Document gbmL1Bd20daj8xLJZ29RJjqr3

StdKlUal B I O T E S T 2aoAci>'UeSf 9*c. i.h REVIEW OF PCB MEETING The central issue in question is whether the PCB's are carcinogens or not. The long term studies conducted at BIO-TEST indicate that the answer is no. D rs. Ward Richter and Donovan Gordon are of this opinion which is shared by M. L. Keplinger and J. C. Calandra. On the other hand, a study conducted by Dr. Renata Kimbrough presents evidence that in fem ale rats of the Sherman strain, liver carcinom as were found. This is the only study in which this finding is reported in rats. BIO-TEST has no basis for refuting the findings of Kimbrough except to take exception to the design of the experim ent that used only fem ale rats and to point out that to our knowledge no one else has reported sim ilar results in rats. It should be noted that the earlier allegation by Kimbrough that bladder cancers developed in fem ale rats fed PCB was successfully counteracted by BIO-TEST and Monsanto personnel. Kirnura^ worked with K anechlor-400, a com m ercial brand of PCB and in a rat study of 400 days' duration concluded that "PCB's induced a benign neoplastic change, though it seem ed to be still short of m alignancy, and that the change appeared exclusively in the fem ales. The author expressed concern that the benign nodules in the liver may progress to carcinom as if "specific or non-specific stim uli are introduced into the anim al. " NEV 000002 $ndi4iJal B I O - T E S ^ ^ J aluyLoWueS, Hkc. i.Ek -> Ito conducted a study in m ice and found "hyperplastic nodules and well-differentiated hepatocellular carcinomas" at a dose level of 500 ppm of Kanechlor 500. Hepatocellular carcinom as were not in duced by Kanechlor 300 and Kanechlor 400. The evidence to date indicates that m ale rats are m ore resistant than'fem ales to the formation of nodular hyperplasia as w ell as hepato cellular carcinom a. Rats also are m ore resistant to the induction of these lesion s than m ice. To return to the BIO-TEST studies on FOB, it should be noted that the liver sections which were read by the pathologists and reported in IBT No. 641-06672 and dated March 24, 1975, w ere not the same slid es or section s as those reported bn origin ally. The p reserved livers w ere reprocessed by taking 4 "cuts" from different areas to obtain as large a representative sample as possible. It is not surprising that under these circum stances a different tabulation of the various p rim ary liiv e r le sio n s w as found. Studies on thyroid h yp erp lasia and by Richter's associate, Dr. Stanley V esselinovitch, have shown that this procedure generally results in a different qualitative and quantitative line-up of lesions that are reported by the sam e pathologist. Ideally one would like to be able to reaffirm the original findings by this procedure, but this is not always possible because of the additional variables introduced. Serial sections of the liver would NEV 000003 D ttdustiial B I O - T E S ITfe J.alsoMiiyu&i, 9kc. A . va 3 elim inate some of the covariants. The important point in the m ost recent study of the sections is the fact that no hepatocellular carcinom as w ere found which is in agreem ent with the earlier findings. It m ust be em phasized that the diagnosis of "hepatoma" by Gordon and Richter connotes a benign p rocess and m ust not be confused with the cla ssical definition of the term by "human" pathologists. Further, Dr. Squires reviewed a'number of the sam e slides on A roclor 1260 with D rs. Gordon, D evinskas, Kimbrough and Richter and agreed with the BIO-TEST pathologists that liver carcinom as were not present in the slid es. In addition, the original slides have been in the possession of FDA since June, 1973 and to date we have not been informed of any disagreem ent with BIO-TEST findings. Dr. Squires has stated in a letter to Dr. Kimbrough dated N ovem ber 12, 1974, that "I define 'd isc r ete nodules' and .'trabecular (basophilic) hyperplasia' as precancerous lesions and thus indicative of carcinogenic response." This reflects a viewpoint which is not shared by a ll p ath ologists and there is nothing that BIO -TEST can do to change this definition except for its pathologists to accept or reject the view . Drs. Richter and Gordon do not accept Dr. Squire's definition. W orkers in the field have published extensively on the pathogenesis of hepatocellular carcinom a in recent years and the concepts have undergone considerable changes since the preparation NEV 000004 9tuL*ii'uaL B I O - T E 5 &tayueSt 9*vu ,. 4 of the final BIO-TEST report on chronic oral toxicity studies. One m ust note that Popper in his studies on Aram ite in i960 postulated that hyperplastic nodules were transform ed into hepatocellular cancer; however, this concept was not generally accepted by the scientific com m u nity. An excellent paper which describes "the highlights of some new er developm ents in our under standing .of liver carcinogenesis" has been published by Farber. 4 If the concepts presented in this paper as w ell as those of Squires, Saffiotti and others are accepted, a number of substances would have to be reclassified as liver carcinogens. Carried to extrem e, we could argue that any substance that results in stim ulation of liver m icrosom al enzym es or p ossesses hepatocytoxic properties to any degree is a potential liver carcinogen. BIO-TEST is unwilling to accept these concepts. The lesions seen in the livers of the rats in its PCB studies for Monsanto do not show vascular invasion, m etasteses or anaplasia - all classical features of carcinom a. We continue to view the lesions seen to be benign. Several additional things need to be done by BIO-TEST and these include: (a) R e-exam ine the original liv er slid es. (b) Cut new section s at different le v e ls from o rigin al paraffin blocks and read slides. (c) Tabulate liver findings separately in fem ale and m ale rats. (d) If p o ssib le, develop inform ation on the rev ersib ility of the liver changes. NEV 000005 DhJmjMuoI B I O - T E S Dnc. , 5k 3 It is im portant to point out the following: 1. The B IO -TEST position w as and rem ains that the P C B 's w ere not shown to be liv er carcinogens in its studies. This conclusion is the opinion of its resident pathologists as w ell as its independent consultant. 2. The BIO-TEST results show that a no-effect level for the developm ent of hyperplastic nodules was found in each of its studies* 3. BIO-TEST has no m eans at its disposal to dispute the findings of K im brough that A roclor 1260 in fem ale Sherm an rats is a liver carcinogen except on the basis of experim ental design. 4. BIO -TEST is not in agreem en t w ith the classificatio n by Squire* et al. that considers hyperplastic liver nodules to be precancerous. 5. BIO-TEST studies on PC B 's m eet the scientific standards of Toxicology and Pathology and we are prepared to a ssist M onsanto in any adversary situation in or out of governm ent. J. C. Calandra A pril 18, 1975 R eferences 231 KIPtooim,p puNer.ra,,J.HN.N. TaC.t.a nCGcaaennrnc e16r34:I1:1n00s35t5. ((15I9197:61306))3..7 (1973). 4 F arb e r, E. A rch. Path. 98:145 (1974). NEV 000006