supplemented by diffused hyperpigrventation in the face and by papulopustules on the torso and .ex tremities. Patients who were found to suffer from a disorder in porphyrin metabolism had symptoms of porphyria cutanea tarda in regions exposed to the sun (hyperpigmentatioa and hypertrichosis# blisters# excoriation and small scars) . However# in this grot* there were two patients with prophyria but almost without any acne at all. Histological investigation Is not much help in diagnosis. The symptoms begin with hyperkeratosis at the mouth of tbs follicles. After one to three weeks# the follicle changes into a cystic for mation filled with a h o m y substance [keratin?] (Photograph 11) and to.`a small extent with sebum. However# the epidermal changes are small. After the rupture of the full follicle# the contents of the cyst penetrate into the surrounding tissue and a granuloma of foreign bodies forms around the area (Photograph 12). . The disease normally starts on the.face above the cheek bones. However# in 17 patients the disease started in an unconventional manner by papulcpustular eruptions on the extremities# primarily on the lover extremities. This characteristic# resembling' more acne oleosa# remained in some of the patients for the entire dura tion of their illness. The cost common localizations of acne chlorine were the cheeks# temples and to a lesser extent# the entire face." Eyebrows# eye lids# the perioral region and the scalp and hair area remained free. Paga 12 Other prcdilccted area were the auricles, the back of the neck, the back and the chest in a seborrheic localization and the genitals. The auricles and .genitals and especially the scrotum were stricken by the formation of large cysts (Photographs 8 and 9). Among the five most seriously ill patients, the disease spread all over the body and had a discouraging effect that was heightened by the disease's usual persistence, the long term healing and by medical helplessness (Photographs 10 and 7).` The contents of the cysts produced a repulsive and rancid odor. For some of the patients the disease disrupted their social and family relations and caused severe depressions. Some authors, such as Braun (6], emphasize itching as the initial symptom, but we noted this symptom in only three cases* In 20 patients with extensive symptoms, the occurrence of pustules, cysts and abscesses was also noted in axillae although this location was not mentioned by other authors. Because of the great number of follicles in the axillae and the similarity of the axillary skin to that of the genitals and for several other ^ reasons, this finding appears to be just as valid as localization on the genitals and the genital area. On the other hand,' it is surprising that acne chlorina does not strike at the hairline or scalp'. In the case of one patient, the acne symptoms disappeared in the facial areas when he grew a full beard while in other areas, the symptoms continued without a reduction in intensity. So far there is no explanation for this phenomenon. Hypertrichosis or hyperpigmentation or both were determined in the faces of 19 patients without a laboratory diagnosis of a deficiency in porphyrin metabolism. Blciberg (3] made similar ob servations. These symptoms receded simultaneously with the healing of acne chlorina. More younger persons suffered from acne ct^lorlna than older persons.* This study group contained 50 persons (851) below 30 Translator's note: Beginning of this sentence illegible. Pago 13 years of ago. Hovever, this fact cannot bo used as a hard and fast rulo or to support the findings because tho production plant under study employed mostly young workers. The preillness medi cal history among the patients did not indicate any significant predisposing factors and no incidence of serious illnesses, intoxi cation or etiolation*. Furthermore, no relation to hair color, eye or complexion color, to the degree of body hair, to the per spiration of skin oils or to hereditary follicular hyperkeratosis and other skin* diseases vas noted. Only one patient reported a more severe prior case of acne juvenilis, 12 patients reported mild cases- during puberty and 14 patients reported only insignificant acne juvenilis symptoms. 18 patients also had some infrequent con. tact with mineral oils either during the appearance of the symptoms or at some time in the past. * These patients were mostly involved in maintenance work as mechanics. However none of them had ever had an oil acne in the past. Their illnesses following contact * with tetrachloredibenrodioxine vere of the same character as the illnesses of the other patients. Their diseases were not similar . to acne oleosa either In appearance or in localization. The latent period from the initial contact with the risk substance to the appearnace of symptoms vas quite varied. Some workers became ill after exposure of from several months to several years and the disease in their cases vas rather mild although the indications pointed to a massive exposure. In other cases, severe damage occurred after a very short tine of several weeks and after an apparently small exposure. For example, one of the most seriously ill patients worked under the semiproduction conditions for only two and a half weeks before the outbreak of the disease (acne and porphyria cutanea tarda) After that he had no contact, with the risk materials. It is not clear whether individual predisposition or the level of personal and work hygiene is more responsible for the intensity `Editor's note: This nay be a dubious choice. The Czech *ety lisura* transliterates to "etilism". Paga 14 oi dnnago or latency of the disease. Most authors discount individual predispositon. However it is believed that the deciding factor must be the degree of actual exposure which is undoubtedly dependent on a series of other factors such as work discipline, personal discipline, adherence to preventive measures, frequency of changing work clothes and undergarments, the degree and regularity of hygienic decontamination, work site order and cleanliness, dust in the environment, etc. . These patients also had a series of subjective difficultiess tiredness, weakness in the lower extremities, muscle pains, sleepi ness and insomnia, increased perspiration, lack of apatite, head aches and.other disorders in the mental and sexual spheres. These complaints were more recurrent and more intense in patients with the more extensive'skin symptoms. In more serious acne cases, a. significant weight loss was also noted. It is our opinion that all these difficulties and symptoms are manifestations of a rather overall intoxication than of only the acne chlorine. All the patients were admitted to a dispensary. Regular examinations of their dermatological, internal and neurological conditons were arranged. The patients who were still working were transferred to prevent further contact with any acnegenic factor. All contact with chlorinated hydrocarbons of any type was prevented even with those 'substances whose acengenic effects have not been thoroughly proved. Furthermore, all contact with mineral oils and tar and its products were prevented. The application of mineral bnced ointments was discounted for external therapy. The plant's medical doctors were cautioned against prescription of any internal medication with an acnegenic effect (iodine and bromium preparations corticoids and others). The patients were given detailed medical directions concerning their dally regimen, perso'nal 'and work hy giene and secondary disease prevention and treatment. All available medications for acne were utilized in the treat ment. The expressions of comedones and the pressure relief off the contents of cysts and abscesses necessitated many periods of Pag 15 hospitalization and special ambulatory treatment hours attended by a specially trained nurse. No special results were observed as a result of repeated hospitalization. The best results were noted after the expression of comedones by the use of a sauna constructed for the patients by the factory on the author's re commendations. It was not possible to test the effects of vitamin A acid (retinoic acid) which has been praised by some authors In the medical literature. However# in agreement with the findings of other authors, it was determined that no local or internal medication exists which has an effective and permanent healing effect on acne chlorina-. Some of the patients have been under observation for eight years and their disease still persists Dr. Schulz's [33] patients have manifested continuous symptoms for more than ten years. Goldmann [11] has now been treating on patient with comedones and cysts on his penis and scrotum for 18 years! In most of the patients discussed by these authors# the symptoms and manifestations of the disease progressed and reached a maximum after about one year# even after transfer of the patient from the high risk work area. A regression takes place after tw> or three years at the earliest. In some isolated cases# the pro-- gross of a mild course of the disease was observed even after five years. However, the regression of the disease in all the patients was very slow and# it may be said, even lasts a number of years. Of the 75 patients treated by the authors# 76 suffered from acne chlorina. Of these, 11 simultaneously had hepatic lesions with a deficiency in porphyrin metabolism. Two patients did not have acne chlorina. One of these two had porphyria and the second one died in 1966 from acute Intoxication* Pentachlorophenol was considered to be the cause of death in that instance. When the toxicological analysis was carried out at that time# the investi gators were unaware of tetfachlorodibenzodioxine anc$# therefore# it is our contention now that in that case, this highly toxic substance was primarily responsible for the acute intoxication. Paga 16 Combos 1133 mentioned one patient with acne chlorina and porphyria in connection with this production process. The authors analyzed 55 patients internally and neurologically in detail About half of these patients had a deficiency in lipid metabolism and "in nore than one-third, some minor biochemi cal deviations and mild hepatic lesions were noted in the first stages of the disease. In 17 patients, the authors found symptoms of central nervous system disorder, the majority with lesions off the peripheral neurons off the lower extremities (verified by EHG examination). In most of the patients, physical disorders, pri marily an acute neurasthenic syndrome', were diagnosed. In addi tion to the death due to acute intoxication (pentachlorophenol? tetrachlorodibenzodioxine?), three more patients died. In one * patient, the porphyria developed unusually rapidly into an arteriosclerosis of the brain with an atypical morphological diag nosis and demention. Two patients died from bronchogenic carcinoma. All these patients with their complete symptoms are discussed in other papers (32,23]. Discussion In agreement with Kimnig and Schulz, we cite the tetrachloro dibenzodioxine which is formed during the production process as the main reason for the skin symptoms as well as for all the other deficiencies mentioned and diagnosed in the authors' patients. This toxic compound was confirmed in considerable quantities in the final product (Arboricide E50), in the butyl trichlorophenoxyacetate and also in the mortar and wall paint of the factory building. Even adjacent rooms such as worker dressing and locker rooms were contaminated with this compound. Test rabbits placed into these rooms soon died. In his monograph, Braun (5] cited the following chlorinated hydrocarbons as the then known causes of acne chlorina: chloro- *r benzenes with various degrees off chlorination, chlorinated phenols tsodium tetrachlorophcnolate, pentachlorophenol), para-nitrochlorobenzene, sodium tetrachloro-o-phenylpher.olate, chlorinated Paga 17 naphthalenes, various chlorinated diphenyls, trichloroxydiphcnyl, chlorinated diphenyl oxidc3, sod inn <?~(2-chlorophenyl)phenolate and others. However, Kinunit and Schulz C25J ascertained that pure pcntachlorophenol and pure 2,4,5-trichlorophcnoxyacetic acid do not have any acnegenic effects. Therefore, they checked the prosuned effects of the other substances that were blamed for causing acne and found that neither pure nor chlorinated benzenes (from 1 to 3 chlorinated positions) nor chlorinated diphenylethers have any acnegenic effects. A definite acnegenic effect was proved only for the following substances: chlorinated naph thalenes (5 and 6 chlorinated positions) in agreement with Shelley and Klingman [41], higher chlorinated dibenzofurans (diphenyl oxides) and 2,3,6,7-tetrachlorodibenzodioxine. Therefore, it is possible and even probable that some chlor inated hydrocarbons that have been previously considered to have an acnegenic effect do not have this effect and the actual causes - were other ballast chlorinated hydrocarbons contained in those hydrocarbons. Tetrachlorodiphenylene oxide (tet'rachlorcdibenzofuran) 2,3,6,7-tetrachlorodibenxodioxine (tetrachlorodiphenylene dioxide) In an anir.al experiment, Kimnig and Schulz found an ex ceptionally high toxicity for tetrachlorodibenzodioxine. In a local application on rabbits' auricles (keratosis test), this com pound produced a strong reaction even at a concentration of 0.0011. Also, a skin application of this substance at the same concentra tion produced acne chlorina (Schulz [38]). Tetrachlorodibenzofuran was proved to be 10 to 20 times weaker. Chlorinated naphthalenes had a thousand times weaker effect. Generally, acne chlorina is r caused by the direct contact of tctrachlorobenzodioxine with the skin. Absorption through the skin is not ruled out and an effect r: Pago It through the ingestivo or respiration tracts is also conceded. However, in a pure ingestivo experiment with a test animal, acne chlorina did not occur. However, the eases off acne chlorine con tracted after the ingestion off chlorinated naphthalenes as food - fat substitutes should not be forgotten [19,9). Tctrachlorodibenzodioxine used internally has a strong hepatotoxic effect. A dose off 20 to 50 ng per kg of rabbit's body weight causes death In all the test animals by yellow liver atrophy. Because off this enormous toxicity, all the preventive measures taken at the high risk processes in East Germany and Czechoslo vakia were proved to be completely ineffective. The only de pendable solution to that problem was the reduction of the re action temperature and pressure during the alkaline hydrolysis of tetrachlorophenolate to sodium trichlorophenolate. In East Germany, the- decontamination cost of the high risk areas and buildings was extremely high. One chemical plant attempted to use for other purposes a contaminated building which had not been decontaminated after the building had remained unused for two years, but new cases of acne chlorina were shortly reported. Kith normal decontamination procedures new outbreaks of the disease occurred and therefore, decontamination had to be carried out using special pressurized chemical protective suits with pressurized breathing 'apparatus because gas masks were not sufficient. Doors, windows, the wooden trim and other wooden building components had to be burned; the steel construction materials in the building had to be sandblasted; the plaster, facade and floors had to be torn out and cast into cement blocks together with the tubing, plumbing and other equipment. These blocks were then transported to the Atlantic Ocean and sunk. The disposition of those non flammable materials by burying would have run the danger of con taminating the subterranean water supply. Only the most expensive . components, autoclaves and some valves, were successfully decon taminated by repeated washing with special detergents. The Czechoslovakian plants are still closed and their fate is still undecided. The patients are still under a continuous ob servation. r^ References 1. Caidrr. C. \T,, r , II. p . JbIo u o Ixm J w la (m tjcbloffibr^oL Ind. X!J. iu r e . 7J. l i l l . . n i . -- 2. C X Iiaia-C Clilcr-Aluc. ria X-*n.>icrc Fen re a K->.wk*Uvt |iuvaiM kafe. m te k . o e d . VVfcCUr, 17. lv j|. . 7 . -- 3. Veifcjrf. ^ U 'a llji, H,, CreilkJ*. Ut InJuiU U U f MQslv * 4 pai) L /ri . Arck. Uff e t . IX 1S1X * 7 3 ] - 7 j . -- X C **ia, X X M w m a 4 M. t J CUortene (a tt* uxmiXictcr o t DOU . Arch. Ocra. 5rPX JC ileccaI. 7X XSS7. x. 713-7CX -- X U n, FX: X ^ U ra X u . Ma* , n arrj^ j;-a :ur Z eirO f. D erurtarm atcc*. , fia a i L, A u l^ d a c ip W 'a i l t , P dl'toa C xatac: . 3HX . JX -- X t r i a a . \f.s KKtaluU B*a* * ' *l u t i l i ! : ! te t Zatiiehoa j i r C U oraco*.^ CjliuUu*XH 1UX ,JlJ-- llV-- VntHfc-J* p i r a , roiacblrrpbcact -- VerUItx a j. V a n n e . Ccwc/LU-xtX 7 i^ > la H t - a L VX 1*53 -- OL b u r - t t - t r . a * p n l k . D. t : A c tm o t certa! cMcrfaanrd . nepLUlcac* M lU liner. Trac, Soc. n ^ . BloX Med, IX 1E3X`. 113-- 12X -- % chi, n d t. O rn a -- X -- IX C ixxU sn. V. >Ll 0 jvileccarle ic to ie rs iB lw e t cW* rlro M u jrd i tu li iti* or. VXtta. D s s t, V t* ` ter, UU, e.X S.3X -- 12.CtfdTin.X. ScbwcrU: Vvta CSilenVss d crc h T U - tLX a 1A ffisi Z utlr s s c y s l a X a . A r t b - n d illi (ASAU 7. 1372. . 12--I X -- 1X~ `.O illn ti , r . I l Schwrrxla i m i C ito . `e lsa , eli M b u n b tu iV it! dorch X A * I O, 7-Tt.Use t! ardii-cnai1 ' * H a w .V rJJtti^ -JS X -7-^7 ; bUstl/Av !- " e1:! U rd /p r l *jtbc cikKclfcb 1 . la ir to r. ArsL IO . LM* e IX. -- 14. lii*X Ch. C. i r a i ala t.CLkti m SyplL (CXtcioX X M -- 15. C fU in ir, IU A la* dcrch ctlorlcria a iiU^L-f^felfe. ZfcX Arliz 7X -- IX nitltfiMi. 1 Seta. e d . 1CJ2. X. 731 27. !lcr;X UM OUluxxl fcrcnt. l u i D--k t r i a . .42. -- LX Itcrsfcclccf. 1 * J.Sach. f u i iTxelir. JIcrrLarjc. J. p C h iariti. cU c rlcrltra r.*r.'Ra. De . 15:7. l e i -- r i n i T u .So c h e f Fat i l t t e r d e l crarep:=c, Zlirh. d. Zc tiMVuLHjhrLiiitrlrhia _ -- eIL Crea 5. -- 2L Ilftleiira* IL TL-i Vorlr. iVcrL2rclc-Xr:!:rcnT. L a : Di-rt>c:*a. 5505 -- eli. llaaer CL -- ZL Iloti rc^iec. T-- CL'.cracaa a. r t n t L m X h c X Arrfx. l l y c , 117, 15JX X i- tc u rc ic n a -- cu. f - i w L -- 7L J lilu X X. C rlrt^ IL. - IX. F i l i n w i , J. t *Lr K l a i k y u>l'-o>I IdtoilXae m Lnj cbtsctua pt luLl LcjJI-- p-'ipaawAno 1t-A^ __ Pag 19 2 L Jaarx h >r, /Jd en , IX Cd An acaeforM dcrajOL-r^otlL Aich. D n a SfjiX IChhv** . c u l. IX 1^`X L 1L22--IwlX -- 2X KiiUiUX P SlUuIl C I P ScniCiich AVn (&r> ChloraLaeJ durch cM arleru rocuiU cb zrhMKhr Ather. D :r= u u U cU x H X 1C57, . jl 3 0 --5:3. -- 2d. U!>n3i. X. I P Xxpert.*>enlet!fi SiuJlea liter dc* C larittu lech* Ucta a. brsicoiub withliccr Car? a.tu n * i s aol dca OrfanluauL XX Sludla* fitter .Chloralne*. Arch, l i f t , id. 1V0X s. 522-- 33X -- clL llrina X -- 37. Trh. U x ` Ober Chiera kqa. Arch. D ena. 77, 197X 4 . 2CS-241. 1bidea 333--3IX -- XX M*)riX X IX. SHrerter^. H. p a t s coadUioe* .Tcudiim Iron crpouuc to c sru ta chUrlA* `led k firK u b ao i. X todortc U ft. Tosicel .20, ISIS, a. 2U-ZSX ClL B n v a X - . itarrli, C. p Tabaedmr, t , X> .Cibi i . r u h * -- A not oa a o r c le m Mg ula* ' tnr& X A acr. Bed. l i t , U X U IX X 1*2-- f 11X -- dX f in e s X -- 30. Odtad, U s XB: xtticha 32. Hcri.ijm iBrBicH JCrtuSem pA ( *<?att faoc^lozischcQ C srh o h leam iscn taC - * lea; ala ti-llra* tn n P^:aa-7roh?rai. W w i r J* Zrrio KKiIerrat, Dad DdrtliclflX 3SS% ctX* <X --* 3X*OnwX7,r e j i D U k I V . peAAitc*.a*k CtlnLa Jm** 7X -- -5X5^. ra/J.f-.i, I. LbUX c, XjilLJIofXip n- : rdide,L, KUstiJe/,P riO^A. U 1UiX* * A . K liacaci i p JlIo*. p T d U liA l t d f l i l fIU b M 0 :l pfl fto U r.4PS-,tlcbW4ctcAAX|`* Al %%* .f-*/.. i>'tLxa,Ul. I* UcLmL -- ICIadSL ik f C rw rin iM f wohn ( I h la w a u m ) . r r a , Z3X U7tX A. 220-- P LobalUl--dlnLt der u a c iu j eLf Vltaicto X> X `l37X t . AC5-- C?X -- * osluCoa p ra rirc J a d k chbaic; d/Sciftjo lUUl'C. S e a . s ix , 133X . - r t l - X S rli lx IX 2 .;>cri::tc:itL]l Un:cr>ucbun* jc-i'a Act UiUwacne. ArdX ,-r a , 253. 2SS7. s. lC * -X !i3 . -- . L_ 1L: Zur t l p i k xl AlUdoft ArLfcUtiitdUlM (>\5.1X 5 . 25--30. -- 3L S c h a b , K. lt d O uPcit jL -- 2 1 Sellwarlc, JO Derxckilfis a tptlziic real cd ewex. Auce. U A .IX HUP, IX 1U0. L 3M --3hX -- < x Acharartz, L ; Aa cLlLnuli 07 ILaloteax acme f o i b l e r iJ j * ) a^ c sc rU V lrtU A L X At&cr. mrd. A x i. M L 2312, r. 1C1 -- U . ^ iL clby, Of. a , VlUc*-30. X M - Tba u p * * rlneatai jirriacv'ca of eciac !*> pe-ti- a4 PcxacMaiLuef-liUPoti. Arch, llc n a . 5 P . iO U cJrol. 7*X lV tf, u O i l -- <3. TiLcl.7; L : Dm herrutJk.'^olLcU {L Ltonthoe}. CllA. U K h f . U . 1V27. L W S -A 'J , lU L r a 07-- SQL -- O. Tb>Ucrwa AutA coeideA ncraliiir dec lln h ^ a llu pfalcu le.itl- U d i vifHori chlerlqert. S ea. m id^ 2!CX i . 2X ClL Bra S. -- Pag* 20 IL TW .1lo . \ C , T 4 f rn.rt, I h.: L`*C*t ij,.. HOJL'I. fc. i l i - l -- Ct*. P .ju j S. -- ISL L , S f l t i l f , B " u i l . i l , I , Ae t fa ; 11 c a t le J c t i i t l l k i j4f Dull. 1oc. ti r a . M P . II. lVlL a- : - - : > A -- *J. J\. L`f.- r J'.IJc ta .CLL* <". Irtawi;- n l lvi. U l^l'c. :yil. -- CL 5. -- <7. V .'jkcr: CcM.'blItl.c itr;c H * :* c Cureta )wiZc.:wij;w rklc/.'ltr i r c i o i 'a u l * Lent. ZW. Cc^.*rU`h>e, 1. SM*, v lid -- j cl -- <l irtuiLir, IL* r*ir a i t i i |r r_*vra!.:^ij. ?- JI.-L C.*srMWfc, H . J i L i. <3i--*VL -- IX I n e t. L. S*!, * .1 1 , i,*W c . 'l t u / ,, D r tkTv'Jl L w ***\ tel cr ltff .icUu.1* es Cl-"i*lcflC- * VVi LJp3ca reW Caxrtib.T^'.LL C*''' **trer^.), 11,ldl,X Sil-JA [10) Pathogenesis of photode roatides from chlorinated naphthalenes [13]' Combos, et al., Porphyria cutanea tarda and acn* chlorine occurring during the production of cyclic chlorinated hydro carbons. [23] Symptoms of total intoxication in acne chlorine during the production of herbicides - in final preparation for printing. [31] Discussion on paper by Jones [24] [32] Health hazards to workers in production of sodium 2,4,5-tri-- chlorophenoxyace tate. fi*'t. ir- -1 Paga 21 TABLE I. Production Scheo Plant for production of KCH (hexachlorocyclohexane) 1,2,3-trlchlorobearen And It isorers (1,3,5- And 1,2,40) Plant for production of penta- j-.f*'*.;.--- $ t >t<...r . ***''*.***.'/ chloropher.ol ar.d sodiun salt* c/~T-\-Cl V *v**.'.*-V.*:- V. , trichlorophenoxyacatic acid .! / / '-- / V . _ * "'.Vi* -.w,; =.; a, a a cl- -< t**** .. ' . . . . .. I y * . . ^,, p ^ 1 * 1,2,4,S-ttr*chlorobnzta' Q * * * rophenolat TiT-fc.-riVLW-Vaea "2* . \--a *.r .^'"v* s * ; '"ifr:* ^ ^'**--* *-?>';V% >':T*-V*v* *-* Sodiun salt of 2.4,5-trl- \ *. peatAchlorophool chloropher.oxyace tic acid :.v. ` ,-* .1 . :. . *_' < a - O - o a ^ o s . a -(7}-' . /./i.; .a - -- 1 ,1 *; . . 7 :.3;.7- ?' /; a aa . . -- V - v - i f---. 'V., ' .VC'.: *. V-.*;*-* .-I/*,;.* - Plant for preduction * - v * *;-v . ; ^ _*.. *-->>*%* of butyl *scr , a * wC- --4% V *" '' a--//..T.VVoaaaii^^ocaoaaia^ii^in^^iirr^^. , - ' -.V-- /1 ;,** -.-r *- 'V`.l` Q; v- -~'i' butyl ester of trichlcorophenoxyacetic Acid