Document 2jQRzBGeOVByD1MvgZ7dqEyQ5

. Letter to Dr. Selinkoff: T.ielec(2oppyagtoes: DDrr.. CBraosweny Thank you for the informative meeting and hospitality you extended to Dr, Qfl&iu?w*yk and me last Wednesday. We were most interested in the several potential approaches you outlined for treatment of our PCB exposed employees. On Thursday, March 17, Dr. Bmwii and I had the opportunity to review your preliminary thoughts with our management and they enthusiastically supported the notion of working with you and your associates in this general area.. At this meeting, n presented an overview of data accumulated relative to the toxicity of PCBs. Before finalizing a joint program with Mt. Sinai, Dr. John F. Welch, Vice President and Group Executive of the Components and Materials Group, who has responsibility for the Hudson Falls operation, asked-tiefe n - run > i n , TTj, nin* presentation to you and'your associate^. We want to be sure that any proposed therapeutic methodology be relatable to the overall patterns of PCB accumulation, persistence, and toxicology revealed by the available scientific literature, and to the substantial evidence for large differences in such patterns between PCB specimens that differ in brand, grade ,( i.e ., homolog distribution), or specimen history ( i.e ., impurity levels), In order to explain why we are so concerned about these issu e s, let ame sujmyVmuaaJijiLze-. mCLu*sclhcLta^f Drr^. BBr^rgyyrmnVfs-background information about the nature of the PCB literature, the comparative toxicology of PCB products, the nature of PCB effects on humans, and their Implications regarding the design of therapeutic treatments for persons exposed to capacitor-grade PCBs. (tiChtosronluteignvhueefli.rw"sitthpalraasgtrpaparhagornapphagoen1p0ag"e ..1...."..B.yanedaarulyg,m, .e.n"ting GENP 003260 771425 Casey-Selikoff Letter#. Middle Section DRAFT of 3/21/77 J.F. Brown# Jr. In addition to being concerned about having something available for treatment of FCB-exposed individuals in the event that it should be // / j needed# X'believe it most in^or^ant that have something that /can be rigorously de f e n d e d as the right thing to' use for the particular PCB // / and exposure pattern involved. We cannot ignore the prospect of in tense7public scrutiny of any proposed therapeutic methodology by the press# .the Union, the FDA, and the NYS Health Department. T o be de i `fensible, a p r o p o s e d approach must-be relatable to the overall patterns of PCB accumulation# persistence# and toxicology revealed by the avail/ able'scientific literature# and to the substantial evidence for large differences in such patterns .between PCB specimens that differ in brand# i/ ; gr^de homo^og distribution), or specimen history (i*e.f impurity l e v e l s j ^ I n order to explain why we are so concerned about these issues let mu say a h i U m s m a about the nature of "the PCB 'literature, the comparative toxicology of PCB products, the nature of PCB effects on humans# end their in d i c a t i o n s regarding the design of therapeutic treatments for persons exposed to capacitor-grade PCB's. 1 A y e r a s u r e on PCB Effects^ _ By early 1976# approximately 1500 publications on the chemical# physical# biological; and environmental properties of PCB*a had ap peared in the technical and semi-technical literature* A published bibliography (Quinby, 1972) covered the 670 reports appearing through 1971, and about 600 subsequent titles were listed by the Chemical GENP 003261 771426 A Abstracts and Toxline computerized search services. An excellent reference work on the chemistry of the PCB's was also available (Hutzinger, 1974). Of these 1500 publications, nearly 400 presented some kina of description of biological effects, though not necessarily toxic ef fects. A bibliography listing and classifying such reports appearing through 1975 has bee n p r e p a r e d (Bellamy, I976;j-cupy iiLlSL'liuiI). Sev eral fairly extensive reviews of the biological effects of PCB's have also appeared. Notable are those of Kimbrough (1972, 1974); Fishbein (1974); Feakall (1975) and N i s b e t (1976). ^ X n addition, three signi ficant publications of symposium proceeding.*- '---- ------- ------- -- the December 1971 NIEHS symposium on PCB's April 1973 NIEHS Symposium on chlorinated dinenzoaioxms ana a m e n z o - v furans (NIEHS, 1973); and one on the November 1975 National Conference^ on the PCB's (EPA, 1976). J i An unusual strength of the toxicological literature on PCB's i3 the presence of a large amount of h u man case material. In fact, it is probably safe to say that PCB-related toxicants are one of the few such groups where the effects on humans are better characterized than those on experimental animals. This has resulted largely from the massive and continuing efforts of the Fukuoka group in Japan to analyse the cause and effects of the "Yusho" incident, in w h i c h some 1200 people were poisoned by rice oil that had been contaminated with heat-aged Kanechlor-400 from a leaky heat exchanger. Two excellent English language summaries of the 50-odd Japanese reports on this effort have GENP 003262 771427 -3- appeared; one covering the w o r k through 1971 w as re p o r t e d -aptsat!ie ^ _I371 MTEttfl Oympu j lum (Kuratsune, 1972} ; the s e c o n d , covering the work through 1975# at the 1975 SPA Symposium (Kuratsune# 1976). In ad dition# there are some very significant^ a l b e i t long-overlooked^ observations in the older industrial hygiene literature on the effects of PCB exposure in manufacturing plants. ) A peculiar wea k n e s s of the toxicological lit e r a t u r e on PCB's is the almost universal absence of information on the chemical composi tion of the materials fed to experimental animals# particularly as re gards the content of the highly toxic polychlorinated dibenzofurans CPCDF'a}. Despite the fact that PC2 toxicity in humans was immediately- recognized as impurity-dependent (Jones and A l d e n # 1936) # despite the fact that the agent responsible for the characteristic edema disease teratogenicity in chickens (Vos and Koeman, 1970) and for the characteristic dermal and hepatic effects in rabbits (Vos and Beems, 1971) was identified as PCDF, and despite the p r o m i n e n c e given these latter findings in subsequent symposium reports and review articles (notably, N I E H S # 1972; NIEHS# 1973; and Fishbein 1974)# only one of the many animal toxicity studies (other than V o s 1) re p o r t e d in the 1970-75 period included a determination of the PCDF content of the PCB being used. This one (Ax and Hansen, 1975) showed that even specially- synthesized individual isomers could be c ontaminated with PCDF's, and, in fact, that the o n l y correlations between P CB composition and bio logical effects in chickens that could be drawn were those based on GENP 003263 771428 .1 -4PCDF content. The failure of most of the other experimental toxico logists to analyse their PCB samples has led to a toxicological litera ture characterized by^/^grotesgue^inconsistencies and m u c h discussion of putative correlations between PCB molecular constitution and biological activity that probably have no "basis in f a c t Q To dramatize this point I am reminded that when we were visiting you on the 16 th, y o u p o i n t e d out that polych l o r i n a t e d dibenzodioxins (PCDD's) , w h i c h are known to be very similar to PCDF's in their manner .and degree of toxicity (Kimmig and Schultz, 1957; Bauer, Schultz, and Spiegelburg, 1961) have just been shown to be carcinogenic at the partsper-trillion level. This means that the reported carcinogenicities (at the 100 p p m feeding level) of Aroclors 1254 and 1260 (which contain about, 1 p p m FCDF, see T a b l e IX below) can be fully accounted for on the basis of the PCDF content alone. In fact, at present there does not seem to be any evidence that all the toxic effects associated with chronic feeding of PCB'e to warm-blooded animals cannot be associated to the PCDF impurities rather than to the PCB's themselves. Comparative Toxicology of PCB Products. - Whether or not the implications of the above-mentioned defect in the PCB literature . a- . be quite as dramatic as just p o r t r a y e d ,'the fact remains that different i* v PCB products can differ enormously in both accumulation and\ toxicity. This is not unexpected in view of their marked differences in chemical composition. As you know, the major constituents of the commercial PCB products are complex mixtures of isomers of homologous PCB species representing varying levels of chlorine content. ,The distribution of GENP 003264 771429 if A -5- sucb homologous species (each representing a family of isomers) is shown in the appended Table I From this, one may note, for example, that Aroclor 1016 has essentially no components in common with Aroclor 1260# and typically only 0.05-0*2% of the penta-, hexa-, and hepta- chlorobiphenyls (i.e., the "higher homologs") that make up the great bulk of A roclor 1254. Thus, there is no p a r t icular reason to expect that biological effects exhibited by Aroclor 1254 or 1260 will also be manifest for Aroclor 1016. The minor constituents of the commercial PCB products Include traces of polychlorinated methylbiphenyls# terphenyls# naphthalenes, and dibenzofurans. The available data on the latter are shown in Table II. Evidently, the PCB specimens examined to date have exhibited a >12,000#000-fold range in PCDF content. This PCOF apparently has two sources; first# particularly in the European and Japanese PCS's, there may be several ppm PCOF already in the PCB at the time it leaves the factory; second# PCDF can be generated in PCB by thermal aging in the presence of air, and c onceivably by other forms of aging, as well. The available data on PCB ma c cumulation and persistence (inverse of elimination rate) in m a n y types of organisms, and of toxicity to fish frnir g n m r r M i n n n n t h r f i-- rffir 1,f"TT u r ing. massive bioarmTnnT nfi nnl can be correlated closely with the average degree of chlorination of the PCB. The data on toxicity to warm blooded animals can be no more than roughly correlated with degree of chlorination alone. Thus, Kimbrough and her colleagues have reported that Aroclor 1254 or 1260 in rats could provoke a progression of hepatic GENP 003265 771430 i.r -6changes, beginning with hypertrophy and hyperplasia, and going on to adenofibrosis, neoplastic nodules, and carcinomas, whereas with Aroclor 1016 or 1242 no such changes occurred; however, between the two toxic Aroclors, the activity level appeared slightly greater for 1254 than for 1260. In hopes of better defining the comparative toxicology of different PCB/FCDF compositions, we have drawn together the best estimates of (in mammals) maximum no-effect chronic dosages*that we could extract from the litera ture. These are presented in Table III, This shows that the toxicity probably correlates more closely with the estimated PCDF content than with the degree of chlorination, and at any event, there appears to be a 2000-fold range in the toxicity levels reported to date. Toxic Effects of FCB/PCDF Compositions in Humans. - In humans, FCB/FCDF-containing products induce a characteristic pattern of highly persistent derma], effects (chloracne), sometimes hyperpigmentation (common in the Japanese Yusho eases, where the exposure was by inges tion; rare in the older US and Italian cases, w h e r e it was by vapor contact), general lassitude and discomfort, and a variety of other symptoms (Jones and Alden, 1936; Kuratsune, 1972; Kuratsune, 1976). The characteristic chloracne has now been observed in connection with the 1200 Japanese affected by PCB/FCDF in the 1968 Yusho incident, and perhaps 30?-40 Am e r i c a n and Italian factory w o r k e r s affected in the four previously reported episodes of PCB/FCDF poisoning (Jones and Alden, 1936; Puccinelii, 1954; Hoffman and M e n e g h i n i , 1962; Meigs et al., 1954; Birmingham, 1964). It is a serious and persistent GENP 003266 771431 acneform eruption accompanied by significant histopathological changes in the skin. The pattern pre s e n t e d bears no relationship to that seen in allergic dermatitis. This latter is a mild, transient condition, produced in small m inorities of the population, b y PCB's as well as by many other common materials, including (according to recent news reports) almost all cosmetics on the average drug store shelf. The incidence and persistence of ch lor acne were observed by the Japanese investigators to correlate with, the PCDF contents of the PCB's involved. Thus, chlor&cne was rarely observed among production work ers exposed to Kanechlors containing, presumably, ca. 2-33 ppm PCDF, despite the appearance o h i g h levels of P CB in their blood. (This cor relates with the general U.S. and Italian industrial experience show ing no problems arising from the handling of ordinary Aroclors, pre sumably running 0-2 ppm PCDF*s; all of the reported chloracne cases involved contact with heat-aged or recognizably contaminated PCB's). Likewise, the chloracne and hyperpigmentation produced in the Yusho episode was observed to persist long after the PCB levels in the bodies of the victims had returned to normal ranges. The persistently toxic agents that remained, however, w e r e the P C D F 's, particularly the higher homologs (e.g., the penta- and hexachloro-PCDF's), which were specifically retained in the liver. It is noteworthy that these chronically-accumulated toxic agents could not be formed from a material like Aroclor 1016, which is lacking in penta- and hexachlorobiphenyis. Despite repeated searches, no evidence of liver damage arising from PCB/PCDF poisoning of men or monkeys has ever been reported. GENP 003267 771432 :_r -8This stands in sharp contrast to the human effects of chlorinated naphthalenes (Halowaxes), which produced several episodes of fatal liver disease during the 1930*5 and 1940*6, or the effects of PCB/ PCDF's on other experimental animals. Implications Regarding Design of Therapeutic Treatments. - It seems to me that the above considerations pose three m a i n questions as re gards the development of PCB-antidotes or other therapeutic treatment methodologies. First, there is little evidence thus far of any need for treatment. The epidemiological studies^ have not indicated any PCB-rSlatable chronic disease in the Hudson Falls plant population. The main PCB used since 1971 (Aroclor 1016) has been reported as of only minimal toxicity in animal studies, and that used over the period 1954-71 (Aroclor 1242) as only slightly l e s s i'fnnocuous)i I n addition, all PCB's used for GE capacitor production since the 1930's have been subjected to a fuller's e a rth purif i c a t i o n treatment that w o u l d also remove PCDF's; this is very likely the reason why no chioracne has ever been seen among GE capacitor workers. A t any event, the absence of chioracne, classically the first and most conspicuous symptom of PCB/PCDF poison ing, argues strongly that o t her manifestations of such poisoning will also fail to appear. ___ ___________ Second, it is not y e t obvious which specific ^ p e c i e s) one should o attempt to develop the antidote for, or even how to go about tracking their levels so as to establish the need for such antidotes. Pre sumably, anyone recently exposed to Aroclor 1016 still has traces of a GENP 003268 . 771433 few of its less readily metabolized isomers in his blood and fatty tissues, along with the ubiquitous 1-2 ppm of the Aroclor 1254 type of PCB isomers that everyone else has as well, and all these could be readily analysed and followed over the course of time. However, Kuratsune's findings have shown that such gross FCB levels bear little relationship to the clinical status of the patient; hence there may be little point in either following their progression or in developing antidotes for them* Of greater significance might be data on the PCDF's, or on other toxic FCB impurities, conversion products, or metabolites* These, however, present great problems in measurement because of their extraordinarily low levels. Kuratsune's liver-PCDF data came from massive samples obtained from former Yusho patients at autopsy, and any data on the presumably far lower tissue-PCDF levels in capacitor workers w o u l d undoubtedly also have to be restricted to specimens of that type* Third, it is not yet obvious what sort of therapeutic strategy should be employed to get the PCB/PCDF-associated toxicants out of the body. The PCB's themselves are very similar to fats in their solubility/ adsorption behavior, and appear in the body non-selectively distributed throughout its fatty tissues* Removal by an adsorption or stimulated excretion route would: require massive non-metabolic removal of fat as well. The normal m e c hanism for PCB removal from the body appears to be via microsomal oxidation to soluble metabolites. This could un doubtedly be accelerated by dosage with agents that would stimulate the activities of drug-metabolizing enzymes; however, there are always the risks that (a) this w o u l d also accelerate the formation of GENP 003269 771434 :.r - 10- toxic metabolites , (b) the liver might be d a m aged by the treatment, and (c) that the metab o l i c a l l y - i n e r t PCB isomers being attacked are 0 harmless anyway. Conversely, if it really is the PCDF's, not the PCB's that one may want to get out of the body tissues, then a very different - though possibly simpler - therapeutic strategy may be appropriate* The PCDF's are probably capable of specific binding to certain tissue macromolecules, and their elimination and/or functional suppression may require no more than an identification of the normal biochemical species that w o u l d otherwise be attached to the P CDF (or PCDD??) binding site and augmenting its level. f 1 liupe that this lanytlsy m c i L a l -about the complexities of the i PCB literptpre, comparative toxicology of the PCB's, and the nature of PCB effect/ in hynansjhas n o t^discouraged ydu., or lejd you to suspect that ye ipay be trying to discourage further res e a r c h on/PcB effects // / /' / '' or treatment or PCB exposure. Quite the contrary,*' The same inter disciplinary/ team (under John Brown of our Corporate Research and / /, ' t: / Development' Center) that conducted the literature search and analysis '/ ./ *^ th4at ledi to all the ctoncerns I've just s t a t e d is also available to /: / help you*'work o ut a defensible p r o gram for attacking the PCB/FCDF /j i / treatment problem, and to collaborate as necessary in its implementa- S i ,/ tion. !If y o u ' r e siarious about w a n ting to find o u t w h a t really should r be done for p e o p l e who have ha d p a s t exposures ,to capacitor grade PCB, t/ so are we. I'd s u g g e s t that y o u invite Dr. B r own down for a seminar on GENP 003270 771435 2. Letter to Dr. Selinkoff (continued) I hope 's background information which Thave described in more detail than I originally intended, Is helpful in developing your therapeutic plan. I suggest that it might be helpful if this same inter disciplinary team, lead by Dr. Brown who conducted the search and analysis which 1 have just summarized, could visit with you and your associates to work out a mutually satisfactory research program In this area. After the joint meeting with our research team. Dr. Welch would be most Interested in visiting Mt. Sinai to review a more formal proposal for General Electric sponsored research in this area. I can assure you that he is sincere in his desire to support efforts aimed at a better understanding of this PCB issue and w ill be an enthusiastic supporter of a well thought out proposal on the subject. Again, my thanks for your continuing support. 1 will look forward to your reaction to the thoughts I have outlined in this letter. Very truly yours Dr. T. R. Casey 771436 - I T A BLE I. D I S T RIBUTION O F P C B ' HOMOLOGS IN AROCLORS / Empirical Formula .C. C12H10 C12H9C1 CX2B8C12 CX2H7CI3 C12H6CI4 CX2H5CX5 CI2H4CI6 CI2H3CI7 CI2H2CI8 CI2HCI9 _ _ _ _______________________A r o c l o r Grade 1221 1016 -- u n --------- - r m -- V/ 11 <0.1 51 1 32 20 4 .57 2 21 < 0.5 <ic ND - <0. I e ND ND ND ND -- <0.1 1 16 49 25 8 1 <0.1 ND - <0.1 <0.1 0.5 1 21 48 23 6 ND - im CG (d,a 12 38 41 8 a. Hu t z i n g e r et al., 1974, p. 23 b. N one detected, <0.01% = N D c. Product specification, <0.4% for total of all homologs above C 12H 6C I 4 in degree of chlorination. O b s e r v e d values in 1972-1975 Aroclor 1016 shipments in range 0.05-0.2%. d. O l d e r data, m a y b e less accurate 771437 TABLE II. POLYCK LOKOQID EN 2O FU17AMS (PCDF'fi) l:< PCp-':: Rr i-v::/grade % a History PCDF Content 7',.!f-*r*'iii*** Phono d o r DP-6 Phencclor D P -6 fcO Clophen A-60 Clophen A-60 LO frO Kaneclor 300 Xaneclor 400 Kaneclor 400 Vi V* V Kaneclor 400 va Kaneclor 500 Kaneclor 600 Aroclor 1248 Aroclor 1254 Aroclor 1254 Aroclor 1260 Aroclor 1260 Aroclor 1016 sv SH O HI ^20 - 13.4 0, 5 - 8.4 Unused Unused Used in heat ex changer Ditto, for "Yusho" oil production Unused Unused 1.5 18-33. 300. 5,0001 2 ,0 0 0 . 2.5 2.7 1969 Product. X969 1970 X969 * Lot AK3 2.0 1.7 1.5 1.0 0.8 1972 Product. <o.oox V ... ' * r IViwtG j.T ., V'*'' Vos ot al., 1 9 V; Bowes et a l ., 1975 Kuratsune, 1976 Kuratsune, 1976 Kuratsune, 1975 a Kuratsune, 1976 Kuratsune, 1976 Xuratsune, 1976 Bowes et al., 1975 Bowes et al., 1975 Bowes et al,, 1975 Bowes et al., 1975 Bowes et al., 1975 Bowes et al., 3975 a. Verbal r e p o r t at N a t i o n a l Conference on PCB's, November 19-21, 1975, Chicago, 111., not included in formal pa p e r subsequently published ao nirafauni. 1976. GENP 003272 iLZiooa, CD Test Subject Kur.an Kor.key Monk cy (infant) Mink TV r* -J r+t^*1L. t* 00 m. ; o 3,0 * ABLE m . CALCULATION OF MAXIMUM NO-EFFECT DOSE RATE FOR PCB/PCDF COMPOSITIONS (2) PCB/PCDP Tested 13) Ppm PCDF In PCB (Estimated) CO Major Toxic Effect MPeCfafBxe.(cSitnn),popf-omod bkInogdt.afyokoewCdOtr/.k-adgtae. y# mNdbMoogodsa.-Peyx(eViCmflr)fBiuaet/m.ctk-etgd..a y Kaneclor-400 I0,000a Dermal ( 0 .5 g .)c {`VIOOQ day)* A-o.007 (heat aged) . Aroclor-1243 1*1 Dermal . <2.5d 0.04 <0.1 (shelf aged) Aroclor-1243 * ^lb Dermal >300; 0.04 > 1/2.' Arcclcr-1254 ^0 Hepatic <0.6* Q-05 <0.03 (metabolized) Aroclor-1254 Aroclor-1260 Aroclor-1254 Aroclcr-1242 :.b ^1 _ _b * lb n .H e p a t i c u * ii <5. 5 <>M1100O00.., h 1 ii * 0 .1II10 3 <0.25 ^<> 330 ... 3 Aroclor-1260 Arcclcr-1254 Aroclcr-1242 Aroclcr-1016 a i o 1M b Vib Hepatic] aim " ") ob ii ilOO^ 0.05 0.5 it a<5. a. K u r a t s u n s # 1976. b* Bowes e t al., 1975. c. K u r a t s u n e , 1972. cl. B a r s o t t l e t al., 1975. e. Acrahar.son and A l l e n , 1973. f. P l a t a n o w a n d K a r s t c d 1973. g. R i n g e r et al.,1972, h. Ksplinge: e t al., 1971? C & l a n d r a , 1975? as i n t e r p r e t e d b y FDA, 1973. i, K e p l i n g e r et al., 1971; C a l a n d r a , 1975; Kir.ibrcugh et al., 1972? as i n t e r p r e t e d b y F D A 1973. j. B u r s c et al., 1974. k. A s s u m p t i o n of FDA, 1373. ns. A x and Hansen, 1975. n. E s t i m a t e d from p r o g r e s s i v e i n c r e a s e s i n t o x i c i t y o b s e r v e d in going from early to late (Ref,a) tests, o. Estimated from use of liver, known to concentrate r c o ? relative to P C S {Re:!.a) as m i n k food. k This figure is the naxi-um no-effect dose in grams of PCB. i* - - This is FDA's assumption of number of days over which dose is accumulated by humans. :J G E KERAL<&$ ELECTRIC CGrtPOaATt RESEARCH AND DEVELOPMENT SCHENECTAOY, p, N. o. Y. b1o33x01a D IA L COMM 8 *235- Building -K-l, Room 3B35 March 21, 1977 J.r. W e l c h , J r Vice President and Group Executive Components and Materials Group 1 Plastics Avenue Pittsfield, Mass. Subject: Proposed Middle Section of Letter from , Casey to Selikoff Regarding Proposed R&D on PCB Antidotes Dear Jack, The attached represents the technical draft that you re quested on March 17. Even after someone shrinks it down to single spacing it will still be a bit longer than you originally asked for; however, I think it may represent the level of detail needed to get our point across to Selikoff. I've also rushed the schedule a bit in hopes of hand delivery this afternoon. Let me know if a revision is needed. Sincerely cc: TR Casey, M.D., Fairfield (t draft and attach.) M Avon LS Moody AM Bueche John F Brown, Jr. Mgr. - Life Sciences Branch PHYSICAL CHEMISTRY LABORATORY PLAINTIFF'S EXHIBIT GENP 003259 771424