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NOTICEi Thu material may ba protectad by copyright. chapter k Occupational exposure RENATE D. KIMBROUGH roiicalot/ Branch. Ctnttrfor Dtttmst Control, Dtportmtni of Htalth and Human Strains, Public Httlih Servtee, Atlanta, CA 30533, V.S.A. 9C.1. Introduction Reports of illness associated with exposure to chlorinated organic chemicals of the type discussed in this book date back to the latter part of the 19th century (Herxheimer, 1899) and the early part of the 20ih century (Betunann, 1901; Wtuer, 1918; Lehmann. 1903). Extensive outbreaks following exposure to chlorinated naphthalenes occurred during World War I, 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 clinical syndrome that is produced by the halogenatcd biphenyls, naphthalenes, dibenzodioxins and dlbcnxofurans. It ia presently not known whether halogenated terphenyit may cause similar problems. Some of the signs and symptoms observed following exposure to toxic levels of these compounds have been noted frequently (Table 9C.1). In all instances, the skin lesion, chioracnt. was usually one of the first signs noted. Signs and symptoms such as weight loss, general malaise, nausea. loia of appetite, impairment of liver function, hepatic prophyria (porphyria cutanea 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 afl of the observed signs have been reported for all of the chemicals under discussion. Chloracne, weight toss and impaired liver function haw been most frequently associated with exposure to toxic levels of these chemicals. As outlined in Chapter 7, 2,4.3-trichloropbenol and all chemicals made from It may be contaminated with 2J.7,8-<etrachlorodibenzodioxin. Pcntschlorophenoi Kimbrouth ltd.) Hufottnaltd hiphtnyts, ttrphtnyls. naphthalenes. dibenzodioxins and rtitled products Elsevier/North-Holland OiomtOicof Prtss I9W NONE 221406 TAILS 90 Symptoms and reporie after occupational eiporure. System Lesion Cheat!cal Icfntw* Oeneral Moodihot eyn, tinHudc. headache, abdominal pain, impotence. wet*t loti, intonmia, alopecia, disturb* .anee in tauc chlorinated napfabalenet technical pentacMoeophcnol 2.1,7 .t-tnracMotadtbentodietia chlorinaied biphenylt Good and Peasty, 194) laadet and Sauer, 1951; Sehrbabf, mf Jirairt et al., (974 loner and AMea. 191* Skin* liver chloracnr. piIfit m acute ycRnw atrophy. bepotuerSnlar nevTOdt, mtU flbtodt, fatly chanye, abnormal Iteer function, porphyria cutanea tarda 2.J.7J-TCDO chlorinated biphenyls chlorinated napbtbaicnci lech, pemachtotophcuol other Mtfc. chlorinate phenols cMwkncrf Hiifkilulrm pent**, beta-) 2.J.74-TCUO Hctit pcvilicMtroplwMt aptotii^phRlaWriapaMJn^ Mpncuyn (abnormal hver function lntt| Kinunina ae Schutt, (9)7 Jitter and Ahfen, I9M (rood ae I'emiy, I<H1 Itehthohm. 19)9 Stintily. 1940; DufOh and Cotomb, 19)4 CnM. 1*4) Sauer n al., (Hi; Bkibrrf ei al., 1944; Goldnmna, 1972; Jirateh et al., 1974 Tmhaut et si , 19)2; Gordon, Owr ei al.. 1974 tract anoreria, votnlHn*, hemotrhote chlorinate nrptMiulcnrr 2.], 7,1-mfacMotodibefuodioiiia Good and Pemly, 194); Dwyer, 1944 Hofmann. 1*57; GoWmann, 1972 Peripheral nervous lyttetn wwi netieopoihy, peripheral neurUh 2,).7,t-Mt/achlore4ibeiuodiowt Goldmaim, 1972; Jiratrh cl al-, 1974 Respiratory lywetu bronchitl*. reduced vital capacity technical pcntachlornpltcntit polychlorinated blphen)h Reader and ILniet, 1951 Warthairct ).. 1979 a. The lymptonH and Ufni hue nett otemid by a number of other authors. The references Sued verve merely at cvimr*c b, nepfametualltm nai refutltd in btacht fur rtdminaied naphlliatem I by Outer (1944), K .D Kimbrough NOUS 221407 Occupational exposure 375 may be contaminated with more highly chlorinated dibenzodioxins, dibenzofursns and hexaehlocobenzene. The polychlorinated biphenyl* contain trace amounts of chlorinated dibenxofurans and chlorinated naphthalenes. Whether chlorinated naphthalenes arc contaminated with chlorinated dibenzodioxins and chlorinated dibenxofurans 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 cases of chloracne which Herxlteimer reported (JI99) occurred in a room where caustic potash was produced by the electrolysis of potassium chloride. The chlorine was reacted with calcium to give calcium chkiride. Hcntheimer laMaUy assumed that nascent chlorine had caused the dermatitis. Crow (1970k) primal out that, although many authort clung to the nascent chlorine theory, the cause was halogenated hydrocarbons which originated from the tar lining la the absorption towers, or the anodes of tar, bitumen and charcoal that were used in the eieciroiytk manufacture of hydrochloric add and similar substances. Theta 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 acncgenk agents and also cause some of the systemic toxic effects. Mott chlorinated biphenyl mixtures are contaminated with 2,),7l8-tetrachlorodibeuofuran which may contribute to tbeir toxirity. Certainly the contaminants in 2,4,5-lrichloropbenol and related products are the agents rcsponsibla for chloracne (Kimming end Schulz, 1957). Most likely the contaminant hexachlorodtbcnzodioxin in pentachlorophenol 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 10 as chlor acne after having had exposure to the halogenated cjclic compounds mentioned above for several weeks or months. Following exposure to high concentrations of 2,),7,8-tetrachlorodibentodioxins, the onset may be more rapid. Even after a single exposure 10 2.J.7,8-tetrachlorodfbenzodioxtns. the onset of chloracne may be delayed for several weeks, but if the exposure is severe, it may appear in as lactic as 2-) days. One, or repeated short-term, exposure to 2.3,7,8-teirachlorodibenzo- dioxin usually occurs during the production of 2.4^-(richlorophcaol when the reaction overheats, resulting in the increased production of the unwanted contamin ant 2,3,7,8-cetrachlorodibcnsodioxin. This exothermic reaction may give rise to explosions (Milncs, 1971). ^ The clinical features of chloracne, regardless of the type of chemical that caused it, have been most consistent. The most distinctive cutaneous lesion is (he 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.2). Usually these lesions start over the maxillary bone, then involve the HONS 221408 376 R.D. Kimbrough Fig. 9C, I. Only mild cMoncw over maxillary bone is noted. entire face, the neck and ears. Often the nose and nasolabial folds are not as extensively involved. In males, the genitalia may be involved. Furthermore, lesions may be present on the back, arms and legs, and other areas of the body, particularly where gar menu are in close eontact with the skin. Depending on the severity, the skin contains only a few lesions (Fig. 9C.1) or the lesions are so close together that they give the skin a rough, grayish-brown appearance. The comedones and eysts can become secondarily infected and large pustules may form. Cysu may rupture and eause foreign body granulomata. The chloracne-type skin lesion may be preceded by a faint rash which, in some cases, itehes 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 chloracne. Since the workers are often exposed to the chloracnegenic agent, such as TCDD, as well as other chemieals, such as 2,4,5-irichlorophenol. it is not entirely dear whether the early rash is pro duced by the TCDD or due to the irritating effect of the 2,4,3-trichlorophenol or other substances, Once ehloracnc has developed, it may remain active for many years, and particu larly when secondary infections occur, deep-pitied sears may remain as a residual effect. These scars ean be quite disfiguring (Fig. 9C.3). No specific treatment is available and most palliative means have not been very effective. Treatment in the mons 221409 Occupational exposurt Fig. 9C.2. A worker with acute extensive ehloracnc. put has included Vitamin A add, UV light, X*rty, lancing and expressing or pustules. However, the best treatment is prevention, although dermabrasion has also been effective (Crow, 1970a), The manufacture of these chlorinated hydrocarbons and the coating of wires and condensers with insulating materials and other industrial processes should be dona 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 are not delayed. Schwartz and Peck (1943) suggested synthetic wetting agents instead of soap as cleanser. They also recommended monthly skin examinations and liver function tests. In the United Sutts, recommendations for a lower polychlorinated biphenyl standard were made by the National Institute of Occupational Health in 1977 (NIOSH. 1977) which suggests proper hygiene procedures to avoid dermal contaci and recommends that occupational exposure be controlled so that no worker is exposed to PCBs at a concentration greater than 1.0 *g/m} of air deter- MOMS 221410 J7 R-D, Kimbrough mined is a time,weigh ted average (NJOSH, 1977a). The existing standards Tor occupational exposure to PCBs in different countries have been summarised by the International Labour Office (1970). They range from 0.3 mg/m1 to 1.0 mg/m5 in many countries. It is particularly important that no potentially contaminated clothes are taken home sinee chloraene has been transmitted by this vehicle to other members of the family. A skin lesion exactly like chloraene 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-disease develops following exposure to compounds that produce chloraene 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 ei al., 1977). Prior to the ability to detect chloracnegenic compounds by chemical analysts, the rabbit ear test was utilized to screen technical products for their presence (Adams et al., 1941) (see also Chapter 5). In rabbits, monkeys and men, the microscopic appearance of the skin lesion varies, depending on the interval between last exposure and the time the biopsy wU obtained. Microscopic examination of human skin biopsies from chloraene cases or tissue sections from rabbit ears with hyperkeratosis show markedly dilated hair follicles that are filled with keratin. Eventually the entire follicular appendage becomes transformed into a sac of keratin (Figs. 9C.4 and 9C.S). 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 folliclesThis is followed by intrafollicular collections of leukocytes, microvesetdes and abccsses within the follicular wall. Subsequently the follicular wall is destroyed and an abcess may develop. According to Shelley and Kligman (1937). who induced chloraene experimentally in 31 male adults with chlorinated naphthalenes, the sebaceous glands returned gradually months after the last application. Eventually, the epithelium lining the keratin-filled follicles atrophies. Although on casual examination, chloraene resembles juvenile aene, the distri bution of chloraene is quite different as is frequently the age of onset. Juvenile acne is characterized by papular eruptions due to inflammation with the accumulation of secretion of the sebaceous glands. Hyperkeratosis and atrophy of sebaceous glands does not occur in juvenile acne. la a few instances in which workers developed chloraene following exposure to 24,7,4-tetrechlorodibenzodioxin. hypertrichosis and hyperpigmentation was pro nounced (Jirasek et at., 1976; Bteiberg et al., 1964). For many years, it was believed that chloraene was due to external contact and not the result of systemic exposure to the aenegenic agents. However, this belief is refuted by two episodes of accidental poisoning following ingestion of t he aenegenic compounds. In one episode, *Yusho` rice bran oil became contaminated with a hons 2214U Occupational exposure 379 F)|. fC.3. Residual Kan subsequent to chtorecne. F1|. 9C.4. Follicular appendage of the tkin from a normal rabbit car. MOMS 221412 380 R D. Kimbrough Fi(. 9C.5. Follicular appendage from a rabbit car affected by chloracnegcnic i|em. mixture of chlorinated biphenyls, quarterphenyls and dibenzofurans (Rappe et al.. 1977; Miyaia et al., 1978), and resulted in illness which included chloracne (Chapter 9B.I). In 1943, six people fried vegetables in a fat-like substance thought to have been hexachloronaphthalene which they found in the bomb ruins of Berlin in Germany (Heruberg, 1947) and subsequently developed chloracne. Similar skin lesions can also be produced in primates by oral exposure to chlorinated biphenyls or chlorin ated dibenxodioxins (Bartoni and Alien, 1973; Allen et al., 1977). In rabbits, depending on the dose, application of acnegenic agents on the ear may either only result in local hyperkeratosis or at higher doses also produce a toxic effect on (he liver (Kimbrough, 1977). Thus, local dermal application of these compounds, particularly the 2,3,7,8-tetrachlorodibenzodioxin may also lead to systemic disease. More recently, occupational exposure to 3,4-dlchloroanjline and some herbicides made from it, such as propenil (/v-{3,4-dichlorophcnyl)propsnafntde) have also produced chloracne. In these instances, the toxic contaminant is tetrachloroazobenzene or tetrachloroazoxy benzene (Morse et al,, 1979). These compounds are not as stable as the chemicals discussed in this book, and hence may be less of a problem. HONS 221413 Occupational txporurt 311 9C.3. Presence of halogenated aromatics In human tissues aMi body fluid* Of ail the chemicals discussed, only the chlorinated biphenyl* have been measured with any frequency in human tissues. Chlorinated dibenzofuraos were found in patients suffering from Yusho (Chapter 9BI) and in om instance, tissue was analyzed for 2,3,7,1-tctrachlorodibenzodio.xin from a resident living in the Seveso area in Italy (Chapter 9B2). Brominaied biphenyls are not as prevalent in human tissues a* chlorinated biphenyls and are primarily found In the population of the state of Michigan, U.S.A. (Chapter 9A). Since the chlorinated biphenyls are Kpo> phi lie. the highest concentration is found in adipose tissue, although proportionally lower concentrations are present in other organs as well as blood. The different chlorinated biphenyl isomers are metabolized at different rates (Chapter 4) resulting in shifts in the gafchromatographic pattern. The ratio of polychlorinated biphenyls between adipose tissue, other organs and blood varies somewhat, depending on whether exposure is current or took plaee in the past and whether the blood specimen was fasting. Pregnancy, weight ton and kidney disease may also affect this ratio, in order to determine the body burden of these compounds, ediposa tissue would he tltt most suitable specimen for most of the halogenated 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 idem of the levels of exposure. A person with a polychlorinated biphenyl blood level of 10 ppb (>tg/D might at the most have adipose tissue levels of a few ppm (mg/kg) or less, while those with blood levels of 100 ppb (pg/D might have adipose levels anywhere from 20 to 30 ppm (mg/kg). Since the chlorinated dtbenzodioxins and chlorinated dibenzofurant, particularly the 2,3,7,8-teua- isomer, are so extremely toxic, illness would be expected to be present at lower concentrations than for chlorinated bi< TABLE 9C.Z Partial Du or chemical COfflpBJtlBi Of WddflR ftkast or larpe quaauba of TCDD has occurred Serins >ht production at i.Sj-tricfaloreplisnol and island products.' Name or rampiny Pteee Year Mtaenee Mnac--> EadiicSd And* end Soda Pabrik Philips Dunbar Ud. Coalhe aad Owadcsl Products Lid. J CMESA Nhre, W.Va, U.SJL ludwlBihaha. khda. G.FJL Aawntdaei district. Harlow, i no fmnirHiw GriaohU. Frame Mmr.UJL 19* I9JJ 1941 1944 1941 Kamburs. G-f.IL I9M Severn. Italy 1914 IAEC, 1991 Kofnwaa, 1*57 Dalderop. 1994a. 1994b Dafois and Coiomb. 19)4 Mar. 1991 Scbals. I9S9-. Ktmfniai aad Schuta. 1*59 Hay. 1979 s. Additional compands set listed by Hay 0979). HOMS 221414 382 R.O. KimbroufH phenyls, These chemicals are also more polar and il is possible lhai Iheir concen tration in the liver may be different relative to the concentration in adipose tissue. However, this was not the case for the one resident from Scveso, Italy, who was studied in this respect (Chapter 9B2). Low back|round levels of PCBs can be found in blood and other tissues of the general population of industrialized nations (Chapter 9A), Such background levels need to be considered when occupational exposure is evaluated. Since PCBs are mixtures of chemicals, quantitation is quite difficult and a number of different ways of quantitating them have been proposed, such as adding the PCB peak heights of the gas chromatograms and comparing it to a known amount of standard (see Chapter 2). Because of these differences in quantitation, the differences in isomeric composition of the different PCB mixtures, and differences in individual susceptibility, it can presently not be predicted with certainty what a toxic blood or adipose tissue level constitutes in each case. How ever, in some individuals, PCB concentrations of 50 ppb (ng/g) in blood were associated with abnormal liver function tests (MMWR, 1971), while in other studies (Karppanen and Kolho, 1973), this was not the case. In capacitor plants where PCBs art heated and, therefore, voliialized, considerable respiratory exposure occurs (Table 9C.4). If PCBs are handled at room temperature as in the production and repair of transformers, dermal exposure may predominate. Very little information is available linking PCB air levels to PCB blood levels, PCB adipose tissue levels or symptoms (Table 9C.3). Since PCB air levels may fluctuate a great deal, air monitoring may. not adequately reflect exposure. No published information is available on the presence of halogenated naph thalenes and terphenyls in workers. Neither have the chlorinated dibenzodioxins or dlbenzofurans been extensively measured in the occupational setting. TABLE 9C.) PCB eornmirmUoai in the occupational environment end in blood or worker* capoacd to PCBt. Duration of PCB exposure PCB leveli Environmental (ntf/mb Erfectt reported Blood tppbj Reference Not known 4--1 mo. <1-10 yr. 1.J yr, eve. -(in 14 mo. 1-23 yr. Up to 15 yr. 10 J-T 04-1.* nor reported 0.01J-04T 0.1 0.11-1.44 nor rtperted <1 m, tv*. IM. 4vt. l*-2lt - >100 7-500 74-1.900 unbearable irritation clilorecne chloracae, hyperpt*men- tation. liver injury eblorecne irritation, liver injury cbioraCM. liver injury ctitorvne, liver injury rhloracne, elevated trialyetndee no effect Elkim, 1959 PiKCineili. 1954 Hesttbwa ei el.. 1971 Klttmure ei tl.. 1973 Levy ei el -. 1977 Metpi ei al.. 1954 Ouw t el.. 197* Hera ei at.. 1974 Hera ei al.. 1973 Karppanen end Kolho. 197) HONS 221*15 Occupational exposure jlj 9C.4. Polychlorinated biphenyls Chlorinated biphenyls (PCBs) were introduced into industry around 1929 and in (he early 1930s. They were primarily used as dielectric fluids in capacitors and trans formers. In capacitor plants, the chances of being exposed to PCB vapors were greater than in transformer plants. Later, (he use of polychlorinated biphenyls expanded to other areas (Chapter I). One of the first reports on health effects of polychlorinated biphenyls was made by Jonei and Alden (1936), These authors examined |7 of 23 workers that were engaged in the production of polychlorinated biphenyls, AU of the workers had chloracne, The chloracne involved the face, genitalia, trunk and extremities in many of the workers. Prior to the outbreak of chloracne in the plant, the electrical property of the chlorinated biphenyls had fallen below specifications and the color of the product had deepened. It was not deter mined whether this was caused by a change in the chemical composition of the material. The symptoms of illness in the report were more extensively described in the first worker that presented himself with chloracne. This worker complained of lassitude, loss of appetite and loss of libido. Unfortunately, it is not clear from the report whether a more than cursory attempt was made to determine systemic health effects, In 1937, Drinker et al, reported their efforts to determine whether chlorin ated biphenyls had systemic health effects. Their studies were prompted by three fatal cases of jaundice in workers who had been exposed to chlorinated naphtha lenes and chlorinated biphenyls. In only one of these three cases is the presence of chloracne mentioned. Exposure tn all three instances was to tetra- and pcntachloronaphthalenc and 109b chlorinated biphenyls. Drinker et al. (1937) mention and warn against the use of carbon tetrachloride as a solvent since it may have additive toxic effects on the liver. Following these studies, a tabulation of 14 chlorinated hydrocarbons with permissible safe concentrations in the air of work-rooms was made (Drinker, 1939), Over the years, other cases of chloracne following exposure 10 chlorinated biphenyls were reported in the literature. Most of these involved exposure to vapors which developed when polychlorinated biphenyls or mixtures of chlorinated terphenyls were heated (NIOSH, 1977). At timm, the skin rashes that workers developed were accompanied by puritu*. Some of these workers had other complaints, such as burning of the eyes, nose and throat, dry throat, nausea and dizziness. Many of the workers were also exposed to irichlorobenzen*. Meigs et al. (1934) reported chloracne In worker* who had had exposure to polychlorinated biphenyl vapors for 3-14 months. The concentration of polychlorinated biphenyls in the workers' breathing zone was determined to be 0.1 mg/mJ. Evidence of slight liver injury was also present in these workers. Air level determinations in the earlier outbreaks of chloracne were not reported. Only recently have better and more accurate methods of PCB quantitation been developed. Thus, Ouw et al. (1976) found air levels in a capacitor plant which ranged from 0,32 mg/ro* Arodor 1242 (PCBs) to 1.44 mg/m1. Workers in this environment complained of burning of the eyes, face and skin, and persistent body NOUS 221616 3S4 R.D, Ktmbroufh odor. Nineteen of the 34 workers were employed in an impregnating room and had heavy exposure while the remainder of the workers assembled Aroclor dipped capacitor components and had less exposure. One worker suffered from chloracne and five complained of eczematous rashes. A few of the workers had abnormal liver function tests, elevated serum protein levels and others showed low levels of serum ai-globulin. These workers had a mean PCB blood level of about 400 ppb (|ig/kg). The control group in this study had no detectable PCB blood levels. This lack of PCB background levels in the general population of New South Wales was explained by the fact that environmental pollution with PCBs in that part of the world is much lower. In most studies of workers w ith chloracne, evidence of liver injury was also found and in one study, abnormal liver function tests were present in workers who did not have chloracne (N)OSH. 1977). Elevated serum triglycerides have been found in exposed workers in the United States (Fishbein et al., 1979) and in Japanese studies. Similarly, Smith et al, (1978) found slightly alevated triglyceride levels and lower high and low density lipoproteins in workers slightly and moderately exposed to PCBs when fasting plasma levels were compared to controls. Similarity, Sak and Ahlcrs (1977) observed significantly elevated serum concentrations of triglycerides, total cholesterol and phospholipids in workers occupationally exposed to poly chlorinated biphenyls, Many factors can influence serum lipoprotein levels (Beaumont et al., 1970), such as diet, excessive alcohol consumption, pregnancy, exercise, emotional stress, smoking, estrogens, other hormones and medications, such as salicylates. In addition, hyperlipoproteinacmil also occurs in a number of common diseases, such as hypothyroidism, insulin-dependent uncontrolled diabetes, nephrotic syndrome, biliary obstruction, pancreatitis, dysglobulinemia, or auto-immune hyperlipoproteinemia. It would be of great importance to determine whether halogenated biphenyls and related compounds do generally also have such an effect as a few studies suggest, and at what exposure levels this effect occurs. Animal studies suggest that lipid metabolism in the liver may be affected by halogenated biphenyls (Kimbrough et al., 1972). Another effect of PCBs on the liver Is the Induction of mixed-function oxidases. This has been studied extensively in animals, Alvares at al. (1977) determined that in 5 workers occupationally exposed to Aroclor 1016, a PCB mixture primarily com posed of di-, tri-s tetra- and pentachlorobiphenyls, plasma antipyrtne half-life was significantly lower than in matched controls. These workers had been exposed to Aroclor 1016 for at least 2 years and had no obvious signs or symptoms of PCB poisoning, such as chloracne or abnormal clinical liver function test results. Other health effects that have been reported more recently are eye and upper respiratory irritation. Thus, Warshaw et al. (1979) studied a group of 326 workers in a capacitor plant with a mean employment of more than 15 years and a mean age of 41.1 years for mates and 47.3 years for females. Work-related eye or upper respiratory irritation was reported by 48rt of the workers, and 109b had experienced tightness in the chest. Spirometric studies were conducted on 309 workers; 66 of them were HONS 221417 Occupational exposure 315 dropped from the study because Of exposure to talc, textile dust or asbestos, leaving 243 for analysis. In mates, there were about twice as many smokers and exsmoken as nonsmokers. In females, the proportion of nonsmokers was higher. Thirty-four of the workers (144) had a reduced vital capacity and 27 of these demonstrated a restrictive pattern of impairment (FEV/FVC>0,7). According to Warshaw et al. (1979), the prevalence of restrictive impairment in the capacitor workers is comparable only to that found in asbestos workers. The vital capacity ' PCB workers that had no opportunity to be exposed to asbestos should be studied to confirm these findings. No conclusive evidence has thus far been reported which demonstrates that occu pational exposure to PCBi has caused an increased incidence of cancer. Bahn et al. (1976) reported results of a preliminary investigation. This study consisted of a March of chan records of a group of 51 research and development employees and 41 refinery plant employees at a New Jersey petrochemical facility. Between 1949 and 1957, these workers had been exposed to Aroclor 1254, a PCB mixture composed of chlorinated biphenyl homoioga from mono- to heptachlorobiphenyl. Three melanomas and two carcinomas of the pancreas were found. This incidence was significantly higher than the expected rates. Since exposure to othar chemicals alio occurred and tinea the cohort was small, funbar studies arc necessary to determina whether PCBa have caused cancer in humans. A retrospective mortality study conducted by the U.S. National Institute of Occupational Health (CDQ may provide additional information in the near future. 9C.S. Chlorinated naphthalenes Following i he early repons of chloracne which were caused by chlorinated tar products (Herxhetmer. 1899; Benman. 1901), the second episode of outbreaks of occupational chloracne occurred during the first World War following exposure to the chlorinated naphthalenes. Chlorinated naphthalenes (haiowaxes) were used in the production of gas masks. Waucr (1918) referred to chloracne as 'pemakrankhen'. The term `perna' originated from `perchlornophthalin'. The chlorinated naphthalenes were also used to impregnate fabrie and to make solas for shoes (Teleky, 1927). After World War 1, this use of chlorinated naphthalenes stopped. A few years later, the chlorinated naphthalenes were used in the mining industry as water and fire resistant insulating material for detonators. This resulted in outbreaks ef chloracne in 1926 and 1927 among workers that, produced such detonators (Teleky, 1927). Subsequently, around ,1930. chlorinated naphthalenes (Mayen and Silverberg, 1931) and chlorinated diphenyls were used as insulating materia) for cables and condensers. In the United States, several hundred cases of illness following exposure to chlorinated naphthalenes were reported. Among them were several deaths due to acute yellow atrophy of the liver (Jones, 1941; Sulzberger et al,. 1934. Flinn and Jarvik, 1936). However, such cases were isolated and it is possible that such additional factors as infectious viral hepatitis may have contri- MONS 221418 386 R.D. Kimbrough buted to the disease. Since workers in many instances were exposed to mixtures of chlorinated naphthalenes and biphenyls, it was not clear what actually caused the systemic illness. The industries concerned then initiated a study of the toxicity of these products (Drinker et al.. 1937). This resulted in improved occupational hytienc and the establishment of exposure limits at the work place and the use of lower chlorinated substances which seemed to cause leu health effects. During World War 11, chlorinated naphthalenes and chlorinated biphenyls wore extensively used in the ship-building industry. Painting the surface of the ships with these chemicals neutralized them against magnetic contact mines. Furthermore, the chlorinated naphthalenes were also used as insulating material for cables. In this industry, illness was observed not only in the workers who insulated the cables, but also in the workers who handled the cables after they had been manufactured. Although the use of chlorinated naphthalenes has declined, they are still used occasionally because of their low cost. Weber (1969) reported chloracne in the cable industry where chlorinated naphthalenes were used. Kleinfeld et al. (197Z) described an episode in 1972 where 92 workers were exposed to a mixture of tetra- and pentachloronaphthalenes in the manufacture of insulated electrical coils. In many of the industrial processes, the chlorinated naphthalenes were heated, producing vapors to which the workers were exposed. Although the fact that these compounds caused chloracne had been known for yean, the serious systemic effects were not generally recognized until the 1930s and 1940s. The first complaints of the workers were digestive disturbances, burning of the conjunctivas, and in some instances sexual impotence and hacmaturia (Von Wcdel et al., 1943). Other complaints were blood shot eyes, lassitude, headaches, abdominal pain, weight loss, insomnia, alopecia, and disturbances in taste (Good and Pensky, 1943). A number of case reports appeared in the literature in the '30s and '40s describing patients who worked with chlorinated naphthalenes, developed acute yellow atrophy of the liver and died (Greenburg et al,, 1939). Cotter (1944) described a number of such cases. Most of these palienu were exposed to chlorinated naphthalenes for several weeks to several months before they became ill. In many instances, chloracne was not recorded in the case reports, and in some instances it was pointed out that it was not present. The following account by McLetchic and Robertson (1942) gives a description of the typical clinical course of these workers: "This 41-year-old female was admitted with a history of nausea, vomiting, and jaundice of four weeks duration. She had been employed for the past six months at a process which exposed her to fumes of chlorinated naphthalenes. A number of her coworkers had developed an acneform dermatitis, but there was no other case of jaundice. About 8 weeks before admission, the patient began not to feel well and noticed that in the evening, her feet and anklet became swollen. Permanent puffi* nets developed around tha eyes. Two weeks later, she became breathless on slight exertion, jaundice developed four weeks prior to admission. Shortly after onset of jaundice, troublesome nausea developed. However, she did not lose any weight. Vomiting also occasionally occurred. The patient noticed that her urine was MOMS 221619 Occupational exposure 317 becoming darker while her stools were grayish in color. Physical examination on admission revealed a well-nourished patient which showed no signs or any great discomfort and was mentally alert. A definite but not deep icteric tinge of the skin and con junctivae was present and a faint purpuric rash was noted on the legs and lower abdomen. There was also slight edema around the ankles and puffiness of ihc tissues around the eyes. The physical findings were essentially negative except for a slight increase in the area of cardiac dullness and a slightly diminished liver dullness. The urine was dark brown and contained bile. On the third day after <tmii th patient became drowsy and the jaundice increased in int*:aity. Muscular twitching of all limbs developed. A patchy-brown discoloration of the skin over the area and the chest was noted. The patient continued in coma, the pulse rapidly increased in rate, and she died on the fifth day after admission. On post-mortem examination, two pints of straw-colored fluid were found in the peritoneal cavity and there was marked edema of the loose retroperitoneal tissues. The liver wu very small, shape less, collapsed under a wrinkled capsule, toft in consistency with few firm nodules scattered throughout. The nodules varied in size from a few millimeters to 2.5 an la diameter. The liver weighed 650 grams (normal 1,500 grams). On section, the nodules were of a dull-yellow color. The intervening soft tissue was mainly red. The gallbladder was normal; the stomach contained much dark-brown mucus. The kidneys were stained deep green, and the heart revealed moderate hypertrophy end slight dilitation of the right ventricle. The cardiac valves showed chronic rheumatic endocarditis. On histologic examination, the liver showed a varying picture of acuta damage, fibrous proliferation and regeneration. Large areas of autolyzed, necrotic, hepatic parenchyma were noted. Islets of surviving epithelial tissue in areas with collapsed sinusoids where dead hepatocytes had been resorbed were noted. In theta areas, congestion, hemorrhage, and round cell infiltration was also present. Furthermore, small areas of liver parenchyma were surrounded by bands of young connective tissue which contained many poorly formed bile ducts. The pancreas showed minute ares of necrosis in the pancreatic fat. No other findings of note were made." The livers of the fatal cases reported by Cotter (1944) showed in many arena complete absence of hepatic ceils, bile duct proliferation, hemorrhage, and aa inflammatory reaction. None of his cases showed typical chloracne although one patient had a papular rash of the forearms. Cotter points out that in blacks, depig mentation of the skin may be one of the early manifestations of illness. Another interesting observation among the seven cases reported by Cotter was the fact that one worker became jaundiced after a year of working with chloronaphthaienes. He was transferred to a department where he did not come in contact with these chemicals and his jaundice subsided, but recurred when he was put back on his original job. Although in most of these instances, the workers were exposed to vapors of chlorinatsd naphthalenes. Peck (1944) noted an increasing incidence of acne-like lesions in electricians who were installing cables on ships during the second worid war. These cables had been coated with chlorinated naphthalenes and chtoro- MONS 221420 R D. Kimbrough diphenyls. The chloracne w-a* usually found in electricians engaged in stripping (the coated cables). The halowax which was stripped off was impregnated in asbestos which was wrapped around the wires as insulation. Experimental studies were-carricd out with the chlorinated naphthalenes which caused outbreaks in different working situations. These mixtures were composed of chlorinated naphthalenes with various percentages of chlorination. Teleky (1927) pointed out that in factories where the substances used contained only 147* chlorine, the incidence of chloracne was much reduced. In one of the companies, the health status of the workers was greatly improved when naphthalenes with only 7-l9fc of chlorine were substituted for those with higher percentages of chlorine. A number of experimental studies stimulated by the health problems observed in workers exposed to these chlorinated naphthalenes demonstrated that the pentaand hexachloronaphthalenes seemed to be the most toxic. This experimental work also indicated that mixtures of chlorinated naphthalenes with chlorinated diphenyls increased the toxicity of these materials (Von Wedel et al., 1943). During that time, the most extensive studies were done by Bennett et al. (1931). In these studies, the trichlomaphthalenes were less hepatotoxic than the higher chlorinated compounds and the chlorinated diphenyls were considered to be the most toxic of all. However, no chemical analyses for any of these compounds were performed at the time to determine whether any toxic impurities might be present. Similarly, Shelley and Kligman (1937) tested a number of halowaxes for acncgenic potential in humans. The following mixtures of chlorinated naphthalenes were tested: Mono- and dichloronaphthalenes (Halowax 1000), tri- and tetrachlornaphthalenes (Halowax 1001), pema- and hexachlornaphthalene (Halowax 1014), hepuchlornaphthalene (Halowax 1032) and octachlornaphthalene (Halowax 1031). Of these, only the mixture of penta- and hexachlornaphthalene produced chloraene. The other four chlorinated naphthalene mixtures were without effect. However, Mayers and Silverberg (1931) reported a series of patients who had developed chloracne after being exposed to a mixture of tri- and tetrachlornaphthalenes. Again, no chemical analysis of this particular mixture was done. On the other hand, studies in rabbits injected with mixtures of tri- and tetrachlornaphthalene. or tetraand pentachlomaphthaiene or penta- and hexachlornaphthalene only showed liver damage when they were given the penta- and hexachlornaphthalenes. but not when they were given the mixtures of the other chlorinated naphthalenes. Thus, most of the clinical observations as well as the available experimental data seem to indicate that the penta- and hexachloronaphthalenes are the most toxic components of the mixtures of chlorinated naphthalenes. 9C4. Contaminants (chlorinated dibentodioxins and chlorinated dlbenxofuranti Chlorinated dibenzodioxins and chlorinated dibenzofurans are contaminants of a number of commercial products (Chapters I, 2). The only documented episode of substantial exposure of humans to chlorinated dibenzofurans occurred in Japan, MOMS 221421 Occupational exposure 319 and these subjects were also exposed to polychlorinated biphenyls (Chapter 9BI). It is known that products such as pentachlorophenol are contaminated with chlorin* ated dibenzodioxins and chlorinated dibenzofurans. but in the published reports dealing with occupational exposure to technical pentachlorophenol no efforts have been made to distinguish the effects of these trace contaminants from those of pentachlorophenol per se. Through the efforts of Kimming and Schulz (I9S7), it is known, however, that to a large extent, illness caused by technical 2,4,3-trichlorophcnol and all products r.ade from 2.4,3-trichlorophenol is actually caused by TCDD. TCDD is the most toxic isomer of the group of chlorinated dibenaodtadns (Chapter 5). Occupational exposure to TCDD may occur in the production of 2.4.5-trichlorophenol and all products for which 2.4,3-trichlorophenol is used as startina material. In addition, exposure to commercial products 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-trichiorophcnoi and its end products. In this type of setting, chloraeae developed gradually in some workers after they have been exposed for several weeks or months. In addition, these workers may also show systemic illness. The other type of occupational Illness has a more sudden onset. When 2,4.3trichlorophenol is produced from tetnchlorobciuene, 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 160*C. increasing amounts of TCDD are also formed. Exposure of workers to TCDD during the explosion and subsequently during clean-up operations has often been quite heavy and has resulted in the onset of chloracne in a week or two, somttimes accompanied by systemic illness. A number of such episodes have been published in the literature and some are listed in Table 9C.2. Cteeo-up crews and maintenance men are particularly endangered. Acute symptoms occurring after such accidents have consisted of headaches, nausea and dizziness. Rarely, 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 end systemic illness, such a* weight lots, easy fatigueability aad aching muscles, particularly in t.ic lower extremities and chest, may be present. Other complaints often recorded were insomnia, irritability and lots of libido. The liver may become tender and enlarged, and sensory changes, particularly in the lower extremities, have bean obeervsd. Total serum lipids may be increased and the prothrombin time may be prolonged. Symptoms may be quite persistent, particularly the seme aches and pcins which are manifestations of peripheral neuropathy and the fatigueability (IARC, 1971; Bauer et al.. 1941; Bleiberg et al., 1964; May, 1973; Jensen and Walker, 1972; Oliver, 1973). Unfortunately, since chloracne is the most obvious manifestation of TCDD poisoning, the systemic effects have been lees well studied MONS 221422 390 R.D. Kimbrough and reported. While in some episodes, chloracne seems to 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 1949 or the health effects observed in the Philips Duphar Co. in the Netherlands. The reports made by Bauer et al. (1961), Schulz (1937), Bletberg et al. (1964), Oliver (1973), Goldman (1972) and Jirasek et al. (1976) describe systemic effects in more detail. Most of the persons exposed in iustrial settings were exposed to a mixture of chemicals, such as 2.4,3-trichloro,...enol, TCDD, 2,4,3trkhlorophenoxyacctic acid. and. in the episode reported by Jirasek (1976), also to pentachlorophenol. It is, therefore, not dear whether all effects were solely caused by TCDD. Only the two laboratory workers studied by Oliver (1973) had exposure to pure TCDD. Systemic illness is usually reported only in workers with chloracne. However. Jirasek et al. (1976) cite 4 workers with systemic illness without chloracne. From the other published reports, it is not dear whether all exposed workers were examined for systemic illness or whether they were selected on the basis of chloracne 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 had porphyria cutanea tarda. In addition to the chloracne. hypertrichosis and hyperpigmentation were noted. Abnormal liver function test results (elevated SCOT and SGPT) were obtained for 11 of 10 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 8- 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 Blclberg et al. (1964), a number of workers had, in addition to chloracne, abnormal excretion of urinary uroporphyrins, hirsutism, and hyper pigmentation. Six years later, in a followup study of the same plant, only one worker had persistent uroporphyrinuria (Poland et al., 1971). In addition, a number of authors (Schulz. 1937; Bauer et al,, 1961; Jirasek et aL, 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 Goltz 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 infUmmatory reaction, and in two instances, `perihepatic' changes and a brown pigment which stained partially positive for ironA liver biopsy from another showed a gray pigment which was not positive for iron. Among the long-term followup studies reported thus far in workers exposed to moms 221423 Occupational txposurr J9I TODD is one by Thiess and Goldmann (1976). Of the S3 original workers exposed to TCDD in 1953, 22 were still employed by BASF in 1976; 3 workers received partial compensation - I Tor persistent chloracnc, I for residual paresis or the left leg, and I because of deafness. Apart from residual scars, the other II workers had no persistent skin lesions in 1976. Causes of death were as follows: 2 - myocardial infarct, 4 - cardiovascular decompensation, 4 - 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 chloracnc may be in some individuals. Recently, a followup study was also conducted on the workers in Nitro, Watt Virginia (Zack and Suskind, 1910) 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 1930 had an enlarged liver and a deleyed prothrombin time at that time. A regression of symptoms and signa was observed in these workers whan they were reexamined in 1953. The mortality experience of 121 of thee* workers who had developed chloracnc following the explosion in 1949 was also reported. Among this group of workers, 32 deaths wera 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 Brassow, 1971). 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. Hardell and SanditrOm (1979) have reported an increased incidence of mesenchymal tumors in workers who wen either exposed to technical 2,4.5.trichk>roph*nol or 2.4.5'irichloroptienoxiacetlc acid. The problem with all of these studies is that the number of cases examined is small. Hardell and SandstrOm tried to control for that by conducting a case control study where they matched 4 control* 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, pemachlorophenoi. is used extensively u a wood preservative and fungicide. This product is contaminated with chlorinated dibetuodtoxins and chlorinated dlbouofurans, but usually with the hexa-. hepta- and octahomoiogs (Chapter 2). Occasionally, workers engaged in the production of pentachtorophenol have also developed chloracnc (Baader and Bauer, 1951) and com plaints such as neuralgic pain in the lower extremities, persistent bronchitis and eye irritation (Behrbohm, 1959). The bronchitis seems to be more prevalent in workers exposed io technical pemachlorophenoi than to the other technical products HONS 221424 ft. D. Kimbrough discussed in (his chapter. Workers dealing wiih wood preservatives again experience mixed chemical exposure. Other chemicals used in such industries include organic arsenic and tin compounds, copper derivatives and creosotes. Pentachlorophenol per se is an uncoupier or oxidative phosphorylation and, like 2,4-dinitrophenol. increases the metabolic rate, resulting in hyperthermia, profuse sweating and weight loss. A number of fatalities following exposure to pentachlorophenol have been described (Mason et al., 1963, Bergner et a!.. 1965). In these cases, absorption of srveral hundred mg of pentachlorophenol has usually occurred in severe or fatal poisoning and pentachlorophenol blood levels as high as 10-20 ppm Ug/g) have been measured soon after exposure. On the other hand, workers in wood-treating plants may reach pentachlorophenol blood and urine concentrations as high as 10-20 ppm without symptoms or toxicity (Casarett et at.. 1969). Simultaneous exposure to heat may make workers more susceptible to the toxic effects of pentachiorophenol. Since pentachlorophenol is used extensively, detection of ppb (ng/g) concentrations of pentachlorophenol in blood or urine must be considered to repre sent background levels which are frequently detected in the general population (Bevenue et al., 1967*, Casarett et al.,M969). In some fatal human cases, hepato cellular necrosis was observed (Truhaut et al., 1952; Cordon, 19S6). Whether these effects resulted from the simultaneous exposure to toxic contaminants in penta chlorophenol has never been investigated (see also Chapters 2 and 5). Vacuolation of hcpatocytes was also noted in livers of inrants who were accidentally exposed to technical-grade pentachlorophenol in a nursery (Robson et al., 1969). 9C.7. Chlorinated terphenylt and brominated compounds Essentially no information is presently available on halogenated terphenylt and only one preliminary study on workers exposed to brominated biphenyls has been con ducted (Kay, 1977). In addition, Bahn et al. (1980) examined 35 workers of a total cohort of 86 men who had been engaged in the manufacture of decabromobiphenyl and decabromobiphenyl oxide. A total of g9 control subjects were chosen from steel workers and wire men. Studies of thyroid function revealed four cases of primary hypothyroidism in the 33 exposed workers and in none of the controls. This repre sented a prevalence of ll.44fc which is statiatiemUy significantly higher than the background incidence of 2.88k 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 bow prevalent hypothyroidism is following exposure to these types of compounds. Summary The occupational diseases caused by halogenated biphenyls, terphenylt. naph thalenes. dibenzodioxins and dibenzofurans were reviewed. Occupational illness has primarily occurred following exposure to 2.3,7,8-tetrachlorodibenzodioxin, chlorin- MONS 221425 Octupmtlwwl txposurt J9J ated biphenyls and chlorinated naphthalenes. The health problems associated with exposure to these compounds include chloracne, liver disease, porphyria cutanea tarda, and neuropathies. Not much is known about the other compounds mentioned. References Adams, E.M., Irish, D.D., Spencer. H.C. and *owc, V.K. (tMl) The response of rabbit skin to compounds reported 10 have caused acnefora dermalitit. tad. Mad. 2, t-4. Allen, J.R., Banotti, D.A., Van Miller, J.P.. Abrahamson, UJ. and LaNch, JJ. (1177) Morphoiofical changes in monkeys consumint a diet conuiadat low levels ( T.1.T-B mil chlorodibenzo-p-diosiit. Pood Cosmet. Toxicol, is. 401-410. Alvaras, A.P.. Rschhetn, A., Anderson. K.E. and Kappas. A. (1177) Altcmtitma tat dmg metabolism ia workers exposed to polychlorinated biphenyls. Gin, Phana. Thanp, 22, 140-140. Baadar, E.W. and Baum, H.J. (1131) Industrial intoxication due to pcatacMorophenol, lad. Mad. Sur|. 10, 214-290. Baba. A.K,, Roeeuwaike, I., Hermann. N.. Grover, P., Stallman, J. and O'Leary. K. (1171) Melanoma after exposure to PCBs. N.En*. J. Med. 213, 430. Balm, AJt,, MUk, J.A.. Snyder. PJ.. Gann, P.H., Houwa. U Bialik. O.. HoAnam. L. and Utloar. R.D. (IMO) Hypothyroidism In workers exposed to poiybwmintied klpbanyh. N.Eap. J. Med. M2. JI-J3. Banotti, D.A. and Aden, J.R. (1173) ErTeets of polychlorinated biphsuyis on npseduetiaa in the primate. Fad. Proe. 34, IM. Bauer, H.. Schulz. K.H. and Spiepribcip. U. (1141) Beruftkbe Verphutipn bti dcr Hematlimp von CWorphenot-Verbtaduapca. Arch. Gewerbepaihoi. Gewerbeby*. IS, JJt-333. Beaumont, J.L., Carlson. L.A., Cooper, G.R., Ftjfar, A., Fredrickson. DJ. and Stratsar. T. (1170) Memoranda: Gattiflcaiioa of hypariipidaemiai and hyperlipoproteinemias. Bud. WHO 43, 191-104. Behrbohm. P. (IMl) Uber Gcfthran bdm Umpanp mil chlorienen Phcnolen. Duds. Gesundhciuwfa. 14.414-411. Bennett. G.A.. Drinker, C.K. and Warren. M.F. (IMS) Murphoioskal ehantes m the Even of rats resutunf from exposura to certain chlorinated hydrocarbons. J. Ind. Hyp. Toxicol. 20. 17-123. Bcrpncr. H.. Coaatontiaidia. P. and Manin, J.H. (IMS) Industrial pentsrtdorophenol potsorunp ia Wbuupcp. Can. Mad. Aside. J. 92. 441-431. Betimatui, $. (1101) Chleracne, cine bntsdm Form von professsondkr Hauterfcraafcuap, Dtaeh. Mod. WotbcMChr. 27.437. Bcvenuc, A., Wilton, J., Casarat, LJ. and Klammer. H.W. (19*7) Asarveyof peataebiorophenol tomcat la human urine. BuM. Environ. Contain. Toxicol. 2.319-322. Bleibarp. J,, WaBan, H, Brodkhi, k. and Appkbsum, l.L. 11944) Industrially acquirad porphyria. Arch. DcnmieL SI, 713-797. Brown. D.P.. and Jona*. M.. personal eommunication. UJ. Dept. HHS, PHS, CDC NI08H. OWrikaa Surveilianra. Hazard Evaluations and Field Studies, Cincinnati, Ohio. 41231 Caanrcu, LJ.. Bcvenuc. A., Ytoper, Jr., W.L. and Whalen, S.A. (1941) Observations on pemarblcrophsnni ia human blood and urine. Am. Indust. Hyp* Assoc. J. 30, 340-341 Collier, E. (1943) Poitoninp by chlorinated naphthalenes. Lineal 1.72-74. Coticr, L.H. (1144) Penuehtertnaicd naphihakncs in industry. J. Am. Med. Assoc. 123, 273 -274. MQNS 221426 394 R.D. Kimbrougn Craw, K.D. (1970a) Chloracne. A critical review including comparison of two senes of eaaat of acne from ehlornaphihaiene and pitch rumes- Trans. St. Johns Hosp. Dermatol. Soc. 34, 79-99. Crow, K.D. (1970b) Chloracne. Br. J. Derm. 13, 399-400. Dalderup, L.M. (1974a) Safety measures for takini down buildinis contaminated with io\>c material I. J. Soc. Geneesk. 5', 312-313. Dalderup. L.M. (1974b) Safety measures for takini down buildinis contaminated with toxic material II. J. Soc. Ceneesk. 32. 616-423. Drinker, C.K.. Warren, M.F. and Bennett, C.A. (1937) The problem of possible systemic effects from certain chlorinated hydrocarbons. J. ind. Hy|. Toxicol. 19, 213-111. Drinker, C.K. (1939) Further observations on the possible systemic toxicity of certain of the chlorinated hydrocarbons with suggestions for permissible concentrations in the air of workrooms. J. Ind. Hyi. Toxicol. 21. 133-139. Dtiiois, P. and Colomb. L. (1934) Acne chlorique au 2-4-3 trichlorophenol. Lyon Med. SI. 444- 447. Dwyer, J.M. (1946) Polychlornaphthalenes and liver necrosis. Med. J. Austr. 2. 703-703. Elkins, H.B. (1939) The Chemistry of industrial Toxicotoiy. 1st Edn. John Wiley and Sons. New York, pp. U9-IS0, 319-321. Fiscbbein, A.. Woirr. M.D-, Ulis, R.. Thornton, J. and Selicorr, l.J. (1979) Clinical findings amoni PCB exposed capacitor exposed manufacturing workers. Ann. N.Y. Acad. Sd. 320. 703-713. FKon, F.l. and Jarvtk, D.E. (1934) Action of certain chlorinated naphthalenes on the liver. Proc. Soc. Exp. Biol. Med. 33. I IB-120. GoMmann, P.J. (1972) Schwrrste ekute Chlorcknc durch TrichlorphcnoUenctzungsprodukte. Arbctumed. Sozialmcd. Arbcttshyg. 7, 12-11, Coed, C.K. and Pensky, N, (1943) Halowax acne ('cable rash') a cutaneous eruption <n marine electricians due to certain chlorinated naphthalenes and diphenyls. Arch. Dermatol. Syphilol. 4B, 231-237. Gordon, D. (1934) How dangerous is pcatachlorophenol? Med. J. Aust. 2), 4S3--411. Cretnburg, L., Mayers, M.R. and Smith. A.R, (1939) The systemic effects resulting from exposure to certain chlorinated hydrocarbons. J. )nd. Hvg. Toxicol. 21. 29-31. Hambrtck. G.W. (1937) The effect of substituted naphthalenes on the piloscbaceous apparatus of rabbit and man. J, Invest. Dermatol. 21.19-103. Hara. 1., Harada, A.. Kimura. S., Endo, T. and Kawano. K. (1974) Follow-uo studv of condenser factory after use of PCB discontinued (Pan I). Jpn. J. Ind. Health 16, 365 -- 344 (in Japanese). Hara, 1,, Harada, A,. Kimura. 5., Endo. T. and Kawano. 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