|
Sign In to gain access to subscriptions and/or personal tools.
|
Expectations for Transgenic Rodent Cancer Bioassay Models
John Ashby
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, United Kingdom, John.Ashby{at}Syngenta.com
The results of the present study have advanced dramatically the database on transgenic mouse abbreviated carcinogenicity bioassay models. As such, it will provide a secure foundationfor future evaluations of these assays and for their eventual validation as models for the prediction of possible human carcinogens. Based upon the results derived from the present study, it is suggested that 5 areas require discussion as a prelude to the further evaluation of existing models and the future evaluation of new models. First, there is the need to agree a standard list of calibration chemicals to be studied and to derive agreement on optimal bioassay group sizes, statistical methods, and exposure periods. Second, general agreement must be reached regarding the classes/types of known rodent carcinogens so that it is acceptable for the new models to fi nd negative, by implication, those rodent carcinogens considered not to pose a carcinogenic hazard to humans. Third, current understanding of mechanisms of carcinogenesis should be integrated into the evaluation of new bioassay models. Fourth, any changes made to the standard rodent carcinogenicity bioassay protocol will require compromises being made, and these should be commonly owned between interested parties in order to reduce the number of regional/agencyspecifi c carcinogenicity testing schemes. Fifth, a mechanism needs to be developed by which assays can be adopted or rejected for use in the routine bioassay of chemicals. In the absence of such initiatives the increasing number of new bioassay models will come to exist along side of the standard 2-species bioassay, and this may potentially lead to confusion regarding the true future role of these assays.
Key Words: Carcinogen • cancer bioassay • cancer model evaluation.
References
- Anonymous (1977). Bioassay of dichlorvos for possible carcinogenicity. NCI Carcinogenesis TR 10.
- Anonymous (1989). Toxicology and carcinogenesis studiesofdichlorvosin F344/N rats and B6C3F1 mice (gavage studies). NTP Carcinogenesis TR 342.
- Ashby J. (1997). Identifying potential human carcinogens—the role of genetically altered rodents. Toxicol Pathol 25: 241—243.[Free Full Text]
- Ashby J., Paton D. (1995). Chemicals for evaluating the sensitivity and specifi city of reduced/transgenic rodent cancer bioassay protocols. Mut Res 331: 27—38.[Web of Science][Medline]
[Order article via Infotrieve]
- Ashby J., Tennant RW (1991). Defi nitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mut Res 257: 229—306.[Web of Science][Medline]
[Order article via Infotrieve]
- Davies TS, Lynch BS, Monro AM, Munro IC, Nestmann ER (2000). Rodent carcinogenicity tests need be no longer than 18 months: an analysis based on 210 chemicals in the IARC monographs. Food Chem Toxicol 38: 219— 235.
- Dunson DB, Haseman JK, van Birgelen Apjm, Stasiewicz S., Tennant RW (2000). Statistical analysis of skin tumor data from Tg.AC mouse bioassays. Toxicol Sci 55: 293—302.[Abstract/Free Full Text]
- Haseman J., MelnickR., Tomatis L., Huff J. ( 2001). Carcinogenesisbioassays: study duration and biological relevance. Food Chem Toxicol 39:739—744.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Huff J. ( 1999). Long-term chemical carcinogenesis bioassays predict human cancer hazards. Issues, controversies, and uncertainties. Ann N Y Acad Sci 895:56—79.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Iarc (1974). Monographs on the Evaluation of the Carcinogenic Risks of Chemicals to Man, 5. Some Organochlorine Pesticides. IARC, Lyon, France.
- Iarc (1991). Monographs on the Evaluation of Carcinogenic Risks to humans, 53. Occupational Exposures in Insecticide Application, and Some Pesticides. IARC, Lyon, France.
- Iarc (1999). Species Differences in Thyroid, Kidney and Urinary Bladder Carcinogenesis. Publication No. 147. IARC, Lyon, France.
- Robinson D. (1998). The International Life Sciences Institute's role in the evaluation of alternative methodologies for the assessment of carcinogenic risk. Toxicol Pathol 26: 474—475.[Free Full Text]
- Spalding JW, French JE, Stasiewicz S., Furedi-Machacek M., Conner F., Tice RR, Tennant RW (2000). Responses of transgenic mouse lines p53 +/- and Tg AC to agents tested in conventional carcinogenicity bioassays. Toxicol Sci 53: 213—223.[Abstract/Free Full Text]
- Tennant RW, French JE, Spalding JW (1995). Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ Health Perspect 103: 942—950.[Web of Science][Medline]
[Order article via Infotrieve]
- Tennant RW, Spalding J., French JE (1996). Evaluation of transgenic mouse bioassays for identifying carcinogens and non-carcinogens. Mut Res 365: 119—127.[Web of Science][Medline]
[Order article via Infotrieve]
- Yamamoto S., Urano K., Nomura T. (1998). Validation of transgenic mice harboring the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing. Toxicol Lett 102—103: 473—478.[CrossRef][Web of Science]
Toxicologic Pathology, Vol. 29, No. 1 suppl,
177-182 (2001)
DOI: 10.1080/019262301753178591
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
W. Bursch, M. Chabicovsky, U. Wastl, B. Grasl-Kraupp, K. Bukowska, H. Taper, and R. Schulte-Hermann
Apoptosis in Stages of Mouse Hepatocarcinogenesis: Failure to Counterbalance Cell Proliferation and to Account for Strain Differences in Tumor Susceptibility
Toxicol. Sci.,
May 1, 2005;
85(1):
515 - 529.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Syrian Hamster Embryo Assay Working Group, R.J. Mauthe, D.P. Gibson, R.T. Bunch, and L. Custer
Response to "Alternative Models for Carcinogenicity Testing: Weight of Evidence Across Models" Sam Cohen, Toxicologic Pathology (2001) 29(Suppl.): 183--190
Toxicol Pathol,
February 1, 2002;
30(2):
292 - 293.
[PDF]
|
|
|
|
|
