Endocrine Disruption as the pilote of mapping the Human Toxome - PowerPoint PPT Presentation

Endocrine Disruption as the pilote of mapping the Human Toxome Thomas Hartung Doerenkamp-Zbinden Professor and Chair for Evidence-based Toxicology, EHS Director, Center for Alternatives to Animal Testing (CAAT) Joint appointment: Molecular Microbiology and Immunology Bloomberg School of Public Health, Johns Hopkins University, Baltimore, US Professor of Pharmacology and Toxicology, University of Konstanz, Germany

100,000 in commerce Human endocrine <3% tested for health effects endocrine or including cancer? reproductive tox.

Endocrine ECVAM Task force • disruption • QSAR workshop Validation • ReProTect • CAAT White paper • • NIH consortium Conference Rome • 17 Dec 2012

Toxicology - $3 billion of testing to regulate $10 trillion of trade Problems • Throughput • Costs • Predictivity • Too precautionary • Animal use • New products • New hazards • Mixtures • Individuals

7’2010: 21 st Century Validation for 21 st Century Tools All current toxicological information to date strongly suggest that the routine rodent models are inadequate for detection of EAS and assumed endocrine effects in humans

Hershberger • Not sensitive & enough uterotrophic • Unsuitable validation design • Abrogation of peer-review

Animal test Reprotox 8 months $0.6 million/chemical 3,200 animals/chemical 64% positive Estimate human 2-3% positive Problem inter-species differences mice, rat, rabbit, guinea pig predict each other with 60% correlation

Serious doubt remains as to a major impact of more than a few chemicals as ED But society wants problem addressed

Combine the drivers of change from EU and US EU: legislation, funding, integrated testing, organizations US: technologies, Tox- 21c, TSCA reauthor.

The pipeline 12 articles published Ambassadors (5 responses in Nature / Science) Bas Blaauboer Alan Goldberg 6 articles in preparation Thomas Hartung Marcel Leist 5 workshop reports published 7 reports pending 5 workshops planned

Scientific roadmap for the future of animal- free systemic toxicity testing May 2011: EC report on status of alternatives Sep 2011: Independent review by 19 international experts Oct 2011: Five white paper on the way forward Consensus workshop with 35 experts Feb 2012: Roadmap published Mar 2012: Stakeholder Forum in Brussels with 150 experts Early 2013: US Stakeholder Forum

NAS vision report Tox-21c “With an advanced field of An atmosphere of departure in regulatory science, new toxicology tools, including functional genomics, proteomics, New technologies from metabolomics, high- biotech and (bio- throughput screening, and systems biology, we can )informatics revolution replace current toxicology assays with tests Mapping of pathways of that incorporate the mechanistic underpinnings of disease and of underlying toxicity (PoT) toxic side effects.” M.A. Hamburg, FDA 2011 “We propose a shift from primarily in vivo animal studies to in vitro assays, in vivo assays with lower organisms, and computational modeling for toxicity assessments” F. Collins, NIH, 2008

Initiatives implementing Tox-21c Organization Approach Purpose Outcome Chemical “Biological US EPA & Tox21 High-throughput prioritization signatures” (ToxCast Program) testing (initially) Hamner Institute Case studies “Just do it” Proof-of-principle NIH project Pathway ID & Pathway mapping Human Toxome (CAAT-US) annotation

ToxPi - Endocrine Disruption Prioritization HPTE Linuron 309 Chemicals sorted by ToxPi score Methoxychlor Rotenone BPA Pyrimethanil Tebuthiuron Other TR XME/ADME ER Other AR NR Disease LogP_TPSA classes Ingenuity CaCO-2 KEGG path path highest lowest ToxScore Office of Research and Development ToxPi National Center for Computational Toxicology Reif et al, EHP, 2010

The concept of (finite number of) pathways of toxicity Annotation to: Toxicant - Hazard - Toxin (class) - Cell type - Species Toxicant Comprehensive list (Human Toxome) Negatives

Starting point: (Pre-)Validated Models Robust protocols, good cell models Regulatory acceptance Available reference substances Thresholds of adversity defined $300 million of research & validation spent Estrogenic endocrine disruption - PoT-based, well understood - many other tests - Testing needs Reference substances Metabolomics and Transcriptomics Emerging bioinformatic integration for pathway identification

PoToMaC - The Pathways of Toxicty Mapping Center European branch? Transformative Research Grant: Mapping the Human Toxome by Systems Toxicology 7 companies, 3 stakeholders

“Driven both by legislative mandate and scientific need, a new suite of in vitro and cell culture-based animal-free methods are gaining a foothold in toxicology labs.” 2 Mar 2012

Evidence-based Toxicology “Evidence-based medicine goes toxicology!” Hoffmann and Hartung “Toward an evidence-based toxicology”, Human Exp. Tox., 2006

Mar 2011: US EBTC Oct 2011: Secretariat at CAAT Jan 2012: First conference hosted by EPA

The difficulty lies, not in the new ideas, but in escaping from the old ones. John Maynard Keynes (1883 - 1946)