Alternatives to the carcinogenicity bioassay: in silico methods, and the in vitro and in vivo mutagenicity assays.
BACKGROUND
Carcinogenicity and mutagenicity are toxicological end points posing considerable concern for human health. Due to the cost in animal lives, time and money, alternative approaches to the rodent bioassay were designed based on: i) identification of mutations and ii) structure-activity relationships.


METHODS
Evidence on i) and ii) is summarized, covering 4 decades (1971 - 2010).


RESULTS
A comprehensive, state-of-the-art perspective on alternatives to the carcinogenicity bioassay.


CONCLUSIONS
Research to develop mutagenicity-based tests to predict carcinogenicity has generated useful results only for a limited area of the chemical space, that is, for the DNA-reactive chemicals (able to induce cancer, together with a wide spectrum of mutations). The most predictive mutagenicity-based assay is the Ames test. For non-DNA-reactive chemicals, that are Ames-negative and mutagenic in other in vitro assays (e.g., clastogenicity), no correlation with carcinogenicity is apparent. The knowledge on DNA reactivity permits the identification of genotoxic carcinogens with the same efficiency of the Ames test. Thus, a chemical mutagenic in Salmonella and/or with structural alerts should be seriously considered as a potential carcinogen. No reliable mutagenicity-based alternative tools are available to assess the risk of non-DNA-reactive chemicals.
Benigni
Romualdo
R
Istituto Superiore di Sanita, Environment and Health Department, Viale Regina Elena 299, 00161 Rome, Italy. romualdo.benigni@iss.it
Bossa
Cecilia
C
Tcheremenskaia
Olga
O
Giuliani
Alessandro
A
D000826:Animal Testing Alternatives / Q000379:methods* / Q000639:trends; D000818:Animals; D001681:Biological Assay / Q000009:adverse effects / Q000379:methods* / Q000639:trends; D015197:Carcinogenicity Tests / Q000009:adverse effects / Q000379:methods / Q000639:trends; D006801:Humans; D023421:Models, Animal; D009152:Mutagenicity Tests / Q000379:methods / Q000639:trends; D013329:Structure-Activity Relationship; D018675:Toxicity Tests / Q000379:methods* / Q000639:trends