Unexpected tumour findings in lifetime rodent bioassay studies - What to do?

Toxicology Letters

Volumn 128, Issue 1-3, 2002, Pages 17-33

  Ettlin, R A ^a   Prentice, D E ^b  

^a NOVARTIS PHARMA AG   (Switzerland)

^b PreClinical Safety Consultants Ltd   (Switzerland)

Author keywords

Carcinogenicity testing; Confounding factors; Lifetime rodent bioassay; Mechanism of tumour formation; Risk assessment

Indexed keywords

CARCINOGEN;

BIOASSAY; CANCER INCIDENCE; CARCINOGEN TESTING; CARCINOGENESIS; CARCINOGENIC ACTIVITY; CARCINOGENICITY; DISEASE MODEL; EVALUATION; FOOD INTAKE; KINETICS; MUTAGENICITY; NONHUMAN; PATHOLOGY; PRACTICE GUIDELINE; PRIORITY JOURNAL; REVIEW; RISK ASSESSMENT; SPECIES DIFFERENCE; SURVIVAL;

ANIMALS; BIOLOGICAL ASSAY; CARCINOGENICITY TESTS; FEMALE; HUMANS; MICE; RATS;

ANIMALIA; RODENTIA;

EID: 0037051158     PISSN: 03784274     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0378-4274(01)00530-6     Document Type: Review

References (209)

1. Mononuclear cell leukemia in aged Sprague-Dawley rats
2. Neoplastic lesions of questionable significance to humans
3. A critical appraisal of the value of the mouse cancer bioassay in safety assessment
4. Maximum dosage level in testing low-toxicity chemicals for carcinogenicity in rodents
5. Aspects of database construction and interrogation of relevance to the accurate prediction of rodent carcinogenicity and mutagenicity
6. Prediction of non-genotoxic carcinogenesis
7. The influence of chemical structure on the extent and sites of carcinogenesis for 522 rodent carcinogens and 55 different human carcinogen exposures
8. Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis
9. Risk assessment of low-level chemical exposures from consumer products under the US Consumer Product Safety Commission chronic hazard guidelines
10. RITA-Registry of Industrial Toxicology Animal-data-Guides for organ sampling and trimming procedures in rats
11. Mechanisms of action of known human carcinogens
12. Prediction of rodent carcinogenicity of further 30 chemicals bioassayed by the US National Toxicology Program
13. Dose selection for carcinogenicity studies of pharmaceuticals: Systemic exposure to phenacetin at carcinogenic dosage in the rat
14. Statistical issues in the analysis of the long-term carcinogenicity bioassay in small rodents: An empirical evaluation of statistical decision rules
15. Incidence of spontaneous tumors in laboratory rats
16. Spontaneous tumors in NMRI mice from carcinogenicity studies
17. Experimental investigations into the carcinogenic effect of antitumor and immunosuppressive agents
18. Review of interspecies risk comparisons
19. Profiles of induced tumors in animals
20. A strategy for establishing mode of action of chemical carcinogens as a guide for approaches to risk assessments
21. Benefits from caloric restriction: Is it hormesis?
22. Chemical carcinogenesis: Epigenetic mechanisms and dose response
23. Can the concept of hormesis be generalized to carcinogenesis
24. The significance of mouse liver tumor formation for carcinogenic risk assessment: Results and conclusions from a survey of ten years of testing by the agrochemical industry
25. Non-genotoxic carcinogens. Approaches to their risk assessment
26. Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans?
27. Toxicogenomics a new discipline in drug development
28. Effect of dietary optimization on growth, survival, tumor incidences and clinical pathology parameters in CD Sprague-Dawley and Fischer-344 rats: A 104-week study
29. The power and interpretation of the carcinogenicity bioassay
30. Role of cell proliferation in regenerative and neoplastic disease
31. Human relevance of animal carcinogenicity studies
32. Use of cell proliferation data in modeling urinary bladder carcinogenesis
33. Rodent bladder tumors do not always predict for humans
34. Relationship between in vitro relaxation of the costo-uterine smooth muscle and mesovarial leiomyoma formation in vivo by beta-receptor agonists
35. Carcinogenesis: Basic principles
36. Time-to-tumour risk assessment for 1,3-butadiene based on exposure of mice to low doses by inhalation
37. The rodent carcinogenicity bioassay produces a similar frequency of tumor increases and decreases: Implications for risk assessment
38. Marketed human pharmaceuticals reported to be tumorigenic in rodents
39. The international harmonisation of guidelines in the future: A viewpoint from the industry
40. Incidence of spontaneous neoplastic and nonneoplastic lesions in Charles River CD-1 mice varies with breeding origin
41. Professional opportunities for toxicologists: The requirements of the private sector for education/teaching
42. A brief review of modern toxicologic pathology in regulatory and explanatory toxicity studies of chemicals
43. Morphological, immunohistochemical, stereological and nuclear shape characteristics of proliferative Leydig cell alterations in rats
44. Overview of quantitative methods in toxicologic pathology
45. Causes of death in rodent toxicity and carcinogenicity studies
46. Careers in toxicology in Europe - Options and requirements. Report of a workshop organized on behalf of the Individual Members of EUROTOX during the EUROTOX Congress 2000 in London (17-20 September 2000)
47. IFSTP guidelines for the design and interpretation of the chronic rodent carcinogenicity bioassay
48. Risk assessment of environmental chemicals
49. Part XII, Department of Health and Human Services, International Conference on Harmonisation; Guidance on dose selection for carcinogenicity studies of pharmaceuticals
50. Part II, Department of Health and Human Services, International Conference on Harmonisation; Guidance on dose selection for carcinogenicity studies of pharmaceuticals: Addendum on a limit dose and related notes
51. International Conference on Harmonisation; Guidance on testing for carcinogenicity of pharmaceuticals
52. Principles for the selection of doses in chronic rodent bioassays
53. Toxicologic risk assessment and prevention: Rational and irrational approaches (German)
54. Fine structural changes in the liver of young and old rats as influenced by microsomal enzyme inducers
55. Dose-response trend tests for tumorigenesis, adjusted for body weight
56. Extrapolation of carcinogenicity between species: Quantitative and qualitative factors
57. Comparison of target organs of carcinogenicity for mutagenic and non-mutagenic chemicals
58. Guidelines for measuring chemically induced cell proliferation in specific rodent target organs
59. Mode of action considerations in the use of transgenic animals for mutagenicity and carcinogenicity evaluations
60. Role of persistent, non-genotoxic tissue damage in rodent cancer and relevance to humans
61. Species differences in carcinogenicity: The role of metabolism and pharmacokinetics in risk assessment
62. Interspecies comparison of liver carcinogenesis: Implications for cancer risk assessment
63. De novo cancer in cyclosporine-treated and non-cyclosporine-treated adult primary renal allograft recipients
64. The role of plasma transport proteins in hormone homeostasis, with particular reference to thyroid hormone
65. Risk assessment of d-limonene: An example of male rat-specific renal tumorigens
66. Factors influencing laboratory animal spontaneous tumor profiles
67. Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice
68. Use of statistical decision rules for evaluating laboratory animal carcinogenicity studies
69. Data analysis: Statistical analysis and use of historical control data
70. The relationship between use of the maximum tolerated dose and study sensitivity for detecting rodent carcinogenicity
71. Analysis of National Toxicology Program rodent bioasssay data for anticarcinogenic effects
72. Comparison of site-specific and overall tumor incidence analyses for 81 recent National Toxicology Program carcinogenicity studies
73. Carcinogen risk assessment
74. Tumor induction as a result of pharmacological effects of drugs
75. Gastric enterochromaffin-like cell hyperplasia and neoplasia in the rat: An indirect effect of the histamine H2-receptor antagonist, BL-6341
76. Mechanisms, chemical carcinogenesis, and risk assessment: Cell proliferation and cancer
77. Long-term chemical carcinogenesis bioassays predict human cancer hazards. Issues, controversies, and uncertainties
78. Long-term chemical carcinogenesis experiments for identifying potential human cancer hazards: Collective database of the National Cancer Institute and National Toxicology Program (1976-1991)
79. The US Environmental Protection Agency's risk assessment guidelines
80. Quantitative analysis of smooth endoplasmic reticulum proliferation in periportal, midzonal and perivenular hepatocytes of mice after administration of phenobarbital
81. Diet, overfeeding, and moderate dietary restriction in control Sprague-Dawley rats: II. Effects on age-related proliferative and degenerative lesions
82. Need for dietary control by caloric restriction in rodent toxicology and carcinogenicity studies
83. Toxicological sciences. The role of diet and caloric intake in aging, obesity and cancer
84. Epigenetic mechanisms of chemical carcinogenesis
85. The relevance of hepatic peroxisome proliferation in rats to assessment of human carcinogenic risk for pharmaceuticals
86. The relevance of rodent tumors in assessing carcinogenicity in human beings
87. Evaluation of reduced protocols for carcinogenicity testing of chemicals: Report of a joint EPA/NIEHS workshop
88. Mechanisms of hepatocarcinogenicity of peroxisome-proliferating drugs and chemicals
89. Coumarin metabolism, toxicity and carcinogenicity: Relevance for human risk assessment
90. Quantification of hepatocytic proliferation in the laboratory mouse. A comparative study using immunohistochemical detection of bromodeoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) expression
91. Overall false positive rates in tests for linear trend in tumor incidence in animal carcinogenicity studies of new drugs
92. Anticarcinogenic responses in rodent cancer bioassays are not explained by random effects
93. Weight and survival depression in rodent bioassays with and without tumor decreases
94. Relevance of carcinogenicity bioassays in mice in assessing potential health risks associated with exposure to methylene chloride
95. Spontaneous tumors and lifespan of female NMRI mice of the outbred stock Sut:NMRT during a lifetime study
96. Perspectives on pathology. Peer review
97. Screening for possible human carcinogens and mutagens. False positives, false negatives: Statistical implications
98. Dose-response relationship and low dose extrapolation in chemical carcinogenesis
99. A true threshold dose in chemical carcinogenesis cannot be defined for a population, irrespective of the mode of action
100. Toxicokinetic and mechanistic considerations in the interpretation of the rodent bioassay
101. Mortality, major cause of moribundity, and spontaneous tumors in CD-1 mice
102. Effects of caloric restriction on rodent drug and carcinogen metabolizing enzymes: Implications for mutagenesis and cancer
103. Confounded carcinogenicity study of sodium fluoride in CD-1 mice
104. Thyroid gland neoplasia: Non-genotoxic mechanisms
105. Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment
106. Risk assessment and biological mechanisms: Lessons learned, future opportunities
107. Guidelines for combining neoplasms for evaluation of rodent carcinogenesis studies
108. A report on methods to reduce, refine and replace animal testing in industrial toxicology laboratories
109. Spontaneous tumors in SENCAR mice
110. Cell proliferation and chemical carcinogenesis: Symposium overview
111. Implications for risk assessment of suggested nongenotoxic mechanisms of chemical carcinogenesis
112. Editorial: RITA-Registry of Industrial Toxicology Animal-data: Optimization of carcinogenicity bioassays
113. Recent progress in the field of toxicologic pathology in Europe and the need for standardization
114. Tumor registry data base - Suggestions for a systematized nomenclature of pre-neoplastic and neoplastic lesions in rats
115. Are lifespan rodent carcinogenicity studies defensible for pharmaceutical agents
116. High dose levels are not necessary in rodent studies to detect human carcinogens
117. Evaluation of the carcinogenic potential of pharmaceuticals. Opportunities arising from the International Conference on Harmonisation
118. Variations in prevalence of endocrine tumors among different colonies of rats? A retrospective study in the Hannover registry data base
119. Visual documentation of neoplasms as part of the Registry nomenclature information system
120. Modulators of carcinogenesis
121. Strain-specific mammary tumor virus activity in blood of C3H and BALB-c f. C3H mice
122. Early indicators of carcinogenesis in hormone-sensitive organs
123. Predictive value of carcinogenicity testing in drug evaluation
124. Morphometry and immunocytochemistry
125. Topics in cancer risk assessment
126. Predictions of rodent carcinogenicity testing results: Interpretation in light of the Lave-Omenn value-of-information model
127. Effect of immunosuppression on the growth of six murine tumors
128. Post-transplant malignancy: The role of immunosuppression
129. Proliferating cell nuclear antigen expression in Wistar rat livers. A retrospective immunohistochemical study of normal and neoplastic livers
130. Biostatistical issues in the design and analysis of animal carcinogenicity experiments
131. Spontaneous neoplasms in control Wistar rats: A comparison of reviews
132. A review of drug-induced Leydig cell hyperplasia and neoplasia in the rat and some comparisons with man
133. Mesulergine-induced Leydig cell tumors - A syndrome involving the pituitary-testicular axis of the rat
134. Thresholds in chemical carcinogenesis
135. Morphologic and immunohistochemical characterization of Leydig cell tumor variants in Wistar rats
136. Nongenotoxic (epigenetic) carcinogens: Pesticides as an example: A critical review
137. New diet (NTP-2000) for rats in the National Toxicology Program toxicity and carcinogenicity studies
138. Structure-based methods for predicting mutagenicity and carcinogenicity: Are we there yet
139. Bromocriptine
140. Comparison of the induction of hepatic peroxisome proliferation by the herbicide oxadiazon in vivo in rats, mice, and dogs and in vitro in rat and human hepatocytes
141. Registry of industrial toxicology animal data: Optimisation of carcinogenicity bioassays
142. Incidence and spectrum of spontaneous neoplasms in Han:NMRI mice of both sexes
143. Liver tumors in rodents: Extrapolation to man
144. Let us forget 'tumour promotion' and start thinking about mechanisms of non-genotoxic carcinogenicity
145. Non-genotoxic carcinogenesis: Implications for testing and extrapolation to man
146. Historical histopathological control data for laboratory rodents: Valuable treasure or worthless trash
147. A brief history of the use of laboratory animals for the prediction of carcinogenic risk for man with a note on needs for the future
148. The Biosure study: Influence of composition of diet and food consumption on longevity, degenerative diseases and neoplasia in Wistar rats studied for up to 30 months post weaning
149. Structural relationships between mutagenicity, maximum tolerated dose, and carcinogenicity in rodents
150. Utilization of genetically altered animals in the pharmaceutical industry
151. Influence of food intake and sexual segregation on longevity, organ weights and the incidence of non-neoplastic and neoplastic diseases in rats
152. Use of 'secondary mechanism' in the regulation of carcinogens; a chronology
153. Mechanistic studies in man, laboratory animals and in vitro systems
154. Active cell death (apoptosis) and cellular proliferation as indicators of exposure to carcinogens
155. Role of receptors in human and rodent hepatocarcinogenesis
156. The effect of body weight on tumor incidence and carcinogenicity testing in B6C3F1 mice and F344 rats
157. Spontaneous tumors in control F344 and Charles River-CD rats and Charles River CD-1 and B6C3HF1 mice
158. Receptor-mediated biological processes: Implications for evaluating carcinogens
159. Mechanisms of nongenotoxic carcinogenesis and assessment of the human hazard
160. Prolactin and growth hormone levels in different inbred strains of mice: Patterns in association with estrous cycle, time of day, and perphenazine stimulation
161. Evaluating chemical risks: Results of a survey of the British Toxicology Society
162. Society of Toxicologic Pathologists' position paper on blinded slide reading
163. Peer review in toxicologic pathology: Some recommendations
164. Carcinogenicity testing of pharmaceuticals in the EU: A workshop report
165. Alpha 2u-globulin nephropathy: Review of the cellular and molecular mechanisms involved and their implications for human risk assessment
166. Clinical relevance of laboratory and animal data on tamoxifen
167. Species-specific mechanisms of carcinogenesis
168. Spontaneous tumors in aging (C57BL/6N × C3H/HeN)F1 (B6C3F1) mice
169. Implications of hormesis on the bioassay and hazard assessment of chemical carcinogens
170. Evaluation and validation issues in the development of transgenic mouse carcinogenicity bioassays
171. Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models
172. Genetically engineered cancer models: Three viewpoints on issues from testing to risk assessment
173. Subcutaneous soft tissue tumours at the site of implanted microchips in mice
174. Incidence and spectrum of spontaneous neoplasms in male and female CBA/J mice
175. Carcinogenicity of medical drugs: A survey of IARC monographs
176. Short-and medium-term carcinogenicity tests: Simple initiation-promotion assay systems
177. Relationship of body-weight gain to longevity and to risk of development of nephropathy and neoplasia in Sprague-Dawley rats
178. Review of alternative methods of carcinogenicity testing and evaluation of human pharmaceuticals
179. The utility of two rodent species in carcinogenic risk assessment of pharmaceuticals in Europe
180. Biological considerations for combining carcinogenicity data for quantitative risk assessment
181. Cancer risk assessment: Historical perspectives, current issues, and future directions
182. Cell proliferation not associated with carcinogenesis in rodents and humans
183. Peer review in toxicologic pathology
184. The role of genotoxic carcinogens and of promoters in carcinogenesis and in human cancer causation
185. Saccharin mechanistic data and risk assessment: Urine composition, enhanced cell proliferation, and tumor promotion
186. d-Limonene mechanistic data and risk assessment: Absolute species-specific cytotoxicity, enhanced cell proliferation, and tumor promotion
187. Butylated hydroxyanisole mechanistic data and risk assessment: Conditional species-specific cytotoxicity, enhanced cell proliferation, and tumor promotion
188. Phenobarbital mechanistic data and risk assessment: Enzyme induction, enhanced cell proliferation, and tumor promotion
189. DNA reactive and epigenetic carcinogens
190. Safety assessment of pharmaceuticals: Examples of inadequate assessments and a mechanistic approach to assuring adequate assessment
191. Chemical carcinogen mechanisms of action and implications for testing methodology
192. Variability in gene expression and tumor formation within genetically homogeneous animal population in bioassays
193. Cyclosporine promotes the induction of thymic lymphomas in C57BL/6 mice initiated by a single dose of gamma-radiation
194. Role of disrupted gap junctional intercellular communication in detection and characterization of carcinogens
195. A blind reanalysis of a random subset of NCI bioassay studies: Agreement between rats and mice
196. Mutagens that are not carcinogens: Faulty theory or faulty tests
197. Comparative anticancer effects of vaccination and dietary factors on experimentally-induced cancers