【正文】 are pounds that induce cells, like the mutated cancer initiator cell, to grow and divide, making more Fifteen example key events representing diverse carcinogenic modes of action DNA reactivity (covalent binding) Gene mutation Chromosomal breakage Aneuploidy Enzymemediated effects on DNA damage or repair Epigeic effects Cell signaling: nuclear receptormediated Cell signaling: other than nuclear receptormediated Immune response modulation Inflammation Cytotoxicity and pensatory cell proliferation Mitogenicity Chronic metabolic or physiologic overload Nutrient deficiency related Interference with intercellular munication ICH Guideline S1B on Testing for Carcinogenicity of Pharmaceuticals choosing one 2year rodent carcinogenicity study (rat) plus one other study that supplements the 2year study and providing additional information that is not readily available from the 2year study: either (1) a short or mediumterm in vivo rodent test system or (2) a 2year carcinogenicity study in a second rodent species (mouse). the short or mediumterm models was intended to focus on the use of in vivo models providing insight into carcinogenic endpoints such as initiation–promotion rodent models and models of carcinogenesis using transgenic or neonatal rodents 藥物致癌性評價方法 Stipulated Rationale for Choosing a Short or MediumTerm Test System as Supplement to One 2 Year Bioassay ? The mechanism of carcinogenesis in the model should most likely be relevant to humans, and therefore the use of the model should be applicable to human risk assessment. ? The use of the model should supplement the 2year carcinogenicity study and it should provide additional information that is not readily available from the 2year study. ? Animal welfare, animal numbers, and overall economy of the carcinogenic evaluation process should be considered. Twoyear Carcinogenesis “Bioassay” Protocol Current Global Carcinogenicity Study Requirements Standard Tissue List Kidney Urinary bladder Aorta Heart Trachea Lungs Liver Gallbladder Pancreas Fat Salivary gland Spleen Cervical lymph node Mesenteric lymph node Thymus Tongue Esophagus Stomach Duodenum Jejunum Ileum Cecum Colon Mammary gland Skin Skeletal muscle Sciatic nerve Parathyroid Thyroid Adrenal gland Pituitary Prostate Seminal vesicles Testes Epididymides Ovaries Oviducts Uterine horns Uterine body Cervix Vagina Brain Spinal cord Sternum Rib/bone Eyes Harderian glands BM smear Nares Clitoral/preputial gland Zymbal ’ s gland Gross lesions 美國毒性病理學會（ STP）建議致癌試驗進行組織病理學檢查的最基本的受檢內容目錄 Tumor Bearing Animals in Control Groups from Rodent Studies Source : J. K. Haseman (unpublished summary of . NTP data). Comparative Percent Incidence of Pertinent Neoplasia in Different Strains of Rats and Mice (104 Weeks Old) Note : F344, Fischer 244 rats。 B6C3F1, mice, (C57BL/6N+C3H/HeN)F1。 NA, nonapplicab