Document 914xRok5YDvqObnEwgaDQJzb5

K TOXICQlOaT (NVIHQNMCNTAi tCItNCKS CMCMiiriT AUNT CIINCCI MKOieAk seiKMcta !}tukAtf/u&L BIO -TEST JtcrfytfjObbyuAb, JJnc. 1810 S*ONTAG8 *OAO NORTH8ROOK. ILLINOIS 60062 March 24, 1975 ** COOK Jil rCLCMONC I7MOJO George J. Levinskas, Ph. D. Monsanto Company 800 N. Lindbergh Blvd. St. Louis, Missouri 63166 Dear Or. Levinskas: . I am enclosing the trip reports prepared by Or. Richter and myself regarding our meeting at N. C. I. on January 31, 1975 with Ors. Kimbrough and Squire on Aroclor 1260 (IBT No. 622-07298). . .. _, . . . ' . *. t The micro-slides of the liver sections from all these animals and' those from Aroclor 1242 and 1254 will be forwarded today, under separate cover. We are also mailing the reports relevant to these studies today. The charges for this additional work will be billed under a new Number (IBT No. 641-06672) instead of the previous number. Sincerely O. . Gordon, D. V. M., Ph. D Section Head, Pathology Dept. DEG:hb Enclosure DEPOSITION } EXHIBIT | /S'! SCM 023632 HARTOLDMON0022694 February 2, 1975 Trip Report On January 31, 1975; Ora. Richter, Levinskas and myaelf met with Drs. Squire and Kimbrough at the National Cancer Inetitute in Bethaeda, Maryland. The purpoae of thia meeting wee to review the slides and data from a 23 month oral feeding atudy with Aroclor 1260 in rata that waa con ducted by Or. Kimbrough while at the E. P.A. In her atudy, 200 female rata (Sherman atrain) were fed 100 ppm of Aroclor 1260 in the diet for 21 months, while 200 female rate of the same atrain served as controls and were fad Purina Rat Chow. The Sherman Rat is a random-bred animal . ' .. ` ,. ***.* . derived from the Osborn Mendel Strain. The animals were 21-26 days of ' age when the atudy began, and were sacrificed after 23 months on the study. Therefore, there was a 2 month recovery period at the end of the atudy in which the teat material waa removed from the diet. The details of the ex perimental design, procedures and results that were forwarded to Or. Lav- inskaa are attached. In summary. Dr. Kimbrough found a rather high inci dence of hyperplastic (nodular hyperplasia) and neoplastic (hepatomas, car cinomas) lesions in the liver of the test animals. The slides were subsequently reviewed by Dr. Robert Squire, Head of the'Tumor Pathology Brlnch of The National Cancer Institute, who concurred with her findings, although, the ' . terminology he used in classification of the lesions varied slightly from Dr. Kimbrough's. In this regard, it was his impression that all hyperplastic nodules should be regarded as "pre-cancerous lesions" and the term "hepatomas" SCH 023633 000CI3 HARTOLDMON0022695 Trip Report 2 bo deleted and re-classified a* carcinomas or naoplaatic nodulaa. Tbia classification system waa baaad on a Liver Tumor Workshop that was held on Dec. 11-13, 1974 in Silver Springs, Maryland which waa attended by a small group of pathologists from the regulatory agencies, research labora tories and Industry. In view of Dr. Kimbrough's findings, additional sections of liver from a 2-Tear Oral Feeding Study With Aroclor 1260,. in rats, conducted at Indus trial Bio-Test were processed and evaluated. In this study, there was a 3, 8 and 14 month interim sacrifice which enabled one to determine the ap proximate time of onset of the liver changes. No interim sacrifices were, conducted in Dr. Kimbrough's study. The additional flides prepared at . . Bio-Test were examined by Dr. Richter and a tabulation of the liver findings are attached. These slides were reviewed by Drs. Kimbrough and Squire at our meeting. Although there was some disagreement on the terminology used in classification of the lesions, it was apparent that the incidence and severity of liver lesions (hyperplasia, nodular hyperplasia and neoplastic changes - carcinomas) was greater in Dr. Kimbrough's study when compared with the results of the Bio-Test Study, even though the same level of test material was administered in the diet. There are two possible explanations for this difference: 1.) The strain of rat. When questioned. Dr. Kimbrough had no informa tion on the spontaneous incidence of hyperplastic or neoplastic liver . lesions in the Sherman strain. However, the incidence of spontaneous liver cell hyperplasia would appear to be extremely low since this finding was reported in only 4 controls. The incidence of liver hyperplasia among control rats of the Bio-Test study was also very low. The Incidence of spontaneous hyperplastic liver nodules reached 20f* in the Fischer Rat 000041 HARTOLDMON0022696 Trip Report 3 and In loma of the other strains. 2.) Sex difference* On the basis of our atudiee and thoae of other in ' read gator a in rata and mice, it waa found that the incidence of hyper* plaatic and neopiaatic liver lealone are much higher in femalee. The reaulta of the liver tumor workahop are to be publiahed in the near future and will include the participante* The viewa of thia group, regarding claaaificatioa of hyperplaatic and neopiaatic liver laaiona is based on the pathogeneaia of auch leaione in rats that have been Induced by known carcinogens auch as the nitroaoaminea and 2. - acetylagdnoflorine (2-AAF). The adaption of this terminology and claaaification ayetem by the scientific community will have wideapread implicationa regarding aaaeaament of aafety of chemicals and drugs currently on teat and thoae previously studied. Attached are Dr. Richter's comments in regard to Dr. Kimbrough's findings. . Donovan E. Gordon, D.V.M. ,Ph. D. DlpL., Am. College Vet. Path. HARTOLDMON0022697 Or. Donovan Gordon Indue trial Bio-Teat Laboratories February 3, 1975 I wish to summarize my observations of the lesions seen in Or. Kimbrough's study of Aroclor 1260 and the comparison of diagnoses with Or. Kimbrough and Dr. Squire. 1. ) The criteria that I used for diagnosis of the lesions are similar to what they used. 2.) My evaluation tends to be a little more conservative than theirs. For example: they ^tould call some of my hepatomas careinoma but with some question. 3.) Therefore, if we both read the same slides there might be a little variation in numbers of lesions in the different categories but no major difference. 4.) Dr. Squire and Or. Kimbrough are using a new and revised terminology for the categories and list them as follows: My Terminology (Classical Use) Dr. Squire's (Revised Terminology) Focal Hypertrophy Cellular Alteration Nodular Hyperplasia! Hepatoma J Nodular Neoplasia or Neoplastic Nodule Carcinoma Carcinoma 5.) However, the lesions in Or. Kimbrough's study were more severe those in the Bio-Test study. The lesions that she and Or. Squire are calling carcinoma are also carcinomas by my criteria. I would HARTOLDMON0022698 conclude from in exunimtioa of their miteriil thit Or. Kimbrough*a tudy demonetrited cireinogenieity. Ward R. Richter, D. V. M. Dipl. Am. College Vet. Pith. SCM 023637 0000-17 HARTOLDMON0022699