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ENVIRONMENTAL RESFARCH 20, 225-266 (1979)

Hexachlorobenzene (HCB): A ReviewK. DIANE COURTNEY

U.S. Environmental Protection Agency. Health Effwis Research Luhorator?,Research Triangle Park, North Carolina -7771 I

Received November 6, 19781. Introducrion. II. Human Toxicity. A. PCT Epidemic in Turkey. I. Human Toxic Expo-sure. 2. Clinical Symptoms o f PCT in Turkey. 3. Laboratory Results. B. Other ToxicExposures in Human Beings. III. Occurrence of HCB. A. Human Beings. B. Food. C. WildMammals. D. Birds. E. Fish. F. Soil. IV. Porphyria. V. HCB Toxi~if?:--Euperirnenfcrl. A.Rats. I . Toxicity and Pathology. 2. Cutaneous Lesions. B. Rabbits. C. Guinea Pigs. D.Mice. E. Hamsters. F. Monkeys. G. Dogs. H. Sheep. J. Pigs. K. Birds. 1. Chickens. 2.

Quail. 3. Kestrel. VI. Reproduction and Development. A. Multigeneration Studies. B.Teratology. C. Placental Transfer. D. Lactational Transfer. VII. DisrrihutioniMetaholism.VIII. Effects on Enzymes. IX. Conclusion.I. INTRODUCTION

Hexachlorobenzene (HCB, perchlorobenzene, C&l,) is a fungicide registeredfor use on seed grains such as wheat, barley, oats, and rye. The major use is tocontrol bunt on wheat, and a minor use is for seed treatment of onions andsorghum. Technical grade material contains about 98% HCB and 1% pentachloro-nitrobenzene (PCNB). HCB should not be confused with the improperly namedinsecticide benzene hexachloride Oindane, BHC) which is hexachlorocyclohexane(C6H,C16). In addition, HCB should not be confused with hexachlorobiphenyl, anisomer of PCB (polychlorinated biphenyl).

ClCl /0 ClCl \ IClCl H ClCl HH 0 ClCl HH ClCl H

HexachlorobenzeneHCB

HexachlorocyclohexaneBenzene HexachlorideLindane, BHC

HCB occurs as an industrial waste product in the manufacture of per-chlorethylene, chlorine, carbon tetrachloride, other chlorinated solvents, andpesticides. It is also used as a peptizing agent in the manufacture of nitroso rubberfor tires, and is present in the wastes from some of these processes at levels oflo- 15%. These waste products are referred to as hex wastes. The wastes havebeen disposed of in landfills and methods are being developed for alternate meansof disposal (Quinlivan and Chassemi, 1977). HCB is also a contaminant in theherbicide dachthal and the fungicide PCNB. The level of HCB in these pesticides

2250013-9351/79/060225-42$02.00/O

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226 K. DIANE COURTNEYwas about 10% until the last few years when new manufacturing processes wereable to reduce the level to less than 5%.Several commercial products of HCB have been shown to contain octachloro-dibenzofuran and octachlorodibenzo-p-dioxin as contaminants (Villaneuva et al.,1974). Since these contaminants belong to classes of compounds which are knownfor their potent toxicity, Goldstein et al. (1978) evaluated their role in the toxicityattributed to HCB. The porphyria, cutaneous lesions, hyperexcitability, increasein liver weight, changes in liver enzymes, and morphological changes in liver werebasic manifestations of HCB toxicity and could be produced by purified HCBwhich lacked the contaminants.It was estimated that 15,000 lb/year of HCB were produced for fungicidal usewhile 250,000 lb per year were produced as a contaminant in dacthal and 1,400,000lb per year were produced in PCNB. In the various industrial processes, it wasestimated that 4,300,OOO lb per year of HCB were produced as an unwantedby-product (EPA, 1975; Quinlivan and Chasseni, 1977).

HCB is not a naturally occurring compound (Steinwandter and Brune, 1977) andonce it enters the ecosphere, it is very persistent. HCB is volatile and sublimes atair/soil interfaces and enters the atmosphere. HCB bioaccumulates in both terres-trial and marine animals and is not readily metabolized. Although it has verylimited water solubility it has been recognized as one of the major marine waterpollutants (Morse, 1975).

II. HUMAN TOXICITYA. PCT Epidemic in TurkeyI. Human Toxic ExposureThe toxicity to human beings of long-term low-level exposure to HCB has been

documented following an epidemic of HCB-induced porphyria cutanea tarda(PCT) in Turkey from 1955 to 1959. In 1954, two fungicides were introduced toTurkey, Chlorable and Surmesam; both contained about 10% HCB. The routineprocedure was to mix 20 g of fungicide with each 100 kg of seed wheat. During aperiod when wheat for bread was unavailable, the seed wheat was used for foodinstead of its intended agricultural use. It was estimated that 0.05 to 0.2 g of HCBwere consumed per day per person eating contaminated wheat. The fungicidescontaining HCB were withdrawn from the market by the Turkish government in1959 and the PCT epidemic subsided. It was estimated that 3,000 to 5,000 peopleacquired PCT with a mortality of 10% (Dogramaci ef al., 1962a; Dogramaci, 1964;Patel, 1963; Peters er al., 1966; Schmid, 1960; Cam and Nigogosyan, 1963; Cam,l%Oa).PCT occurred more frequently in children from the ages of 6 to 16 with only 10%of the patients over 16 years of age (Dogramaci et al., 1962a; Dogramaci, 1964).Among patients in another survey, 75% were from 4 to 9 years old, 20% from 15 to30 years old, and 4% older than 30 years (Mazzei and Mazzei, 1973). Anotherreport of 600 cases of PCT stated that 80% were in the 4- to 14-year-old group witha marked predilection for males who comprised 76% of the cases (Cam andNigogosyan, 1963). However, in a carefully controlled epidemiology study, Dog-ramaci et al. (1962a) found no sex difference. In the populations of children that

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HEXACHLORO BENZENE: A REVIEW 227they observed there was a preponderance of males both with and without HCBtoxicity, and there was no significant difference between males and females insusceptibility to HCB toxicity.In the survey of 600 cases of PCT, Dogramaci found that about 5% were lessthan 5 years of age, and the disease was considered rare in children less than 4years old. However, at the time of the PCT epidemic, Cam and Nigogosyan werediagnosing a distinct disease in children under 5 years old. The clinical symptomswere demonstrable by 2 months of age, and occurred in children of mothers whohad clinical symptoms of PCT or who ingested contaminated bread during gesta-tion or lactation or both (Cam, 1960b). They described the disease as pink soreor pembe yara. This disease also achieved epidemic scale during the time HCBwas being ingested. There was a 95% mortality incidence in these infants whichvirtually eliminated all children between the ages of 2 months and 5 years in manyof the villages. Porphyria was not observed in these infants; however, milk sam-ples of the mothers demonstrated the presence of HCB (Peters et ul., 1966). Thissuggested that pembe yara was a manifestation of HCB toxicity and could be theforerunner of porphyria in infants. In conjunction with this, there was a very highincidence of stillbirths.2. Clinical Symptoms of PCT in Turkey

Porphyria cutanea tarda (PCT) is a disease of disturbed porphyrin metabolismmanifested by cutaneous lesions. Patients reported that the first sign of the diseasewas weakness, occasionally with loss of appetite, and then cutaneous photosen-sitivity and porphyrinuria. Hypertrichosis (hairiness) and hyperpigmentation werethe next two common symptoms which developed eventually in most patients.There was no regular development of the signs and the time factor was not pre-dictable (Dogramaci et al., 1962a).The photosensitivity with subsequent skin lesions on exposed parts of the bodywas reported at some time by almost all patients. The lesions consisted of bullaeor vesicles containing clear, rarely hemorrhagic fluid, and ranged in size from 0.5mm to 5 cm. In more advanced cases, comedo and milium-like lesions developedand eventually the vesicles became encrusted ulcers which left large scars. Thecutaneous lesions healed very poorly and were often infected. In areas exposed tosunlight, the keratin layer of the skin would have a black discoloration producingthe hyperpigmentation. Five years after onset, only 1% of the patients werephotosensitive (Dogramaci, 1964 ).Hypertrichosis was observed in children of both sexes. The hair covered theface around the eyes, chin, and extremities. Occasionally, the entire body wouldbe covered (Dogramaci, 1964). Children with extensive hypertrichosis and blackdiscoloration of the keratin layer of the skin were described as having monkeydisease due to their appearance (Cetingil and Ozen, 1960).About one-third of the patients had hepatomegaly which was painful on palpa-tion. Although thyroid enlargement was reported, most of the patients were fromareas with a high incidence of endemic goiter and epidemiological studies indi-cated that there was no relationship between thyroid enlargement and HCB inges-tion (Dogramaci et al., 1962a).

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228 K. DIANE COURTNEYA rheumatoid arthritic change was found in 36% of the children in the begin-ning; in a follow-up examination from 3 to 5 years later, the incidence had in-creased to 55% while many of the other symptoms had subsided (Dogramaci,

1964; Dogramaci et al., 1962b). The arthritic changes were seen mainly in the 7- to18-year old group with no sex difference in incidence or severity. A fe w patientsdeveloped osteoporosis, mainly of the phalanges, and some showed resorption ofthe digits while others had a reversal of the bone thinning with a return to normaldensity. In many people, joint lesions persisted. Five patients less than 7 years ofage did not show any arthritic changes.

HCB-Exposed children had a cachetic appearance (Cetingil and Ozen, 1960).Their subsequent growth was significantly retarded compared to nonaffectedschoolmate controls. Dogramaci et al. (1962a) thought this was probably due tothe HCB toxicity but did not rule out the fact that many of these children had beensick for more than 2 years. The very young infants with pembe yara also displayedthe cachetic appearance.Infants with pembe yara often had fevers, diarrhea, vomiting, and cutaneouslesions on the hands, legs, and feet. The lesions first appeared as papules whichwere red or rosy in color and hence the term pink sore. Later these sores wouldform oval or circular plaques with the central part becoming brown or black. Dean(1961) described the disease as pigmented patches on the skin rather like aringworm or fungus infection. Pink sore disease was seen in infants from 2months to 5 years of age who also displayed anorexia, atrophy of muscles, andsluggish behavior. The clinical findings of note were the enlarged livers, hyper-chromic anemia, and hyperplasia of the sebaceous hair follicles. Mortality wasexceptionally high and the only cause reported was secondary pulmonary infec-tions (Cam, 1960).3. Laboratory Results

Urines had the characteristic red port-wine color which usually turned verydark on exposure to light. The red fluorescence of the urine with exposure toultraviolet (uv) light was indicative of porphyrins. Some older children had anormochromic anemia while the infants had a hyperchromic anemia. The serumproteins were normal but the A/G ration was reversed. The teeth would oftencontain porphyrins which would fluoresce red with uv light. Glucose tolerance testswere normal as well as the lipidogram. There was no fluorescence of the bonemarrow or blood smear, but liver biopsies did show a fluorescence with uv light.The liver biopsies revealed advanced hydropic and granular degeneration of theparenchyma. Both uroporphyrins and coproporphyrins were excreted in largeamounts (Soysal et al., 1959; Cetingel and Ozen, 1960; Dogramaci, 1964).

6. Other Toxic Exposures in Human BeingsAnother outbreak of HCB toxicity occurred in 1967 in Doha, Saudi Arabia. Inthis situation, the exposure was an acute high dose. A number of people becamesick on the same day with abdominal pain, nausea, vomiting, mental confusion,and convulsions. A total of 490 were admitted to the hospital and 7 died. A publichealth inspection revealed that HCB was inadvertently incorporated into breadmade by a large bakery that supplied homes, restaurants, and hotels (Mauranges,

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HEXACHLOROBENZ ENE: A REVIEW 2291970). Since the acute LD,, for the rat is 10,000 mg/kg (Ben-Dyke et al.. 1970). itwould be quite difficult to have enough HCB in bread to cause human death. Areport by Curley et nl. (1970) revealed that endrin was the cause of an epidemicpoisoning in Doha in 1967. Endrin toxicity would cause the clinical symptomswhich were observed.Four workers in Argentina whose occupation required the handling of HCBshowed the prominent signs of PCT with cutaneous lesions on the hands and face.hypertrichosis, and hyperpigmentation. The urine of one worker was found tocontain increased amounts of both uroporphyrins and coproporphyrins. Thisworker had 0.383 ppm HCB in the blood. A year after leaving the job and withtreatment, the skin lesions subsided, and the blood level declined to 0.268 ppm(Mazzei and Mazzei, 1972).

Morley (1973) reported a study of 54 workers in a factory that treated grain withHCB. There was only one worker with increased porphyrins in the urine and hehad worked with HCB for 25 years. He had no other signs of HCB toxicity.III. OCCURRENCE OF HCB

A. Human BeingsHCB blood residues were found in 19 of 20 vegetable spraymen who werespraying with dacthal which was widely used in the Rio Grande Valley as anherbicide. The mean blood concentration was 40 ppb with a range of 1 to 310 ppb.None had cutaneous lesions or other indications of PCT. Blood samples analyzedfrom 96 migrant or seasonal farm workers from the same area revealed only twoindividuals with HCB residues (24 and 12 ppb) (Burns et al., 1974).In an industrialized parish of Louisiana bordering on the Mississippi River, anumber of people and many cattle became contaminated with HCB due to thetransport of hex wastes from local industries to a landfill where they werespread over the entire dump to serve as a fly repellent. A systematic sampling wasdone on every 12th household in the area for blood samples for HCB analysiswhich showed that 99% had HCB concentrations greater than 1 ppb and a mean of2.4 ppb. There were 22 husband-wife pairs in the survey and the mean blood levelof 5.10 ppb HCB in the males was significantly higher than the average blood levelof 1.70 ppb in the women. A group of 46 individuals not residing in the immediatearea served as controls and their blood level averaged 0.5 ppb HCB. Blood sam-ples from 11 chemical plant workers of that area demonstrated a range of HCBconcentration from 14 to 233 ppb (Burns and Miller, 1975).The presence of HCB in people with no known exposure to HCB was estab-lished by Acker and Schulte (1970, 1971) in Germany. In 1970 in a routine analysisof human fat and human milk for DDT and PCBs, they detected HCB at levels of6.3 ppm in the fat and 0.153 ppm in the milk. When HCB was calculated on amilk-fat basis, the concentration was 5.3 ppm. Zeman et czl. (1971), in Germany,confirmed the presence of HCB in human serum. A more recent survey showedthat HCB can still be found in the milk of many women (Rappl and Waiblinger,1975). A report on blood samples from 194 children from Upper Bavaria showedthat HCB was detectable in all samples. Half the children were from urban areasand half from rural. The average concentration of HCB was 16.5 ppb ranging from

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230 K. DIANE COURTNEY2.8 to 77.9 ppb. The lowest value of 2.8 ppb was found in a l-year-old infant(Richer, 1976; Richter and Schmid, 1976).

Siyali (1972) in Australia determined the presence of HCB in occupationallyexposed people. The blood analyses showed an average of 55.5 ppb with a rangeof 21-100 ppb. Another survey of four pest control operators in Australia re-vealed 0.92 ppm HCB in the fat and I5 ppb in the blood (Siyali, 1973). He thentested people with no known exposure to HCB and found that all had detectablelevels of HCB with an average blood level of 22 ppb.The Australian studies were expanded to a survey of perirenal fat samples fromautopsy material of a random selection of human beings at the city morgue inSidney. HCB was present in 100% of the samples and in 62% of the samples theconcentration ranged from 0.1 to 1.0 ppm while in 33% of the samples the concen-tration exceeded 1.0 ppm. A problem of contamination of food with HCB inAustralia was known in the 1960s when a shipment of powdered eggs was rejectedfrom import into the USA by the FDA. By 1967, it was known that levels of HCBof the order of 0.1 ppm were found in the eggs sold in Australia. A limit of 0.1 ppmhad been set by the Department of Health. A routine analysis of animal fat de-tected HCB in 70% of the samples at a mean concentration of 6.44 ppm. It wasassumed that the animals (beef and sheep) were being fed cereal grains that hadbeen treated with HCB which was illegal. For a comparison, samples of body fatfrom people in Papua and New Guinea had an average concentration of HCB of0.26 ppm which was considerably lower than that found in the Australian survey(Brady and Siyali, 1972).Stacey and Thomas (1975) analyzed the milk of 23 mothers from Western Aus-tralia during the period of 1970- 1971. All samples contained HCB with an aver-age concentration of 0.025 ppm. Miller (1973) in 1971- 1972 extended these studiesto samples of milk from women from both urban and rural areas. There were 20samples from each area and all contained HCB. The milk from women in the ruralarea had 0.079 ppm HCB and the milk from women in the urban area had 0.028ppm which was significantly less. However, both values exceeded the limit forcows milk established by WHO in 1970 (WHO, 1970). The authors calculated adaily excretion rate in the milk of 0.0395 mg per person per day assuming an intakeof 500 g of milk in a 4-kg baby. In another study with rural and urban mothers inAustralia, the milk values were 0.042 and 0.063 ppm, respectively. Although theurban mothers had the higher average, there was no significant difference (New-ton and Greene, 1972). These values are in the same range as the study just cited.A recent report from Norway (Baaken and Seip, 1976) had indicated that in 50samples of milk collected from women with no occupational exposure, all samplescontained low levels of HCB with a mean concentration of 9.7 ppb. Seven of thesamples had values greater than 20 ppb which was set as the maximum concentra-tion for HCB in cows milk by WHO. The Norwegian values are slightly lowerthan some recent values from Germany of 29 ppb HCB in human milk.In Canada, between 1972 and 1974, the level of HCB residue in the human fatappeared to be constant at 0.1 ppm with no correlation with age. Analyses ofhuman milk which started in 1973 showed a mean concentration of 0.1 ppm (VanHove Holdrinet et al., 1977). Other milk samples collected from rural areas in

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HEXACHLOROBENZENE: A REVIEW 231Arkansas and Mississippi in the USA were analyzed by Strassman and Kutz(1977) who reported no detectable HCB in 57 samples.

In 241 samples of fat from autopsy material from Japan there was an average of0.08 ppm HCB (Curley et al., 1973). Other human adipose tissue samples fromTokyo had an average of 0.21 ppm HCB (Morita et a/. , 1975a). Since HCB was notused as a fungicide in Japan, the authors assumed the contamination was the resultof industrial uses. The HCB levels in the human fat samples in Japan were gener-ally lower than those reported from Australia and Germany, but in keeping withthose reported from Canada.Of the 49 human milk samples supplied by the Pasteur Institute in France toGoursaud et al. (1972) for analysis, 18 of the samples contained HCB in concen-trations ranging from 0.001 to 0.17 ppm HCB. These studies were extended tomilk samples collected from women from nine different geographical areas inFrance for analyses of HCB content. Based on the fat content of the milk, the

average HCB concentration was 0.98 ppm with a range of 0.50 to 3.50 ppm. Therewere some regional differences in the milk contamination, but no seasonal varia-tion (Luquet et al., 1975).8. Food

Eggs and meat (beef and sheep) were found to be contaminated with HCB inAustralia. The most likely source of contamination was by feeding livestock withHCB-treated grains (Brady and Siyali, 1972). In Europe, meat and meat productsfrom beef and pork have been shown to contain HCB in readily detectableamounts (Dejonckheere et al., 1975a).Johnson and Manske (1976) and Manske and Johnson (1977) have reported onthe market basket surveys conducted for the FDA of total diet samples for theyears 1972- 1974. HCB was found in about 5% of the composite food samples withconcentrations ranging from 0.3 to 7.0 ppb. It was detected mainly in dairy, meat,poultry, fish, and root vegetables. Cerna et al. (1976) reported from easternBohemia that some samples of milk, butter, and cheese exceed the FAOWHOstandards. Recent reports by Leoni et al. (1975a, b), on a survey of uncookedfoods in Milan and Naples, found an average HCB concentration that would resultin a consumption of 4.3 pug per man per day which was 12% of the WHO ADI.HCB residues above the accepted tolerance were detected in lambs from Texasand Arizona (Booth and McDowell, 1975).Excessive levels of HCB were measured in adipose tissue and milk of cattleraised in the industrialized area of Louisiana cited above which necessitatedquarantining large herds of cattle (Laska et al., 1976). Cattle from 157 herds weretested and 29% of the cattle from 34% of the herds had fat samples with more than0.5 ppm, the acceptable limit (Booth and McDowell, 1975). It was suspected thatthe disposal of hex wastes from chemical plants in the area was the source of HCBwhich was detectable in the air, soil, and grass. The cattle with the highest con-centrations of HCB in their fat were located along a 1Zmile road over which thehex wastes (liquid) were transported to the dump. Results of analysis of soilsamples taken from this landfill showed an average value of 5000 ppm HCB. Airsamples taken at the landfill had 14 ppb or 16 pg/m (EPA, 1973; Laska et (11..

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232 K. DIANE COURTNEY1976). There was also a detectable level of HCB in the regional waters of theman-made levees of the Mississippi River. Many samples of water and riverbottom mud had levels of HCB up to 900 ppb, especially those taken near thelarger chemical plants.

HCB has routinely been found in lettuce and endive grown in Belgium, France,and the Netherlands where PCNB was widely used as a fungicide on these crops.Samples of soils, lettuce, and endives from greenhouses or fields using PCNB withHCB as an impurity had levels of 0.85 ppm HCB in the soil and 0.05 ppm in thegreens. The ratio of HCB to PCNB was the same in the soil and greens as in theproduct used (Casanova and Dubroca, 1972; Dejonkheere et al., 1975b; Dejon-kheere et al., 1976; deVos et al., 1974). Dunsing and Wildschill (1976) showed thatlettuce and soil recently treated with PCNB containing HCB as a contaminant hadresidues of 3.5 ppm HCB at 5 days and 0.6 ppm HCB at 4 weeks after exposure.The ratio of HCB to PCNB remained constant.Cows which were fed endives grown in soil treated with PCNB had HCB intheir milk at levels of 0.13 to 26 ppm. No PCNB was detected in the milk. Afterthis observation, experimental studies in cows confirmed that endives could ac-cumulate HCB from PCNB-treated soil and cows eating these endives wouldexcrete HCB in the milk (Goursaud et al., 1972; Dejonckheere et al., 1976).

C. Wild MammalsKoss and Manz (1976b) reported from Germany on the residues of HCB in wildfox, wild boars, and deer that were captured in their natural habitat. The mean

concentration of HCB in the subcutaneous fat of 21 foxes was 0.26 and 0.41 ppmfor seven boars. One boar had 3.11 ppm HCB in the fat. In contrast, only four ofsix does had detectable HCB with a mean concentration of 0.03 ppm. The fox andboar prey on small animals such as mice while the does are herbivorous. Thissuggested that HCB could accumulate in the food chain and become biomagnified.

D. BirdsPredatory birds have been shown to have high concentrations of HCB(Cromartie et al., 1975; Best, 1973; Vos et al., 1969; Vos et al., 1972, Fuchs et al.,1972). Bald eagles found dead or moribund in the United States were collected forresidue analysis of the carcasses. An average concentration of 0.30 ppm was in thecarcass and 0.14 ppm in the brain of 4 of the 12 birds assayed. In predatory birds in

the Netherlands, liver levels of 0.80 to 862 ppm HCB were measured in sparrowhawks, long-eared owls, kestrels, and buzzards.Cormorants which were found dead or moribund in the Netherlands wereanalyzed for HCB content. The whole body values ranged from 0.4 to 25 ppm witha mean of 6.9 ppm. The average concentration of HCB in the livers and brains ofthese birds were 10.9 and 18.0, respectively. Normal healthy birds which werecaptured to obtain control values had whole body concentrations of 0.63 ppm foradults and 0.15 ppm for young nestling birds. These values are much lower thanthose found in the dead or moribund birds (Koeman et al., 1973).Common tern eggs collected in 1970 from colonies on two islands in HamiltonHarbor at the west end of Lake Ontario in Canada had an average concentration of7.67 ppm HCB. The authors speculated that the high level of HCB in the eggs

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HEXACHLOROBEN ZENE: A REVIEW 233probably reflected the contamination of the small fish such as alewives and smeltwhich were the source of food for the colony. In 1971, these terns had a very lowbreeding success with a high proportion of eggs failing to hatch. The source ofHCB had not been located but was presumed to be industrial since there was littleagriculture in the area (Gilbertson and Reynolds, 1972).A comparable situation existed for the Great Lakes herring gulls (Gilbertsonand Fox, 1977). In 1974, the embryonic survival and hatching success of thesebirds was very low, so the following year eggs were collected and incubated in thelaboratory. In the embryos, an accumulation of a mucoserous exudate in theregion of the pectoral muscle and abdomen was observed. Eggs collected fromcontrol areas (northern Alberta and New Brunswick) had an 8% incidence ofmucoserous exudate. Of the Great Lakes eggs that hatched, only 10% showed themucoserous exudate while 50% of those which died while pipping had the condi-tion. A clear or slightly cloudy fluid was observed in the peritoneal cavity of thedead embryos. Pericardial fluid was slightly greater in volume in the embryoswhich died while pipping. The total liver porphyrin levels of the embryos of theGreat Lakes region were significantly higher than those of the control embryos.Those which died prior to hatching had greater elevation of porphyrins than thosewhich hatched.Analysis of the embryos showed DDE, dieldrin, PCBs, a chlordane derivative,heptachlor epoxide, and HCB. HCB was present at levels of 4.30 ppm. Theporphyrin concentrations in the liver were positively correlated with the presenceof the three compounds : heptachlor epoxide; a derivative of chlordane; and HCB.Of these three compounds, HCB is the most potent porphyrogenic compound inbirds and can induce porphyria in Japanese quail at diet levels of 1 ppm.The pericardial fluid volume was correlated only with the PCB content of theliver. This syndrome is comparable to chick edema disease in poultry which iscaused by chlorinated-p-dioxins (Firestone, 1973). Chlorinated-p-dioxins andchlorinated dibenzofurans have not been detected in the Great Lakes herring gulleggs.In a 3-year monitoring program of residues of chlorinated hydrocarbons in eggsof double-crested cormorants from the Bay of Fundy. Canada, the average HCBconcentration for 1973, 1974, and 1975 was 0.016, 0.016, and 0.017 ppm. respec-tively. The Bay of Fundy is generally considered an area of low contamination(Zitko, 1976).

E. FishIn an Australian survey of fish and shellfish samples, the average concentrationof HCB was found to range from nondetectable to 9 ppb (Neuhaus, 1973). How-ever, fish from the Mississippi River near the industrial sites in Louisiana hadmuch higher values. Gambusia and mosquito fish had whole body concentrationsof 72 to 320 ppb. This was a biomagnification of 172 times the water concentration.Crayfish from the same area had concentrations ranging from 22 to 184 ppb whilethe mud samples (dried) had 160 to 874 ppb of HCB.Zitko (1971) analyzed eel and pickerel taken from several lakes and from the St.John River system in New Brunswick, Canada, as an example of fresh water fish.

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234 K. DIANE COURTNEYCod, plaice, and ocean perch were taken on the Nova Scotia banks, and mackereland herring from the Bay of Fundy as examples of marine fish.HCB was detected in the fresh water fish with whole body concentrationsranging from 3 to 12 ppb. Of the marine fish, one sample of mackerel had 1 ppbwhole body concentration of HCB. None was detected in the other fish. HCB hasalso been detected in fish and mussels from the Rhine River (Koeman er al., 1969)as well as coastal fish from Japan (Morita et al., 1975a).In a model ecosystem, Metcalf et al. (1973) added HCB to water and found thatit was readily taken up by algae, snails, mosquitos, water fleas, and fish (Gam-busia). HCB was found in substantial amounts in the organisms with little indica-tion of degradation. Similarly, Zitko and Hutzinger (1976) maintained juvenileAtlantic salmon either in water to which HCB had been added or in nontreatedwater with HCB-treated food. In each case, the salmon concentrated HCB in theirbodies. Although HCB has very limited water solubility, it was considered a majormarine pollutant problem by the National Academy of Sciences (Morse, 1975).

F. SoilHCB occurs in the soil from the use of PCNB as a fungicide which was dis-cussed above. Another source is industrial wastes in both landfills and river bot-tom mud which was also discussed above. These sources of contamination arrivefrom direct application of HCB to the soil or river water. However, airborne soilcontamination has been shown. Soil samples from an area in Louisiana that had

20,000 cattle with HCB levels in excess of the maximum permissible levels indi-cated that the HCB could not have come from its use as a fungicide and thusairborne industrial contamination was suspected. This prompted Beall (1976) tostudy the persistence of aerially applied HCB to grass and soil. There was anextremely rapid rate of loss of HCB from grass surfaces within the first 2 weeks,but after that there was a steady decline in the rate of loss with less than 0.01% ofthe initial concentration detectable after 19 months. Application of HCB to the soilshowed that there was rapid loss by volatilization from the surface of the soil;however, HCB within the soil was persistent. In the top 2 cm of the soil after 19months, there was 3.4% of the Day 1 concentration. In the 2- to 4-cm layer of thesoil, the average concentration of 0.11 ppm showed no significant change over the19 months.Isensee et al. (1976) treated soil with HCB and stored it under aerobic (sterileand nonsterile) and anaerobic nonsterile conditions for 1 year in covered contain-ers to retard the volatilization of HCB. None of the HCB was lost under anystorage condition indicating the HCB is very persistent in soil.

IV. PORPHYRIAPorphyrias are metabolic disorders of porphyrin metabolism which are charac-terized by increased excretion of porphyrins and their precursors. The varioustypes of porphyrias have been well presented in some recent reviews (DeMatteis,1967; Granick, 1965; Snell et al., 1972; Tschudy and Bonkowsky, 1972). Thefollowing discussion relates to porphyria cutanea tarda, sometimes known asporphyria turcica, which is induced by HCB.In porphyria cutanea tarda (PCT), the cutaneous lesions are the obvious man-

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236 R. DIANE COURTNEYGlycine + Succinyl CoA

I

h-ALA rynthetare

in mitochondria6 -aminolevulinic acid in cytoplasm

&ALA dehydrataseporphobilinogen (PEG1

uro I synthetate coproporphyrinogen I(PBG) deaminase)