UNIVERSITY OF ZAGREB FACULTY OF FOOD TECHNOLOGY AND BIOTECHNOLOGY LABORATORY FOR TOXICOLOGY
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Endocrine disruptors and Endocrine disruptors and animal-free toxicologyanimal-free toxicology
Teuta Murati, Ivana Kmetič, Jasna Kniewald, Branimir Šimić
Zagreb, May 11, 2013
ENDOCRINE DISRUPTING COMPOUND (EDC)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)
synthetic chemicals:• industrial chemicals and their byproducts (PCBs, PBBs, TCDD) • plastics (BPA) • plasticizers (phthalates) • pesticides (methoxychlor, chlorpyrifos, DDT) • fungicides (vinclozolin) • pharmaceutical agents (DES)....
natural chemicals found in human and animal food (phytoestrogens)
ENDOCRINE DISRUPTING COMPOUND (EDC)ENDOCRINE DISRUPTING COMPOUND (EDC)
Frye, C. (2012) J. Neuroendocrinol. 24, 144-159.
DES
DDT
BPA
TCDD
PCBs genistein
Sources of EDCs
• Diet
• Environmental
Contamination
• Plastic
• Medical compounds
Effects
• Sexually dimorphic behaviors
• Reproduction
• Neurodevelopment
Critical Periods
• Intrauterine
• Perinatal
• Puberty
• AdultMechanisms
• Hormone precursors
• Metabolism of steroids
• Steroid receptors
• Steroid-sensitive
substrates
From Rachel to REACHFrom Rachel to REACH
1962 Silent Spring by Rachel Carson
2007 REACH (Registration, Evaluation, Authorisation and Restriction of Chemical substances)
source: Web of Science (May, 2013)
0
100
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1996
1997
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2012
year
nu
mb
er o
f p
ub
licat
ion
s
Number of scientific publications on endocrine disruptors published during 1996 - 2012
Source: U.S. Department of Agriculture, Animal and Plant Health Inspection Service, September 2008
year
num
ber
of a
nim
als
used
• Safety Evaluation Ultimately Replacing Animal Testing (SEURAT)
“We are not 70 kg rats” (Hartung, T.)
• since 1986 the EU has invested some $300 million on the development and validation of alternative approaches
The 3RsThe 3Rs
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
ReductionReduction
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)
RefinementRefinement 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)
ReplacementReplacement
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
ValidationValidation
Manou, I. et al. (2005) Altern. Lab: Anim. 33, 21-26.
Estimated time required to achieve the full replacement of animal testing with alternative method
http://alttox.org/ttrc/validation-ra/validated-ra-methods.html
The Dawning of a New Age of ToxicologyThe Dawning of a New Age of Toxicology
2007 Toxicity testing in the 21st century: a Vision and a Strategy
Leist, M et al. (2008) ALTEX 25, 103-114.
Approach to toxicity testing suggested by the US National Research Council
“Sometimes, in vitro is better” (Perkel, J.M.)
Thank you for your attention
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