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Overview of existing in vitro methods and methods under development of regulatory interest in Denmark, Sweden and Finland

(status of October 4th 2005)

by Marie Louise Hagen, secretary of Nordic co-ordination group for the development of test methods in toxicology and ecotoxicology (Nord-UTTE),

as a reply to the ECVAM survey on major players in the field of alternative methods

Denmark

Endocrine disruption

University of Southern Denmark, Odense (Poul Bjerregaard):

• Survey of estrogen activity in Danish freshwater environments (YES assay)

 Danish Institute for Food and Veterinary Research (Anne Marie Vinggaard):

• Examination of combined effects of pesticides with anti-androgenic activity

• Gathering of data for a QSAR model of the anti-androgenic effect of chemicals (AR reporter gen assay)

• Examination of Ah-receptor assay (CALUX) for use in screening of foodstuffs and feed for contents of dioxin-like chemicals

• Assays which has previously been used, but are not used at the moment: 1) estrogen-receptor assay (MCF-7 and MVLN cells), 2) aromatase activity (JEG cells and placenta microsomes).

• Development and pre-validation of steroid synthesis assay (H295R cells) for determination of anti-androgens working through inhibition of steroid synthesis.

University of Southern Denmark, Odense (Helle Raun Andersen): 

• Examination of the combined effects of pesticides with estrogenic activity (MCF7 cells)

• Examination of human serum for total content of estrogen-like chemicals in MCF7 cells (the natural estrogens are removed with HPLC)

• Skin penetration assay for human dermal absorption of especially pesticides.

Århus University (Eva Bonefeld Jørgensen):

• Examination of the effects of chemicals on the functions of thyroid hormone (GH3 cells), estrogen-receptor activity (MCF-7 og MVLN cells), Ah-receptor activity (Hepa1.2 & TV101l cells), androgen-receptor activity (CHO-K1 cells), aromatase activity (JEG cells).

• Examination of human serum for xeno-hormone activities. Natural hormones are removed with HPLC before analysis of ER- and AR-activity (MCF7- and CHO-K1 cells). Plans of developing a similar method for analysis of thyroid hormone like activities of environmental contaminants in human blood.

• Examination of total dioxin-like activity in human blood

• Development of thyroid specific analysis: Effects of environmental contaminants on growth of rat pituitary gland cells in culture and analysis of effects of environmental contaminants on rat growth hormone.

• Examination of the inflammatory potential in human full blood: Determination of the effect of environmental contaminants and other allergenic agents in the environment on cytokine gene expression and release of cytokines from cells in the blood.

• Determination of in vitro gene expression after exposure to environmental contaminants (animal and human cell lines). Focus on genes known to be regulated by hormones. 

Reproductive toxicity

Danish Institute for Food and Veterinary Research (Otto Meyer)

• REPROTECT – an ECVAM lead project, in which Sweden also participates. Aims at developing a test strategy that can replace in vivo test methods. Otto Meyer is in the Supervising Board.

Carcinogenicity

Copenhagen University, Panum (Anja Wellejus)

Testes cancer

• Oxidative damage in testes cells by exposure to estrogens (comet assay)

 Danish Institute for Food and Veterinary Research (Christine Nellemann)

Breast cancer

• Searching for biomarkers present both in vivo and in vitro – for the purpose of refining or replacing the in vivo tests with two in vitro assays, using a human breast cancer cell line (MCF-7) and rat breast cancer cell line (CRL 1743)

Sweden

Endocrine Disruption

Karolinska Institutet ( Helena Håkansson)

• Development of a multivariate approach for toxicological validation with emphasis on Ah-receptor mediated toxicity in vitro.

Umeå University (Per-Erik Olsson)

• Development of novel methods (in vitro and refinement of in vivo) for determination of endocrine disruption.

Akademiska Sjukhuset, Uppsala (Matts Olovsson, Carolina Bredhult)

• Evaluation of cultured cells from the human reproductive system as a model for studying endocrine disrupters potential effects on human reproduction.

Carcinogenicity

University of Lund (Kersti Alm, Stina Oredsson)

• An in vitro test system to replace tests for tumorigenic properties in mice.

Genotoxicity

Stockholm University (Thomas Helleday)

• Effects on DNA repair systems (DRAG-test)

Karolinska Institutet  (Ulla Stenius)

• In vitro-method for determination and classification of genotoxicity: MDM2-phosphorylation /accumulation in syncronised cells.

Karolinska Institutet (Annelie E. Meijer, Kerstin Holmberg)

• Chromosomal instability in human lymphocytes – an alternative in vitro system for testing cancer risks of chemical substances.

Acute toxicity

Cecilia Clemedson, scientific coordinator

• A-Cute-Tox, optimisation and pre-validation of an in vitro test strategy for predicting human acute toxicity .

Eye irritation

Stockholm University (Anna Forsby)

• Development of an in vitro test for prediction of weak eye irritants.

Sensitisation

University of Gothenburg (Ann-Therese Karlberg)

• Development of in vitro tests to assess the sensitising properties of chemicals.

Swedish National Food Administration (Ulf Hammarling)

• Computer based evaluation of allergenic potential of proteins, especially in food allergy.

Neurotoxicity

Karolinska Institutet (Sandra Ceccatelli)

• Development of methods for in vitro toxicity testing of neurotoxic volatile compounds.

University of Gothenburg (Margareta Wallin Peterson)

• An in vitro method for testing neurotoxic compounds.

Ecotoxicity

Karolinska Institutet (Inger Kuhn, Jenny Gabrielsson)

• Microbial Assay for Risk Assessment (MARA).

Additional

Karolinska Institutet (Maria Falkenberg Gustafsson)

• Development of in vitro tests that can replace animal models for assessment of the mitochondrial toxicity of nukleoside-analogues.

Huddinge University Hospital (Suchitra Holgersson)

• Generation of foetal liver stem cells for testing of drug toxicity.

Stockholm University (Igor Belyaev)

• Validation of a residual foci method aimed at replacing animal drug tests with a fast and sensitive in vitro method.

University of Gothenburg  (Anders Lindahl)

• Development of test systems for analysis of  toxicity based on human embryonal stem cells.

Uppsala University (Lennart Dencker)

• A toxicogenomic approach to developmental toxicity.

Umeå University (Mikael Harju)

• Prediction of the binding affinity of brominated flam retardants to the androgenic receptor. Development of  quantitative structure activity relationships (QSAR).

Karolinska Institutet (Monica Lind, Annika Hanberg)

• Development of an in vitro test system for screening of substances potentially toxic to bone.

NOVUM, Huddinge (Lennart Möller, Hanna Karlsson)

• Evaluation of the toxicity of particles using the CULTEX-system and cultured human lung cells.

Finland

Endocrine disruption

University of  Turku, Department of Biology, Department of Physiology (Jorma Toppari, Jorma Paranko)

• E.g. follicular steroidogenesis in vitro (isolated rat ovarian follicles).

National Public Health Institute, Department of Environmental Health (Matti Viluksela):

• E.g. effects of POPs in mesenchymal stem cell differentiation, toxicity in different cell lines (osteosarcoma cell line)

Carcinogenicity/Tumor Promotion

National Public Health Institute, Department of Environmental Health (Hannu Komulainen, Jorma Mäki-Paakkanen):

• Effects of chemicals on gap junction intercellular communication (GJIC) in vitro

• Mutagenicity and genotoxicity tests in vitro, two-stage cell transformation test in vitro

Neurotoxicity

University of Tampere, Medical School, Cell Research Center (Tarja Toimela, Hanna Tähti):

• E.g. cytotoxicity and mechanisms of toxicity of metals, in vitro models of blood-brain barrier, eye toxicity in vitro

University of  Kuopio, Department of Pharmacology and Toxicology (Jarkko Loikkanen):

• E.g. cellular mechanisms of neurotoxicity  (for example lead)

Immunotoxicity

National Public Health Institute, Department of Environmental Health (Maija-Riitta Hirvonen):

• Cytotoxicity, cytokines, apoptosis in immunocompetent cells

Kinetics

University of Kuopio, Department of Pharmacology and Toxicology (Kirsi Vähäkangas):

• An in vitro model for evaluation of  placenta perfusion.

Ecotoxicity

University of  Turku, Department of Biology (Piia Leskinen, Matti Karp)

• yeast ER assay for screening estrogenic potential

• other in vitro screening tools

VTT Biotechnology (Merja Itävaara)

• DNA microchip development for ecotoxicity and biodegradation potential assays

Finnish Environment Institute, Research Department (Eija Schultz, Tarja Nakari, Jukka Ahtiainen):

• luminescent bacteria tests (standard and kinetic flash- version for solid and turbid samples)

• RET (reverse electron transport) assay with mitochondrial particles

• VTG fish (rainbow trout) liver cell assay

• Vitotox- genotoxicity assay (Salmonella)

• soil enzyme activity assay (Zym profiler) for soil quality and chemicals' effect assessments