S70 Abstracts / Toxicology Letters 221S (2013) S59–S256

P03-02Breast cancer in Danish women: A prospectivecase–control study on breast cancer risk uponexposure to perfluorinated compounds

Eva Cecilie Bonefeld-Jorgensen ∗, Manhai Long, Stine F. Overvad,Jørn Olsen

Department for Public Health, Aarhus University, Denmark

Breast cancer (BC) is the most common cancer for women in thewestern world. Exposure to persistent organic pollutants (POPs)such as polychlorinated biphenyls (PCBs) might contribute to therisk of BC. Animal studies indicate that perfluorinated compounds(PFCs) impact on mammary tissues causing increases in mammaryfibroadenomas. Recently, we demonstrated a significant associa-tion between serum PFC and BC risk in Greenlandic Inuit.

The aim of the present prospective study was to evaluate asso-ciations between serum levels of PFCs in young Danish women andthe risk of BC later in life.

The study includes samples from 250 BC cases and 233 con-trols prospectively sampled during 1996–2002. The serum levels of16 PFCs (perfluorocarboxylated acids (PFCAs), perfluorosulfonatedacids (PFSAs) and perflurooctane-sulfonamide (PFOSA)) weredetermined by liquid chromatography-tandem mass spectrome-try with electrospray ionization in negative mode. Questionnairesdata for sampling age, body mass index before pregnancy, parity,oral contraceptives use, menarche age, smoking, beer and winedrinking, maternal education and physical activity.

Data quartiles showed that the BC cases had significantly higherserum level of perfluorooctanoic acid (PFOA) and PFOSA than thatof controls after adjustment for age, BMI, parity, OC use, menar-che age, smoking, beer and wine drinking, maternal education andphysical activity. An increased tendency of odds ratio in quartilesof PFOA, sum PFSA and sum PFCA upon adjustment for confounderswas observed.

In summary, the serum level of PFCs is a risk factor for develop-ment of BC in Danish women supported by our previous study inGreenlandic Inuit.

http://dx.doi.org/10.1016/j.toxlet.2013.05.049

P03-03Carcinogenicity testing of eliglustat in themouse and rat

Rafif Dagher 1,∗, Judith Marquis 1, Malene Watzinger 2, RoyForster 2

1 Genzyme Corporation, Waltham, USA, 2 CiToxLAB, Evreux, France

Eliglustat is in development for oral treatment of the inheritedmetabolic disorder Gaucher disease type 1 (GD1). This lysoso-mal storage disease results from a deficiency of the catabolicenzyme acid-(�)-glucosidase leading to accumulation of glycolipid.The principal substrate of acid-(�)-glucosidase is glucosylceramide(GL-1); eliglustat acts to reduce production of GL-1 by inhibition ofglucosylceramide synthase. Since treatment of GD1 patients willrequire chronic treatment with eliglustat, carcinogenicity stud-ies are required. We have evaluated potential carcinogenicity inchronic (2-year) bioassays in the Swiss CD-1 mouse (by dietaryadministration) and Sprague-Dawley rat (by oral gavage). In themouse study, treatment with eliglustat did not influence overallsurvival rates of treated mice at dose-levels up to 75 mg/kg/day.Reduced bodyweight gain at the high dose level indicated that theMTD had been achieved. At histopathology, no treatment related

increases in tumour incidence were observed in any groups ofeliglustat treated mice. Similarly, in the rat study there was no effectof eliglustat on the overall survival rates up to the high dose level(75 (males) or 50 mg/kg/day (females)). Reduced bodyweight gainat the high dose level indicated that the MTD had been achieved. Athistopathology, no treatment related increases in tumour incidencewere observed in any groups of eliglustat treated rats. The onlyneoplastic lesions that were noted were among those that occurspontaneously in these animal models. It was concluded that eliglu-stat is not carcinogenic after oral administration to mice or rats.

http://dx.doi.org/10.1016/j.toxlet.2013.05.050

P03-04Cigarette sidestream smoke is a source ofenvironmental estrogen

Lih-Ann Li ∗, Lun-Cheng Kuo, Chun-Ju Lin, Pei-Rung Wu

Division of Environmental Health and Occupational Medicine,National Health Research Institutes, Zhunan, Miaoli, Taiwan, ROC

Serum estrogen level and tumor aromatase expression exhibitan inverse association with poor prognosis of lung adenocarcinoma,suggesting that estrogen plays a role in promoting this cancer.Exposure to exogenous estrogen is expected to increase the risk oflung adenocarcinoma. Secondhand cigarette smoke, a major envi-ronmental risk factor for never smokers, contains vast amountsof aromatic compounds in the particulate phase. In this study,we examine whether the extract of cigarette sidestream smokeparticulates (CSSP) has estrogenic and/or antiestrogenic effects inlung adenocarcinoma cells. Our results demonstrate that the CSSPextract contains a dose-dependent estrogenic effect and activatesER� cumulatively with 17�-estradiol (E2) in lung adenocarcinomacells. ICI 182,780 antagonizes CSSP-induced ER� transcriptionalactivity as well as that induced by E2. However, the CSSP extractregulates the nuclear entry, serine phosphorylation, and proteindegradation of ER� in a similar but different manner from E2. Ascompared with E2 and ICI 182,780, ER� is rather stable under theCSSP treatment, suggesting that CSSP has a long-lasting estrogeniceffect.

http://dx.doi.org/10.1016/j.toxlet.2013.05.051

P03-05Combined effect of the SOD mimicMnTnHex-2-PyP5+ and doxorubicin on themigration and invasiveness of breast cancercells

A.S. Fernandes 1,2,∗, A. Flórido 1,2, M. Cipriano 2, I.Batinic-Haberle 3, J. Miranda 2, N. Saraiva 1, P.S. Guerreiro 2, M.Castro 2, N.G. Oliveira 2

1 CBIOS, University Lusófona, Campo Grande 376, 1749-024 Lisboa,Portugal, 2 Research Institute for Medicines and PharmaceuticalSciences (iMed.UL), Fac. Farmácia da University Lisboa, Av. Prof.Gama Pinto, 1649-003 Lisboa, Portugal, 3 Department of RadiationOncology, Duke University Medical School, Durham, NC, USA

Breast cancer metastases are a major cause of cancer mortal-ity. Reactive oxygen species (ROS) have been greatly implicated incancer at different levels, including in cell migration and invasion,which are key determinants for the metastatic process. MnTnHex-2-PyP5+ is a porphyrin-based potent superoxide dismutase mimic