Factors contributory to early death of young CD-1 mice in carcinogenicity studies.
It is often difficult to determine the cause of early or sporadic deaths in toxicity studies, making interpretation difficult. To help in the interpretation of early deaths, it is critical that the background incidence of factors contributing to death be recorded and archived. Information was gathered from the control groups of 20 CD-1 mouse carcinogenicity studies. Route of administration was either dietary or oral gavage, and animals were housed in groups of one to four in wired or solid bottom cages. Analysis was confined to sporadic deaths in control groups occurring during the first 50 weeks. Of the 1453 mice in each sex, there were 40 (30 (2.06%) males; 10 (0.69%) females), and 170 (101 (6.95%) males; 69 (4.75%) females) decedents recorded from up to week 20 and week 50 of study, respectively. There was statistical difference in the probability of survival between the sexes (P=0.002 for up to week 20; P=0.016 for up to week 50), in favour of females, at both 20 and 50 weeks of study time points. Analysis of factors contributing to death up to 20 weeks of study revealed that 14 (46.7%) males had non-neoplastic changes, 3 (10%) males had neoplastic lesions, 4 (13.3%) males died from other causes and 9 (30%) males died from unknown causes; 4 (40%) females had non-neoplastic lesions, none (0%) had neoplastic lesions, 2 (20%) females died from other reasons, and 4 (40%) died from unknown causes. For up to 50 weeks study, these figures were 49 (48.5%), 27 (26.7%), 10 (9.9%) and 15 (14.9%) in male mice and 24 (34.8%), 28 (40.6%), 7 (10.1%), and 11 (15.9%) in female mice for non-neoplastic, neoplastic, other, and unknown findings, respectively. Up to 50 weeks of study, the following factors contributing to death were recorded. One of the most common non-tumour factors contributing to death was kidney diseases (nephropathy and glomerulonephritis), followed by urinary obstruction in males, which was considered to play an important role in a high proportion of male decedents. Other causes of death such as haemorrhagic ovarian cysts, cardiomyopathy, arteritis, liver necrosis, and hepatic angiectasis were also reported in occasional mice. A high proportion of factors contributing to death were due to lesions such as ulceration, abscessation and pyogranulomatous inflammation of the skin or muscle. Of the neoplastic causes of death, haematopoietic tumours were the most common. There were also some sporadically occurring tumours including osteosarcoma of the bone and occasional tumours in the skin and mammary glands in the female mice. Some tumours such as bronchiolo-alveolar adenoma of the lungs and hepatocellular adenoma of the liver were identified as incidental tumours. Some animals died from trauma/fracture or dosing accidents or were sacrificed due to poor clinical condition. A number of animals were found dead without any significant clinical or histological findings. The aim of this report is to provide toxicologists with a useful reference guide to aid sound interpretation.
Son
Woo-Chan
WC
Department of Pathology, Huntingdon Life Sciences, Woolley Road, Alconbury, Huntingdon, Cambridgeshire PE28 4HS, UK. wcson@ukorg.huntingdon.com
D000375:Aging / Q000502:physiology; D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002423:Cause of Death; D005260:Female; D008297:Male; D051379:Mice; D009026:Mortality; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D012737:Sex Factors; D016019:Survival Analysis
D002273:Carcinogens