Mechanistic investigations of test article-induced pancreatic toxicity at the endocrine-exocrine interface in the rat.
Pancreatic toxicity commonly affects the endocrine or exocrine pancreas. However, it can also occur at the endocrine-exocrine interface (EEI), where the capillary network of the islet merges with the capillaries of the surrounding acinar tissue, that is, the insulo-acinar portal system. The goal of this article is to describe a novel, test article-induced pancreatic toxicity that originated at the EEI and to summarize investigations into the mechanistic basis of the injury. This injury was initially characterized by light microscopy in 7/14 day-toxicity studies in Sprague-Dawley (Crl: CD®[SD]) rats with undisclosed test articles. Microvascular injury at the interface resulted in peri-islet serum exudation, fibrin deposition, hemorrhage, inflammation, and secondary degeneration/necrosis of surrounding exocrine tissue. More chronic injury presented as islet fibrosis and lobular atrophy. Direct cytotoxicity affecting the capillary endothelium at the EEI was confirmed ultrastructurally on day 4. Endothelial microparticle and blood flow studies further confirmed endothelial involvement. Similar lesions occurred less frequently in 2 other rat strains and not in the mouse, dog, or cynomolgus macaque. In summary, in vivo and investigative study data confirmed primary endothelial cytotoxicity in the pathogenesis of this lesion and suggested that the lesion may be rat/rat strain-specific and of uncertain relevance for human safety risk assessment.
1Pfizer, Worldwide Research & Development, Andover, Massachusetts, USA.
Karrie A
KA
Brenneman
Shashi K
SK
Ramaiah
Cynthia M
CM
Rohde
Dean M
DM
Messing
Shawn P
SP
O'Neil
Lauren M
LM
Gauthier
Zachary S
ZS
Stewart
Srinivasa R
SR
Mantena
Kimberly M
KM
Shevlin
Christopher G
CG
Leonard
Sharon A
SA
Sokolowski
Hungyun
H
Lin
Deborah C
DC
Carraher
Michael I
MI
Jesson
Lindsay
L
Tomlinson
Yutian
Y
Zhan
Walter F
WF
Bobrowski
Steven A
SA
Bailey
W Mark
WM
Vogel
Dale L
DL
Morris
Laurence O
LO
Whiteley
John W
JW
Davis
D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006439:Hemodynamics; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology; D007854:Lead / Q000633:toxicity*; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology; D046790:Pancreas, Exocrine / Q000187:drug effects* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology*; D011168:Portal System / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018570:Risk Assessment; D023382:Toxicity Tests, Acute
D007854:Lead
endocrine–exocrine; hemorrhage; interface; microvasculature; pancreas; peri-islet; rat; toxicity