IN-VIVO TRANSGENIC BIOASSAYS AND ASSESSMENT OF THE CARCINOGENIC POTENTIAL OF PHARMACEUTICALS

Citation
Jf. Contrera et Jj. Degeorge, IN-VIVO TRANSGENIC BIOASSAYS AND ASSESSMENT OF THE CARCINOGENIC POTENTIAL OF PHARMACEUTICALS, Environmental health perspectives, 106, 1998, pp. 71-80
Citations number
82
Categorie Soggetti
Public, Environmental & Occupation Heath","Environmental Sciences
ISSN journal
00916765
Volume
106
Year of publication
1998
Supplement
1
Pages
71 - 80
Database
ISI
SICI code
0091-6765(1998)106:<71:ITBAAO>2.0.ZU;2-I
Abstract
There is general agreement in the scientific community on the need to improve carcinogenicity testing and the assessment of human carcinogen ic risk and to incorporate more information on mechanisms and modes of action into the risk assessment process. Advances in molecular biolog y have identified a growing number of genes such as protooncogenes and tumor-suppressor genes that are highly conserved across species and a re associated with a wide variety of human and animal cancers. in vivo transgenic rodent models incorporating such mechanisms are used to id entify mechanisms involved in tumor formation and as selective tests f or carcinogens. Transgenic methods can be considered an extension of g enetic manipulation by selective breeding, which long has been employe d in science and agriculture. The use of two rodent species in carcino genicity testing is especially important for identifying transspecies carcinogens. The capacity of a substance to induce neoplasia across sp ecies suggests that the mechanism(s) involved in the induction of the neoplasia are conserved and therefore may have significance for humans . Based on available information there is sufficient experience with s ome in vivo transgenic rodent carcinogenicity models to support their application as complementary second species studies in conjunction wit h a single 2-year rodent carcinogenicity study. The optional substitut ion of a second 2-year rodent carcinogenicity study with an alternativ e study such as an in vivo transgenic carcinogenicity study is part of the International Conference on Harmonization guidance S1B: Testing f or Carcinogenicity of Pharmaceuticals. This guidance is intended to be flexible enough to accommodate a wide range of possible carcinogenici ty assessment models currently under consideration or models that may be developed in the future. The use of an in vivo transgenic mouse mod el in place of a second ii-year mouse study will improve the assessmen t of carcinogenic risk by contributing insights into the mechanisms of tumorigenesis and potential human relevance not available from a stan dard 2-year bioassay. II is envisioned that this will stimulate the fu rther development of more efficient and relevant methods for identifyi ng and assessing potential human carcinogenic risk, which will benefit public health.