ASAT: Reversing the Paradigm in Toxicity Testing!
He has recently retired from Unilever as Senior Vice President of Safety and Environmental Assurance. He was Professor in Clinical Toxicology at the Faculty of Medicine in Utrecht, head of the Poison Control Centre of the National Institute for Public Health and the Environment and head of the Intensive Care department of the University Hospital Utrecht.
Subsequently he was Director Public Health at the Institute for Public Health and the Environment. Before joining Unilever he was Director General for Health at the Ministry for Health, Welfare and Sports in the Netherlands.
In this section of AltTox, “The Way Forward”, an excellent summary of the NAS paper has been provided by Andersen et al. (2). In 2008 Kim Boekelheide, also writing on AltTox, states that “A Paradigm Shift in Toxicity Testing Is Inevitable” (3). And he is right. In his paper he gives all the reasons to change, to fundamentally change. The arguments range from the limitations of the current system to the opportunities that are offered by science and technology that have arrived only yesterday.
Whilst surrounded by opportunities to get ready for the future we should not forget to pay tribute to the classical approach to safety that has served us well for about 40-50 years. Huge safety factors have reduced the probability that the hazard based NOAEL in experimental animals might be a wolf in sheep’s clothing threatening our health.
The main objective of toxicity testing is to deliver “safety” to man and the environment. We all know that safety as such is not achievable and actually does not exist. We therefore acknowledge that safety equals an acceptable health risk for man and the living environment.
Toxicity testing starts from the chemical and its biological effects. These effects need interpretation and the results have to be extrapolated to man. There is a generally felt need for an improved capability to interpret toxicological data. Toxicological risk assessment is seeking new approaches such as translational toxicology, the threshold of toxicological concern concept and intelligent testing.
Since safety stands for an acceptable health risk, it’s appropriate to ask what that health risk or better health risks might be. In other words what health damage and what disease have we considered and prevented when we declare something safe? Honesty dictates to admit we don’t know exactly what health risks we have reduced to an acceptable level when, for example, the use of a chemical is declared safe.
In the world of safety there is a need for Toxicology to better predict effects in man and for Public Health and Occupational Health to more explicitly indicating what human health risks have to be managed. This happens to coincide with the arrival of new science and technology with a huge potential to better understand the underpinning biology of man. It is plausible that the required improvement can be achieved by reversing instead of shifting the paradigm, in conjunction with all the other efforts that are currently going on.
In 2004 Fentem et al. (4) published an approach that shows what this reversed paradigm might be able to deliver. It proposes to start from the (public) health risks that have to be assessed. It seeks the potential of new science and technology and puts human biology centre stage. It advocates building in vitro and in silico models for the human biology that is responsible for the risks to be assessed. Exposing these models to chemicals and their metabolites will generate the data and information that is necessary for the assessment of the various risks. The objective is to deliver safety, health protection, using human data only. That is why last but not least it provides a perspective that makes animal testing as a means to generate data and information for risk assessment redundant.
In 2007 Fentem and Westmorland (5) published their paper “RISK ASSESSMENT + NEW TECHNOLOGIES: Opportunities to Assure Safety Without Animal Testing and Better Protect Public Health?” in this section of AltTox. This paper provides a comprehensive overview of the science involved, the hurdles that have to be taken and the research programme that is being carried out at Unilever.
It is the Netherlands’ research organisation ZonMw (6) that can take credit for inventing the acronym ASAT, Assuring Safety without Animal Testing, in 2005. It used ASAT to describe the approach in a letter to the Minister for Health, Welfare and Sports informing him about the outcome of an invitational conference on the subject that had been organised by ZonMw and the Royal Netherlands Academy of Arts and Sciences (KNAW) at the request of this and several other Cabinet Ministers. The Minister for Health is also responsible for government policy on animal testing.
The ASAT-Initiative, summarized in the accompanying figure, was subsequently developed to raise awareness of the proposed approach for public health based health protection–awareness amongst scientists and safety professionals in the private as well as the public sector such as regulatory agencies. It aims at raising awareness and interest in its opportunities amongst stakeholders such as policy makers and politicians, funding organisations and NGOs. By operating in a transparent way it seeks to inform the public as well. It is obvious that the ASAT-Initiative has been seeking a wider audience than the Netherlands.
With the arrival of a new Netherlands’ Government, a proposal was developed in 2006 and submitted in January 2007. During 2007/8 at the request of the Ministry several working conferences were held involving scientists from across Europe and the US, with a background ranging from food to pharma and from the public as well as the private sector. The objectives were to asses support for the approach and provide recommendations to the Minister. This resulted in the release of €1.2 million for 2008/9. SenterNovem (7) was asked to carryout the ASAT-Innovation Programme and advise the Ministry by the end of 2009 on how to proceed.
Turning the ASAT-Initiative into reality will be a huge effort requiring the input of many: scientists actually generating the knowledge and building the models, and safety professionals ranging from the public to the private sector and ranging from the world of food additives to cosmetics and pesticides. The same applies to input from and interaction with stakeholders ranging from policy makers to politicians, NGOs and the media. A possible approach for such an open, international and multidisciplinary enterprise is given in the report ASAT Starting the Programme, that was delivered in March 2008 (8).
The ASAT-Foundation was started late 2008. Its objective is to support and advance the ASAT-Initiative.
©2009 Bart Sangster
- National Research Council (NRC). (2007). Toxicity Testing in the 21st Century: A Vision and A Strategy. National Academy Press, Washington, DC. Available here.
- Andersen, M.E., Krewski, D., Mantus, E. & Zeise, L. (2008). Toxicity Testing in the 21st Century. http://www.AltTox.org. Available here.
- Boekelheide, K. (2008). A Paradigm Shift in Toxicity Testing is Inevitable. http://www.AltTox.org. Available here.
- Fentem, J., Chamberlain, M. & Sangster, B. (2004). The feasibility of replacing animal testing for assessing consumer safety: a suggested future direction. Altern. Lab. Anim.32, 617-623.
- Fentem, J. & Westmoreland, C. (2007). RISK ASSESSMENT + NEW TECHNOLOGIES: Opportunities to Assure Safety Without Animal Testing and Better Protect Public Health? http://www.AltTox.org. Available here.