Projects

These are the projects of the Doerenkamp-Zbinden Foundation.

A Transatlantic Think Tank of Toxicology (t4)

2009 - 2024

The concept: t4 was created with the following aims: • to analyze current tools and programs and model/forecast the likely outcome with regard to safety and economic burden (cost/benefit analyses) • to compare different approaches on an international scale (especially transatlantic) and support harmonization • to further the concept of an evidence-based toxicology (EBT) following the role model of evidence-based medicine • to develop and assess the conceptual needs to enable the change of approaches (predictive toxicology, integrated testing, systems toxicology, organotypic, and stem cell cultures) • to create and maintain information platforms (AltWeb, ALTEX, TestSmart workshops, etc.) to further the paradigm change in toxicology

Development of a comprehensive test battery for neuroteratogenicity

2013 - 2015

Less than 5% of the major industrial chemicals produced at high volumes (> 1000 tons/year) have been characterized for their potential hazard to fetal and neonatal brain development. Chemical-induced disturbances of nervous system development (= neuroteratogenicity) are well known for few compound (e.g. mercury, PCBs and toluene), and are therefore likely to occur for many others.

Human dopaminergic neurons (LUHMES cells) as substitute for transgenic animal models in neurodegenerative disease and as platform to map pathways of toxicity

2011 - 2014

In the first funding phase, LUHMES cells have been developed by the DZ chair in Konstanz as new cell model, made broadly available to laboratories world-wide.

First in vitro approaches to address repeat dose long-term toxicity

2012 - 2014

The project was designed to test the hypothesis that many compounds with a different primary mode of action would trigger developmental toxicity by a common mechanism: a change of how the genetic information of a cell is stored and accessed.

Identification of biomarkers for human neurodevelopmental nanotoxicity (Nano-DNT) in a hESC-derived in vitro model

2012 - 2013

Background: Engineered nanoparticles (NP) are entering consumer products and our environment at a fast pace. Nanoparticles can be found in food items, cosmetics, electronics and are likely to be used increasingly in medicine, where they will be actively introduced into the body. In addition, it has been shown that NP can cross the blood brain barrier and the placenta, and reach the adult as well as the fetal brain. Currently, there is no unified regulation governing nanoparticle-based products (not even separate CAS-numbers).

Modeling of pathways of developmental neurotoxicity as pilot of a paradigm shift for regulatory safety assessments of chemicals - creation of the ReTox-21c Centre-

2009 - 2012

There is a critical lack of information concerning the effects of chemicals on the developing brain. Current animal based approaches cost $1.4 million per substance. Experts have recommended the development of screening approaches based on alternative in vitro methods. The project aims to comply with this recommendation by developing a rapid systems biology approach for the assessment of developmental neurotoxicity. Expected results will demonstrate the significance of a systems biology approach to assess developmental neurotoxicity in a faster, more scientific and more humane manner.

Development of a high-throughput in vitro system to test the carcinogenic potential of chemicals

2011 - 2012

The aim of the European Community Regulation on the Registration, Evaluation, Authorisation and Restriction of Chemicals is to improve the protection of human health and the environment through the better and earlier identification of the toxic properties of chemical substances, including their carcinogenic potential. In this context thousands of chemicals have to be investigated in the next few years. In this context it is generally agreed that the number of animal experiments will drastically increase. In order to avoid the use of a very high number of animals for long-term carcinogenicity studies it is imperative that an in vitro system to test the carcinogenic potential of a high number of chemicals in a highly reproducible manner within a short period of time is developed.

Production of recombinant antibodies

2009 - 2011

Animals are frequently used to produce specific antibodies destined to a variety of protocols in fundamental research laboratories (e.g. immunoflurescence, histology, etc...). Over the last 15 years, new systems have been developed to select and produce recombinant antibodies with the help of phage display. This approach is now well established, and has the potential to virtually completely replace the use of animals for the isolation of specific antibodies. However, this technology is spreading extremely slowly, if at all, in academic research laboratories. Rabbits and mice remain the usual method for developing antibodies destined to research uses.

Establishment and validation of an improved in vitro model of the blood brain barrier

2009 - 2011

The blood brain barrier (BBB) is an important physiological and anatomical structure, and knowledge about its function is pivotal for toxicological and pharmacological predictions. In vitro models of the BBB depend on the availability of the constituting cell types. Therefore, this project was set up to generate such cells from embryonic stem cells or by immortalization of brain cells, without further need of animal tissue or animal experimentation.

Development of in vitro embrionic stem cell-based cell assays to screen for toxicity of emerging nanomaterials

2009 - 2011

Nanomaterials and nanoparticles (NPs) are revolutionizing our environment and are starting to be incorporated massively into consumer goods, will likely be used on a large scale for soil and water remediation, and are very promising for future applications in medicine. Nevertheless, not much is known about their toxicity and potential for bioaccumulation in the food chain. It is likely that expected future regulation of nanomaterials will entail a large deployment of animal testing, with long to life-time, likely painful, exposure, and sacrificing of the animals to assess long-term effects and tissue distribution/acc

Development of in vitro quality control tests to replace animal based potency tests for diphtheria and tetanus toxoid vaccines

2009 - 2011

Vaccines play a crucial role in preventive health care and consequently these products are being produced worldwide. To guarantee that vaccine lots produced are safe and potent, quality control of each lot is statutory required, many tests have to be performed. Traditionally, tests for quality control of the conventional vaccines, the products still widely used, are based on animal models.

Human dopaminergic neurons as substitute for animal models of Parkinson’s disease and for transgenic models with modified expression of PARK genes

2008 - 2010

Research in Parkinson’s disease is experiencing an upswing at the moment, on one hand due to a lack of curative drugs for the large number of patients, on the other hand due to the recent discovery of the PARK genes in families affected by the genetic form of the disease. Drug testing is nearly exclusively performed in vivo in the so-called MPP, methamphetamine and 6-hydroxydopamine models requiring tens of thousands of animals.

In vitro cell differentiation assays to replace rodent and companion animal use in tests of neurotoxicity and embryotoxicity

2008 - 2010

The requirement for a second species in chronic and developmental toxicitystudies will have a major impact on the use of rabbits and dogs in Europe, if no alternatives can be applied. A second, non-rodent species like dogs or rabbits is used not just for chemicals, but in many areas of toxicology. This happens where rodents do not sufficiently-well predict the human toxicity, and therefore a safety gap would exist if only rats and mice were used.

Development of an in vitro method for the determination of tetanus toxicity in tetanus vaccines

2009 - 2010

Tetanus vaccines are produces by treating tetanus neurotoxin (TeNT) with formalin. As a result of the formalin treatment a toxoid is produced which is still immunogenic but not toxic. In order to exclude any toxic potential of a tetanus toxoid it must be tested for “Absence of toxin and irreversibility of toxoid”. This test is mandatory according to the European Pharmacopoeia and is performed on animal models.

Replacing animal use in teaching in Eastern European universities

2010

To explore ways in which the successful introduction of alternatives (computer-based and other) into the curricula could significantly reduce the number of animals used in teaching physiology and pharmacology in Eastern and Central European* universities (*for the purposes of this proposal these include: Czech Republic, Hungary, Poland, Slovakia, Slovenia, Belarus, Estonia, Latvia, Lithuania, Ukraine, Albania, Bulgaria, Bosnia and Herzegovina, Croatia, Serbia, Republic of Macedonia, Romania, Montenegro, Turkey and Russia.)

2006 Angelo Vedani

2006 - 2008

Poor pharmacokinetics, side effects and compound toxicity are not only frequent causes of latest age failures in drug development but also a source for unnecessary animal tests.

Analysis of current reproductive toxicity assessments to reduce animal use

2007 - 2008

Under the EU REACH chemicals regulation, assessments of reproductive/developmental toxicity will be a key component for the risk assessment of chemicals. Recent impact studies have demonstrated that new toxicity testing for these endpoints using currently available methods will account for nearly 80% of all animals used (up to 18 million rats and rabbits) for fulfilling REACH information requirements.

Use of a particle exposure system to investigate the inflammation and toxicity of nanoparticles in an epithelial airway barrier model

2007

There is evidence that the inhalation of particulate matter cause increased pulmonary morbidity and mortality. Recent studies indicate a specific toxicological role of nanoparticles (<0.1μm), coming from combustion engines and from other sources (nanotechnology). There is hardly any information available on their effect on cells, tissues and organs.

Cytokine secretion profiles of immortalized human corneal cells and 3-dim human corneal constructs

2007

Aim of the project is the development of an alternative method for the Draize rabbit eye irritation test on the basis of artificial human cornea equivalents. Although different ex vivo models like the BCOP-test, isolated eye tests or the HET-CAM assay, are accepted as alternative test methods in some EU member states, none of these methods meets all the requirements to fully replace the Draize rabbit eye test.

I-CARE 2007: THE FIRST NATIONAL CONGRESS ON ALTERNATIVES TO THE USE OF ANIMALS IN RESEARCH & EDUCATION

2007

The Intenational Center for Alternatives to Research & Education (I-CARE), is an unit of People for Animals (PfA)– the largest animal welfare movement in India. The PfA was started by world renowned environmentalist and animal activist Maneka Gandhi in 1995. Today she continues to be its chairperson, governing over 160 PfA chapters across India.

InterNICHE 2007: Outreach and resources to catalyse widespread replacement in education in Latin America

2007

InterNICHE has a growing experience with outreach and training in alternatives, and with negotiating for replacement with teachers. InterNICHE resources such as the international Alternatives Loan System, the Humane Education Award grant program, and freeware production have supported this work.

set/DZF Project ProteoSys

2006

General background: Neural derivatives of human and murine embryonic stem cells (hESC and mESC) as potential replacement of animal models for stroke, Alzheimer, multiple sclerosis and ALS. The aim of this project is the characterization of endpoints from murine and human stem cell models for the quantification of neuroprotective effects of therapeutic compounds.

DZF Project Spanish version of InterNICHE book

2006

The 520–page book from Guinea Pig to Computer Mouse (InterNICHE 2003) is the primary resource for teachers, students, ethics committees and others for practical information about realistic alternatives to harmful animal use in higher education.

DZF-Project: Doris Höschele

2004

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) are the cornerstone of HIV-therapy. These agents suppress HIV-replication by blocking HIV reverse transcriptase. NRTIs can also be substrates for mitochondrial (mt) DNA polymerase g leading to depletion and mutation of mtDNA with subsequent mitochondrial dysfunction.

DZF-Project: C. Ross Ethier

2001

Background: Glaucoma describes a group of ocular conditions that involve progressive optic nerve damage causing loss of visual function. Glaucoma occurs in 0.5 to 1% of the general population in Western countries, and its prevalence increases with age, affecting up to 2.5% of those over 65 years of age

Virtual Pharmacology Lab - a repository of free educational resources to support animal-free pharmacology teaching

1990 - 2000

The Virtual Pharmacology Lab is an open access repository of quality assured learning objects designed to support pharmacology practical teaching.

DZF-Project: Karim R. Sultan

2000

First the topic was introduced by theory in a 1-2 h lecture. Then the participants were introduced to the set-up of a cell culture lab, and they started with the basics of cell culture and its handling by the “learning by doing” strategy.

DZF-Project: Jan van der Valk / David Dewhurst

2000

Background: Over recent years, there have been considerable developments in alternatives to animal experiments in teaching the bio-medical sciences.

DZF-Project Günter Niemeyer

1998

Background: Long-term general intubation-anesthesia is required to modulate the glucose level of cats by either insulin- or glucose infusion to study effects on the retina.

DZF-Project: C. Ross Ethier

1996

Background: Diseases of the cardiovascular system are the leading cause of death in Western society. It is well known that arteries have the ability to remodel in response to blood flow patterns, and that blood flow patterns play a role in the pathogenesis and progression of a number of arterial diseases, such as atherosclerosis and distal anastomotic intimal hyperplasia.

DZF-Project: Joachim Seelig

1996

Magnetic Resonance (MR) has helped to reduce the number of animal experiments since the animal can be measured non-invasively over an extended period of time and needs not to be sacrificed.

DZF-Project: Mario Raggenbass

1994

Background: In the motor system, brainstem and spinal cord motoneurons play a pivotal role. They receive and integrate movement-related information coming from the brain and control the contraction of the muscle fibers they innervate.

DZF-Project: Richard T. Robertson

1994

Background: The study of brain circuitry has attracted the attention of a large number of neuroscientists in recent years, and we now have a good understanding of the basic morphological and physiological organization of the nervous system.

DZF-Project: Michael Sittinger

1994

Background: The isolation of mammalian cells and their culture in monolayer system is a basic procedure for investigations in cell biology, intercellular molecular signals and the etiology of many diseases.

DZF-Project: Scott M. Thompson

1994

Background: Barbiturates and benzodiazepines are widely used as anti-convulsant drugs in epilepsy treatment, and also in numerous other pathologies such as anxiety and insomnia.

DZF-Project: Gerard J. Mulder

1991

In 1991 the Doehrenkamp-Zbinden foundation enabled Prof. Dr Gerard J. Mulder of the Division of Toxicology of the Leiden/Amsterdam Center for Drug Research (LACDR) at Leiden University to buy a Flow cytometer to be used in the research of the division.

DZF-Project: Arie Bruinink

1990

Background: Cell culture systems may be used to elucidate the toxicomechanisms of compounds of interest which are difficult to assess using in vivo systems. At start of the project no serum-free in vitro system was available to study neurotoxic compounds.