Our vision is to apply pathways-based risk assessment approaches to identify and characterise the key impacts of Home and Personal Care ingredients on human health or the environment.

In so doing, we aim to remove our dependence on apical endpoint (eco)toxicological studies thereby reducing our overall uncertainty and better informing decisions on the use of chemicals within consumer products.

We are developing novel mechanistic chemistry tools and new capabilities to enhance our understanding/prediction of the interaction of chemicals with biological systems(in-vitro and in-vivo).

An integrated wet/dry cycle approach is being taken and aligned to the ‘source to outcome pathway’ conceptual framework with a specific focus on developing understanding of molecular initiating events in order to make specific decisions on the toxicity pathways of relevance for given ingredients.

Informed by the recent OECD report ‘The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins’, we are developing two linked mechanistic mathematical models that aim to reliably predict the magnitude of the human T cell response that would result from a defined skin exposure to a direct-acting sensitising chemical.

The US National Academy of Sciences/National Research Council report on TT21C (Krewski et al 2010) proposes an in-vitro approach to toxicity testing that aims to describe perturbations in critical cellular processes that lead to adverse events (toxicity pathways), and a safety assessment approach that ensures human exposure is kept below a level that is expected to cause adverse effects.

The Nrf2/Keap1 pathway and its role in cellular defences to oxidative stress provides one of the case studies to develop our understanding of approaches to drive the TT21C approach forward with a practical application.

The key components incorporate a computational systems biology model of the Nrf2 pathway aligned to cellular assay biomarkers to predict where low dose alterations in redox potential are considered to remain with a region of safety for human exposure.

This collaborative research with the Chinese Academy of Military Medical Science is to explore a TT21C-based risk assessment by characterising tipping points/saturation of oxidative defence mechanisms based on two mitochondrial pathways (Nrf-2 & PGC-1α) in relation to mitochondrial dysfunction/toxicity in human cells induced by chemical exposure.

High Content Analysis provides a key tool in developing our understanding of cellular response to low dose perturbation sufficiently to predict a safe region of exposure. Its key advantage lies in the multiplexed automated analysis of signal transduction, biochemical and morphological events occurring at an individual cell and population level.

The approach to risk assessment of novel chemicals has remained largely unchanged for some decades. Computational models offer a way to revolutionise risk assessment through prediction of the complex molecular interactions and the subsequent dynamic responses that may occur at an intracellular, cellular, organ, individual and population level.

In a pathway-based risk assessment, the hazard quantity derived from in vitro data will be in units of concentration (µM), not in units of applied dose (mg/kg). Physiologically-based toxicokinetic (PBTK) information is required to predict concentrations in target tissues following consumer exposure, for comparison with the novel hazard quantity in risk assessment..

Our vision is to apply pathways-based risk assessment approaches to identify and characterise the key impacts of Unilever ingredients on human health or the environment. In so doing, we aim to remove our dependence on apical endpoint (eco)toxicological studies thereby reducing our overall uncertainty and better informing decisions on the use of chemicals within consumer products.

Dose-response relationships in combination with extrapolation modelling are one of the four cornerstones of the U.S. National Research Council’s strategic vision for Toxicity Testing in the 21st Century. In vitro assay systems are key to both the establishment of thresholds of toxicological concern in vitro as well as the provision of parameters needed for in silico modelling of human-relevant, toxicologically relevant doses.

Activities within QIVIVE are aimed at understanding, measuring and/or modelling biologically relevant concentrations in in vitro assay systems and developing models to translate these concentrations into exposure limits in vivo.

The majority of the industrial chemicals in use today have narcosis as the only mode of action in aquatic systems. To support the environmental risk assessment of these chemicals we are using the Adverse Outcome Pathways framework to develop case studies to elucidate key events leading to adverse effects, and to identify knowledge gaps for future research.

We are currently exploring several new approaches in ecological modelling for use in higher tier environmental risk assessment of key ingredients in home and personal care consumer products. The ultimate goal is to identify models that can extrapolate from individual effects to effects on populations, communities and ecosystems.

Lung fibrosis was previously determined as a key sensitive endpoint for inhalation risk assessment. Using data and informatics driven approaches, centred on human mechanisms of lung fibrosis, we have defined the key biological events and biomarkers to develop an AOP.

In collaboration with partners, a range of cell systems and alternative readouts is being examined to evaluate specific toxicological responses related to the AOP. Our aim is to develop a system that is testable, robust enough to be acceptable by industry, and provide scientific confidence. This is being combined with exposure based waiving approaches to enable future risk assessments without the use of animal testing.

INTRODUCTION

Unilever’s Safety & Environmental Assurance Centre is an organisation that constantly seeks to bring new science 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”.

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. For example, a large-scale effort is being developed in the context of the OECD ‘Adverse Outcome Pathway’ (AOP) work programme. This also has particular relevance in environmental toxicity assessments, where new thinking is emerging with respect to Source to Outcome pathway (S2OP) risk assessments. Overall, 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 risk assessment of the effects of new chemicals on both human health and the environment.

This website represents the efforts Unilever and 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.

ABOUT SEAC

The role of the Safety and Environmental Assurance Centre (SEAC) is to assure the safety and environmental sustainability of Unilever products, and the processes used to manufacture them. SEAC has a diverse range of scientific expertise that is dedicated to providing risk assessments for the consumer, occupational and environmental safety, and assessments of environmental sustainability across the life cycle of products and processes.

SEAC has built extensive information systems, scientific capability and experience over 50 years within Unilever. Our experts continue to develop capability through active collaboration with other leading edge scientists outside of the company. Read More

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