Cutaneous signs of systemic toxicity due to dioxins and related chemicals

Journal of the American Academy of Dermatology

Precursors to malignant melanoma

Division of Cancer Biology and Diagnosis National Cancer Institute National Institutes of Health Bethesda, MD Martin C. Mihm, Jr., M.D. Professor of Pathology Harvard Medical School Dermpath Unit Massachusetts General Hospital Boston, MA Fitzhugh Mullan, M.D. Chief Medical Officer Office of Medical Applications of Research Office of the Director National Institutes of Health Bethesda, MD Elliott H. Stonehill, Ph.D. Assistant Director National Cancer Institute

Office of Medical Applications for Cancer Research (OMACR) National Institutes of Health Bethesda, MD Jerome W. Yates, M.D. Associate Director Centers and Community Oncology Program Division of Resources, Centers, and Community Activities National Cancer Institute National Institutes of Health Bethesda, MD The Conference was sponsored by: National Cancer Institute Vincent T. DeVita, Jr., M.D., Director Office of Medical Applications of Research J. Richard Crout, M.D., Director

Cutaneous signs of systemic toxicity due to dioxins and related chemicals* William G . Dunagin, M . D . Columbia, MO The controversy about dioxin effects on human health received a great deal of attention recently when the State of Missouri was declared to have a dioxin crisis. However, dioxin and several related chemicals are widespread throughout the world. Cutaneous signs play an important part in evaluating toxicity of dioxin and similar chemicals. Chloracne is the most sensitive indicator of significant dioxin exposure. Porphyria cutanea tarda and hyperpigmentation are other known cutaneous effects, and malignant fibrous histiocytomas of the skin may possibly be associated, although data are inconclusive on this point. The AMC Council on Scientific Affairs recommended that all physicians become familiar with chloracne and other toxic effects of dioxin. Dermatologists, especially, should be aware of the problem and may discover early cases of previously unsuspected exposure to this group of chemicals. (J AM ACAD DERMATOL 10:688-700, 1984.)

From the Division of Dermatology, University of Missouri--Columbia and Harry S Truman Veterans AdministrationHospital. Reprint requeststo: Dr. William G. Dunagin, Divisionof Dermatology, Universityof Missouri--Columbia, M173 Medical Center, Colombia, MO 65212. *Views expressed in this paper are those of the author and do not necessarilyrepresent the view of the VeteransAdministration.

688

Times Beach, M O , recently achieved a unique place in history as the first town to be bought out completely by the federal and state governments in order to turn it into a " N o M a n ' s L a n d " because of contamination with dioxin. H o w e v e r , the problem of dioxin is not strictly a local concern or a

Volume 10 Number 4 April, 1984

Abbreviations used American Medical Association AMA Centers for Disease Control CDC DMBA Dimethylbenzanthracene Food and Drug Administration FDA Lethal dose, 50% LDs0 Polybrominated biphenyl PBB Polychlorinated biphenyl PCB Polychlorinated dibenzodioxin PCDD PolycMorinated dibenzofuran PCDF Porphyria cutanea tarda PCT parts per billion ppb parts per million ppm parts per trillion ppt TCDD tetrachlorodibenzo-p-dioxin 2,4,5-T 2,4,5-trichlorophenoxyacetic acid

quirk of fate. Dioxin and related chemicals have been found in significant levels at numerous sites throughout the United States, Japan, and Western Europe. Millions of people are exposed to smaller amounts of this group of chemicals in ordinary house dust contaminated with fly ash from municipal waste incinerators, 1'2 in edible fish, 3 from herbicide spraying, 4'5 and possibly even from wood-burning stoves .6 Dioxin has been the central focus of a vocal segment of the environmental movement concerned with toxic waste disposal. Dioxin has been tagged with the sobriquet "most toxic chemical known to man. ,,7 Some popular writers have said that the dioxin problem may be worse than the problem of nuclear waste disposal.S Dermatologic findings have been the most common objective signs of toxicity in previous known episodes of mass exposure to dioxin. The significance of the skin effects is somewhat controversial. One recent monograph on dioxin (which is also known as TCDD) concluded, "If there is no medical history of chloracne, then the likelihood of a significant exposure to, or adverse health effects from, TCDD is remote. Hence, chloracne is the clinical marker of TCDD exposure. ,,9 Similarly, the Italian medical commission which studied a large number of people exposed to dioxin after an industrial accident in Seveso, Italy, concluded "that chloracne has been the most frequent and most reliable sign of exposure of TCDD and that its incidence in the population was related to the

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Table I. Possible means of exposure--dioxin and related chemicals i. Manufacture of chlorinated phenols (dioxin contaminant) 2. Spraying of herbicide 2,4,5-T (dioxin contaminant) 3. Production of hexachlorophene from 2,4,5-trichlorophenol (dioxin contaminant) 4. Pentachlorophenol used as fungicide and wood preservative (hepta- and octa-chloro-dibenzodioxin contaminants) 5. Transformer and heat exchange fluids (polychlorinated biphenyls) leakage or inadvertent switching of products 6. Heating increases the formation of dibenzofurans from PCBs in transformer fluid 7. Investment casting (PCBs, terphenyls) 8. Burning of pentachlorophenol or 2,4,5-T-treated wood or brush (dioxins, dibenzofurans) 9. Municipal incinerators burning organochlorine refuse (dioxins, dibenzofurans) 10. Chlorinated naphthalenes formerly used in ship building 11. Eating fish with high levels of dioxin or dibenzofurans (concentration in aquatic ecosystems)

severity of the exposure. ''1~ However, other writers have implied that skin findings are not important and that dioxin may cause significant problems no matter how small the dose. 7 EXPOSURE

The complete chemical name of dioxin is 2,3,7,8-tetrachlorodibenzo-p-dioxin, usually abbreviated TCDD. The term dioxin has generally been used as a synonym for TCDD in the popular media. But there are many other isomers of dioxin and most are much less toxic than 2,3,7,8-tetrachlorodibenzo-p-dioxin. For the remainder of this paper, the term dioxin will be used to mean 2,3,7,8-TCDD in keeping with common usage, unless specifically qualified as some other isomer. There is no industrial use for dioxin. It is intentionally synthesized only in a few research laboratories. The problem is that dioxin is an unwanted by-product in small quantities from the production and use of chlorinated phenols. The chlorinated phenols do have a number of important industrial applications. In fact, about 150,000 tons of chlorinated phenols are produced worldwide each year. 11 Smaller amounts of dioxin may be pro-

690

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Cl ~

0

-

~

,

C

1

Table II. Comparison of concentration terms Concentration

1 part per million 1 part per billion 1 part per trillion 1 part per quadrillion 1 part per quintrillion

C1~ 0 ~ ' ~ I C I 2,3,7,B" tetrachl orodibenzodioxin

Cl C 0 Cl 2,3,7,8-tetrachl orodibenzofuran

cl

C1

C1 3,4,5,3~,4" ,5~ hexachlorobiphenyl

Br ~

[

Br

Time analogy 30 sec in 1 year 30 sec in 1,000 years 30 sec in 1 million years 30 sec in 1 billion years 3 sec in life o f universe

group of chemicals, and the most extensively investigated. Some of the other compounds that have similar toxicity are polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), polychlorihated dibenzofurans (PCDFs), polychlorinated naphthalenes, and polychlorinated terphenyls. All of these compounds have a similar chemical structure, consisting of aromatic rings in a planar configuration with four halogen atoms at the corners of a rectangle ~2 (Fig. 1). Some compounds in this series may have more chlorine atoms at sites in addition to the four corners, but are less toxic. The basic rectangular structure is recognized by cell membrane receptors 12-14 that may activate several enzyme systems, but the exact mechanisms of toxicity are not fully known. Although the biologic effects of all of these compounds are very similar, the relative doses required to produce toxicity may be several orders of magnitude apart. 11 Dioxin is the most potent, followed by dibenzofurans, and the others are much less potent. LEVELS OF TOXICITY

Br

Br

2 , 3 , 6 , 7 - t etrabromona p htha 1 e n e Fig. 1. Dioxin and other chemicals with similar toxicity.

duced by the combustion of other organochlorine chemicals, such as the burning of municipal refuse. There is controversy about the possibility of dioxin being formed during combustion of natural materials such as coal 1 or wood. 6 Some of the possible means of exposure to dioxin, as well as other related chemicals that have similar toxicity, are listed in Table I. Dioxin is the prototype of this

There is no question that dioxin in its pure form is a very toxic substance. Fortunately, for practical purposes it occurs only as trace quantities in the parts per billion or parts per million range as a contaminant of other products. In the case of fish and other food sources, the levels are parts per trillion. Many people worry about the contamination of ground water from toxic waste dumps. This is probably not an important problem, however, because dioxin is poorly soluble in water, with levels in the parts per quintillion range (see Table II for a comparison of concentration terms). The degree of hazard of any substance is proportional to the inherent toxicity times the exposure. Although the toxicity of dioxin is very high, the ex-

Volume 10 Number 4 April, 1984

Cutaneous signs of toxicity due to dioxins

Table HI. Single dose LDs0 values for TCDD*

691

Table IV. Relative toxicity of several chemicals

i

Species

[

/~g/kg body wt

I

Guinea pig Rat, female Rat, male Monkey Rabbit Mouse C57BL/6J DBA/2J B6D2F1/J ~ Ha mster

2 25 60 50 115 132 620 300 > 3,000

*Modified from Neal RA, et al: Drug Metab Rev 13:355-385, 1982.

posure is usually very low. On the other hand, PCBs are much less toxic, but some workers may be exposed to high concentrations of PCBs in transformer oils and heat exchange fluids. There is a marked species difference in susceptibility to dioxin, and even differences between sexes and among different strains of mice (Table III). 1~ The exact LD~0 for humans is not known. There are several ways to make rough estimates, such as comparison with the known levels of dibenzofurans in Yusho poisoning 16 and relative toxicity of dibenzofurans and dioxin. In any case, it is apparent that humans are less sensitive to dioxin than are guinea pigs, which are more than ten times as sensitive to dioxin as any other mammalian species.15 It is interesting to compare the toxicity of dioxin to some of the most toxic drugs familiar to physicians (Table IV). Although dioxin is very toxic, it is not totally out of the range of some familiar substances. Botulism and diphtheria toxins are much more toxic than dioxin. Digitoxin may be roughly equal in single dose toxicity. Nicotine and cantharidin are roughly one order of magnitude less toxic than dioxin, but are used at concentrations several orders of magnitude higher than any known environmental concentration of dioxin, t7 Ironically, all of these other agents are biologic products. Among synthetic chemicals, dioxin may well be the most toxic one tested to date. The main concern with dioxin is for people who actually live on a contaminated site and may have low-level exposure over a long period of time. The most toxic isomers of dioxins and furans may ac-

Agent

Dioxin* Hydrogen cyanide Cyanide salts Cantharidin Nicotine Colchicine Digitoxin

Lethal dose

(/zg of chemical) (kg of body wt)

50 1,000 2,000 900 600 100 50

*Data on human dosage levels of TCDD are scant. Neal has estimated that lethal doses for humans are greater than 100/~g TCDD/ kg body weight (Neal RA: Interim Report of the Missouri Dioxin Task Force, June 1, 1983, pp. 40-43). 50/.~gTCDD/kg body weight is the LDs0 for rhesus monkeys, 1~ the phyllogenetically closest species tested to date. This value is also close to the median for all mammalian species. The values for other chemicals are average adult lethal dose data from accidental poisoning episodes in humans based on 70 kg body weight (Gosselin RE, Hodge HC, Smith RP, et ah Clinical toxicology of commercial products, ed. 4. Baltimore, 1976, The Williams & Wilkins Co., sect. II, pp. 158, 160, 175; sect. 111,pp. 106-109).

cumulate because they are excreted slowly. After the Yusho episode in Japan, dibenzofurans were still present in blood, liver, and kidneys, 11 years after exposure. 18'1~ Some isomers of polychlorinated biphenyls (PCBs) are also known to persist in human adipose tissue for many years? ~176In fact, most of the general population of Europe has low but detectable levels of PCBs in fat3 ~ There are no data for the rates of elimination of dioxin from human tissues, but dioxins are not as persistent in laboratory animals as other compounds such as polybrominated biphenyls. 22 ABSORPTION

During the declared dioxin crisis in Missou. public apprehension extended even to people who had no direct contact with dioxin, Schoolmates and co-workers avoided people who lived anywhere near possible contaminated areas. Actually, dioxin does not have distant effects such as the public perception of radiation. The vapor pressure is so low (1.7• 10-6 mm Hg) that vapors are not a problem. Dioxin must first be absorbed into the body before any effect on health can occur. From a theoretical standpoint, the possible methods of absorption are percutaneous penetration, ingestion, or inhalation of particulate matter. Parenteral

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T a b l e V. Dermal absorption of dioxin* Vehicle

Percentage

Methanol Polyethylene glycol Vaseline Soil-water 26 ppm 0.5 ppm Activated carbon 26 pprn 0.5 ppm

40 25 4 6 0.1 <0.1 <0.1

*From data in Poiger H, Schlatter C: Fd Cosmet Toxicol 18.477481, 1980. The soil used in this experiment was from Seveso.

administration has been used in laboratory animals, and surprisingly, it is often less toxic than oral administration, an indication that concentrated oral solutions may have a local toxic effect on the gastrointestinal mucosa. 15 Data derived from oral dose animal studies may indicate greater toxicity than might be expected from percutaneous absorption. The percutaneous absorption of dioxin varies greatly depending on the vehicle, as might be expected for any chemical applied topically.23 Poiger and Schlatterz4 studied the absorption of dioxin through the skin of hairless rats, as measured by uptake in liver. When the dioxin was administered in methanol and occluded with aluminum foil for 24 hours, about 40% was absorbed compared to administration by stomach tube. Dioxin in a soilwater mixture was about 5% absorbed at a high concentration (26 ppm) but less than 1% absorbed at concentrations below 1 ppm. Most environmental dioxin concentrations in soil are considerably below 1 ppm. When dioxin was applied in activated charcoal, almost none was absorbed (Table V). O f course, the absorption of dioxin by dermal contact would also depend on frequency and duration of contact. There have been several situations in which humans had daily exposure to dioxin; some idea of the levels necessary to cause toxicity by dermal absorption can be gathered from this information. In 1971 waste oil containing dioxin was applied to settle dust in horse arenas in Missouri. The people who lived at these sites had daily exposure in their occupation and play for 3 months. The level of dioxin in a soil sample taken

after 3 months was 32 ppm. 17 The original level in the waste oil may have been higher, because of some dissemination over the 3-month interval. The humans exposed to these levels on a daily basis developed chloracne and other symptoms typical of dioxin toxicity. 1~ When re-examined 5 years later, these patients had no laboratory abnormalities, chloracne resolved, and there were no apparent sequelae from dioxin. 2~ It is also known that workers involved in spraying 2,4,5-T herbicide in the 1960s and 1970s came in contact with 1-30 ppm dioxin in the concentrate. 27 There is no evidence that people with daily exposure to these levels developed chloracne. Currently, the use of 2,4,5-T is restricted and the level of dioxin in the concentrate is less than 100 ppb. From these two examples, it appears that the amount of dioxin necessary to cause objective effects is in the 10-30 ppm range in an oily vehicle assuming daily exposure. In a soil-water vehicle, the level would probably be 10 to 100 times as much. If the patients in these examples absorbed some dioxin orally, the calculated levels would be even higher. Even with daily skin contact, soil concentrations of dioxin necessary to produce objective toxicity as shown by chloracne most likely exceed 100 ppm. Another possible route of exposure is inhalation. This may be an important route in some industrial accidents where aerosols may be released into the atmosphere. However, inhalation of dust does not seem to be important. If the level of dioxin in dust is one ppb, the daily amount inhaled has been calculated as 1.4 picograms/day. 28 This level is insignificant. The FDA has calculated a no-effect level of 70 ng/man/day. 29 Ingestion of materials contaminated with dioxin or related chemicals is the most important route of absorption when the toxins are present at low concentrations. Eating soil, pica, is a well-known problem in some children. Fish and beef fat from a few locations have contained low levels of dioxin. PCBs and dibenzofurans have caused problems when cooking oil was inadvertently contaminated. Polybrominated biphenyls contaminated dairy products in Michigan in 1973, when PBBs were accidently used in place of a feed supplement for

Volume 10 Number 4 April, 1984

cattle20, al All of these episodes were localized in geographic extent and duration. Fears expressed about continuing environmental contamination leading through the food chain to widespread poisoning of food supplies for the entire country are unfounded. For example, periodic monitoring of beef fat samples has shown no dioxin in most samples, and sporadic, insignificant levels in others, with no trend for increasing contamination. There is no evidence that dioxin willcause the collapse of western civilization as some have suggested.* DOSE RESPONSE All animal experiments show that dioxin toxicity is dose-related, a2-a4 as would be expected by analogy with most other known toxins. At very low doses, there are no observed effects in animals. In rats, there is about a one hundred-fold difference in dose between the "no observed effects level" and the mortality levels. 32 Doseresponse was also established for Yusho disease in humans where the severity correlated with the amount of rice oil (containing dibenzofurans) consumed, l",a'~ People with low levels of consumption showed no effects. Although the dose relationship seems obvious, a great deal of public consternation has been caused by statements that any amount of dioxin, no matter how small the dose, is dangerous.Z TOXIC EFFECTS IN HUMANS Most of the information about human health is derived from accidents in which humans have inadvertently been exposed to large enough concentrations of dioxin or other chemicals to cause clinical effects. Several of the most important examples are industrial accidents, where large amounts of dioxin were released in a small area and workers were exposed, ar-'~~ It is difficult to estimate the absorbed doses in such workers, but most likely these doses were very large compared to populations with environmental exposure. Another source of information is Seveso, Italy, where an industrial accident released a cloud of trichlo*Nriagu JO: Quoted in "Here's lead in your wine." Newsweek, March 28, 1983, p. 53.

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rophenol and dioxin which spread over several square miles of populated territory, s0 Information about dibenzofurans is available from two episodes where transformer fluid was inadvertently mixed with rice oil (Yusho) and affected several thousand people at two localities in Japan and Taiwan. 16'a5 Chlorinated naphthalenes were used widely in electrical cables and shipbuilding 30 to 80 years ago. Chloracne was apparently much more prevalent among workers then than now. ~1 Chlorinated naphthalenes are seldom used today because superior products have been developed. The importance of chloracne is that it seems to be the most likely objective sign to occur at the threshold dose for humans. In other words, chloracne is the most sensitive clinical indicator of dioxin exposure in population groups.9 In most studies, 85% to 100% of patients who have any of the more severe objective effects also have chloracne. This is an extremely important fact in evaluating large groups of people exposed to unknown chemicals, or where the magnitude of exposure cannot be determined. However, there does seem to be a small percentage of patients who are resistant to getting chloracne? ~'a7 So for any given individual, one cannot determine with absolute certainty whether a toxic dose has been absorbed by the presence or absence of chloracne alone. Other objective signs of toxicity in humans that have occurred in several different studies and appear to be significantly increased compared to control populations are porphyria cutanea tarda, 9,36-44,49 hyperpigmentation, 16,a8,46-49 elevation of hepatocellular enzymes in serum,36'4~'45 and peripheral neuropathy, which can be demonstrated by electromyography as conduction abnormalities. 16,ar'37,a9,41,46'47 Other findings that have been attributed to dioxin are elevated triglycerides and elevated cholesterol in blood. However, it is not clear that lipids are significantly elevated above the levels of a suitable control population. In one follow-up study, the lipid levels did not decrease when other signs of toxicity (chloracne, liver enzymes, uroporphyrins) returned to normal, ar There are some other effects which may possibly be due to dioxin and related chemicals. For the most part these effects have only been noted in a few individuals in one or two studies. Elevated

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Table VI, Human health effects of dioxin and related chemicals Relative dose

I

Low Higher

Possible very high dose effects; data not sufficient

Subjective

Headache; fatigue The above plus: Neurasthenia Nausea Anorexia Muscle pain The above

prothrombin time has been reported 5~ and along with elevated triglycerides may be related to acute liver damage. Only one severe case of hepatic and pancreatic necrosis has been seen after human exposure to dioxin, and that example may have involved other factors as well. 44 When halogenated naphthalenes were widely used in shipbuilding, several deaths from liver necrosis occurred in workers who had chloracne, zt,5~ Swelling of the eyelids due to involvement o f meibomian glands was a common finding in humans exposed to dibenzofurans in the Yusho episode, t8 The toxic effects of dioxin and related chemicals in humans are summarized in Table VI. TOXIC EFFECTS IN ANIMALS Numerous studies of the effects of dioxin on laboratory animals have been conducted. There is some difficulty in applying the information to humans because effects in one animal species are often quite different from another. 22 Of the animals that have been studied, rhesus monkeys are ~he closest phyllogenetically to humans. Chlora~ne and meibomian gland swelling are the most serlsitive indicators of dioxin or dibenzofuran toxicity in rhesus monkeys.34,53,54 Meibomian glands are modified sebaceous glands, and the histologic changes observed in the meibomian glands of rhesus monkeys 54 were analogous to chloracne, where the target organ is also the pilosebaceous unit. Clearly these two findings are variants of the same end organ toxicity. 48,49 High dose effects in animal experiments include hepatic necrosis and T cell depression in m a n y species,2Z but it is unclear if any humans have been exposed to equivalent doses.

[

Objective

Chloracne Worse chloracne; meibomian gland changes; hyperpigmentation; porphyria cutanea tarda; elevated liver enzymes; sensory peripheral nerve impairment; nerve conduction abnormalities Hepatic necrosis; hypertriglyceridemia; T cell depression; prolonged protime; thrombocytopenia; diarrhea C H L O R A C N E AS A M A R K E R

Dioxin was first discovered as a toxic contaminant when Schulz 55 was investigating the etiology of chloracne. The initial lesions of chloracne are open comedones. There are very few of the pustular or nodular lesions typical of acne vulgaris. Another concomitant of disordered follicular keratinization is the formation of milia and small straw-colored epidermoid inclusion cysts in more involved cases. 4s,49 Initially, these lesions are quite distinctive from the pseudocysts of acne vulgaffs. Primary lesions are not inflammatory. However, with time, rupture of the follicular lining may occur which stimulates an inflammatory response simulating the psudocystic lesions of acne vulgaris. Another characteristic of chloracne is metaplasia of sebaceous epithelium to a keratinizing epithelium. This may progress to complete atrophy of the sebaceous gland, in marked contrast to the increased sebaceous gland activity of acne vulgaris. Chloracne often involves the meibomian glands, a characteristic that does not occur in acne vulgaris. The distribution of chloracne differs from acne vulgaris. The most heavily involved areas are the malar areas, ears, and postauricular areas. The nose is usually spared. The axillae and groin are often involved with chloracne, an indication that systemic exposure may be more important than topical exposure. Chloracne also differs from acne vulgaris in that it can occur in any age group, including prepubertal children. At Bolsover, England, an explosion in a trichlorophenol plant occurred at night, and the

Volume 10 Number 4 April, 1984

plant was not reoccupied for 10 days. The only means of absorption was probably from dermal contact with greasy residue containing dioxin deposited on walls and other surfaces. There were seventy-nine cases of chloracne, but no other serious systemic sequelae. 45,52 Similar accidents in Amsterdam and in Grenoble, France, produced chloracne without other serious problems. An increase of myocardial infarctions in Amsterdam workers was probably coincidental. 9'38 Several thousand people were exposed to dioxin in Seveso, Italy, and panic developed after the deaths of rabbits and other herbivores which consumed dioxin-tainted vegetation. An extensive health survey by the Lombardy Regional Government examined dermatologic, neurologic, hepatic, renal, reproductive, and immunologic parameters. They found 187 cases of chloracne, mostly in Zone A, the most heavily contaminated area. However, no other objective toxicity could be attributed to dioxin.~'l~ Most of the cases of chloracne resolved in a short period of time. There were some cases of peripheral neuropathy, but only in people over the age of 55 who had diabetes or alcoholism. These cases were not attributed to dioxin. Some surveys showed an increase in spontaneous abortions after the accident in Seveso. ~9 However, it is also known that many women left Italy to have therapeutic abortions in other countries because of fear engendered by all the media publicity following the accident. 1~ Some of these may have been misinterpreted as spontaneous abortions in post hoc surveys. Most experts now believe there was no increase in abortion or birth defects.6~ Accidents occurring in trichlorophenol plants at Nitro, WV, ~~and New Jersey4~ and a laboratory accident in England47 were probably associated with higher absorbed doses of dioxin. Inhalation of aerosols or oral absorption was likely the most significant route. Chloracne was more persistent and was also associated with eyelid irritation, profound neurasthenia, hyperpigmentation, and (at Nitro) peripheral neuropathy and liver impairment. Porphyria cutanea tarda occurred in eleven of seventy-three New Jersey workers. Severe hyperpigmentation in a sun-exposed distribution was described at Nitro, but uroporphyrin tests were not done. Hyperpigmentation and hirsutism after the

Cutaneous signs of toxicity due to dioxins

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laboratory exposure in England are also suggestive of PCT. Although the report stated that no porphyrins were found in urine, there was no mention of whether uroporphyrins or other types of porphyrins were tested. The most severe human exposures were at trichlorophenol plants in Ludwigshafen, West Germany, 38,44 and Czechoslovakia. a6,~7 Neuropathy and liver damage occurred in about one third of patients. Most also had severe chloracne, but one patient had other toxic effects without chloracne. There is also a possibility that some workers in peripheral areas of a plant may not have absorbed significant levels of dioxin, had no chloracne, but attributed unrelated health problems to dioxin. In experimental studies of polychlorinated naphthalenes applied to human volunteers, chloracne occurred in a widespread distribution, not just at sites of topical application, n~ This indicates that chloracne is a manifestation of systemic toxicity. Tetrachloroazoxybenzene has structural similarities to other chemicals shown in Fig. 1 but is less potent. It has caused chloracne at a manufacturing plant in Arkansas ,61~62but no hepatotoxicity or other objective systemic effects have been reported to date. Hexachloro-, heptachloro-, and octachloroisomers of dioxin are much less potent than TCDD. These higher chlorinated compounds are contaminants in pentachlorophenol, a commonly used wood preservative. Cases of chloracne occurring in workers exposed to the mixture6t are due to the contaminants because pure pentachloophenol has a different mechanism of toxicity than chloracnegen chemicals. In some industrial accidents there was a single acute exposure; in others there were daily exposures for a prolonged period of time. But all point to the conclusion that chloracne is a good indicator of toxicity in population groups. In late 1982 and 1983, Missouri was faced with a "dioxin crisis" in the words of Governor Bond. 7 This was despite the fact that dioxin had been present in the involved areas for more than 10 years, and no definite cases of chloracne had been seen by local dermatologists. Results of a joint study by the Missouri Division of Health and the

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CDC also found no cases ofchloracne.* Nevertheless, local newspapers carried front page headlines about the danger of dioxin almost daily. Even respected national publications picked up on the tone of coverage with comments about dioxin "ravaging every system in the b o d y , " ~ and that it "threatens human health throughout their state. "$ TERATOGENESIS AND CARCINOGENESIS Later data from the Missouri dioxin study showed no evidence o f porphyria cutanea tarda, nerve conduction abnormalities, or immunosuppression. Liver and kidney function tests were not statistically different from matched controls.* Media coverage then shifted from the direct toxic effects to warnings about latent problems of teratogenesis and carcinogenesis. Dioxin is not teratogenic in rats and most other species, but has caused cleft palate and variations of the renal pelvis in mice .z7 The doses required for teratogenesis in mouse studies were greater than levels that produce clinical toxicity in the mother. 6a Similarly, an increased incidence of cancer has been observed in most species of laboratory animals given dioxin; however, the doses required also produced overt signs of direct toxicity. 6a The covalent binding of dioxin to deoxyribonucleic acid (DNA) is 4 to 6 orders of magnitude less than values for most known chemical carcinogens. 64 Most authorities believe that dioxin is unlikely to initiate somatic mutation, but may act as a promoter. ~5 The calculation of relative risk for chemicals that may be promoters is not as well established as for initiators of carcinogenesis. There is controversy about models used to extrapolate to lower doses than available experimental data. In some studies, dioxin and related chemicals have actually inhibited the formation of skin cancers induced by dimethylbenzanthracene (DMBA) in rats. 66 Epidemiologic studies of workers exposed to *Donnell HD, Hoffman RE: Letter to all Missouri physicians and press release, Oct. 16, 1983, and Symposium "Dioxin: Lessons from the Missouri Experience," St. Louis, Dec. 9, 1983. tMason J: The ordeal of a poisoned town. Life, pp. 58-64, May, 1983. :~Beck M, Junkin D, Taylor J, et al: The toxic waste crisis. Newsweek, pp. 20-24, March 7, 1983.

dioxin after industrial accidents have shown no increase in the overa/1 incidence of cancer. az,zs,44,45,5~ These studies concerned patients who had absorbed enough dioxin to cause chloracne. Some authorities analyzed data from several industrial accidents for specific types of cancer and reported a greater than expected number of soft tissue sarcomas. 6z-7~ However, when scientists from the National Institute for Occupational Safety and Health re-examined original materials, they found that two of the four cases were misdiagnosed.* The two confirmed soft tissue sarcomas were malignant fibrous histiocytomas. Further epidemiologic studies are underway, but the current evidence does not demonstrate an increased incidence of soft tissue sarcomas compared to levels expected by chance. Soft tissue sarcomas comprise about 2% of all cancer deaths in the United States. 71 Populations with less exposure as shown by absence of chloracne would have a lower risk for carcinogenesis than workers. Still most newspaper articles have implied that people with no evidence of dioxin toxicity today nevertheless have a ticking time bomb that may strike as cancer any day. Similarly, studies of teratogenesis are continuing, but so far studies from Seveso, t~ New Zealand,r2 and Alsea, OR ~ have not shown a greater incidence of birth defects than expected. TISSUE ASSAYS The chemical analysis of specimens to detect dioxin at the part per trillion (ppt) level is a very complex, expensive process. There are a few laboratories in the world that have perfected assays to a detection limit of 1 to 4 ppt.l" Information to date suggests widespread background levels in the general population. The Veterans Administration conducted a small feasibility study to detect dioxin in Vietnam veterans who claimed adverse effects *Fingerhut, M.A: Reinterpretation of recent US occupational softtissue sarcoma cases. Symposium on Public Health Risks of the Dioxins, Rockefeller University, Oct. 19-20, 1983. tRyan JJ, Williams DT: Analysis of human fat tissue from the Great Lakes area for 2,3,7,8-tetrachlorodibenzo-p-dioxin and -furan residues. Preprint extended abstract presented before the Division of Environmental Chemistry, American Chemical Society, Washington, DC, September, 1983.

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from Agent Orange..,74 Ten control patients who had never been in Vietnam had levels from 0 to 14 ppt in adipose tissue. Eighteen of twenty Vietnam veterans had levels from 0 to 13 ppt. The two other veterans had levels of 29 and 81 ppt. Both of these men had civilian jobs in which they may have been exposed to industrial chemicals after serving in Vietnam. There was no correlation between symptoms and dioxin levels. Levels of dioxin ranging from 4 to I30 ppt were found in twenty-two of twenty-three human adipose tissue samples from Kingston and Ottawa, Canada.I" These samples were from autopsies of randomly selected patients with no known symptomatology of dioxin. The Environmental Protection Agency (EPA) has found levels of 5 to 12 ppt in six adipose tissue samples from the general population in Ohio.$ In contrast, a patient with known exposure to dioxin at Seveso, Italy, had 1,850 ppt of dioxin in adipose tissue.7'~'TsThis patient lacked symptoms of dioxin toxicity but did live in the same household as two children who developed chloracne. Laboratory mice have shown levels of 540 ppt in the liver with no evidence of toxicity or effect on reproduction, zr Mice with toxic but nonfatal effects have shown levels of 5,100 ppt. Natural populations of beach mice (Peromyscus polionotus) living in contaminated soils have been noted to have dioxin concentrations up to 2,900 ppt with no evidence of toxicity noted except for increased endoplasmic reticulum in liver cells. 7s These data on tissue levels combined with clinical studies such as Seveso indicate that in patients lacking objective signs such as chloracne, subjec*Hobson LB, Lee LE, Gross MO, Young AL: Dioxin in body fat and health status: A feasibility study. Preprint extended abstract presented before the Division of Environmental Chemistry, American Chemical Society, Washington, DC, September, 1983. ~Ryan JJ, Williams DT: Analysis of human fat tissue from the Great Lakes area for 2,3,7,8-tetrachlorodibenzo-p-dioxin and -furan residues. Preprint extended abstract presented before the Division of Environmental Chemistry, American Chemical Society, Washington, DC, September, 1983. SKutz FW: Chemical exposure monitoring in the EPA office of pesticides and toxic substances. Presented to Veterans Administration Advisory Committee on Health Effects of Herbicides, Nov. 19, 1983, Washington, DC.

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five symptoms do not correlate with absorbed dose. Tissue levels for polybrominated biphenyls were analyzed in Michigan after livestock feed was accidentally contaminated with PBBs in 1973. The only people with chloracne were workers in the manufacturing plant. People who ate dairy and meat products had no chloracne or other objective problems. The workers had higher PBB levels in serum than people without chloracne. z9 Among people without chloracne, there was no correlation between severity of subjective complaints and the serum levels of PBBs.S~ The serum level closely parallels total body levels for PBBs? ~ Again, chloracne (halogen acne)was the most sensitive indicator of true toxicity. SUMMARY

Dioxin in very small quantities is nearly ubiquitous. Only accidental episodes with much greater exposure than background levels have resulted in clinical signs and symptoms in humans. The AMA Council on Scientific Affairs recently recommended that all physicians learn to recognize chloracne and other effects of dioxin (TCDD). 82 Dermatologists especially should be aware of dioxin toxicity because they are most likely to detect early cases of chloracne and porphyria cutanea tarda. Dioxin is also important as a prototype for a group of related chemicals, which all have similar chemical structures and patterns of toxicity? 4''~ The biologic effects of dioxin and related chemicals are dose-related. Several of the chemicals are only found in trace quantities as contaminants of other products. Although there are many warnings about the great toxicity of these chemicals, high toxicity is mitigated by the extremely low concentrations involved. Chloracne is the most sensitive clinical indicator of exposure. Other objective signs are porphyria cutanea tarda, hyperpigmentation, nerve conduction abnormalities, and sensory deficits. Subjective symptoms of headache, fatigue, and others may accompany true toxicity. However, most episodes of proved exposures fail to show that subjective symptoms in the absence of any objective signs are true toxic effects. The question of cancer risk is still controversial. Epidemiologic studies of workers with the highest

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k n o w n e x p o s u r e s f a i l to s h o w a n i n c r e a s e i n c a n c e r s to date.

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REFERENCES 1. Bumb RR, Crummett WB, Cutie SS, et al: Trace chemistries of fire: A source of chlorinated dioxins. Science 210:385-390, 1980. 2. Eiceman GA, Clement RD, Karasek FW: Analysis of fly ash from municipal incinerators for trace organic compounds. Anal Chem 51:2343-2350, 1979. 3. Stalling DL, Smith LM, Petty JD, et al: Residues of polychlorinated dibenzo-p-dioxins and dibenzofurans in Laurentian Great Lakes fish, in Tucker RE, et al, editor: Human and environmental risks of chlorinated dioxins and related compounds. New York, 1983, Plenum Press, pp. 221-240. 4. Westing AH: The safety of 2,4,5-T. Science 206:11351136, 1979. (Letter to Editor,) 5. Young AL: Long-term studies on the persistence and movement of TCDD in a natural ecosystem, in Tucker RE, et al, editor: Human and environmental risks of chlorinated dioxins and related compounds. New York, 1983, Plenum Press, pp. 173-190. 6. Nestrick TJ, Lamparski LL, Shadoff LA, et al: Methodology and preliminary results for the isomer-specific determination of TCDD's and higher chlorinated dibenzo-p-dioxins in chimney particulates from woodfueled domestic furnaces located in eastern, central, and western regions of the United States, in Tucker I~E, et al, editor: Human and environmental risks of chlorinated dioxins and related compounds. New York, 1983, Plenum Press, pp. 95-112. 7. Sun M: Missouri's costly dioxin lesson. Science 219:367-369, 1983. 8. Brown MH: Speech at the University of MissouriColumbia, October, 1981. Similar comments in Laying Waste, New York, 1979, Pantheon Books Inc., pp. 283-296. 9. Beljan JR, Irey NS, Kilgore WW, et al: The health effects of "Agent Orange" and polychlorinated dioxin contaminants. Chicago, 198 l, American Medical Association, 1981, p. 11. 10. Reggiani G: Localized contamination with TCDDSeveso, Missouri, and other areas, in Kimbrough RD, editor: Halogenated biphenyls, terphenyls, naphthalenes, dibenzo dioxins and related products. Amsterdam, 1980, Elsevier/North Holland, pp. 303-371. 11. Rappe C, Buser HR, Bosshardt HP: Dioxins, dibenzofurans and other polyhalogenated aromatics: Production, use, formation, and destruction. Ann NY Acad Sci 320: 1-18, 1979. 12. McKinney J, McConnell E: Structural specificity and the dioxin receptor, in Hutzinger O, editor: Chlorinated dioxins and related compounds. Oxford, 1982, Pergamon Press, pp. 367-392. 13. Sweeney GD, Jones KG: Studies of the mechanism of action of hepatotoxicity of 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD) and related compounds, in Tucker RE, et al, editor: Human and environmental risks of chlori-

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46. Kimbrough RD: The toxicity of polychlorinated polycyclic compounds and related chemicals. CRC Crit Rev Toxicol 2:445-498, 1974. 47. Oliver RM: Toxic effects of 2,3,7,8-tetrachlorodibenzo 1,4-dioxin in laboratory workers. Br J Ind Med 32:4953, 1975. 48. Crow KD: Chloracne. Semin Dermatol 1:305-314, 1982. 49. Crow KD: Significance o f cutaneous lesions in the symplomatology of exposure to dioxins and other chloracnegens, in Tucker RE, et al, editors: Human and environmental risks of chlorinated dioxins and related compounds. New York, 1983, Plenum Press, pp. 605-612. 50. Zack JA, Suskind RR: The mortality experience of workers exposed to tetrachlorodibenzodioxin in a trichlorophenol process accident. J Occup Med 22:11-14, 1980. 51. Shelley WB, Kligman AM: The experimenta! production of acne by penta- and hexa- chlornaphthalenes. Ardh Dermatol Syph 75:689-695, 1957. 52. Jensen ME, Sneddon IB, Walker AE: Tetrachlorodibenzodioxin and chloracne. Trans St. Johns Hosp Dermatol Soc 58:172-177, 1972. 53. Allen JR, Barsotti DA, Van Miller JP, et al: Morphological changes in monkeys consuming a diet containing low levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fd Cosmet Toxicol 15:401-410, 1977. 54. McConnell EE, Moore JA: Toxicopathology characteristics of the halogenated aromatics. Ann NY Acad Sci 320:138-150, 1979. 55. Schulz KH: Klinische und experimentelle Untersuchungun zur ~tiologie der chloracne. Arch Klin Exp Dermatol 206:589-596, 1957. 56. Pocchiari F, Silano V, Zampieri A: Human health effects from accidental release o f tetrachlorodibenzo-p-dioxin (TCDD) at Seveso, Italy. Ann N Y Acad Sci 320:311320, 1979. 57. Reggiani G: Estimation of the TCDD toxic potential in the light of the Seveso accident. Arch Toxicol 2(suppI):291-302, 1979. 58. Caramaschi F, Del Corno G, Favaretti G, et al: Chlorache following environmental contamination by TCDD in Seveso, Italy. Int J Epidemiol 10:135-143, 1981. 59. Tognoni G, Bonaccorsi A: Epidemiological problems with TCDD (a critical view). Drug Metab Rev 13:447469, 1982. 60. Editorial: Seveso after five years. Lancet 2(8249):731732, 1981. 61. Taylor JS: Environmental chloracne: Update and overview. Ann NY Acad Sci 320:295-307, 1979. 62. Taylor JS: Chloracne from manufacture of a new herbicide. Arch Dermatol 113:6t6-619, 1977. 63. Kociba RJ, Schwetz BA: Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Drug Metab Rev 13:387406, 1982. 64. Poland A, Glover E: An estimate of the maximum in vivo covalent binding of 2,3,7,8-tetrachlorodibenzop-dioxin to rat liver protei n, ribosomal RNA, and DNA. Cancer Res 39:3341-3344, 1979. 65. Kouri RE, Rude TH, Joglekar R, et al: 2,3,7,8tetrachlorodibenzo-p-dioxin as cocarcinogen causing 3-methylcholanthrene-initiated subcutaneous tumors in

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mice genetically nonresponslve at Ah locus Cancer Res 38 2777-2783 1983 Beny DL Slaga TJ DiGiovanm J Zuchau MR Studies with chlonnated dibenzop dmxms polybrommated btphenyls and polychlorinated blphenyls m a two stage system of mouse skin tumorigenesis Potent ant~carclnogemc effects Ann NY Acad Sm 320 405 414 1979 Honchar PA Halperln WE 2 4 5 T tnchlorophenol and soft tissue sarcoma Lancet 1 268 269 1981 (Letter to Editor ) Cook RR Dloxm chloracne and soft t~ssue sarcoma Lancet 1 618 619 1981 (Letter to Editor) Coggon D Acheson ED Do phenoxy herbicides cause cancer m man'~ Lancet 1 1057 1059 1982 Fmgerhut MA Helperm WE Dmxln exposure and sarcoma JAMA 249 3176 1983 (Letter to Editor ) Tucker MA Fraumem JF Soft tissue tn Schottenfeld D Fraumem JF editor Cancer eptdemiology and preventmn Philadelphia 1982 W B Saunders Co pp 827835 Smith AH Metheson DP Fisher DO et al Prehmmary report of reproductive outcomes among pesticide applicators u s m g 2 4 5 T N Z M e d J 93 177 179 1981 Wagner SL Wltt JM Noms LA et al A scientific cHnque of the EPA Alsea Ii Study and Report Corvallis Oct 25 1979 Enwronmental Health Sciences Center Oregon State University Young AL, Kang HK Shepard BM Chlorinated dtoxtrts as herbicide contaminants Environ Sci Technol 17 530A-540A 1983

75 Facchettt S Fornarl A Montagna M Distribution of 2 3 7 8 tetrachlorodlbenzo p dtoxm in the tissues of a person exposed to the toxic cloud at Seveso Forensic and Environment Apphcatlon 1 1405 1414 1981 76 Regglam G Medical survey techniques in the Seveso TCDD exposure J Appl Toxlcol 1 323 331 1981 77 Komba RJ Keyes DG Boyer JE Results of a two year chronic toxicity and oncogenicity study of 2 3 7 8 tetra chloro&benzo p dmxm In rats Toxlcol Appl Pharmacol 46 279 303 1978 78 Thalken CE, Young AL Long term field studms of a rodent population continuously exposed to TCDD m Tucker RE et al e&tor Human and environmentalrisks of chlorinated dloxins and related compounds New York 1983 Plenum Press pp 357 372 79 Regglanl G Toxicology of TCDD and related corn pounds Observations m man in Hutzmgei 0 et al editor Chlonnated dloxln and related compounds Ox ford 1982 Pergamon Press pp 463 493 80 BuddML Hayner NA Humphrey HEB Polybrommated blphenyl exposure--Mmhtgan MMWR 27 115 121 1978 81 Landrigan PJ Wilcox KR Silva J Cohort study of Michigan residents exposed to polybrommated blphe nyls Epldemtologic and lmmunologm findings Ann NY Acad Sci 320 284 294 1979 82 Gunby P Light at end of tunnel m Orange controversy JAMA 24'7 1382 1982

ABSTRACTS

N a s a l p r u r i t u s as atypical a n g i n a 9 Remhstem RP, S t e m W G 1983 (letter to Editor)

N E n g l I Meal 309 66],

Entirely convincing is this thorough study of a 60 year old man who complained of recurrent pruritus of the bridge of has nose a symptom that was proved to be caused by three vessel coronary vascular disease This variation of angina was treated successfully

PCA

Childhood Kohlmeler-Degos disease with atypical skin lesmns Sotrel A, Lacson A G , H u f f KR Neurology (NY) 33 1146-1151 1983 A severe case of Koh[memr Degos &sease in childhood is reported with cutaneous findings as follows diffuse maculopapular rash often the earliest sign of the disease followed by cystm cutaneous nodules Ophthalmologle problems are common Severe injury to the b~am may be the cause of death m this disease which ts characterized also by level recurrent abdominal pain and enlargement of the hver and spleen

PCA

Myasthenm gravls associated with Satoyosht syndrome Muscle cramps, alopecta~ and dt~rrk~ Satoh A, Tsujlhata M Yostumt~ra T, et al Neurology (NY) 33 1209 1211 1983 Satoyoshi s syndrome is pamful voluntary muscle spasms and diarrhea associated with total alopecta In this young woman myasthema graws was also present possibly as one of the immune dysfunctions often hnked to this syndrome Deposmons of IgG and complement were found at motor endplates in the biceps muscle

PCA

D~etary management of oculocutaneous tyrosmemla m an ll.year-old child Ney D, Bay C, Schneider JA A m J Dis Child 137 995-1000 1983 Plantar keratoses occular keratltlS and excesswe tyrosme in plasma characterize this syndrome which responds well to a special &et

PCA