ABSTRACT

Genetically modi‹ed animals (GMA) have been developed to produce animal models of human disease and for research, to produce therapeutic or industrial products, to enhance animal food production, to improve disease resistance and animal health, and to enhance companion animals (FDACVM, 2009). Mice (Mus muscularis) are the most frequently used GMA in toxicology but this review will also reference the uses and issues associated with other GMA in toxicology. The ‹rst GMA, transgenic mice, were ‹rst reported (Gordon and Ruddle, 1981) and then shown to express activity of

CONTENTS

Introduction .................................................................................................................................... 935 GMM in Toxicology Programs ...................................................................................................... 938

In Vivo Pharmacology and Ef‹cacy Studies ............................................................................ 939 Absorption, Distribution, Metabolism, Excretion, Pharmacokinetics and Drug-Drug Interactions ................................................................................................................................940 Safety Pharmacology ................................................................................................................ 941 Genotoxicity .............................................................................................................................. 941 Biologics, Gene Therapy, Vaccines and Immunotoxicity ......................................................... 942 Developmental and Reproductive Toxicology (DART) and Juvenile Toxicology .................... 942 Photosafety Studies ................................................................................................................... 943 Short-Term Carcinogenicity Models ......................................................................................... 943

Transgenic CByB6F1-Tg(HRAS)2Jic Oncogene Model (Formerly rasH2) .........................944 Transformation Related Protein 53 Deletional (Trp53+/−) Model (Formerly p53+/−) ............946 FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Transgenic Model (Tg.AC) ............................. 947 Homozygous XPA Knockout (Xpa−/−) Model ...................................................................... 947 XPA and Trp53 (Xpa−/−/Trp53+/−) Double Knockout Model ................................................ 947 Other GMM Models of Carcinogenicity ..............................................................................948

Therapeutic Products Derived from Transgenic Animals .............................................................948 Genetically Animals as Sources of Food, Medical Devices and Xenotransplants .......................948 Genetically Modi‹ed Rats in Toxicology Programs ..................................................................... 949 References ...................................................................................................................................... 949