Table 1.
Study details and histopathology findings
| Strain/dosing/frequency/v ehicle | Tissues examined | Necropsy time (hour or day) /dose in mg/kg | Histopathological findings (grade) [number of animals with finding/total number of animals per group] | |
|---|---|---|---|---|
| Studies with pancreas toxicity | ||||
| MRK1-A | SD/oral/daily/A | P,L,K,M,H | 6 h/100 | Pancreas: atrophy (2) [2/5], edema [4/5], inflammation (1) [3/5], vacuolation (1) [5/5] |
| 6 h/500 | Pancreas: atrophy (1–2) [2/3], edema [3/3], inflammation (1) [3/3], vacuolation (2–3) [3/3] | |||
| D2/100 | Pancreas: deg/necrosis (2–3) [5/5], atrophy (2–4) [5/5], edema [5/5], inflammation (3–4) [5/5] | |||
| D2/500 | Pancreas: deg/necrosis (2–3) [4/4], atrophy (4–5) [4/4], edema [4/4], inflammation (2–3) [4/4] | |||
| D3/100 | Pancreas: deg/necrosis (2–3) [5/5], atrophy (5) [5/5], edema [5/5], inflammation (4–5) [5/5] | |||
| D3/500 | Pancreas: deg/necrosis (2–3) [5/5], atrophy (5) [5/5], edema [5/5], inflammation (4–5) [5/5]; liver: necrosis (1) [1/5] | |||
| MRK1-B | SD/oral/daily/A | P,L,K,M,H,SI, St,Bl,Co | D3/100 | Pancreas: degeneration (3) [4/4], atrophy (1) [4/4], inflammation (3) [4/4] |
| D3/500 | Pancreas: degeneration (4) [4/4], atrophy (1) [4/4], inflammation (3) [4/4] | |||
| D8/100 | Pancreas: degeneration (1–2) [3/3], atrophy (3–4) [3/3], inflammation (2–3) [3/3] | |||
| D8/500 | Pancreas: degeneration (1) [1/2], atrophy (2–4) [2/2], inflammation (2–3) [2/2] | |||
| Caerulein | SD/IP/4 doses in 1 day/D | P,L,K,M,H | 4 h/40 | Pancreas: degeneration (1–2) [8/8], atrophy (1) [8/8], inflammation (1) [8/8] |
| 4 h/120 | Pancreas: degeneration (2–3) [8/8], atrophy (1) [8/8], inflammation (1) [8/8] | |||
| D2 40 | Pancreas: degeneration (1–2) [8/8], atrophy (1) [7/8], inflammation (1) [4/8], fibrosis (1) [6/8] | |||
| D2 120 | Pancreas: degeneration (1–2) [8/8], atrophy (1) [8/8], inflammation (1) [8/8], fibrosis (1) [8/8] | |||
| D4 40 | Pancreas: atrophy (1–2) [7/8], inflammation (1) [1/8], fibrosis (1–2) [5/8] | |||
| D4 120 | Pancreas: atrophy (1–3) [7/8], inflammation (1) [3/8], fibrosis (1–3) [8/8] | |||
| Caerulein + cyclosporin + ETOH | SD/IP, 4 doses in one day */C | P,L,K,M,H | D2/ 0.12 | Pancreas: degeneration/necrosis (2–3) [6/6], atrophy (3) [6/6], inflammation (2–3) [6/6]; kidney: degeneration (1) [6/6]; liver: necrosis (1) [1/6] |
| D9/0.12 | Pancreas: degeneration(1) [6/6],atrophy (1–2) [6/6], fibrosis (1–2) [6/6], islet vacuolization (2) [6/6]; kidney: degeneration (1–2) [4/6]; heart: necrosis (1) [1/6] | |||
| D15/0.12 | Pancreas: degeneration (1) [8/8], atrophy (1) [1/8], fibrosis (1–2) [8/8], islet vacuolization (1–2) [8/8]; kidney: degeneration (1–2) [8/8]; heart: necrosis (1) [1/6] | |||
| Dibutyltin dichloride | SD/IV/ 1 dose/F | P,L,K,M,H | D2/8 | Pancreas: edema-lobular (1–2) [2/9], vacuolation (1) [1/9]; Kidney: tubule necrosis-epithelial (1–2) [3/9]; Liver: focal necrosis (1) [4/9] |
| D5/8 | Pancreas: atrophy (4) [1/8], edema-lobular (1–2) [4/8], fibrosis (2) [1/8], vacuolation (1) [1/8]; Kidney: tubule necrosis-epithelial (1) [1/8]; Liver: focal necrosis (1–3), [2/8] | |||
| D8-9/8 | Pancreas: atrophy (3–4) [3/3],edema-lobular (1–3) [3/3], fibrosis (2–3) [3/3]; Liver: focal necrosis (4) [1/3] | |||
| D14/8 | Pancreas: atrophy (3–4) [3/6],edema-lobular (1–2) [2/6], fibrosis (2–4) [3/6]; Liver: focal necrosis (1–4) [3/6] | |||
| D33/8 | Pancreas: atrophy (4) [5/8], fibrosis (1–2) [4/8]; Liver: focal necrosis (1) [3/8] | |||
| L-arginine | SD/IP/ 1 dose/D | P,L,K,M,H,A | D3/5000 | Pancreas: acinus degeneration (1–5) [8/10], inflammation (2) [3/10] |
| 1-cyano-2-hydroxy-3-butene | SD/SC/1dose/D | P,L,K,M,H | 6 h/50 | Pancreas: peri- and interlobar interstitial edema (2) [1/8] |
| 6 h/200 | Pancreas: peri- and interlobar interstitial edema (3–4) [4/5] | |||
| D2/50 | Pancreas: necrosis (1–3) [7/7], atrophy (1–2) [3/7], peri- and interlobar interstitial edema (1) [2/7], vacuolation (2) [1/7] | |||
| D4/50 | Pancreas: necrosis (1–3) [7/8], atrophy (1) [1/8] | |||
| DL-Ethionine | W/diet/daily/E | P,L,K,M,H,T, | D7/0.25% | Pancreas: degeneration/necrosis (1–3) [8/8], atrophy (1–2)[4/8], inflammation (2) [2/8]; kidney: necrosis (1–3) [8/8] |
| D30/0.25% | Pancreas: degeneration/necrosis (2–3) [8/8], atrophy (1)[2/8], inflammation (1–2) [8/8]; kidney: necrosis (3) [1/8]; liver; necrosis(1) [7/8],heart: necrosis(1) [1/8]; testes: degeneration/necrosis (1) [8/8] | |||
| Streptozotocin | SD/IV/1dose/B | P,L,K,M,H,T | 6 h/30 | Pancreas: islets necrosis (1–2) [5/5] |
| 6 h/60 | Pancreas: islets necrosis (3) [5/5] | |||
| D2/30 | Pancreas: islets necrosis (1) [2/5], islet decreased size (1) [4/5] | |||
| D2/60 | Pancreas: acinus necrosis (1) [1/5], islets necrosis (1) [4/5], islet decreased size (1) [5/5] |
| Study | Strain/dosing/frequency/vehicle | Tissues examined | Necropsy time (day) /dose in mg/kg | Histopathological findings (grade) |
|---|---|---|---|---|
| Studies with non-pancreas toxicity | ||||
| Acetaminophen (liver) | SD/oral/ 1 dose/A | P,L,K,M,H,SI,LI,St,bone, MA | D2/1000 | Liver: necrosis (1–3), inflammation (1) |
| Bromobenzene (liver) | W/IP/1dose/G | L,K,M,H | D3/300,750 | Liver: degeneration/necrosis (1–4), inflammation (1–2) |
| Carbon Tetrachloride (liver) | W/oral/1daily/G | L,K,M,H | D3,4,8,15/120 | Liver: degeneration/necrosis (1–4) |
| MRK2 (GI) | SD/oral/daily/A | P,L,K,M,H,SI, LI,St | D2,3/100 | Duodenum, Epithelium, Single cell necrosis (0–3) |
| MRK6 (liver, testes) | W/oral/daily/H | P,L,K,M,H, T, SI,brain, thymus | D8/10,50 | Bile duct necrosis mucosal (0–4), testis: seminiferous tubule, degeneration (0–2) |
| Thioacetamide (kidney) | SD/oral/1 dose/I | L,K,M,H | D2/50,100,200 | Kidney: tubule degeneration (1–2), liver: degeneration/necrosis (1–4), inflammation (1–3) |
| Cisplatin (kidney) | SD/IP/1 dose/D | L,K,M,H | D5/10,50 | Kidney: tubule degeneration (0–3) |
| Fenoldopam (vascular) | SD/SC/daily/D | P,L,K,M,H,T,M,A | D2,3,7/5 | Mesenteric Vessels, Inflammation, perivascular (0–2), artery, degeneration, medial (0–3); pancreas inflammation perivascular (0–2), artery degeneration, medial (0–3) |
Strain: SD sprague–dawley, W Wistar-Han, Route: IV intravenous; IP intraperitoneal, SC subcutaneous
Vehicle: A 0.5% [w/v] methylcellulose in water; B 4.45 mg/mL trisodium citrate buffer in 0.9% sodium chloride (pH ~ 4.5); C olive oil; D 0.9% NaCl in water; E standard diet; F 40% EtOH 60% glycerol; G corn oil; H 95% Capmul MCM EP/5% polysorbate 80, I water
Tissues: P pancreas, L liver, K kidney, M muscle, H heart, T testes, SI small intestines, St stomach, Bl bladder, Co colon, A adrenal, LI large intestines, MA mesenteric artery
*Animals received EtOH in the diet from 23 days prior to caerulein injection until necropsy; 20 mg/kg cyclosporin was administered daily from 8 days prior to caerulein injection until the day prior to necropsy