Developing New Approaches for the Safety Assessment of Cosmetics to Replace the Use of Animal testing.
Submitting Institution
Liverpool John Moores UniversityUnit of Assessment
Allied Health Professions, Dentistry, Nursing and PharmacySummary Impact Type
TechnologicalResearch Subject Area(s)
Chemical Sciences: Organic Chemistry, Other Chemical Sciences
Medical and Health Sciences: Pharmacology and Pharmaceutical Sciences
Summary of the impact
The European Union Cosmetics Directive (adopted in 2003) banned the use
of animals for testing cosmetic ingredients and the final deadline for
compliance was March 2013. The development of alternative methods of
safety assessment was therefore essential to ensure both consumer
protection and viability of the cosmetics industry. Our research has
focussed on the development of computational alternatives to animal
testing, including the identification of structural alerts that have been
encoded into computational workflows to support toxicity prediction. These
methods have delivered tools to the cosmetics industry in Europe and
worldwide to enable them to comply with the directive and develop new
products. Our findings have also been used to inform thinking and policy
in Europe and to develop a new approach to the safety assessment of
cosmetics.
Underpinning research
On March 11th 2013 the final phase of the European Cosmetics
Directive came into force banning the use of animal testing on any
cosmetic ingredient. In light of this, new methods were required by
industry to replace the use of animals in the safety assurance of cosmetic
ingredients. We have been at the forefront of developing essential,
alternative (including computational) methods for toxicity prediction for
over 25 years so were well placed to apply and build upon this research to
advise the regulators and help provide a solution for the cosmetics and
personal care industries. Our research (Cronin, Madden and Enoch) has
focussed on the investigation of the relationship between physico-chemical
and structural features of compounds and their associated
activity/toxicity. Knowledge of these structure-activity relationships has
been directed towards an investigation of the applicability, to cosmetics,
of the Threshold of Toxicological Concern (TTC) approach to risk
assessment and the development of Adverse Outcome Pathways (AOPs) to
provide a mechanistically-based framework to capture information relating
to toxicity pathways. Some of the projects that have contributed to this
research are outlined below:
As a postdoctoral researcher (PDRA) at LJMU (1991-1994; funded by
Unilever) Cronin developed (Quantitative) Structure-Activity Relationships
((Q)SARs) for human health endpoints relevant to the personal care
industry with an emphasis on modelling skin absorption and sensitisation
[3.1]. This research formed the basis of the IMAGETOX EU FP5 project
(2000-2004; employing Netzeva as a PDRA), the outcome of which was a
series of models, databases and techniques that were successful in
predicting the toxicity of chemicals capable of binding covalently to
proteins; a process crucial to skin sensitisation. This led to the CAESAR
project (EU FP6, 2006-9) employing Enoch as a PDRA, who further developed
the work on chemical reactivity, focussing on electrophilic mechanisms
[3.2]. This research produced improved models for predictivity and
applicability for skin sensitisation and, alongside other models generated
via CAESAR; were incorporated into a suite of software for toxicity
prediction currently distributed online via VEGA (Virtual models for
property Evaluation of chemicals within a Global Architecture). Structural
alerts developed for skin sensitisation were also coded into the freely
available Toxtree software (http://toxtree.sourceforge.net/).
Concurrently, a DEFRA-Link project (2007-2010; employing Bajot as a PDRA)
in collaboration with Unilever, Proctor & Gamble, Shell, Lhasa, Marks
and Spencer and the University of Tennessee continued investigations into
the role of electrophilic reactivity in skin sensitisation. Further
fundamental research into reaction rate chemistry was performed [3.3] and
a database of the reactivity of organic chemicals was developed [3.4].
Understanding the mechanistic chemistry behind toxic effects (such as skin
sensitisation) is essential to toxicity prediction and has been a
continuing theme in the development of our models. Unilever funded a
further collaborative project (2008-2011; with Ledbetter as a PhD student)
to develop HPLC and molecular fragment based approaches to model the
uptake of molecules across biological membranes [3.5].
The expertise gained from the above research enabled us to participate in
the Seurat-1 Cluster of projects, working towards the replacement of in
vivo repeat dose systemic toxicity testing. Within this we co-ordinate the
COSMOS Project (2011-2016; total funding of €6.7million) which aims to
develop methods and freely available computational tools to predict the
effect of long term exposure to cosmetic ingredients and determine their
safety in humans. At LJMU, (previously with Enoch as a PDRA and currently
employing Richarz as project manager, Przybylak and Mellor as PDRAs and
Steinmetz and Nelms as post-graduate students) we have developed models
for predicting organ level toxicity following repeat-dose exposure. New
data were harvested and curated within the COSMOS database from sources
not previously available (e.g. US FDA legacy data) using database and
quality control procedures developed within the project. Computational
models developed to predict activity (toxicity) of chemicals based on
their structure relationships were investigated in terms of the
mechanistic chemistry involved in the interaction of a chemical and a
biological target, and a database of reactive organic chemistry was
compiled [3.6].
One of the new paradigms in toxicity assessment is the development of
Adverse Outcome Pathways (AOPs). These provide a knowledge framework to
support chemical risk assessment by enabling information on key steps in
toxicity pathways to be logically organised. For example, fundamental
knowledge of the relationships between structure and activity (e.g. the
ability of a chemical to bind covalently to a protein) can be captured and
linked to the potential to initiate an adverse effect (e.g. skin
sensitisation). Using our previous research we developed structural alerts
to provide information for AOPs and also devised a template for developing
and assessing AOPs which formed the basis of the OECD AOP development
program launched in 2012 [5.6]. The TTC approach has not yet been utilised
in the cosmetics sector. As part of the COSMOS project, we have
investigated the applicability of this method for cosmetics, performing an
analysis of the chemical space of the COSMOS cosmetics inventory compared
with the chemical space of an established TTC dataset.
References to the research
3.1 to 3.5 were all published in peer reviewed journals (citations from
Web of Science)
[3.1] Cronin, MTD and Basketter, DA (1994) Multivariate QSAR analysis of
a skin sensitization database, SAR and QSAR in Environmental Research,
2, 159-179.
DOI: 10.1080/10629369408029901. Citations: 75.
[3.2] Aptula AO, Enoch SJ and Roberts DW (2009) Chemical mechanisms for
skin sensitization by aromatic compounds with hydroxy and amino groups. Chemical
Research In Toxicology, 22, (9), 1541-1547. DOI: 10.1021/tx9000336.
Citations: 9.
[3.3] Koleva, YK, Madden, JC and Cronin, MTD (2008) Formation of
categories from structure- activity relationships to allow read-across for
risk assessment: Toxicity of alpha,beta-unsaturated carbonyl compounds. Chemical
Research in Toxicology, 21, 2300-2312. DOI: 10.1021/tx8002438.
Citations: 25.
[3.4] Schwöbel JA, Koleva YK, Enoch SJ, Bajot F, Hewitt M, Madden JC,
Roberts DW, Schultz TW and Cronin MTD (2011) Measurement and estimation of
electrophilic reactivity for predictive toxicology. Chemical Reviews,
111, 2562-2596. DOI 10.1021/cr100098n. Citations: 17.
[3.5] Ledbetter, MR, Gutsell, S, Hodges, G, O'Connor, S, Madden, JC,
Rowe, PH and Cronin, MTD (2013) Prediction of immobilised artificial
membrane chromatography retention factors using theoretical molecular
fragments and structural features. SAR and QSAR in Environmental
Research, 24, 661-678. DOI: 10.1080/1062936X.2013.792872. Citations:
0.
The following funds were awarded to the QSAR and modelling group with
Prof. Mark Cronin as PI:
Title |
Awarding body |
Date |
Value |
IMAGETOX RTN |
EU FP5 IMAGETOX RTN |
2000-04 |
€190,000 |
ReProTect |
EU FP6 ReProTect |
2004-9 |
€167,000 |
CAESAR |
EU FP6 CAESAR |
2006-9 |
€150,000 |
DEFRA-LINK |
DEFRA-LINK |
2007-10 |
£323,000 |
Lhasa PhD studentship |
Lhasa |
2008-11 |
£50,000 |
Hydrophobicity PhD studentship |
Unilever |
2008-11 |
£66,000 |
COSMOS (Project co-ordinator) |
EU FP7 |
2011-16 |
€1 million |
Details of the impact
The cosmetics industry in Europe employs approximately 1.7 million people
and is worth an estimated €70 billion. It is a high-profile industry with
a need to continually develop innovative products to remain competitive
within the market. This case study describes the impact of research
undertaken at LJMU in the development of computational alternatives to
animal testing and the provision of expert opinion on the use of these
alternatives that has informed policy making at the European level. Our
research has provided impact in two ways (i) providing highly curated
databases and computational models that are of use to the cosmetics
industry as alternative methods to animal testing and (ii) influencing the
future direction in which safety assessment may be performed i.e. the
application of AOPs and the TTC approach to cosmetic ingredients.
(ia) The outcome of the CAESAR project was a suite of freely
available software for toxicity prediction (released 2011 and now
distributed via the VEGA website (http://www.vega-qsar.eu/use-
qsar.html). VEGA supports the correct use of in silico/QSAR models
for the evaluation of chemical safety for regulatory purposes and to
reduce the impact of chemicals on humans and the environment. The VEGA
platform is a series of QSAR models (many developed within CAESAR) that
predict a series of properties of environmental, ecotoxicological and
toxicological interest for regulatory purposes. It is freely available
both online and as a standalone application to download. Over 1000 users
had downloaded this software by April 2013. Skin sensitisation is an
important element of assessing the toxicity of cosmetics and personal care
products and the alerts we developed for skin sensitisation, alongside
other models developed within the CAESAR project, were incorporated into
predictive models that showed substantial improvement on previous
approaches both in predictivity and applicability and importantly are
freely available to any user [5.1]. Structural alerts developed for skin
sensitisation were also coded into the Toxtree software by Ideaconsult,
now freely distributed within ToxPredict platforms; (https://www.ideaconsult.net/)
[5.2], and over 19000 downloads of Toxtree have been recorded since
January 2008 (http://toxtree.sourceforge.net/).
(ib) Our collaborations with Unilever, Proctor & Gamble,
Shell, Lhasa, Marks and Spencer, the University of Tennessee and other
academic institutions (as part of the DEFRA-Link, InSilicoTox projects and
the Unilever-funded studentship), demonstrated the high level of
cross-sector industry interest in developing and using these predictive
techniques, particularly as the deadline for the Cosmetics Directive
approached. Full compliance with the Directive required alternatives to be
developed to predict more complex endpoints, such as repeat-dose toxicity
and because traditional QSAR approaches were inadequate for these
endpoints, industry recognised that a new way of approaching the problem
needed to be developed. To address this problem the European Trade
Association for Cosmetics Industries, Cosmetics Europe (formerly Colipa),
entered into a unique partnership with the European Commission to fund the
Seurat-1 Cluster of Projects. Funding (€50 million) was provided to seven
projects and LJMU co-ordinated the COSMOS consortium of 15 partners
including world leaders committed to donating software and algorithms to
support open architecture workflows. Data from our research have been
harvested and curated within the COSMOS database that links chemical
structure to repeat dose toxicity [5.3] COSMOS combines new and current
databases in a single state-of-the art, freely available public resource
delivering a single, comprehensive resource for repeated dose toxicity
data and although several other databases for chronic toxicity are
available, other than COSMOS, there is no other single repository that is
open, transparent and includes all aspects of the data available. Research
has been carried out to assess the applicability of the TTC approach to
cosmetics, including assessment of the chemical space of the cosmetics
inventory (compiled by COSMOS) in relation to chemical space of an
existing TTC database.
(iia) As a member of the European Centre for the Validation of
Alternative Methods (ECVAM) and European Chemical Bureau working groups
(2003 and 2010), Cronin had an advisory role in developing policy for
alternatives to animals for skin sensitisation testing. These working
groups provided realistic estimates of timescales for the replacement of
animal testing by alternative methods and recommendations on how to
achieve this. This resulted in an increase in efforts to accelerate the
availability of alternative tests to enable industry to comply with the
deadlines of the Cosmetics Directive (March 2009 and March 2013) [5.4].
Due to his considerable expertise in this area Cronin was also invited to
attend the working group of an international panel of experts, organised
by the European Commission, to present on-going research in the area. This
resulted in a publication used to inform policy development on the use of
alternatives for cosmetic safety assessment [5.4]. In 2012 Madden also
provided advice to the Scientific Committee on Consumer Safety (the
European statutory committee that regulates cosmetic ingredients), the
outcome of which is to serve as a basis for the SCCS guidance on dermal
safety assessment [5.5].
(iib) Recently there has been much interest in the development of
AOPs as a framework for organising chemical and biological information
associated with toxic events. Knowledge acquired through our fundamental
research into chemical-biological interactions is currently being used to
inform the development of AOPs. In 2012 we produced a template and wrote
guidance for the development and assessment of AOPs which has been
incorporated into the framework adopted by the OECD for the development of
AOPs [5.6].
(iic) One of the major impacts of our research has been on the
thinking behind a new way towards risk assessment as demonstrated by the
influence of COSMOS (led by LJMU) in raising the possibility of extending
to cosmetics the TTC approach used by regulators for assessing food
contact substances. This is now being considered at the European level via
expert groups co- ordinated by ILSI-EU which addresses major scientific
issues relating to public heath [5.7]. In 2012, a joint report
(SCCP/1171/08) by the Scientific Committee on Consumer Safety (SCCS),
Scientific Committee on Health and Environmental Risks (SCHER) and
Scientific Committee on Emerging and Newly Identified Health Risks
(SCENIHR) published the opinion that the TTC approach "in itself is
scientifically acceptable for human health risk assessment of systemic
toxic effects caused by chemicals present at very low levels''. The report
acknowledged the work of COSMOS in developing a new TTC dataset more
relevant to cosmetics and the characterisation of the COSMOS cosmetics
inventory developed within the project [5.8].
In summary, research from LJMU has provided databases and computational
models for skin sensitisation that have been incorporated into freely
available predictive software for use by regulators and the cosmetics and
personal care industry for safety assessment of cosmetic ingredients. It
has also influenced debate at the European level concerning the
possibility of extending the current regulatory TTC approach to cosmetic
ingredients.
Sources to corroborate the impact
[5.1] Personal comments on the use of Toxtree and CAESAR for in
silico consultancy and regulatory purposes can be obtained from the
Managing Director (1) and/or Research Scientist (2) at S-IN.
[5.2] http://toxtree.sourceforge.net/skinsensitisation.html
http://toxtree.sourceforge.net/proteinbinding.html
Confirms our contribution to the development of the protein binding and
skin sensitisation rules.
[5.3] http://www.seurat-1.eu/pages/library/seurat-1-annual-report.php
Provides links to Seurat-1 annual reports which details the work of the
COSMOS consortium within the Seurat-1 cluster.
[5.4] Adler, S et al (2011) Alternative (non-animal) methods for
cosmetics testing: current status and future prospects-2010. Archives
of Toxicology, 85, 367-485. DOI: 10.1007/s00204-011-0693- 2.
Citations: 52 (from Web of Science).
[5.5]
http://ec.europa.eu/health/scientific_committees/newsletters/index_en.htm -
December 2012 newsletter (p1) confirms outcome of this meeting (minutes
can be supplied to confirm attendance)
[5.6] http://www.oecd.org/env/ehs/testing/adverse-outcome-pathways-molecular-screening-and-
toxicogenomics.htm#Documents.Guidance document and template for
developing and assessing AOP Series on Testing and Assessment No 184
(2013). Authorship is not acknowledged in the report but the associated
report from the OECD (available on request) quotes "The guidance
document on developing an AOP and a glossary of terms associated with
AOPs by Liverpool John Moores University (LJMU) are complete. The
guidance on developing an AOP and the glossary of terms associated with
AOPs are to be combined and moved forward at OECD for declassification
and will serve as the basis for the work flow at the Adverse Outcome
Pathways Programme (AOPP) at OECD."
[5.7] http://www.ilsi.org/Europe/Pages/HomePage.aspx
- Links to 2013 ILSI Europe Activity Document confirming role of
ILSI within the working group
[5.8] http://www.bibra-information.co.uk/news_story-525.html
- Links to the joint committees report sccs_0_092.pdf (SCCP/1171/08)
confirming the contribution of COSMOS in developing the TTC approach.