Pathology of the Gastrointestinal Tract and Exocrine Pancreas

  • Mark J. Hoenerhoff
  • Arun Kumar R. PandiriEmail author


Xenobiotic-induced adverse effects in the alimentary system can result in a significant liability in drug development as well as after environmental exposures. Many of these adverse effects are manifested as functional disturbances such as nausea and diarrhea, but with increased exposures (dose or time), there can be morphological changes resulting in various nonneoplastic and neoplastic conditions. As the first site of exposure to ingested substances, the alimentary system serves as the first line of defense against xenobiotic exposure, and the target organs of injury or carcinogenesis depend not only on the xenobiotic but also on the animal model being used. Significant species differences in anatomy and physiology require an understanding of how these differences relate to human health risk, as well as to appropriate model selection for preclinical or hazard identification studies. This chapter will focus on the functional anatomy and physiology, background, and species-specific pathology of various species used in preclinical studies. In addition, various background and test article-related lesions in various organs in the alimentary system such as the oral cavity, salivary glands, esophagus, stomach, small and large intestine, and exocrine pancreas will be discussed. Additionally, discussion of various animal models used to study test article-related effects and recapitulate gastrointestinal disease in humans will be reviewed.

Key words

Alimentary Pathology Toxicology Gastrointestinal Oral cavity Salivary gland Esophagus Stomach Small intestine Large intestine Exocrine pancreas Animal models 


  1. Afonso-Pereira F, Dou L, Trenfield SJ, Madla CM, Murdan S, Sousa J, Veiga F, Basit AW (2018) Sex differences in the gastrointestinal tract of rats and the implications for oral drug delivery. Eur J Pharm Sci 115:339–344PubMedCrossRefGoogle Scholar
  2. Al-Saffar A, Nogueira da Costa A, Delaunois A, Leishman DJ, Marks L, Rosseels ML, Valentin JP (2015) Gastrointestinal safety pharmacology in drug discovery and development. Handb Exp Pharmacol 229:291–321PubMedCrossRefGoogle Scholar
  3. Anonymous (2012) ICH harmonized tripartite guideline: safety pharmacology studies for human pharmaceuticals S7A.
  4. Aps JK, Martens LC (2005) Review: the physiology of saliva and transfer of drugs into saliva. Forensic Sci Int 150:119–131PubMedCrossRefGoogle Scholar
  5. Arany S, Benoit DS, Dewhurst S, Ovitt CE (2013) Nanoparticle-mediated gene silencing confers radioprotection to salivary glands in vivo. Mol Ther 21:1182–1194PubMedPubMedCentralCrossRefGoogle Scholar
  6. Bertaccini G, Coruzzi G, Poli E (1991) Review article: the histamine H3-receptor: a novel prejunctional receptor regulating gastrointestinal function. Aliment Pharmacol Ther 5:585–591PubMedCrossRefGoogle Scholar
  7. Bertram TA, Ludlow JW, Basu J, Muthupalani S (2013) Digestive tract. In: Haschek WM, Rousseaux CG, Wallig MA (eds) Haschek and Rousseaux’s handbook of toxicologic pathology, vol 3. Academic Press, New York, pp 2277–2359CrossRefGoogle Scholar
  8. Betton GR, Dormer CS, Wells T, Pert P, Price CA, Buckley P (1988) Gastric ECL-cell hyperplasia and carcinoids in rodents following chronic administration of H2-antagonists SK&F 93479 and oxmetidine and omeprazole. Toxicol Pathol 16:288–298PubMedCrossRefGoogle Scholar
  9. Bhaskaran M, Cornwell PD, Sorden SD, Elwell MR, Russell NR, Pritt ML, Vahle JL (2018) Pancreatic effects of a Bruton’s tyrosine kinase small-molecule inhibitor in rats are strain-dependent. Toxicol Pathol 46:460–472PubMedCrossRefGoogle Scholar
  10. Blom H (1986) Alterations in gastric mucosal morphology induced by long-term treatment with omeprazole in rats. Digestion 35 Suppl 1:98–105PubMedCrossRefGoogle Scholar
  11. Bockman DE, Guo J, Buchler P, Muller MW, Bergmann F, Friess H (2003) Origin and development of the precursor lesions in experimental pancreatic cancer in rats. Lab Investig 83:853–859PubMedCrossRefGoogle Scholar
  12. Bode G, Clausing P, Gervais F, Loegsted J, Luft J, Nogues V, Sims J, Steering Group of the RETHINK Project (2010) The utility of the minipig as an animal model in regulatory toxicology. J Pharmacol Toxicol Methods 62:196–220PubMedCrossRefPubMedCentralGoogle Scholar
  13. Boorman GA, Banas DA, Eustis SL, Haseman JK (1987) Proliferative exocrine pancreatic lesions in rats. The effect of sample size on the incidence of lesions. Toxicol Pathol 15:451–456PubMedCrossRefGoogle Scholar
  14. Booth WD, Hay MF, Dott HM (1973) Sexual dimorphism in the submaxillary gland of the pig. J Reprod Fertil 33:163–166PubMedCrossRefGoogle Scholar
  15. Botts S, Leininger JR (2018) Salivary glands. In: Boorman GA (ed) Boorman’s pathology of the rat. Academic Press, London/San Diego, pp 23–34CrossRefGoogle Scholar
  16. Botts S, Jokinen M, Gaillard ET, Elwell MR, Mann PC (1999) Salivary, Harderian, and lacrimal glands. In: Maronpot RR (ed) Pathology of the mouse. Cache Valley Press, St. Louis, pp 49–79Google Scholar
  17. Breider MA, Bleavins MR, Reindel JF, Gough AW, de la Iglesia FA (1996) Cellular hyperplasia in rats following continuous intravenous infusion of recombinant human epidermal growth factor. Vet Pathol 33:184–194PubMedCrossRefGoogle Scholar
  18. Brenneman KA, Ramaiah SK, Rohde CM, Messing DM, O’Neil SP, Gauthier LM, Stewart ZS, Mantena SR, Shevlin KM, Leonard CG, Sokolowski SA, Lin H, Carraher DC, Jesson MI, Tomlinson L, Zhan Y, Bobrowski WF, Bailey SA, Vogel WM, Morris DL, Whiteley LO, Davis JW 2nd. (2014) Mechanistic investigations of test article-induced pancreatic toxicity at the endocrine-exocrine interface in the rat. Toxicol Pathol 42:229–242PubMedCrossRefGoogle Scholar
  19. Brenner GM, Stanton HC (1970) Adrenergic mechanism responsible for submandibular salivary glandular hypertrophy in the rat. J Pharmacol Exp Ther 173:166–175PubMedGoogle Scholar
  20. Britton RA, Young VB (2014) Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology 146:1547–1553PubMedPubMedCentralCrossRefGoogle Scholar
  21. Burger GT, Frith CH, Townsend JW (1985) Myoepithelioma, salivary glands, mouse. In: Jones TC, Mohr U, Hunt RD (eds) Digestive system. Monographs on pathology of laboratory animals. Springer-Verlag, Berlin, pp 185–189Google Scholar
  22. Cattley RC, Popp JA, Vonderfecht SL (2019) Liver, gall bladder, and exocrine pancreas. In: Sahota PS et al (eds) Toxicologic pathology nonclinical safety assessment. CRC Press, Boca Raton, pp 451–484Google Scholar
  23. Caverly Rae JM, Frame SR, Kennedy GL, Butenhoff JL, Chang SC (2014) Pathology review of proliferative lesions of the exocrine pancreas in two chronic feeding studies in rats with ammonium perfluorooctanoate. Toxicol Rep 1:85–91PubMedPubMedCentralCrossRefGoogle Scholar
  24. Chadwick KD, Fletcher AM, Parrula MC, Bonner-Weir S, Mangipudy RS, Janovitz E, Graziano MJ, Roy D, Reilly TP (2014) Occurrence of spontaneous pancreatic lesions in normal and diabetic rats: a potential confounding factor in the nonclinical assessment of GLP-1-based therapies. Diabetes 63:1303–1314PubMedCrossRefGoogle Scholar
  25. Chamanza R, Marxfeld HA, Blanco AI, Naylor SW, Bradley AE (2010) Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity studies. Toxicol Pathol 38:642–657PubMedCrossRefGoogle Scholar
  26. Chandra SA, Nolan MW, Malarkey DE (2010) Chemical carcinogenesis of the gastrointestinal tract in rodents: an overview with emphasis on NTP carcinogenesis bioassays. Toxicol Pathol 38:188–197PubMedCrossRefGoogle Scholar
  27. Cheville NF (1979) Uremic gastropathy in the dog. Vet Pathol 16:292–309PubMedCrossRefGoogle Scholar
  28. Chiu T, Chen HC (1986) Spontaneous basophilic hypertrophic foci of the parotid glands in rats and mice. Vet Pathol 23:606–609PubMedCrossRefGoogle Scholar
  29. Creutzfeldt W, Stockmann F, Conlon JM, Folsch UR, Bonatz G, Wulfrath M (1986) Effect of short- and long-term feeding of omeprazole on rat gastric endocrine cells. Digestion 35 Suppl 1:84–97PubMedCrossRefGoogle Scholar
  30. Dalziel JE, Young W, Bercik P, Spencer NJ, Ryan LJ, Dunstan KE, Lloyd-West CM, Gopal PK, Haggarty NW, Roy NC (2016) Tracking gastrointestinal transit of solids in aged rats as pharmacological models of chronic dysmotility. Neurogastroenterol Motil 28:1241–1251PubMedCrossRefGoogle Scholar
  31. Dardick I, Jeans MT, Sinnott NM, Wittkuhn JF, Kahn HJ, Baumal R (1985) Salivary gland components involved in the formation of squamous metaplasia. Am J Pathol 119:33–43PubMedPubMedCentralGoogle Scholar
  32. de Rijk EP, Ravesloot WT, Hafmans TG, van Esch E (2003) Multifocal ductal cell hyperplasia in the submandibular salivary glands of Wistar rats chronically treated with a novel steroidal compound. Toxicol Pathol 31:1–9PubMedCrossRefGoogle Scholar
  33. Denny PC, Ball WD, Redman RS (1997) Salivary glands: a paradigm for diversity of gland development. Crit Rev Oral Biol Med 8:51–75PubMedCrossRefGoogle Scholar
  34. Dethloff LA, Robertson DG, Tierney BM, Breider MA, Bestervelt LL (1997) Gastric gland degeneration induced in monkeys by the CCK-B/gastrin receptor antagonist CI-988. Toxicol Pathol 25:441–448PubMedCrossRefGoogle Scholar
  35. Dincer Z, Jones S, Haworth R (2006) Preclinical safety assessment of a DNA vaccine using particle-mediated epidermal delivery in domestic pig, minipig and mouse. Exp Toxicol Pathol 57:351–357PubMedCrossRefGoogle Scholar
  36. do Nascimento A, Barreto Rde C, Bozzo L, de Almeida OP (1985) Interaction of phenytoin and inflammation induces gingival overgrowth in rats. J Periodontal Res 20:386–391PubMedCrossRefGoogle Scholar
  37. Dominick MA, Bobrowski WF, Metz AL (1990) Proliferative exocrine pancreatic lesions in aged Wistar rats. Toxicol Pathol 18:423–426PubMedCrossRefGoogle Scholar
  38. Dressman JB (1986) Comparison of canine and human gastrointestinal physiology. Pharm Res 3:123–131PubMedCrossRefGoogle Scholar
  39. Duarte-Vogel SM, Lawson GW (2011) Association between hair-induced oronasal inflammation and ulcerative dermatitis in C57BL/6 mice. Comp Med 61:13–19PubMedPubMedCentralGoogle Scholar
  40. Elmore SA (2006) Enhanced histopathology of mucosa-associated lymphoid tissue. Toxicol Pathol 34:687–696PubMedPubMedCentralCrossRefGoogle Scholar
  41. EPA (2005) Guidelines for carcinogen risk assessment, 40CFR part 261. US Government Printing Office, Washington, DCGoogle Scholar
  42. Esposito I, Konukiewitz B, Schlitter AM, Kloppel G (2014) Pathology of pancreatic ductal adenocarcinoma: facts, challenges and future developments. World J Gastroenterol 20:13833–13841PubMedPubMedCentralCrossRefGoogle Scholar
  43. Frith CH, Heath JE (1994) Tumours of the salivary gland. In: Turusov VS, Mohr U (eds) Pathology of tumours in laboratory animals, vol 2. IARC Scientific Publications, Lyon, pp 115–139Google Scholar
  44. Frith CH, Townsend JW (1985) Histology and ultrastructure, salivary gland, mouse. In: Jones TC, Mohr U, Hunt RD (eds) Digestive system. Monographs on pathology of laboratory animals. Springer-Verlag, Berlin, pp 177–184Google Scholar
  45. Fujimiya M, Ataka K, Asakawa A, Chen CY, Kato I, Inui A (2012) Regulation of gastroduodenal motility: acyl ghrelin, des-acyl ghrelin and obestatin and hypothalamic peptides. Digestion 85:90–94PubMedCrossRefGoogle Scholar
  46. Furness JB, Poole DP (2012) Nonruminant nutrition symposium: involvement of gut neural and endocrine systems in pathological disorders of the digestive tract. J Anim Sci 90:1203–1212PubMedCrossRefGoogle Scholar
  47. Gelberg HB (2014) Comparative anatomy, physiology, and mechanisms of disease production of the esophagus, stomach, and small intestine. Toxicol Pathol 42:54–66PubMedCrossRefGoogle Scholar
  48. Gold LS, Slone TH, Stern BR, Bernstein L (1993) Comparison of target organs of carcinogenicity for mutagenic and non-mutagenic chemicals. Mutat Res 286:75–100PubMedCrossRefGoogle Scholar
  49. Gold LS, Manley NB, Slone TH, Ward JM (2001) Compendium of chemical carcinogens by target organ: results of chronic bioassays in rats, mice, hamsters, dogs, and monkeys. Toxicol Pathol 29:639–652PubMedCrossRefGoogle Scholar
  50. Gopinath C, Prentise EE, Lewis DJ (1987) Atlas of experimental toxicologic pathology. In: Gresham GA (ed) Current histopathology. MPT Press, Lancaster, p 64Google Scholar
  51. Greaves P (2012) Histopathology of preclinical studies. Interpretation and relevance in drug safety evaluation. Elsevier, AmsterdamGoogle Scholar
  52. Hai B, Yang Z, Shangguan L, Zhao Y, Boyer A, Liu F (2012) Concurrent transient activation of Wnt/beta-catenin pathway prevents radiation damage to salivary glands. Int J Radiat Oncol Biol Phys 83:e109–e116PubMedPubMedCentralCrossRefGoogle Scholar
  53. Havu N (1986) Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion 35 Suppl 1:42–55PubMedCrossRefGoogle Scholar
  54. Hayakawa Y, Fox JG, Gonda T, Worthley DL, Muthupalani S, Wang TC (2013) Mouse models of gastric cancer. Cancers (Basel) 5:92–130PubMedCentralCrossRefPubMedGoogle Scholar
  55. Hirth RS, Evans LD, Buroker RA, Oleson FB (1988) Gastric enterochromaffin-like cell hyperplasia and neoplasia in the rat: an indirect effect of the histamine H2-receptor antagonist, BL-6341. Toxicol Pathol 16:273–287PubMedCrossRefGoogle Scholar
  56. Horn CC, Kimball BA, Wang H, Kaus J, Dienel S, Nagy A, Gathright GR, Yates BJ, Andrews PL (2013) Why can’t rodents vomit? A comparative behavioral, anatomical, and physiological study. PLoS One 8:e60537PubMedPubMedCentralCrossRefGoogle Scholar
  57. Igarashi T, Nakane S, Kitagawa T (1995) Predictability of clinical adverse reactions of drugs by general pharmacology studies. J Toxicol Sci 20:77–92PubMedCrossRefGoogle Scholar
  58. Kanda N, Seno H, Kawada M, Sawabu T, Uenoyoma Y, Nakajima T, Konda Y, Fukui H, Takeuchi T, Chiba T (2006) Involvement of cyclooxygenase-2 in gastric mucosal hypertrophy in gastrin transgenic mice. Am J Physiol Gastrointest Liver Physiol 290:G519–G527PubMedCrossRefGoogle Scholar
  59. Kararli TT (1995) Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm Drug Dispos 16:351–380CrossRefGoogle Scholar
  60. Kinoshita H, Abe J, Akadegawa K, Yurino H, Uchida T, Ikeda S, Matsushima K, Ishikawa S (2006) Breakdown of mucosal immunity in gut by 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD). Environ Health Prev Med 11:256–263PubMedPubMedCentralCrossRefGoogle Scholar
  61. Klein-Szanto AJ, Martin D, Sega M (1982) Hyperkeratinization and hyperplasia of the forestomach epithelium in vitamin A deficient rats. Virchows Arch B Cell Pathol Incl Mol Pathol 40:387–394PubMedCrossRefGoogle Scholar
  62. Kostic AD, Xavier RJ, Gevers D (2014) The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146:1489–1499PubMedPubMedCentralCrossRefGoogle Scholar
  63. Kramer AW Jr, Dougherty WJ, Belson AR, Iatropoulos MJ (1985) Morphologic changes in the gastric mucosa of rats and dogs treated with an analog of prostaglandin E1. Toxicol Pathol 13:26–35PubMedCrossRefGoogle Scholar
  64. Latimer KS, Rakich PM, Purswell BJ, Kircher IM (1986) Effects of cyclosporin A administration in cats. Vet Immunol Immunopathol 11:161–173PubMedCrossRefGoogle Scholar
  65. Leininger JR, Schutten M (2018) Oral cavity, teeth, and gingiva. In: Boorman GA (ed) Boorman’s pathology of the rat. Academic Press, London/San Diego, pp 15–21CrossRefGoogle Scholar
  66. Leininger JR, McDonald MM, Abbott DP (1990) Hepatocytes in the mouse stomach. Toxicol Pathol 18:678–686PubMedCrossRefGoogle Scholar
  67. Leininger JR, Jokinen MP, Dangler CA, Whiteley LO (1999) Oral cavity, esophagus and stomach. In: Maronpot RR (ed) Pathology of the mouse. Cache River Press, St. Louis, pp 29–48Google Scholar
  68. Logsdon CD, Lu W (2016) The significance of Ras activity in pancreatic cancer initiation. Int J Biol Sci 12:338–346PubMedPubMedCentralCrossRefGoogle Scholar
  69. Lowenstine LJ (2003) A primer of primate pathology: lesions and nonlesions. Toxicol Pathol 31 Suppl:92–102PubMedGoogle Scholar
  70. MacDonald JS, Scribner HE (1999) The maximum tolerated dose and secondary mechanisms of carcinogenesis. In: Kitchin K (ed) Carcinogenicity: testing, predicting, and interpreting chemical effects. Marcel Dekker, New York, pp 125–144Google Scholar
  71. Maekawa A, Enomoto M, Hirouchi Y, Yamakawa S (1996) Changes in the upper digestive tract and stomach. In: Mohr U, Dungworth DL, Capen CC, Carlton WW, Sundberg JP, Ward JM (eds) Pathobiology of the aging mouse, vol 2. ILSI Press, Washington, DC, pp 267–286Google Scholar
  72. Marks L, Beard E, Cobey D, Moore N, Motyer V, Valentin JP, Ewart L (2013) An evaluation of the non-invasive faecal pellet assessment method as an early drug discovery screen for gastrointestinal liability. J Pharmacol Toxicol Methods 68:123–136PubMedCrossRefGoogle Scholar
  73. Matsuzaki J, Suzuki H, Minegishi Y, Sugai E, Tsugawa H, Yasui M, Hibi T (2010) Acid suppression by proton pump inhibitors enhances aquaporin-4 and KCNQ1 expression in gastric fundic parietal cells in mouse. Dig Dis Sci 55:3339–3348PubMedCrossRefGoogle Scholar
  74. Mazzacca G, Cascione F, Budillon G, D’Agostino L, Cimino L, Femiano C (1978) Parietal cell hyperplasia induced by long-term administration of antacids to rats. Gut 19:798–801PubMedPubMedCentralCrossRefGoogle Scholar
  75. McInnes EF (2012) Background lesions in laboratory animals: a color atlas. Elsevier, EdinburghGoogle Scholar
  76. McQuade RM, Stojanovska V, Donald E, Abalo R, Bornstein JC, Nurgali K (2016) Gastrointestinal dysfunction and enteric neurotoxicity following treatment with anticancer chemotherapeutic agent 5-fluorouracil. Neurogastroenterol Motil 28:1861–1875PubMedCrossRefGoogle Scholar
  77. Merchant HA, McConnell EL, Liu F, Ramaswamy C, Kulkarni RP, Basit AW, Murdan S (2011) Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug development. Eur J Pharm Sci 42:3–10PubMedCrossRefGoogle Scholar
  78. Merchant HA, Rabbie SC, Varum FJ, Afonso-Pereira F, Basit AW (2014) Influence of ageing on the gastrointestinal environment of the rat and its implications for drug delivery. Eur J Pharm Sci 62:76–85PubMedCrossRefGoogle Scholar
  79. Miller H, Zhang J, Kuolee R, Patel GB, Chen W (2007) Intestinal M cells: the fallible sentinels? World J Gastroenterol 13:1477–1486PubMedPubMedCentralCrossRefGoogle Scholar
  80. Nolte T, Brander-Weber P, Dangler C, Deschl U, Elwell MR, Greaves P, Hailey R, Leach MW, Pandiri AR, Rogers A, Shackelford CC, Spencer A, Tanaka T, Ward JM (2016) Nonproliferative and proliferative lesions of the gastrointestinal tract, pancreas and salivary glands of the rat and mouse. J Toxicol Pathol 29:1S–125SPubMedPubMedCentralCrossRefGoogle Scholar
  81. NTP (2000) NTP toxicology and carcinogenesis studies of methyleugenol (CAS NO. 93-15-2) in F344/N rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Rep Ser 491:1–412Google Scholar
  82. Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, Van Deun K, Smith P, Berger B, Heller A (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32:56–67PubMedCrossRefPubMedCentralGoogle Scholar
  83. Opoka W, Adamek D, Plonka M, Reczynski W, Bas B, Drozdowicz D, Jagielski P, Sliwowski Z, Adamski P, Brzozowski T (2010) Importance of luminal and mucosal zinc in the mechanism of experimental gastric ulcer healing. J Physiol Pharmacol 61:581–591PubMedGoogle Scholar
  84. Pandiri AR (2014) Overview of exocrine pancreatic pathobiology. Toxicol Pathol 42:207–216PubMedCrossRefGoogle Scholar
  85. Poh AR, O’Donoghue RJ, Ernst M, Putoczki TL (2016) Mouse models for gastric cancer: matching models to biological questions. J Gastroenterol Hepatol 31:1257–1272PubMedPubMedCentralCrossRefGoogle Scholar
  86. Proctor DM, Gatto NM, Hong SJ, Allamneni KP (2007) Mode-of-action framework for evaluating the relevance of rodent forestomach tumors in cancer risk assessment. Toxicol Sci 98:313–326PubMedCrossRefGoogle Scholar
  87. Qiu W, Su GH (2013) Challenges and advances in mouse modeling for human pancreatic tumorigenesis and metastasis. Cancer Metastasis Rev 32:83–107PubMedCrossRefGoogle Scholar
  88. Raffa RB, Mathiasen JR, Jacoby HI (1987) Colonic bead expulsion time in normal and mu-opioid receptor deficient (CXBK) mice following central (ICV) administration of mu- and delta-opioid agonists. Life Sci 41:2229–2234PubMedCrossRefGoogle Scholar
  89. Randelia HP, Lalitha VS (1988) Megaoesophagus in ICRC mice. Lab Anim 22:23–26PubMedCrossRefGoogle Scholar
  90. Reindel JF, Pilcher GD, Gough AW, Haskins JR, de la Iglesia FA (1996) Recombinant human epidermal growth factor1-48-induced structural changes in the digestive tract of cynomolgus monkeys (Macaca fascicularis). Toxicol Pathol 24:669–680PubMedCrossRefGoogle Scholar
  91. Reindel JF, Gough AW, Pilcher GD, Bobrowski WF, Sobocinski GP, de la Iglesia FA (2001) Systemic proliferative changes and clinical signs in cynomolgus monkeys administered a recombinant derivative of human epidermal growth factor. Toxicol Pathol 29:159–173PubMedCrossRefGoogle Scholar
  92. Ruehl-Fehlert C, Kittel B, Morawietz G, Deslex P, Keenan C, Mahrt CR, Nolte T, Robinson M, Stuart BP, Deschl U, RITA Group, NACAD Group (2003) Revised guides for organ sampling and trimming in rats and mice--part 1. Exp Toxicol Pathol 55:91–106PubMedCrossRefGoogle Scholar
  93. Savage NW, Barber MT, Adkins KF (1986) Pigmentary changes in rat oral mucosa following antimalarial therapy. J Oral Pathol 15:468–471PubMedCrossRefGoogle Scholar
  94. Scarpelli DG (1989) Toxicology of the pancreas. Toxicol Appl Pharmacol 101:543–554PubMedCrossRefGoogle Scholar
  95. Schmassmann A, Peskar BM, Stettler C, Netzer P, Stroff T, Flogerzi B, Halter F (1998) Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. Br J Pharmacol 123:795–804PubMedPubMedCentralCrossRefGoogle Scholar
  96. Seely JC (1996) Salivary glands. In: Mohr U, Dungworth DL, Capen CC, Carlton WW, Sundberg JP, Ward JM (eds) Pathobiology of the aging mouse, vol 2. ILSI Press, Washington DC, pp 261–265Google Scholar
  97. Shreiner AB, Kao JY, Young VB (2015) The gut microbiome in health and in disease. Curr Opin Gastroenterol 31:69–75PubMedPubMedCentralCrossRefGoogle Scholar
  98. Simren M, Barbara G, Flint HJ, Spiegel BM, Spiller RC, Vanner S, Verdu EF, Whorwell PJ, Zoetendal EG, Rome Foundation Committee (2013) Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut 62:159–176PubMedCrossRefGoogle Scholar
  99. Stephens LC, Ang KK, Schultheiss TE, King GK, Brock WA, Peters LJ (1986a) Target cell and mode of radiation injury in rhesus salivary glands. Radiother Oncol 7:165–174PubMedCrossRefGoogle Scholar
  100. Stephens LC, King GK, Peters LJ, Ang KK, Schultheiss TE, Jardine JH (1986b) Unique radiosensitivity of serous cells in rhesus monkey submandibular glands. Am J Pathol 124:479–487PubMedPubMedCentralGoogle Scholar
  101. Straub RH, Wiest R, Strauch UG, Harle P, Scholmerich J (2006) The role of the sympathetic nervous system in intestinal inflammation. Gut 55:1640–1649PubMedPubMedCentralCrossRefGoogle Scholar
  102. Streett CS, Robertson JL, Crissman JW (1988) Morphologic stomach findings in rats and mice treated with the H2 receptor antagonists, ICI 125,211 and ICI 162,846. Toxicol Pathol 16:299–304PubMedCrossRefGoogle Scholar
  103. Suklabaidya S, Dash P, Das B, Suresh V, Sasmal PK, Senapati S (2018) Experimental models of pancreatic cancer desmoplasia. Lab Investig 98:27–40PubMedCrossRefGoogle Scholar
  104. Sundberg JP, Hanson CA, Roop DR, Brown KS, Bedigian HG (1991) Myoepitheliomas in inbred laboratory mice. Vet Pathol 28:313–323PubMedCrossRefGoogle Scholar
  105. Surh I, Brix A, French JE, Collins BJ, Sanders JM, Vallant M, Dunnick JK (2013) Toxicology and carcinogenesis study of senna in C3B6.129F1-Trp53 tm1Brd N12 haploinsufficient mice. Toxicol Pathol 41:770–778PubMedCrossRefGoogle Scholar
  106. Suttie AW, Masson R, Schutten M (2018) Exocrine pancreas. In: Boorman GA (ed) Boorman’s pathology of the rat. Academic Press, London/San Diego, pp 107–122CrossRefGoogle Scholar
  107. Suzuki I, Cho YM, Hirata T, Toyoda T, Akagi JI, Nakamura Y, Park EY, Sasaki A, Nakamura T, Okamoto S, Shirota K, Suetome N, Nishikawa A, Ogawa K (2016) 4-Methylthio-3-butenyl isothiocyanate (raphasatin) exerts chemopreventive effects against esophageal carcinogenesis in rats. J Toxicol Pathol 29:237–246PubMedPubMedCentralCrossRefGoogle Scholar
  108. Takahashi M, Hori M, Mutoh M, Wakabayashi K, Nakagama H (2011) Experimental animal models of pancreatic carcinogenesis for prevention studies and their relevance to human disease. Cancers (Basel) 3:582–602CrossRefGoogle Scholar
  109. Tamamori Y, Tamura Y, Yamazaki T, Ohya K (2005) Establishment of rat model of drug-induced gingival overgrowth induced by continuous administration of phenytoin. J Pharmacol Sci 98:290–297PubMedCrossRefGoogle Scholar
  110. Tsutsumi O, Taketani Y, Oka T (1993) Evidence for the involvement of epidermal growth factor in fertility decline in aging female mice. Horm Res 39 Suppl 1:32–36PubMedCrossRefGoogle Scholar
  111. Ueda Y, Tsuboi M, Ota Y, Makita M, Aoshima T, Nakajima M, Narama I (2011) Gastric mucosal changes induced by polyethylene glycol 400 administered by gavage in rats. J Toxicol Sci 36:811–815PubMedCrossRefGoogle Scholar
  112. Uehara T, Elmore SA, Szabo KA (2018) Esophagus and stomach. In: Boorman GA (ed) Boorman’s pathology of the rat. Academic Press, London/San Diego, pp 35–50CrossRefGoogle Scholar
  113. Valentin JP, Bialecki R, Ewart L, Hammond T, Leishmann D, Lindgren S, Martinez V, Pollard C, Redfern W, Wallis R (2009) A framework to assess the translation of safety pharmacology data to humans. J Pharmacol Toxicol Methods 60:152–158PubMedCrossRefGoogle Scholar
  114. Vidal JD, Mirabile RC, Thomas HC (2008) Evaluation of the cynomolgus monkey stomach: recommendations for standard sampling procedures in nonclinical safety studies. Toxicol Pathol 36:250–255PubMedCrossRefGoogle Scholar
  115. Wallig MA, Sullivan JM (2018) Exocrine pancreas. In: Wallig MA et al (eds) Fundamentals of toxicologic pathology, vol 2. Academic Press, London, pp 443–458CrossRefGoogle Scholar
  116. Ward JM, Yoon M, Anver MR, Haines DC, Kudo G, Gonzalez FJ, Kimura S (2001) Hyalinosis and Ym1/Ym2 gene expression in the stomach and respiratory tract of 129S4/SvJae and wild-type and CYP1A2-null B6, 129 mice. Am J Pathol 158:323–332PubMedPubMedCentralCrossRefGoogle Scholar
  117. Ward JM, Schofield PN, Sundberg JP (2017) Reproducibility of histopathological findings in experimental pathology of the mouse: a sorry tail. Lab Anim (NY) 46:146–151CrossRefGoogle Scholar
  118. Wester PW, Kroes R (1988) Forestomach carcinogens: pathology and relevance to man. Toxicol Pathol 16:165–171PubMedCrossRefGoogle Scholar
  119. Whittaker P, Dunkel VC, Bucci TJ, Kusewitt DF, Thurman JD, Warbritton A, Wolff GL (1997) Genome-linked toxic responses to dietary iron overload. Toxicol Pathol 25:556–564PubMedCrossRefGoogle Scholar
  120. Whittle MC, Hingorani SR (2017) Understanding disease biology and informing the management of pancreas cancer with preclinical model systems. Cancer J 23:326–332PubMedPubMedCentralCrossRefGoogle Scholar
  121. Wood JD (1999) Mixing and moving in the gut. Gut 45:333–334PubMedPubMedCentralCrossRefGoogle Scholar
  122. Yoon YS, Shin JW, Park CB, Oh YS, Lee IS, Lee HS, Lee JS (2000) Morphological structure of accessory spleen in Chinese hamsters. J Vet Sci 1:73–75PubMedCrossRefGoogle Scholar
  123. Yoshizawa K, Marsh T, Foley JF, Cai B, Peddada S, Walker NJ, Nyska A (2005) Mechanisms of exocrine pancreatic toxicity induced by oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Harlan Sprague-Dawley rats. Toxicol Sci 85:594–606PubMedCrossRefGoogle Scholar
  124. Yu S, Yang M, Nam KT (2014) Mouse models of gastric carcinogenesis. J Gastric Cancer 14:67–86PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.In Vivo Animal Core, Unit for Laboratory Animal MedicineUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Molecular Pathology Group, Division of the National Toxicology ProgramNational Institute of Environmental Health SciencesResearch TriangleUSA

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