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UNIVERSITY OF ZAGREB FACULTY OF FOOD TECHNOLOGY AND BIOTECHNOLOGY LABORATORY FOR TOXICOLOGY Endocrine disruptors UNIVERSITY OF ZAGREB FACULTY OF FOOD TECHNOLOGY AND BIOTECHNOLOGY LABORATORY FOR TOXICOLOGY Endocrine disruptors and animal-free toxicology Teuta Murati, Ivana Kmetič, Jasna Kniewald, Branimir Šimić Zagreb, May 11, 2013

ENDOCRINE DISRUPTING COMPOUND (EDC) “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, ENDOCRINE DISRUPTING COMPOUND (EDC) “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental process” (EPA) Ø synthetic chemicals: • industrial chemicals and their byproducts (PCBs, PBBs, TCDD) • plastics (BPA) • plasticizers (phthalates) • pesticides (methoxychlor, chlorpyrifos, DDT) • fungicides (vinclozolin) • pharmaceutical agents (DES). . Ø natural chemicals found in human and animal food (phytoestrogens)

ENDOCRINE DISRUPTING COMPOUND (EDC) Sources of EDCs • Diet • Environmental TCDD Contamination DDT ENDOCRINE DISRUPTING COMPOUND (EDC) Sources of EDCs • Diet • Environmental TCDD Contamination DDT • Plastic • Medical compounds Critical Periods • Intrauterine • Sexually dimorphic behaviors • Perinatal • Reproduction • Puberty BPA Effects • Neurodevelopment • Adult DES Mechanisms • Hormone precursors • Metabolism of steroids • Steroid receptors • Steroid-sensitive substrates PCBs Frye, C. (2012) J. Neuroendocrinol. 24, 144 -159. genistein

From Rachel to REACH 1962 Silent Spring by Rachel Carson Number of scientific publications From Rachel to REACH 1962 Silent Spring by Rachel Carson Number of scientific publications on endocrine disruptors published during 1996 - 2012 source: Web of Science (May, 2013) 2007 REACH (Registration, Evaluation, Authorisation and Restriction of Chemical substances)

number of animals used “We are not 70 kg rats” (Hartung, T. ) year number of animals used “We are not 70 kg rats” (Hartung, T. ) year Source: U. S. Department of Agriculture, Animal and Plant Health Inspection Service, September 2008 • since 1986 the EU has invested some $300 million on the development and validation of alternative approaches • Safety Evaluation Ultimately Replacing Animal Testing (SEURAT)

The 3 Rs 1959 W. Russell and R. Burch The Principles of Humane Experimental The 3 Rs 1959 W. Russell and R. Burch The Principles of Humane Experimental Technique (http: //altweb. jhsph. edu/pubs/books/humane_exp/het-toc) goal: improve existing methods so fewer animals are required goal: refine studies so animals experience as little pain and stress as possible goal: develop and implement alternatives to replace animal testing wherever possible

Reduction § rational and efficient use of animals (pilot studies) § appropriate experimental design Reduction § rational and efficient use of animals (pilot studies) § appropriate experimental design and statistical analysis of data derived from experiments § variety of animal species (greater sensitivity) Refinement § improved housing conditions and experimental techniques § use of animal species that are less sensitive to pain and suffering § reducing pain and suffering of animals to a minimum (anesthesia/analgesia, the use of the least invasive methods) § improved animal welfare 'mouse house' (MRC National Institute for Medical Research)

Replacement alternatives include the use of: physical and chemical analysis techniques mathematical and computer Replacement alternatives include the use of: physical and chemical analysis techniques mathematical and computer models (molecular modelling, (quantitative) structure-activity relationship (Q)[SAR] approaches, physiologically based pharmacokinetic [PBPK] modelling) -omics technologies in vitro systems (subcellular systems, primary cell cultures, cell lines, stem cells, whole tissues and perfused organs) organisms not classed as protected animals early developmental stages of protected animals species, before the regulations apply to them

Validation Estimated time required to achieve the full replacement of animal testing with alternative Validation Estimated time required to achieve the full replacement of animal testing with alternative method Manou, I. et al. (2005) Altern. Lab: Anim. 33, 21 -26. http: //alttox. org/ttrc/validation-ra/validated-ra-methods. html

The Dawning of a New Age of Toxicology 2007 Toxicity testing in the 21 The Dawning of a New Age of Toxicology 2007 Toxicity testing in the 21 st century: a Vision and a Strategy Approach to toxicity testing suggested by the US National Research Council Leist, M et al. (2008) ALTEX 25, 103 -114. “Sometimes, in vitro is better” (Perkel, J. M. )

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