S34 Abstracts / Toxicology Letters 221S (2013) S31–S56

individual exposure to pesticides, to be used in studies on healtheffects. We will present here a synthesis of data obtained in vine-growing (Bordeaux area, France) from 2001 to 2007.

Sixty-seven operators, 46 re-entry workers and 48 harvesterswere observed in relation with dithiocarbamate or folpet treat-ments. Detailed information on the tasks (general conditions,operator, farm and equipment characteristics) were considered anddermal contamination was measured (patches and hand-washing).During treatment tasks, the exposure was mainly determined bythe number of phases, characteristics of the equipment, educationallevel of the operator, his status (farm -worker or -owner), and gen-eral characteristics of the vines. For re-entry and harvesting, thetype of task was the parameter the most strongly associated withcontamination. During re-entry, the highest contaminations wereobserved during raising of wires and cutting of branches. Duringthe harvest, the contamination was maximal for grape-picking. Thedelay since the last treatment and the rate of pesticide per hectareplayed a role, together with meteorological factors, crop and farmcharacteristics, gloves and clothes.

Algorithms were built to estimate daily external contaminationaccording to these relevant parameters. With additional informa-tion of frequency and duration of use, they will enable to calculateexposure indices usable in studies on farmers’ health.

http://dx.doi.org/10.1016/j.toxlet.2013.06.224

Workshop 3: Carcinogenicity testing for pharmaceuticals

W03-1Carcinogenicity testing for pharmaceuticals - anupdate

Paul Baldrick

Nonclinical Regulatory Strategy, Covance Inc., Harrogate, UK

Carcinogenicity testing is a requirement for pharmaceuticalsto be used for >6 months clinical administration or for intermit-tent clinical use exceeding this duration. For many years, standarddesign rodent bioassays have been performed to assess tumouri-genic potential but in recent times drug companies and regulatoryagencies have been looking at the robustness and suitability ofthese designs as appropriate for tumour risk assessment. Further-more, there is a greater understanding on how to interpret andextrapolate findings in carcinogenicity studies. An introduction intocurrent testing practices will be given along with comment on areassuch as survival, tumour findings and risk assessment as well asindication of potential/ongoing areas of change.

http://dx.doi.org/10.1016/j.toxlet.2013.06.118

W03-2Practical considerations when setting up andconducting a carcinogenicity study

Guy Healing

AstraZeneca, Macclesfield, UK

The key components of a rodent in vivo carcinogenicity studywill be discussed, including the preparation, conduct and reporting.The required facilities, equipment, skills, training and backgrounddata required if setting up a study will be detailed, as well asthe animal strains that are commonly used, their age, housing,numbers and why they are selected. Dose routes and the relativerisks of cross-contamination, in-life parameters and how regularly

they should be measured will be covered, with particular refer-ence to palpation, clinical pathology and toxicokinetics.Finally thepathology considerations will be detailed and specific consider-ations for interpreting, peer reviewing and reporting the studiesdiscussed.

http://dx.doi.org/10.1016/j.toxlet.2013.06.119

W03-3Transgenic versus conventional carcinogenicitytesting

David R Jones

MHRA, London, UK

Carcinogenicity testing is a requirement for most pharmaceu-ticals intended to be used for long term clinical administration.Standard design life-span rodent bioassays have been conductedto assess carcinogenic potential for many years. However, in recenttimes drug companies and regulatory agencies have been look-ing at alternative assays using transgenic animals in an attemptto increase the predictability for human cancer. The talk will dis-cuss regulatory experiences with assays using transgenic animalsand their usefulness.

http://dx.doi.org/10.1016/j.toxlet.2013.06.120

W03-4Case studies or how to deal with ‘difficult’results

Martin Bopst

Non-Clinical Safety, F. Hoffmann –La Roche AG, Basel, Switzerland

The discussion on the usefulness of carcinogenicity testing hasbeen going on for a long time. Questions raised are on dose levelselection, study designs, relevant models, inclusion of newer end-points/measurements, and of course also on the interpretation ofdata. In particular, when it comes to the translation of rodent datato the human situation, the topic becomes very interesting andchallenging. This talk will provide some recent examples and alsoinclude aspects and case studies of how to interpret “difficult”results.

http://dx.doi.org/10.1016/j.toxlet.2013.06.121

Workshop 4: Advances in the application of the Threshold ofToxicological Concern (TTC) as a pragmatic risk assessment toolfor cosmetics

W04-1Chemical risk assessment in absence ofadequate toxicological data

Benoît Schilter

Nestlé Research Center, Lausanne, Switzerland

There is an increasing demand for methodologies to establishlevels of safety concern for chemicals without toxicological testing.This has concernedfor examplesemergency situations requiringfast decision making, but also the setting of priorities for furtherinvestigations, as well as the design of safe chemicals.In this con-text, the Threshold of Toxicological Concern (TTC) has been the

Abstracts / Toxicology Letters 221S (2013) S31–S56 S35

first attempt to formally combine structural chemical informa-tion with statistical processing of existing toxicological data inorder to derive generic safe levels of exposure for toxicologicallyuncharacterized chemicals. The TTC concept has been widely usedby the food sector.More recently significant improvements havebeen achieved in the field of computational, or in silico, toxicol-ogy. A number of (Q)SARmodels are currently available to predictnot only hazard or mechanism related properties (e.g. genotoxi-city, estrogenicity), but also complex quantitative endpoints suchas chronic toxicity and carcinogenicity potency. Read-across tech-niques have also significantly evolved in recent years. Within theframe of anILSI-Europe expert group, a decision tree (DT) reflect-ing the risk assessment paradigm has been developed to integrateexposure information with predicted toxicological values obtainedthrough (Q)SARsoftwares and read-across techniques. This novelapproach is considered as complementary to the TTC, allowingan improved exploitation of all information available for chemi-cals related to the substance investigated. Its application is likelyto bring additional confidence and accuracy to establish levels ofsafety concern in absence of toxicological data.

http://dx.doi.org/10.1016/j.toxlet.2013.06.123

W04-2TTC Task Force: Development of a cosmeticsdatabase to support application of TTC tocosmetic ingredients (EU Cosmos project)

Helli M. Hollnagel, Massimo Ambrosio, Alan R.Boobis, Mark Cronin, Susan P. Felter, Detlef Keller,K.L. Muldoon Jacobs, R. Safford, Vessela Vitcheva,Andrew P. Worth, Chihae Yang

COSMOS is a Framework Programme 7 Collaborative Project onIntegrated In Silico Models for the Prediction of Human RepeatedDose Toxicity of Cosmetics to Optimise Safety. As one of the sci-entific projects, COSMOS and the ILSI Europe TTC (Threshold ofToxicological Concern) Task Force collaborate to advance the appli-cability of the TTC concept in cosmetics safety assessment.TwoExpert Groups were established to address the issues aroundthe oral TTC dataset for cosmetic-related substances and oral-to-dermal extrapolation.

EG#1 advises on the structure and creation of the database forcosmetics by recommending inclusion criteria for chemicals andtoxicological studies (quality and selection) and supports the eval-uation of the data collection. The resulting new non-cancer TTCdataset builds on the original Munro TTC dataset but was enlargedsignificantly by the addition of approximately 500 cosmetics-related substances with non-cancer endpoint N(L)OAELs from oralstudies. The cosmetics-related substances are defined by chemi-cals found in the EU-COSING and US PCPC databases. Using thisnew database, the expert group will investigate the application ofTTC to cosmetics by evaluating how the chemical space of cosmeticingredients compares to the existing Munro database, whether theexisting Cramer Classes are appropriate, and whether additionalTTC tiers and thresholds need to be established.

http://dx.doi.org/10.1016/j.toxlet.2013.06.124

W04-3Threshold of toxicological concern (TTC) taskforce: a strategy to support application of TTC todermally applied cosmetic ingredients

Faith M. Williams 1, Massimo Ambrosio 2, G. Barrett 3, MarkCronin 4, R.H. Guy 5, J. Plautz 6, C. Roper 7, Helga Rothe 8, D. Rua 9,M. Verwei 10, Chihae Yang 11

1 Newcastle University,Newcastle upon Tyne, UK, 2 ILSI Europe,Brussels, Belgium, 3 Health Canada, Ottawa – Ontario, Canada,4 Liverpool John Moores University, Liverpool, UK, 5 University ofBath, UK, 6 DSM Nutritional Products, Basel, Switzerland, 7 CharlesRiver Laboratories, Edinburgh, UK, 8 The Procter & Gamble Company,Darmstadt, Germany, 9 US FDA, USA, 10 TNO,Zeist, The Netherlands,11 Altamira LLC, Columbus, OH, USA

Threshold of Toxicological Concern (TTC) is a tool developed forchemicals at low levels in the diet for the safety assessment of sub-stances whentoxicity data are not available. It provides a healthprotective human exposure threshold value for chemicals from abroad range of structure categories.

The aim of the group,as part of the EU COSMOS Project, has beento adapt the TTC concept and extend its applicability to cosmeticswhich are applied to the skin. A decision tree approach has beendeveloped based on estimated usage/skin exposure, maximumpossible dermal absorption derived from the J max prediction orexperimental absorption data to estimate systemic dose for rankingagainst TTC, incorporating structural categories and Cramer class. Anew dermal absorption database enriched with cosmetics-relatedchemicals has been established; the chemical space and domain ofcosmetics-related chemicals have been also defined.Where avail-able experimental dermal absorption data is ranked with predictedJmax values Bioavailability modeling (PBPK) will help develop asystematic approach to assessing the effect of route of exposure(dermal rather than oral) on systemic dose and the application ofTTC.

Also assessed isthe importance of local metabolism in differ-ences between the oral and dermal routes and influence in decisionmaking and use of TTC. To support our approaches,examples fromthe literature are presented as a case study.

This strategy should demonstratethe use of TTC for cosmeticsand enhance acceptance of TTC approaches by regulators.

http://dx.doi.org/10.1016/j.toxlet.2013.06.125

W04-4Risk assessment of genotoxic carcinogens taskforce: use of TTC for contaminants withpotential genotoxic hazard

Alan R Boobis

Imperial College London, UK

The TTC approach is based on generic human exposure thresh-old values (TTCs), below which the probability of adverse effects onhuman health is considered to be very low. The threshold values arebased on distributional analysis of compounds sharing broad struc-tural characteristics, which can be determined for any chemicalgiven only its structure. Thus, unless a specific adverse effectcan be predicted from structure, the TTCs should be sufficientlyconservative to cover such an effect. This includes carcinogenicity,which cannot be reliably predicted from structure alone. However,the carcinogens of most concern are those with a genotoxic modeof action, and genotoxicity is largely predictable from structure.