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The Center for Alternatives to Animal Testing - Europe (CAAT-EU): a Transatlantic Bridge for the Paradigm Shift in Toxicology


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The Center for Alternatives to Animal Testing - Europe (CAAT-EU) was founded based collaboration between the Johns Hopkins Bloomberg School of Public Health and the University of Konstanz. CAAT-EU, housed at the University of Konstanz, will coordinate transatlantic activities to promote humane science in research and education, and participate, as partner or coordinator, in publicly and privately funded European projects. Thomas Hartung will serve as program liaison representing Johns Hopkins University and Marcel Leist as the University of Konstanz liaison. CAAT-EU aims to: 1) Set up transatlantic consortia for international research projects on alternative methods. 2) Establish a CAAT Europe faculty and advisory board composed of sponsor representatives and prominent academics from Europe . 3) Participate in the Transatlantic Think Tank for Toxicology (t4) devoted to conceptual work for the paradigm shift in toxicology. 4) Coordinate a series of information days in Europe on relevant developments in the US, similar to the 2009 series CAAT held in the US on EU issues (one on the 7th Amendment to the EU Cosmetics Directive and one on EU and US chemical regulation). 5) Support ALTEX as the official journal of CAAT and CAAT-EU. 6) Develop strategic projects with sponsors to promote humane science and new toxicology, especially with CAAT faculty members. 7) Develop a joint education program between Johns Hopkins and the University of Konstanz, such as e-courses and the existing Humane Science Certificate program developed by CAAT, a student exchange program, and collaboration with the International Graduate School "Cell-based Characterization of De- and Regeneration" in Konstanz.
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ALTEX 27, 1/10 63
The Center for Alternatives to Animal
Testing – Europe (CAAT-EU):
a Transatlantic Bridge for the Paradigm
Shift in Toxicology
Mardas Daneshian 1, Marcel Leist1,2 and Thomas Hartung1, 3
1CAAT-EU and 2Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz,
Germany; 3CAAT, Doerenkamp-Zbinden Chair for Evidence-based Toxicology, Johns Hopkins University, Bloomberg School
of Public Health, Baltimore, USA
1 Introduction
W. M. S. Russell and R. L. Burch introduced The Principles
of Humane Experimental Technique (Russell and Burch, 1959),
dening the 3Rs – replacement, reduction, and renement – as
the key strategies for humane research. Russell and Burch’s
work has led to a continually evolving search for non-animal
alternative methods. In Europe in particular, this has resulted
in funding programs and a horizontal laboratory animal welfare
legislation. In addition, legislation specic to industrial sector
chemicals and cosmetics has become the driving force for a
paradigm shift in toxicology. In fact, the 7th Amendment to the
Cosmetics Directive has become an engine of change, due to
the unprecedented commitment of the cosmetics and consum-
er product industries to meet its challenges (Hartung, 2008c).
REACH (Registration, Evaluation, Authorisation and Restric-
tion of Chemicals), a recent attempt to improve consumer pro-
tection, is unparalleled in size. REACH is the European Un-
ion’s program to evaluate the safety of at least 30,000 synthetic
chemicals (Rovida and Hartung, 2009) that are already in use
(Hartung, 2010b).
More recently, in the US, an exciting discussion has begun.
Generally referred to as Toxicology for the 21st century (Tox-
21c), this approach derives from a report published by the Na-
tional Research Council /National Academy of Sciences in 2007
(NRC, 2007). It is prompted less by animal welfare considera-
tions than by concerns regarding the limited quality and through-
put of traditional approaches. Tox-21c embraces the latest tech-
The Center for Alternatives to Animal Testing – Europe (CAAT-EU) was founded based a collaboration
between the Johns Hopkins Bloomberg School of Public Health and the University of Konstanz. CAAT-EU,
housed at the University of Konstanz, will coordinate transatlantic activities to promote humane science
in research and education, and participate, as partner or coordinator, in publicly and privately funded
European projects. Thomas Hartung will serve as program liaison representing Johns Hopkins University
and Marcel Leist as the University of Konstanz liaison.
CAAT-EU aims to:
Set up transatlantic consortia for international research projects on alternative methods
Establish a CAAT Europe faculty and advisory board composed of sponsor representatives and prominent
academics from Europe
Participate in the Transatlantic Think Tank for Toxicology (t 4) devoted to conceptual work for the
paradigm shift in toxicology
Coordinate a series of information days in Europe on relevant developments in the US, similar to the
2009 series CAAT held in the US on EU issues (one on the 7th Amendment to the EU Cosmetics Directive
and one on EU and US chemical regulation)
 SupportALTEXastheofcialjournalofCAATandCAAT-EU
Develop strategic projects with sponsors to promote humane science and new toxicology, especially
with CAAT faculty members
Develop a joint education program between Johns Hopkins and the University of Konstanz, such as
program, and collaboration with the International Graduate School “Cell-based Characterization of
De- and Regeneration” in Konstanz
Keywords: 3Rs, Tox-21c, dissemination, science strategy, international harmonization
Daneshian e t a l .
ALTEX 27, 1/10
CAAT has organized regular meetings of global 3Rs centers at
the last three World Congresses on Alternatives and has devel-
oped a joint 3Rs and Alternatives Organizations website (http://
The establishment of CAAT-Europe (CAAT-EU) will bring to-
gether a number of activities in the eld of alternatives to animal
experiments and novel approaches in toxicology at the Universi-
ty of Konstanz and combine them strategically with the activities
of CAAT at Johns Hopkins University in Baltimore. The core of
this partnership is formed by the respective chairs for alternative
approaches in Konstanz and Baltimore, both endowed by the Do-
erenkamp-Zbinden Foundation (
(Wendel, 2002; Leist, 2006). This transatlantic partnership will
enable coordinated activities aimed at promoting research and
instruction in humane science (Hartung et al., 2009), developing
strategic partnerships with stakeholder organizations, and raising
funds from industrial and private sponsors, as well as participat-
ing in and/or coordinating EU-funded projects.
2 CAAT-US: the Johns Hopkins Center for
Alternatives to Animal Testing, Johns Hopkins
University, Bloomberg School of Public Health
(Baltimore, USA)
Henry Spira (1927-1998) is widely regarded as one of the most
effective animal rights activists of the 20th century (Singer,
1998). Spira is credited with formulating the idea of “reintegra-
tive shaming,” a technique the animal protection movement uses
to convince opponents to change and encourages working with
them, rather than rejecting and vilifying them. Working with
Animal Rights International, a group he founded in 1974, Spira
is particularly remembered for his 1980 full-page advertisement
in The New York Times. This famous ad, featuring a rabbit with
sticking plaster over the eyes, asked, “How many rabbits does
Revlon blind for beauty’s sake?” The day the ad appeared, Spira,
nologies. Today, research into alternative approaches extends to
the development of human cell-based high throughput and high-
content methods, as well as computational techniques in the eld
of safety control, exploiting state-of-the-art knowledge of bio-
chemical and genetic changes (Collins et al., 2008; Hartung and
Leist, 2008; Leist et al., 2008; Kavlok et al., 2009). However, we
are still far from dening reliable test procedures with human-
relevant alternative assessment methods (Hartung, 2009a).
The increasing interest in the eld of alternatives has led to
the establishment of national, international, governmental, and
non-governmental institutions, programs and competence cent-
ers, which are committed exclusively or in part to the issue of
alternatives to animal experiments. These include the Organi-
sation for Economic Co-operation and Development (OECD),
Interagency Coordinating Committee on the Validation of Alter-
native Methods (ICCVAM), the European Centre for the Valida-
tion of Alternative Methods (ECVAM), FRAME (Fund for the
Replacement of Animals in Medical Experiments), and others.
The Johns Hopkins Center for Alternatives to Animal Testing
(CAAT) is a prominent US institution that has been promoting
3Rs research and human-relevant safety testing for almost three
decades (Zurlo and Goldberg, 1996; Goldberg, 2008; Gold-
berg, 2010). The Center is well known for its effectiveness in
the communication, dissemination, and promotion of scientic
information about humane science.
The challenge for competence centers dealing with alterna-
tive methods is a) to bridge the gaps in communication between
the chemical, pharmaceutical, and cosmetic industries and sci-
entists or regulatory authorities, b) to acquire and coordinate
scientic projects aimed at developing new, relevant alternative
methods and disseminating information on these, and c) to sup-
port the implementation of alternative methods by regulatory
bodies. Up to now, the different national and supranational com-
petence centers in this eld have worked independently of each
other at the expense of their impact. In an effort to change this,
Fig. 1: Scheme of the current CAAT-EU sponsor and collaborator network
Daneshian e t a l .
ALTEX 27, 1/10 65
Center for the Evaluation of Alternative Toxicological Methods),
IIVS (Institute for In Vitro Sciences, Inc., Gaithersburg, http://, and ECOPA (European Consensus Platform for
Alternatives,, making ALTEX a primary
information source for alternative approaches.
CAAT’s efforts include close collaboration with legislators to
explore the legal changes necessary to bring about the imple-
mentation of alternative innovations, e.g. the concept of Tox-
21c. CAAT’s impact in the eld is substantial, and for nearly
three decades, the Center has been a key player in many activi-
ties and meetings of the US government concerning safety test-
ing and alternative methods.
The establishment of the Transatlantic Think Tank for Toxi-
cology (t4), with partners in Utrecht (Bas Blaauboer) and Kon-
stanz (Marcel Leist), enables conceptual work to be developed
for the paradigm shift in toxicology without the pressures of
regulating or being regulated. For this purpose, t4 organizes
workshops and stimulates analyses and studies for reporting
in ALTEX. These include state-of-the-art reviews of method-
ologies and cost/benet analyses, as well as economical, ethi-
cal, and philosophical analyses. Systematic reviews translating
dressed in a bunny costume, paraded with a few hundred pro-
testers in front of Revlon’s headquarters in New York. Within
a year, Revlon had donated $ 750,000 to a fund to investigate
alternatives to animal testing at Rockefeller University. The US
Cosmetic, Toiletry, & Fragrance Association (CTFA, now known
as PCPC) then collected substantial donations from Avon, Bris-
tol Meyers, Estée Lauder, Max Factor, Chanel, and Mary Kay
Cosmetics. These funds led to the creation of the Center for Al-
ternatives to Animal Testing ( at the Johns
Hopkins University in Baltimore, headed by Alan Goldberg for
27 years. A wide variety of industries, foundations, and partner
organizations have joined the program over the years. CAAT is
now directed by Thomas Hartung, the former (2002-2008) Head
of the European Centre for the Validation of Alternative Methods
As one of the rst competence centers in the eld of 3Rs re-
search, CAAT has been a most effective promoter of human-rele-
vant methodology and the 3Rs principles since 1981. Today CAAT
enjoys broad support from various industries and foundations
(Tab. 1). The advisory board of CAAT consists of representatives
from the scientic community, sponsoring industries, regulatory
authorities, and animal welfare organizations. This stakeholder
representation, unique in the US, has facilitated communication
and the ow of information, which are essential for the implemen-
tation of innovative and relevant alternative test methods.
As a scientic and academic center, one of CAAT’s most ef-
fective and inuential roles is to stimulate and fund the develop-
ment of alternative methods. Since its inauguration, CAAT has
funded more than ten scientic projects per year, injecting more
than $ 6 million into research on alternatives. Here, the unique
composition of the advisory board makes it possible to explore
required and relevant alternative methods based on actual de-
mands. CAAT also offers periodic workshops that are highly
respected and draw attendees from around the world.
The mission of CAAT also includes communication and ex-
change between scientists and institutions on alternative methods.
The World Congress on Alternatives & Animal Use in the Life
Sciences, conceived and organized by CAAT in 1992, is the larg-
est platform for the exchange of information and updates in the
eld. The World Congress regularly draws close to 1,000 scien-
tists, regulatory authorities, animal welfare advocates, students,
and other interested participants from a variety of disciplines.
From the outset, CAAT has been a major force in the dissemi-
nation of information about the 3Rs. CAAT’s internet portal,
Altweb (, is a pivotal access source for
international news and information about alternative methods.
Altweb attracts more than 500 visitors per day, illustrating both
great public interest in the eld of alternative methods and also
the signicant role CAAT plays in the ow of information.
As of 2009, CAAT also serves as the US editorial ofce of the
scientic journal ALTEX. Now entirely in English and available
at reduced rates for members of select alternatives organizations,
ALTEX is becoming one of the leading international journals in
its eld. Most recent additions are regular “news corners” for spe-
cic organizations. These include ICCVAM/NICEATM (The In-
teragency Coordinating Committee on the Validation of Alterna-
tive Methods and the National Toxicology Program Interagency
Tab. 1: Companies and foundations supporting
Abbott Laboratories
Alberto-Culver Company*
Alternatives Research and Development Foundation
American Chemical Council
Beiersdorf (CAAT-EU)*
Bernice Barbour Foundation Inc.*
Bristol-Myers Squibb
Charles River Foundation
Clorox Company
The Coca-Cola Company*
Dial Corporation
Doerenkamp-Zbinden Foundation
ExxonMobil Biomedical Science, Inc.*
Humane Society of the US
Johnson & Johnson*
L’Oréal (CAAT-EU)
Lucille Ellis Simon Foundation
Procter & Gamble Company*
Research Institute for Fragrance
Materials (RIFM)
Shell Oil Company*
*sponsors, i.e. > 60.000 $/€
Daneshian e t a l .
ALTEX 27, 1/10
students. It has a strong tradition in in vitro pharmacology and
toxicology, and established Europe’s rst chair for In Vitro
Toxicology and Biomedicine. The University of Konstanz has a
biomedical focus – unique in Germany – in the Department of
Biology, which recently led to the installation of “Disease Biol-
ogy” as a new focal area within the Biological Sciences masters
program. However, this reects only the most recent of two dec-
ades of developments in biochemical pharmacology and mo-
lecular toxicology, including the development of special lecture
series, several graduate schools, and research groups nanced
by the German Research Council, and an innovative concept of
combined animal housing and alternative method development
under one roof. In this context, alternative methods have been a
focus of the University for many years with:
Marcel Leist, PhD, Co-Director of CAAT-EU, Doerenkamp-
Zbinden Endowed Professor and Chair for In Vitro Toxicology
and Biomedicine. His work focuses on neurotoxicity, including
the use of human stem cells (Leist et al. 2008c). He holds an
MSc in toxicology and a PhD in biochemical pharmacology. He
was assistant/associate professor of toxicology at the University
of Konstanz from 1995-2000. Until 2006, he worked as Head
of Department on a broad range of toxicological and pharma-
cological projects within an industrial setting at H. Lundbeck
A/S (Copenhagen, DK). He has published more than 120 peer-
reviewed papers.
Alexander Bürkle, MD, Professor and Chair of Molecular Toxi-
cology, whose focus is on genetic toxicology, poly(ADP-ribo-
syl)ation, neurotoxicology, and prion diseases. Among others,
the group established an improved, automated version of the
uorescence-detected alkaline DNA unwinding (FADU) assay
to quantify formation and repair of DNA strand breaks in living
Daniel Dietrich, PhD, Chair of Environmental Toxicology at
the University of Konstanz, with adjunct professorships at the
Institute of Technology (ETH) in Zurich, Switzerland, and the
University of Pittsburgh, School of Public Health, Pittsburgh,
USA. Dr. Dietrich has been on several task forces at ECVAM, is
an expert for the US Environmental Protection Agency (EPA),
presently co-chair of the Validation Management Group “Non-
Animal Testing” of the OECD, and a major partner in several
FP7 EU-funded projects aimed at better use and predictivity of
high-throughput techniques (CHEMSCREEN) as well as im-
proved safety sciences education in the pharmaceutical industry
(IMI-JU SafeSciMET).
Thomas Hartung, MD, PhD, honorary full professor of pharma-
cology and toxicology, in parallel with his position as Director
of CAAT at JHU.
Albrecht Wendel, PhD, Professor and Chair emeritus of Bio-
chemical Pharmacology, Presently CEO of the Interfaculty
Center for Pharmacogenomics and Pharma Research (ICEPHA)
at the University of Tübingen, Germany, and formerly CEO of
the Steinbeis Technology Transfer Center for In vitro Pharma-
cology and Toxicology (STZ InPuT) 1996-2008. The center has
carried out more than 100 contracts with companies and the
public sector in eight countries.
Franz Gruber, DVM, PhD, acting as hon. assoc. professor, Pres-
ident of the Doerenkamp-Zbinden Foundation, Switzerland;
methods of evidence-based medicine to toxicology are of par-
ticular interest. The Chair for Evidence-based Toxicology aims
to promote this concept (Hoffmann and Hartung, 2005, 2006;
Griesinger et al., 2009; Hartung, 2009b) and to foster links with
the US Cochrane Center at Johns Hopkins. A sabbatical pro-
gram is in preparation, which will allow colleagues to join the
Chair for a couple of months to work on a dedicated project.
CAAT’s long-standing commitment to developmental neuro-
toxicity (DNT), as evidenced by the organization of TestSmart
workshops in 2005 and 2008 and a joint workshop with EC-
VAM in 2005, has enabled the establishment of research labora-
tories addressing DNT. Organotypic cell cultures, human stem
cell models, mass-spectrum based metabolomics, and genomics
are used to identify pathways of toxicity. This work builds upon
earlier studies conducted at ECVAM (van Vliet et al., 2007,
2008; Hogberg et al., 2009a,b) and will be continued at CAAT
by Erwin van Vliet and Helena Hogberg, who joined the CAAT
team as post-docs.
The CAAT team includes:
Thomas Hartung, Director of CAAT, Co-Director of CAAT-
EU, Professor and Endowed Chair (Doerenkamp-Zbinden
Foundation) for Evidence-based Toxicology, Bloomberg
School of Public Health, Johns Hopkins University. He holds
a diploma in biochemistry, a PhD from Konstanz (Biochemi-
cal Pharmacology) and an MD from Tübingen (Toxicology).
From 1996-2002 he was CEO with Albrecht Wendel of the
Steinbeis Technology Transfer Center for In Vitro Pharma-
cology and Toxicology (InPuT). In 2003, he became hon-
orary full professor for pharmacology and toxicology at the
University of Konstanz. From 2002 to 2008, he was Head
of ECVAM (Joint Research Centre, JRC, Italy). He has au-
thored more than 340 publications and participated in more
than 20 EU projects. He is Vice-President of EUSAAT and
board member of ECOPA.
Alan Goldberg, PhD, Founding Director of CAAT (1981-
2008) and Professor, Chairman of the Board of CAAT
Assoc. Professor Paul Locke, JD, DrPH, Deputy Director
CAAT policy program
Dr. Joanne Zurlo, Deputy Director CAAT science strategy
Ruth Brady, Carol Howard, Michael Hughes, Betsy Merrill,
Liza Mohamed, Marilyn Principe, CAAT staff
CAAT faculty, a number of professors associated with CAAT
and serving on the Board and various projects, including Drs.
Jim Yager (JHU-SPH), Mike Trush (JHU-SPH), Joe Bressler
(Kennedy-Krieger Institute, Baltimore), Pamela Lein (UC
Davis), Gihan Tennakoon (Children’s Hospital of Philadel-
phia), Bernard Robaire (McGill University, Montreal), Sid
Green (Howard University, Washington DC), and Wally
Hayes (Harvard).
3 The unique biomedical competence at the
University of Konstanz
The University of Konstanz ( is one
of the nine German excellence universities and has about 11,000
Daneshian e t a l .
ALTEX 27, 1/10 67
Editor-in-chief of ALTEX, the 25-year-old journal on alterna-
tives to animal experimentation, edited by the Swiss Society
ALTEX Edition and published by Springer. ALTEX is also the
ofcial journal of EUSAAT and CAAT.
Sonja von Aulock, PhD, lling the position of an assoc. profes-
sor; in vitro pharmacology, toxicology and immunology, includ-
ing work on the alternative pyrogen test; subeditor of ALTEX.
At the University of Konstanz an alternative pyrogen test was
developed (Hartung and Wendel, 1995; Daneshian et al., 2009)
and validated (Hoffmann et al., 2005; Schindler et al., 2006,
2009), which was accepted by the European Pharmacopoeia and
the US Food and Drug Administration (FDA) in 2009. The test
will be marketed by Biotest microbiology unit (hycon@biotest.
de). The development of this in vitro kit, containing all neces-
sary components, under the name of Pyro-Detect System is in
its nal stage. First test kits for customer trial are available.
4 Necessity of transatlantic collaboration
For North American and European countries the last decades
were characterized by a rapid development of industry, associ-
ated economic benets, and individual comfort. This comfort is
largely based on products from the chemical, cosmetic, and phar-
maceutical industries, but toxicological data for approximately
86% of the synthetic chemicals in use today are fragmentary or
lacking (Hartung, 2009c). It seems obvious that this large quan-
tity of information, so vital to consumer protection, can be gath-
ered most effectively in a joint effort between governments and
the scientic community on both sides of the Atlantic.
Although the US and Europe have attained comparable lev-
els of development and, therefore, have the same needs, their
emphases on regulation and scientic attention differ in vari-
ous areas (Hartung and Bottini, 2009). This is especially so
for the role of alternative approaches. Where the Europeans
started with REACH and the 7th Amendment to the Cosmetics
Directive, i.e., the characterization of synthetic chemicals and
the legal restriction of animal tests, the US National Academy
of Sciences, with “Toxicity Testing and Assessment in the 21st
Century” (Tox-21c), stress the implementation of high-through-
put, human-relevant alternative methods in regulatory safety
control. These are not developments heading immediately in
opposite directions, but their different approaches mean that US
companies will have difculties targeting the European market,
and Europeans may be left behind, lacking the potential impact
of the Tox-21c in their regulatory toxicology.
As multinational companies are global players and their small-
er national providers indirectly depend on the same markets,
their struggle through the rampant jungles of national and supra-
national regulatory affairs are economically counterproductive.
Science is borderless; academics contribute to regionally differ-
ing safety approaches pending current local political decisions,
so any lack of collaboration is also scientically counterproduc-
tive. Most notably, industries as well governments benet eco-
nomically and scientically from harmonization of transatlantic
regulations. The not-always-harmonized current state throws a
wrench into the economies on both side of the Atlantic. Taken
together, both sides are on a par with regard to their needs and
are at a similar stage of industrial and scientic development.
Moreover, both the EU and the US have taken on pioneering
roles in protecting consumer safety. Unfortunately, the differ-
ent directions and speeds of development on each side of the
Atlantic may constrain both sides, whereas harmonization could
lead to synergy. We have seen the tremendous impact of harmo-
nization on OECD and ICH levels on avoiding duplicate animal
testing (Bottini et al., 2007). This success may have overshot its
goal, however, leading to a high inertia with respect to further
changes and making it difcult to further optimize the guide-
lines, e.g. in adaptation to technical progress.
5 CAAT-EU: Center for Alternatives to Animal
Testing – Europe at the University of Konstanz,
Germany, the first international academic
competence center for alternative approaches
The unique and promising concepts upon which CAAT is
founded have served the eld of alternative methods and safety
control well in the US for nearly three decades. Its concepts and
structure will be adapted for the establishment of its European
counterpart. CAAT and CAAT-EU are committed to the critical
evaluation of in vivo (Hartung, 2008), in vitro (Hartung, 2007),
and in silico (Hartung and Hoffmann, 2009) approaches, espe-
cially those that follow principles of evidence-based toxicol-
ogy (Hoffmann and Hartung, 2006) and the Tox-21c movement
(Hartung, 2009a,c). CAAT’s efforts – on both sides of the Atlan-
tic address cosmetics (Hartung, 2008), chemicals (Hartung,
2010), food (Hartung and Koëter, 2008), and pharmaceuticals.
The creation of CAAT-EU was announced at the 7th World
Congress on Alternatives and Animal Use in the Life Sci-
ences, held in Rome, Italy (August 30 - September 3, 2009).
The Memorandum of Understanding between the Johns Hop-
kins Bloomberg School of Public Health and the University of
Konstanz was signed in December 2009, and the rst sponsors
came onboard immediately: BASF, Beiersdorf, L’Oréal, and the
Doerenkamp-Zbinden Foundation.
CAAT-EU at the University of Konstanz will be established in
rooms currently used by Professors Leist, Hartung and Bürkle.
Dr. Mardas Daneshian will direct its daily activities, with the aid
of administrative staff.
The goals and visions of this transatlantic competence center
Establishing a European advisory board consisting of experts
from basic science, regulatory agencies, industry, and animal
welfare. This synergy will lead to innovative and relevant al-
ternative testing methods and research tools, lending support
to the search for realistic decisions on ongoing projects (for
example, REACH). The CAAT-EU faculty and board will in-
clude sponsor representatives, as well as prominent European
academics (including Prof. Dr. Michael Schwarz, Tübingen,
Germany; Prof. Dr. Bas Blaauboer, Doerenkamp-Zbinden
Professor for Alternative Methods, Utrecht, The Netherlands;
Prof. Dr. Walter Pfaller, Medical University of Innsbruck,
Austria; and Dr. Joanna Jaworska, P&G, Brussels, Belgium).
Daneshian e t a l .
ALTEX 27, 1/10
“consensus” meaning that the major stakeholders, i.e. animal
welfare, industry, academia, and governmental institutions,
are equally represented. ECOPA is active in science, educa-
tion, and ethical issues with respect to 3Rs alternatives with 16
national platforms. EuroGroup for Animals – the leading ani-
mal welfare organization of the EU – has represented its more
than forty member organizations for more than 25 years. The
group provides advice and expertise on animal welfare to the
European institutions – the Council of Ministers, the European
Parliament, and the European Commission.
6 Additional remarks
Due to the hesitant awakening and high inertia of regulatory
toxicology, academics still have to struggle with rigidities in
this eld, and huge numbers of animals are used in tests that
may not be relevant for increasing safety of humans. Here the
paradigm shift in toxicology leads to a change in the underly-
ing theoretical concept of safety sciences. The term “human-
relevant method” is often misunderstood as just a technical im-
provement of methods. This human-centric idea tends to ignore
the value of the animal. Indeed, the community probably runs
the risk of forgetting that education toward the involvement of
non-animal methods is pivotal for installation of ethical values
into the scientic community.
At this point we wish to stress that CAAT-EU advocates and
welcomes the paradigm shift in toxicology but also denes the
“ethical idea of 3Rs” and “human-relevant methods” as two
sides of the same coin.
Bottini, A. A. and Hartung, T. (2009). Food for thought … on eco-
nomics of animal testing. ALTEX 26, 3-16.
Bottini, A. A., Amcoff, P. and Hartung, T. (2007). Food for thought
… on globalization of alternative methods. ALTEX 24, 255-
Collins, F. S., Gray, G. M. and Bucher, J. R. (2008). Toxicology
Transforming environmental health protection. Science 319,
Daneshian, M., von Aulock, S. and Hartung, T. (2009). Assessment
of pyrogenic contaminations with the validated human whole
blood assay. Nature Protocols 12, 1709-1721.
Goldberg, A. M. (2009). The role of an academic center. ATLA, in
Goldberg, A. M. (2008). The science of alternatives: 25 years and
tomorrow. AATEX 14, Spec. Issue, 29-36.
Griesinger, C., Hoffmann, S., Kinsner-Ovaskainen, A., Coecke, S.
and Hartung, T. (2009). Proceedings of the First International
Forum Towards Evidence-Based Toxicology. Conference Cen-
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28, 81-163.
Hartung, T. (2010a). Lessons learned from alternative methods and
their validation for a new toxicology in the 21st century. J. Toxi-
col. Environ. Health, in press.
Establishing a broad industrial sponsor base and developing
strategic projects with sponsoring industrial partners to pro-
mote humane science and new toxicology in projects, espe-
cially with CAAT faculty members.
Setting up and partnering in transatlantic consortia. First ex-
amples addressed nanotoxicology and several applications in
the call for proposals put forward by the EU and cosmetic
industry, making available € 50 million for systemic toxicity
alternatives. The focus will be on human-relevant alternative
methods making safety control and research more ethically
Setting the course for transatlantic convergence in regula-
tory toxicology and 3Rs research. CAAT-EU promises a real
transatlantic dialogue as a credible academic platform.
Developing joint education programs between Johns Hopkins
University and the University of Konstanz that involve addi-
tional academic institutions (Hartung et al., 2009), for exam-
ple the e-courses and certicate programs on humane science
developed by CAAT, student exchange, and collaboration in
the International Graduate School (International Research
Training Group – IRTG 1331 – “Cell-based Characterization
of De- and Regeneration”, Konstanz, Germany and Zürich,
Switzerland), which is currently applying to the German Re-
search Council (DFG) for an extension.
Providing a strong academic voice as expert counsel for
questions concerning current and developing non-animal
safety methods and research tools, as well as supporting fur-
ther developments in these elds in different countries.
Participating in programs, projects, congresses, and work-
shops worldwide that deal with the issues of safety control
and in vitro test methods. The center will participate in the
Transatlantic Think Tank for Toxicology (t4), devoted to
conceptual work for the paradigm shift in toxicology. The
center will offer a series of information days in Europe on
relevant developments from the US, similar to the programs
held on developments in Europe by CAAT in the US. The
rst information day, planned for June/July 2010, will pro-
vide an overview of US activities toward “Toxicology for
the 21st century”. A workshop on education in alternative
approaches is planned for October 2010.
Supporting ALTEX as the ofcial journal of CAAT and
CAAT-EU, and disseminating information on achievements
in the eld of alternative testing via Altweb (http://altweb.
Making industrial partners aware of the evident synergistic
benet of transatlantic CAAT boards: direct interaction and
collaboration with regulatory authorities, access to sound,
substantive scientic knowledge, and rsthand updates on
scientic and regulatory developments.
Steering the conceptual draft for a global human toxicology
project (Hartung, 2010a; Seidle and Stephens, 2009).
CAAT-EU has initiated the rst strategic collaborations with
ECOPA ( and EuroGroup for Animals
(, which are represent-
ed on the CAAT-EU board. ECOPA is a quadripartite NGO-
organization that promotes the 3Rs in Europe. It brings togeth-
er national consensus platforms on alternative methods, with
Daneshian e t a l .
ALTEX 27, 1/10 69
Leist, M., Kadereit, S. and Schildknecht, S. (2008b). Food for
thought ... on the real value of 3R approaches. ALTEX 25, 17-
Leist, M., Bremer, S., Brundin, P. et al. (2008c). The biological and
ethical basis of the use of embryonic stem cells for in vitro tests
and cell therapy. ALTEX 25, 163-190.
Leist, M. (2006). What can a chair on alternatives to animal experi-
mentation effectuate? ALTEX 23, 211-213.
NRC – National Research Council US (2007). Committee on tox-
icity testing and assessment of environmental agents, National
Research Council: Toxicity testing in the 21st century: a vision
and a strategy (pp. 196). The National Academies Press. http://
Rovida, C. and Hartung, T. (2009). Re-evaluation of animal num-
bers and costs for in vivo tests to accomplish REACH legislation
requirements for chemicals – a report by the transatlantic think
tank for toxicology (t4). ALTEX 26, 187-208.
Russell, W. M. S. and Burch, R. L. (1959). The principles of hu-
mane experimental technique. London, England: Methuen.
Schindler, S., von Aulock, S., Daneshian, M. and Hartung, T.
(2009). Development, validation and applications of the mono-
cyte activation test for pyrogens based on human whole blood.
ALTEX 26, 293-305.
Schindler, S., Spreitzer, I., Loschner, B. et al. (2006). International
validation of pyrogen tests based on cryopreserved human pri-
mary blood cells. J. Immunol. Meth. 316, 42-51.
Seidle, T. and Stephens, M. L. (2009). Bringing toxicology into the
21st century: A global call to action. Toxicol. In Vitro 23, 1576-
Singer, P. (1998). Ethics Into Action: Henry Spira and the Animal
Rights Movement (pp. 223). Lanham, USA: Rowman and Lit-
tleeld Publishers.
van Vliet, E., Morath, S., Linge, J. et al. (2008). A novel in vitro
metabolomics approach for neurotoxicity testing, proof of prin-
ciple for methyl mercury chloride and caffeine. Neurotox. 29,
van Vliet, E., Stoppini, L., Balestrino, M. et al. (2007). Electro-
physiological recording of re-aggregating brain cell cultures on
multi-electrode arrays to detect acute neurotoxic effects. Neuro-
tox. 28, 1136-1146.
Wendel, A. (2002). Do we need a “Chair of alternative methods”,
and where? ALTEX 19, 64-68.
Zurlo, J. and Goldberg, A. M. (1999). The Role of an Academic
Center in Promoting Common Goals. Cambridge Quarterly of
Healthcare Ethics 8, 58-63.
Correspondence to
CAAT-EU at the University of Konstanz
Dr. Mardas Daneshian
Universitätsstr. 10
78464 Konstanz
Phone: +49 7531 884685
Hartung, T. (2010b). Food for thought … on alternative methods
for chemical safety testing. ALTEX, this issue.
Hartung, T., Blaauboer, B. and Leist, M. (2009). Food for thought
on education of alternative methods in toxicology. ALTEX
26, 255-263.
Hartung, T. (2009a). A toxicology for the 21st century: Mapping
the road ahead. Tox. Sci. 109, 18-23.
Hartung, T. (2009b). Food for thought … on evidence-based toxi-
cology. ALTEX 26, 75-82.
Hartung, T. (2009c). Toxicology for the twenty-rst century. Na-
ture 460, 208-212.
Hartung, T. and Hoffmann, S. (2009). Food for thought on …. in
silico methods in toxicology. ALTEX 26, 155-166.
Hartung, T. and Rovida, C. (2009). Chemical regulators have over-
reached. Nature 460, 1080-1081.
Hartung, T. (2008a). Towards a new toxicology – evolution or rev-
olution? ATLA 36, 635-639.
Hartung, T. (2008b). Food for thought … on animal tests. ALTEX
25, 3-9.
Hartung, T. (2008c). Food for thought ... on alternative methods for
cosmetics safety testing. ALTEX 25, 147-162.
Hartung, T. and Koëter, H. (2008). Food for thought ... on food
safety testing. ALTEX 25, 259-264.
Hartung, T. and Leist, M. (2008). Food for thought … on the evo-
lution of toxicology and phasing out of animal testing. ALTEX
25, 91-96.
Hartung, T. (2007a). Food for thought on cell culture. ALTEX
24, 143-147.
Hartung, T. (2007b). Food for thought … on validation. ALTEX
24, 67-72.
Hartung, T., Balls, M., Bardouille, C. et al. (2002). Report of
ECVAM task force on good cell culture practice (GCCP). ATLA
30, 407-414.
Hartung, T. and Wendel, A. (1995). Die Erfassung von Pyrogenen
in einem humanen Vollblutmodell (Detection of pyrogens using
human whole blood). ALTEX 12, 70-75.
Hoffmann, S. and Hartung, T. (2006). Towards an evidence-based
toxicology. Human Exp. Toxicol. 25, 497-513.
Hoffmann, S. and Hartung, T. (2005). Diagnosis: Toxic! – Trying
to apply approaches of clinical diagnostics and prevalence in
toxicology considerations. Tox. Sci. 85, 422-428.
Hoffmann, S., Peterbauer, A., Schindler, S. et al. (2005). Interna-
tional validation of novel pyrogen tests based on the human fe-
ver reaction. J. Immunol. Meth. 298, 161-173.
Hogberg, H., Kinsner, A., Hartung, T. et al. (2009). Gene expres-
sion as a sensitive endpoint to evaluate cell differentiation and
maturation of the developing central nervous system in primary
cultures of rat cerebellar granule cells (CGCs) exposed to pesti-
cides. Toxicol. Appl. Pharmacol. 235, 268-286.
Hogberg, H. T., Kinsner-Ovaskainen, A., Coecke, S. et al. (2010).
mRNA expression is a relevant tool to identify developmental
neurotoxicants using an in vitro approach. Tox. Sci. 113, 95-115.
Kavlock, R. J., Austin, C. P. and Tice, R. R. (2009). Commentary
– Toxicity Testing in the 21st Century: Implications for Human
Health Risk Assessment. Risk Analysis 29, 485-487.
Leist, M., Hartung, T. and Nicotera, P. (2008a). The dawning of a
new age of toxicology. ALTEX 25, 103-114.
... In 2010, the Center for Alternatives to Animal Testing in Europe (CAAT-EU), located at the University of Konstanz, was founded. 23 CAAT-EU coordinates the transatlantic activities to promote the development of new and improved methods in toxicology together with CAAT at Johns Hopkins University, Baltimore, USA. ...
... 26 CAAT-USA is part of the Johns Hopkins University Bloomberg School of Public Health, Baltimore, now with a European branch (CAAT-Europe), located at the University of Konstanz, Germany since 2010. 23 This transatlantic organisation, with ties to all parts of the world, promotes humane science by supporting the creation, development, validation and use of alternatives to animals in research, product safety testing and education. Internationally, CAAT for many years organised Three Rs centre meetings as satellites to world conferences, and maintained a joint platform on the AltWeb website (now transitioned to ...
... CAAT-Europe was founded in 2010 to coordinate transatlantic activities around the development of new and improved methods in toxicology, to be a partner in strategy development, to provide platforms for different stakeholders, to exchange ideas and to support the Three Rs principles of humane science in different ways. 23 Dr Thomas Hartung serves as programme liaison representing Johns Hopkins, and Dr Marcel Leist serves as the University of Konstanz co-director. CAAT-Europe's key areas are consumer protection, human health, new approach methodologies (NAMs), the Three Rs in general, toxicological testing strategies and systems toxicology, information and education on NAM and the Three Rs. [27][28][29][30][31][32][33][34][35][36][37][38][39] Charité 3 R : Charité 3 R ( ...
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Public awareness and discussion about animal experiments and replacement methods has greatly increased in recent years. The term 'the Three Rs', which stands for the Replacement, Reduction and Refinement of animal experiments, is inseparably linked in this context. A common goal within the Three Rs scientific community is to develop predictive non-animal models and to better integrate all available data from in vitro, in silico and omics technologies into regulatory decision-making processes regarding, for example, the toxicity of chemicals, drugs or food ingredients. In addition, it is a general concern to implement (human) non-animal methods in basic research. Toward these efforts, there has been an ever-increasing number of Three Rs centres and platforms established over recent years - not only to develop novel methods, but also to disseminate knowledge and help to implement the Three Rs principles in policies and education. The adoption of Directive 2010/63/EU on the protection of animals used for scientific purposes gave a strong impetus to the creation of Three Rs initiatives, in the form of centres and platforms. As the first of a series of papers, this article gives an overview of the European Three Rs centres and platforms, and their historical development. The subsequent articles, to be published over the course of ATLA's 50th Anniversary year, will summarise the current focus and tasks as well as the future and the plans of the Three Rs centres and platforms. The Three Rs centres and platforms are very important points of contact and play an immense role in their respective countries as 'on the ground' facilitators of Directive 2010/63/EU. They are also invaluable for the widespread dissemination of information and for promoting implementation of the Three Rs in general.
... An important element will therefore be a series of consensus workshops defining the database, its content, its validation, and its governance. CAAt and its transatlantic think tank for toxicology (t 4 ) (Daneshian et al., 2010) aim to organize these. ...
... In parallel with the experimental bench work in the laboratory, we also try to contribute to the field in other ways through CAAT-Europe (14). This institution works very hard on animal replacement, by supplying scientific information to the field in the form of workshop reports (15,16), and by lobbying and communicating at the level of politicians and other stakeholders relevant to in vitro toxicology applications. ...
The complex toxicological fields of repeat dose organ toxicity (RDT) and developmental and reproductive toxicity (DART) still require new concepts and approaches to achieve a fully animal-free safety assessment of chemicals. One novel approach is the generation of relevant human cell types from pluripotent stem cells, and the use of such cells for the establishment of phenotypic test methods. Due to their broad endpoints, such tests capture multiple types of toxicants, i.e.They are a readout for the activation of many adverse outcome pathways (AOPs). The 2016 Lush Science Prize was awarded for the development of one such assay, the PeriTox test, which uses human peripheral neurons generated from stem cells. The assay endpoints measure various cell functions, and these give information on the potential neurotoxicity and developmental neurotoxicity hazard of test compounds. The PeriTox test method has a high predictivity and sensitivity for peripheral neurotoxicants, and thus addresses the inherent challenges in pesticide testing and drug development. Data from the test can be obtained quickly and at a relatively high-Throughput, and thus, the assay has the potential to replace animal-based safety assessment during early product development or for screening potential environmental toxicants.
... The workshop and the preparation of the five whitepapers were supported by CAAT-Europe (Daneshian et al., 2010) and the Doerenkamp-Zbinden Foundation. T. Hartung would like to thank Andre Kleensang and Robert Borotkanics for input on the ...
... A recent report published by the European Commission stated that sufficiently validated methods are not yet available in these domains. This opinion was confirmed by a large expert panel (Hartung et al., 2011) assembled by the Center for Alternatives to Animal Testing in Europe -CAAT-Europe (Daneshian et al., 2010). Thus, test development and validation are well under way, with high pressure in these domains. ...
... there is some similarity with the effort of mapping the human genome (HUGO), but here annotation was easy, i.e., a sequence of four bases. CAAt (Daneshian et al., 2010) will host a series of workshops starting later this year to develop consensus on PoT identification, definition, validation, annotation, and sharing. Uri Alon (Alon, 2007, fig. ...
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... Since its founding in 2010 (Daneshian et al., 2010), CAAteurope has been interested in all european projects that focus on the development of new strategies for toxicity testing in the interest of the 3Rs, and in the promotion of the vision depicted in the tox21c document (NRC, 2007), which seeks a toxicology that is based on the mechanisms of action in humans rather than on animal models whose relevance is questionable. For this reason, CAAt-europe accepted the role as co-partner in the organization of a final event that had the goal of presenting the achievements of the Sens-it-iv project in combination with the latest discoveries by other research teams that are active in the field of skin and respiratory sensitization. ...
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The 3Rs of alternatives started to be recognized at the end of the 60s with the establishment of FRAME and then experienced explosive growth in the 80s. The last 25 years have been remarkable, with the establishment of centers and programs dedicated to the 3Rs all over the world. This World Congress, being held in Japan, marks a milestone in the global reach of the 3Rs. Like all endeavors, what one learns at the beginning may not hold true as a field develops and matures – initial truths may not be current realities -the theme of this presentation. When William Russell and Rex Burch published "The Principles of Humane Experimental Technique" in 1959, the concept of replacement was that a non-whole animal assay would replace an animal test. The initial truth, a one for one replacement, has been superceded by a new reality – the necessity for batteries of tests and strategies for in vitro testing approaches. From method development to validation, the simple initial truths have been replaced by complex current realities. In 25 years, we have experienced, in the words of Thomas Kuhn, a scientific revolution. The presentation will look at the last 25 years of initial truths and will explore our current realities and our successes. In 1959, the goals laid out by Bill Russell & Rex Burch were far reaching almost beyond comprehension and a distant, very distant dream. That dream is our current reality.
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Europe and the United States further the development of new toxicological tools in different ways. While the replacement of animal tests has been promoted strongly in Europe over the last decades (following the 3Rs principles--reduce, replace, refine), in the United States the vision for a toxicology in the 21st century (Tox-21c), which was prompted by the National Research Council document only 3 years ago, dominates the discussion. In both cases, there is significant political support. However, while in Europe the horizontal animal welfare legislation from 1986 (which urges the use of 3Rs methods wherever possible) currently under revision and cosmetics and chemical legislation are the primary drivers, in the United States it is mainly federal agencies, most prominently the U.S. Environmental Protection Agency (EPA), that made the implementation of the NRC report their toxicity testing strategy only in 2009. This preempts such likely legislative measures as the reauthorization of the Toxic Substances Control Act (TSCA) in the United States. The European implementation is characterized by substantial broad funding programs to develop 3Rs methods and can be termed a "bottom-up" approach; in contrast, the Tox-21 program represents a "top-down" approach, where programmed research is carried out and commissioned. It is postulated that the two approaches are two sides of the same coin, and instruct and complement each other. However, more importantly, if brought together they can result in a Human Toxicology Project and a real revolution in regulatory toxicology.
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Microorganisms such as Gram-negative or Gram-positive bacteria, viruses and fungi contain components that activate the innate immune system. These components, called pyrogens (Greek: pyros=fire), can occur independently of viable microorganisms and are a major safety concern in parenterally administered drugs, since they can cause severe reactions such as fever, organ failure, and shock in the recipient. So far these drugs have been tested by injecting them intravenously into rabbits and measuring their fever reaction or, alternatively, by the Limulus Amoebocyte Lysate (LAL) test, employing the coagulation of the hemolymph lysate of Limulus polyphemus. Both tests have inherent limitations. A new in vitro monocyte activation test (MAT) based on human whole blood, capable of measuring all pyrogens relevant to the human patient, introduced in this journal in 1995, was validated and recently accepted by European Pharmacopoeia and US FDA. This review describes its principle, development, validation and the wide spectrum of applications, such as for testing of medical devices, blood products, toxic or immunomodulatory drugs, dialysis liquids, lipidic parenterals, and air quality. This alternative method promises to replace the rabbit pyrogen test fully and to overcome several limitations of the LAL assay.
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The EU REACH legislation for chemicals of 2006 represents the largest investment into consumer product safety ever. A reanalysis of cost and animal use estimates was carried out based on the final legislation, test guidance for industry published by the European Chemical Agency, and the preregistration completed in December 2008. The new estimates for the number of substances falling under REACH range from 68 to 101,000 chemicals, substantially exceeding the earlier estimates of 29,000 substances. The latter estimates were, however, based on data before 1994 and both expansion of the EU and growth of the chemical industry since have contributed to higher numbers today. The lower estimate of 68,000 chemicals was carried through current testing requirements with due regard to emerging alternative approaches, using in all cases the most optimistic assumptions (minimal animal numbers per test and neglecting most triggering of additional tests and confirmatory (re-)tests as well as tests requested but not yet defined for endocrine disruption, respiratory irritation, respiratory sensitization and developmental neurotoxicity). The most demanding studies are in the area of reproductive toxicity testing with about 90% of all animal use and 70% of the required costs for registration. The overall result suggests a demand of 54 million vertebrate animals and testing costs of 9.5 billion euro. This clearly challenges the feasibility of the program without a major investment into high-throughput methodologies.
On FRAME's 40th anniversary, I had the opportunity to examine FRAME and CAAT's missions as closely linked to those of their universities. The roles of education, research and service are key, both to the universities and to our two centres. By examining the current programmes, and identifying the needs of the future, the research activities, policy studies and training, it becomes clear that the Three Rs of alternatives contribute significantly to our respective universities' missions.