Document ZmOOQa8QaV7a4ByzgLeQ5xE0

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 Tide: Combined Chronic Toxicity/Oncogenicity Study with Linur-on, C8 and Wyl4,643. Conclusion of the review: The overall conclusion of 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 of APFO in the 3M study was considered to be a decreased sensitivity for the development of pancreatic acinar effects, combined with an under-reporting of the acinar hyperplasia that was present. The DuPont study showed the full spectrum of APFO-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 of the study but merely reflects the fact that knowledge, and discrimination of 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. Summary of the review: 1. All o f the 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 he 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 El during the review process which were not originally diagnosed as such. '5. In spite o f these changes th 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, of the pancreas slides from approximately 30 animals (selected by Dr Frame), several acinar hyperplasias were confirmed in the 3M study and although all of 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 of Review: The review took place at DuPont Haskell Laboratories, NewArk, Delaware on 28tlLNovember 2001. Those Present: - Dr Randy Frame - Study Pathologist, DuPont Haskell Laboratories, Delaware, USA Dr John Hansen - Head of Pathology, DuPont Haskell Laboratories. Delaware, USA Dr G K ennedy-Head of Toxicology, DuPont Haskell Laboratories. Delaware, USA. Dr C R Elcom.be, Biochemical Toxicologist, Dundee University, UK. Dr John Butenhoff, Toxicologist, 3M, Minnesota, USA Dr John R Foster, Reviewing Pathologist, 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 die 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 of the original diagnoses. 5. Dr McConnell initially reviewed the pancreas slides from only those group HI animals where the presence of either acinar hyperplasia, adenoma, or carcinoma had been recorded. In addition he reviewed the pancreas slides from all of the 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 the same animals as Dr McConnell from group HI hut, in fee 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 were compared. 8. Any disagreements between the reviewing pathologists were then reviewed together on a two-headed microscope and a consensus agreed in consideration of both the additional review of 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 of the proceedings and circulate it to the attending members for comment after which the reviewing pathologists, and Drs Frame and Hansen would sign the final version as an accurate representation of the proceedings. 3 12 Table 1: Summary of JRF's review of the DuPont pancreas slides. EEMcC/JRF Consensus - Adenoma NAD. Adenoma NAD - Agree/ Disagree V An. No R49469 J j- .... V .. v . J X R494673 R494674 R494675 R494677 R494683 R494685 R494689/4 R494689 R494693 X R494702 J ' R494706 R494707 J R494711 J R494715 V R494717 X R494719 V R494721 X R494724 V R494725 J R494727 V R494734- J R494748 J R494754 v R494762 'J EEMc not reviewed V V EEMc not reviewed EEMc not reviewed EEMc not reviewed EEMc not reviewed R494768 R494773 R494775 R494781 R494790 R494793 R494800 R494803 Review Diagnosis Original Diagnosis 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) (haemorrhage/nuclear atypia) + carcinoma Diffuse change Hyperplasia (1) Hyperplasia Hyperplasia (3) Hyperplasia Hyperplasia (2) Hyperplasia. 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) Hypoplasia Hyperplasia (1) 4 /3 Basophilic focus EEMc not reviewed EEMc not reviewed J X J J J V R494808 R494811 R494506 R494509 R494513 R494514-.. R494547 R494552 Adenoma J R494611 J R494611-2 J R494633 X R494633-2 J R494638 J R494638-2 Hyperplasia Hyperplasia NAD Hyperplasia Basophilic focus' Hyperplasia Hyperplasia 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 of proliferative lesions in the acinar pancreas between original and review. Original Diagnosis Acinar hyperplasia Acinar adenoma Acinar carcinoma Total Group 2 8 1 0 9 Group 3 28 6 1 35 Reviewing Diagnosis Acinar hyperplasia Acinar adenoma Acinar carcinoma Total 6 1 0 7 17 8 1. 25 Total animals on study 79 76 J R Foster 1st December 2001 5 //