Document XzNd5vRNLaXBj51Oqjxj1Rx6w

TENACIOUS TOXINS OF INDUSTRIAL ORIGIN: POLYCHLORINATED BIPHENYLS (PCBs) -j&LLat&t& it ; iU: >li.: mfft;iI t : '> i.iij !|! N1 BY RICHARD E. JOHNSEN, PH.D. ILLUSTRATIVE FACTUAL PROBLEMS North Coro/i'na: Dirt contaminated by PCB illegally sprayed along state roodwoys four years ago was trucked and dumped at a landfill in Warren County. Minnesota, Iowa and Wisconsin: Produce from 700 grocery stores was recalled by a food wholesale firm because of a leak of PCBs at a warehouse in Hopkins, Minnesota. The leak from an electrical transformer may have contaminated sweet corn, raisins, and prunes.-, Montana: . - High levels of PCBs, 17 times higher than the amount allowed in domestic poultry, were found in ducks ond predator birds. It is not known how the PCBs entered the food chain. Hunters were warned not to eat wild gome birds without trimming all fat and discarding internal organs, skin and drippings; and to cook the bird thoroughly without stuffing. Pregnant and ladating women were advised not to ' eat the game birds. ' Michigan: ' Grain silos built or repaired between 1941-1966 used a PCB-containing sealant to prevent corrosion of the silos' linings. A survey begun in May 1981 showed PCBs in 253 of 8569 silos built by one com pany who also built silos in Ohio. California: leaking of PCB, an oily flame retardant widely used in capocitors, transformers and other electrical equipment, has become a nation-wide health danger, according to EPA in 1981. The California legislature held hearings on a bill requiring marking of utility poles holding electrical equipment containing PCBs. Firemen testified that the location of these utility lines is often unknown, and that they are endangered by leaking PCBs in power line fires. In August 1981, firefighters noted traces of PCB escaped with a gas line rupture in San Francisco. The utility company said it is their policy to notify firemen and people in the area of PCB leakage. Cleanup of highly toxic PCB from a rupture elec trical capacitor required a crew of 8 men to remove fences, shrubs ond boxes of earth from three back yards in Orange County. Tests inside three homes in the area were done by wiping samples on gauze; these samples were sent to a laboratory for analysis of contamination by PCBs. A capacitor attached to a utility pole caught fire . 7 AUGUST 1963 2: 45 jllV I! ;U*i ji yiLiii >. !*:.<. i: if i It! l! i.iiJI N'iii j; L I i! "iit'j-; S*ii,iii,.ii (j il|! ?i:;ij!lJ mm l vrL-i : -ti I;T I;: M.l l i -I - '. ~r r --- -- wiZ- ii.iwI*|Lw PCB-ARCH-EXT0378233 TRAUMA at 4 p.m., spilling two gallons of fluid containing PCBs. The spill did not touch any people, but several vehicles and the sidewalk area around the pole were sprayed. Utility company crews cleaned up the spill and continued to monitor the area the following morning. Chicago, Long Island and Southern California: Liquid PCB has been found in natural gas systems in these three areas. Southern Californio Gas Co. found liquid PCB as high as 200 parts per million in some samples; San Diego Gos and Light Co. tests showed a sample with 1000,parts per million. A Long Island gas firm found PCBs when testing an oily resi due in a gas meter. EPA's "guess" is that entry of PCBs into the gas systems occurred from a lubricant for pipelines or compressors, possibly many years ago. As of March 1981, EPA did not have meth odology for testing natural gas for' PCB, and testing for airborne PCBs in homes and businesses would be difficult. New York: An 18-story building in Binghamton was contami nated inside and out by PCB-containing ash after an electrical transformer burst during a fire in the base ment. The building was evacuated, and clean-up begun. 2: 46 RICHARD E. JOHNSEN, Ph.D., is Associate Professor, Depart ment of Zoology and Entomology, Colorado State University, Fort Collins. He received his M.A. and Ph.D. degrees in Entomology from Iowa State University, Ames. Since 1965, he has organized and supervised the Pesticide Research Laboratory, as well as teoching insecticide toxicology, medical entomology, zoology and other related subjects. Dr. Johnsen's major research interest is the nature, distribution and persistence of pesticide residues in plants, animals and the environ ment; and he has published over 22 articles in his field of interest. He is certified and licensed to use radio-labelled materials in metabolic studies, and has extensive experience with gas-liquid, thin-layer and column chromatography, infra-red and ultraviolet spectrophotometry, and wet-chemical techniques in sample analysis. His professional mem berships include the American Chemical Society, ACS Division of Pesti cide Chemistry, Entomological Society of America, American Associa tion for the Advancement of Science, American-Society for Microbiology, Society of Sigma Xi, Gamma Sigma Delta, and the New York Academy of Science. Dr. Johnsen has also been a consultant on toxicology to the City of Fort Collins on PCB pollution, the Colorado Department of Agriculture on special need registration of pesticides in the state, and to attorneys on insecticide toxicology. TRAUMA . VOL. 23 PCB-ARCH-EXT0378234 POLYCHLORINATED BIPHENYLS (PCBs) f mssamm TRAUMA U CHECKUP PREVIOUS RELATED ARTICLES TOXICITY OF DDT TO MAN AND ITS RELATION TO DOSAGE by Wayland J. Hayes, Jr. M.D., Ph.D. Vol. 15, No. 5 LOCATING THE EXPERT IN TOXICOLOGY by Robert H. Cravey, D.A.B.F.T. Vo!. 21, No. 1 CHEMICAL TRAUMA FROM PESTICIDES (PARTS 1, 2 & 3) by Charles G. Wilber, Ph.D. Vol. 20, Nos. 2, 3, & 5 OCCUPATIONAL CANCER by R. R. Merliss, M.D. . Vol. 19, No. 4 AGENT ORANGE AND DIOXIN: DO 2.4 MILLION PLAINTIFFS HAVE A CAUSE OF ACTION? by Charles G. Wilber, Ph.D. Vol. 22, No. 1 (Anatomy and Physiology of Liver) HEPATIC INJURIES by W. W. Glas, M.D. Vol. 7, No. 3 (Physiology of Menstruation and Reproduction) TRAUMA AND THE MENOPAUSE by Edward J. Bomze, M.D. ' Vol. 5, No. 6 UPDATE ON AGENT ORANGE by Marshall Houts, J.D. Vol. 24, No. 2 NO. 2 AUGUST 18 63 4rVi'Yy -ftyw 2: 47 PCB-ARCH-EXT0378235 TRAUMA INTRODUCTION SCOPE OF PROBLEM j The natural world today contains a Mr. Russell Train, EPA Administrator : vast assortment of man-made chemicals, in 1976, presented a statement before a many of which have no known counterpart congressional sub-committee on January to the equally vast array of biologically de 28, where he outlined the problem with rived chemicals. PCBs (Train, 1976). , Because of their uniqueness, biological systems have not been able to metabolize or degrade them readily as they do bio PERSISTENT SOURCES logical chemicals, with the resultant effect that they can accumulate in various com ponents of the ecosystem. This is evident for the well-known insecticide DDT and its major persistent metabolite DDE. Pollution of the global environment by the activities of mankind is justifiably re ceiving greatly increased attention. The He estimated that over the past 45 years (through 1975), some 1.4 billion pounds (700,000 tons) of PCBs were produced in the U.S., and over half of this amount had already entered the environment through discharges to the air, water and land. He stated further that, although some had been ! : j f ; serious ecological concerns brought on by the large-scale use of agricultural pesti degraded, the vast majority is contained in: - cides, especially those of the chlorinated hydrocarbon insecticides such as DDT, en- 1) Landfills. 2) Soils. ' drin or dieldrin, or herbicides such as 2,4,5-T, have made the general public keenly aware of environmental contamina 3) Sediments of rivers, lakes and coastal waters. tion and potential or real health effects. These concerns have culminated in the ban USES ning of both DDT and 2,4,5-T and very re strictive use patterns for dieldrin and endrin in recent years. Mr. Train reported that over 700 mil lion pounds were currently in use in: Since the late 1960s, public and govern mental eyes were focused on still another 1) Electrical equipment such as trans chlorinated hydrocarbon, the polychlori formers and capacitors. nated biphenyls, commonly referred to as 2) Hydraulic equipment. PCBs. The PCBs are industrial chemicals 3) Paper products. of great utility which had been produced 4) Other commercial and industrial since 1929, and it wasn't until 1966 that products. evidence of their widespread environmen tal incidence became known. They were not "Without preventive measures, he stated even suspected of being potential pol that essentially all of these PCBs could lutants because they were never distributed ultimately enter the environment. His talk deliberately into the environment as were was a prelude to the passage of the Toxic pesticides, and their use patterns differed Substances Control Act, passed by Con markedly. gress later in 1976. 2: 48 TRAUMA VOL. 25 '-i-TJ - 5W.3EUST?? ---------------- ~1 1 1 """"1--1,1 `-------------------------------^ PCB-ARCH-EXT0378236 I POLYCHLORINATED BIPHENYLS (PCBs) YUSHO DISEASE: OVER 1000 DEVELOPMENT CASES OF PCB POISONING The PCBs were known as early as 1881 The human health significance of the (Schmidt and Schultz, 18S1), but large PCBs came to public attention in 1968 when scale production did not begin until 1929 over 1000 Japanese became ill after eating when commercial quantities of inexpensive rice oil contaminated with PCBs from an undetected leak in heat-transfer equipment biphenyl became available (Jenkins et ah, 1930) and the physical characteristics and used to heat the rice oil: the illness was called `'yusho" or rice oil disease. commercial possibilities were publicized (Penning, 1930). f SYMPTOMS The exposed people subsequently devel oped: SYNONYMS The following are all synonyms for the PCBs: " 1) Chloracne. 1) Chlorinated biphenyl. . 2) Headache. 2) Chlorinated diphenyl. 3) Nausea. 3) Chlorobiphenyl. 4) Vomiting. 4) PCB. 5) Peripheral numbness. 5) Polychlorinated biphenyl. 6) Menstrual irregularity. 6) Polychlorobiphenyl (IARC, 1978). 7) Gastrointestinal disturbances. . S) Many other non-specific signs and ffc r i: symptoms (Kuratsune et al.,1972). COMMERCIAL PREPARATION ? `-1 PCBs are prepared commercially by re 11' PCBS DETECTED IN HUMAN AND ANIMAL TISSUES . acting biphenyl with anhydrous chlorine at elevated temperatures using a catalyst i; 1; J! Since 1966, PCBs have been detected in human foods and tissues, including milk, many forms of wildlife, especially fish, and numerous other components of the environ ment in the U.S. and other industrialized parts of the world (WHO, 1976). such as ferric chloride or iron turnings. The products are complex mixtures of chlo rinated biphenyls whose degree of chlori nation depends upon the contact time of the biphenyl with chlorine. After washing, the chlorinated products are batch-distilled . to remove color and traces of hydrogen LONGTERM CONSEQUENCES UNKNOWN The longterm consequences of PCBs to chloride (EPA, 1976). Details of manu facture can be found in Hubbard (1964). humans generally are unknown, although information indicates they may be car cinogenic to laboratory rodents (Kim brough and Linder, 1974; Kimbrough et al., 1975). Domestic production of PCBs was stopped in October 1977 by the sole U.S. manufacturer (Hatton, 1979). INDUSTRIAL USES Commercial development expanded in re sponse to the electrical industry's need for an improved dielectric fluid (non conduct of direct current) for use in trans formers and capacitors to provide fire re sistant qualities and to replace the mineral : NO. 2 AUGUST 1963 2: 49 mm, PCB-ARCH-EXT0378237 TRAUMA oil formerly used in these applications (Hatton, 1979). Their fire resistant nature made them excellent choices as hydraulic and heat transfer fluids; and PCBs were found to increase the waterproofing characteristics of surface coatings and to be advantageous to manufacturers of carbonless copy paper, printing inks, plasticizers, paints, adhe sives, lubricants, vacuum pump fluids and many other applications (Hatton, 1979; Hubbard, 1964). , ' t ' CHEMICAL COMPOSITION . MANY COMPONENTS WITH VARYING CHLORINE CONTENT Commercial PCB products are mixtures, of many components with varying chlorine content. The properties of these compo nents, and hence the products, are vastly different and very complex to study. ' AROCLOR Although PCBs have been produced in about eight countries, the sole U.S. pro ducer, until cessation of production, was the Monsanto Co. which marketed as many as 13 products under the trade name Aroclor. The PCBs in the Aroclor series are iden tified by a four-digit numbering code. The first two digits, 12, indicate the parent ma terial is biphenyl, and the last two digits the weight percent of chlorine. For exam ple, Aroclor 1248 is a chlorinated biphenyl containing 48% chlorine. Aroclor 1016 is an exception. It is of more recent vintage being a distillation product of Aroclor 1242 containing less than 1% of components with five or more chlorine atoms (WHO, 1976) even though it contains 41% chlorine (Mieure et al., 1976). Each Aroclor mar keted is a complex mixture varying from 6 components in 1221 to more than 70 for 1254 (Sissons and Welti, 1971). Terphenyls (3 phenyl groups) are indicated by a 54 in the first two digits and blends of biphenyls and terphenyls by either a 25 or 44 (75% and 60% PCBs, respectively) (Hutzinger et ah, 1974). / ' " ` Figure 1 illustrates that with biphenyl as the parent material, there are 209 the oretically possible chlorinated products from the 10 positions on the biphenyl mole cule (as numbered) available for chlorine substitution. From Figure 1, one can conclude that there can be 3 different monochloro deriva tives, 12 different dichloro, 42 tetrachlorobiphenyls, etc. However, it is highly un likely that all of them will be formed. Most likely absent would be a PCB fully chlori nated on one ring and not at all on the other (e.g. 2,3,4,5,6-pentachlorobiphenyl) (Hut zinger et ah, 1974). A good description of the system of nomenclature for the various PCB derivatives can be found in Hutzinger etah (1974). IDENTIFYING INDIVIDUAL PCBs There have been several studies to iden tify individual PCBs in commercial prep arations. Sissons and Welti (1971) sepa rated the components of Aroclor 1242, 1254 and 1260 using both column and gas-liquid chromatography (GLC) and characterized many of the peaks by mass spectrometry (MS) and high resolntion nuclear magnetic resonance spectroscopy (NMB). They found in excess of 70 peaks by GLC for Aroclor 1254 which included identification of 16 major components and characteriza tion of 56 minor constituents. They also identified the structure of 45 components in 1242 and 7S in Aroclor 1260. Many of  -- *-=.* * 5-. v - 'w~- ..***,5**Sfc>*.J^-t'*> J' #CJ***-* - - : ..^.--.---<-&,*--Att~fA<fLti!*" POLYCHLORINATED BIPHENYLS (PCBs) '. <V~ . y*.u ^ r-b+S&r -' /y^-Y';Jt.\"V\ o i<*ua"*v '&:**& __ 5/6 ' ~ yj^ino^v'*- ^ *" -^swKssig^^qh'l orines on nngc O'. 1 Chlorines on B ' 0-1.1 3. ^6 6 ^3 Ilk;v6' 18' 18' .9 2 t zr 36' 18 ring ,, 21' '18 V:"-` ZjsS^fe" 6 I. s ,':ig*MTWOta 1 svT~9~ 45 81, 54 20 210. _. i P IiIi 1** -a mod ified ;f r om ;'C ook ( 1972) " '* "r ** -- . ...W- jyt_:a. -.- ' FIG. L The Numbering .System^for-the- Biphenyl Structure and the Theoretical a *' # % , ?* * Numbers of Combinations' Possible of Chlorines in the Two Rings of .Biphenyl. i. ; ... ; Table 1 TYPICAL" PERCENTAGE OF COMPOSITION OF SOME AROCLORS r. *' l v No. of Cl/ .' o.i. " *".<.%- :i =*** TJT~ Aroclor ' biphenyl V -1221* ..A. 1242V' .' 1016* . 1248b 1254* 1260b l l 0 1 11 . . 51 jjj-r-j . . 1 ..._. . 1 '__ __ 0.1 0.1 __ __ h i :' 2 - V 32 Jr; .16 W&r 20 2 0.5 ` ---- 3 - ... v 4.,-. 49 . 57 18 1 -- 4 . 2 25, ,., 21 5 . V*>-JaW*S : _ ' ^ 0.5r OQ'ws : =-r. 1X 6 'N.D:* '"w: "1- - 0.1 -T " 7 8 ---. 9 - -VN.D. 0.1":;v N.D. -^N.D S'D..r/N.D. 40 21 . . 1 36 48 12 4 23 ' . 38 ___ 6 '. '41 N.D. 8 -- -- , 1 `Mieure et &L (1976).: b Hammond et aL (1972) * None detected (<0.01%) these components in 1254 were found also in 1242 and 1260, with the former contain ing lower chlorinated derivatives and the latter more highly chlorinated products. They found the predominant species in 1254 to be pentachlorobiphenyls, in 1242 to be tri- and tetrachloro derivatives and in 1260 to be liexa- and heptachlorobiphenyls. Table 1 summarizes the typical composi tion of several Aroclors. NO. 2 - AUGUST 1963 2: 51 PCB-ARCH-EXT0378239 -ft. *v RAUMA ' * - ?'! , . * J*' _ - . VARIATIONS IN COMPOSITION FROMgSgzzh 'j: - : . BATCH TO BATCH , f-t Table 2 'w'J -ts*. r . PCB IDENTIFYING CHEMICAL DATA `C ., `w - It should be acknowledged that comrner-^rrj- AND TOXICITY" f cial PCBs are not sold on-a composition - ;-y~ basis but rather on their physical proper- - Name CASb r-: LDm' ties so there can be variations in composi -' 'A-4 Biphenyl 92-42-4 3280 . ' tion from batch to batch of the same/Aro- A .? Polychlorinated biphenyls'1 1336-36-3 . -- : si clor or other tradename. .' ' 7 ' - Aroclor 1221 11104-28-2 3950 Sissons and Welti (1971) noted that Aroclor 1232* 11141-16-5 4470 2,4,6-substitutions rarely occur and 3-, 3,5- ,Aroclor 1242 and .2,3-substitutions", occur infrequently. Aroclor 1248* Webb,' and McCall': (1972) idehtified;|the Aroclor 1016 ' GLC peaks in Aroclors 1221-i2547^with-_.. Aroclor 1254 7 y?' Aroclor 1260* - ' . - 53469-21-9 , 12672-29-6 -- 27323-18-8 11096-82-5 4250 . 11000 ^ -- . 1295 1315 ' ;; - . Aroclor 1262* 37324-23-5 11300 ' - * ' A' Aroclor 1268* Jensen and Sunstrom (1974), imtheimost . P Aroclor 2565 extensive study, were able to characterize Aroclor 4465 and quantify 60 components of Clophens - r-'Aroclor 5442 A-50 and A-60 from Germany which indi . ( i; Aroclro 5460 cated the close similarity of components. 11100-14-4 10900 37324-24-6, . 6310 ... 11120-29-9 16000 ' 12642-23-8 10600 . 11126-42-4 19200 of Aroclor 1254 and Clophen A-50.:^XwrX The listing of PCBs marketedjm the U.S.-:- by Monsanto along with identifying Chemi- ' cal Abstracts Registry Number'and'acute - * Data from NIOSH, 1979 _* Chemical Abstracts Registry Number . * Oral lethal dose fatal to 50% of exposed rats; mg/kg of body -weight ' 4 A listing of CAS numbers for 38 individual chlorinated toxicity are presented in Table 2. . PCBs can be found in IARC (1978) `Discontinued manufacture prior to 1976 (Mieure et al, 1976) " r-..-- , - .r-irr * NO HIGH ACUTE TOXICITY; EFFECTS ' FROM PROLONGED, CHRONIC EXPOSURE V PRODUCTION Produced commercially since 1929 in the It should be noted that none of the PCBs ,, U.S., it has been estimated that some listed have high acute toxicity. As will be- -. 495,000 tons of PCBs had been sold in . shown, the deleterious effects :.arise' pri-......North America by 1970 (Interdepartmental marily from prolonged" chronicTexposure. -Task Force on PCBs, 1972). Another ref-. ` In Germany, products marketed as Clo- erence reported domestic sales of 795 mil- . phen A50 and A60 contained 54-and 64%... lion lbs (398,000 tons) of PCBs for the chlorine, respectively; in France, Pheno-' years 1957 through 1974 (Klleinert, 1976). . clor DP6 contained 60% chlorine; and in If these figures are both correct, then Japan, Kanechlor 300, 400, 500, and 600 domestic sales were expanding markedly, contained approximately 42, 48, 54, and ' especially in the 1960s. Table 3 lists do- 60% chlorine, respectively (NIOSH, 1977). mestic production by Monsanto from 1960 These products are very similar to their to 1971 (Anonymous, 1971) and indicates Aroclor counterparts in composition. this growth. 2: 52 TRAUMA VOL. 25 PCB-ARCH-EXT0378240 'SSSibMZ&iSBSia^XZL.wcatotMis ;t ! :. >.!: i POLYCHLORINA.. TE" D''B. I.PHE!N> YV LS (PCBs) - .'- - -is*& "t Mt,;;-'-: * Jy ...% a-i'i'f-r " -: ` * < * ._ :.^^-rs**&% ?,, ^vagsa ... v*"".%si,.-^r>j0{);^'3- Sf&t-ry**,. *> w -> DOMESTIC PRODUCTION OF PCBs. BY MONSANTO CO. .... ,-;^^"|N 'SHORT TONS i-- " - M t> l, .p . '. jfef = >fcj -^. . T-i^rY 2 Year 4Ts;AlL.AT'.t~r;';'"DoMESTic Sales - U.S. y*~rs;c. Insulating . Production .'. T Liquids* r3"' Otb"ersb Exports 1960 ... . 20,786""f%xil2,444 ' 5,163 . 1,827 1961 20,333 h'A. 11,108 7,661 2,076 1962 20,986 % .11,683 . 7,339 ' 1,809 1963 22,367.'.'"f";'11.448 * ** 7,618 1,824 1964 ' 25,417 -+"13,969 V 8,666 ' 2,048 1965 30,240 AeA^l 6,203 tSSSS-" 9,695 2,117 . 1966 32,925 +v".T.; 18,897,'^ 4A-' 10,642 3,426 . 1967 - ' ' 37,655 APhLv. 20,387' >10,846 ' ' 4,062 1968 . .. 41,427 20,568 .11,990 -- 5,616 1969 ' ' 38,194 '^% ''18;564::r^"" 15,034 " " 5,312 1970- "V - 42,527-^ g 20,268 -p - 16,263 - 6,826 . 1971 ` 20.236c ::: 14,417 ~ : 4,401 ; ' -4,938 ^ -5. r. - -- Totals - - : ;353,093- ? ` 189,756 - ' -T-' 115,318 * 41,881 Tf * For closed electrical systems-traisformers and capacitors _ ` Includes heat-transfer systems, hydraulics/lubricants, and plasticisers " Estainated^,5??n^a3sa^xi^si^a^,^;.., . . - , --Li.' <.'?'&z VOLUNTARY RESTRICTION OF PRODUCTION.:-; ; 1975 to be about 700,000 tons with over - .v-ir... half-of this, 350,000+ tons, already in the Table 3 indicates that 1971 production ,C environment. Data for production esti was less than half its 197.0 production and" ' -; mates of individual Aroclors are scarce ` that PCB sales for uses other than elec-^^ and should indicate relative volumes of trical insulation had dropped -more^than*-^ different Aroclors. Available data is pre 70% to 4,401 tons. This latter point'was sented in Table 4 and does not include ex --doubtless due to .Monsanto in];mid-1970 sports or total production figures. `^voluntarily.restricting sales of PCBs for ; Table 4 indicates that there was a wide uses where end-product disposal could not variation in production, with Aroclor 1242 ... be controlled due to the overwhelming ac having over three times the tonnage of the cumulation of evidence of its environment runner-up Aroclor 1254. It is interesting . tal contamination. ' -S to note that in only four years, there were over 34,000 tons of Aroclor 1016 sold. Aside OVER 350,000 TONS IN ENVIRONMENT from 1016,. the production of PCBs of 42 60% chlorine accounted for almost 88% Train (1976), cited earlier, had estimated of the total sales of Aroclors during this total U.S. production from 1929 through period.. : w 5: i !; lit '"5 i f 1fa5v..5-if>j .' *?. f*. lrlibBIfi?l<,l1 24r< jfp. & : ^ > lil! Jj|,l g; *; ifilgi B. f- ir W* b8-; im %;*S 1 k- I IP U Pi Mfi- tp.i 5 ill r H 5. Si ;. p -! \ \ C 2 AUGUST 1963 2: 53 j ij . -i ? *rt PCB-ARCH-EXT0378241 rr-^hL: t 3, J Z`**.S?.v: 'V"T .-.Vs"' _.-y-,..y>.r.*7S\.v-Jx _; TRAUMA 7 f*i*SV ... -r. * **-- -It ;r '" "Table 4_`'S_S&_ .vr. SjfefeS_s' .... Table 6 lists the manufacturers of prod ' ' DOMESTIC SALES^ Of:.L ucts containing PCBs as of 1979, (EPA, DIFFERENT AROCLORS FROM^'V--- '1979). As is indicated, there are many in ' 1957 THROUGH 'V974 ~ ` dustrial concerns involved in ^utilizing " - ' .-'7 ` ,, : ,, - Arocolor' 1221" W - 1232* - :: 1242 Tons: , yl>y ir~~4V 2,TGi'wwn;^-1.019^::'' .. 215j 608""^. PCBs, although Monsanto was the sole pro ducer with plants in Anniston, Alabama, where PCB production ended in 1970, and' Sauget, Illinois, where production ceased in 1977 (NAS, 1979). . 4 . 1248b V : . 29,603*-".... \ 1254 .r. t. .;6i,86r^:u;... ~ ' ' ... ,,,, 12605.4>v - -rc*r> 45,774 . *... 1262s A,;.v ,.A:".7,175:AA " T: - . CAPACITORS AND TRANSFORMERS . ' Most of those listed inv Table 6 are in 'A,r`l268-&w ' volved in manufacturing sealed-use prod * -.... ' .:l016a '/T" "#i:34,861-fp3- ucts such as capacitors, and transformers. _ . , Total .. v'issswi-.* Reference: Bremer (1975)'"'~J *** Zero sales starting in 1972*; - ^ . 1973*; 1971* T^V-iSvS - 4 Sales began in 1971: .. , . ' ... , .>i-.* * . , . ... . .-.' -VS***- . -< -'.C*-.rPW^-X-c JO ----.*'.. .,. * ti.m. ...... FOREIGN PRODUCTIONo&h-p-?.-' , Data for PCB production .-and;sales by other countries is quite limited. Japan first produced PCBs in 1954, the. Kanechlor se ries, and by 1972 bad produced 58,787 tons with over 11,000 tons in 1970 alone, but suspended all ^production 'in-.1972 (Tatsukawa, 1976)..In 1973, production" exporta tion and importation in a number of coun tries were reported as shawm .in Table 5. .vter FOREIGN PCS USAGE ` Data for PCB usage in other countries 4 is either absent or few in number. IARC (1978) reported uses of PCBs in 1973 for the U.S. (19,000 tons), France (5936 tons), Italy (2932 tons), Canada (1422 tons), UK (1268 tons) and Belgium (783 tons) with considerably smaller amounts for several other OECD members. Bergland (1972) reported that Sweden in 1970 imported about 500 tons with about 50% of this ex ported to other countries in electric ca pacitors and that, in 1968, 65 tons were used in dyes which was reduced to 35 tons in 1970. ' . USES The PCBs are a class of aromatic, chemi cally inert, chlorinated hydrocarbons which have had very broad applications until being severely restricted in 1971. Although manufacture of PCBs ceased in October 1977, residues of PCBs from prior and cur rent uses are still appearing in environ mental media. ' '1,000,000 TONS PRODUCED SINCE 1929 ' With Train (1976) estimating that U.S. total production through 1975 was some 700,000 tons, it can' be surmised that total world production since 1929 could approxi mate 1,000.000 tons. Such an estimate under scores the concern produced worldwide and the continuing efforts to understand the po tential toxicological implications. (Text continued on page 2:57) 2: 54 TRAUMA VOL. 25 S,_,- I^ -- A I I MMn 1 -- JJ PCB-ARCH-EXT0378242 a! "; PO L YCH LO RJN ATE DJBI PHENYLS .CPCBs) > .^*^r^^iteRC=S8K^ste5:2.___ . -1 . . '- ^^'^m^ableS^ - 51 '.........................." .4; r. PRODUCTION EXPORTATION. AND IMPORTATION OF PCBs . . - .. '"'^'"-BY'COUNTRY.'IN 1973 " ' -, ,:... -'- -^Production* 'L Exportation. Importation Country TSgAggSf tonsV't^.'SET.A (tons) . . . (tons) ->h * >"*?^*W?V*S`' '' ' ' '^V - ,./ > "itUnited States'* . France . ' k United Kingdom . Italy .. . "ftnrmrl;) " ^ .^Finland -*= gJ?.New Zealand ;*-2-0,233_ S.M*S"6p5&v*j;_:3gS.i 10,6927;':TM 4,519 7;" 756^7 , ";. 1 2,698 5.071 4,189 1,213 __ - V~-- ' = 258 331 '' 5 1,764 1,213 S' 266 .20 * - 20 -.. 350 N'LL''"Austria, Czechoslovak^'West Germany':(FRG), Spain and the USSR pro- ` ' Cr duced PCBs in 1973 but quantities unknown. " . *" " ' . * `U.S. data for 1974.' . -. - .-- jjv ui-vifir' ` ' ... .IReferences: Hutzinger (1974).; EPA;:(1?76); IARC (1978); Durfee (1976). ;7*' ,---fr.* - o; * -wen jVSi'V ?% -r 4 7 &*<'.'*'V`5,-s^5^r,rT * - * ^ ''' ; - ' ** y r. ..<*" -.--*: - *j'...' .:t, c tti*. "'- '>^^avsS;>*5fcC.z*4.*,iy*^&*voti~^i*jrr5.I--..--=r;#s:*^*^S..~'47<rs>*. i*.?>-e^-^>-'..-r - ^ ^ = ,-' - ' ' Tot/e 6 4_. ' ' ' "-^-""'/MNUFACTURERS A'ND'TrXdeTNAMES OF PCBs BY COUNTRY Many manufacturers have-used .PCBs1 in\tbeir products and/or marketed them under various trade names. This list may not be complete or current. A. United States: C or T indicates manufacturer of capacitors or transformers. ^ > __ *' /.Uv , i.'JfS'Ur*vA .>2iuur.ic,, , , Manufa cturer ' ' .J - . U "-'Zrvi'--^yJ 'tZ'nZrA- (' - v - Trade Name " * Aerovox (C) . Hyvol ' Allis-Chalmers i ,, ^'.1 .. Chlorextol American Corp._ , .' Asbestol ' . 1 Axel Electronics (C) , . -. ' Capacitor Specialists (C) --- " ^ -- . ' .- ' ' Cornell Dubilier (C) ... Dykanol . . Dings Co. . _ T: -- ^^.^#7'---'" ' -- Electric Utilities Corp. (C) :- i:=V TLIL. . Eucarel Electro Engineering Works .(T -- " Electromagnetic Filter Co.M- "7'T' " -- Envirotech Buell . .. .7*-? -- EriezMagnets ' ' Pyranol ESCO Manufacturing Co. (T) . Askarel1 Ferranti-Packard Ltd. ' Askarel1 General Electric (C,T) ' . Geneva Industries Pyranol -- NO. 2 AUGUST 106S 2: 55 ill JIM? f -!||--.;.\ II iPi?lf`j tf p| 1111 HU Ilii j6[ 1 rn' J _v;M` i %: j; i *2- t >: 'i j |t| 1i Py-HeI: U-'i I j PCB-ARCH-EXT0378243 . s * ^ -fSS' " S *v?- ' K^^TRAUMA . . . . -- ,, - ?. ' v*. Manufacturer JSL Table 6 (continued) Trade Name -fi' 7*?* t v , '-' *' " ~. - _ A *.;. f3f : =-. ~ V-- H. K. Porter (T) ------:. Helena Corp. HEVI-Duty Electric (Tj,^%::.^i.3u:i--,-C. , ' ` ; .``5 e - " "jA:V ` '-- -- - -- ,, a. -*< .-= . - J ! .v ' - S".# -. Ota**-i-'A i -'r- >-. - J **- -/ ' <* - * I.T.E. Circuit Breaker^fe^^tr^ .! Non-Flammable Liquid / - ) a :h; Jard Corp. (C) ^JSgg&j^^ Kuhlman Electric Co. -(T)'~ * . A~` Clorphen - .. ' ,, - 'Saf-T-Kuhl ' 1 %-A-A McGraw-Edison (C) Elemex Maloney Electric - Monsanto ' .. Aroclor) Tberminol12 . Niagara Transformer.,Corp.-( T) ;P. K Mallory & Co^fCiJsSSSS^^^^ Power Zone transformer;^?-. R. E.'Uptegraff Mfg. (T? R. F. Interonics (C) SSVZfil.-- ....-A' Pydraul3, Santovac 1&2 Askarel1, EEC-18 Aroclor B .. T': EEC-18 ;f .; I _ |*> A -- -** ? :" v: J :. Reliance Electric Co. A * * * Research Cottrell (T)^., Askarel1 Sangamo Electric (C)..^v.l.rJ~j^.f^r.V'.v Diaclor --- Sprague Electric Co. (C) ^r"v"i"- *' Chlorinol Standard Transformer Corp. (T.) , )..... Stens Magnetics . Tobe Deutschmann Labs'(C) -A'Y>--r. ' Universal Manuf. Co. '(C) 'v!: ^ Askarel1 " Van Tran Electric (T)~v^-- -,-. Wagner Electric " , No-Flam ol Westinghouse Electric (C;T)' Inerteen York Electronics (C) B. Other Countries Country - v* fc,* M-- a--- n--- ufacturer ^ i Czechoslovakia f*s; -Chemko ; France r ^Trodelec'g^f,-^^ -* Germany (FRG)' '"Farb'enfabriken Bayer Italy ) . ' Caffaro . Japan Kanegafuchi Chemical Co. Japan ^s\ Mitsubishi-Monsanto United Kingdom Monsanto USSR -A Sovol . -r; ' Trade Name - Phenoclor, Pyralene4 ' ,, .. v. Clophen - , . Dk, Fenclor, Inclor,- Kanechlor . ; ' Santotherm FR Aroclor, Pyroclor, Santotherm FR 1 Askarel is the generic name for non-flammable insulating fluids in capacitors and transformers. 5 Tberminol included various products used as beat transfer fluids (e.g. Tberminol FB-O) s Pjdraul included various products used as hydraulic fluids (e.g. Pydraul A-200). 4 These products as now formulated, do longer contain PCBs. Beferences: EPA (1979), Hatton (1979), Durfee (1976). 2: 56 TRAUMA VOL. 23 aiiiSsi&P&iPI; PCB-ARCH-EXT0378244 -f-i jrc.W..i**STL*f.rt--< sJsa^fe^aSJSScrifi-- - ..., POLYCHLORINATED BIPHENYLS ''Sf* *.**.>._?T $>r . #'f- r*.ja'fr^u *i7,q ` ri?r?5'A "i-** sa<T^v ---. .* * 111 **c **> *-- **.#-.- A ' . ;able 7 - .> (PCBs) -........... v- USES OF PCbT'IN "the"UsTby'AROCLOR TYPE SINCE 1970 -End Use ::^P^1016^ 1221^: 1232 1242 ; 1248 1254 _ 1260 1262 JuJlUllL<luli-ll,.ll I.IUU.. ., juujIWlUiU|, ': l i ; .- ,3*tj : 1268 Current Users:' ` Capacitors'-'""^ Transformers -*; . id ;. - ">->r ,. X1 2 3 'x Former Uses;,,. >..v^r ~f**- -*`-h ^.- "<-V\*r ,*->;* * - Heat transfer Hydraulic/Lubricants Hydraulic Fluids ~ X X Vacuum p*umps -` - Gas-transmission *"iT*IT7 turbines >;'. ^1 Sl^*St>r!3-n:*iw !|XrX.s, ~2~'*^'*^<0^*t--~- l .. X X X' - x --' XX^ Plasticizers^;"*~':V ' RubbersV~'~- Soynuthieutic resins Carbonless paper . :rr"; , ' X ' ~-w X X l? X X X -X X Miscellaneous'' " - .'-Vtli.lx/j a l' ~ r - -*-- r*.\r* Adhesives >; .-X A ivi- X . X "Wax extenders "- - >yj-- -. *>*>:( - *: - --.< ; yjrttU.'---rtwi-f -ji.Vi.Tyn . w xf X Deducting agents.,;-. : ' X ' Inker _ - . --r U... $* .- ------- =-- X ncyv^1;.; '* '-wr Cutting-oils rs i^JmLs1 ly-jysiWV^ X Pesticide extenders V X Sealants & caulking compounds sSfc2s^fs$|ii,: - X i r .,;La4A* ** X X * Discontinued use - Beference: EPA (1976) ^ "is? '" -. - -*r-'.' A11-a-sriiL" .-Ct*',.' rpfr --,- , -, - v -^CURRENT AND .FORMER lUSESZ. 4) Corrosion inhibitors (Hubbard, Principal current and ;fdrmer end uses - 1964). of PCBs,,:in the U.S.-are^presented'in?T<^^r * All these uses ended ostensibly in 1971 ble 7. 'with Monsanto's restricted sale of PCBs There have been many other applications^.: only for sealed systems. . ' , not listed or not such as: " PRESENT USES 1) Flame-proofing cellulose'fabrics.V^h,-.. 2) Constituents in elastomers,; paints, lacquers, pigments and dyes. 3) Protective coatings.,for wood, metal and concrete. ' ' . Principal uses today for PCB fluids are in the electrical industry and, with their superior cooling, insulating and dielectric properties, are used widely in capacitors and transformers. PCBs also give electri- NO. 2 AUGUST l&BS 2: 57 PCB-ARCH-EXT0378245  <16;'. >* Ei'iv4*>;f--r,^^&f T_ RAUMA V. ` f'-z ' " cal. equipment the critical^dyantages ;qfi.;' MIXTURES OF PCBs DIFFERENT FROM _ reliability, long life and compactness:;. PCBjss, , , INDIVIDUAL COMPONENTS . impregnated capacitors,' for. example,. arey - 'markedly more reliable and long-lived, are', ' Individual PCBs are of little commercial ,one-sixth tbe size, one-fifth the weight and ;'-,, value whereas the mixed chlorinated com one-fourth the cost tofij. comparable,,. oik:~ ponents have considerable commercial sig impregnated capacitors Anonymous," nificance. Mixtures of PCBs, as in the com-' 1972)...:; mercial Aroclors, have physical properties which are quite different from those of the LIFE-EXPECTANCY OF PCB-CONTAINING ...yy . ~ TRANSFORMERS %ND CAPACITORS - .ivl'_.y individual components as can be seen in data of Hubbard (1964) and Hutzinger et al. (1974). ^.-.y y ,y ,,>/ : ;. -- According to Durfee ;( 1976), :transform-~.-.. ^ When isolated in pure form by recrystal- refs' containing' PCBsr cdmpfiselbhlyiabbutfi'" -lization from suitable solvents, individual. - o%' * of the/*U '.S.- >tvrran-sfo- rmerH.-nj* a?. r.k.e t and are,',. PCBs are usually white or colorless crys used only.where safety., andhreliability?are tals , but commercial products;'usually are7 -of 'primeMmportance.'TAfeTexpectancy, of y" liquids' because the melting point is de- si* such PCB containing"transformers>was;re-^;; pressed when components are mixed to ported to .`be over. '30 ,years, ' and some ' - gether (IARC, 1978). . 135,000 have'7 been' put into"'seryice.,` since ', ' 1932 vrith virtually all (as. of,,1973), still inA, service.'The average transformer'contains ' _ INSULATION AND NON-FLAMMABILITY about 3,000 ::lbs of-Askarelifluifls-of-which 2,154 lbs- are PCBs (NAS,,,19.79.) ..which can. ... The widespread adoption of PCBs by give one' an' estimaterof._totalluse; in,this , 'application alone. , Durfee (1976) reported data frourGen-" the electrical industry was due mainly to their excellent dielectric (insulating) prop erties and non-flammability. As their chem eral Electric which indicatedl'that^aboutT- , t, - . --------------O::?-. million capacitors containing^PCBs are ical and physical properties became known, uses for PCBs multiplied. Table 8 is a brief made in .the U.S. ahnuallyrihost for 'first-. 'summary of their chemical -and physical time use' in products," arid^their* life* ex--r properties. pectancy is over 10 years 'for. lighting' ap-' plications.;, and overS20,Eyears..Un,.electric ' utility ser\fieeJ"The~f'NAS^1979)^ report' listed a higb-voltage;capacitor as weighing . t : ,i i'evc, - r- :s *<'# - v-*' - 120 lbs and containing-.-24^1bs;pf >PCBs, _ while a low-voltage"capacit`of"weighTab6ut~ ACCUMULATION OF PCBs IN FATTY TISSUES The solubility of PCBs in water is very low and decreases with increasing chlorine 20 lbs and contains 3.5 lbs of PCBs. content; PCBs, therefore, accumulate in living matter,-particularly in tissues and PROPERTIES organs rich in lipids (Hutzinger et al., 1974). ~ What properties do the PCBs have that A listing of the chemical and physical have led to such widespread application over the years? properties of representative Aroclors can be found in Hammond et al. (1972). 2: 58 TRAUMA VOL. 25 PCB-ARCH-EXT0378246 i ; POLYCHLORINATED BIPHENYLS (PCBs) s ;i i n I ! Table 8 I CHEMICAL AND PHYSICAL PROPERTIES OF PCB MIXTURES ! ii 1. Very high boiling point (very low vapor pressure) 2. Very low water solubility (high lipid solubility) 3. High dielectric constant (non-conducting) , 4. High thermal stability (to 1600F) ! 5. High resistance to acids, alkalies and corrosive chemicals. i 6. High resistance to oxidation and environmental deterioration. ! i 7. Permanently thermoplastic. 8. Vary from oily liquids to hard transparent resins. ; ; Reference: Hubbard (1964) TOXIC IMPURITIES PCDFs AND TCDDs ("DIOXINS") >' i Confounding the determinations of The PCDFs chemically are quite similar relative toxicities and potential and real to the polychlorinated dibenzodioxins ("di environmental effects of PCBs are the find oxins" or PCDDs) which gained world ings that similar PCBs from different wide notoriety during and subsequent to manufacturers show marked differences in July 1976 when a chemical cloud was re toxicities to test animals. leased from the ICMESA plant at Seveso, Vos and Koeman (1970) and Vos and Italy. This cloud contained not only caustic Beems (1971) found that Phenoclor DP-6 and Clopben A-60'.were much more toxic 2.4.5- trichlorophenol but also 2,3,7,S-tetrachlorodibenzo-p-dioxin (TCDD) (Holm- !. ` to chicks and rabbits than Aroclor 1260, stedt, 1980). This form of TCDD is one of even though all three contain approxi the most toxic chemicals known with an mately the same degree of chlorination LD50 to male guinea pigs of 0.6 ug/kg and (60%). . 22 ug/kg to male rats (Schwetz et al., 1973). Half a dozen books plus numerous publications resulted from this incident. PCDFS AND PCNS TCDD is also discussed, in many publica tions relating to the use of the herbicide Subsequently, Vos et al. (1970) found that 2.4.5- T in agriculture and the related Agent the Phenoclor and Clopben mixtures con Orange as a defoliant in the Vietnam con tained parts per million (ppm; ug/g) levels flict (see Wilber, 19S0). ; of: Representative structures of a PCDD, I i PCDF and a PCN are given in Figure 2. 1) Polychlorinated dibenzofurans (PC- DFs), both tetra- and pentachloro forms. 2) Polychlorinated naphthalenes (PC- BURNING OF PCB-CONTA/N/NG FLUIDS: FORMATION OF "DIOXINS" AND PCDFs Ns), both hexa- and heptachloro It should be pointed out that dioxins in forms. general, and TCDD in particular, have not . NO. 2 AUGUST 19 63 2: 59 ' ' .....' r TJ-il'JU.U,'.!,!)1.:. - T- PCB-ARCH-EXT0378247 ' :r,':":sssrh. *r_;: sssi 'ixs^r.s - - -....... ..... " ' ' - ' : ------r: '-' - TRAUMA BBSBjag^'aagagay 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 2,3,7,8-tetrachlorodibenzofuran (TGDF) 2,3,6,7-tetrachloronaphthalene (TCN) FIG. 2. Structures of a PCDD(A), PCDF(B) and a PCN(C) been found in copunercial PCBs, only PCDFs and PCNs.; However, burning of PCB-containing transformer fluids such as Askarels, containing also chlorinated ben zenes, has led to the formation of both PCDDs and PCDFs (Schecter et al., 1981); and pyrolysis of PCBs can lead to PCDFs (Buser et al., 1978a). Buser and Rappe (1978) indicated that there are 75 positional compounds which could exist for the PCDDs containing from 1-8 chlorine atoms; and a number of these are known to be extremely hazardous com pounds, especially the 2,3,7,8-TCDD. Buser et al. (1978b) reported that there are 135 positional isomers (isomerism--the pos session by two or more distinct compounds of the same molecular formula, each mole cule possessing an identical number of atoms of each element, but in different ar rangement) possible for the PCDFs and some of these are about equally toxic or biologically active as the most highly toxic PCDDs. This was reported true for .the 2,3,7,8-tetra- and 1,2,3,7,8- and 2,3,4,7,8penta CDFs. '%- POLYCHLORINATED DIBENZOFURANS (PCDFS) PRESENCE IN PCB PREPARATIONS ' Bowes et al. (1975) found PCDFs, tetra-, penta- and hexachloro congeners, in all PCB preparations analyzed, except Aroclor 1016. They were found to be present at levels totaling from 0.8-2.0 ppm (ug/g) in . Aroclor 1248 and two lots each of 1254 and 1260, and at 8.4 ppm in Clophen A-60 and 13.6 ppm in Phenoclor DP-6. Their findings indicate that the Clophen and Phenoclor contained 11 and 17 times more total PCDFs than the comparable Aroclor 1260 (0.8 ppm).~ ` As large amounts of PCBs have entered the environment, it can be assumed that quantities of PCDFs have also been re leased in proportional amounts. PCDFs IN PCB-CONTAMINATED RICE OIL PCDFs have been isolated from the PCB-contaminated rice oil that was in volved in the 196S Yusho incident in Japan (Morita et al. 1977). This rice oil was re ported to contain from S30-1030 ppm of Kaneclor KC-400, a Japanese PCB very similar to Aroclor 1248 in gas-chromato graphic profile (Kuratsune et al., 1976); such rice oil also had a much higher level of PCDFs than the KC-400 by a factor of 250. That is, the pure KC-400 PCB con tained 20 ppm of PCDFs and the Yusho oil with ca. 1000 ppm PCBs had 5 ppm PCDFs. This higher level of PCDFs in the rice oil containing "used" PCBs implies that usage of the KC-400 as a heat transfer 2: 60 TRAUMA VOL. 25 ?**ituaMttfaa^^,........ aasfijj&saigfi^^ > OWHimli1 POLYCHLORINATED BIPHENYLS (PCBs) medium resulted in increased PCDF for mation. . OTHER EXAMPLES OF PCDFs IN USED PCBs Morita et al. (1977) found a 4-fold in crease in PCDFs in a PCB used for two years as a heat exchanger. They also reported an increase in PCDFs when PCBs were heated with air in a sealed glass tube at 300C for two weeks. t VARIETY OF PCDFs WITH VERY HIGH . ACUTE .TOXICITY . Buser et al. (1978c) found that the Yusho oil contaminated with used PCBs contained more than 40 different PCDFs. They iden tified 2,3,7,8-tetra- and 2,3,4,7,8-penta-CDF as major constituents, both of which are reported to have very high acute toxicity. . . Liver Necrosis As early as 1961 (Bauer et al., 1961), it was shown that a single oral dose of 0.5-1.0 mgAg of a mixture of tri- and tetraPCDFs caused severe and often lethal liver necrosis in rabbits; application to the rab bit ear resulted in chloracne (see section on Chloracne). For 2}3,7,8-TCDD, a single oral dose of 0.05-0.10 mgAg (Vioth the pre vious dose) caused a lethal liver necrosis in the rabbit and also caused chloracne when applied to the ear. TCDF: ORAL LD50/30_ Moore et al. (1976) reported that the oral LD50/30 (the dose causing 50% mor tality in a 30 day period) of 2,3,7,8-TCDF to Hartley guinea pigs was 2.0 ugAg, which compares quite closely to that of 2,3,7,8-TCDD cited earlier (0.6). Oral dosage of this TCDF to 1 day old chicks at 5 ugAg per day resulted in their death in an average of 11.5 days; at 1 ug/ kg/day it was felt by the author that all or most of the chick would have died by 30 days (experiment ended on day 21). PATHOLOGICAL CHANGES The most striking gross pathological change noted was the accumulation of clear fluid, as indicated by marked subcutaneous . edema, ascites (fluid in abdomen), and hv- dropericardium (abnormal accumulation of serous fluid in the pericardial cavity). A second pronounced change was a marked decrease in size of the thymus and spleen (Fig. 3), found also in the guinea pigs. _ . Somewhat surprising, oral dose levels of this TCDF up to 6000 ugAg in C57BL/6 mice or 1000 ugAg in rats failed to produce any toxic effects. These levels are consider ably higher than toxicity induced by TCDD in these species. TCDF STUDIES WITH MONKEYS Moore et al. (1970) extended these stud ies to include 2.3,4,7,S-penta CDF and rhesus monkeys. At a 1000 ugAg (1 mg/ kg) oral dosage of 2,3,7,8-TCDF, 2 of 4 monkeys died 25 and 31 days later; at 1500 ugAg both monkeys died 14 and 23 days after dosing. Delayed Toxic Response and Dose Related They found the toxic response to be dose related and did not manifest itself clini cally until 7-10 days after dosing. Symptoms Monkeys at this time developed: 1) Some facial edema (of the eyelids and , lips). NO. 2 AUGUST 1983 2: 61 s. A_~' - - - - - ----- ----------------- -*------ - ----- * -- - - -V us*;**<*-. 1 mi-..... . -- 4? PCB-ARCH-EXT0378249 2: 62 MITT**1. FIG. 3. Endocrine and Salivary Glands; Spleen, Liver, Pancreas; ' Kidneys and Ureters Note the thymus gland (12) and the spleen (13), two of the organs of the lymphoid system which contain lymphocytes. The lymphocytes, small white blood cells, are the basis for an animal's (including human's) immune system. Sublingual gland Thyroid gland Parathyroid gland 4) Pancreas Liver Kidney Urinary bladder 8) Urethra 9) Pituitary gland 10) Parotid gland 11) Submaxillary gland 12) Thymus gland T3) Spleen 14) Adrenal gland 15) Ureter 16) Gonad TRAUMA VOL. 29 PCB-ARCH-EXT0378250 POLYCHLORINATED BIPHENYLS (PCBs) 2) Anorexia. TCDF STUDIES WITH GUINEA PIGS 3) Occasional vomiting and depression. 4) Loss of facial hair, especially the eye lashes. Moore et al. (1979) in this paper re ported the acute oral LD50 to guinea pigs c of this TCDF to be > 5 and < 10 ugAg and for the 2,3,4,7,8-PCDF to be > 3 and Loss of toenails and fingernails occurred also and the skin developed a dry leathery < 10 ugAg. indicating that both PCDFs are extremely toxic in a single dose to \A texture (hyperkeratosis). guinea pigs. Clinical Pathology . At necropsy, they found no difference in the pattern of lesions to guinea pigs for Clinical pathology included mild anemia, TCDF or PCDF. They cited a marked re consistent lymphopenia (decrease in blood duction in thymus size, lack of body fat and t, ;i; lymphocytes), marked neutrophilia (in crease in blood neutrophil leukocytes), a reduced muscle mass. Histopathology re vealed a loss of lymphoid cells in the thy m Fit IT 33-50% decrease in serum cholesterol, and mic cortex and hyperplasia (abnormal moderate decreases in total serum proteins ' increase in cell numbers or arrangement) U and serum albumin. of epithelial cells in the renal pelvis, ureter, n l*j;j and urinary bladder. Post-Mortem Findings These and other lesions not cited were fcvi: Post-mortem examination indicated a similar to those described in guinea pigs H spectrum of lesions in the treated monkeys poisoned by TCDD (Gupta et al., 1973). which reflected the clinical findings above. An LD50 value has not yet been estab These included a moderate to severe loss lished for TCDF in the rat or mouse, al of body fat, enlarged bile ducts, hyperemia though some toxic signs were noted at 1-10 i :i! (excess of blood in parts), scattered areas mgAg body weight (Moore et al., 1976, of petechial (pinpoint spots) hemorrhage, 1979; Birnbaum et ah, 19S0). facial ulceration and small bubble-like cysts k ji in the fundic and duodenal areas of the stomach and proximal small intestine. Cutaneous, eyelid, external ear canal and DISPOSITION OF TCDF IN BODY OF TEST ANIMALS toe nail lesions were apparent in all ani Birnbaum et ah (19S1) found that TCDF mals. disposition in monkeys is similar to that : i Ft Atrophy of the thymus and spleen {Fig. in rats, but monkeys clear TCDF from the 3) were pronounced at.the 1500 ug dosage, body more slowly than do rats and are but no liver lesions were observed. Hyper therefore more sensitive to TCDF intoxi plastic changes were noted in the bile duct cation. and gall bladder epithelium and^a degranu In guinea pigs, Decad et ah (1981), lation of exocrine pancreatic cells. found, after 6 or more weekly doses of The authors established that the LD50/ TCDF at 1 ugAg, that TCDF was accumu 60 of 2,3,7,S-TCDF for rhesus monkeys as lated in the liver, adipose and skin. 1000 ugAg, a dose that is about 20 fold "When a body burden of only 5.6-6.6 ug/ higher than that estimated for 2,3,7,8- kg was attained, they found that the tox TCDD (McC-onnel et; al., 1978). icity of this compound was irreversible and AUGUST IS 33 2: 63 Baaaes* TRAUMA resulted in progressive weight loss and death. The reason mice, and perhaps rats, are more resistant to TCDD has been sug gested in studies by Nagayama et al. (1980). They found that more than 80% of PCDFs given orally to mice were elimi nated rapidly thus minimizing absorption. Intraperitoneal dosing, bypassing the di gestive tract, resulted in very high liver accumulation. PROBLEMS IN ASSESSING TOXICOLOGICAL STUDIES . for 18 days after mating or for 14 days after delivery. They found that PCDFs were transferred across1 the placenta to the fetuses and to the offspring in milk. The amounts transferred through milk were much larger than across the placenta. The liver Avas the greatest site for accumulation of PCDFs. This is in marked contrast to the PCBs Avhich preferentially are seques tered in adipose tissues. Both 2,3,7,8-tetraand 2,3,4,7,S-penta-CDFs %vere found in the suckling mice and accumulated in the liver of the dams. HIGH TOXICITY OF CONTAMINANTS TO SEVERAL ANIMAL SPECIES . The very high toxicity of several PCDFs to several animal species (guinea pigs, rab bits, chickens, and monkeys) point up the concern induced by findings of these chemi cals in commercial PCBs and at higher levels in "used" PCBs. Their presence has made it difficult to assess the- many toxi cological studies done if this contaminant problem was not addressed directly. Other concerns follow. CHLORACNE The PCDFs also are known to induce choracne (see Chloracne section), a cutane ous effect where inflammatory changes in the skin occur due to plugging and rupture of the sebaceous glands (McConnel and Moore, 1979) and can be a very long lastr ing lesion (Urabe et al., 1979). Chloracne is one of the first signs of intoxication from chronic exposure. PCDFs TRANSFERRED ACROSS PLACENTA AND THROUGH MILK: ACCUMULATION IN LIVER Nagayama et al. (1980) fed a mixture of seven PCDFs at 0.6 ppm in the diet to mice PCDFs IN TISSUES OF YUSHO PATIENTS PCDFs have also been found in the tis sues of patients with Yusho from Japan. Nagayama et al. (1977) reported finding 2.3.6.8- and 2,3,7,8-tetra- and 1,2,4,7,8- and 2.3.4.7.8- penta-CDFs and a hexa-CDF as well as PCBs in tissues of Yusho patients, but only PCBs in normal patients. It is noteAvorthy that some PCDFs, espe cially 2,3,4,7,8-penta-CDF, Avere still pres ent in the tissue of patients more than 9 years after the Yusho incident. Toxic Effects to Liver This penta-CDF plus 2,3,7,8-CDF were reported by Poland et al. (1976) to be among the most toxic PCDFs and to be bound strongly to hepatic cytosol proteins and to be powerful inducers of the liver enzyme, arylhydrocarbon hydroxylase. The highly toxic TCDD also induces this en zyme (Goldstein et al., 1978); and because of this and their similar patterns of toxic effects, suggests a similar mechanism of action (Moore et al., 1979). It is therefore prudent to consider the toxic potential of the PCDFs and the PCNs (following sec tion) in assessing the toxicity of PCBs. 2: 64 TRAUMA VOL. 25 PCB-ARCH-EXT0378252 JglMllLL.il POLYCHLORINATED BIPHENYLS (PCBs) POLYCHLORINATED NAPHTHALENES (PCNS) SOURCE OF PCNs IN PCB MIXTURES The PCNs found in PCB mixtures un doubtedly resulted from the presence, in small amounts, of naphthalene in the origi nal biphenyl used to manufacture the PCB. COMMERCIAL USES OF PCNs -'PCNs are also commercially available industrial chemicals marketed in the U.S. by the Koppers Co. under the tradename Halowax. They have a wide variety of sug gested uses related to their electrical, flame retardant, and fungus-resistant properties, stability and compatibility with other ma terials (Anonymous, Undated). The PCNs have been used as: 1) Boat hull coatings, because of their antimagnetic properties. 2) In the electronics, radio and-tele vision industries as insulating waxes, sealing compounds, and dielectrics for condensers. 3) High pressure lubricant additives. 4) Wood preservatives (Taylor, 1979). ANIMAL STUDIES OF PCN TOXICITY The finding of hexa- and heptachloro PCNs in commercial PCBs is significant. X~Dlsease in Caffle Bell (1952), studying the mysterious X-disease in cattle, later called bovine hy perkeratosis (hypertrophy of the corneous layer of the skin), induced by a lubricant, identified the toxic factor in the lubricant as a highly chlorinated naphthalene. He found that toxicity of PCN in cattle was. produced by a total dose of 1.0 mgAg of body weight given'during a 7-day period. At this dose, signs of intoxication appeared on the 12th day after administration began. Bell (1953) in testing different PCNs found that hexachloronaphthalene was the most toxic, with hepta- > octa- > penta> tetra- > di- and tri-chloronaphthalenes next. With hexa-PCN, five calves developed symptoms by the 5th day after oral ad ministration and all came to autopsy by day 15-29 after receiving total doses of 0.5-4.6 g in small doses over several days. Symptoms included lacrimation, nasal discharge, sali vation, red areas on oral mucosa, anorexia, depression, indentation of horn and finally extreme weakness or prostration. Chronic intoxication in cattle produced cutaneous hyperkeratosis and an excessive drop in vitamin A level. Study of Sheep Brock (1959) found sheep to be 10 times more resistant than cattle. Sheep fed 1.1, 11, or 27.5 mg/kg body weight of Halowax 1014, a mixture of tetra-, penta- and hexachloronaphtbalene, died on average after 106, 27, or 20 days, respectively. About 4 g of this PCN was the smallest lethal dose to sheep. PCNs CONTRIBUTE TO TOXICITY OF PCBs These data indicate the relative toxicity of PCNs to two animals and give an indi. cation that they too can contribute to the toxicity found for PCBs, as will be cov ered later. The historical coverage of PCNs from an industrial exposure setting can be found in NIOSH (1977) and EPA (1975) has reviewed their hazard potential. RESTRICTIONS IN USE OF PCBs Japan prohibited the production of PCBs in 1972 in light of the health implica- T|. 44r.. iter:>'ii: if SN ski i m r Ifei mi If J S'- S ': Sr,:: ` \ : fchV, J pf Esf l: ; ft - - PFfe:i;44i-f ^$ p: 14 M Hfp. > pppj! nv" 5! 11 f- Si SIi ii *, I ! ;; ; i i ii.;i !i ! !' : I NO. 2 . AUGUST l8S 2: 65 PCB-ARCH-EXT0378253 TRAUMA tions of exposure and the earlier "Yusho" human poisoning incident (IARC, 1978). In the United Kingdom, PCB manufactur ers sell PCBs only when used in dielectric fluids while in West Germany manufactur ers can sell PCBs only as dielectric, heat- transfer and hydraulic fluids (IARC, 197S). Switzerland and Sweden since 1972 have restricted PCB sales to heavy indus trial use with authorization (IARC, 1978). Monsanto limited U.S. sales of PCBs in 1971 to use in closed systems, and in 1972 discontinued sales for heat-transfer appli cation (IARC, 1978), and all production of PCBs ceased in October 1977 (NAS, 1979). ' ' On 2 February 1977, EPA issued regula tions prohibiting PCB manufacturers and transformer and capacitor producers from discharging PCBs into waterways; the PCB level in ambient water was limited to 0.001 ug/1 (EPA, 1977). TOXIC SUBSTANCES CONTROL ACT The demise of PCB production was sig naled by the passage on 11 October .1976 of Public Law 94-469, the long sought for Toxic Substances Control Act. Section 6(e) of TSCA specifically: 1) Prohibits production of PCBs in the U.S. : 2) Regulates disposal of PCB contami nated materials. 3) Restricts the use of such materials already in service (NIOSH, 1977). The net effect of this law should be to. eliminate releases of PCBs into the en vironment and, eventually, to reduce exist ing environmental PCB levels. ENVIRONMENTAL LEVELS CANNOT BE REDUCED FOR MANY YEARS Due to the extreme stability of PCBs, however, environmental levels will not be reduced substantially for many years, and the problem remains of dealing with exist ing PCB reservoirs in the environment (NAS, 1979). PERMITTED EXPOSURE OR RESIDUE LEVELS OSHA STANDARDS OSHA (U.S. Occupational Safety and Health Administration) has published standards which require that employee's exposure to PCBs containing 42% chlorine (Aroclor 1242) cannot exceed an 8-hour time-weighted average (TWA) of 1 mg/m3 and exposure to PCBs of 54% chlorine (Aroclor 1254) cannot exceed a similar TWA of 0.5 mg/m3 for any 8-bour shift of a 40-hour work week (OSHA, 1977). In the USSR and East Germany (GDR) these values are 1.0 mg/m3 for both, in Sweden 0.5 mg/m3 for both, and in West Germany (FRG) and Czechoslovakia are the same as in the U.S. (Winell, 1975). FDA: PCB RESIDUE LEVELS IN FOOD PRODUCTS The FDA (U.S. Food and Drug Admin istration) in April 1977 set lower tolerance (residue) levels of PCBs in various food products to reduce buriian exposure (FDA, 1977). ' ` Milk and dairy products (fat basis) were reduced from 2.5 to 1.5 ug/g (parts per million; ppm); in poultry (fat basis) from 5 to 3 ppm; in eggs from 0.5 to 0.3 ppm: in fish and shellfish from 5 to 2 ppm. Tolerance levels left unchanged were: 2: 66 TRAUMA - VOL. 25 PCB-ARCH-EXT0378254 POLYCHLORINATED BIPHENYLS (PCBs) infant and junior foods, 0.2 ppm; in fin ished animal feeds, 0.2 ppm; in animal feed components, 2.0 ppm; and in food-packag ing paper materials without a PCB barrier, 10 ppm. These data may not reflect the most recent situation since such regulations are constantly subject to change. It should not be implied that other countries do not have similar regulations. r INCINERATION OF WASTE PRODUCTS A sixth could be added which would be volatilization of PCBs during incineration of waste products in small commercial, municipal or domestic incinerators and from open-burning dumps where tempera tures are too low or residence time too short. A residence time of 2 seconds at 2000F is recommended (Nisbet and Saro fim, 1972). ROUTES AND RATES INTO ENVIRONMENT ENVIRONMENTAL LOSSES With about 1,000,000 tons of PCBs produced worldwide from 1929 through 1977, about half still in service and the other half in various environmental com partments, how did they get into the en vironment? Since initial studies indicated very low acute toxicities, there was little These authors estimate annual environ mental losses to be: 1) 1,500-2,000 tons.'into the atmosphere. 2) 4-5,000 tons into fresh and coastal waters. 3) 18,000 tons into dumps and landfills. concern over possible environmental/ human exposure except in industrial/occu SOURCES OF PCBs pational settings. From their data, they estimate that only about 20% of 1970 sales in North America, POSSIBLE ROUTES some 7,000 tons, represented a net increase As with most industrial chemicals, loss figures for PCBs are essentially non-exist ent. A primarily qualitative assessment of rates and routes of PCBs into the environ ment has been made by Nisbet and Sarofim (1972). They list the possible routes into the environment to include: in the amount of PCBs in use in transform ers, capacitors and heat exchangers. The remainder (almost 30,000 tons; see Table 3) was assumed to have been dis charged into the environment with: 22,000 tons by disposal in dumps, land fills and incinerators. 1-2,000 tons by evaporation of plasticiz 1) Leaks from heat exchangers and ers. sealed transformers. 4-5,000 tons by leaks and disposal of hy 2) Leaks from hydraulic systems of draulic fluids and lubricants plus small fluids containing PCBs. quantities by disposal of heat transfer and 3) Losses and spills of PCB fluids dur- transformer oils. ing manufacture. They estimate only 10-20% (ca. 3,000 4) Improper disposal of PCB-containing tons) were destroyed by burning. fluids or waste PCBs. The NAS (1979) report estimated (page 5) Leaching or volatilization from PCB- C) that total cumulative PCB use from U.S. ; : containing formulations. sources through 1975 as 6S3,000 tons, and NO. 2 AUGUST 19 63 I i 2: 67 i ! V 1 ....... PCB-ARCH-EXT0378255 TRAUMA losses of PCBs which entered the mobile environmental reservoir based on produc tion and use data, to have been over 90,000 tons. Converting this figure to pounds, ISO,000,000 lbs., gives one a better perspec tive of total environmental pollution. WHERE DID WASTE PCBs GO BEFORE 1972?' Nisbet and Sarofim (1972) pointed out the problem of what became of scrap or waste PCBs by reporting that Monsanto in 1971 set up a disposal system for their customers, and within a year of announce ment of this service, 500,000 lbs. of waste PCBs had accumulated at the disposal site pending completion of an approved incin erator. The question that remains is where did these waste PCBs go before? Much of it undoubtedly went into sewers, waters, and dumps and landfills. The problems of disposal and environ mental pollution have been stupendous. Hopefully, the passage in 1976 of the Toxic Substances Control Act has rectified these problems and we can concentrate on im proving the situation. DESTRUCTION AND DISPOSAL OF PCBS CRITERIA FOR SAFE COMPLETE DESTRUCTION OF PCB PCBs and PCB-bearing materials can safely be destroyed by incineration, but kiln temperature and residence time are important criteria in assuring complete destruction. Nisbet and Sarofim (1972) re port that municipal incinerators which meet design guidelines of a residence time of 2 seconds at 2000F are necessary to preclude the vaporization of PCBs during incineration. PRESENCE OF PCDDs AND PCDFs IN FLY ASH AND FLUE GAS Olie et al. (1977) reported the presence of PCDDs and PCDFs in the fly ash and flue gas from municipal incinerators in the Netherlands but no quantitative data are given. In Switzerland, Buser and Bosshardt (1978) found the total amounts of PCDDs and PCDFs in the fly ash to be 0.2 and 0.1 ppm, respectively and in fly ash from an industrial heating facility 0.6 and 0.3 ppm, respectively. The number of individual isomers and congeners was quite large; as many as 30-40 isomers/ congeners of PCDDs and PCDFs were found. In other studies (Buser et al. 1978b and c), it was shown that in fly ash the ex tremely toxic PCDDs (2,3,7,8-tetra- and 1.2.3.7.8- penta-CDDs) are present in minor amounts, but the highly toxic PCDFs (2,3,7,8-tetra- and 2,3,4,7,8-penta-CDFs) are the major constituents. UNCONTROLLED BURNING AS SOURCE OF HAZARDOUS PCDFs Buser et al. (1978a) found that pyrolysis of technical PCBs yielded about 30 major and more than 25 minor PCDFs, with 2.3.7.8- tetra-CDF, the most toxic PCDF, being one of the main constituents. The yield of PCDFs, considering the amount of PCB recovered and the pyrolysis tempera ture, was between 3-25% calculated on the amount of PCB decomposed. These results indicate that uncontrolled burning of PCBs can be an important environmental source of hazardous PCDFs. When comparing the PCDF pattern in fly ash and the pyrolysis of commercial PCBs, there is a striking similarity which suggests that PCBs are the precursors of the PCDFs found in fly ash. This also 2: 68 TRAUMA * VOL. 25 y - vr",y-.-5y.'-* rwvi?-, PCB-ARCH-EXT0378256 / -V. ^^tr-SWir, Itf Jj;^J.,:,uuiJ l,KUMJ^L.Mtf**fa.t,.****** tV^-TW POLYCHLORINATED BIPHENYLS (PCBs) points out that destruction of PCB-contain- APPROVAL OF INCINERATORS AND LANDFILLS ing wastes in incinerators must be carefully controlled. Both incinerators and landfills have to be approved by EPA, and approvals are slow and fraught with delays. EXAMPLE OF BUILDING CONTAMINATION FROM As of September 1980, EPA had ap i` CRACKED TRANSFORMER IN ELECTRICAL FIRE proved only three non-commercial incin I erators for private on-site plant use (Anon A serious incident occurred in Bingham ymous, 1980b); one approved in late 1979 ton, New York in the early morning of 5 was on General Electric property at Hud February 19S1 when an intensely hot elec son River, N.Y. (Anonymous, 1979). This trical fire adjacent to a transformer pvrolyzed an estimated 90 gallons of Askarel reference cited a listing by EPA of eight landfills for disposal of large PCB-contain- I fluids when the transformer cracked ing capacitors; but on March 1, 1981, EPA \ (Schecter et al., 1981). The Askarel con banned capacitor landfilling after ENSCO tained 65% Aroclor 1254 and 35% chlori . (Engineering Specialities Co.) of El Do nated benzenes (mainly tri- and tetrachlo- rado, Arkansas gained approval January robenzene), and when pyrolyzed spread 19S1 for its commercial capacitor incin throughout the 18-story structure as a fine erator (Anonymous, 1981a). It was re oily soot. Surface swabs of open office ported that ENSCO had' a capability of spaces yielded an average of 162 ug/m2 of about 17,500 capacitors/month with an es i Aroclor 1254, and two composite soot sam timated 20,000 capacitors/month being re i ples yielded levels of 2.8 and 2.9 ppm moved from service. A second commercial i 2.3.7.8- TCDD and 273 and 124 ppm of incinerator approved by EPA in January 2.3.7.8- TCDF. The TCDD ("dioxin") was 1981 was that of Rollins Environmental thought to arise from the chlorinated ben Services of Deer Park, Texas (Anonymous, zenes and the TCDF from the PCBs. 1981b); test burns in 1979 of oils contain Cleanup of the building was suspended ing 47 and 80% PCBs for ENSCO and when the high concentrations of TCDD and Rollins, respectively, destroyed greater especially TCDF were found. than 99.999% of the PCBs. CHANGING RULES FOR DESTRUCTION AND DISPOSAL OF PCBs One of the prime problems in destruction and disposal of PCBs is that the ground rules keep changing. Current EPA regu lations (Sept. 1980) prescribe that sub stances contaminated with more than 500 ppm of PCBs are to be destroyed in spe cial incinerators. (Anonymous, 1980a). Materials with 50 to 500 ppm may be buried in chemical waste landfills or burned in special high-efficiency boilers. . CAPACITOR TREATMENT SYSTEM A second capacitor treatment system was approved for Environmental International, Inc. of Kansas City, Kansas by EPA Re gion VII (Anonymous, 19S2). This firm was purchased in April 1982 by Chemical Waste Management of Chicago, which owns the Vulcanus incinerator ship. This .latter company received a six-month EPA permit to burn 3.6 million gallons of PCB laden liquids at sea using the Vulcanus, which left port in December 19S1 to con- NO. 2 AUGUST 1963 2: 69 TRAUMA duct a five-day 'shipboard test burn of 500,000 gallons of oil containing more than 500 ppm PCBs (Anonymous, 1981c & d). CHEMICAL PROCESSES FOR PCB DESTRUCTION There are several chemical processes for PCB destruction. Acurex "Waste Technolo gies of Mountain View, Calif., as of March 1982, has EPA approval for its proprietary portable chemical detoxification system in Regions I, V, l7! and VLL. Sunohio of Can ton, Ohio has another process called PCBX which uses a proprietary reagent to strip away chlorine atoms to form harmless residues and restores the oil for re-use free of PCBs (Anonymous, 1980a). Goodyear Tire and Rubber Co. uses sodium naphthalide as the reagent to strip chlorines off and form sodium chloride (Anonymous, 1980b). Other technologies also are being investi gated. The American Chemical Society held a two-day symposium in New York on Au gust 24-25, 1981, entitled "Detoxification of Hazardous Wastes," where a number of the above processes were discussed. HEALTH EFFECTS This section will include a discussion of the following: 1) Chloracne. 2) Various effects of the human poison ings in Japan and Taiwan. 3) Human residues. 4) Enzyme induction and its effects. 5) Immune effects. . 6) Lung effects. 7) Reproduction and endocrine effects. 8) Neurological and behavioral effects. 9) Liver effects. CHLORACNE Chloracne, one of the first signs of1 i2n3 4 5 6 7 8 9 toxication from PCBs or its impurities, is a skin disorder described as a refractory follicular dermatosis produced by environ mental exposure to certain halogenated (halogen refers to any of the four very ac tive, non-metallic elements--chlorine, bro mine, iodine and fluorine) aromatic (de noting a compound characterized by a ben zene ring) compounds, which may be ac companied by systemic toxicity (Taylor, 1974). = FROM OCCUPATIONAL AND ' NON-OCCUPATIONAL EXPOSURES Initially just an industrial problem, first observed in 1S97, most cases up to World War II involved exposures to PCNs aud PCBs; but new outbreaks of the disorder have occurred and include non-industrial populations exposed to these and other halogenated chemicals such as PCDDs, PCDFs, brominated biphenyls and benzo- furans, and contaminants in various herbi cides (Taylor, 1979). Chloracne has been reviewed also by Crow (1970) and Von Weirich (197S). An early history of occupational Chloracne due to PCBs and PCNs can be found in NIOSH (1977). Chloracne is also one of the most constant and prominent features of exposure to 2,3,7,8-TCDD ("dioxin") (IARC, 1977). PCN FUMES MOST POTENT CHLORACNEGEN Crow (1970) has concluded that for the PCNs, fumes are the most potent chloracnegens, solutions less so, and solids rarely cause chloracne. Shelly and Kligman (1957), in human 2: 70 TRAUMA VOL. 2 3 nyj.uu^t PCB-ARCH-EXT0378258 ,, ; m , i i., * li .11. , 11-'|L -- 1 ` `ii i -............ .---*---------~r"-- iggaMiiH3aBsa*ggaisa--narvyaaBBBaawaa-.- POLYCHLORINATED BIPHENYLS (PCBs) studies, reported that penta- and hexaPCNs were potent acnegens (substances that cause acne), whereas tri-, tetra-, hepta-, and octa-PCNs were not. As men tioned earlier, hexa-PCNs were found as contaminants in PCBs and may add to the toxicity syndrome picture of the PCBs. Yon Weirich (1978) reported that the tri- and tetra-CDFs are both potent cbloracnegens and hepatotoxins (toxins affect ing the liver), and the penta- and hexaCDFs are also potent acnegens. CHANGES IN SEBACEOUS GLANDS Chloracnegens, such as the PCBs, PCNs, PCDFs or PCDDs, cause changes in the sebaceous glands (glands of the skin, se creting an oily substance, sebum), as ob served clinically in monkeys by the cutane ous, eyelid and auditory lesions found (McConnell and Moore, 1979). These changes resulted from a metaplastic change to a squamous-type epithelium that alters the character of the gland secretions from normal oily to keratinous (of the nature of keratin, an albuminous substance forming the principal matter of hair, nails, horn, etc.), resulting in a dry skin and blepharitis (eyelid inflammation). 'This often results in plugging and rupturing of the glands with inflammatory changes (chloracne). Concurrently with these lesions, hyper keratosis (overgrowth of the corneus layer of the skin) of the hair follicles often oc cur. A similar pathogenesis of chloracnelike lesions is observed in rabbits. ' INITIAL SYMPTOMS IN YUSHO DISEASE Initial symptoms experienced by 136 pa tients with "Yusho" were increased eye discharge and swelling of upper eyelids (blepharitis) (3S.3%), followed by acne- form eruption (chloracne) and follicular accentuation (33.1%), and pigmentation of the skin (9.6%) (Kuratsune et al., 1972). DERMAL CONTACT, INHALATION OR INGESTION Although chloracne typically occurs from external dermal contact, inhalation or in gestion can be important as the Yusho example illustrates for ingestion. PERSISTENCE OF CHLORACNE Chloracne was reported by Taylor (1974) to persist for as long as 15 years after exposure terminated. By 1975, the mucocutaneous lesions of Yusho victims poisoned in 1968 showed improvements in only 64% of the patients (Urabe et al., 1979). By 10 years post-outbreak (1978), these lesions were greatly improved but have been superseded by systemic disor ders. The paper by Umeda (1972) contains photographs of Yusho victims with chlor acne which dramatically demonstrate the lesions. HUMAN POISONINGS Two PCB poisoning episodes involv ing thousands of people eating PCB-con taminated cooking oil have occurred in the Far East and provide us. with data on the effects of PCBs on the human animal. The first incident occurred in Japan on the southwestern island of Kyusho in Fukuoka Prefecture in 1968. The second episode oc curred in Taiwan in 1979 and data on this incident are still fragmentary. YUSHO DISEASE OUTBREAK OF SKIN DISEASE This first episode in Japan had its be ginnings in March 1968 when an epidemic 11 m: m VO. Z . AUGUST ise3 2: 71 PCB-ARCH-EXT0378259 TRAUMA of a peculiar skin disease similar to chlor- 1) Latent. acne was reported in Fukuoka Prefecture 2) Visceral. which later spread to over 20 other prefec 3) Manifest. tures in western Japan (Kuratsune et al., 4) Tardive. 1972). After clinical and chemical analyses, in August 1968, it was determined that the - c In the latent type, the patient has no f disease was induced by organic chlorides, and in November 1968 that the specific significant physical nor subjective symp toms of Yusho. Examples of this type were cause of the disease was rice oil contami nated with Kanechlor 400 (KC-400), simi lar to Aroclor 1248 (Umeda, 1972). * , apparent from women without symptoms who gave birth to babies displaying typical symptoms and women who breast-fed ba- ;! i bies whose babies displayed pathological symptoms in six months or later. MINIMUM AND AVERAGE CONSUMED DOSE. . The visceral type has no characteristic j dermatological signs but displays visceral j The concentration of KC-400 in the rice symptoms such as: j oil was 2,000-3,000 ppm and the average consumption of contaminated rice oil was 1) General fatigue. j about 800 ml, making the average ingestion 2) Nausea or vomiting. j of C-400 to be about 2 grams (g) (28 grams 3) Mild jaundice. j to an ounce) (Kuratsune et al., 1972). The 4) Abdominal pain (colic-like). i minimum dose of KC-400 consumed was 5) Diarrhea. 1 estimated to be about 0.5 g. The disease was 6) Productive cough. called "Yusho" or oil disease. 7) Chronic bronchitis. 8) Asthmatic attacks or pneumonia. NUMBER OF VICTIMS By August 1971, there were 1057 patients (Kuratsune et al., 1972); but by the end of 1977, the victims numbered 1665 (Urabe et al., 1979). Umeda (1972) claims there The manifest type is the typical Yusho victim with chloracne. comedo-like (like blackheads) eruptions and follicular ac centuation of the skin. Other symptoms include: are an estimated 15,000 victims of the dis 1) Dark-brown pigmentation _pf the ease hut far fewer have been "officially" skin and nails and of the mucous diagnosed as having Yusho. The most-, membranes of the eyes and mouth. highly contaminated rice oil was traced 2) Hypersecretion of cheese-like dis back to its origin in being produced or charge from the eyes. - shipped on February 5 and 6,1968 (Kurat- 3) Loss of hair. ' j sune, 1976). 4) Loss of libido. i 5) General fatigue. t 6) Headache. f SYMPTOMS OF FOUR TYPES OF "YUSHO" 7) Stomachache: j DISEASE S) Numbness of theextremities. \ Umeda (1972) revealed there are' four 9) Nausea, vomiting. ! types of the disease: 10) Dizziness. j 2: 72 TRAUMA VOL. 25 PCB-ARCH-EXT0378260 i- >f.z.-><^yl^^fe.vs^y>^.ga8agiSB^^ . '': POLYCHLORINATED BIPHENYLS (PCBs) 11) Disturbances of higher nervous ac tivities (e.g., forgetfulness). - . 12) Local impairment of blood circula tion. 13) Deformation of nails. 14) Deformities of joints and bones (fin gers, toes, ankles and -wrists). 15) Poor teeth development in children. 16) Pathological changes in teeth. 3) Pigmentation and flattening of the nails. 4) Skin pigmentation (Kikuchi and Masuda, 1976). These cutaneous lesions are described in detail by Urabe andKoda (1976). AUTOPSY FINDINGS The tardive type is a delayed appearance of physical signs and symptoms specific to Yusho -which appear one to three years after exposure. The photos in this report visually present the manifest type of ' Yusho. CHICKEN POISONING FROM OIL-CONTAMINATED FEED PRECEDED YUSHO INCIDENT It should be mentioned that in FebruaryMarch 1968, an accidental mass poisoning of over 2 million chickens, -with over 400,000 reported as dying, occurred in western Japan (Kuratsune et ah, 1972). Its cause -was traced to a dark oil used in the chicken feed which was found to contain 1,300 ppm Kanechlor 400. This oil was from the same company involved in the Yusho incident. This epizootic among chickens and the epi demic of Yusho had been very closely con nected in time, although the chicken episode preceded the Yusho incident in severity by several months. Kikuchi and Masuda (1976) reviewed the autopsy findings of five Yusho patients and one stillborn child born to a Yusho mother. They found .that PCB concentration rates in the autopsy cases exhibited no definitive differences from control cases suggesting that the cutaneous changes found might be residual effects occurring at the acute or subacute toxic stage. Autopsies were performed 12-46 months after the first appearance of skin lesions; . and apart from the skin lesions, no defini tive changes in the visceral organs were seen. Amounts of KC-400 ingested in these cases were not known exactly except in one where ingestion of 1.6 g of KC-400 was es timated. NON-DERMAL MANIFESTATIONS OF PCB POISONING Apart from the cutaneous changes noted, non-dermal manifestations of PCB poison ing included the following disorders: ' 1) Neurologic. ' CLINICAL FINDINGS * 2) Endocrine. 3) Respiratory. - - The main clinical findings of Yusho pa 4) Hematologic. tients concern dermatosis. Major cutaneous 5) Hepatic. changes include: 6) Metabolic. 1) Acneform eruptions. 7) Bone and joint. 2) Prominent enlargement and elevation S) Dental. of the follicular openings. 9) Ophthalmic. f -il Ullls (l-ii : ifc " W Ki;ji fL-- 1.1! -.9 i. ' ' -l! m: St: o! n Mi Sit) jMi, il!i P Vr m S"T I:! ii h ii:!: > i ' hi NO. 2 AUGUST 1963 2: 73 PCB-ARCH-EXT0378261 TRAUMA 10) Effects on infants and children (Hi rayama, .1976). Neurological Disorders For neurologic disorders, about 50% of Yusho patients complained of headaches, numbness, hypoestbesia (dulled sensation), and neuralgic limbs. Clinical observations suggest that there are no significant in volvements of the central nervous system, but rather of the peripheral nerves and almost exclusively, sensory nerves (Hira- yama, 1976). Endocrine Disorders Endocrine disorders suggest some degree of adrenocortical dysfunction and abnor mal ovarian function in females. This lat ter point may be due to enhanced degrada tion of sex hormones by enzymes induced by PCBs. This is discussed later. Respiratory Disorders ,, Respiratory disorders appear to be ex emplified by chronic bronchitis. Following ingestion of PCBs, most PCBs enter the blood stream via the thoracic duct and hence reach the respiratory system and have been detected in the lung and sputum of patients (Hirayama, 1976). The cause of bronchitis seems obscure, but the PCBs appear to affect some defense mechanism. Hematological Disorders . Hematology findings correspond to the features of inflammatory-disorders (Hira yama, 1976). Serum levels of immuno globulins, especially those of IgA and IgM were decreased generally, suggesting B cell lymphocyte dysfunction. The B cells are responsible for humoral immune responses based on antibodies. Chronic infections ob served generally in patients may be the result of some immunological deficiency. This will be detailed later. Liver Disorders and Enzyme Alterations Hepatic disorders observed are related directly to the fact that the PCBs are known to be powerful inducers of liver enzymes, especially the microsomal drugmetabolizing enzymes (mixed-function oxidases, MFO) and mitochondrial -amino levulinic acid, ALA) synthetase. This mi crosomal enzyme induction results in an increased rate of metabolism of both en dogenous substances, such as hormones, and xenobiotic substances, such as drugs and pesticides. Degradation of Hormones and Menstrual Disorders Since PCBs cause increased degradation of hormones, including estradiol, a de crease in circulating estradiol may be re sponsible for the menstrual disorders seen in female Yusho patients (Hirayama, 1976). The enzyme ALA-synthetase is the first and rate-limiting enzyme in the biosyn thetic pathway of heme (constituent of hemoglobin) (Woods, 1973) and could lead to an overproduction of porphyrins (im portant chemical substances which form the basis of the respiratory pigments of animals and plants, hemoglobin is the res piratory pigment of the blood) by the liver resulting in porphyrinuria (Poland and Glover, 1973). Related to this enzyme induction were the liver findings of a marked proliferation in the smooth endoplasmic reticulum and morphological heterogeneity (i.e., varia tions in size and form) of the mitochondria with some patients showing a slightly en larged liver (hepatomegaly) (Hirayama. 1976). 2: 74 TRAUMA VOL. 23 PCB-ARCH-EXT0378262 s&s&ise-gsfeft POLYCHLORINATED BIPHENYLS (PCBs) Metabolic Disorders Metabolic disorders center around altera tions in general lipid (fat) metabolism probably as a result of PCB concentration in adipose tissue or skin, the latter lead ing to cutaneous manifestations already discussed, the former resulting in elevated serum triglycerides (Hirayama, 1976). Other findings suggest abnormal calcium metabolism resulting in the bone and den tal disorders mentioned which may result from vitamin D deficiency caused indirectly by enzyme induction noted above (Hira yama, 1976). . TOXIC IMPURITIES IN PCB As discussed earlier under Toxic Im purities, the presence of toxic PCDFs in KC-400, and even more so in the Yusho oil, make evaluation of Yusho toxicity on a cause and effect basis very difficult. Kurat- sune et al. (1976) reported the presence of PCDFs in the fat of tissues of Yusho pa tients of autopsy. These data are condensed and rearranged in Table 9. . As mentioned earlier, the ratio of PCBs to PCDFs in the Yusho rice oil was about 200; but in these autopsy cases, the liver has shown a pronounced persistence and hence concentration of PCDFs. Of these PCDFs, 2,3,4,7,8-penta-CDF was the most abundant found by Masuda et al. (19S2) in rice oils of both the Taiwan and Japan poisoning episodes; and Kuroki and Ma suda (1978) reported it to be one of, if not the most accumulative of the PCDFs in humans. This accumulative factor deserves closer scrutiny. TAIWAN POISONING EPISODE The second, large-scale human poisoning episode by PCBs occurred in central Tai wan in March 1979, 11 years after the Yusho incident, with reports of a peculiar skin disease (Chen et al., 1980). CAUSE AND NUMBER OF VICTIMS In October the cause was identified as being due to ingestion of rice oil contami nated with PCBs, an almost exact replica of the Yusho accident; and by "May 19S0, the victims numbered 1900. These authors found that the PCB ingested was closer to KC-500 and thus would have higher levels of more highly chlorinated PCBs (pentato heptachlorobiphenyls), and these would be expected to be more persistent. 11 `j 4 fS j r i i i \\l l fjf i if m in i ffl: : t 51 ri A k ['ll ill I Mi !! l J, * ,1: r ;I; H; y Table 9 PCBs AND PCDFs IN PPM (FAT BASIS) OF TISSUES OF YUSHO PATIENTS AT AUTOPSY Year of Death Case No. Adipose PCBs PCDFs Ratio PCB/PCDF Liver PCBs PCDFs Ratio PCB/PCDF 1969 1 3.4 0.03 113 4.7 2.3 2 1969 2 8.5 0.04 213 5.6 1.1 5 1972 3 2.1 0.01 210 3.5 0.3 12 Mean 4.7 0.03 157 4.6 1.2 4 NO. I - AUGUST ises 2: 75 & y lr * ? It i j: I- - ~ ~ ` ` .........nr'"' ' TRAUMA COMPARISONS OF CONTAMINATED RICE OILS Masuda et al. (19S2) compared the PCBs in the two rice oils causing these two poi sonings. They found the rice oil from Tai wan (two samples) to contain 60 and 100 ppm of PCB while the Japanese rice oil analyzed contained 900 ppm PCB. The dif ference was that the Taiwanese samples were more similar to KC500 (54% chlo rine) while the Japanese sample was simi lar to KC-400 (48% chlorine). They also found several PCDFs totaling 2.02 ppm in the Japanese and 0.08 and 0.10 ppm in the Taiwan samples. - - PCQs AS ADDITIONAL CONTAMINANT IN RICE OILS Am interesting recent discovery, high lighted in the paper by Masuda et al. (1982), was the presence of polychlorinated p-quarterphenyls (PCQs) and PCQ ethers in both the Japanese and Taiwan rice oils. The PCQs contain four phenyl groups bonded together in a linear array and are akin to the chlorinated terphenyls. The above authors reported they contained 6 to 10 chlorines with 800 ppm in the Japa nese oil and 90 and 100 ppm in the Tai wanese samples. Kamps et al. (1978) ear lier identified the presence of PCQs in Yusho oil but no quantitative data were given. Yamaryo et al. (1979) found the PCQs could be formed from KC-400 by heating for several weeks. At 300 and 350C, PCQs increased to about 10% of the KC-400 after several weeks. . The presence of PCQs in these rice oils adds yet another dimension to the com- plexity of the PCB situation, and their role in the toxicity syndromes observed is un known at this time. HUMAN RESIDUES Although many reports exist in the open literature on PCB residues in aquatic and terrestrial animals, this aspect will not be covered and the reader is referred to reviews by Hutzinger (1974), NAS (1979) and Wasserman et al. (1979). METABOLISM AND EXCRETION: PROBLEMS OF ANALYSIS When PCBs enter biological systems, the composition of the original PCBs changes, due to metabolism and/or excretion of pri marily the lower chlorinated congeners (a chemical compound closely related to an other in composition and exerting similar antagonistic effects), so that GLC (gasliquid chromatography, a technique for separating and identifying compounds) chromatograms ho longer match closely standard reference PCBs, such as the com mercial Aroclors (Price and Welch, 1972). This complicates the quantitative aspect of analyses. ACCUMULATION IN FATTY TISSUES PCBs are lipophilic and hence accumu late in fatty tissues. Human exposure to PCBs was reviewed by Cordle et al. (1978); and they emphasize that in the U.S., minimal exposure occurs through air, water and most food, fresh water fish being the exception, while sig nificant occupational exposure can occur in industrial workers. MONITORING OF PCB LEVELS IN HUMAN FAT TISSUE INCREASING LEVELS Price and Welch (1972), as part of the National Human Monitoring Program for 2: 76 TRAUMA VOL. 23 PCB-ARCH-EXT0378264 :^sts!mss^^isssmsi POLYCHLORINATED BIPHENYLS (PCBs) Pesticides sponsored by EPA, reported that of 196 human adipose samples ana lyzed, S3 (42%) had levels of 1 ppm or more PCB, and only four were negative (based on wet weight). In samples col lected in 1973 (1277) and 1974 (1947), 35 and 40%, respectively, of adipose samples (wet weight), had 1 ppm or more of PCBs ; and in 1973, 24.5% had no PCBs detected. In 1974, only 9.1% had undetectable levels (Kutz and Strassman, 1976). Most of these residues contained five to seven chlorines per biphenyls. Yobs (1972), from earlier sampling, reported that 235 of 688 samples (34.2%) were negative for PCBs and 32.5% (224) had 1 ppm or more PCBs. These data indicate that the incidence of PCB residues was increasing; and by 1974, over 90% of the adipose tissues were positive for PCBs. HIGHER LEVELS USUALLY INDICATE OCCUPATIONAL OR RELATED EXPOSURES Occasionally much higher levels are found which usually indicates occupational or related exposures. Biros et al. (1970) estimated 200 and 600 ppm of PCBs in two . human adipose samples consisting of at least 14 isomers and congeners ranging from penta- to decachlorobiphenyl. Price and Welch (1972), on a fat basis, reported PCBs in an autopsy case of a 77-year-old man of 115-180 ppm in three adipose sam ples, 250 ppm in liver, and 125 ppm in kid ney. In neither study were the causes of the high levels ascertained. West Germany (FRG) (7.9) with Denmark (5.0), Austria (4.6), East Germany (GDR) (6.4), Japan (4.7), and Israel (3.6) in the middle. The U.S., Canada, and U.K. were 1.2, 1.2, and 1.3 ppm, respectively. CANADIAN STUDY: MORE PCBs IN OLDER AND MALE PEOPLE A recent study (Mes et al., 1982) re ported that all 99 adipose samples of Ca nadians were positive for both Aroclor 1242 and 1260. On a wet weight basis, the mean, for 1260 was 0.94 ppm with a range of 0.04-6.80 and for 1242 the mean was 0.31 and range of 0.05-2.30. The authors also found older people to have more PCBs than younger ones and- males had more 1260 than females. HIGHEST VALUES IN FISHERMEN These data indicate the world-wide scope of the PCB problem. Generally, the high est values were found in fishermen (IARC, 1978), presumably because they ate more contaminated fish than the average person. PCB LEVELS IN BLOOD Finklea et al. (1972) analyzed blood sera from 616 residents of urban and rural South Carolina and found measurable quantities in 270 (43.8%), ranging from a trace to 29.0 parts per billion (ppb; ng/g). ASSOCIATION WITH RACE AND RESIDENCE WORLD-WIDE LEVELS NAS (1979) summarized data of PCBs in human adipose tissues and reported the lowest ppm values (fat basis) in New Zealand and Norway (0.9) and highest in They found PCB levels were not related, to age or sex of the donor but were asso ciated with race and residence. The rural black donors had the lowest incidence of measurable PCB levels (5 of 107 = 4.7%) rural white had 119 of 192 positive (62.0%) VO. 2 AUGUST I 63 2: 77 ' * 1 - ; i m' ! it Lt g' m : zr. L!; id A H if If it |i! > nins. *: 'A ft a its; V f i1 ! r f:! I r i :* i i i PCB-ARCH-EXT0378265 TRAUMA and urban white had 89 of 166 positive (53.6%) for PCBs. The average of measur able concentrations for these groups were 9.4, 5.2, 5.1 and 4.4 ppb, respectively. ' LEVELS IN HOSPITALIZED PATIENTS Hesselberg and Scherr (1974) analyzed venous blood from nine hospitalized pa tients with severe wasting diseases due to concern with release of PCBs during mobi lization of body fat. They were unable to detect PCB in blood of. 15 healthy control subjects but found values of 10 to 100 ppb in the patients. DELAYED TESTING OF YUSHO PATIENTS Unfortunately, levels of PCBs in blood of Ynsho patients were only carried out four years after the incident so levels dur ing acute stages of poisoning are not avail able. Kuratsune et al. (1976) reported PCB plasma levels found in January 1972 for 15 Yusho patients to be 6.3 ppb (range 2-15) about twice that of 82 non-Yusho persons which had 3.0 ppb (range 1-7). In the more recent Taiwan PCB incident, blood analyses were done from nine months to one year after intoxication. Chen et al. (1980) found whole blood concentrations of 66 Taiwanese patients to have a mean value of 49 ppb with a range of 11 to 720 ppb. The 720 ppb value, was considerably higher than others, and this patient had abnormal hepatic and renal functions. Ex cluding this value, the mean falls to 39 ppb, still considerably higher than normal. LEVELS IN EXPOSED WORKERS Kuratsune et al. (1976) also reported ' whole blood PCB levels in 23 workers ex posed to Kanechlor 200-600 and found the mean to be 364 ppb with a range of 60-920 ppb. Two of these workers showed dermal toxicity signs. These latter values un doubtedly were approaching the toxicity threshold. PCB LEVELS IN HUMAN MILK In human milk from two California cities (Risebrough and Brodine, 1970), the mean PCB level was 0.06 ug/ml (2.0 ppm in fat based on 3% fat). Based on fat content, analysis of 80 samples of human milk from across the U.S. had a mean value of 1.7 ppm with a range of 0.4-10.6 ppm (New York State Health Planning Commission, 1977). Only two samples were negative. From 19694974, PCBs in human milk fat averaged close to 1.2 ppm in Ontario resi dents (Grant et al., 1976). Wickizer et al. (1981) analyzed breast milk samples of 1057 nursing mothers in Michigan from 1977-1978 and found 100% to contain PCBs ranging from a trace to 5.1 ppm (fat basis) with a mean of 1.5 ppm. PCB levels of 2 ppm or more were found in 23.5% of sam ples and 49.5% of samples had 1-2 ppm. ESTIMATED 60DY BURDEN OF PCBs IN INFANTS EXCEEDS RECOMMENDED EXPOSURE LEVELS Numerous animal studies plus the above reports indicate that PCBs are secreted readily via the mammary glands into the milk. The human public health significance of this phenomenon is unclear at this time. IVickizer et al. (1981) estimated that a child nursing for eight months at the mean PCB level would have an estimated body burden of 0.S9 ppm PCB. Risebrough and Brodine (1970) estimated, assuming a daily intake of 150 ml/kg body weight, that breast-fed infants ingested about 9 ugAg 2: 78 TRAUMA VOL. 25 1 * " * PCB-ARCH-EXT0378266 m POLYCHLORINATED BIPHENYLS (PCBs) bw/day of PCBs. Cordle et al. (1978) re ports that the maximum allowable inges tion of PCBs recommended for protracted exposure to PCBs is 1 ugAg bw/day and that the total PCB dose has a 200 mg safety limit. This level of 1 ugAg/day, is ex ceeded by the breast-fed infants above, and also in many study subjects in projects reviewed by Cordle et al. (1978). DIFFICULTIES IN DOCUMENTATION OF CHEMICAL EXPOSURE A recent JAMA article (Rogan, et al. 1983), pointed out the difficulties in docu' mentation of chemical exposure to PCBs. The presence of PCBs and other chemicals in breast milk and the possible effects has been studied since 1978 at Wake Area Health Education Center, East Carolina University School of Medicine, and the Durham Women's Clinic in North Carolina. About 900 breast-feeding children are ex amined and followed up. In addition to interviews with the mother, review of the child's medical record, physical examina tion and use of standard development scales, samples of breast milk and serum . were collected and analyzed for PCBs on a gas chromatograph with electron-capture detection. In June 1978, a tanker truck dis charged hundred of gallons of a used com mercial PCB mixture along North Carolina roads. Comparing the levels of PCBs in milk samples of the exposed women with those of other study participants showed no differences. The chromatograms using capillary gas chromatograph analysis showed unusual peaks that indicate the presence of heavily chlorinated PCBs of the kind that were spilled. The authors reported they had not seen illness in the children attributable to PCBs in the milk they received. ENZYME INDUCTION LIVER EFFECTS FROM PCBs PCBs produce a number of effects on the liver including: 1) Weight increase. 2) Fatty liver. 3) Porphyria. 4) Even cell necrosis (death) at high dose levels (Kimbrough, 1974;'Biocca etal.,1976,1981). METABOLISM OF FOREIGN COMPOUNDS: LIVER FUNCTION Many organic compounds, falling out side of the category of carbohydrate, pro tein, fat, steroid or vitamin, are consid ered foreign to the body. These foreign (xenobiotic) compounds, such as pesticides, drugs, food additives, and including PCBs, are metabolized in the microsomal portions of various tissues, particularly the liver. "MIXED FUNCTION OXIDASE SYSTEM": MFO The most important reactions involve a general oxidation system referred to as the "mixed function oxidase system" or MFO. This MFO activity usually concen trates in the smooth endoplasmic reticulum (SER) which is particularly abundant in liver cells. When liver cells are ruptured by homogenization, the SER undergoes frag mentation : and when these fragments are separated from other cell components by ultracentrifugation, they are commonly called "microsomes." This microsomal fraction is the source of the xenobiotic (foreign body compound) metabolizing en zymes (MFO). The MFO requires NADPH as a cofac tor and an electron transport system with ? * 5! if A* ill !i :- I5; UV .*.:: *t : Y f.v':*- NO. 2 AUGUST 19 83 2: 79 . i : 1 PCB-ARCH-EXT0378267 TRAUMA cytochrome P-450 as the terminal oxidase. P-450 is so named because in the reduced state it exhibits an absorption band at 450 nm wavelength. More details can be found in the works of Gillette et al. (1969) and Loomis (1978). DETOXIFICATION OR 70X/CA770N FROM CHEMICAL-INDUCED ACTIVITY OF MFO ENZYMES t The total quantity of MFO enzymes can be increased in man and many animals by prior administration of a variety of chemi cal substances such as anesthetics, seda tives, analgesics, and insecticides, espe cially chlorinated hydrocarbons like DDT anddieldrin (Loomis, 1978). This induction of enzymes represents a mechanism of adaptation by the animal to repeated assaults by xenobiotics and is usually temporary with effects lasting sev eral weeks. This phenomenon of chemicalinduced activity of enzyme systems that are responsible for their own degradation, may be protective to the animal (when detoxi cation is involved) or detrimental (when toxication occurs) (Loomis, 1978). INDUCERS OF LIVER MFO PCBs are potent inducers of the hepatic microsomal monooxygenases (MFO), re sponsible for the oxidation of xenobiotics and steroids, in man and experimental ani mals (Litterst et al., 1972.; Alvares et al., 1973) . . Most inducers of MFO can be divided into two groups (Echobichon and Comeau, 1974) . Prototype chemicals of these groups are phenobarbital (PB) and 3-metbyl- cholanthrene (3-MC). PB induces cyto chrome P-450 and increases the metabolism of a number of substrates while 3-MC in duces a distinct subspecies of cytochrome P-450, termed P-448 (or Pj-450), which differs in spectral qualities and substrate specificity from P-450 (Goldstein, 1979). Commercial PCBs inhibit enzyme-induc ing properties that are termed mixed; i.e. they appear to induce both cytochromes P-450 and P-44S which are classically asso ciated with PB- and 3-MC-induction, re spectively (Elcombe et al., 1979). The cytochromes from Aroclor 1254-indueed rats are indistinguishable from those in duced from PB -f- 3-MC induced rats (Goldstein, 1979). Aroclor 1254 induces ethylmorphine N-demethylase, preferen tially induced by PB, and aryl hydrocarbon hydroxylase (AHH), an enzyme preferen tially induced by 3-MC. PCDDs AND PCDFj MORE POWERFUL INDUCERS OF ENZYMES Complicating the PCB-enzyme induction studies is the fact that certain of the PCDDs and PCDFs, especially those chlo rinated in the 2,3,7,S-positions, are potent inducers of AHH and cytochrome P-44S, similar to 3-MC, but 30,000 times more powerful (Lucier et al., 1973; Poland and Glover, 1974). It recently was estimated that some Yusho patients consumed as much as 200 ug of PCDFsAg body weight (Hoyabuchi et al., 1979). The fact that PCDFs may be 500 times more toxic than the parent com pound makes it imperative that doserelated biological effects of the PCDFs be thoroughly understood (Jonsson et al., 1981). INCREASED ENZYMATIC ACTIVITY CAN UPSET NORMAL METABOLISM The proliferation of the SER (smooth endoplasmic reticulum) in liver cells is an 2: 80 TRAUMA VOL. 25 PCB-ARCH-EXT0378268 Brf,SAia'ffH gS^lil&iV.S^ra&&^^&ig^fia*^zsmasaaSnzgalfEfiHSiiam fc-.^/_ ^_ g_ v^ m iili r=? * POLYCHLORINATED BIPHENYLS (PCBs) observed effect of exposure to PCBs, PCTs and PCDDs (Norback and Allen, 1972). and is the morphological expression- of in creased enzymatic activity that can upset normal metabolic pathways in the cell. For example, relatively innocuous substances could be metabolically altered within the liver to produce hepatotoxicity or within the kidney to produce nephrotoxicity due to induced drug-metabolizing activity. r ENHANCEMENT OF LIVER INJURY Recknagel and Glende (1973) reported that inducers of cytochrome P-450 (e.g., PB-pbenobarbitol) can enhance liver in jury by carbon tetrachloride. Docks and Krishna (1976) found that the hepatotox icity of chloroform is augmented by PB pretreatment. Similarly, PB-liver induc tion enhanced liver injury by bromoben: zene (Reid et al., 1971); and the anesthetic halothane was hepatotoxic following PCBpretreatment (Reynolds and Moslen, 1977). BENEFICIAL ENZYME INDUCTION: DETOXICATION Examples could be cited where enzyme induction could be. beneficial by enhancing detoxication of poisons. , Whether the induction of the cytochrome P-450-containing monooxygenase enzyme systems leads to an increase or a decrease in the toxicity of a particular compound is dependent on the toxic properties of the compound in question. If the MFO metabo lism of the' compound leads to less toxic products, then MFO induction will usually result in a decrease in toxicity. The oppo site case would apply when MFO induction yields metabolites more toxic than the par ent compound (Doull et al., 1980, p. 68). PCBs CAPABLE OF CAUSING REPRODUCTIVE ABNORMALITIES Induced MFO enzymes also can enhance metabolism of endogenous compounds such as the sex hormones. Aroclor 1262 has an estradiol degrading potential four to five times that of the enzyme inducers p,p'- DDE or technical grade DD.T (Edwards, 1971). * PCBs are capable of causing reproduc tive abnormalities in monkeys related to the changes in the sex hormones and in clude : 1) Irregular and prolonged menstrual cycles. 2) Excessive and prolonged hemorrhage during menstruation. 3) Reduced conception rate. 4) A high incidence of early abortions (Allen etal., 1979). Orberg (1978) reported that female mice dosed at 0.5 mg/day of 2,5,4'-TrichloroBP or 2,4,5,2',4',5'-hexachloro BP, for six consecutive days starting on day 1 of preg nancy, have significantly lower frequency of implanted ova than control females which correlated with the significantly in creased liver levels of cytochrome P-450. ABNORMAL OVARIAN FUNCTION IN YUSHO PATIENTS Female Yusho patients showed symp toms suggesting abnormal ovarian func tion with over 60% showing menstrual cycle abnormalities and 55% with abnor mal menstrual flow durations (Hirayama, 1976; Kuratsune et al., 1972, 1976). PCBs also have been shown to reduce the sleeping time induced by hypnotic drugs like PB, pentobarbital and hexobarbital, the time of zoxazolamine-generated paralysis, and the time of action of is u i i- i i i i if H NO. 2 - AUGUST 19 63 2: 81 PCB-ARCH-EXT0378269 TRAUMA other drugs; all attributed to enzyme in duction which enhanced metabolism of these chemicals (Wasserman et al., 1979). VARIATIONS AMONG FOBS AS ENZYME INDUCERS Not all PCB isomers (any of two or more chemical compounds having the same elements in the same proportion by weight but differing in physical or chemical prop erties because of differences in the struc ture of their molecules)' or congeners are potent enzyme inducers or even result in the same type of induction. The commercial mixtures generally, as stated earlier, are mixed inducers, inducing enzymes characteristic of both PB and 3-MC. Individual PCBs may induce either type. Goldstein et al. (1979) found 2,4,5,2',4',5'-hexachloro-BP resembled PB as an inducer while 3,4,5,3',4',5'-hexachloroBP resembled 3-MC induction, and neither produced a mixed response at any dose. She found the latter and 3,4,3',4'-tetra-BP to be the only PCB congeners to be 3-MC type inducers. She found striking struc tural similarities between these two bi phenyls and 2,3,7,8-TCDD and TCDF, all potent P-44S inducers, although the PCB isomers are 1000 times less potent than TCDD. Goldstein (1979) reported that most of the hexachlorobiphenyls (2,3,4, 2',3',4'; 2,4,5,2',4',5'; and 2,3,5,2',3',5') to.be relatively potent PB-type inducers and . others (2,4,6.2',4',6' and 2,3,6,2',3',6') to be relatively weak. Most tetrachloro isomers are weak or inactive, with the exception of 2,4,2', 4'. ments appear to be the presence of at least two adjacent chlorines in the lateral posi tions of the biphenyl and an absence of chlorines in the ortho positions. The addi tion of one or two ortho chlorines to the biphenyl abolishes 3-MC-type induction. Therefore, 2,3,3',4'-tetra-, 2,3,4,2',3',4'-hexaand 2,3,4,5,3',4',5'-hepta chloro-BP are in-, active 3-MC type inducers. She found that ortho substitution prevents PCBs from assuming a planar configuration character istic of the toxic PCDDs and PCDFs which are locked into a rigid, relatively planar structure. The "mixed" inductive effects and much of the toxicity of PCB mixtures are due to the presence of compounds structurally re lated to the active PCDFs or 3,4,3',4'tetrachloro-BP. IMMUNE EFFECTS Current procedures for testing the real or potential toxicity of chemicals on animals underestimate the importance of the immune system, especially in chronic studies. As a result, limited data are in the literature on immunosuppressive proper ties of chemicals. LYMPHOCYTES AND LYMPHOID SYSTEM: BASIS FOR IMMUNE SYSTEM An animal's immune system is based on small white, blood cells called lymphocytes. These cells circulate in the blood, and large populations can be found in tissues of the lymphoid system: PRESENCE AND POSITION OF CHLORINES For the 3-MC-type inducers, Goldstein (1979) concluded that structural require 1) Bone marrow. 2) Thymus. 3) Lymph nodes (Fig. 4). 4) Spleen. 2: 82 TRAUMA . VOL. 25 ___,, PCB-ARCH-EXT0378270 "** ^ * tin .iKiT.fl-Jli^^k., -h'i '!' 4iMi_M*altni^iU >&i) ` m > , POLYCHLORINATED BIPHENYLS (PCBs) iaaaa&aaaaij .*. .i,!! (i-H:i *j"f:i'--1,< ` U &: ? irt ;Si: f&f 5 'J J j .` f.i \ jltlpf j i : E *:: I ? FIG. 4. Lymphatic System and Lymph Nodes This drawing shows the location of some of the lymph nodes (4 & 7), small ovol masses scattered throughout the body. Spaces within the lymph node are occupied by lymphocytes. The lymph nodes supply certain defense cells to the lymph stream and also purify the lymph as it posses through. The lymph is conveyed to and from the nodes by lymph tubes. Phogocytic (scavenger) activity takes place within the node by macrophages ond reticular cells. 1) Internal jugular vein 2) Left subclavian vein 3) Entrance of thoracic duct 4) Axillary lymph nodes 5) Thoracic duct 6) Cysterno Chyli 7) Inguinal lymph nodes SC. 2 AUGUST IB 65 ; I 2: 83 .tessr-yxsTkV PCB-ARCH-EXT0378271 TRAUMA 5) Appendix. 6) Tonsils. - , 7) Adenoids. 8) Patches of the small intestine. Lymphoid tissues and organs function as cell production centers and as sites for some immune responses. TWO TYPES OF LYMPHOCYTES BASED ON FUNCTION: T-CELLS AND B-CELLS / All lymphocytes originate as stem cells in the bone marrow but are classified into two types based on their functions. T-Cells . . .. Some pass through the thymus (Fig. 3) becoming T-cells and specialize mostly as killer T-cells which directly attack their targets (bacteria, fungi, etc.). B-Cells The other cells, called B-cells, are proc essed elsewhere, and when stimulated by antigen, become plasma cells and indirectly attack their targets by producing huge numbers of large proteins called "anti bodies." Immunoglobulins These proteins or immunoglobulins (Ig) consist of three main classes called: 1) IgG. . . 2) IgA. 3) IgM. IgG is the most abundant antibody pro duced during a secondary response to an tigen (antibody-generator) which combats microbes and their toxins. IgA defends the external surfaces of the body while IgM is produced early in response to an infec tion and functions as an agglutinator. CELL-MEDIATED IMMUNITY AND HUMORAL ' IMMUNITY The T-lymphocytes are responsible for what is termed "cell-mediated immunity," while the plasma cells from B-lymphocytes give rise to "humoral immunity." These two distinct systems of specific immunity are not entirely independent. In addition, fixed and free macrophages and their precursors (promonocytes in blood) comprise a group of cells which constitute the "mononuclear phagocyte system" (MPS).. Macrophages are inti mately involved' in the initiation and effec tor phases of both humoral and cell- mediated immune reactions. Further de tails can be found in the review by Vos (1977). * CONDITIONS AFFECTING IMMUNE SYSTEM There is a wide variety of conditions that can affect the immune system, including: 1) Glucocorticosteroid hormones. 2) Specific nutritional deficiencies. 3) Sex hormones. 4) Stress factors. 5) Infections. 6) Irradiation. 7) Chemical treatment (Vos, 1977). ANIMAL STUDIES ON PCB EFFECTS ON IMMUNITY INCREASED SUSCEPTIBILITY TO HEPATITIS The first paper on PCB effects on im munity was that of Friend and Trainer (1970) who found PCB-treated mallard 2: 84 TRAUMA VOL. 25 PCB-ARCH-EXT0378272 Sajgta'wcjaMmiaiifaiaa POLYCHLORINATED BIPHENYLS (PCBs) ducklings to have increased susceptibility to duck hepatitis virus. They found two-'to four-fold increases in mortality in treated ducklings over that of just virus-stressed birds. Vos and Beems (1971) found that der mal application of 3 different PCBs (60% chlorine) resulted in toxic effects which included: 1) Thymus atrophy. 2) Lymphopenia (decrease of propor tion of lymphocytes in the blood). 3) Spleen and lymph node effects. _ . REDUCTION IN GAMMA GLOBULIN CONTAINING CELLS In a subsequent study with guinea pigs fed Aroclor 1260 at 10 and 50 ppm, Vos and de Boij (1972) reported no effect on spleen weight and leucocyte count; but the number of y-globulin containing cells (hu moral immune response) in the popliteal lymph nodes was reduced significantly. Another paper (Vos and van DrielGrootenhuis, 1972) also involved feeding Aroclor 1260 to guinea pigs'at 50 ppm re sulting in lymphopenia and depressed sec ondary antibody response (depressed hu moral immunity) to tetanus toxoid. Aspects of these two papers above using Clophen A-60 were deleted because of the known contamination with PCDFs. THYMUS ATROPHY . The extremely toxic 2,3,7,8-TCDF has been shown to cause severe thymus atrophy in chickens, mice, and guinea pigs (Moore et ah, 1976); and the thymus is the central lymphoid organ concerned with cellmediated (T-cell) immune responses (Vos and Van Genderen, 1973). Additional im mune effects can be found in Luster et al. (1979). REDUCTION IN PRIMARY ANTIBODY RESPONSE Roller and Thigpen (1973) studied the effects of Aroclors 1221, 1242, and 1254 on rabbit response to pseudorabies virus. The number of plaque-forming cells (primary antibody response), was reduced signifi cantly with 1242 and secondary response was depressed significantly in all treat ments. Loose et al. (1977) found a 69% decrease in the number of plaque-forming cells per million spleen cells during the primary: antibody response to sheep red blood cells (SBBC) in mice fed 1242 for 6 weeks. In contrast to the previous paper, Silkworth and Loose (19S1) did not ob serve the impairment of B-lymphocyte re sponse to mitogen until after 40 weeks of exposure to Aroclor 1016. This was prob ably due to differences between 1016 and 1242, the latter having considerably more PCB congeners with five or more chlorines. They also found no alterations from con trol values of body weight or relative spleen or thymus weights but did find sig nificantly greater liver weight due to pro liferation of SER. ALTERATION OF CELL AND HUMORAL IMMUNE RESPONSES WITH SUB-TOXIC AMOUNTS OF CHEMICALS Street and Sharma (1975) studied the alteration of cell and humoral immune re sponses by 1254 and the insecticides DDT, . carbaryl, carbofuran and methyl parathion in rabbits. The rabbits were fed graded . doses of clinically sub-toxic amounts of these chemicals for 4 weeks followed by a NO. 2 AUGUST 1&6S 2: 85 .;^.'>^*SidBsSSSBSSBSSSSaSB '' ' t ' ' PCB-ARCH-EXT0378273 TRAUMA challenge with SBBC and Freund's ad MECHANISMS OF IMMUNOSUPPRESSION juvant antigens and tested for an addi UNKNOWN tional 4 -weeks on the same diet. They According to Luster et al. .(1978), there found decreased numbers of plasma cells are no data to show that PCBs cause their in the popliteal lymph nodes, except for immunosuppressive effects directly and carbaryl, reduction in spleen germinal that they may alter physiological or patho centers and increasing atrophy of the thy logical conditions which indirectly affect mus cortex; such responses were dose- the immune system. Luster et al. (1979) dependent which included both cell- claimed that the mechanisms of immuno- j mediated and selected humoral immune response reductions. The paper by Loose et al. (1981) indicated that no alteration suppression for environmental chemicals, including PCBs, PCDDs or PCDFs, are presently unknown. 1 [ j occurred in in vitro phagocyte activity or capacity or microbiocidal activity of mac rophages from mice fed 1242 at 5 and EFFECTS OF MONKEY MOTHERS FED PCB 100 ppm in their diets. Weirda et al. (19S1) DIET PASSED TO OFFSPRING f found that 1254 could preferentially inhibit the generation of antibody-producing cells Allen et al. (1980) in rhesus monkeys, j in mice. non-human primates, fed 2.5 or 5.0 ppm of Aroclor 1248 in their diets for 18 months PCBs AND SELECTIVE TOXICITY ON DIFFERENT PORTIONS OF IMMUNE SYSTEM and after being on PCB-free feed for about 1 year, were bred. After birth, their off spring were nursed for 4 months and then The above papers suggest that PCBs can weaned. Two of seven offspring from express selective toxicity on different por mothers fed 2.5 ppm PCB and two of four tions of the immune system and that the from mothers fed 5.0 ppm PCB died after target site for the resultant reduction in weaning. Histology of tissues fromthese \ humoral (antibody-mediated) immunity is four infants showed kypoeellularity of the j a mechanism and/or cell type distinct from cortical and medullary zones of the thymus, : components of^ cell-mediated immunity and the spleens also were small with very (Silkworth and Loose, 19S1). The paper of few lymph nodules. The lymph nodes were Vos and Van Driel-Grootenhuis (1972) and hypocellular and devoid of germinal cen- | Street and Sharma (1975) involving thy ters, and the bone: marrow was hypoactive j mus effects by PCBs, indicate toxic effects with most ceils present being of the mature J also on cell-mediated immunity which, all variety. These infants had essentially no \ in all, indicate species differences in the thymus and only rudimentary lymphoid I susceptibility to PCB-induced immunotox- tissues and had many other signs of PCB icity. Interestingly, Battson et al. (19S1) intoxication even through their mothers found the very persistent 2,4,5,2',4',5'- were not exposed to PCBs for approxi hexachlorobiphenyl given orally to mice to mately 2 years. Their deaths were attrib have very marginal effects on the immune uted to immunologic deficiency. Even system. The other results cited above may, though the mothers appeared healthy, at least partly, mirror effects induced by these female primates were capable of car contaminants. rying sufficiently high PCB body burdens, 2: 86 TRAUMA VOL. 25 PCB-ARCH-EXT0378274 POLYCHLORINATED BIPHENYLS (PCBs) after exposure was terminated, to produce bronchitis seen may be due to a PCB effect severe ill effects, including death, in their on some defense mechanism. ; offspring through their contaminated milk. CHRONIC BRONCHITIS LIMITED DATA ON IMMUNE Chronic bronchitis in Yusho victims was j EFFECTS IN YUSHO PATIENTS indicated by respiratory symptoms of pro- j Surprisingly, there are essentially no data on immune effects of PCBs in Yusho patients. Ueda (1976) reported data on Yusho victims suggesting a reduced resist ance to respiratory infection. This was based on findings in a few cases of markedly reduced levels of IgA. He reported that serum IgA and IgM levels were decreased and IgG- levels increased in 1970 (2 years fuse expectoration, cough and bronchographic findings (Kuratsune et ah, 1976). Shigematsu et al. (197S) conducted clinical, laboratory, and pathological studies in 401 Yusho patients to assess respiratory effects. They found the incidence and severity of respiratory symptoms to correlate well with PCB concentrations in the blood and sputa. i ') : : j j post incident) but generally were in the normal range by 1972. Those patients with severe dermatological symptoms had sig IMPAIRMENT IN LUNG VITAL CAPACITY IN WORKERS nificantly lower levels of IgM. EXPOSED TO PCBS PCBs AFFECT THYROID FUNCTION IN ANIMALS There is little question that the PCBs affect the thyroid function of animals (Barsans, 19S1), leading to decreased serum thyroxine levels. Such effects can indi rectly have a deleterious affect on the im- ' mune system (Vos, 1977). LUNG EFFECTS In both clinical and epidemiological stud ies, the respiratory system has been sus pected to be one of the target sites for PCB poisoning in man. RESPIRATORY FINDINGS IN YUSHO PATIENTS Hirayama (1976) reported PCBs in the lung and sputum of Yusho patients, and postulated that the many cases of chronic Warshaw et ah (1979) reported an in creased prevalence in restrictive impair ment in lung vital capacity in workers exposed to PCBs. They found 34 of 243 workers in capacitor manufacturing with reduced spirometric measurements. ANIMAL STUDIES SHOWING ACCUMULATION OF PCBS IN BRONCHI. LARYNX.AND TRACHEA Brandt (1975a) found that 14C-labeled 2,4,5,2',4',5'-hexacbloro-BP accumulated and was retained in the bronchial mucosa and in the mucosa of the larynx and tra chea in mice. Berlin et ah (1975) found a similar distribution for 2,4,5,2',5'-pentachloro-BP. This site of accumulation of PCBs was considered unique by Brandt since previous studies (Brandt, 1975b) in dicated that PCBs were not taken up by the bronchi but were evenly distributed PCB-ARCH-EXT0378275 "*S, TRAUMA throughout the lung parenchyma (func tional element of an organ) as shown with both 213J4J6,2%4'- and 2,4,6,3',4',5'- hexa- chloro-BPs. , Brandt et. al. (1976), using 14C-labeled PCBs, showed that PCBs with chlorines in positions 2,5,4' and hydrogens in 3,6,3',6' are accumulated in the bronchial mucosa as shown using 2,4,2',5'-tetrachloro-BP. Brandt (1977) reported that both re labeled 2,5,4'-tri- and 2,4,5,2',4',5'-hexa- chloro-BP showed a remarkably strong and persistent accumulation of radioactiv ity in the entire bronchial lining of mice following i.v. (intravenous) or i.p. (intra- peritoneal) injection. . COMPOUNDS PASSED THROUGH PLACENTA BARRIER He found also that both compounds passed through the. placental barrier of pregnant mice and were concentrated in a similar manner in the bronchi of the fetal lung. - PCBs WITH SPECIFIC AFFINITY FOR LUNG PARENCHYMA In a recent paper, Brandt et al. (1981) reported that a number of pentachloro-BP with chlorines in the 2,3,6-positions pos sess a specific affinity for the lung paren chyma. This is in contrast to his previous work which showed that a 2,4,5-substitu tion pattern is characteristic for all. the bronchial-seeking compounds. This recent work Avas done with 2,3,6,2',3'-, 2,3,6,3',4'-, 2,3,6,2',5'-, and 2,4,5,3',5'-pentachloro-BPs. The first three showed a specific accumu lation in the lung parenchyma whereas the last did not accumulate in lung tissue.. Bergman et al. (1979) found that, of 17 PCB congeners studied, 2,5,4'-tri-, 2,4,2',5'- tetra-, ,and 2,4.5,2',5'-pentachloro-BPs oc curred in the lung tissues of mice treated i.v. with these PCBs as methylsulfonyl PCB metabolites. This suggested that these metabolites are responsible for the specific bronchial accumulation found earlier (Brandt 1977). They also found the lung/ liver concentration ratio to increase with time. The above findings, that certain defined PCBs accumulate in the lung parenchyma whereas others accumulate in the bronchial mucosa, may lead researchers to the mech anism behind the respiratory involvement of PCB poisoning. REPRODUCTION AND ENDOCRINE EFFECTS Various studies have shown the limi tation of rodents as animal models in in vestigations of PCB toxicity effects. For example, Allen et al. (1976) found that rats on diets containing 100 ppm of Aroclor 1248, 1254 or 1262 were able to survive for 1 year without showing signs of illness. This is in marked contrast to the monkey data below. TOXICOLOGICAL SIGNS IN MONKEYS SIMILAR TO THOSE IN MAN Allen et al. (1979) reported on studies of PCB effects on reproduction in non-human primates, rhesus monkeys, an animal model whose toxicological signs produced by PCBs are similar to those produced in hu mans (Allen and Norback, 1976).' ALTERATIONS IN MENSTRUAL CYCLE Adult female monkeys were fed 2.5 or 5.0 ppm Aroclor 124S in their diets and 2: 88 TRAUMA VOL. 25 r i iI ! -riUaSSS.::. PCB-ARCH-EXT0378276 .^.Vi i& aSMaafiBa POLYCHLORINATED BIPHENYLS (PCBs) within 4 months had markedly altered men strual cycles (Figs. 5 & 6). They found menses to be 5-7 davs longer than control animals with an accompanying increase in menstrual bleeding. They observed also a flattening and prolongation of the serum progesterone peak during the menstrual cycle. ' REPRODUCTIVE EFFECTS t These females were bred after 7 months on this diet (having consumed 105-210 mg PCB) with all control and all animals on the 2.5 ppm diet and 6 of 8 females on the 5.0 ppm diet conceiving. The remaining two were bred on five separate occasions with out conceiving. However, 3 of the 8 females on the 2.5 ppm diet and 4 of 8 on the 5.0 ppm diet experienced early abortions or resorptions and 1 female on the 5.0 ppm diet delivered a stillborn infant. Only 1 female at the 5.0 ppm diet while 5 females on the 2.5 ppm diet were able to carry their infants to term. CHANGES IN SEX HORMONES Allen et al. (1979) related the above problems to changes in the sex hormones. They found that those monkeys showing no alterations in serum estradiol and pro gesterone experienced none of these repro ductive problems whereas in those animals with the most dramatic hormone changes, the reproductive alterations were most se vere even leading to anovulatory (absence of discharge of ovum) states in some cases. These hormone changes may he due to the degradation of hormones resulting from increased levels of induced liver MFO enzymes. . Allowable PCB in Food for Human Consumption It is noteworthy that PCB levels up to 3.0 ppm presently are permitted in food intended for human consumption. TRANSPLACENTAL MIGRATION AND MILK INGESTION OF PCBs Allen and Norback (1976) reported that all infants born to Aroclor 1248-exposed female monkeys contained PCBs in their tissues at birth due to transplacental mi gration. These infants were exposed continuously to PCBs by ingestion of milk from their lactating mothers and developed skin le sions, and 50% died from PCB intoxica tion within 4 months. EFFECTS OF LOW LEVEL DIET Barsotti and Allen (1975) and Barsotti . et al. (1976) found that rhesus monkeys which were fed low levels of Aroclor 1248 developed, besides chloracne: 1) Menstrual irregularities. 2) Increased excretion of urinary total ketosteroids. 3) Reduced conception rates. 4) Increased incidence of abortions. 5) Birth of small infants. STUDY OF YUSHO PATIENTS SUGGESTED ABNORMAL OVARIAN FUNCTION Hirayama (1976) summarized results on female Yusho patients whose symptoms suggested abnormal ovarian function. He reported that: . * 1) Over 60% of these patients showed abnormalities in their menstrual cycle. NO. 2 - AUGUST 1063 2: 89 PCB-ARCH-EXT0378277 HYPO THALAMUS TRAUMA BRAIN PITUITARY GLAND ADRENAL ADRENAL OVARY OVARY 2: 90 (ENDOMETRIUM) FIG. 5. Diagrammatic Sketch Showing Functional Interrelationships of Endocrine Glands Involved in Menstrual Cycle Normal menstrual function is dependent on the integrated action not only of the ovaries and uterus, but also of the thyroid gland, pituitary gland, hypothalomus and adrenal glands. Upon stimulation by the hypothalamus, the pituitary gland produces the gonadotrophic hormone. The gonadotrophic hormone is composed of two components known as the follicle-stimulating hormone (Prolan A) and the TRAUMA . VOL. 25 POLYCHLORINATED BIPHENYLS (PCBs) i: Ii.: 2) About 55% bad abnormal durations PATIENTS' COMPLAINTS I! I1 of menstrual flow. - 3) S5% showed an abnormal pattern in They indicated that even many of those i :i i 11S I *1 4 basal body temperature. who appeared to be clinically improving ! :;I* had several serious complaints, all pointing z - ' ' t This latter point indicated corpus luteum to neurologic disorders, such as: H {Figs. 5 & 6) insufficiency, retarded follicle maturation or no ovular cycle. There was also a low output of urinary estrogen and 1) Persistent headache. 2) General fatigue. 3) Feelings of weakness and numbness . i* U ;l ' I pregnanediol, especially in the luteal phase. in limbs. He concluded that these abnormalities may : n have resulted from primary ovarian dis ; i- i orders, secondary suppression by other PERIPHERAL NEUROPATHY SELECTIVE FOR ! vi s: glands, or some abnormal function of the SENSORY NERVES i: : r?t target organs. Mnrai and Kuroiwa (1971) found neuro : f It should be considered that these prob logical symptoms of Yusho patients also lems may be due, at least partially, to- ab comprised headaches, numbness, hypo- normal degradation of sex hormones by esthesia, and neuralgia. They found a pe PCB-induced MFO enzymes in the liver. ripheral neuropathy selective for sensory nerves in studies on nerve conduction ve NEUROLOGICAL AND locity. This sensory neuropathy was docu 3 BEHAVIORAL EFFECTS mented in 10 out of 12 patients with known | The area of neurological and behav PCB poisoning. i f. ioral effects is a relatively poorly re searched area regarding PCB effects. POSSIBILITY OF FUTURE WIDER NEUROLOGICAL EFFECTS FINDINGS IN YUSHO INCIDENT Hirayama (1976) carried out neurologi f In the summer of 1970, more than 2 years after the Yusho incident, Kuratsune et al. cal and electrophvsiological examinations to elucidate the neurological disorders re 1 i I iI (1972) found that about 50% of 159 pa ported by Kuratsune et al. (1972). He tients examined showed clinical improve found no symptoms or signs which indi ment ; the remaining half did not and more cated involvement of the cerebellum, spinal than 10% showed worsening symptoms. cord or cranial nerves. He did report, how- FIG. 5. Diagrammatic Sketch Showing Functional Interrelationships of Endocrine Glands Involved in Menstrual Cycle-continued (see page 2: 90) luteinizing hormone (Prolan B). Each of these two substances oppears at its own specific time in the menstrual cycle, and each produces a specific effect on the ovary for a specific period of time. The follicle stimulating hormone appears at the beginning of a cycle, and its function is to stimulate the ovary to mobilize and prepare one of its ovo for fertilization. no. : August tees 2: 91 PCB-ARCH-EXT0378279 TRAUMA 1 GROUP OF PRIMITIVE EGGS ATRETIC FOLLICLE 2: 92 FIG. 6. Diagrammatic Sketch Showing Structures Associated with Menstrual Cycle The increasing output of follicle stimulating hormone causes the ovum to move from the deeper central portion of the ovary to the outer margin until it approaches the surface of the ovary. As the ovum is changing its location over a period of 12 to 14 days, other changes take place in the follicle, the structure surrounding the egg. Cells become rearranged and increased in number and size, as well as activity, forming the graafian follicle, which contains the egg and estrogen-producing cells and a clear fluid. Estrogen enters the blood vessels, uterine wall. musculature and especially the lining of the uterus cavity (the endometrium) and its gland. The principal effect of these stimulatory changes is to increase the amount of fresh blood to the endometrium and to change other substances and enzymes . necessary for transport of spermatozoa and sustenance of the fertilized egg. The developing graafian- follicle gradually increases through the first three fourths of the cycle. Ovulation occurs when the follicle ruptures and releases the egg and fluid around it. The chemical changes associated with ovulation cause certain cells in j the pituitary gland to produce a second gonadotrophic hormone substance, known j as the luteinizing hormone or prolan B. This chemical agent acts on o group of j cells which hove grown into the ruptured follicle and have formed a' hormone- ; producing gland called the corpus luteum. The corpus luteum produces a second I female hormone, progesterone, which is essential to the development of a fertilized i TRAUMA . VOL. 23 PCB-ARCH-EXT0378280 a<gS&jS POLYCHLORINATED BIPHENYLS (PCBs) ,i : i i ever, significant involvement of the periph 32 mgAg/day of the toxic 3,4,3',4'-tetra- eral nerves, almost exclusively sensory chloro-BP during gestation days 10 through nerves. He concluded that present findings 16. Induction of this permanent syndrome (up to 1975?) may have revealed only the in mice strongly indicates that this PCB early manifestations of wider neurological . congener is not only fetotoxic and terato < ! effects. genic but also neurotoxic for the develop r ing central nervous system. This FCB iso f. BEHAVIORAL DEFICITS IN mer resembles the highly toxic 2,3,7,8- i MONKEY OFFSPRING TCDF. The roles that PCDFs and PCQs \ play in these effects are unknown at this Indirectly related to neurological effects, time. are the findings by Bowman et al. (1978) The above data indicate the need for that monkeys have behavioral deficits when more extensive studies on neurological ef weaned from mothers fed 2.5 ppm PCBs fects, especially with monkeys, and also in their diets. Only 3 of such 5 infant mon continued follow-up of the human victims i keys born to these mothers survived past of PCB poisoning in Japan and Taiwan. weaning at 4 months of age. Behavioral tests with these 3 survivors plus 4 normal controls revealed hyperlocomotor (exces LIVER EFFECTS sive movement from place to place) activ The liver is one of the most suscepti ity at 6 and 12 months which correlated ble organs to the effects of both acute and i with peak PCB body burdens. The monkey chronic doses of PCBs, both commercial with the lowest body burden at 4 months of mixtures and pure isomers. age (21 ppm, their point estimate for a zero-effect level) still exhibited some be havioral defects persisting through the final testing at 24 months of age. LIVER ENLARGEMENT A number of authors has described liver M. li ! I enlargement as a consequence of PCB ex "SPINNING SYNDROME" IN MICE posure which has been considered due primarily to hypertrophy (overgrowth) of i i I Chou et al. (1979) reported that a strik the smooth endoplasmic reticulum (SEE) ing motor dysfunction, "spinning syn of the liver cells (Allen et al., 1973; Kim drome," developed with a high frequency brough, 1974; Nishizumi, 1970; Vos and in weanling mice whose mothers received Beems, 1971). I I FIG. 6. Diogrammatic Sketch Showing Structures Associated with Menstrual Cycle --continued (see page 2: 92) egg. If no pregnancy occurs, the corpus luteum degenerates because of declining production of luteinizing hormone by the pituitary and a rapid decrease of pro gesterone. With a lack of essential supporting chemicals, the endometrium de generates. A shedding off and expulsion of obout 80% of this lining, together with a varying amount of blood, is expressed externally as the menstrual flow. NC. 2 AUCUST 1BS 2: 93 gmjjMKfeg 1 PCB-ARCH-EXT0378281 TRAUMA MfO ENZYME INDUCTION This increase in the SER of liver cells is accompanied by an induction of micro somal MFO (see section on Enzyme Induc tion, p. 79) and is more marked -with the more highly chlorinated PCBs and rela tively low with Aroclors 1221 and 1016 (Echobichon and Comeau, 1974). This has also been demonstrated with single pure PCBs where a greater degree of enzyme induction occurs with the higher chlori nated isomers (Johnstone et ah, 1974). HEPATOMEGALY IN ALL SPECIES AT BELOW LETHAL LEVELS McConnell and Moore (1979) concluded that pathology of the liver by PCBs is in teresting because it is so conspicuous in some species (mice, rats, rabbits and chick ens) and so minimal in others (guinea pigs and monkeys). However, they report hepa tomegaly (both absolute and percent of body weight) to be observed consistently in all species and at exposures considerably below the lethal dose. Koller and Zinkel (1973) found that the hallmark of acute toxicity in rabbits was hepatocellular necrosis with hemorrhage. VARYING TOx'lCITIES OF PCB ISOMERS Biocca et ah (1981) studied the toxicity of four symmetrical hexachloro-BPs in young female mice dosed at levels from 0.3 to 300 ppm in the diet for 28 days. These PCB isomers were chlorinated in the 3,4,5 or 2,4,5 or 2.3,6 or 2,4,6 positions. The 3,4,5,3',4',5'-hexachloro-BP was by far the most toxic isomer causing mortality, body and organ weight effects at all levels and was the only isomer which produced ex cess porphyrin accumulation. The liver ef fects it caused were enlargement, accentu ated lobular markings, fatty infiltration, hepatocellular swelling and necrosis. The 2,4,6 and 2,4,5 isomers caused the same, le sions but to a lesser degree, and the 2,3,6 isomer was the least toxic. Biocca- et ah (1976) noted that the effects of the 3,4,5 isomer mimic those caused by the PCDFs. PORPHYRIA Goldstein et ah (1974) fed; female rats 100 ppm Aroclor 1254 in the diet for up to 13 months. Hepatic porphyria (excess for mation of porphyrin in the liver) occurred in all rats fed for at least 7 months and was characterized by delayed onset, excre tion of large amounts of 7- and 8-carboxyporphyrins in the urine and accumulation of uroporphyrins, in the liver. Porphyria is a disturbance in porphyrin metabolism characterized by a marked increase in for mation and excretion of porphyrins which resembles human porphyria cutanea tarda. This syndrome is characterized biochemi cally by an increase in the activity of the mitochondrial enzyme a-arcinolevulinic acid synthetase (ALA), which is the first and rate-limiting enzyme in the heme biosyn thetic pathway (Woods, 1973). Goldstein et al. (1974) found that no induction of ALA synthetase could be demonstrated prior to the onset of porphyria in rats. ` Goldstein et al. (1976), using the same symmetrical hexachloro-BPs as Biocca et al. (1981) cited above plus the 2,3,4 isomer, found all hexachloro-BPs to cause uropor phyrin accumulation and increased ALA synthetase activity in chicks but only the 3,4,5 and 2,3,4 and 2,3,5-hexachloro-BPs produced gross accumulations of hepatic porphyrins. .It is notable that all three of the. above hexachloro-BPs with potent ef fects had chlorines in both the meta- and para-positions. Goldstein et al. (1976) 2: 94 TRAUMA VOL. 25 PCB-ARCH-EXT0378282 POLYCHLORINATED BIPHENYLS (PCBs) found the S^S^'^S'-isomer to accumulate the most in fat and liver of chicks and was lethal. Interestingly, 2,3,7,8-TCDF did not cause these effects in chicks. Their results indicate that TCDF plays no significant role in the production of porphyria by PCB mixtures. PORPHYRIAS ACCOMPANIED BY CHRONIC LIVER DAMAGE the U.S. (FDA, 1977). They stated that it is unlikely that present levels of PCBs in the environment of the U.S. today will re sult in porphyria in humans. However, one should remember that accidental poison ings, such as the Yusho incident in Japan and the more recent episode in Taiwan, do occur and there have been several incidents of other food materials being contaminated with PCBs (Heritage, 1978). Strik (1979) stated that chronic hepatic porphyrias were always accompanied by BIOLOGICAL DATA chronic liver damage and existed in clini RELEVANT TO HUMANS cally latent and manifest stages. He said these stages could be both recognized and differentiated on the basis of the charac teristic porphyrin excretion in urine, fluo Data from many animal studies may give clues to similar effects in humans. The following are discussed in this section: `h rescence of porphyrins in liver prepara 1) Metabolism. tions and the accumulation of uro- and heptacarboxylic porphyrin in the liver. He 2) Tissue distribution, accumulation and depletion of PCBs. ; could characterize the chronic stages into 3) Carcinogenicity. types A, B, and C according to the type of 4) Teratogenicity. porphyrin in the liver, the extent of por 5) Effects on digestive system. phyrinuria, and the relative distribution 6) Vitamin effects. of uroporphyrin, coproporphyria and por phyrins with 5 to 7 caboxylic groups in METABOLISM it the urine. Type A, the mildest form, marked the start of the progression. Strik (1979) reported on a study that indicated that a significant difference was not found Many halogenated hydrocarbons are excreted slowly from humans and animals and thus may persist in the tissues for i i ii in liver function tests, urinary' total por phyrins and porphyrin pattern between 16 Yusho patients and Japanese control sub jects. This, however, was done several years after the incident. years. It has been assumed that these chem icals, including PCBs, are inextricably de. posited in fatty (adipose) tissues based on evidence of limited biotransformation with minimal urinary excretion and high lipid (fat) solubility. i11 it i! I HUMAN PORPHYRIA POSSIBLE FROM HIGH-LEVEL PCB CONTAMINATION OF FOOD QUALITATIVE AND The dietary level of Aroclor 1254 used by Goldstein et al. (1974) to produce por QUANTITATIVE DIFFERENCES IN BIOLOGICAL EFFECTS phyria in female rats (100 ppm) is at least 30 times higher than the 0.2 to 3 ppm tol Considerable amounts of data are now extant which indicate that there are very erances set by FDA for PCBs in foods in important qualitative as well as quantita- NO. 2 AUGUST 1663 2: 95 PCB-ARCH-EXT0378283 TRAUMA live differences in the biological effects of different PCB congeners (chemical com pounds closely related to another in com position). ' Hansen (1979) pointed out that disap pearances of PCB residues are dependent on absorption, distribution, metabolism and excretion which vary from PCB con gener to congener and from species to species. CHLORINATION OF BIPHENYL MOLECULE MARKEDLY AFFECT,S METABOLISM AND DISPOSITION ' The unsubstituted biphenyl molecule is readily metabolized by the hepatic MFO. The two phenyl rings have a directing ef fect on the enzymatic attack on the biphenyl molecule. The major metabolite of biphenyl is the 4-hydroxy derivative with 2-hydroxy biphenyl as a secondary metabolite (Bil lings and McMahon, 1978). These two metabolites may be formed by different enzymes since the 4-hydroxy biphenyl is induced by pretreatment with PB while 3-MC is a . better inducer of 2-hydroxy biphenyl formation. . Chlorination of biphenyl has marked ef fects on its metabolism and disposition. Block and Cornish (1959) found that addi tion of a single chlorine directs the hy- droxylation to the unchlorinated ring. With the addition of two or more chlorine atoms on biphenyl, the position of chlorination becomes of critical importance in the rate of metabolism and thus of the biological half-life of the PCB (Matthews and Kato, 1979). ` "NIH-SHIFT" OF CHLORINE ATOM AND FORMATION OF ARENE OXIDE INTERMEDIATE In the rat, the initial half-life of 4,4'dichloro-BP is about 1 day, twice as long as that of 4-chloro-BP (Matthews and An derson, 1975a). The major metabolite of 4,4'-dichloro-BP excreted by the rat is 4-hydroxy-3-4'-dichlorobiphenyl indicating the famous ``NIH-shift'' of a chlorine atom; this implies formation of an arene oxide intermediate between chlorinated and non-chlorinated carbon atoms (Hess et al., 1977). ' SPECIES DIFFERENCES IN METABOLISM There are species differences in metab olism of the para-chlorinated 4,4'-dichloro- BP. The rat and dog metabolize and ex crete it to indicate a half-life of 1 day. The monkey metabolizes and excretes it much more slowly, and the initial half-life in the monkey is 2-3 weeks (Matthews and Kato, 1979). Therefore, this PCB can bioaccumu late in the monkey but not in the rat and dog. POSITION OF CHLORINATION INHIBITS METABOLISM, AFFECTING HALF-LIFE The position of chlorination can con fer metabolic hindrance to varying de grees. For example, the initial half-life of 2,4,5,2',5'-pentaehloro-BP in rats is twice as long as 4-4'-dichloro-BP (Matthews and Anderson, 1975b). Adding an addi tional chlorine in the 4'-position to form 2,4,5,2',4',5'-hexaehloro-BP inhibits the me tabolism of this PCB so greatly that its.- half-life exceeds the lifetime of the animal (Matthews and Anderson, 1975a). Jensen and Sundstrom (1974) found this hexachloro-BP to be in the highest concentra tion of any PCB found in adipose tissue samples from Sweden. METABOLIC STUDIES A substantial number of metabolic stud ies of commercial mixtures, individual 2: 96 TRAUMA . VOL. 25 POLYCHLORINATED BIPHENYLS (PCBs) PCB congeners and metabolites have been reported and comprehensive reviews have been published (Hutzinger et al., 1974; Sundstrom et al., 1976; NIOSH, 1977; IARC, 1978). EASE OF METABOLISM DECREASES WITH INCREASING CHLORINE CONTENT In PCB-treated animals, GLC peaks with retention times corresponding to di-, tri- and tetrachlorobiphenyls are diminished or absent in tissue extracts which is indica tive of metabolism of these components in commercial mixtures. This was evident in studies with mice, rats, birds and cows (Hutzinger et al., 1974). One can conclude that the ease of metabolism decreases with increasing chlorine content. Available data indicate also that chlorine positioning on the biphenyl rings influence metabolic be havior. The reviews, cited above, indicate that ease of metabolism decreases in the order mammals > birds > fish, and that PCBs are metabolized to mono- and dihydroxy- lated metabolites dependent on extent and position of chlorine substitution. They con cluded that fecal extracts usually contain the free phenol while urinary metabolites are both free and conjugated. Hutzinger et al. (1972) studied the meta bolic behavior of four pure PCBs in pi geons, rats, and brook trout. Their results showed that rats and pigeons could con vert 4-mono, 4,4'-di- and 2,5,2',5'-tetra- chloro-BPs into monohydroxylated deriva tives, but no hydroxyproducts were found in excreta of brook trout. No hydroxylated products of 2,4,5,2',4',5'-HCB were detected in excreta of rats, pigeons or brook trout. Jensen and Sundstrom (1974b) did report this HCB to be only slowly hydroxylated in mice. VARYING PERSISTENCE OF PCBs IN ENVIRONMENT Ballschmiter et al. (1978) reported the extreme persistence of several penta-, hexa- and octachloro BPs while certainothers do disappear from the global en vironment. These data are presented in Table 10. table 10 SOME EXTREMELY PERSISTENT AND LESS PERSISTENT PCB CONGENERS Extremely Persistent Less Persistent 2,4,5,2',4,-pentacliloro . 2,3,4,2',4'-pentachloro 2,3,4,5,2,4'-hexacli]oro 2,3,4,2',3',5'-liexacliloro 2,3,4,5,6,2',3,,5,-octacliloro 2,3,4,5,6,2',3,,4',5,-octachloro 2,3,4,5,6,2,,,3',4'-octachloro 2,3,4,5,2',4',5,-octachloro 2,3,4.2',3'-pentachloro 2,3,4.5,2',3'-hexachloro 2,3,4,6,2',5'-hexacliloro 2,3,4,5,6,2',3'-heptachloro * Penta- and hexachloro-BP are present mainly in Arocloro 1254 and Clophen A-50 while hepta- and octachloro-BP are present mainly in Aroclor 1260 and Clophen A-60. . NO. 2 AUGUST 1983 2: 97 PCB-ARCH-EXT0378285 TRAUMA METABOUZATION TO SULFUR DERIVATIVES The PCBs, although chemically stable, are known to be metabolized by various animal species to hydroxylated derivatives (reviewed by Sundstrom et al., 1976) and are now known to be metabolized to sulfur derivatives as well. Mio et al. (1976) iden tified two metkylthio and two methylsulfonyl derivatives from excreta of mice treated with 2,5,2',5'-tetrachloro-BP. Jen sen and Jansson (1976) found large num bers of methylsulfonyl derivatives from tri-, tetra-, penta-, and hexacbloro-BPs in blubber of seals from the Baltic Sea. Berg man and Wacbtmeister (1978) also re ported unpublished data of finding methyl sulfonyl metabolites in fat samples from a number of other species as well. These data indicate that these transformations repre sent a general metabolic pathway of most, if not all, PCBs (Bergman et al., 1979). Jensen et al. (1979) found that, in con trast to phenolic metabolites ` of PCBs which are rapidly excreted from the body, the methyl sulfones are accumulated. FORMATION OF ARENE OXIDE INTERMEDIATES: TOXIC AND CARCINOGENIC PROPERTIES OF. PCBs cleophiles, including such macromolecules as DNA, RNA and protein. The importance of two adjacent unsubstituted carbon atoms to the metabolism of PCBs was emphasized by Matthews et al. (197S) since formation of arene oxides was greatly facilitated by this requirement. Morales and Matthews (1978) found that exposure of mice to 2,3,6,2',3',6'-hexachloro-BP led to arene oxide formation which became covalently bound to nucleic acids and protein of a number of mouse tissues. The toxicologic significance of such covalent binding re mains to be determined. One can conclude, however, that the pro duction of less chlorinated PCB formula tions (Aroclor 1016) and the decline in production of more highly chlorinated PCBs (Aroclor 1242) may have helped to alleviate some long-term residue problems only to intensify other problems. TISSUE DISTRIBUTION, ACCUMULATION AND DEPLETION OF PCBS ACCUMULATION The PCB problem may be further com plicated by metabolism since those PCB congeners most easily metabolized and ex creted are those most likely to form arene ' oxide intermediates (Matthews et al., 1978). ' Jerina and Daly (1974) found that meta bolic formation of arene oxides explains many toxic and/or carcinogenic proper ties of aromatic hydrocarbons. They re ported that arene oxides, in which an. aromatic double bond has undergone epoxi- dation, in addition to isomerizing to phe nols, react readily with a variety of nu Since PCBs are extremely water-insolu ble, and therefore lipophilic, it has been well-established that they accumulate in the fatty tissues of animals. After an oral dose of 500 mg/kg of Aro clor 1254 to rats, Grant et al. (1971) found concentrations of PCBs in fat, liver and brain of 996, 116, and 40 mgAg (ppm), respectively, 4 days after dosing. "With the same PCB, similar high fat concentrations were found in rats after administration orally (Curley et al., 1971), in cows (Platonow and Chen, 1973), and in boars (Platonow et al., 1972). 2: 98 TRAUMA . VOL. 25 PCB-ARCH-EXT0378286 POLYCHLORINATED BIPHENYLS (PCBs) STUDIES USING RADIOACTIVE- LABELED PCBS . TISSUE DISTRIBUTION Using pure 14C-labeled PCBs, more de tailed data od tissue distribution can be obtained. Labeled 2,4,5,2',5'-pentachloro- BP was given orally to mice by Berlin et al. (1975) who found radioactivity to rap idly enter the circulation to be distributed largely to: , 1) Liver. 2) Kidneys. 3) Lungs. 4) Adrenals. They found radioactivity to be maxi mum in the fat within 4-24 hrs, and to have a special affinity for the skin, the bronchiolar epithelium of the lungs, and certain glandular secreting tissue. EXCRETION Radioactivity appeared in the bile and was excreted in the feces shortly after ad ministration. Matthews and Anderson (1975b) found that in rats given intrave nous (i.v.) doses of the same 14C-labeled PCB, greater than 90% was removed from blood within 10 minutes, with most of the radioactivity deposited initially in the liver and muscle and later transferred to skin and fat. They found metabolism was a prerequisite for excretion, primarily via bile and less than 7% was found in the urine after S-9 davs. tetra (TCB) and 2,4,5,2,,4',5'-hexachlorobiphenyl (HCB) in rats. DISTRIBUTION The distribution, 24 hours after oral dosage, of 3H remaining is tissues, as per centage of dose, for both isomers, was highest in: 1) Skeletal muscle. 2) Skin. 3) Liver. 4) Small intestine. EXCRETION The major difference was in biliary ex cretion where 42.2% of TCB was excreted by male and 25.7% by female, while for HCB only 0.5% was excreted by male and 1.1% by females. This difference was attributed to a slower rate of HCB metabo lism due to the chlorines in the 4,4'-positions in HCB. Urinary excretion was of minor signifi cance for both PCBs. They found absorp tion, distribution and excretion, generally, to be similar in both sexes. Yakusbiji et al. (1979) found relatively large amounts of tri- and tetrachloro-BPs in human milk with these having 4,4'-substitution patterns except for 2,5,2',5'-tetrachloro-BP. Of the 15 major peaks identified in human milk, 12 had 4,4'-substitution pat terns and two had one 4-substitution. This finding emphasizes the importance of chlo rine position on persistence. TRITIUM-LABELED PCB STUDY Petersen et al. (1976) studied the ab sorption, distribution and excretion of two 3H-labeled (tritium-labeled) PCBs, 2,5,2',5'- .SUMMARY OF STUDIES Hansen (1979) summarized much of the data related to this section when he con cluded that: i! l &- ;? :: NO. 2 AUGUST 1993 2: 99 i i PCB-ARCH-EXT0378287 TRAUMA 1) Absorption of different PCB compo nents varies not only with chemical structure but with gastrointestinal physiology. 2) Distribution rates and patterns of PCB components within the animal differ when the components are part of a commercial mixture or when they are administered as pure materials. 3) PCB residue disappearance rates are dependent on absorption, metabolism, distribution and ,excretion, all of which are variable from PCB con gener to congener and from species to species. CARCINOGENICITY Cancer is an uncontrolled growth of abnormal forms of cells and a chemical carcinogen is a chemical which can pro duce a cancer or carcinoma. Various stud ies have indicated that PCBs, as a group, are considered to be carcinogens. There are several stages of cancer devel opment leading to tumors which may be come malignant. YUSHO DEATHS DUE TO MALIGNANT NEOPLASMS Up to Sept. 1973, 22 deaths had occurred among 1200 Yusho patients in Japan, with nine of these deaths diagnosed as being due to malignant neoplasms (tumors), or 41 % of the deaths (Kuratsune, 1976). This is suggestive of an excess mortality due to these tumors; however, no conclusive evi dence for PCB involvement is available. STUDIES OF LIVER TUMORS IN ANIMALS Ueda (1976) reported on studies in Japan where induction of hepatomas (liver tumors) occurred in 7 of 12 mice fed 500 ppm of Kanechlor 500 for 32 weeks. No tumors were found at lower levels of KC500 or with KC-300 and 400 or in control animals. The involvement of PCDFs or ' PCQs in these tumors is unknown. ' SYNERGISTIC EFFECT OF PCBs WITH OTHER CHEMICALS IN TUMOR PRODUCTION Additional studies (Ueda, 1976) indi cated a synergistic effect for liver tumor induction when mice were fed PCBs' and a-benzene hexaehloride, an isomer of the insecticide lindane. He reported that either chemical alone at the same levels did not lead to hepatoma formation. Jonsson et al. (1981) found that rats fed both DDT and PCB- (Aroclor 1242) at 75 ppm caused atypical centrolobular degen eration of the liver, occasionally forming nodules resembling small tumors. Nishizumi (1976) found that the inci dence of liver tumors produced in rats by N-nitrosodiethylamine was enhanced by subsequent dosing with KC-500. These, and other studies, indicate that PCBs can have a synergistic effect with other chemicals in tumor formation. CARCINOMAS AND NEOPLASTIC NODULES Kimbrough (1976) summarized her work by reporting that in the mouse, neoplastic : nodules (hepatomas, hyperplastic nodules) developed after dietary exposure to Aro clor 1254. She also found that female rats, fed 100 ppm Aroclor 1260 for 21 months, developed hepatocellular carcinomas as well as neoplastic nodules in the liver. She also reported adenofibroses (fibroid changes in a gland) of the liver in both mice and rats, a persistent lesion which does not disappear after cessation of PCB exposure. 2: 100 TRAUMA VOL. 23 PCB-ARCH-EXT0378288 +*+*Ui tV VrFCrrWr^afrr.Vr?^ aaggg*i ss^gg-' asssaagsgaaagigv;.- POLYCHLORINATED BIPHENYLS (PCBs) Neoplastic nodules are a part of the spec trum of response to hepatocarcinogenic agents and must be included in the evalua tion of tumorigenesis. The significance of adenofibrosis (cholangiofibrosis) to the de velopment of hepatocarcinomas is not un derstood to date (Kimbrough, 1979). It also is unknown whether hepatic porphyria is related to the induction of hepatocellular carcinomas (Kimbrough, 1979). CARCINOMAS AND ADENOCARCINOMAS OF GASTROINTESTINAL TRACT Other studies have summarized research on carcinogenic effects (NIOSH, 1977; ` IABC, 1978; WHO, 1976; Higuchi, 1976) most of which have been centered on the liver. Additional studies by NCI (1978), however, have found a few carcinomas (malignant new growth made up of epithe lial cells) and adenocarcinomas (carcinoma made up of glandular tissue) of the gastro intestinal tract in rats treated with Aroclor 1254 for 104-105 weeks while none were seen in control animals. Hepatocellu lar hyperplastic nodules were observed in 11/48, 17/46 and 29/48 rats at 25, 50, or 100 ppm in their diet, respectively, with none in control animals. TERATOGENICITY PCBS IN EMBRYONIC AND FETAL TISSUES PCBs have been found in embryonic and fetal tissues of humans (Shiota et al., 1973), experimental animals (Takagi et al., 1976; Vodicnik and Lech, 1980) and mon keys (Allen and Barsotti, 1970) after exposure of the pregnant mother; and although considerably more PCBs are transferred to nursing offspring via the mammary glands than to fetuses via the placenta (above citations), the potential for direct teratogenic (pertaining to the production of physical defects of offspring in utero) effects exist. STUDIES SHOWING NO TERATA NIOSH (1977) reviewed a number of Japanese publications which indicated that no terata (a fetus or infant with pronounced developmental anomalies as to be con sidered grotesque; monster) were reported in Yusho babies at birth. No terata were reported in the twogeneration feeding study of PCBs to rats by Linder et al. (1974) using Aroclor 1254 and 1260 up to 100 ppm. Allen and Norback (1976) reported no terata in monkeys fed 2.5 or 5.0 ppm for 6 months prior to breeding although over half the animals aborted. BIRTH DEFECTS IN MICE AFTER SUBCUTANEOUS INJECTION In mice injected subcutaneously with PCBs for 10 days from day 6 of gestation, various teratogenic effects were found by Watanabe and Sugahara (1981). They re ported cleft palate formation which they attributed to specific effects of PCBs and not to its general toxicity. Cleft lip, brachydactvly (short digits) and syndactyly (web bing between digits) also were found. Their results demonstrated a ter,atogenic effect of PCB in strain ddY mice after subcutane ous injection. TERATOGENIC POTENTIAL FOR PCBs IN HUMANS Although no terata have been reported to this author's knowledge in primates, i!! p*r-t; 3/ 1 I .4/ i r. rifts- m NO. 2 AUGUST 1S62 2: 101 ~ ~ *-*.**- ***.' - ` !'"' A--Y;. * `x ................ ' PCB-ARCH-EXT0378289 TRAUMA man or monkey, these data do indicate there is teratogenic potential for PCBs in hu mans, and additional studies in this area are needed. EFFECTS ON DIGESTIVE SYSTEM PROLIFERATIVE LESIONS FROM CHRONIC EXPOSURE McConnell and Moore'.(1979) concluded that proliferative lesions of the gastroin testinal tract are a feature of especially chronic exposure to PCBs by non-human primates. HYPERPLASIA The initial response in the gastric mu cosa was a loss of parietal cells with re placement by mucus-secreting cells accom panied by hyperplasia (increased number of normal cells) with subsequent invasive downgrowth of the glandular epithelium into subjacent tissues. INDICATIONS OF CARCINOGENIC POTENTIAL Hyperplasia and dysplasia are consid ered to be the first and second stages, re spectively, of cancer formation. Allen and Norback (1973) found that male rhesus monkeys fed a diet containing 300 ppm of Aroclor 1248 for 3 months developed edematous thickening (several fold) of the stomach wall and"-marked hy pertrophy (cell enlargement) of the pyloric and fundic areas of the gastric mucosa (Figs. 7 & 8). Each treated monkey showed widespread penetration of the muscularis mucosa and invasion of the mucosal epithelium in the stomach. They found the hypertrophy, hyperplasia, and dysplasia (alteration in size, shape and or ganization of adult cells) of the gastric mucosa to be short of neoplastic transfor mation but indicative of the carcinogenic potential of PCBs. SIMILAR EFFECTS FROM SINGLE ORAL DOSE In a later study, Allen et al. (1974) re ported similar effects on the same animals given a single oral dose of 1.5 or 3.0 g/kg of body weight of Aroclor 1248. By 14 days, gastric hypertrophy and hyperplasia and focal ulceration of the stomach lining (Fig. 8) were prominent lesions. Kimbrough (1974) reported ulceration of the gastric and duodenal mucosa in rats given single oral doses of 3 gAg of either Aroclor 1254 or 1260. DOWNGROWTH OF MUCOUS GLANDS IN FATAL DOSE McNulty (1976) found extensive down- growth of mucous glands into the sub mucosa (Fig. 8) of the stomach of a rhesus monkey who died after 8 months on a diet containing only 3 ppm of Aroclor 1242. Becker et al. (1979) reported total mucous conversion of the gastric epithelium, growth of the gastric glands down through the muscularis mucosae into the submucosa . and eventually the formation of cysts lined by mucus-secreting columnar epithelial cells in monkeys fed 1242 at 2-100 ppm in their diets. 1 McNulty et al. (1980) and Silverman et al. (1979) tested 3,4,3',4'-tetrachloro-BP on immature monkeys fed 3.0 ppm, later reduced to 0.3 ppm. in their diets. They also found gastric hyperplasia to result. The former paper reported no effect for the 2,5,2',5'-isomer also tested; but the 3,4,3',4'-isomer caused the simian analog 2: 102 TRAUMA ... VOL. 23 ^ ^ ^ ^ ^ r "S?PCB-ARCH-EXT0378290 mama wittTbaaj POLYCHLORINATED BIPHENYLS (PCBs) I.M B>M 9yi : : fevef'rv. mi FIG. 7. Diagrammatic Sketch of Normal Stomach and Duodenum The stomach is the most dilated part of the digestive tube, situated between the end of the esophagus and the beginning of the small intestine. The opening com municating with the duodenum is known as the pyloric orifice; the opening which communicates with the esophagus is the cardiac orifice. The fundus of the stomach is the musculomembranous expansion of the alimentary canal between the esopha gus and duodenum. The antrum is a short, conical portion of the esophagus with its base contiguous with the orifice of the stomach. &--r At A'{ of chloracne in humans (swelling and red dening of the eyelids due to squamous metaplasia of the meibomian glands), weight loss, and death in 1 to 6 months. The latter paper reported that autopsy of 2 of the monkeys that died revealed a broad thick lesion occupying portions of the body and antrum {Fig. 7) of the stomach. PCB POISONING OUTBREAK FROM CONCRETE SEALANT A spontaneous outbreak of PCB poison.ing in rhesus monkeys was reported by Altman et al. (1979) and McConnell et al. (1979) due to PCBs present in the concrete sealant on the cage floors. The former NO. 2 AUGUST 186S 2: 103 1 PCB-ARCH-EXT0378291 TRAUMA ] 2 3 4 .5 FIG. 8. Diagrammatic Sketch .of Gastroduodenal Junction The stomach is lined by a mucous membrane, which is permeated by tubular glands throughout its entire length. The glands differ in their cell structure and also in their secretions. The layers below the mucous lining or coat are the submucous coat, a muscular coat, and an outer peritoneal or serous coat. The duodenum is the first portion of the intestinal Iract. The gastroduodenal junction is shown in the small, upper drawing (1), and the cell structures (histology) of this area are shown in the lower drawing. 2: 104 TRAUMA . VOL. 25 n t>---- ft Mt .df4MhMAf.-M.J . --s jv. -- ---C* *.-?.1*r r - > PCB-ARCH-EXT0378292 ------------ 7----------- _ -- . rr~y------ t r-------"i yn------- ti-- in .- % jisjatfirsar- POLYCHLORINATED BIPHENYLS (PCBs) paper reported a high incidence of abor tions and stillbirths with a high infant mortality rate. The latter paper reported severe hypertrophy of the glandular stom ach and a similar hut less severe lesion in the colon. YUSHO VICTIMS: SOME DIGESTIVE COMPLAINTS These studies point out the sensitivity of rhesus monkeys to PCBs. It is not known at this time if humans develop similar di gestive lesions; but early reports of nau sea. anorexia, etc. may point to some effects in the Tusho victims. VITAMIN EFFECTS VITAMIN A: PCB EFFECTS ON STORAGE AND UTILIZATION quail fed Aroclor 1242 at 100 ppm in the diet. EFFECTS ON GROWTH Innami et al. (1974) described a study showing significantly decreased hepatic A content in rats fed a 0.1% PCB diet (PCB unspecified). They found that rats given a vitamin A deficient diet with 0.1% PCB showed a significant growth retardation when compared to rats given a normal diet with 0.1% PCB. They also reported that rats fed a 0.1% PCB diet supplemented with vitamin A (3,400 IU) showed better growth than those given a PCB diet alone which indicated that vitamin A supple mentation prevented, to some extent, the growth retardation by PCBs. They con cluded that PCB-fed rats required more vitamin A than usual and that this vitamin may play a role in PCB detoxication. Several groups of researchers have been investigating the effects of PCBs on vitaruin storage and utilization in light of data SKIN APPLICATIONS AMELIORATED HUMAN CHLORACNE that showed that some chemically related Calabrese (1980) reviews other PCB- insecticides (e.g., DDT and dieldrin) had related work on vitamin A and reported an affect on liver storage of vitamin A. that vitamin A skin applications had an U: i One of the first studies to report such an ameliorative effect on human chloracne effect was Villeneuve et al. (1971) who due to PCB exposure. found that pregnant rabbits dosed with Aroclor 1254 (1 and 10 mgAg) had about half of the normal hepatic vitamin A val B VITAMINS ues. Cecil et al. (1973) found similar ef There are very few reports of PCB ef Iii! fects in male and female rats and Japanese fects on the B vitamins. Fugiwara and FIG. 8. Diagrammatic Sketch of Gastroduodenal Junction --continued (see page 2: 104) 1) Gastroduodenal junction 2) Circular muscle 3) Longitudinal muscle 4) Peritoneum 5) Pyloric sphincter 6) Gastric mucosa T) Submucosa 8) Lymphoid nodule 9) Brunner's glands 10) Mucous membrane of duodenum NO. 2 AUG UST less 2: 105 PCB-ARCH-EXT0378293 TRAUMA Kuriyama (1977) studied PCB effects on pyridoxal phosphate (vitamin B6) and riboflavin (B.,). They fed a mixture of KC300 to 600 to male rats (10 and 100 mg/kg) for 4 weeks and found no significant changes in riboflavin tissue content hut found that PCBs did cause a marked re duction in B6 liver levels. They suggested that this decrease in B6 levels may be as sociated with skin-lesions observed in PCB poisoning, such as chloracne. Other reports summarized by Calabrese (19S0) indicated that deficiencies of thi amine and B,, enhance the toxicity of PCBs. VITAMIN C DEFICIENCY IMPAIRS METABOLISM OF INSECTICIDES Street and Chadwick (1975) reported that a dietary deficiency of vitamin C (as corbic acid) in guinea pigs impaired the metabolism of a variety of. chlorinated pesticides, such as DDT. Guinea pigs share with primates (apes, monkeys,-and man) the inability to syn thesize their own dietary requirements of vitamin C so their requirements must be met by dietary inputs. Zannoni and Sato (1975) found that low'levels of dietary vi tamin C in guinea pigs resulted in a de creased capacity to induce hepatic micro somal enzymes which suggested that this could be the cause of decreased chlorinated pesticide metabolism. REDUCTION OF PCB TOXICITY Chakraborty et al. (1978) reported data that indicated that vitamin C could reduce PCB toxicity by increasing the metabolism and excretion of PCBs. Kato et al. (1977) found that the dietary addition of 2000 ppm of ascorbic acid to guinea pigs fed 500 ppm Aroclor 1248 significantly prevented PCB- induced growth retardation when com pared with animals on diets with only 50 ppm vitamin C. Calabrese (1977) and Fu- giwara and Kuriyama (1977) concluded that PCB exposure resulted in an increase in hepatic metabolism of vitamin C which may be associated with an adaptive in crease (induction) in detoxification mecha nisms. Calabrese (1977) also indicated that a possible cause of PCB toxicity may be due to insufficient conjugate formation, via glucuronides, of hydroxyl metabolites of PCBs. Chakraborty et al. (1978) showed that vitamin C supplementation (20 mg/ ' 100 g/day) provided protection against PCB-induced alterations in hepatic vitamin C metabolizing enzymes and some histo logical liver damage. , ROLE OF VITAMIN C IN DETOXIFICATION OF CARCINOGENS AND DRUGS Calabrese (1980) reviewed some addi tional data and concluded that vitamin C metabolism is not only altered by PCBs but that L-ascorbic acid can prevent some of the PCB-induced toxicity symptoms. He concluded further that "the evidence is clear that dietary ascorbic acid does play an important role in the detoxification of certain drugs and carcinogens within guinea pigs, a species which, like humans, does not synthesize its own ascorbic acid." . It can be assumed that humans will ex hibit a similar dependency on ascorbic acid for these functions. FEW STUDIES ON NUTRITIONAL FACTORS AFFECTING PCB TOXICITY It is apparent that much more research needs to be done on the potential protective effects of vitamin supplementation to PCBexposed or poisoned persons. It should be 2: 106 TRAUMA . VOL. 23 iSiMesSS PCB-ARCH-EXT0378294 POLYCHLORINATED BIPHENYLS (PCBs) apparent that despite hundreds of papers on PCB toxicity, there are very, very few on nutritional factors that may affect its toxicity. The compendium by Calabrese (19S0) is a valuable contribution to this general area. terious effects are through relatively lowlevel, chronic exposures. Thousands of papers describing their distribution, tox icity, metabolism, health effects, etc. are in the literature today and yet much still needs to be known. SUMMARY AND CONCLUSIONS LARGE RESERVOIR OF PCBS It can be approximated that from 1929 through much of 1977, approximately 1,000,000 tons of PCBs have been produced world-wide with the large majority pro duced in the U.S. Estimates, ranging up to half of this total, place much of this production as al ready existent in various environmental compartments, including landfills, dumps, fresh and marine waters, air, sediments and in the tissues of various life forms. - Most of the remainder apparently is still in service, primarly in transformers and capacitors, while only relatively low quan tities have been destroyed either biologi cally, chemically, or thermally. There thus remains a large reservoir of PCBs world wide, especially in the U.S., which are po tentially capable of entering the mobile environment. Hopefully, the 1976 passage of the Toxic Substances Control Act and rigorous enforcement of its specifications, coupled with terminated PCB production, can minimize environmental inputs of PCBs. POTENTIAL EFFECTS THROUGH LOW-LEVEL. CHRONIC EXPOSURES Although the PCBs have relatively low acute toxicity, their potential and real dele COMPLEX NATURE OF PCBs The complex nature of a commercial PCB, not uncommonly consisting of more than 70 components, makes it an exceed ingly arduous chore for researchers to sort out the effects due to a single PCB. POSSIBLE SYNERGISTIC EFFECTS Compounding this problem are the pos sible synergistic effects, some already known, which may occur between PCBs and other environmental pollutants, such as pesticides, or with drugs, food additives, and other chemical compounds. METABOLISM TO POTENTIAL CARCINOGENS OR TOXIC EFFECTS FROM PCBs IN TISSUES Two adjacent unsubstituted carbon atoms in the PCB molecule are important in the metabolism of PCBs since it facili tates the formation of arene oxides by the .MFO of the liver, metabolic intermediates implicated as potential carcinogens. This poses a dilemma because those PCB con geners which can be metabolized and ex creted rapidly may do so via a carcinogenic intermediate, whereas those which are not metabolized readily are extremely persist . ent in body tissues and may exert other toxic effects, as noted for the common 2,4,5,2',4/,5'-bexachlorobiphenyl isomer, such as chloracne, liver damage and he patic porphyria. NO- 2 AUGUST 1863 2: 107 PCB-ARCH-EXT0378295 TRAUMA MORE RESEARCH ON . NON-HUMAN PRIMATES NEEDED OVERT EFFECTS EASILY OVERLOOKED Most of the research on PCB effects has PCBs are known to cause various overt been done with rodents, such as mice and effects that are easily overlooked or not rats, some on guinea pigs, chickens, and investigated. These include both neurologi rabbits, and relatively little on mammals cal and behavioral effects, endocrine and most closely related to man, the non-human reproductive effects, effects on both the primate. Yet it appears that rhesus mon lungs and the immune system, carcino keys are very susceptible to PCB intoxica genic and mutagenic effects and even tion at much lower dose levels than mice changes in vitamin levels. or rats and the effects - are more pro i nounced, aside from liver effects. Certainly, 1 i more research on PCBs should be directed MUST CONTROL DISPOSAL toward use of such a non-human primate. OF PCBS Disposal of used PCBs must be care SEVERE PCB INTOXICATION FROM LEVELS NOT MUCH HIGHER THAN FDA PERMITTED LEVELS In addition, severe PCB intoxication has been shown to occur in chronic feeding studies with these monkeys at levels not much higher than FDA permitted levels in some human foods. It has also been shown . that monkeys and humans display similar signs and lesions of PCB intoxication. fully controlled to not only prevent con tinued release of PCBs into the environ ment but also to prevent the additional formation of the toxic PCDFs by improper combustion. The book on PCBs is far from being closed; The ban on manufacture of PCBs should not deter research to be continued on their effects on animals, especially mon keys, and also the humans who are acci dental poisoning victims. PCB residues in the environment will be with us for many years to come, as will the ramifications TOXICITY OF CONTAMINANTS Besides the PCBs themselves, a serious cause for concern are the impurities found of their effects on various organisms, be cause of the vast amount of PCBs still ex tant in the environment today. to be present in commercial samples--the PCNs, the PCDFs, and more recently the PCQs. While the PCNs generally are slightly less toxic than PCBs, 'the PCDFs are up to several hundred fold more toxic, while essentially nothing is known of the PCQs. In addition, it is known from the Ynsho incident and other research, that PCDFs are often in considerably greater concentration in used or aged PCBs than REFERENCES Allen, J. R. and Barsotti, D. A. 1976: The ef fects of transplacental and mammary movement of PCB's on infant rhesus monkeys. Toxicology 6(3) : 331-340. Allen, J. R. and Norback, D. 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