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I < ( REVIEW OF THE TECHNICAL AND REGULATORY ASPECTS OF AROCLORS On the b a s is of the r e s u lt s obtained in the chronic stu d ie s on the variou s P C B 's at B IO -T E ST , the conclusion has been reached that these m aterials are not carcinogenic. The slides have been reviewed th ree tim es by D rs. D, Gordon and W. R ich ter and th eir findings support this conclusion. C ertain liv e r changes occu r in varying degree with the different A ro c lo rs .hat a r e su b ject to s e v e r a l in te rp re tatio n s, a s w ell a s nom en clature and classification . In the c la s s ic a l p ath o lo gical se n se the liv e r a lte ra tio n s seen with the A ro c lo rs a r e benign in c h a ra c te r. L e sio n s of this type have been shown to be re v e rsib le . F u rth e r, the benign fe atu re s include lack of vascu lar invasion and lack of m tastas s a s well a s lack of transplantability. The liver changes such as focal h yperplasia, hypertrophic nodules, and adenofibrosis m ay be induced by other chlorinated arom atic and aliphatic hydrocarbons. Som e of the latter m a te ria ls that m ay produce these lesion s, such a s dieldrin, aldrin, and carbon tetrachloride, are co n sidered to be carcin ogen ic by the EPA and the N ational C an cer 710335 ( (2 Institute. In fa c t, these gro u p s have redefined th ese te rm s a s w ell a s the concept of benign and m alignant lesion s a s they have been used traditionally. The view of these groups is that any tum or induced by a ch em ical is m alignant d esp ite the ab sen ce of the c l a s s i c a l h isto lo g ic a l featu res of m alignancy. The le g a l division of the EPA has en th u siastically em braced this approach and h as u sed it su c c e ssfu lly to cancel the registration of dieldrin and aldrin and are about to launch litigation ag a in st chlordane and h eptach lor. It is expected that the re g istra tio n of the la tte r m a te r ia ls w ill be in due c o u rse ca n ce lle d . In the c a s e of liv e r c h an g e s, the E P A and the N ation al C a n c e r Institute have adopted the view that in the extrem e any m a te ria l which induces liv e r m ic r o so m a l en zy m es i s a su sp e c t carcin o gen . In addition, fo cal h y p erp lasia of the liv e r produced by ch em icals is being c la ssifie d a s a prem alignant change and the ch em icals involved are being c la ssifie d a s suspect carcinogens. Additional histological effects such as nodular hyperplasia are a lso considered to be prem alignant. The philosophy that has been adopted by these agen cies is that substan ces which cause the above liv e r changes are in fa c t carcin ogen ic. This philosophy p erm eates the extensive EP A b rie f in the legal proceedings to cancel the re g istra tio n of dieldrin and ald rin a s w ell a s in its p relim in ary le g al presen tation on chlordane and h ep tach lo r. NV Oll Od^t 710336 ( <3 The EPA is supported by the N ational C ancer Institute a s re p re se n te d by D rs. U. S affio tti, R. S q u ire s, and W. H eston. In addition, non-government affiliated pathologists such as D rs. E. F arb er, and M. R eu b er, H. P opper and S . E p stein support the a g e n c ie s' view s. On the other hand, a num ber of p ath o lo g ists such a s D rs. J . N ew b em e, W. B u tler, G. J o n e s , A . Stein, G. Kent, D. G ordon, and W. R ich ter do not a g r e e w ith the agen cy definitions o r with the p resu m ed end-point of the liv e r le s io n s - c a n c e r. In this r e g a r d , it should be mentioned that the FD A had the B IO -T E ST A roclor slid e s fo r 3 y e a r s and to this date no a d v e rse com m ents have been receiv ed . Without question the A ro c lo rs a s w ell a s other P C B -lik e m a te ria ls a re directly involved in this situation. The opinion cf D r s. G ordon, R ich te r, C a la n d ra , K ep lin ger and K in osh ita, on the b a s i s of th eir own stu d ies on A r o c lo r and on th eir e xp erien ce, is that A ro clo rs are not carcinogen ic. However, the attitudes and findings of oth ers m u st be placed in p e rsp e c tiv e and w eighed, each accordin g to its own m e r its in a c c o r d with the data g en erated . The findin gs of Ito, ^ K im brough and o th ers a r e re le v an t in this context. Ito conducted a study in m ice and found "h y p erp lastic nodules and w ell-differentiated hepatocellular carcin om as" at a dose level of 50 ppm of Kanechlor 500. However, hepatocellular carcin om as w ere not induced by Kanechlor 400 and Kanechlor 300. No specific inform ation about the purity o r com position of the products tested is NEV 0 1 1 0 8 5 710337 ( (4 available. F o r exam ple, w ere chlorinated dibenzofurans present? 3 It has been shown by Vos that certain b io lo gical changes can be induced by K an ech lo rs that do not o ccu r with A r o c lo r s . Ito 's w ork involved feeding levels of 500 ppm , 250 ppm and 100 ppm of each of the th ree te s t m a t e r ia ls fo r 32 w eeks to gro u p s of 6-12 m ale m ice. The a rtic le is sketchy and it is not po ssib le to evaluate the sign ifican ce of the findin gs. No h istological d escrip tio n s a re presen ted. The study obviously does not m eet the scien tific re q u ire m ents fo r a m eaningful b io a ssa y for carcin o gen esis a s defined by the N ational C ancer Institute. The groups a re much too sm all and only m ale m ice w ere u sed . Su rp risin gly , the K anechlor 500 m ate rial produced hepatom as and the K an echlor 400 and K anechlor 300 m a te ria ls did not. It is not p o ssib le fro m the a r tic le to a s c e r ta in that the h epatom as a r e in fa c t h e p a to ca rcin o m a s. In g e n e ra l, th is study a s p resen ted is not acceptab le and cannot be u se d to p ro p erly evaluate the carcin ogen ic activity of P C B 's without additional inform ation. With referen ce to the u se of the m ouse in carcinogenicity 4 testin g, G r& sso and Compton have review ed the value of this anim al in testin g fo r e ffe c ts in the liv e r a s w ell a s other v ario u s organ sy ste m s. They note that a num ber of c o v ariab le s significantly influence the incidence of hepatom as in m ice. T hese include diet, presen ce or absence of ''g e rm s," sex, age and strain susceptibility. They state, "It thus a p p e a r s that fa c t o r s unconnected with the ad m in istratio n of the NEV 0 1 1 0 8 6 710338 ( (5 t e s t compound m ay have a c o n sid e ra b le influence on the inciden ce of hepatom as in m ice, so that other evidence is required if claim s of carcin o g en icity b a se d on the induction of this type of tum or a r e to be seriously considered. " A study conducted by Kimura on Kanechen 400 u tiliz e d 20 ra ts aged 10 w eeks in the te st group and 10 r a ts in the co n tro l grou p equally divided a s to sex . The dietary level fo r the single te st group v aried fro m a low of 38. 5 ppm to a high of 616 ppm. L iv e r changes included hypertrophy and fatty degeneration. "M ultiple adenomatous nodules" w ere seen in 6 test fem ale ra ts and in 2 control fem ale r a ts. M ale ra ts in eith er the teat or control grou p s did not develop the n odu les. The auth ors specu lated that the nodules "in the p resen c e o f other stim u li m ay p r o g r e s s " to m alignant ch an ges. Once again , this study does not m eet the technical crite ria fo r ch em ical carcin ogen esis b io a ssa y p ro ced u res despite the negative re su lts. The re su lts confirm ed the higher d egree of su scep tib ility of fe m a le s to the developm ent of h y p er plastic liver nodules. No specific conclusions, however, can be reached. A sh o rt term study in m ice (26 w eeks) by N ishizum i^ did not reveal liv er changes consistent with either prem alignant o r m alignant hepatocellular lesions. A study by K im brough^ in m ale and fem ale Sherm an r a ts fed A roclor 1260 and 1254 at le v e ls in the diet ranging from 0-1000 ppm for NEV 0 1 1 0 6 7 710339 ( 6 8 months did not indicate the p resen ce of h epatocellu lar carcinom a. Under light m ic ro sc o p y the ch an ges seen w ere hypertrophy of the liv e r c e lls , in clusion s in the cy top lasm , brown pigm ent in the Kupfer c e lls , lipid accum ulation, and at the higher dietary le v e ls, ad en o fib ro sis. Another study by Kimbrough with A ro clo r 1260 (Lot No. AK-3) in fem ale Sherm an ra ts at a d ie ta ry le v e l of 100 ppm w as conducted for 21 m onths. The r e su lts w ere strik in g ly d ifferen t than those obtained e a r lie r . In the la tte r study a high inciden ce of h e p a to ce llu la r carcin o m a w as seen which i s contrary to the findings of B IO -T E ST . It is note worthy that the incidence of h epato cellu lar carcin om a ap p ea rs to be related to the new classific atio n of liv e r lesio n s by NCI. The r e s u lt s have so m e re le v an ce in the reso lu tio n of the carcinogenic potential of P C B 's; how ever, the study does not m eet the crite ria for a valid rat carcinogenicity b io assay . The evidence presented at this time is at best presum ptive and does not take precedence over the chronic stu dies conducted in m ale and fem ale rats at B IO -T E ST . The liv e r slid e s from the latte r study have been reviewed by a num ber of pathologists including D rs. Squires and Kim brough, who agreed with the a sse ssm e n t that no h epatocellular carcinom as were present. A number of questions can be ra ise d about the Kimbrough study which ra ise serio u s doubt a s to the value of the study a s presently constituted. In and of i t s e l f , it is not the fin al an sw er and does not per se prove that P C B 's are carcinogenic. * NfcV 011088 710340 c (7 K im brough and Lender^ conducted a study in B A L B /c j m ale m ice fed 300 ppm A ro clo r 1254 fo r 11 and 6 m onths. The 6 m onths feeding group w as maintained for an additional 5 month recovery period (tra n sfe rre d to control d iet). The two sign ifican t h isto lo g ical fin din gs w ere ad en o fib ro sis of the liv e r and h epatom as. A den ofib rosis is not con sidered by ex p erts in the fie ld (Stew art and Snell*) to be a p r e ca n cer ous le sio n . The h ep ato m as w ere w ell d ifferen tiated and the authors (Kim brough and Linder) a re of the opinion that these are potentially carcinogenic; how ever, no direct evidence of m alignancy was noted. To fu rth er add to the confusion of the findings and relevan ce of the Kim brough studies a re the re su lts obtained in still another ex p erim en t.* F ifty m ale Sherm an strain ra ts w ere fed 500 ppm A ro clo r 1254 for 6 months and at monthly intervals th ereafter 5 ra ts w ere sa c rific e d and the liv e rs examined by light and electron m icroscopy. Ten months after exposure 1192 ppm P C B w as p re se n t in the ad ip o se tissu e and 22. 65 ppm in the liv e r . In th is study which u se d m a le Sherm an r a ts only, no sp e c ific mention of fo cal hyperplasia o r h yperplastic nodules is m ade. The principal lesion described is ad en ofib rosis. No evidence of hepatocellular carcinom a is presented. I to 12 con firm ed this in a study in which m ale r a ts w ere fed K anechlor 300, 400 and 500 fo r up to 52 w eeks. T hese su bstan ces produced nodular h yperplasia but did not induce hepatocellular carcinom as in r a ts . NEV 0 1 1 0 8 9 710341 8 ( Norbeck and Allen 1^ fed m ale ra ts 100 ppm of A ro c lo r 1248, 1254, or 1262 fo r up to 52 w eeks and did not find evidence of hepato cellular carcinom a. However, hepatocellular hypertrophy associated with p roliferation of the endoplasm ic reticulum w as seen. Mixed function oxidase m icro so m al enzym es w ere in creased . A dditionally M a k iu r a ^ fed r a ts P C B 's alone and in conjunction with acetylam iaofluorene, diethylnitrosam ine and 3'm ethyl-4-dim ethylam inozobenzene and found that "P C B 's inhibited developm ent of nodular hyperplasia, oval cell infiltration, and bile duct proliferation" (adenofib ro sis). Of sp e c ia l in te re st is the inform ation that fo cal nodular h y p erp lasia i s seen in the human bein g. 15 It is a r a r e benign tum or that h a s been studied and followed clin ically in m an without evidence of subsequent m alignant transform ation. The is s u e of c la ssific a tio n of the liv e r tum ors and the presum ption that focal hyperplasia and nodular hyperplasia are pre-m alignant liver lesio n s and that these in variably lead to h epatocellu lar carcinom a needs to be d iscu sse d . A number of contrary opinions to this philosophy are # available so that this consideration need not be decisive. . However, it is im portant to note that the le g a l branch of EPA h as clearly adopted these definitions. NEV 0 1 1 0 9 0 710342 (9 When the question at is s u e is review ed in the light of the regulatory agen cies that m ay be involved, sev eral points m ust be considered. The E P A , b a se d on the d ield rin and ald rin re g istra tio n can cellatio n s and the im pending litig atio n on. h eptachlor and ch lordan e, are com m itted to the NCI philosophy of liv e r tu m origen esis and a lso that ch em ical ag en ts which produce benign tu m o rs a r e co n sid e re d to be carcinogenic fo r the purposes of regulatory procedures. In addition , ^ the follow ing 9 p rin c ip le s a r e being follow ed at the p resen t tim e by the EPA to evaluate the can cer hazard of environm ental chem icals: 1. A carcinogen is any agent which in c re a se s tum or induction in m an or an im als. 2. W ell-established crite ria ex ist for distinguishing between benign and m align an t tu m o rs; how ever, even the induction of benign tum ors is su fficien t to c h a ra c te riz e a ch em ical a s a carcinogen. 3. The m ajority of human can cers are caused by avoidable exposure to carcin ogen s. 4 . While ch em icals can be carcinogen ic agen ts, only a sm all , percentage actually are . 5. C arcinogenesis is ch aracterized by its irre v e rsib ility and long latency period follow ing the initial exposure to the carcinogenic agent. 6. T here is g reat variation in individual su scep tib ility to c a rc in o g e n s. 7. The concept of a 'threshold" exposure level for a carcin o genic agent has no p ra c tic a l sign ifican ce b ecau se there is no valid method fo r establish in g such a level. NEV 0 1 1 0 9 1 710343 ( ( 10 8 A carcin o gen ic agen t m ay be identified through a n a ly s is of tum or induction re su lts with lab oratory an im als exposed to the agen t, or on a p o st hoc b a s is by p ro p e rly conducted epidem iological studies. 9. Any substan ce which produces tum ors in an im als m u st be c o n sid e re d a ca rcin o g e n ic h azard to m an if the r e s u lts w ere achieved acco rd in g to the e stab lish e d p a ra m e te rs of a valid carcinogenesis test. . In c o n tra st to th is, the FD A in a le tte r 17 w ritten by the A sso c ia te C om m ission er of Science to Senator H art, indicated, "Although the Agency (EPA) stated that 'the above p rin cip les rep resen t the m o st advanced research findings and policy of both national and international cancer experts and a g e n c ie s,' it should be em phatically em phasized that there is by no m ean s u n iv e rsa l acceptan ce of m any of the above principles * s well as classification of tu m o rs." A review of the sta tu s of P C B 's by L . L . R a m se y , 18 A sso c ia te D irector of Regulatory P ro g ram s of the FDA, includes a number of im p o rtan t o b se rv a tio n s which h ave a b e arin g on the ran ge of str a te g y and the p o ssib ilitie s that a r e av ailab le to reso lv e the issu e of P C B . 1. The o v e rall a v e ra g e of P C B 's in a ll packaged food w as 0.1 ppm. 2. This survey probably reflects sam ples of at least one y e a r old and the in d u stry h as furnished us with data on m ore recent sam p les indicating that the co rrectiv e action they have taken is alread y effective: these PCB resid u e data appear to be significantly low er both in food and in its p ap er pack agin g. 3. In ligh t of a l l a v a ila b le data including an im a l feeding stu d ie s, the human data fro m the Ja p a n e se Yusho incident and a h isto ry of use fo r about 40 y ears with out d eleteriou s e ffects in m any being reported, the FDA has concluded that there is no im m ediate hazard NEV 0 1 1 0 9 2 710344 11 (( to the public health fro m the low level of environm ental contam ination leadin g to re sid u e s in food, but that it is prudent to reduce the long term exposure of m an. Steps have been taken which w ill reduce the long term exposure of m an and a ll evidence to date points to a su ccessfu l outcom e. The m o st recent m ark e t b ask et su rvey by the FDA did not show P C B 's to be p resen t in any of the foods analyzed. Another very im portant asp e c t of the regu latory question can be in ferred from the reco m m en d ation s^ proposed by the EPA for dieldrin and aldrin which they have concluded is a carcinogen according to their r ia T . .The -EP-AJhas reco m m en d ed Jh e continued nee o f th e se m a t e r ia ls fo r application d irectly to so il in m a te r ia ls bu ried in s o il, e . g . , term ite control in foundations and seed treatm en ts when p roperly applied. Gn the b a sis of this attitude it is apparent that P C B 'a m ay continue to be u sed in controlled situations including su pervised d isp o sal w here the benefit to r isk is obvious d espite the outcom e of the questions raise d about the liver changes. The recent additional evidence concerning biodegradability lends further support to this approach. F o r the present it is recom m ended that the FD A and EPA (if n e c e ssa ry ) be provided with the fin al A ro clo r rep o rts on the chronic o ra l toxicity studies including the la s t addendum of the path ologists without additional comm ent. Jun e 27, 1975 J . C . C alan dra, Ph.D ., M.D. NEV 0 1 1 0 9 3 710345 (< REFERENCES 1 N. Ito. Cana 63:805 (1972). 2 N. Ito. J . Nat. C aac. Inst. 1:1637 (1973). 3 J . Voa. Environ, Health P e rsp , h l 0 5 (1972). 4 P . G ra sso , R. C ram pton. Food C osm etic Toxicology 10:418 (1974). 5 N. K im u ra. Gann 64:105 (1973). 6 M. N ishizum i. A rch. Environ. Health 21:620 (1970). 7 R. Kim brough. Ibid 25:354 (1972). 8 P rivate communication. 9 R. Kim brough. R. Lin der. J . Nat. Cane. Inst. 3:547 (1974). 10 H. S tew art, K . S p e ll. A cta Unio. Int. C o n tra. C an cru m 13:770 (1957). 11 R. K im brough. A rch . E n viron . H ealth 27:390 (1973). 12 N. Ito. Gann 65:545 (1974). 13 D. N orbeck and J . A lle n . A b stra c t. A m . A s s o c . P ath . 8t B a c t. M arch 4, 1975. 14 S . M ak iu ra. J . N at. C an e . In st. 3,: 1253 (1974). 15 G . M angold. D tsch . M ed. W sch r. J 0 :2 4 l (1975). 16 E P A D ieldrin /A ldrin B r ie f, Sept. 16, 1974. 17 P riv a te com m unication, L . B . T e p p e r, N ov. 28 , 1975. 18 L . R a m se y . FD A O ffic ia ls o f U. S. Q u art. B u ll. 37:157 (1973). 19 F e d . R eg. 39 (203): F r i . , O ct. 18, 1974, p. 37251. NEV 0 1 1 0 9 4 710346