Document ykENEERzL00gVLyLaZzKoQkrn

Reprinted from the Archives of Pathology August 1972, Volume 94 Copyright 1972, American Medical Association PZSTIClOg "'-'`nri Toxicity of Chlorinated Hydrocarbons dnd i Related Compounds f > ,,, , C'Vi.r V A Review Including Chlorinaled Uilierundioxins and Chlurinaled DibenzofiiranK "'Jl1 Ilpnotr I). Kimbrough. Ml). Chumblcr. (it uaMA-W Various chlorinaiad technical compounds, namely, 2,4,5-trlehlorophenoi, 2,4,5-trlchlorophenoxyacatlc acid (2,4,5-T), and European chlori nated biphenyls (Phenoclor DPS and Clophen A0O), have been found to be contaminated with trace amounts of chlorinated dtbenzofurans or chlorinated dlbenzodloxins. Toxic fat which pro duces hydropericardium in chickens also contains chlorinated dlbenzodloxins. These and other tech* nlcal chlorinated compounds such as Ihe tech nical pentachlorophenol have been implicated In causing chloracne, liver disease, teratogenicity, x*dlsease in cattle, and chlek edema. The litera ture on the toxicity of the chlorinated technical compounds is reviewed. It Is mentioned that ?,4,S*T and the chlorinated biphenyls also induce porphyria. Whether the various disease entitles are caused by the contaminants, combinations of the chemical and its contaminants or by the chemicals themselves needs further evaluation. 'ENTLY several chlorinated com pounds, such as the polychlorinated biphe nyl and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T\ have received a great deal of at tention. Polychlorinated biphenyls tPCB> are increasingly found in our environment and 2,4,5,-1' has been used extensively as an herbicide. Occasionally these and other chlorinnU'd technical compounds haw caus'd diseases that bear similarity to each other. Some of these chemicals have been found to bo contaminated with chlorinated dibenzofurans or chlorinated dibenzodioxins. The various diseases produced by one or more of the different technical compounds are dis cussed in this paper. Attention is focused on the various contaminants and their |H)8sible relationship to different diseases in a variety of species. The need for further well-coordi nated epidemiological and experimental ani mal studies is pointed out. Siiiimilled for' |Hibli-Hiion Oi l M. Ii>71. cureptwl Mmeh A. IU72. From the (TinmUlee Toxicology l^lxn-nttn v. Knvi- mnmenlHl I'roU'dion Arcih v. ('hHii>l>Ut\ (<. t<*|inl ii^iiicmIm (< Chumbh-e Toxhofogy lorv. 1'inhHCion Agency. 4770 Hit- foul Hwv. (TmmMee. .HI'MI < I >i Kimlnongli). Chloracne This disease is described by the formation of comedones with or without cysts and pustules, I'he follicular orifices are filled with sebaceous and keratinous material. Melanosis and a secondary inflammatory reaction may exist. Chloracne was described for the first time by Hcrxheimer1 in 1899 who thought it was produced by free chlo rine. Wauer- in 1918 and Teleky:l in 1927 suggested the term "pernakrankheitThey felt that this skin disease was produced by certain chlorinated hydrocarbons. Jones and Aldcn' were among the first to report a case of chloracne in a 26-year-old male Negro who worked for three years distilling chlori nated biphenyls. This patient also com plained of lassitude, loss of appetite, and loss of libido. Chloracne is one of the most frequent forms of occupational dermatitis, and many cases have been reported in the United States as well as in Europe, particularly Germany and England. Telek.y' reported in 1949 that he personal ly had seen at least "150 to 280 workers" in four different factories with chloracne. He stated that liver disease occurs independent ly from chloracne, and usually manifests itself after an exposure time of four to six months, but may occur in as short a time as seven weeks. Occasionally loss of appetite, nausea, and edema of the face and hands are the first symptoms. Abdominal pain and vomiting follow, and then jaundice develops. At autopsy, acute yellow atrophy of the liver is found. He cites Flinn and Jarvik11 who reported cases of acute yellow atrophy with fatal outcome following exposure to Halowaxcs. Hnlownxes, which are chlorinat ed naphthalenes, as well as the PCR lArodors) were increasingly used after 1930 to insulate cables, Teiek.v' cites many other ease reports (Drinker et al,; Jones.* Greenburg et al.1' ('otter.'" MeDxhtehie and Robertson." and ('oilier1- >. Von Orlttn- .l/i h Kncinm Ihiilih--Vul J`>. Attn IU7:f 2 moms OSS'**5 126 TOXICITY OF HYDROCARBONS--KIMBROUGH the rabbit ear. (The rabbit ear test is used as a screening test to determine whether a compound is likely to produce chloracne. The chemical, dissolved in propylene glycol, is painted on the rabbit ear. If the test is positive, erythema occurs within two days and in a few weeks hyperkeratosis de velops.) The rabbit skin offers us an experi mental method that will indicate the ability of substances to produce acneiform derma titis in man.31 Pure 2,4,5-trichlorophenol did not affect the rabbit ear, and neither did 1.2.4.5- tetrachlorobenzene, the starting ma terial in the manufacture of 2,4,5-trichloro phenol. However, technical 2,4,5-trichloro phenol which was used in the production of 2.4.5- T did produce hyperkeratosis of the rabbit ear. It was concluded that by-prod ucts which had resulted during alkaline hy Chemical structure of a chlorinated dibenzodioxin drolysis of 1,2,4,5-tetrachlorobenzene were and a chlorinated dibenzofursn. the causative agents. describes the occurrence of chloracnc in workers exposed to these chem icals. He cites several references which indi cate that dermatitis is the result of the local effect or direct contact with the chemical, while the toxic hepatitis results from absorp tion. Chloracne has been reported in workers exposed to chloronaphthalenes, chlorobiphenyls, chlorodiphcnyloxidcs, certain pe Kimmig and Schulz30 isolated several con taminants and found that some of them, namely tetrachlorodibenzofuran (Figure) at a concentration of 0.05% as well as tetrachlorodibcnzodioxin (Figure) at a concentra tion of 0.005%, produced hyperkeratosis in the rabbit ear. A hepatotoxic effect was also observed with these compounds. They also found that pure pentachlorophenol did not produce hyperkeratosis of the rabbit ear. Chloracne was observed in workers of a troleum products, and solid chlorophenols.11 West German plant who produced tech More recently Meigs et al,s and Hofman nical pentachlorophenol from hcxachloro- and Meneghini10 reported 14 and 13 cases of benzene.33 The technical material also in chloracne, respectively. Exposure to chlori duced hyperkeratosis in the rabbit ear. It is nated biphenyls was established in most possible that technical pentachlorophenol of these - cases. Birmingham" observed contains toxic impurities, particularly since chloracne in 15 employees who had painted pentachlorophenol is produced by alkaline flat sections of glass with enamel and then hydrolysis from hexachlorobenzene. Diben baked it. The enamel had Aroclor (a PCB) zodioxin and dibenzofuran themselves do not incorporated in it. Plewig,,, produced chlor cause liver necrosis or hyperkeratosis when acnc experimentally on the upper back of applied to the rabbit ear; however, they eight male adults by applying Halowax become highly toxic when they contain three 1014, pentachloronaphthnlene, and hexnchlo- or more chlorine atoms.3" Some of the work ronaphthalcnc. ers with chloracne also develop eye irrita Bauer et al111 reported chloracnc in work ers that handled technical 2,4,5-trichlorophenol. In some of these workers neuromus cular weakness, psychopathological changes, blepharoconjunctivitis, and liver involve ment also occurred. Kimmig and Schulz-1* found that pure 2,4,5-trichlorophenol did nol produce hyjjerkeratosis when applied lo tion, hepatotoxicity, intolerance to alcohol, neuromuscular symptoms, porphyria cuta nea tarda, and psychologic alterations.3* Ac cording to Braun,-4 chloracne seems to re sult from direct contact with the chemicals producing it. ('row,":' on the other hand, points out that chloracne can also be pro duced by systemic absorption. Arch F.nciron Health--Vo/ 2~>. Attn IU72 MQNS 085486 Table 1.--Disease Resulting From Exposure Chioracne Certain petroleum products Chloronaphthalenes (mainly pent*, hexa, and hepta) Chlorohiphenylt Chlorodiphenyloxldes Chlorophenols (technical 2.4.5-trichlorn|)henol. pentachlorophenol) Technical 2,4,5-T Pathological Findings of the Liver Birth Defects end Lethal Factor Chlorinated naphthalenes Chlorinated biphenyls Technical 2.4.5T and other chlorophenols Certain technical 2,4.5 T Purified material irom toxic (at* Polychlorinated biphenyls * "Toxic tat" is a term used for fat found in chicken feed that induces chick edema. X-Disoase in Cattle Highly chlorinated naphthalenes Petroleum products tion of the heart and hypertrophy of the that the Aroclors can produce chick edema. cardiac muscle were also present.-1" The Aroclors (PCB) are used primarily as Toxic fat is not the only product capable dielectric fluids for capacitors and trans of producing the chick edema syndrome. formers, as industrial fluids for hydraulic, Chlorinated biphenyl products, used as a for gas turbine and for vacuum pumps, and plasticizer in a paint, have caused hydroper as heat transfer fluids. They are also used as icardium and ascites in chickens,4' and two plasticizers and are widely distributed in the of seven Bengalese finches fed TCB de environment.4" Aroclor is a trade name un veloped hydrojjcricardium.1- The seven der which these compounds are marketed in finches of a total of 56 birds died during the the United States. They can be found in course of tho experiment. A mixture of pen- synthetic resins, synthetic and natural rub tnchloronaphthalene and hcxachloronaphtha- bers, cellulose resins, paint varnish, wax, lone, when fed to chickens, resulted in chick asphalt, and in allyl starch. They have been edema. i:` The toxic fat which contained the employed for dust prevention, moisture chick edema factor was studied intensively. proofing, sealing, impregnation, and vapor Flick et al" separated a purified crystalline suppression to prolong the residual life of concentrate which produced chick edema and insecticides. They increase the toxicity of decreased the hatchability of injected eggs. dieldrin and DDT in insects/41 Depending Embryonic deformities were also produced. on the amount of chlorine they contain they Flick et aP* were not able to produce testic art' assigned certain numbers. Aroclor 1260 ular hy|x>|>lasia in cockerels when they fed for instance, contains 60% chlorine, while low doses of toxic fat (0.6% and 1.0%) to Aroclor 1242 has an approximate chlorine the cockerels for 12 weeks, as had been re- content of 42%. Miller/'4 in 1944, tested a I>or1od by Allen and Ddich.;,H commercial chlorinated biphenyl with 42% In 1967, Cantrell et nl1" reported that chlorine and observed liver damage in rab l ,2,3,7,8,9-hexachlorodiben/.o-/)-dioxin was bits, guinea pigs and rats. Skin changes one of the toxic com|>ounds producing chick were observed in the animals who received edema. Tomita et nl1" had shown earlier subcutaneous injections and application of that the heating of jx'ntachlorophonol pro the material to the skin. The skin lesions duced octachturodiben7.>-p-dioxin. Higgin produced by subcutaneous injection were botham el aPs showed that the chick edema histologically similar to those of chloracne factor reprttsentod chlorinated dibunzo-p-di- in man. Direct application to the skin pro oxins. The two princi|>al compounds iso duced inconsistent lesions compatible with lated were 2,3,7-trichlorodibcny.o-p-dioxin low-grade irritation. Von Oettingen,i"'';,,,,, t"1' and 2,3,7,8,-tetrnehlor(Kiiheny.o-p-dioxin. The discusses some of the earlier work on the authors suggested, as a |>ossible source of toxicity of the Aroclors in his book The contamination, fats and fatty acids contain Hahgenuled Hydrocarbons, Toxicity and ing commercial chlorophenols. When crude Potential Dangers. Nishizumr- observed fats anrl tallows arc* heated to produce fatty changes in the livers of mice and monkeys acids ehloropheno) residues might be con after feeding them chlorinated biphenyls. verted to a chick edema factor. The author undertook this work because of It was mentioned earlier in this article an outbreak of poisoning that involved at \iili fr'nrtrtHt Urntlh -- Vtit '>.>. t ,un IU7J rtONS X-dlscasc naphthalenes, but also with petroleum prod ucts such as crank case oil. Hie toxic prod This disease in cattle was described by ucts were excreted in the milk and produced Olafson20 in 1947. A few years later evi x-disease in the calves drinking the milk. dence was published showing that highly They cited other authors who were able to chlorinated naphthalenes caused the dis produce the disease with a complex wood ease.27 Cattle with x-diseasc show a rapid preservative and a lubricant. decline in vitamin A plasma levels. Symp Bell33 tested the ability of various com toms of poisoning include excessive lacrima- pounds of the chlorinated naphthalene tion, diarrhea, polyuria, marked salivation, group to produce x-disease. He discovered and discharge from the nostrils. A chronic that dichlorinated and trichlorinated naph cough, poor appetite, and numerous red thalenes did not produce the disease while maculae in the buccal mucosa develop, and tetrachloronaphthalene had an effect, and hyperkeratosis of the skin follows. Micro the higher chlorinated naphthalene, penta- scopic examination of autopsy material chloronaphthalene, hexachloronaphthalene, shows central lobular degeneration of liver heptachloronaphthaiene, and octachloronaph cells with bile duct proliferation and dila thalene, caused severe disease. Octachloro- tion of the glands in the wall of the gall nophthalene was less toxic than hexachloro bladder. Cystic dilation of the collecting naphthalene and heptachloronaphthaiene. tubules of the renal cortex, with a moderate degree of fibrosis and degenerated cells ip the pancreas, was also observed.29 In sheep, ne Chick Edema crosis and cirrhosis of the liver, damage to the nephrons, and squamous metaplasia of the endometrium were the principle findings after ingestion of feed containing highly chlorinated naphthalenes.'-* Huber and Link30 fed hexachloronaphthalenes to young In 1957,34-10 a disease occurred in a large number of chickens which, at first glance, seemed to represent an epidemic. It was soon discovered that the residues of certain distilled animal fats produced the condition when they were added to the chicken swine and produced degenerative lesions of the liver and kidneys and hyperplasia of the vaginal epithelium with keratin formation. A depression of the vitamin A plasma level diet.30-17 The disease was called chick edema because it manifests itself with hydroperi cardium and ascites in chickens. Ducks and turkeys experience a reduction in growth. was also observed. Drinker and co-workers7 found that the liver of rats was affected when the ani mals were fed high doses of tetrachloronaphthalene, pcntochloronaphthalene, and Allen and Lalich39 produced hydroperi cardium and ascites in chickens when enough toxic fat was given to kill most of the birds in five weeks. ('Toxic fat" is a term used for fat found in chicken feed that hexachloronaphthalene or chlorinated bi induces chick edema.) When the concentra phenyls. When Schoettle et al:u fed hexa- tion of toxic fat was reduced and fed to the chloronaphthalene to rats, they observed mild chickens for 150 days, hydropercardium and to moderate fatty degeneration of the liver ascites developed less frequently, but testicu with centrilobular vacuolation of hepatic lar hypoplasia became apparent. Simpson el cells. Degenerative changes were observed in al3fl described proliferation and hypertrophy the kidneys and the skin showed hyperkera of the vascular endothelium and possible tosis. necrosis of hepatic and bile duct tissue in It can be concluded from these reports chickens and turkeys. When monkeys (Ma that highly chlorinated naphthalenes pro caco mulatto) were fed toxic fat, alopecia, duce liver changes in several species. In subcutaneous edema, decreased total serum cows, x-disease of the skin, together with a protein (with a reversal in the albumin-glob drop in the vitamin A plasma level, is one of ulin ratio), and reduced hematopoiesis and the leading manifestations of the disease. It spermatogenesis developed. Gastric ulcers is possible that the vitamin A deficiency occurred in 66% of the animals. Focal areas represents a manifestation of concomitant of necrosis and degeneration were observed liver disease. in the liver; and the bile duct epithelium Sikes et al:t- found that x-disease could be was found to be affected when it was exam- produced in cattle with highly chlorinated mod under the electron microscojH*. Dilnta- 2Arch Environ Hrtillh--Vt>l 2't. Ann 11)72 mons oas^aa to Technical Compounds Chick Cdama Toxic fat* Chlorinated biphenyls Mixture of pontachloro- naphthalene and hexachloronaphthalcne Table 2.--Toxic Contaminants Found in Some Technical Compounds* 2.4.5 Irichlorophonol (TetrachloroOibcnrofuran < , Tetrachlorodibenzodioxin 2,4.5-T T eirachlnrodihenzofurati ( 1 Te1(acl'lofO(l.benro<lio*ir> Toxic fat [ 1,2.3.7.8.9 hexachloroitibcnio p dioxin i?,3,7 tnchlorodibenzo-p dioxin 12,3.7,8 telrachiorodibenzo p dioxin European chlorinated biphenyls (Phenoclor DP6 and Clophen A 60) * Listed in Table 1. TetracMorodibenzoturan l Pentachlorodibenzofurari | Hexachloronaphthalene least 600 people in Western Japan who had ingested rice bran oil that had been containmated with chlorobiphenyls, a Japanese PCB (Kancchlor 400). The chlorobiphenyls leaked into the rice bran oil through pin holes in a pipe used for heat exchange in the manufacturing process. An increase in pig mentation and abnormal grayish darkbrown pigment deposits in the skin of still born and newborn infants was observed/'* Stillbirths were unrelated to PCB poisoning of the mother. Adults showed chloracne, an orexia, fatigue, edema of the eyelids, cheese* like discharge from the meibomian glands, and dark-brownish pigmented nails/4 Vos and Kocmanr'*,> studied the toxicity of several polychlorinated biphenyls in chick ens, quail and rats. The authors compared the toxicity of two European commercial polychlorinated biphenyls (Phenoclor Dili and Clophen A60) and one (Aroclor 1260' which was produced in the United States. The European compounds showed higher toxicity and produced centrilobular liver ne crosis. Chick edema was a common finding with European compounds and rare with Aroclor 1260. AH throe compounds pro duced porphyria. Chemical analysis of these three compounds revealed tetrachlorodibenzofuran, pentachlorodibcnzofuran, and hexachloronaphthalene as a contaminant in the European samples but not in the sample from the United StatesTM Since hydroperi cardium occurred occasionally in chicks fed Aroclor 1260, the authors felt that this was indicative of small quantities of n toxic fac tor in this preparation. by Emerson et al`,T found a teratogenic effect of technical 2,4,5-T in rats. Apparently, the technical 2,4,5-T was contaminated with 27 ppm of 2,3,7,8-tctrachlorodibcn/.o-p-di<>xin. In the study published by Courtney et al/" it was stated that the technical 2,4,5-T which was found to be teratogenic in two strains of mice and one strain of rata was con taminated with 30 ppm 2,3,7,8-tctrachlorodibenzodioxin. Emerson et al',; tested 2,4,5T that only contained l ppm 2,3,7,8-trtm- chlorodibcnzo-p-dioxin at comparable dcange levels and did not elicit a teratogenic effect. This finding was substantiated by Sparschu et alv' who studied teratogenic effect of 2,- 3,7,8-tetrochlorodibenzo-p-dioxin in the rat. A slight effect was observed at a dose of 0.125/ig/kg/day when the material was giv en by gavage from day 6 through day 15 of gestation. At the level of 0.5/*g/kg/dny, the effect was quite pronounced. Courtney and Moore"" were able to produce cleft palates and kidney malformations in three strains of mice with high doses < 100 mg/kg subcuta neously daily from day 6 to 15 of preg nancy) of analytical grade 2,4,5,-T that contain<>d less than 0.05 ppm 2,3,7,8-tetrachlorodibcnzo-p-H toxin. Keplinger et a!"' reported a decreased survival of pups in rat reproduction studies when fed 100 ppm of Aroclor 1242 and 125*1, and poor hatchability of eggs from chickens fed 10 or UK) ppm of Aroclor 1242 or UK) ppm of Arochlor 1254. It has been said1 that a purified crystalline concentrate from toxic fat led to the development of embryonic deformities in chickens. Teralogenesls Comment Kccently, liionetics Krsearch Lalxtrutory, In some instances, the same chemical com Bethesdo. Md (unpublished data), as cited IKtunds are restxmsible for the occurrence of Arrh Knrtrttn Hi-alilt-- I'</ J>. \nu M0NS 083489 130 TOXICITY OF HYDROCARBONS--KIMBROUGH chloracne in people, liver disease in several species, x-discasc in cattle, chick edema, and teratologic or other effects on the fetus. Not all of the disease entities have thus far been produced by all of the compounds (Table 1). Some of the compounds in question have been shown to be contaminated with chlori nated dibenzo p-dioxins or chlorinated dibenzofurans (Table 2). The degree of con tamination seems to vary with different compounds. Some companies manufacturing these compounds have instituted clcan-up procedures which remove the greatest part of the contaminants. Improved hygiene among the workers and improved ventila tion of the working area have, in many instances, reduced the incidence of chior- acnc. Whether all disease entities described arc caused by the chlorinated dibenzodioxins or the chlorinated dibenzofurans is not yol known. Some of these chemicals are highly toxic, as illustrated by the fact that two applications of 10/xgof 2,3,8,7,-tetrachlorodibenzo-p-dioxin applied to human skin"produced chloracne-iike symptoms. Single oral doses of 2<Vg to 50/xg/kg/body weight resulted in fatal liver necrosis in rabbits."Therc is no readily available information on the metabolism of these compounds in animals and their breakdown in the environment.'13 It is probable that they are stable. Crosby et al'H found that 2,3,7,8-tetrachlorodibenzo-p-dioxin and its homologucs decomposed rapidly in alcohol solu tion under artificial light and natural light. However, photodecomposition was negligi ble in aqueous suspensions and on wet or dry soil. It is unknown whether the disease entities discussed are the result of one or sev eral contaminants or the combined effect of the chemical compound and its contaminant. Another unsolved problem is the observa tion that some of these compounds such as technical 2,4,5-T induce porphyria.-' The chlorinated biphenyls also cause porphyria.SA Whether porphyria is the result of the chemicals themselves or of the con taminants, or both, is not known. Crow""* suggests that the porphyria produced by technical 2,4,5-T may have been caused by contamination of the chemical with crude chlorobenzenes, which were used to produce the ehlorophenols from which the 2,4.5-T wus made. Hotter awareness of the possible contamination of the technical chemicals with various highly toxic substances, well coordinated epidemiological studies, and ad ditional experimental studies in animals arc needed to clarify these problems. Chloracne has been produced experiment ally in men by Shelley and Kligmnn {Arch Derm 75:689, 1957). The authors cite addi tional references on experimental dermal ex posure of animals and men to chlorinated naphthalenes. References 1. Herxheimer K: Obcr Clorakne. Munch Med Weehr 46:278. 1800. 2. Wauer H: Gewerbliche Erkrankungcn durch gerhlorte Kohlcnwaascrstofle. Zbl Gcw Hyg 6:100. 1918. 3. Teloky T>: Die Pemakrankheit (Chloraknc). Klin Wtchr 6:845-848; 897-901, 1927. 4. Jones JW, Alden HW: An acneifonn dermalcrgoaia. Arch Derm Syph 33:1022-1034, 1036. 5. Telcky 1/ Obcr Neurere Forachungamethodcn und Forachungon nuf dem Gcbiet der Gcwerbekrankheiten. Klin Wtchr 27:249-257. 1949. 6. Plinn KB, Jarvik NE: Actions of certain chlor inated naphthalenes of the liver. Proc Stic Eip Dial Med 35:118-120,1936. 7. Drinker CK. Warren MF, Bennett GA: The problem of possible systemic effects from certain chlorinated hydrocarbons. J Induttr Hyg Toxic 19 282-311. 1937. 8. Jones AT: Tho etiology of scnc with special reference In ame of occupational origin. J Induttr Hyg Toxic 23:290-312, 1941. 9. Greenburg I., Mayers Mil, Boss-Smith A: The systemic elfect resulting from exposure to certain chlorinated hydrocarbons. J Induttr Hyg Toxic 21:20-38, 1038 10. Cotter I.H: Pentachlorinated naphthalenes in industry. JAMA 125:273-274. 1944. 11. Mcliechtchie NGB, Bobcrteon D: Chlorinated naphthalene poiaoning. Brit Med J 1:691-692.1942. 12. Collier E: Poiaoning by chlorinated naphthalenoa. lancet 244:72-74, 1943. 13. Von Oettingen WP: The Halogenated Hydrocarbont, Toxicity and Potential Danger, publication 414. Public Health Service, 1966. 14. Schwartz L, Tulipan I* Birmingham DJ: Oc cupational Diteatet of the Skin, ed 3. Philadelphia, I.ea and Pebiger Publishers, 1967, pp 336-345. 15. Meigs WJ, Albom JJ, Karlin BI,: Chloracne from and unusual exposure to sroclor. JAMA 154:1417-1418, 1954. 16. Hofmann MP, Meneghini Cl.: A prosposito dellc follicolosi da idrocarburi cloiosostituiti (Arne rlorica), G Hal Derm 103:427-450. 1962. 17. Birmingham DJ: Occupational dermatology: Current problema. Sfcin 3:38-42. 1942. 18. Plewig G: Zur Kinetik Her Comedoncnbildung bci Chloracne (Halowaxacne). Arch Klin Exp Derm 238:228-241, 19. Bauer h, Schulz KH. Spicgclberg U: Heruflirhe Vergiftungen bei der Herstellung von Chlorphcnol Verhindungcn. Arch GerwrrbeptUh Gcru-cr behyg 18:538-555,1961. 20. Kimmig J, Schulz KH: Beruflii hc Akne <Sog Arvh Environ Health--VoI 25. Aug l'J7`J HONS 085490 TOXICITY OF HYDROCARBONS--KIMBROUGH 131 Chlorakne) durch chlorierte aromalischc /yklische Ather. Dcrmatologica 115:540-546, 1057. 21. Adams EM. Irish DD, Spencer HC. et a): 'Che response of rabbit akin to compounds reported to have caused acncform dermatitis. Induttr Med Surg 2:1.4, 1041. 22. Deader EW, Bauer HJ: Industrial intoxica tion due to pentnchlorophenol. Ind Med Surg 20:286-290, 1951. 23. Poland AP, Smith D, Metter G, et al: A health survey of workers in a 2,4-D plant and 2,4,5-T plant. Arch Environ Health 22:316-327, 1971. 24. Draun W: Klinischo Boobachtungen zur Entalchung dcr Chloracne. Hautarzt 10:126-129, 1909. 25. Crow KD: Cloracne. Brit J Derm 83:599-600, 1970. 26. Olafson P: Hyperkeratosis (x-discasc) of cat tle. Cornell Vet 37:279-261, 1947. 27. Hansel W. Olafson P, McEntee K: The isola tion and identification of the causative agent of bovine hyperkeratosis (x-discasc) from a processed wheat concentrate. Cornell Vet 45:94-101, 1966. 26. Sikee D, Bridges ME: Experimental produc tion of hyperkeratosis (x-diseasc) of cattle with a chlorinated naphthalene. Science 116:506-607, 1952. 29. Brock WE, Jones EW, MacVicar It, et al: Chlorinated naphthalonc intoxication in sheep. Amer J Vet Ree 18:625-630, 1967. 30. Huber WG, Link RP: Toxic effects of hexachloronaphthalene on swine. Toxic Appl Pharmacol 4:257-262. 1962. 31. Schoettle CE. 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