The OECD Program to Validate the Rat Hershberger Bioassay to Screen Compounds for in Vivo Androgen and Antiandrogen Responses: Phase 2 Dose–Response Studies

OBJECTIVE: The Organisation for Economic Co-operation and Development (OECD) has completed phase 2 of an international program to validate the rodent Hershberger bioassay. DESIGN: The Hershberger bioassay is designed to identify suspected androgens and antiandrogens based on changes in the weights of five androgen-responsive tissues (ventral prostate, paired seminal vesicles and coagulating glands, the levator ani and bulbocavernosus muscles, the glans penis, and paired Cowper’s or bulbourethral glands). Protocol sensitivity and reproducibility were tested using two androgen agonists (17α-methyl testosterone and 17β-trenbolone), four antagonists [procymi-done, vinclozolin, linuron, and 1,1-dichoro-2,2-bis-(p-chlorophenyl)ethylene (p,p’-DDE)], and a 5α-reductase inhibitor (finasteride). Sixteen laboratories from seven countries participated in phase 2. RESULTS: In 40 of 41 studies, the laboratories successfully detected substance-related weight changes in one or more tissues. The one exception was with the weakest antiandrogen, linuron, in a laboratory with reduced sensitivity because of high coefficients of variation in all tissue weights. The protocols performed well under different experimental conditions (e.g., strain, diet, housing protocol, bedding, vehicle). There was good agreement and reproducibility among laboratories with regard to the lowest dose inducing significant effects on tissue weights. CONCLUSIONS: The results show that the OECD Hershberger bioassay protocol is reproducible and transferable across laboratories with androgen agonists, weak androgen antagonists, and a 5α-reductase inhibitor. The next validation phase will employ coded test substances, including positive substances and negative substances having no androgenic or antiandrogenic activity

Opportunities to integrate new approaches in genetic toxicology: An ILSI-HESI workshop report

Genetic toxicity tests currently used to identify and characterize potential human mutagens and carcinogens rely on measurements of primary DNA damage, gene mutation, and chromosome damage in vitro and in rodents. The International Life Sciences Institute Health and Environmental Sciences Institute (ILSI-HESI) Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity Testing held an April 2012 Workshop in Washington, DC, to consider the impact of new understanding of biology and new technologies on the identification and characterization of genotoxic substances, and to identify new approaches to inform more accurate human risk assessment for genetic and carcinogenic effects. Workshop organizers and speakers were from industry, academe, and government. The Workshop focused on biological effects and technologies that would potentially yield the most useful information for evaluating human risk of genetic damage. Also addressed was the impact that improved understanding of biology and availability of new techniques might have on genetic toxicology practices. Workshop topics included (1) alternative experimental models to improve genetic toxicity testing, (2) Biomarkers of epigenetic changes and their applicability to genetic toxicology, and (3) new technologies and approaches. The ability of these new tests and technologies to be developed into tests to identify and characterize genotoxic agents; to serve as a bridge between in vitro and in vivo rodent, or preferably human, data; or to be used to provide dose response information for quantitative risk assessment was also addressed. A summary of the workshop and links to the scientific presentations are provided.International Life Sciences Institute/Health and Environmental Sciences Institute Committe

An increased micronucleus frequency in peripheral blood lymphocytes predicts the risk of cancer in humans

none24noneS. BONASSI; A. ZNAOR; M. CEPPI; C. LANDO; W.P. CHANG; N. HOLLAND; M. KIRSCH-VOLDERS; E. ZEIGER; S. BAN; R. BARALE; M.P. BIGATTI; C. BOLOGNESI; A. CEBULSKA-WASILEWSKA; E. FABIANOVA; A. FUCIC; L. HAGMAR; G. JOKSIC; A. MARTELLI; L. MIGLIORE; E. MIRKOVA; M.R. SCARFI; A. ZIJNO; H. NORPPA; M. FENECHS., Bonassi; A., Znaor; M., Ceppi; C., Lando; W. P., Chang; N., Holland; M., KIRSCH VOLDERS; E., Zeiger; S., Ban; R., Barale; M. P., Bigatti; C., Bolognesi; A., CEBULSKA WASILEWSKA; E., Fabianova; A., Fucic; L., Hagmar; G., Joksic; Martelli, ANTONIETTA MARIA; L., Migliore; E., Mirkova; M. R., Scarfi; A., Zijno; H., Norppa; M., Fenec

Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? II. Construction and analysis of a consolidated database

A Workshop sponsored by EURL ECVAM was held in Ispra, Italy in 2013 to address the question of whether the in vitro mammalian cell genotoxicity test results could complement and mitigate the implications of a positive Ames test response for the prediction of in vivo genotoxicity and carcinogenicity, and if patterns of results could be identified. Databases of Ames-positive chemicals that were tested for in vivo genotoxicity and/or carcinogenicity were collected from different sources and analysed individually (Kirkland et al., xxxx, this issue). Because there were overlaps and inconsistent test results among chemicals in the different databases, a combined database which eliminated the overlaps and evaluated the inconsistencies would be preferable for addressing the above question. A database of >700 Ames-positive chemicals also tested in vivo was compiled, and the results in in vitro mammalian cell tests were analysed. Because the database was limited to Ames-positive chemicals, the majority (>85%) of carcinogens and in vivo genotoxins were positive when tested in both in vitro gene mutation and genotoxicity/clastogenicity tests. However, about half (>45%) of chemicals that were not carcinogenic or genotoxic in vivo also gave the same patterns of mammalian cell results. Although the different frequencies were statistically significant, positive results in 2 in vitro mammalian cell tests did not, per se, add to the predictivity of the positive Ames test. By contrast, negative results in both in vitro mammalian cell tests were rare for Ames-positive carcinogens and in vivo genotoxins but, were significantly more frequent for Ames-positive chemicals that are not carcinogenic or genotoxic in vivo. Thus, in the case of an Ames-positive chemical, negative results in 2 in vitro mammalian cell tests covering both mutation and clastogenicity/aneugenicity endpoints should be considered as indicative of absence of in vivo genotoxic or carcinogenic potential.JRC.I.5-Systems Toxicolog

DATA MINING POTENCY ESTIMATORS FROM TOXICOLOGICAL DATABASES

We discuss use of data mining techniques to study estimators of toxic potency (activity) in toxicological databases. The methods are slight variations on the standard data mining motif, but fit fully within the larger context of knowledge discovery in databases. An example illustrates the general theme of the approach, using results from a U.S. National Toxicology Program Salmonella mutagenicity database

DATA MINING POTENCY ESTIMATORS FROM TOXICOLOGICAL DATABASES

We discuss use of data mining techniques to study estimators of toxic potency (activity) in toxicological databases. The methods are slight variations on the standard data mining motif, but fit fully within the larger context of knowledge discovery in databases. An example illustrates the general theme of the approach, using results from a U.S. National Toxicology Program Salmonella mutagenicity database