Mode of action based risk assessment of chemical ingredients in cosmetics: What can Swedish toxicological sciences contribute in the future? Ian A Cotgreave Swedish toxicology scinces research center Karolinska Institute Gärtuna www.swetox.se
2 Format for the lecture The ban on use of animals in risk assessment of cosmetics ingredients: Cause and effects. Responses to the ban in contemporary scientific efforts. From pathology to pathways in the New Toxicology Examples of current international scientific colaborations IMI, Tox21/ToxCast, human toxome etc Integrated testing strategies, what are they? EPAA SEURAT-1 From tool box, through AOPs to PoCs in safety assessment Examples of coming investments in the EU Swedish commitments to developments in the area VR-M3R, 3R Centre of Excellence Swetox: A potential rallying point for Swedish research into alternatives via the 3Ms and 3Rs? Tool box developments, AOPs and validation of test methods, PoCs in risk assessment and risk mitigation So how can we all help in Sweden. Ideas???
MARCH 2013: THE EU INTRODUCES A TOTAL BAN ON THE USE OF EXPERIMENTALANIMALS IN SAFETY TESTING OF ALL CHEMICAL INGREDIENTS IN ALL COSMETIC PRODUCTS TO BE SOLD WITHIN THE EU
4 So whats driving this paradigm change from a societal perspective? 3R considerations. Need to better predict human risks. Major advancements in biological and computational modeling capabilites. Societal demands
So.. How do we respond to the challenges? How do we seize the opportunities?
6 The predicament: Predictive toxicology: Animals, cells, computers: All three or just one or two? Is this safe??
Traditional pathology-based Predictive Toxicology Pathological observations Pathological observations
8 Emerging trends in predictive toxicology: A paradigm shift in defining the toxome in the new toxicology Pathology Pathway
The Concept of the shift: Via in vitro MOA MOA 3R wins MOA (A +B = C +D)
Via in silico/in vitro MOA MOA 3R wins!! MOA MOA
Our chemical world:
Several international scientific collaborations are currently trying to explore this paradigm shift. INNOVATIVE MEDICINES INITIATIVE (IMI) MIP DILI (HTTP://WWW.MIP-DILI.EU/#2) STEMBANCC (HTTP://STEMBANCC.ORG/) US-EPA TOX21/TOXCAST (HTTP://EPA.GOV/NCCT/TOX21) CAAT HUMAN TOXOME INITIATIVE (HTTP://HUMANTOXOME.COM) EU INTEGRATED TESTING STRATEGIES (ITS) EUC-EFPIA EUROPEAN PARTNERSHIP FOR ALTERNATIVES TO ANMIALS (EPPA) FP7-COSMETICS EUROPE SEURAT-1
But the EU is spear-heading the development of integrated testing strategies, using efforts from all stake holders EU INTEGRATED TESTING STRATEGIES (ITS) EU-EFPIA EUROPEAN PARTNERSHIP FOR ALTERNATIVES TO ANMIALS EPPA FP7-COSMETICS EUROPE SEURAT-1
So what is an ITS and how do the regulatory authorities see them?
EPAA-ITS (2006-) Within the EPAA, we understand ITS as a way of working based on panels of complementary approaches that enable effectively linking different (non-animal) methods in such a way that the combined and reproducible results suffice for appropriate risk assessment/safety assessment of chemical substances or products. ITS can integrate non-animal and animal testing elements as well as non-testing, i.e. computer based methods. We are intimately convinced that such approaches have a concomitant impact on the 3Rs http://ec.europa.eu/enterprise/epaa/index_en.htm 4/14/2014
ITS is a way of working, applied commonly within industry, combining the use of different testing and non-testing methods in an optimal manner for decision making purposes. Within the perspective of the 3Rs, its main goals are to: Improve efficiency, effectiveness and quality of hazard and risk assessment Decrease costs Contribute to the 3Rs while ensuring a sufficient protection of human health and the environment Although regulatory schemes allow for the Implementation of ITS, regulatory acceptance of data generated under ITS needs further improvement http://ec.europa.eu/enterprise/epaa/index_en.htm
SEURAT-1!! (2011-) To define a new mode of action paradigm in human risk assessment based on animal-free, repeated exposure toxicity predictions.
Georges-Pierre Seurat 1859-1891
Background Legislation: The EU "Cosmetics Directive" foresees a deadline in 2013 for animal testing of cosmetic products in the fields of repeated dose toxicity, reproductive toxicity and toxicokinetics To overcome the lack of scientific knowledge for implementation of alternative testing solutions the Health Programme of DG Research and Innovation defined a longterm target: Safety Evaluation Ultimately Replacing Animal Testing (SEURAT) which will have an impact on many different areas including drug development, industrial chemicals, biocides etc
First step: Seurat-1 Research Initiative Towards the replacement of in vivo repeated dose systemic toxicity testing Joint funding by the European Commission and a specific industrial sector (cosmetics industry / Colipa) 25 million EC & 25 million Cosmetics Europe OBJECTIVES Development of an innovative concept for repeated dose systemic toxicity testing. Proof of concept for a future full implementation of a modeof-action strategy. Development of innovative testing methods more predictive than existing testing procedures. ~ 70 research groups from European Universities, Public Research Institutes and Companies (more than 30% SMEs)
28 SEURAT-1 objectives Development of an innovative concept for repeated dose systemic toxicity testing. Proof of concept for a future full implementation of a mode-of-action strategy. Development of innovative testing methods more predictive than existing testing procedures.
The Strategy of SEURAT-1 Selection of well-studied chemicals with evidence of chronic systemic toxicity. Hypothesis-driven approach to elucidating modes-of-action and identifying associated key events and biomarkers. Emphasis on in vitro models that capture modes-of-action directly relevant to human physiology. Exploit stem cell technology to develop in vitro systems with cellular diversity to model higher level functions. Development of in vitro assays suitable for HTS implementation. Use of bioreactors to engineer tissue comprising multiple cell types to model complex toxicological processes.
The Strategy of SEURAT-1 Biokinetic modelling to extrapolate between in vitro test concentrations and repeated dose organ exposure in vivo. Computational toxicology to associate chemicals with molecular initiating events and describe metabolism. Use of high content analysis tools including `omics to describe modes-of-action at the molecular level. Systems biology approaches to model modes-of-action dynamics at the molecular scale for quantitative analysis. Proof-of-concept exercise to demonstrate a mode-of-action based integrated test system to predict sub-chronic liver toxicity. Feasibility study to show how test data can be used in a safety assessment context.
The 7 Building Blocks of SEURAT-1 Call «FP7-health-2010 Alternative Testing» Projects SEP COACH (secretariat) Towards the replacement of in vivo repeated dose systemic toxicity testing ~ 70 research groups from European Universities, Public Research Institutes and Companies (more than 30% SMEs)
SEURAT-1 is built on a pyramid of activities SA POC READ ACROSS AB INITIO AOPS MECHANISMS BIOMARKERS THE TOOL BOX MODELS PHENOTYPIC CHARACTERISATION
SEURAT-1 is approaching this using an Adverse Outcome Pathway (AOP) strategy in harmony with OECD to define PoCs for safety assessment
Another way of looking at it `Slide "borrowed" from Mel Anderson, Hamner Institutes
Beginning to visualize complexity.. AOP Networks Common or 'nodal' KE 1 MIE multiple AO Multiple MIE 1 AO
Making them testable (PoC) and useful in regulatory risk assessment AOPs for regulatory toxicology o Being explicit about toxicological mode of action Sufficient Exposure Triggers Molecular Effects Organelle Effects Cellular Effects Tissue Effects Organ Response Individual Response Population Response o to rationally design integrated prediction systems o fit for the purpose of supporting safety decisions facilitating a shift towards a knowledge-driven paradigm for chemical risk assessment
Two example AOPs for liver toxicity (fibrosis and steatosis) being tested by SEURAT-1 for case-study use LXR activation to steatosis Biological Organization Level MIE Molecular Intermediate Effects Organelle Cellular Tissue ER binding Inhibition of respiration = NAD+ deplition PPAR-α antagonism binding Peroxisomal AOX inhibition Inhibition of the mitochondrial b-oxidation Protein alkylation to fibrosis AOP from LXR LXR activation L-PK ChREBP SREBP-1c ACC FAS Inhibition of the microsomal b-oxidation De novo FA synthesis TGs accumulation Cytoplasm displacement Nucleus distortion Mitochondrial disruption Fatty liver cells Steatosis > 5 10% by liver weight SCD-1 PPAR-γ activation CD36 upregulation Increase of the fat influx from peripheral tissues AhR agonism PXR activation ApoE Induction of CYP3A4 Angptl3 PTLP Inhibition of the TG excretion Modulators Molecular Initiating Event Intermediate events Key events Adverse Outcome Landesmann et al (2012). Description of Prototype Modes-of-Action Related to Repeated Dose Toxicity. JRC report EUR 25631 EN.
SEURAT-1 is now desiging high level PoC study on read-across at the top of the pyramid Categories CAS # Category # Chemical Name 298-00-0 6 Methyl parathion Group 6-ok. 56-38-2 6 Parathion Chemical similarity plausible for read across aassessment? Presence in filtered spreadsheet*? No longer in large spreadsheet once filtered*. No longer in large spreadsheet once filtered*. Availability/Suitability of endpoint data for Seurat-1 purposes** (refer to GRASP spreadsheets)? Suitability of test articles for in vitro assays? Availability of high content information? (cite sources) Background for short listing 122-14-5 6 Fenitrothion 1582-09-8 7 Trifluralin Group 7-ok 1861-40-1 7 Benfluralin Paired with 4- nitrotoluene, 3- nitrotoluene and 2,4- dinitrotoluene in filtered spreadhseet Included in filtered spreadsheet* Included in filtered spreadsheet* COMPOUNDS ARE BEING GROUPED FOR TESTING IN BEST PRACICE AOPS IN BEST PRCATICE SYSTEMS QUANTITATIVE DATA SOUGHT, FOCUS ON POINT OF DEPARTURE FROM SAFETY
Looking forward, what is devloping, and how can we all get involved in Sweden?
41 Exempel på Horizon 2020 program där MoA betyngad forskning är i fokus SFS-12-2014: RESEARCH AND INNOVATION ACTION: ASSESSING THE HEALTH RISKS OF COMBINED HUMAN EXPSOURE TO MULTIPLE FOOD-RELATED SUBSTANCES FÖRBÄTRAD HÄLSA GENOM FÖRFINAD RISKBEDÖMNING AV KEMISKA SUBSTANSER I MAT TOXIKOLOGISK SAMVERKAN AV SUBSTANSER KOMPLEXA BLANDNINGAR MULTIPLA EXPONERINGSVÄGAR BIOANALYTISKA UTMANINGAR RISK-NYTTA BERÄKNINGAR ANVÄNDNING AV OMICS DATA OCH BERÄKNINGSMODELLER SAMVERKAN MELLAN UNIVERSITET OCH INDUSTRIN UTVECKLING AV EN MODE OF ACTION -BASERAD RISKBEDÖMNINGS PARADIGM STARK 3R MOTIVATION 8M EUR TAK
42 PHC-31-2015 HEALTH DEMOGRAPHIC CHANGE AND WELL-BEING ACTION: NEW APPROACHES TO IMPROVE PREDICTIVE HUMAN SAFETY TESTING FÖRBÄTTRAD PREDIKTIV TOXIKOLOGISK TESTNING SOM ETT SVAR PÅ SKIFTANDE REGULATORISKA KRAV UTVECKLING AV READ-ACROSS BASERAD RISKBEDÖMNING STARK MODE OF ACTION OCH MEKANISTISK INRIKTNING UTVECKLING AV NYA HUMAN BIOLOGISKA OCH BERÄKNINGS MODELLER FOKUS PÅ FÖRBÄTTRADE BIOMARKÖRER STARK INTERAKTION MELLAN UNIVERSITET, INDUSTRIN OCH MYNDIGHETER INTERNATIONELL HARMONISERING GENOM SAMARBETE STARK FOKUS PÅ 3R 10-15M EUR TAK
But there is more to come.. Eg. Concerted action in Nano-Safety
So what is happening i Sweden? Can we contribute? VR M3R RESEARCH FUNDING PROGRAM (CIRCA 5-7 MKR PER ANNUM) SPECIFIC CALLS WITH FORMAS? OTHER GRANT FUNDING BODIES? A CENTER OF EXCELLENCE FOR 3RS? (JÖNKÖPING!)
Swetox Swedish Toxicology Sciences Research Center
Swetox (Swedish Toxicology Sciences Research Center) Ett akademiskt forskningscentrum för 11 svenska universitet där innovativ, riktad grundforskning och uppdragsforskning samverkar Bedriver avancerad tvärvetenskaplig forskning inom området kemikalier, hälsa, miljö (hälso- och miljörelaterad toxikologi) Bidra till användning och utveckling av säkrare kemikalier och därmed till en hållbar miljö och till människors hälsa. Koordinera svenska utbildningsinsatser inom toxikologiska vetenskaper och erbjuda riktade spetskurser Etablera starka internationella kontakter/samarbeten 2014-04-14
47 Hur ser profilen av toxikologiska vetenskaper ut? Ekotoxikologi (effekter och mekanismer) Endokrinologi Epidemiologi Miljökemi (kemisk syntes till exponeringsanalys) Miljömedicin/hälsa Miljöstatistik/Databehandling Modellering/Prognostisering (olika inriktningar) Riskbedömning WOE - Policyinterationer Toxikokinitik/Metabolism Toxikologi (effekter och mekanismer) 2014-04-14
Swetox forskning & utbildning
Swetox (Södertälje) blir ett nav för samverkan inom Swetox Hälso- och miljörelaterad forskning/uppdrag Internationella kontakter och samverkan Utbildning
Swetox Hälso- och miljörelaterad forskning i Södertälje 3R: In vitro metodologi prioriteras (Replace, Reduce, Refine; på svenska: ersätt, reducera, förbättra) 3M: Prioritering av studier av mekanismer, markörer och modeller Pelare på Swetox Södertälje: Bioanalytisk forskning Immunologisk forskning In vitro In vivo (bl.a. inhalation) Modellering/beräkningar Riskvärdering
Bidragsgivare/intressenter för ökad kemikaliesäkerhet Hälso- och sjukvård Miljövetenskaper Livsvetenskaper EU Swet Swetox ox Industri Myndigheter Forskningsråd /motsvarande
Finansiering Nuvarande femårs-perspektiv, 2014-2018 FORMAS KAW KI SLL - 30 MKR (över tre år, ytterligare två år (20 MKR) efter utvärdering) - 35 MKR - 50 MKR - 30 MKR (över tre år) 1 Forskningsrådet FORMAS; 2 Knut och Alice Wallenberg Stiftelse; 3 Karolinska Institutet; 4 Stockholms läns landsting 2014-04-14
Swetox Gärtuna, Södertälje SweTox
So..can we use the collective weight of swedish toxicology-related sciences and direct it at the international effort exemplified by the situation i the cosmetics industry??? IDEAS???