Introduction to Safety Science in the 21st Century

Unilever’s Safety & Environmental Assurance Centre is an organisation that constantly seeks to bring new science solutions to the safety and environmental impact assessment of the ingredients in Unilever products. The toxicology that underpins those assessments is rapidly evolving. In 2007 a landmark in the evolution was reached with the publication of the US National Academy of Sciences report ‘Toxicity Testing in the 21st Century [TT21C]: a Vision and a Strategy’. The academy identified the need for a fundamental change in the way safety assessments are carried out, envisioning “a not-so-distant future in which virtually all routine testing would be conducted in human cells or lines in vitro”.

This publication has itself transformed the science of ‘alternatives to animal testing’ from one based on developing in vitro one-to-one replacements for existing animal toxicology tests to a science based on mechanistic understanding of key biological pathways (‘toxicity pathways’) which, if sufficiently perturbed by a chemical, would result in an adverse outcome for the individual or environment that was exposed.

Since the publication of this framework, others in the US, Europe and China have endorsed the approach as a priority for the research needed to implement the vision. These pathway-based approaches to safety aim to apply recent developments in bioinformatics, mathematical modelling and high-content /‘omics’ technologies to take a Systems Biology approach to exposure-led risk assessment of the effects of new chemicals on both human health and the environment.

Such in vitro tools combined with mechanistic chemistry information on ingredients allow the identification of potential biological targets, toxicological liabilities and mechanistic information for elucidation of adverse outcome pathways (AOPs); a new concept in chemical safety assessment introduced by the OECD. Each AOP begins with a ‘Molecular Initiating Event’  in which the chemical interacts with a biological target leading to a potential sequence of events across different levels of biological organisation resulting in an adverse outcome with direct relevance to a given risk assessment context. The OECD has started to formalize a universal chemicals risk assessment framework based on AOPs to capture and peer review the mechanistic understanding of specific toxic effects, and for the evaluation of non-animal methods that aim to predict key events in these pathways.

There is still the need for the development of new tools in this space (e.g. additional methods to address specific organ and specialized cell types, plus the pressing need to consider xenobiotic metabolism). It is also important to consider how such in vitro data could be used in the context of safety decisions for a specific ingredient. Key to such decisions is demonstrating how dose-response information identifying concentrations of ingredients which do not cause adverse effects on pathways in vitro can be combined with exposure information in subjects or target organisms. Decisions on human and environmental safety of chemicals and products should be risk-based and driven by understanding levels of actual exposure. For example, for consumer products used on the skin, traditional toxicological risk assessments have relied on metrics associated with applied dose (e.g. mg/kg/day, µg/cm2) based on information about consumer habits and practice. New risk assessment approaches which are pathways-based require this understanding of the biologically relevant exposure to an ingredient (e.g. bioavailability in the skin, levels of systemic exposure) and many new tools (including physiologically-based pharmacokinetic models to estimate systemic exposure) are being employed in this space. Figure 1 shows an overview of some of the important steps and methodologies required to conduct a pathway-based safety assessment. Examples of bringing pathway-based in vitro data together with such exposure data are beginning to emerge and the efforts of Unilever in this respect will be shared through this website.

The current speed of change in pathway-based risk assessment has introduced very new thinking into the science of ‘alternatives to animal testing’. No longer are toxicologists looking to find a way to do the animal test without an animal. Now many diverse scientific disciplines are working together (mathematical modelling, tissue engineering, mechanistic chemistry, high content imaging, stem cell biology, novel informatics, pathways biology, etc.) to bring increased mechanistic understanding to decisions on human and environmental safety.

This website represents the efforts Unilever and our scientific partners are taking to progress the science of toxicity pathways: to put in place the tools and novel thinking needed to implement TT21C/AOP- based risk assessments. In so doing, we aim to ultimately remove our dependence on apical endpoint toxicological studies and bring novel science to the decisions we make on the safe use of chemicals within consumer products.

tt21 Intro

 

Figure 1 The practical paradigm for Toxicity Testing in the 21st Century. BPAD = Biological pathway altering dose (see Judson R.S. et al. Chem. Res. Toxicol. 24, 451-62 (2011)). QIVIVE = Quantitative in vitro to in vivo