Document wDdQYbQVBDGoYOKBMyZV1zydd

H18636: Slide Review of pancreas lesions from DuPont APFO Study Date of Review: 28thNovember 2001-11-29 Reviewing Pathologists: Dr E E McConnell and Dr J R Foster Study No: HN-18636 Study Title: Combined Chronic Toxitity/Oncogenicity Study with Linuron, C8 and W yl4,643. Conclusion of the review: The overall conclusion o f the review of the two studies was that they were not inconsistent in their findings. The review confirmed the carcinogenic effect of APFO in the DuPont study and the most likely explanation for the lack of an oncogenetic effect o f APFO in the 3M study was considered to be a decreased sensitivity for the development of pancreatic acinar effects, combined with an under-reporting o f the acinar hyperplasia that was present. The DuPont study showed the full spectrum o fAPFO-induced acinar proliferations from hyperplasia through to carcinoma. It should be noted that the comment on under-reporting is not intended as a reflection o f inadequacy in the original interpretation o f the study but merely reflects the fact that knowledge, and discrimination o f these subtle pancreatic lesions, has advanced in the years since the 3M study was reported. A final confirmation of this conclusion awaits a more extensive review of the pancreas slides from the 3M study to be carried out by Dr McConnell. Sum m ary of the review: 1. All o f five neoplastic findings originally diagnosed on the DuPont study were confirmed. 2. Eleven o f the hyperplasias originally diagnosed in group III on the DuPont study were down-graded so as not to be reported as hyperplasia. 3. Two of the hyperplasias originally diagnosed in group I on the DuPont study were down-graded so as not to be reported as hyperplasia. 4. An additional two acinar hyperplasias were diagnosed in group HI during the review process which were not originally diagnosed as such. 5. In spite o f these changes the overall conclusion for the DuPont study remained that APFO in this study had shown a carcinogenic effect for the male rat pancreas. 6. Following a limited combined review by Drs Foster and Frame, o f the pancreas slides from approximately 30 animals (selected by Dr Frame), several acinar hyperplasias were confirmed in the 3M study and although all o f the animals were not reviewed the preliminary conclusion of the limited review was that there did appear to be an APFOinduced increase in acinar hyperplasias on the 3M study. Dr McConnell has been requested to review all of the pancreas' from the 3M study. 1 Introduction: The pathology review of the pancreas' from the two oncogenicity studies conducted in the rat on APFO was initiated because in the 3M study, which was carried out first, the compound was not carcinogenic to the pancreas while in the DuPont study, which was only conducted in the male rat, showed a clear oncogenic effect on the pancreatic acinar cells. The slide review was requested to confirm or refute the findings in the pancreas' from the two studies. Site o f Review: The review took place at DuPont Haskell Laboratories, NewArk, Delaware on 28* November 2001. Those Present: Dr Randy Frame - Study Pathologist, DuPont Haskell Laboratories, Delaware, USA Dr John Hansen - Head o f Pathology, DuPont Haskell Laboratories, Delaware, USA Dr G Kennedy - Head o f Toxicology, DuPont Haskell Laboratories, Delaware, USA. Dr C R Elcombe, Biochemical Toxicologist, Dundee University, UK. Dr John Butenhoff, Toxicologist, 3M, Minnesota, USA Dr John R Foster, Reviewing Paifhologist, AstraZeneca Pharmaceuticals, Cheshire, UK Dr E E McConnell, Reviewing Pathologist, PathLabs, North Carolina, USA Conduct of Review: 1. The STP Guidelines for the diagnosis of Proliferative Lesions of the Exocrine Pancreas (1995) was the basis for the diagnostic criteria used in the review process. 2. Together with Dr Frame, on a two headed microscope, Dr Foster reviewed the pancreas' from approximately 30 animals from the 3M APFO study which included two animals from the control group and the remainder from the top dose group. 3. Dr McConnell was not able to review the 3M study on this occasion but has been given the slides from all o f the animals on this study to review in the near future (report pending). ' 4. For the review o f the DuPont APFO Study the reviewing pathologists (JRF and EEMcC) were given summary tables o f the original diagnoses. 5. Dr McConnell initially reviewed the pancreas slides from only those group HI animals where the presence o f either acinar hyperplasia, adenoma or carcinoma had been recorded. In addition he reviewed the pancreas slides from all of die pair-fed control animals from group II. Pancreas slides from the group I control animals from the DuPont study were not reviewed. 6. Dr Foster then independently reviewed tbe same animals as Dr McConnell from group HI but, in the interests o f time, only reviewed those animals from group II that Dr McConnell had considered showed proliferative lesions and/or those deemed by the study pathologist to have shown lesions from the original report o f the study. 7. The diagnosis from both Drs McConnell and Foster were independently recorded and then ware compared. 8. Any disagreements between the reviewing pathologists were then reviewed together on a two-headed microscope and a consensus agreed in consideration o f both the additional review o f the slides, together with reference to the original diagnosis'. 2 9. Drs McConnell, Foster, Hansen and Frame then met to discuss the findings of the review and were joined later by Drs Elcombe, Butenhoff and Kennedy for a final debrief. 10. It was agreed that Dr Frame would draft a single page report o f the proceedings and circulate it to the attending members for comment after which the reviewing pathologists, and Drs Frame and Hansen would sign file final version as an accurate representation o f the proceedings. 3 Table 1: Summary of JR F's review of the DuPont pancreas slides. EEM cC/JRF Consensus - Adenoma NAD. Adenoma NAD - Agree/ D isagree V V V ... v V V X X V V V -J J X V X V V V J V v- 'J EEMc not reviewed V J EEMc not reviewed EEMc not reviewed EEMc not reviewed EEMc not reviewed An. No R494669 .R494673 R494674 R494675 R494677 R494683 R494685 R494689/4 R494689 R494693 R494702 R494706 R494707 R494711 R494715 R494717 R494719 R494721 R494724 R494725 R494727 R494734R494748 R494754 R494762 R494768 R494773 R494775 R494781 R494790 R494793 R494800 R494803 Review Diagnosis O riginal D iagnosis Adenoma (nuclear atypia Adenoma arising out o f hyperplasia) Hyperplasia Hyperplasia (3) Hyperplasia Hyperplasia (4) Hyperplasia Hyperplasia (1) Adenoma Hyperplasia (2) NAD Hyperplasia (2) Hyperplasia Hyperplasia (2) NAD Eosinophilic focus Hyperplasia (2) Hyperplasia-borderline Adenoma adenoma (multiple) Hyperplasia Hyperplasia (1) Hyperplasia Hyperplasia (3) Basophilic focus Hyperplasia (2) Adenoma (autolysed) Adenoma Adenoma (central autolysis) Adenoma Adenoma (out of Adenoma + hyperplasia);l hyperplasia Hyperplasia (4) Adenoma (solid, no acini) Hyperplasia (4) Basophilic focus Hyperplasia (1) Hyperplasia Hyperplasia (1) Carcinoma Hyperplasia (2) (haemonhage/huclear atypia) + carcinoma Diffuse change Hyperplasia (1) Hyperplasia Hyperplasia (3) Hyperplasia Hyperplasia (2) H yperplasia. . Hyperplasia (2) Adenoma Hyperplasia (3) + Adenoma (multiple) NAD Hyperplasia (2) NAD NAD NAD Basophilic focus Hyperplasia Hyperplasia (1) Hyperplasia (1) Hyperplasia (2) NAD Hyperplasia (1) Hyperplasia Hyperplasia (2) Hyperplasia Hyperplasia (1) 4 Basophilic focus - EEMc not reviewed EEMc not reviewed V X V '</ ' J V R494808 R494811 R494506 R494509 R494513 R494514R494547 R494552 Adenoma _____v _ . V V X J R494611 R494611-2 R494633 R494633-2 R494638 R494638-2 Hyperplasia Hyperplasia NAD Hyperplasia Basophilic focus Hyperplasia H y p o p lasia Basophilic focus . NAD Hyperplasia NAD Basophilic focus; Hyperplasia? NAD Hyperplasia NAD Hyperplasia (2) Hyperplasia (1) Hyperplasia (1) Hyperplasia (1) Hyperplasia (2) Hyperplasia (2) Hyperplasia (1) + basophilic focus Hyperplasia (1) Adenoma Hyperplasia (2) Table 2: Comparison o f incidences o f proliferative lesions in the acinar pancreas between original and review. O riginal Diagnosis Acinar hyperplasia Acinar adenoma Acinar carcinoma T o ta l Group 2 8 1 0 9 Group 3 28 6 1 35 Reviewing Diagnosis Acinar hyperplasia Acinar adenoma Acinar carcinoma T o tal 6 1 0 7 17 8 1. 25 Total animals on study 79 76 J R Foste: 1st December 2001 5