François Busquet: Why Europe needs the Human Toxome Project

It’s necessary because most of the scientific community now accepts that animal models for testing the safety of these products have more limitations than advantages. In basic terms, the loose genetic homology to humans is no match for modern cell-culture technology, which promises to be much more apt to correctly predict toxic effects in humans. These cell cultures can additionally be used in the high-throughput screening (HTS) necessary to test growing numbers of products. In the last 15 years, cell cultures have replaced acute/short-term in vivo tests. However, chronic/long-term tests are the real bottleneck for these models, which do not accurately represent the complexity of multiple mechanisms, and for which it is very difficult if not impossible to maintain integrity (e.g. for a month of exposure). More recently, new environmental and human health challenges have appeared along with the ubiquitous mix of chemicals in the environment, among them endocrine disruptors and nanoparticles, and no test can unequivocally determine the toxicity of – or absence of – these compounds.

In the US, the Toxic Substances Control Act Reauthorization – an equivalent of the REACH programme – might address more than 80,000 chemicals. In preparation, the ToxCast programme for predicting potential toxicity for pesticides or environmental pollutants has been started by the EPA based on HTS, and it has now been extended to nanomaterials, cosmetic ingredients and drugs that failed to make it to market. How is the US dealing with these issues? 2007 was a cornerstone year for Tox-21c and the beginning of a paradigm shift in hazard/risk assessment. The NRC’s hallmark publication “Toxicity Testing in the 21st Century: A Vision and a Strategy” prompted a new, upbeat atmosphere. Its key proposal is to base regulatory toxicology on mechanisms and modes of action (preferably human-based models). The term “pathway of toxicity” (PoT) was coined to describe this concept. Then in 2010, the EPA assessed the safety of the chemical dispersants being used to treat the massive oil spill in the Gulf of Mexico by performing HTS. Analyses were concluded in about two weeks, instead of the six months it would have taken using traditional animal models.

Assuming that the mechanisms of toxicity are finite in number, the next step would be to map and annotate all of these PoT in humans to extrapolate the toxicological effects at the individual scale. To this end, it makes sense to create a public database of PoT – the Human Toxome. This could tackle animal welfare in laboratory experiments, speed up access to market for safer and better products and aid in the development of new analytical tools based on the knowledge gained. Pilot projects steered by CAAT and funded by the NIH and the FDA already exist. At the moment, they are focussed on endocrine disruptors and neurotoxicity pathways respectively. Discussions about a European branch have been initiated for the project, which is likely to be the size of the Human Genome Project – a task not for a single group, but for the international community.

François Busquet

François Busquet studied Biotechnologies at the ENSTBB in France. He graduated from the TU Dresden, completing his PhD at the MerckSerono group in Germany on the development of a new screening assay to detect proteratogenic compounds using zebrafish embryos. After his studies, he worked in ECVAM at the Joint Research Centre (European Commission) in Italy on the coordination of the OECD validation study of the zebrafish embryo toxicity test. Since 2012, Dr Busquet has been responsible for the CAAT-EU Policy Programme in Brussels.