Document pe13og4yB0b0MXdwgdk9qpZN6

w r i i Kw I I i .N\ . \"v \ V-- '--- * O ^'^d CavTC' ^ t r.*V\S <y 'c'^ X c^!fc> w m CHAPTER $C c Occupational exposure * RENATE D. KIMBROUGH Toxicology Branch, Center fo r Disease Control, De/wrtment o f Health and Human Services, Public Health Service, Atlanta, GA 30333, U.S.A, 0 V1 on ozj 13 / 9C.I. Introduction Reports oT illness associated with exposure to chlorinated organic chemicals of the type discussed in this book date back to the latter pan oT the 19th century (Hcrxhcim.er, 1899) and the early part of the 20th century (Betimann, 1901; Wauer, 191E; Lehmann, 1905). Extensive outbreaks following exposure to chlorinated naphthalenes occurred during World War 1, but it was not until the middle of the 20th century that occu pational illness from exposure to the other compounds has become a problem. Review of the available literature suggests a clinical syndrome that is produced by the halogenaicd biphenyls, naphthalenes, dibenzodioxins and dibenzofurans. It is . presently not known whether halogenated tcrphcnyls may cause similar problems. Some of the signs and symptoms observed following exposure to toxic levels of these compounds have been noted frequently (Tabic 9C.1). In all .nstanccs, the skin lesion, chhrucne, was usually one of the first signs noted. Signs and symptoms such as weight loss, general malaise, nausea, loss of appetite, impairment of liver function, hepatic prophyria (porphyria culanca tarda) (see Chapters 7, 8) and sensory neuropathy were less frequently reported. Other effects were occasionally . associated with some outbreaks of occupational illness, but their significance is not well understood. Not all of the observed signs have been reported for all of the chemicals under discussion. Chloracne, weight loss and impaired liver function have been most frequently associated with exposure to toxic levels of these chemicals. As outlined in Chapter 7, 2,4,5'irichlorophenol :and all chemicals made from it may be contaminated with 2,3,7,S-tcirach)orodjbenzodioxin. Pentachlorophenol K im brough fed.) H ologenoted biphenyls, terphenyh, naphthalenes, dibenzodioxins and related uruduct? i.hcvicr- S u r ih 'lh d lu n d UimneJicitl Press 19SU -V * I g iaC 5 3k- i .% :R : TAIll.l; 9C.I Symptoms ;iikI \i|iii's n*j**tlctl aflcr iKVupaiioual c.\|m.vnrc. XVMein t Jeiicral l.CMOU . hlooiUmt eyi>, lavsitink*, lieailuehe, abdominal pain. impoiettee. viidil low, iiwmittiu. diviurb- nnec in taste llicm t^ll. chlorinated naphthalenes iccliuical in'itiaclikiniphcuol 2,3,7.H*ieirelihirodil*en/ixliit\iii chlorinated biphenyl?. Rcii'TvevJ Good ami IVnvky, 194.1 lluudcr and Hauer, 1951: Ik'hrbohm, 1959 Jiravck el ak. I97j Jones arid Ahlen. 1916 Skins 1iver chlnracnc, pitriltiv acute yelknv atrophy, hepatocellular necrosis. mild fibrosis, faiiv chanpc, abnormal liver [uncikm, piirphyrin cutattea lariln 2J,7>-TC'I)1) clikirinalcil biphenyls chlorinated uaplitltalcncv iccli piniaehhm'pheiinl oilier kvli. chlnrinajcd pheuoN ehlorinalcil naphthalenes (ictra-, pciHa*, heva-1 2..1.7.K-TCOD lev'll, pcuincliloropliciinl inilyeltkirtiiateil biphenyls (llmofiuaf liver lunction tests) Kitimtiny and Schulz, 1957 Jones and Alden, 1916 Good and IVrtsky. J*M3 MelirKilun. W) Siiityilv. 194(1; Ihtenis and Colomh, 1956 Collier, I9J.1 Hauer el al.. 1961; 1Heiberg el al.. 1964: Goldman. 1972: Jiravck ci al., 1974 Trulinni cl al.. 1952: Cordon. 1956 On et al.. 1976 Pipeslive irael aimrevitt, vomilittp. heinorrltaye chlorinated naphilink'ncs 2,J.7,Rdcirach'hmxlihcn/odiu\iti tkuxl and I'cnvky, 1943; Dwyer, 19-16 Hofmann. 1957; Goldman. 1972 I'cripheial mcmoiiv lyjacm vetivfiry itenropalliy, ]Krtplter:tl neuritis 2..'.7.S-ieirachliHiHliK'ii/i*duv\in ' Gnhliiinim. 1972: Jiravck el al., 1974 Rrsplfii*/ 'jviirit brimeltiMs, reduced vilal capacity leeltnieal pciitachlorophenol imlyclilori tinted biphetiyU Maader niuMtaucr. 1951 Wnrshuiv el ak, 1979 a. Tbtf b, :,ml MFm ' re obvet veil bv a number oT oilier mlliorv. The references lislcd verve merely its cvmnplyv. Wus reported in blacks for chlnriunicil nnpltlbidcncs by Colter 094-1), ir 3d b 3^ tCnO*cas-r --.v. ntr '< f e On ^ en 3a cnr>r cvOi g=a*>- rO^i tDp^jra z3pzi.*vIHi i--r ii _l 3~n: O ~ C O J J 'D rt oOa ^cDru3w 3 T3r---iDpQii wa= ^ c u*> 3n :m 3 ^n .f?t K - ' ^ - 501*--S-*-- * non Tlir \yiiipipim .-ititi *ipi\ lividi vii* i'I'mtvciI hy n niimkv n^ollivr ,nilltnr\, Tlir rcfcicua'v lividi verve merely-:i\ e^tninpl IX'pipineniiiiiitu wav reported in I'lael.v for chlorinated iinplnlinlciio hy Coder (I'M*!). >ugh Occupational exposure 375 may be contaminated with more highly chlorinated dibenzodioxins, dibenzofurans and hcxachlorobcnzene. The polychlorinated biphenyls contain trace amounts of chlorinated dibenzofurans and chlorinated naphthalenes. Whether chlorinated naphthalenes are contaminated with chlorinated dibenzodioxins and chlorinated dibenzofurans has not been established. In fact, little is known about the complete composition of the technical products that have caused outbreaks of occupational ' illness in the past. The eases of chloracne which Herxheimer reported (1899) occurred in a room where caustic potash was produced by the electrolysis of potassium chloride. The chlorine was reacted with calcium to give calcium chloride. Herxheimer initially assumed that nascent chlorine had caused the dermatitis. Crow (1970a) pointed out that, although many authors clung to the nascent chlorine theory, the cause was 'halogenated hydrocarbons which originated from the tar lining in the absorption towers, or the anodes of tar*, bitumen and charcoal that were used in the electrolytic manufacture of hydrochloric acid and similar substances. These tars were the sources of the cyclic compounds which became halogenated. Thus far, it has not been unequivocally shown whether specific isomers in the mixtures of chlorinated naphthalenes and biphenyls are the acncgenic agents and also cause some of the systemic toxic effects. Most chlorinated biphenyl mixtures arc contaminated with 2,3,7,8-tetrachlorodibenzofuran which may contribute to their toxicity. Certainly the contaminants in 2,-4,5-trichlorophenol and related products arc the agents responsible for chloracne (Kimming and Schulz, 1957). Most likely the contaminant hexachlorodibcnzodioxin in pcmachlorophcnol causes chloracne. 9C.2. Chloracne Depending on the severity of the exposure and the susceptibility of the individual workers, some will develop an occupational disease commonly referred to as chlor acne after having had exposure to the halogcnated cyclic compound* mentioned above for several weeks or months. Following expbsiiTc*lo high concentrations of 2,3,7,S-teirachlorodibcnzodioxins, the onset may be more rapid. Even after a single exposure to 2,3,7,S-letrachlorodibcit/.odioxins. the onset of chloracne may be delayed for several weeks, but if the exposure is severe, it may appear in as little as 2-3 days. One, or repeated short-term, exposure to 2,3,7,8-tclrachlorodibcnzodioxin usually occurs during the production of 2,4,5-trichloropheno! when the reaction overheats, resulting in the increased production of the unwanted contamin ant 2,3,7,8-tetrachlorodibcnzodioxin. This exothermic reaction may give rise to explosions (Milnes, 1971}. The clinical features of chloracne. regardless of Ihe type of chemical that caused it, have been most consistent. The most distinctive cutaneous lesion is the chloracne cyst (Crow, 1970b). This lesion is skin-colored and measures from 1 to 10 mm in diameter with a central opening. The other dominant lesion is the comedo (Figs. 9C.1, 9C.2J. Usually these lesions start over the maxillary bone, then involve the 4 Occupatio 'y & h entire face, ihc neck and cars. Often Ihe nose and nasolabial folds arc not as extensively involved. In males, the genitalia may be involved. Furtherm ore, lesions may be present on the back, arms and legs, and other areas o f the body, particularly where garments arc in close contact with the skin. Depending on the severity, the skin contains only a few lesion*. (Fig. 9C.1) or the lesions arc so close together that they gi\c the skin a rough, grayish-brown appearance. The comedones and cysts can become secondarily infected and large pustules may form. Cysts may rupture and cause foreign body granulom ata. The chloracnc-typc skin lesion may be preceded by a faint rash which, in some cases, itches severely. In areas exposed to the sunlight, a photosensitivity-type reaction may occur and conjunctivitis with swelling of the eyelids and the rest of the facial skin may precede the development of chloracnc. Since the workers arc often exposed to the chloracncgenic agent, such as TCDD. as well as other chemicals, such 2,-1,5-trichloroplicnol. it i> not entirely clcar whether the early rash is pro duced by the TCDD or due to the irritating effect of the 21*J,5-irichlorophcnoI or other substances. Once chloracnc-has developed, it may remain active for many years, and particu larly when secondary infections occur, deep-pitted scars may remain as a residual effect. These <cars can be quite disfiguring (Fig. 9C.3J. No specific treatment is available and most palliative means have not been very effective. Treatment in the :i>v: IFig. 9C.2. past has in pustules, ;1also been The manu fcondensers in enclosed should be h: 1and supers* not dclayc soap -as clei function (cm biphenyl si" 1977 (K contact worker is e] ifir o u g h Occupational exposure V i e not as r, Ifaion* "jcuUrJy rit>, the '.her that cysts car. ;*.ure and . in some .v;:y-;ype e>i of ilie arc of;er. hfrr.ical>. sh is proD'.enol or . panicua rcsidLai a;.men* is t i in the past has included Vitamin A acid. UV light. X-ray, lancing a id expressing of pustules. However, the best treatm ent is prevention, althourV derm abrasion has also been effective {Crow, 1970a). "" ' * The manufacture of these chlorinated hydrocarbons and the Coaling of wires and condensers with insulating materials and other industrial processes should be done in enclosed systems. Protective clothing provided by and laundered by the company should be handed out fresh daily. Shower baths after work should be compulsory and supervised. Sufficient shower facilities should be available so that workers arc not delayed. Schwartz and Peck (19-13) suggested synthetic welting agents instead of soap as cleanser. They abo recommended monthly skin examinations and liver function tests. In the United States, recommendations for a lower polychlorinated biphenyl standard were made b>. the National Institute of Occupational Health in 1977 (NJOSH, 1977) which suggests proper hygiene procedures to avoid dermal contact and recommends that occupational exposure be controlled so that no worker is exposed to PCBs at a concentration greater than 1.0 /ig/m*1of air dctcr- .7 i> rw- 3 3 s 37S /?.>. Kimbrough mined as a timc-wciehled average (NIOSH, 1977a). The existing standards for occupational exposure to-PCBs in different countries have been summarized by the International Labour Office (1970). They range from 0.5 mg/m* to 1.0 mg/m ' in many countries. It is particularly important that no potentially contaminated clothes are taken home since chloracne has been transmitted by this vehicle to other members of the family. * A skin lesion exactly like chloracne can be produced on rabbit ears or hairless mice and the muzzle of rhesus monkeys. In cattle and horses, a microscopically slightly different skin lesion which is also called hyperkeratosis or X.-discasc develops following exposure to compounds that produce chloracne in humans. In cattle and horses, the skin lesion is usually accompanied by hair loss in the affected areas and the epidermis is covered by a thick layer of keratin (Kimbrough, 1974; Kimbrough ct al., 1977). Prior to the ability to detect chloracncgenic compounds by chemical analysis, the rabbit ear test was utilized to screen technical products for their presence (Adams cl al., 1941) (see also Chapter 5). In rabbits, monkeys and men, the microscopic appearance of the skin lesion varies, depending on the intcrval'bciween last exposure and the time the biopsy was obtained. Microscopic examination of human skin biopsies from chloracne cases or tissue sections from rabbit ears with hyperkeratosis show markedly dilated hair follicles that are filled" with keratin. Eventually the enure `follicular appendage becomes transformed into a sac of keratin (Pigs. 9C.4 and 9C.5). The sebaceous glands involute partially or completely. The epithelial cells lining the follicles and adjacent to them proliferate. Acanthosis is present and the individual prickle cells become'enlarged. Polymorphonuclear leukocytes aggregate around hair follicles. This is followed by intrafollicular collections of leukocytes, microvesciclcs and abcesses within i1'.- follicular wall. Subsequently the follicular wall is destroyed and an abcess may develop. According to Shelley and Kligman (1957), who induced chloradnc experimentally in 31 male adults with chlorinated naphthalenes, the sebaceous elands returned gradually months after the last application. Eventually, the epithelium lining the keratin-filled follicles atrophies. Although on casual examination, chloracne resembles juvenile acne, the distri bution of chloracne is quite different as is frequently the age of onset. Juvenile acne is characterized by papular eruptions due to inflam m ation with the accum ulation of secretion of the sebaceous glands. Hyperkeratosis and atrophy of sebaceous glands docs not occur in juvenile acne. In a few in.tances in which workers developed cliloiacne following exposure to 213,7,k-ieirach!orodibcnzodioxin. hypertrichosis and "hyperpiementation was pro nounced (Jirasck ct al., 1976; leiberg ct al., 1964). For many years, it was believed that chloracne was due to external contact and not the result of f\stemie exposure to the acncgcnic agents. Howescr, this belief is refuted by two episodes of accidental poisoning following ingestion of the acncgcnic compounds. In one episode, 'Yusho' rice bran oil became contaminated with a i j i t L - [ i l I. ir* iI f \ i fI t i f i 0 l: Fig. 9C imbrot/gf dards fot :cd by ihe r.g/m*1in ^re laken :crs of ihc or hairless >scopica!!y X-discasc un'.ar.s. In ~.e affected jeh. 1974; pounds by oducis for :kin lesion biopsy was ne cases or .'aied hair appendage sebaceous slliclcs and rieklc cells ir -follicles, icicles and royed and 10 induced aler.es. ihc vcniu?.j*.y, . ihe dX;:i:*er.ilc acne Violation of coui glands e\pcsure io r. as p;o- jorr.ao; and his belief is e arne4a^enicj aied vuih a Occ\tpoiionoJ.exposure' Fic. 9C.4. FollietiLr appendage of the skin from a normal rabbii car. 379 5B'.TrvJT 'HJn: \Zi >/' m -f 30 , /?.D. Kimbrough 1 Fig. 9C.5. Follicular appendage from a rabbit car affected by a chloracncgenic agent. mixture of chlorinated biphenyls, quancrphenyls and diben2ofurans (Rappc ct al., 1977; Miyata et al., 197SJ, and resulted in illness which included chloracnc (Chapter 9B.1). In 19-15, six people fried vegetables in a fat-like substance thought to have been htxachloronnphthalenc which they found in the bomb ruins of Berlin in Germany (Henzberg. 1947) and subsequently developed chloracnc. Similar skin lesions can also be produced in primates by oral exposure to chlorinated biphenyls or chlorin ated dibenzodioxins (larsoui, and Allen, 1975; Allen el al., 1977). In rabbits, depending on the dose, application of acnegenic agents on Lhe ear may either only result in local hyperkeratosis or at higher doses also produce a toxic effect on the i liver (Kimbrough, 1977). Thus, local dermal application of these compounds, particularly the 2.3.7,8-telrachlorodibenzodioxin may also lead to systemic disease. More recently, occupational exposure 10 3,4-dichloroanilinc and some herbicides made from it. such as propatfti (A-C3.4-dichlorophcny!)propanamide) have also produced chloracnc. In these instances, the toxic contaminant is tcirachloro- V/" azobcnzenc or tetrachloroazoxybcnzene (Morse ct al.. 1979). These compounds are not as stable as the chemicals discussed in this book, and hence may be less of a problem. - Oi" j s I Kimbrough :ic agent. lapjx-et a!., *c (Chapter have been in Germany . lesions can s or chlorinIn rabbits, y either only effect on the compounds, :mic disease. ',c herbicides e) have also tetrarhloronpounds are be less of a Occupational exposure ` 381 9C.3. Presence of hulogcnufc'd aromatics in human tissues and body fluids Of all the chemicals discussed, only the chlorinated biphenyls have been measured with any frequency in human tissues. Chlorinated dibenzofurans were found in patients suffering from Yuslio (Chapter 9131) ami in one instance, tissue was analyzed for 2,3,71S-lciradtlorodibcn7.odioxin front a resident living in the Scveso area in Italy (Chapter 9132). Uroniinated biphenyls arc not as prevalent in human tissues as chlorinated biphenyls and arc primarily found in the population of the state of Michigan, U.S.A. (Chapter 9A). Since the chlorinated biphenyls arc lipo philic, the highest concentration is found in adipose tissue, although proportionally Jower concentrations arc present in other organs as well as blood. The different chlorinated biphenyl isomers arc metabolized at different rales (Chapter 4) resulting in shifts in the gas-chromatographic pattern. The ratio of polychlorinated biphenyls between adipose tissue, other organs and blood varies somewhat, depending on whether exposure *is current or took place in the past and whether the blood specimen was fasting. Pregnancy, weight loss and kidney disease may also affect this ratio. In order to determine the body burden of these compounds, adipose tissue would be the most suitable specimen for most of the halogcnated aromatic compounds. Although appropriate for individual cases, it is usually not feasible to obtain adipose tissue samples in large population studies. In spite of the limited value of blood levels as an indicator of body burden, they can give some idea of the levels of exposure. A person with a polychlorinated biphenyl bloo'd level of 10 ppb Oxg/I) might at the most have adipose tissue levels o f a few ppm (mg/kg) or less, while tho*c with blood levels of 100 ppb (/ig/i) might have adipose levels anywhere from 20 to 50 ppm (mg/kg). Since the chlorinated dibcnz.odioxins and chlorinated dibenzofurans. particularly the 2,3,7,8'-iclra- isomer, arc so extremely toxic, illness would be expected to be present at lower concentrations than for chlorinated bi- TABLE 9C .: Partial lisi Q chemical companies where explosions or_yiiddcn accidenia] release of large quantities of TCDD has occurred during the production of 2,4.5-trichlorophcnoI and related products.* Name of company Place Year Reference Monsanto Badische Anilin und StxJa Fabrik Philips Duphar Ltd. Coalite and Chemical Products Ltd. JCM ESA Nitro, W.Va.. U.S.A. I.iitiwipsha fen. Rhein, G.KR. Amsterdam district. Harlem, The Netherlands Grenoble, France Boisover, U.K. 1949 195.1 1963 l%6 1968 Hamburg. G.F.R. Scveso, Italy 1954 - 1976 IARC. I97E Hofmann, 1957 Daldcrup. 1974a. 1974b Duet iis and Colomb, 1956 May. 1973 Schulz. 1957; Rimming and Schulz. 1957 Hay. 1979 a. Additional Companie*, are lisicd by Hay (1979). 382 R.D. Kimbrough Occupati J phenyls. These chemicals arc also more polar and il is possible lhat their concentration in the liver may be different relative to the concentration in adipose tissue. : 9C.4. Pt However, this was not the ease for the one resident from Sev.-so, Italy, who was ChlorinaiJ studied in this respect (Chapter 91)2). early 1930 Low background levels of PCBs can be found in blood and other tissues of the ; formers, general population of industrialized nations (Chapter 9A). Such background levels need to be considered when occupational exposure is evaluated. . - greater tl1 expanded Since PCBs are mixtures of chemicals, quantitation is quite difficult and a polychic number qf different ways of quantitating them have been proposed, such as adding examine, the PCB peak heights of the gas chromatograms and comparing it to a known j biphenvi amount of standard (see Chapter 2). Because of these differences in quantitation, genitalia the differences in isomeric composition of the different PCB mixtures, and chloracn- differences in individual susceptibility, it can presently not be predicted with below sp certainty what a toxic blood or adipose tissue level constitutes in each case. How rained wi^ ever, in some individuals, PCB concentrations of 50 ppb (ng/g) in blood were material. associated with abnormal liver function tests.(MMWR, 1978), while in other studies ^ the first v (Karppanen and Kolho, 1973), this was not the ease. In capacitor plants where PCBs " lassitude,, are heated and, therefore, volitalizcd, considerable respiratory exposure occurs ; repor (Table 9C.4). If PCBs are handled at room temperature as in the production and ( e ff^ " repair of transformers, dermal exposure may predominate. ated*Diph Very liule information is available linking PCB.air Icvels-t-e-RCB blood levels, j fatal ease PCB adipose tissjc levels'or symptoms (Table 9C.3). Since PCB air levels may lencs and fluctuate a great deal, air monitoring may not adequately reflect exposure. : chloracr No published information is available on the presence of halogenatcd naph- ^ naphthe thalenes and terphcnyls in workers. Neither have the chlorinated dibenzodioxins or j warn agi dibenzofurans been extensively measured in the occupational setting. | toxic effi hydrocar; TABLE 9C.3 PCR concentrations in the occupational environment and in blooJ of worker.* c\p*>vcd >o PC`13>. made (Di to chlori Deration of .HCH le*el- Effecti reported PCU exposure Emirojimvnta! tilood ippbl Kcforcncc exposure chlorinat At ftm Noi known --S mo. 0 - 2 0 yr. 10 i-7 0.2-1.6 - - 370. ave. unbearable irritation chloracnc chlorucne. hypei pipmen- Elkins. I9<9 Puccinclli. IVS-i Ha*cp3*v2 et al.. 1972 Some of throat, d trichloro , taiion. liver injury 2. \r. a*c. ,, no! reported Riti. ave. clil or acne Kitamura et i!., 197} :.5 -IS yr. f.O! 3 -0 .:" 3A-2VA irritation, liver injury Levy cl a!.. 197/ N mo. 0.1 - vhlornciu*. Ii*cr injur* Meips et al.. 1954 2-23 yr. 0.32-1.-J >:oo chloracnc. liver injutv Ou*v et al.. 1976 iI Up tu 15 yr. not tepori vd 7-,VX) chloracnc. elevated Hara ci al.. ;974 itiyl* cetitles Mara cl al.. 97} < 1 74- no effect Karppanen ir. I Kolho. 1971 exposure of polyc 0.1 me/ level det recently idcvrl ra. environi 388 R.D. Kimbrough Occupa. I. diphenyls. The.chloracne was usually Found in clcciricians engaged in stripping (the and thei coated cabled). The halowax which was stripped off was impregnated in asbestos is know which was wrapped around the wires as insulation. aled dit : Experimental studies were carried out with the chlorinated naphthalenes which ! :t caused outbreaks in different working situations. These mixtures were composed of i; chlorinated naphthalenes with various percentages of chlorination. Teleky (1927) dealing been m: pentach pointed-out that in factories where the substances used contained only 147o . known, chlorine, the incidence of chloracnc was much reduced. In one of the companies, the phenol i! health status of the workers was greatly improved when naphthalenes with only TCDD. 7-890 of chlorine were substituted for those with higher percentages of chlorine. A i (Chapte number of experimental studies stimulated by the health problems observed in Occu; ii workers exposed to these chlorinated naphthalenes demonstrated that the peniaand hexachloronaphthalcncs seemed to be the most toxic. This experimental work phenol: In addi. also indicated that mixtures of chlorinated naphthalenes with chlorinated diphenyls' result `ta increased the toxicity of these materials (Von Wcdct ci al., 1943). During that time, -Two the most extensive studies were done by Bennett el al. (1938). In these studies, the may be trichlornaphihalcnes were less hepatotoxic than the higher chlorinated compounds and its c and the chlorinated diphenyls were Considered to be the most toxic of all. However, workers no chemical analyses for any of these compounds were performed at the time to 'these wt determine whether any toxic impurities might be present. Similarly, Shelley and . The c Kligman (1957) tested a number of halowaxcs for acncgcnte-polcnlial in humans. Irichlorc The following mixtures of chlorinated naphthalenes were tested: careful!; Mono.- and dichloronaphihalcncs (Halowax 1000), lri- and teirachlor- vessel. { naphthalenes (Halowax 1001), pema- and hcxachlornaphthalcnc (Halowax 1014), ( TCDD': heptachlornaphihalcne (Halowax 1052) and octachlornaphthalcnc (Halowax 1051). ; subsequ Of these, only the mixture of pema- and hcxachlornaphthalcnc produced chloracnc. in the o The other four chlorinated naphthalene mixtures were without effect. However, illness.. Mayers and Silvcrberg (1938) reported a series of patients who had developed 1 are liste chloracne after being exposed to a mixture of tri- and tetrachlornaphihalcncs. endange Again, no chemical analysis of this particular mixture was done. On the other hand, Acute studies in rabbis injected with mixtures of lri- and icirachlornaphthalcnc, or teira- nausea and pcntachjornaphlhalcne or pema- and hcxachlornaphlhalcnc only showed liver other ar i damage when they were given the penfa- and hcxachlornaphihalcncs, but not when ; may als they were given the mixtures of the other chlorinated naphthalenes. Thus, most of j illness,: the clinical observations as well as the available experimental data seem to indicate * ! the lowi V that the pema- and hexachloronaphthalcncs arc the most toxic components of the j were in mixtures of chljrinaied naphthalenes. '* enlarge observe 9C.6. Contaminants (chlorinated dibenzodioxins and chlorinated riibcnz.nfurans) prolong pains" w Chlorinated dihcnzodioxiits and chlorinated diben/ofurnns arc contaminants of a " (JARC. number of commercial products (Chapters ), 2). The only documented episode of Walker substantial exposure of humans to chlorinated dibenzofurons occurred in Japan, , manifes 1 i n&f&ugh t '>:ni (ihe asbestos ` hich ?ostd of y (1927) iy I4 fo nies. th i:h only Oline. A trvcd in. pema\z\ work * iphcnyls tal lime, dies, The npounds !owe v e r, ' lime io !ley and humans. * .rachlor1014), 1051).. Joracne.* 'ever, _ eloped halcncs. er hand, * cr tetraved liver jot when most of indicale is of The ofurans) ms of a iiode of i Japan, Occupational exposure ' 3S9 1 ! j j 1 I : i I ' | j ! I* 1I : ! . : ` | ! and these subjects were also exposed ip polychlorinated biphenyls (Chapter 9B1). It 5 known that products such as pcntachlorophcnol are comaminaicd with chlorin- ated dibenzodioxins and chlorinated dibenzofurans, but in the published reports dealing with occupational exposure to technical pcntachlorophcnol no efforts have been made to distinguish the effects of these trace contaminants front those of pcntachlorophcnol per sc. Through the efforts of Kimniing and Schulz (1957), 1 is known, however, that to a large extent, illness caused by technical 2,4,5-lrichIoro- phenol and all products made from 2,4,5-trichIorophcno! is actually caused by TCDD. TCDD is the most toxic isomer of the group of chlorinated dibenzodioxins (Chapter 5). Occupational exposure to TCDD may occur in the production of 2,4,5-trichIoro- phenol and all products for which 2,4,5-trichlorophcnol is used as starling material. In addition, exposure tocommercialproducts contaminated with TCDD may also result in illness. Two types of exposures have occurred in these occupational settings. Workers may be exposed daily to TCDD during normal production of 2,4,5-trichlorophenol and its end products. In this type of setting, chloracne developed gradually in some workers after they9 have been exposed for several week*s or months. In addition, these workers mav*also show svsiemic illness. The other type of occupational illness has a more sudden onset. When 2,4,5- trichlorophenol is produced from letrachlorobcnzene, unless the reaction is carefully controlled, it may overheat and result in an explosion of the reaction vessel. Once the temperature of the reaction exceeds 160C, increasing amounts of TCDD are also formed. Exposure of workers to TCDD during the explosion and subsequently during cican-up operations has often been quite heavy and has resulted in the onset of chloracne in a week or two, sometimes accompanied by systemic illness. A number of such episodes have been published in the literature and some arc listed in Table 9C.2. Clean-up crews and maintenance men are particularly endangered. . Acute symptoms occurring after such accidents have consisted of headaches* nausea and .dizziness.1Rarely, severe itching, redness and swelling of the face or other areas of the skin may develop, and swelling of the eyelids with conjunctivitis may also be present. Within two or three weeks chloracne develops and systemic illness, such as weight loss, easy fatigueability and aching murcles, particularly in the lower extremities and chest, may be present. Other complaints often recorded were insomnia, irritability and loss of libido. The liver may become tender and enlarged, and sensory changes, particularly in the lower extremities, have been observed. Total serum lipids may be increased and the,prothrombin lime may be prolonged. Symptoms may be quite persistent, particularly the severe aches and pains which are manifestations of peripheral' neuropathy and the fangueabilhy (IARC, 1978; Bauer et al., 1961; Bleibcrg cl a!., 1964; May, 1973; Jensen and Walker, 1972; Oliver, 1975). Unfortunately, since chloracne is the most obvious manifestation of TCDD poisoning, the systemic effects have been less well studied & i j :* ! :E i: *P f S P f:; -Ci 3J*| i.;i 5: ;1 ^ :l ^rl 's ti J-- li n^ v f l <i'i S f ff;[ 2i2 &r- > l i,g4-> *. ai ?J! S4j 4.J Hi-:p 1 ;.N' *vi^gT*lr; #h a- s -:>-r/ ' /LD. AVnibrowgA and reported. While in some episodes, chloracnc seems 10 be the only significant health effect (May, 1973) in most episodes, systemic illness was also noted. Un fortunately, a number of these episodes either have not been published at all or have only been insufficiently reported, such as the accident which occurred in Nitro, West Virginia, in 19-49 or the health effects observed in the Philips Duphar Co. in the Netherlands. The reports made by Bauer ct al. (1961), Schulz (1957), Bleiberg cl al. (1964), Oliver (1975), Goldman (1972) and Jirasek et al. (1976) describe systemic effects in more detail. Most of the persons exposed in industrial settings were exposed to a mixture of chemicals, such as 2,4,5-trichlorophcnol, TCDD, 2,4,5trichlorophtnoxyacclic acid, and, in the episode reported by Jirasek (1976), also 10 pcntachlorophenol. It is, therefore, not clear whether ail effects were solely caused by TCDD. Only the two laboratory workers studied by Oliver (1975) had exposure to pure TCDD. Systemic illness is usually reported only in workers with chloracrye. However, Jirasek et al. (1976) cite 4~workcrs with systemic illness without chloracnc. From the other published reports, it is not clear whether all exposed workers were examined for systemic illness or whether they were selected on the basis of chloracnc which may have led to the prhaps erroneous assumption that in humans, illness caused by TCDD must always be accompanied by chloracne. Jirasek et al. (1976) found that a number of their patients h2d porphyria cutanea tarda. In addition to the chloracne, hypertrichosis and--hyperpiementation were noted. Abnormal- liver function test, results (elevated SCOT and SGPT) were obtained for II of 80 patients. In more than half of the workers, total cholesterol, total lipids, and phospholipids were elevated. Urinary uroporphyrins were elevated in 23 workers. Thin layer chromatography showed that urinary S- and 4-carboxyporphyrin were increased. Both liver and urine .fluoresced under UV light. A peripheral neuropathy was documented in 17 of these workers. In 4 workers, localized effects on the central nervous system were also observed. In the outbreak reported by Blciberg et al. (1964), a number of workers had, in addition to chloracnc, abnormal excretion of urinary uroporphyrins, hirsutism, and hyperpigmentation. Six years later, in a followup study of the same plant, only one worker had persisteni uroporphyrinuria (Poland et aI., 1971). In addition, a number of authors (Schulz, 1957; Bauer et al., 1961; Jirasek et a!., 1976; Oliver, 1975) observed a neurasthenic syndrome characterized by a lack of drive and vigor, sleep disorders, emotional instability and diminished libido or potency (Klcu and Gollz 1971). Bauer et al. (1961) studied three groups of workers in Germany who had developed chloracne and/or systemic illness after working in the production of chlorinated phenols. Liver biopsies of three workers showed in one instance a fatty liver with slight fibrosis and an inflammatory reaction, and in two instances, `perihepatic' changes and a brown pigment which stained panially positive for iron. A liver biopsy from another show ed a gray pigment which was not positive for iron. Among the long-term followup studies reported thus far in workers exposed to nibrotigh nificant v.ed. L'n* or have Sit ro. -,r C o. in leiberg cl systemic ;.gs were 2. 2,4,5), also to iy caused exposure however, from the -.mined nc which 3used by . cutanea on were T) were lesierol, elevated icrboxylight. A' kers, .. .oreak 'ition to j hypermly one number r, 1975) or, sleep id Goliz -ho had ciion of c fatty stances, `or iron, or iron, loscd to uccupottond exposure 391 TCDD is one by Thicss and Goldmann (1976). Of ihc 53 original workers exposed to TCDD in 1953, 22 were siill employed by BASI; in 1976; 3 workers received partial compensation - 1 for persistent chloracnc, 1 for residual paresis of the left leg, and I because of deafness. Apart from residual scars, the other '8 workers had no persistent skin lesions in 1976. Causes of death were as fo''.*us: 2 - myocardial infarct, A - cardiovascular decompensation, A - carcinoma of different sites, I mitral stenosis, 2 - suicide, I - bleeding of the esophagus. As mentioned, one worker had died earlier (Goldmann et al., 1972). No information was given on the 16 retired workers. This study illustrates how persistent the cliloracne may be in some individuals. Recently, a followup study was also conducted on the workers in Nitro, West Virginia (Zack and Suskind, 1980) in which the acute symptoms initially suffered by the workers were described. Aside from the symptoms and signs already mentioned, 4 of 6 workers who were examined in 1949 and 1950 had an enfarged liver and a delayed prothrombin time at that time. A regression of symptoms and signs was observed in these workers when they were reexamined in 1953. The mortality experience of 121 of these workers who had developed chloracnc following the explosion in 1949 was also reported. Among this group of workers, 32 deaths were ' recorded against 46.41 expected. There were 9 deaths from malignant neoplasms with 9.04 expected. There were 5 lung cancer deaths versus 3.02 expected, 1 skin cancer death with 0.15 expected, and 3 deaths from neoplasms of lymphatic and hematopoietic tissue. A followup examination of 11 of 23 workers who had first become sick in * 1953/1954 following exposure to TCDD were reexamined in 1976 (Krause and Bras>ow, 197S). The chloracnc had completely disappeared in only 2 workers. Seven of the 11 still complained of epigastric pain, nausea and intolerance of alcohol. Six of the 11 had an enlarged liver which was not present when they were examined in the 1950s and 6 of the 11 had at least one abnormal liver function test. Furthermore,Hardcll and SandstrOm (1979) have reported an increased incidence of mesenchymal ' tumors in workers who were cither exposed to technical 2,4,5-trichlorophenol or 2,4.5-tnchlor6phcnoxiaccuc acid. The problem'with all of these studies is that the number of cases examined is small. Hardcll and SandstrOm tried to control for that by conducting a case control study where they matched 4 controls to each case by age, sex and locality. However, by excluding all control cases with cancer, they may have biased their study. - Another chlorinated phenol, pcnlachlorophcnol. is used extensively as a wood preservative and fungicide. This product is contaminated with chlorinated dibenzodioxins and chlorinated dibenzofurans, but usually with the hexa-, hepta- and octahomologs (Chapter 2).`Occasionally, workers engagedTn;fhc production of pcnla chlorophcnol have also developed chloracnc (Ilaader and:Bauer, 1951) and com plaints such as neuralgie.pain in the lower extremities, persistent bronchitis and eye irritation (Behrbohm, 1959). The bronchitis seems to be more prevalent in workers exposed to technical pentaehlorophenol than to the other technical products a. M If. i IB 392 R.D. Kimbrough discussed in this chapter. Workers dealing with wood preservatives again experience mixed chemical exposure. Other chemicals used in such industries include organic arsenic and tin compounds, copper derivatives and creosotes. Penlaehlorophenol per sc is an uncouplcr of oxidative phosphorylation and, like 2,4-dinilrophenol, increases the metabolic rate,.rcsulting in hyperthermia, profuse sweating and weight loss. A number of fatalities following exposure to penlaehlorophenol have been described (Mason, et a!., 1965, Bergner et ah, 1965). In these eases, absorption of several hundred mg of penlaehlorophenol has usually occurred in severe or fatal poisoning and penlaehlorophenol blood levels as high as 10-20 ppm (/ig/g) have been measured soon after exposure. On the other hand, workers in wood-treating plants may reach penlaehlorophenol blood and urine concentrations as high as 10-20 ppm without symptoms of toxicity (Casarett et ah, 1969). Simultaneous exposure to heat may make workers more susceptible to the toxic effects of pentachlorophenoh Since penlaehlorophenol is used extensively, detection of ppb (ng/g) concentrations of penlaehlorophenol in blood or urine must be considered to repre sent background levels which arc frequently detected in the general population (Bevenue et ah, 1967; Casarett et ah, 1969). In some fatal human eases, hepato cellular necrosis was observed^Truhaut et ah, 1952; Gordon, 1956). Whether these effects rcfulted from the simultaneous exposure to toxic contaminants in pcniachlorophcnol has never been investigated (see also Chapters 2 and 5). Vacuolation of hepato.yics was.also noted in livers of infants who were accidentally exposed to technical-grade penlaehlorophenol in a nursery (Robson et ah, 1969). . 9C.7. Chlorinated ierphcnyls'and brominated compounds Essentially no information is presently available on halogcnated tcrphcnyls and only one preliminary study on workers exposed to brominated biphenyls has been con ducted (Kay, 1977), In addition, Bahn et ah (1980} examined 35 workers of a total cohort of 86 men who had been engaged in the manufacture of dccabromobiphenyl and dccabromobiphenyl oxide. A total of 89 control subjects were chosen from steel workers and wire men. Studies of thyroid function revealed four eases of primary hypothyroidism in-the 35 exposed workers and in none of the controls. This repre sented a prevalence of 1I.47& which is statistically significantly higher than the background incidence of 2.8^0 found in males in the United Kingdom. Since the group of subjects studied was small, additional studies will have to be done to deter mine how prevalent hypothyroidism is following exposure to these types of compounds. Summary The occupational diseases caused by halogcnated biphenyls, tcrphcnyls, naph 15 - ' ! thalenes. dibenzodioxins and iJibcn2ofurans were reviewed. Occupational illness has primarily occurred following exposure to 2,3,7,8-tctrachlorodibcnzodioxin, chlorin- Occt ated expc tard. men Refe Adat 5k' 'Allei Meh Alva ' tnt 14 Baac M Bahr M Baht an -N. . ' Bars in Baut. lui. Beai T. \V Bchr * G. Beni of 20 Berg PC Beit' D* Bevi pl" Bici! pc Brov N' Ai C a y. ' P> Coli Con 27 cl' alcd biphenyls and chlorinated naphthalenes; The health problems associated with .c exposure to these compounds include chloracnc, liver disease, porphyria cutanea ol tarda, and neuropathies. Not much is known about the other compounds mentioned. .1 :n References 3f a] Adams. E.M., Irish, D.D., Spencer, H.C. and Rowe, V.K. (19-11) The response of rabbit .'c skin to compounds reported to have caused acncform dermatitis. Ind. Med. 2, 1--1. Allen, J.R., Barsotli, D.A,, Van Miller, J.P., Abrahamson, L.J. and Lalich, J.J. (1977) as .Morphological changes in monkeys consuming a diet containing low levels of 2,3,7,8-tctrachlorodibcnzo-p-dioxin. Food Cosnicl. Toxicol. 15, 401-410. JS Alvarcs. A.P., Fischbein, A., Anderson, K.E. and Kappas, A. (1977) Alterations in drug a- metabolism in workers exposed to polychlorinated biphenyls. Clin. Phnrm. Therap. 22, S) 140-146. ; Baader, E.W. and Bauer, HJ . (1951) Industrial intoxication due to pcntnchlorophenol. Ind. Med. Surg. 20, 286-290. m Bahn, A.K.. Rosenwaike, I., Herrmann, N.. Grover, P,, Stcllman, J. and O 'Leary, K. (1976) o- Melanoma after exposure to PCBs. N.Eng. J. Med. 295, 450.* se Bahn, A.K., Mills, J.A., Snyder, P.J., Gann, P.H., Houten. L., Bialik, O.. Hollmann, L. a- and Utiger, R.D. (19RC; Hypothyroidism in workers exposed to polybroniinaied biphenyls. N.Eng. J. Med. 302. 31-3*3. -O Barsoui. D.A. and Allen, J.R. (1975) Effects of polychlorinated biphenyls on reproduction in the primate. Fed. Proc. 34, 33S. Bauer, H., Schulz, K.H. and Spicgclbcrg. U. (1961) Berufliche Vergiftungen bei der Herstel lung von Chlorphcnol-Verbindungen. Arch. Gcwcrbcpathol. Gewerbehyg. IR. 538-555. Beaumont. J.L., Carlson, L.A.. Cooper. G.R., Fejfar. A., Fredrickson, D.S. and Sirasser, T. (1970) Memoranda: Classification of hyperlipidaemias and hyperlipoproteinemias. Bull. IV* WHO 43, 891-90S. Behrbohm, P. (1959) Uber Gefahren beim Umgang^ mit chlorierten Phenolen. Dlsch. 1- Gesundheiiswes. 14, 614-619. ] Bcnnctl, G.A., Drinker. C.K. and Warren, M.F. (1938) Morphological changes in the livers vi of rats resulting from exposure to certain chlorinated .hydrocarbons, J. Ind. Hyg. Toxicol. cl 20. 97-123. 'V Bergner, H.. Consiontinidis, P. and Marlin, J.H. (1965) Industrial pcmachlorophcnol poisoning in Winnipeg. Can. Med. Assoc. J. '92. 448-451. Bfitmann. S. (1901) Chloracnc, eine besondere Form von professioneller I lautcrkrankung. e Dlsch. Med. Woclicnschr. 27. 437. Bevenue, A.. Wilson, J., Casaren. L J . and Klemmer, H'.W. (1967) A survey of pcnlachloro- phenol content in human urine. Dull. Environ. Con mm. Toxicol. 2. 319-322. BIcibcrg, J., Wallen, M.. Brodkirt, R. and Applcbaum, I.L. (1964) Industrially acquired porphyria. Arch. Dermatol. 89, 793-797. Brown. D.P., and Jones, M.. personal communication. Li.S. Dept. HMS. PHS, CDC, NIOSH. Division Surveillance. Hazard Evaluations and Field Studies. Cincinnati, Ohio. 45226. Casaren, L.J., Besenue. A., Yauger. Jr., W.L, and Whalen. S.A. (19.5/) Observations on pentaehlorophcnol in human Mood and urine. Am. Intijsi. Hyg. Assoc. J. 30, 360-366. Collier. E. (1943) Poisoning by chlorinated naphthalenes. Lancet I, 72-74. -S Cotter. L.H. (1944) Pcntachlorinarcd naphthalenes in industry. J. Am. Med. Assoc. 125. 273-274. m