This report presents some of the results of a joint research project, sponsored by Defra and conducted by FRAME and Liverpool John Moores University, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity end-points associated with the REACH system. This report focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for skin sensitisation testing. The manuscript reviews in vitro tests based on protein-ligand binding, dendritic/Langerhans cells and T-lymphocyte activation, and also the QSAR models and expert systems available for this endpoint. These tests are then incorporated into an integrated, decision-tree testing strategy, which also includes the Local Lymph Node Assay (in its original and new reduced protocols) and the traditional guinea-pig tests (which should only be used as a last resort). The aim of the strategy is to minimise the use of animals in testing for skin sensitisation, while satisfying the scientific and logistical demands of the EU REACH legislation.
GrindonC., CombesR., CroninM.T.D., RobertsD.W. & GarrodJ. (2006). A review of the status of alternative approaches to animal testing and the development of integrated testing strategies for assessing the toxicity of chemicals under REACH —A summary of a Defra-funded project conducted by Liverpool John Moores University and FRAME. ATLA34Suppl. 1, 149–158.
2.
Anon. (2006). Defra Science and Research: Review of the status of the development of the alternatives to using animals in chemical safety testing and identification of new areas for development or research in the context of the proposed REACH regulations (CB01067). Available at: http://www2.defra.gov.uk/research/project_data/more.asp?I=CB01067&M=KWS&V=reach&scope=0 (Accessed 01.03.06).
3.
GrindonC., CombesR., CroninM.T.D., RobertsD.W. & GarrodJ.F. (2006). Integrated testing strategies for use in REACH. ATLA34, 407–427.
BasketterD. (2004). Skin sensitization assessment. In Global Cosmetics Manufacturing, April 2004, pp. 32–33. London, UK: Touch Briefings. Available at: http://www.touchbriefings.com/cdps/cditem.cfm?NID=846 (Accessed 23.11.07).
6.
GrindonC. (2007). The new EU REACH regulation has finally been adopted: Is this the end of the campaign trail… or just the beginning?ATLA35, 239–242.
7.
PedersenF., de BruijnJ., MunnS. & van LeeuwenK. (2003). Assessment of Additional Testing Needs Under REACH. Effects of (Q)SARs, Risk Based Testing and Voluntary Industry Initiatives, 33pp. Ispra, Italy:European Chemicals Bureau, European Commission Joint Research Centre.
8.
GrabbeS. & SchwarzT. (1998). Immunoregulatory mechanisms involved in the elicitation of allergic contact hypersensitivity. Immunology Today19, 37–44.
SmithC.K. & HotchkissS.A.M. (2001). Allergic Contact Dermatitis: Chemical and Metabolic Mechanisms, 336pp. London, UK:Taylor & Francis.
13.
MageeP.S. (2000). Exploring the potential for allergic contact dermatitis via computed heats of reaction of haptens with protein end-groups — Heats of reaction of haptens with protein end-groups by computation. Quantitative Structure–Activity Relationships19, 356–365.
14.
RobertsD.W., GoodwinB.F.J. & BasketterD. (1988). Methyl groups as antigenic determinants in skin sensitization. Contact Dermatitis18, 219–225.
15.
AleksicM., PeaseC.K., BasketterD.A., PanicoM., MorrisH.R. & DellA. (2007). Investigating protein haptenation mechanisms of skin sensitisers using human serum albumin as a model protein. Toxicology in Vitro21, 723–733.
16.
AptulaA.O., RobertsD.W. & PeaseC.K. (2007). Haptens, prohaptens and prehaptens, or electrophiles and proelectrophiles. Contact Dermatitis56, 54–56.
17.
PatlewiczG., Gallegos SalinerA., PavanM., WorthA., BenigniR., AptulaA., BassanA., BossaC., Falk-FilipssonA., GilletV., JeliazkovaN., McDougalA., MestresJ., MunroI., NetzevaT., SaffordB., Simon-HettichB., TsakovskaI., WallénM. & YangC. (2007). Chemical Similarity and Threshold of Toxicological Concern (TTC) Approaches. Report of an ECB Workshop held in Ispra, November 2005. EUR 22657 EN, 43pp. Ispra, Italy:European Chemicals Bureau, European Commission Joint Research Centre.
18.
RobertsD.W. & WilliamsD.L. (1982). The derivation of quantitative correlations between skin sensitization and physico–chemical parameters for alkylating agents and their application to experimental data for sultones. Journal of Theoretical Biology99, 807–825.
19.
BerlV., BarbaudA. & LepoittevinJ-P. (1998). Mechanism of allergic contact dermatitis from propacetamol: sensitization to activated N,N-diethylglycine. Contact Dermatitis38, 185–188.
20.
GerberickG.F., VassalloJ.D., BaileyR.E., ChaneyJ.G., MorrallS.W. & LepoittevinJ-P. (2004). Development of a peptide reactivity assay for screening contact allergens. Toxicological Sciences81, 332–343.
21.
AptulaA.O., PatlewiczG., RobertsD.W. & SchultzT.W. (2006). Non-enzymatic glutathione reactivity and in vitro toxicity: A non-animal approach to skin sensitization. Toxicology in Vitro20, 239–247.
22.
de SilvaO., BasketterD.A., BarrattM.D., CorsiniE., CroninM.T.D., DasP.K., DegwertJ., EnkA., GarrigueJ.L., HauserC., KimberI., LepoittevinJ.P., PeguetJ. & PonecM. (1996). Alternative methods for skin sensitisation testing. The report and recommendations of the ECVAM Workshop 19. ATLA24, 683–705.
23.
KimberI., CumberbatchM., DearmanR.J., BhushanM. & GriffithsC.E.M. (2000). Cytokines and chemokines in the initiation and regulation of epidermal Langerhans cell mobilization. British Journal of Dermatology142, 401–412.
24.
JudgeF., BoissierC., Rougier-LarzatN., CorluA., ChesnéC., SemanaG. & HeresbachD. (2005). Regulation by allergens of chemokine receptor expression on in vitro-generated dendritic cells. Toxicology212, 227–238.
25.
JowseyI.R., BasketterD.A., WestmorelandC. & KimberI. (2006). A future approach to measuring relative skin sensitising potency: a proposal. Journal of Applied Toxicology26, 341–350.
26.
CasatiS., AebyP., BasketterD.A., CavaniA., GennariA., GerberickG.F., GriemP., HartungT., KimberI., LepoittevinJ-P., MeadeB.J., PallardyM., RougierN., RoussetF., RubinstennG., SallustoF., VerheyenG.R. & ZuangV. (2005). Dendritic cells as a tool for the predictive identification of skin sensitisation hazard. The report and recommendations of ECVAM Workshop 51. ATLA33, 47–62.
BasketterD., PeaseC., KastingG., KimberI., CasatiS., CroninM., DiembeckW., GerberickF., HadgraftJ., HartungT., MartyJ.P., NikolaidisE., PatlewiczG., RobertsD., RoggenE., RovidaC. & van de SandtJ. (2007). Skin sensitisation and epidermal disposition: the relevance of epidermal disposition for sensitisation hazard identification and risk assessment. The report and recommendations of ECVAM Workshop 59. ATLA35, 137–154.
29.
KimberI., CumberbatchM., BettsC.J. & DearmanR.J. (2004). Dendritic cells and skin sensitisation hazard assessment. Toxicology in Vitro18, 195–202.
30.
VerstraelenS., Van Den HeuvelR., NelissenI., WittersH., VerheyenG. & SchoetersG. (2005). Flow cytometric characterisation of antigen presenting dendritic cells after in vitro exposure to diesel exhaust particlesToxicology in Vitro19, 903–907.
31.
EnkA.H. & KatzS.I. (1992). Early molecular events in the induction phase of contact sensitivity. Proceedings of the National Academy of Sciences of the USA89, 1398–1402.
32.
KimberI. (2000). Skin sensitisation: immunological mechanisms and novel approaches to predictive testing. In Progress in the Reduction, Refinement and Replacement of Animal Experimentation (ed. BallsM., van ZellerA-M. & HalderM.E.), pp. 613–622. Amsterdam, The Netherlands:Elsevier.
33.
KimberI., PichowskiJ.S., BettsC.J., Cumber batchM., BasketterD.A. & DearmanR.J. (2001). Alternative approaches to the identification and characterisation of chemical allergens. Toxicology in Vitro15, 307–312.
34.
SchoetersE., VerheyenG.R., Van Den HeuvelR., NelissenI., WittersH., Van TendelooV.F.I., SchoetersG.E.R. & BernemanZ.N. (2005). Expression analysis of immune-related genes in CD34+ progenitor-derived dendritic cells after exposure to the chemical contact allergen DNCB. Toxicology in Vitro19, 909–913.
35.
GildeaL.A., RyanC.A., FoertschL.M., KennedyJ.M., DearmanR.J., KimberI. & GerberickG.F. (2006). Identification of gene expression changes induced by chemical allergens in dendritic cells: Opportunities for skin sensitisation testing. Journal of Investigative Dermatology126, 1813–1822.
36.
HirotaM. & MoroO. (2006). MIP-1β, a novel bio-marker for in vitro sensitisation test using human monocytic cell line. Toxicology in Vitro20, 736–742.
37.
YoshidaY., SakaguchiH., ItoY., OkudaM. & SuzukiH. (2003). Evaluation of the skin sensitisation potential of chemicals using expression of co-stimulatory molecules, CD54 and CD86, on the naïve THP-1 cell line. Toxicology in Vitro17, 221–228.
38.
AshikagaT., YoshidaY., HirotaM., YoneyamaK., ItakagiH., SakaguchiH., MiyazawaM., ItoY., SuzukiH. & ToyodaH. (2006). Development of an in vitro skin sensitisation test using human cell lines: The human Cell Line Activation Test (h-CLAT) I. Optimisation of the h-CLAT protocol. Toxicology in Vitro20, 767–773.
39.
SakaguchiH., AshikagaT., MiyazawaM., YoshidaY., ItoY., YoneyamaK., HirotaM., ItakagiH., ToyodaH. & SuzukiH. (2006). Development of an in vitro skin sensitisation test using human cell lines: The human Cell Line Activation Test (h-CLAT) II. An inter-laboratory study of the h-CLAT. Toxicology in Vitro20, 774–784.
40.
AzamP., PeifferJ-L., ChamoussetD., TissierM-H., BonnetP-A., VianL., FabreI. & OurlinJ-C. (2006). The cytokine-dependent MUTZ-3 cell line as an in vitro model for the screening of contact sensitisers. Toxicology & Applied Pharmacology212, 14–23.
41.
RégnierM., StaquetM.J., SchmittD. & SchmidtR. (1997). Integration of Langerhans cells into a pigmented reconstructed human epidermis. Journal of Investigative Dermatology109, 510–512.
42.
SchemppC.M., DittmarH.C., HummierD., Simon-HaarhausB., Schulte-MontingJ., SchopfE. & SimonJ.C. (2000). Magnesium ions inhibit the antigen-presenting function of human epidermal Langerhans cells in vivo and in vitro. Involvement of ATPase, HLA-DR, B7 molecules, and cytokines. Journal of Investigative Dermatology115, 680–686.
43.
FacyV., FlouretV., RégnierM. & SchmidtR. (2004). Langerhans cells integrated into human reconstructed epidermis respond to known sensitisers and ultraviolet exposure. Journal of Investigative Dermatology122, 552–553.
44.
FacyV., FlouretV., RégnierM. & SchmidtR. (2005). Reactivity of Langerhans cells in human reconstituted epidermis to known allergens and UV radiation. Toxicology in Vitro19, 787–795.
45.
HauserC. & KatzS.I. (1990). Generation and characterization of T-helper cells by primary in vitro sensitization using Langerhans cells. Immunological Reviews117, 67–84.
46.
CauxC., MassacrierC., Dezutter-DambuyantC., VanbervlietB., JacquetC., SchmittD. & BanchereauJ. (1995). Human dendritic Langerhans cells generated in vitro from CD34+ progenitors can prime naïve CD4+ T cells and process soluble antigen. Journal of Immunology155, 5427–5435.
47.
RustemeyerT., De LigterS., Von BlombergB.M., FroschP.J. & ScheperR.J. (1999). Human T-lymphocyte priming in vitro by haptenated autologous dendritic cells. Clinical & Experimental Immunology117, 209–216.
48.
DaiR. & StreileinJ.W. (1998). Naïve, hapten-specific human T-lymphocytes are primed in vitro with derivatized blood mononuclear cells. Journal of Investigative Dermatology110, 29–33.
49.
GuironnetG., Dalbiez-GauthierC., RoussetF., SchmittD. & Peguet-NavarroJ. (2000). In vitro human T cell sensitisation to haptens by monocyte derived dendritic cells. Toxicology in Vitro14, 517–522.
50.
EU (2003). Directive 2003/15/EC of the European Parliament and of the Council of 27 February 2003, amending Council Directive 76/768/EEC on the approximation of the laws of the Member States relating to cosmetic products. Official Journal of the European UnionL66, 26–35.
51.
BarrattM.D. (2000). Prediction of toxicity from chemical structure. Cell Biology & Toxicology16, 1–13.
52.
LepoittevinJ.P. (1999). Development of structure–activity relationships (SARs) in allergic contact dermatitis. Cell Biology & Toxicology15, 47–55.
53.
CroninM.T.D., JaworskaJ.S., WalkerJ.D., ComberM.H.I., WattsC.D. & WorthA.P. (2003). Use of QSARs in international decision-making frameworks to predict health effects of chemical substances. Environmental Health Perspectives111, 1391–1401.
OECD (2004). OECD Series on Testing and Assessment. No. 49 — The Report from the Expert Group on (Quantitative) Structure–Activity Relationships [(Q)SARs] on the Principles for the Validation of (Q)SARs, 206pp. Available at: http://appli1.oecd.org/olis/2004doc.nsf/linkto/env-jm-mono(2004)24 (Accessed 22.11.07).
56.
DupuisG. & BenezraC. (1982). Allergic Contact Dermatitis to Simple Chemicals: A Molecular Approach, 183pp. New York, NY, USA:Marcel Dekker, Inc.
57.
RobertsD.W., AptulaA.O., CroninM.T., HulzebosE. & PatlewiczG. (2007). Global (Q)SARs for skin sensitisation — Assessment against OECD principles. SAR & QSAR in Environmental Research18, 343–365.
58.
RobertsD.W., AptulaA.O. & PatlewiczG. (2007). Electrophilic chemistry related to skin sensitization: Reaction mechanistic applicability domain classification for a published data set of 106 chemicals tested in the mouse Local Lymph Node Assay. Chemical Research in Toxicology20, 44–60.
59.
BenezraC., SigmanC.C., PerryL.R., HelmesT. & MaibachH.I. (1985). A systematic search for structure–activity-relationships of skin contact sensitizers: methodology. Journal of Investigative Dermatology85, 351–356.
60.
SostedH., BasketterD.A., EstradaE., JohansenJ.D. & PatlewiczG.Y. (2004). Ranking of hair dye substances according to predicted sensitization potency: quantitative structure–activity relationships. Contact Dermatitis51, 241–254.
61.
PatlewiczG., RobertsD.W. & WalterJ.D. (2003). QSARs for the skin sensitization potential of aldehydes and related compounds. QSAR & Combinatorial Science22, 196–203.
62.
PatlewiczG.Y., BasketterD.A., PeaseC.K.S., WilsonK., WrightZ.M., RobertsD.W., BernardG., ArnauE.G. & LepoittevinJ.P. (2004). Further evaluation of quantitative structure–activity relationship models for the prediction of the skin sensitization potency of selected fragrance allergens. Contact Dermatitis50, 91–97.
63.
RobertsD.W. & BasketterD.A. (2000). Quantitative structure–activity relationships: sulfonate esters in the local lymph node assay. Contact Dermatitis42, 154–161.
64.
HostýnekJ.J. & MageeP.S. (1999). Performance of an SAR–QSAR model predictive of human ACD. In Vitro & Molecular Toxicology: A Journal of Basic & Applied Research12, 203–211.
65.
HostýnekJ.J., LauermaA.I., MageeP.S., BloomE. & MaibachH.I. (1995). A local lymph node assay validation study of a structure–activity relationship model for contact allergens. Archives of Dermatology Research287, 567–571.
66.
MekenyanO., RobertsD.W. & KarcherW. (1997). Molecular orbital parameters as predictors of skin sensitization potential of halo- and pseudohalobenzenes acting as SNAr electrophiles. Chemical Research in Toxicology10, 994–1000.
67.
AshbyJ., BasketterD.A., PatonD. & KimberI. (1995). Structure–activity relationships in skin sensitisation using the murine local lymph node assay. Toxicology103, 177–194.
68.
CroninM.T.D. & BasketterD.A. (1994). A multivariate QSAR analysis of a skin sensitisation database. SAR & QSAR in Environmental Research2, 159–179.
69.
CroninM.T.D. & DeardenJ.C. (1997). Correspondence analysis of the skin sensitization potential of organic chemicals. Quantitative Structure–Activity Relationships16, 33–37.
70.
AptulaA.O., PatlewiczG. & RobertsD.W. (2005). Skin sensitisation: reaction mechanistic applicability domains for structure–activity relationships. Chemical Research in Toxicology18, 1420–1426.
71.
EnsleinK., GombarV.K., BlakeB.W., MaibachH.I., HostýnekJ.J., SigmanC.C. & BagheriD. (1997). A quantitative structure–toxicity relationships model for the dermal sensitization guinea-pig maximization assay. Food & Chemical Toxicology35, 1091–1098.
HostýnekJ.J. & MaibachH.I. (1998). Scope and limitation of some approaches to predicting contact hypersensitivity. Toxicology in Vitro12, 445–453.
74.
HostýnekJ.J. & MageeP.S. (1999). Performance of an SAR–QSAR model predictive of human ACD. In Vitro & Molecular Toxicology: A Journal of Basic & Applied Research12, 203–211.
75.
CoeckeS., AhrH., BlaauboerB.J., BremerS., CasatiS., CastellJ., CombesR., CorviR., CrespiC.L., CunninghamM.L., ElautG., ElettiB., FreidigA., GennariA., Ghersi-EgeaJ-F., GuillouzoA., HartungT., HoetP., Ingelman-SundbergM., MunnS., JanssensW., LadstetterB., LeahyD., LongA., MeneguzA., MonshouwerM., MorathS., NagelkerkeF., PelkonenO., PontiJ., PrietoP., RichertL., SabbioniE., SchaackB., SteilingW., TestaiE., VericatJ-A. & WorthA. (2005). Metabolism: a bottleneck in in vitro toxicological test development. The report and recommendations of ECVAM Workshop 54. ATLA34, 49–84.
76.
DimitrovS.D., LowL.K., PatlewiczG.Y., KernP.S., DimitrovaG.D., ComberM.H., PhillipsR.D., NiemeläJ., BaileyP.T. & MekenyanO.G. (2005). Skin sensitization: modeling based on skin metabolism simulation and formation of protein conjugates. International Journal of Toxicology24, 189–204.
77.
PatlewiczG., DimitrovS.D., LowL.K., KernP.S., DimitrovaG.D., ComberM.H., AptulaA.O., PhillipsR.D., NiemeläJ., MadsenC., WedebyeE.B., RobertsD.W., BaileyP.T. & MekenyanO.G. (2007). TIMES–SS — A promising tool for the assessment of skin sensitization hazard. A characterization with respect to the OECD validation principles for (Q)SARs and an external evaluation for predictivity. Regulatory Toxicology & Pharmacology48, 225–239.
78.
PayneM.P. & WalshP.T. (1994). Structure–activity relationships for skin sensitization potential: development of structural alerts for use in knowledge-based toxicity prediction systems. Journal of Chemical Information & Computer Sciences34, 154–161.
79.
CombesR.D. & RodfordR.A. (2004). The use of expert systems for toxicity prediction: illustrated with reference to the DEREK program. In Predicting Chemical Toxicity and Fate (ed. CroninM.T.D. & LivingstoneD.J.), pp. 193–204. Boca Raton, FL, USA:CRC Press.
80.
ZinkeS., GernerI. & SchledeE. (2002). Evaluation of a rule base for identifying contact allergens by using a regulatory database: Comparison of data on chemicals notified in the European Union with ‘structural alerts’ used in the DEREK FW Expert System. ATLA30, 285–298.
81.
LangtonK., PatlewiczG.Y., LongA., MarchantC. & BasketterD.A. (2006). Structure–activity relationships for skin sensitisation: recent improvements to DEREK for Windows. Contact Dermatitis55, 342–347.
82.
FedorowiczA., ZhengL.Y., SinghH. & DemchukE. (2004). QSAR study of skin sensitization using local lymph node assay data. International Journal of Molecular Sciences5, 56–66.
83.
AndersonS.E., WellsJ.R., FedorowiczA., ButterworthL., MeaseB.J. & MunsonA.E. (2007). Evaluation of the contact and respiratory sensitisation potential of volatile organic compounds generated by simulated indoor chemistry. Toxicological Sciences97, 355–363.
84.
EstradaE., PatlewiczG. & GutierrezY. (2004). From knowledge generation to knowledge archive. A general strategy using TOPS–MODE with DEREK to formulate new alerts for skin sensitisation. Journal of Chemical Information & Computer Sciences44, 688–698.
AptulaA.O. & RobertsD.W. (2006). Mechanistic applicability domains for non-animal based prediction of toxicological end points: general principles and application to reactive toxicity. Chemical Research in Toxicology19, 1097–1105.
87.
RobertsD.W., AptulaA.O., PatlewiczG. & PeaseC. (2007). Chemical reactivity indices and mechanism-based read across for non-animal based assessment of skin sensitisation potential. Journal of Applied Toxicology, published online, 17 August 2007. Available at: http://www3.interscience.wiley.com/cgi-bin/abstract/115804901/ABSTRACT?CRETRY=1&SRETRY=0 (Accessed 23.11.07).
88.
SteilingW., BasketterD., BertholdK., ButlerM., GarrigueJ.L., KimberI., LeaL., NewsomeC., RoggebandR., StroppG., WatermanS. & WiemannC. (2001). Skin sensitization testing — new perspectives and recommendations. Food & Chemical Toxicology39, 293–301.
89.
ECVAM (2000). Statement on the validity of the Local Lymph Node Assay for skin sensitisation testing. ATLA28, 366–367.
KimberI., DearmanR.J., BettsC.J., GerberickG.F., RyanC.A., KernP.S., PatlewiczG.Y. & BasketterD.A. (2006). The local lymph node assay and skin sensitization: a cut-down screen to reduce animal requirements?Contact Dermatitis54, 181–185.
93.
CombesR.D., GauntI. & BallsM. (2004). A scientific and animal welfare assessment of the OECD Health Effects Test Guidelines for the safety testing of chemicals under the European Union REACH System. ATLA32, 163–208.
94.
WorthA.P. & BallsM. (eds) (2002). Alternative (non-animal) methods for chemicals testing: Current status and future prospects. A report prepared by ECVAM and the ECVAM Working Group on Chemicals. ATLA30Suppl. 1, 125pp.
95.
HowesD., GuyR., HadgraftJ., HeylingsJ., HoeckU., KemperF., MaibachH., MartyJ-P., MerkH., ParraJ., RekkasD., RondelliI., SchaeferH., TäuberU. & VerbieseN. (1996). Methods for assessing percutaneous absorption. The report and recommendations of ECVAM Workshop 13. ATLA24, 81–106.
96.
BarrattM.D. (1995). The role of structure–activity relationships and expert systems in alternative strategies for the determination of skin sensitisation, skin corrosivity and eye irritation. ATLA23, 111–122.
97.
LangleyG. (2001). The Way Forward — Action to End Animal Toxicity Testing, 36pp. London, UK:British Union for the Abolition of Vivisection (BUAV).
98.
SmithH.R., HollowayD., ArmstrongD.K.B., BasketterD.A. & McFaddenJ.P. (2000). Irritant thresholds in subjects with colophony allergy. Contact Dermatitis42, 95–97.
Anon. (2000). Opinion concerning the predictive testing of potentially cutaneous sensiting cosmetic ingredients or mixtures of ingredients adopted by the SCCNFP during the 11th plenary session of 17 February 2000. Available at: www.ec.europa.eu/health/ph_risk/committees/sccp/docshtml/sccp_out102_en.htm (Accessed 23.11.07).
101.
FentemJ., ChamberlainM. & SangsterB. (2004). The feasibility of replacing animal testing for assessing consumer safety: A suggested future direction. ATLA32, 617–623.
102.
TrombettaE.S. & MellmanI. (2005). Cell biology of antigen processing in vitro andin vivo. Annual Review of Immunology23, 975–1028.
103.
CombesR., BallsM., IllingP., BhogalN., DaleJ., DuvéG., FeronV., GrindonC., GüldenM., LoizouG., PristonR. & WestmorelandC. (2006). Possibilities for a new approach to chemicals risk assessment — The report of a FRAME workshop. ATLA34, 621–649.
104.
RobertsD.W. & BasketterD.A. (2000). Quantitative structure–activity relationships: sulfonate esters in the local lymph node assay. Contact Dermatitis42, 154–161.
105.
RobertsD.W. & BasketterD.A. (1997). Further evaluation of the quantitative structure–activity relationship for skin-sensitizing alkyl transfer agents. Contact Dermatitis37, 107–112.
RobertsD.W., AptulaA.O. & PatlewiczG. (2006). Mechanistic applicability domains for non-animal based prediction of toxicological endpoints. QSAR analysis of the Schiff-base applicability domain for skin sensitization. Chemical Research in Toxicology19, 1228–1233.
108.
RobertsD.W. & PatlewiczG. (2002). Mechanism based structure–activity relationships for skin sensitisation — the carbonyl group domain. SAR & QSAR in Environmental Research13, 145–152.
109.
RobertsD.W. & BenezraC. (1993). Quantitiative structure–activity relationships for skin sensitization potential of urushiol analogues. Contact Dermatitis29, 78–83.
110.
BasketterD.A., RobertsD.W., CroninM. & ScholesE.W. (1992). The value of the local lymph node assay in quantitative structure–activity investigations. Contact Dermatitis27, 137–142.
111.
HatchK.L. & MageeP.S. (1998). A discriminant model for allergic contact dermatitis in anthraquinone disperse dyes. Quantitative Structure–Activity Relationships17, 20–26.
112.
BarrattM.D., BasketterD.A. & RobertsD.W. (1994). Skin sensitization structure–activity relationships for phenyl benzoates. Toxicology in Vitro8, 823–826.
113.
HostýnekJ.J. & MageeP.S. (1997). Fragrance allergens: Classification and ranking by QSAR. Toxicology in Vitro11, 377–384.
114.
FranotC., RobertsD.W., BasketterD.A., BenezraC. & LepoittevinJ.P. (1994). Structure–activity relationships for contact allergenic potential of α,α-dimethyl-γ-butyrolactone derivatives. 2. Quantitative structure skin sensitization relationships for α-substituted-α-methyl-α,α-dimethyl-γ-butyrolactone. Chemical Research in Toxicology7, 307–312.
