title: Effects of reduced food intake on toxicity study parameters in rats.
abstract: This study comprehensively describes the effects of various levels of food reduction on a wide range of toxicological parameters in dietary-optimized rats (fed with approximately 75% of ad libitum food consumption daily; 16 g and 22 g/day for females and males, respectively) that has been established as a nutritionally appropriate and well-controlled animal model in conducting toxicity studies. Toxicological parameters, including general condition, ophthalmology, clinical pathology and anatomic pathology, were examined in dietary-optimized Crl:CD(SD) female and male rats fed 16 g and 22 g/day (control), 12 g and 17 g/day (75% group), 8 g and 11 g/day (50% group), or 4 g and 6 g/day (25% group), respectively for 2 weeks. There was mortality and morbidity including reddish urine in 25% group females. The reddish urine was identified as "hemoglobinuria" that resulted from extra/intra-vascular hemolysis induced by severe food reduction. Hemoconcentration, decreased leukocytes and platelets, decreases in nutritional elements (serum glucose, protein, and lipids), increased aspartate aminotransferase and alanine aminotransferase, imbalanced electrolytes, and/or decreased urinary pH were observed in all restriction groups. Histopathologically remarkable changes included erythrophagocytosis in the spleen/liver and renal tubular necrosis with hyaline cast/droplets in 25% group; in addition to bone marrow depletion, lymphoid depletion in thymus/spleen/lymph node, and/or decreased secretion in the prostate/seminal vesicle in all restriction groups. Most of these changes were considered attributable to nutritional deficiency, dehydration, accelerated protein catabolism, stress and/or hemolysis secondary to severe food reduction. These results will enable toxicologists to help distinguish primary drug-induced effects from secondary changes associated with decreases in food consumption.
authors.affiliation: Tsukuba Safety Assessment Laboratories, Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. tomoyuki_moriyama@merck.com
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Moriyama
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Tsujioka
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohira
authors.forename: Satoko
authors.initials: S
authors.lastname: Nonaka
authors.forename: Hisataka
authors.initials: H
authors.lastname: Ikeda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sugiura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tomohiro
authors.forename: Keiji
authors.initials: K
authors.lastname: Samura
authors.forename: Masaru
authors.initials: M
authors.lastname: Nishikibe
mesh_terms: D000818:Animals; D004435:Eating; D005260:Female; D005508:Food Deprivation; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D018675:Toxicity Tests / Q000379:methods