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
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.