National Toxicology Program

National Toxicology Program
https://ntp.niehs.nih.gov/go/40474

References Relevant to the January 2007 Nomination to ICCVAM for Evaluation of the LLNA for Classification of Sensitizers


Relevant Test Method Guidelines

EPA. 2003. Health Effects Test Guidelines OPPTS 870.2600 Skin Sensitization. EPA 712-C-03-197. Washington, DC: U.S. Environmental Protection Agency.

OECD. 2002. Guideline For Testing of Chemicals, 429, Skin Sensitisation: Local Lymph Node Assay. Paris, France: Organisation for Economic Co-operation and Development.

Background on the LLNA

Sailstad DM. 2002. Murine local lymph node assay: an alternative test method for skin hypersensitivity testing. Lab Animal 31:36-41.

Sailstad D, Hattan D, Hill R, and Stokes WS. 2001. Evaluation of the murine local lymph node assay (LLNA) I: The ICCVAM review process. Regulatory Toxicology and Pharmacology 34:249-257.

Dean J, Twerdok L, Tice R, Sailstad D, Hattan D and Stokes, WS. 2001. Evaluation of the murine local lymph node assay (LLNA) II: Conclusions and recommendations of an independent scientific peer review panel. Regulatory Toxicology and Pharmacology 34:258-273

Haneke K, Tice R, Carson B, Margolin B, and Stokes WS. 2001. Evaluation of the murine local lymph node assay (LLNA) III: Data analyses completed by the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). Regulatory Toxicology and Pharmacology 34:274-286.

Cut-Down Assay

I Kimber, R Dearman, C Betts, G Gerberick, C Ryan, P Kern, et al. 2006. The local lymph node assay and skin sensitization: a cut-down screen to reduce animal requirements? Contact Dermatitis 54:181-185.

LLNA Use to Assess Sensitization Potency

D Basketter, J McFadden, P Evans, K Andersen, I Jowsey. 2006. Identification and classification of skin sensitizers: identifying false positives and false negatives. Contact Dermatitis 55:268-273.

D Basketter, I Kimber. 2006. Predictive test for irritants and allergens and their use in quantitative risk assessment. In: Contact Dermatitis, 4th Edition (P Frosch, T Menn, J-P Lepoittevin, eds.) Heidelberg: Springer Verlag, 179–188.

D Basketter, K Andersen, C Carola, H Van Loveren, A Boman, I Kimber, et al. 2005. Evaluation of the skin sensitizing potency of chemicals by using the existing methods and considerations of relevance for elicitation. Contact Dermatitis 52:39-43.

D Basketter, C Clapp, D Jefferies, R Safford, C Ryan, G Gerberick, R Dearman, I Kimber. 2005. Predictive identification of human skin sensitisation thresholds. Contact Dermatitis 53:260-267.

D Basketter, P Cadby. 2004. Reproducible prediction of contact allergenic potency using the local lymph node assay. Contact Dermatitis 50:15-17.

D Basketter, C Smith Pease, G Patlewicz. 2003. Contact allergy: the local lymph node assay for the prediction of hazard and risk. Clinical and Experimental Dermatology 28:218-221.

D Basketter, L Blaikie, R Dearman, I Kimber, C Ryan, G Gerberick, P Harvey, P Evans, I White, R Rycroft. 2000. Use of the local lymph node assay for the estimation of relative contact allergenic potency. Contact Dermatitis 42:344-348.

D Basketter, L Lea, K Cooper, A Dickens, D Briggs, I Pate, R Dearman, I Kimber. 1999. A comparison of statistical approaches to derivation of EC3 values from local lymph node assay dose responses. Journal of Applied Toxicology 19:261-266.

D Basketter, L Lea, K Cooper, A Dickens, J Stocks, I Pate, R Dearman, I Kimber. 1999. Thresholds for classification as a skin sensitiser in the local lymph node assay: a statistical evaluation. Food and Chemical Toxicology 37:1167-1174.

D Basketter, R Rodford, I Kimber, I Smith, J Wahlberg. 1999. Skin sensitization risk assessment: a comparative evaluation of three isothiazolinone biocides. Contact Dermatitis 40:150-154.

D Basketter, D Roberts, M Cronin, E Scholes. 1992. The value of the local lymph node assay in quantitative structure activity investigations. Contact Dermatitis 27:137-142.

D Basketter, Z Wright, E Warbrick, R Dearman, I Kimber, C Ryan, G Gerberick, I White. 2001. Human potency predictions for aldehydes using the local lymph node assay. Contact Dermatitis 45:89-94.

C Betts, R Dearman, J Heylings, I Kimber, D Basketter. 2006. Skin sensitization potency of methyl methacrylate in the local lymph node assay: comparisons with guinea-pig data and human experience. Contact Dermatitis 55:140-147.

C Betts, R Dearman, I Kimber, H Maibach. 2005. Potency and risk assessment of a skin-sensitizing disperse dye using the local lymph node assay. Contact Dermatitis 52:268-272.

R Dearman, Z Wright, D Basketter, C Ryan, G Gerberick, I Kimber. 2001. The suitability of hexyl cinnamic aldehyde as a calibrant for the using local lymph node assay. Contact Dermatitis 44:357-361.

G Gerberick, C Ryan, R Dearman, I Kimber. 2007. Local lymph node assay (LLNA) for detection of sensitization capacity of chemicals. Methods 41:54-60.

G Gerberick, C Ryan, P Kern, H Schlatter, R Dearman, I Kimber, G Patlewicz, D Basketter. 2007. Updating the compilation of historical local lymph node assay data for the evaluation of skin sensitization alternatives. Dermatitis: MS in preparation.

G Gerberick, C Ryan, P Kern, H Schlatter, R Dearman, I Kimber, G Patlewicz, D Basketter. 2005. Compilation of historical local lymph node assay data for the evaluation of skin sensitization alternatives. Dermatitis 16:157-202.

G Gerberick, Robinson MK, C Ryan, R Dearman, I Kimber, D Basketter, Wright Z, Marks JG. 2001. Contact allergenic potency: correlation of human and local lymph node assay data. American Journal of Contact Dermatitis 12:156-161.

G Gerberick, J Vassallo, L Foertsch, B Price, J Chaney, J-P Lepoittevin. 2007. Quantification of chemical peptide reactivity for screening contact allergens: a classification tree model approach. Toxicological Sciences 97:417-427.

P Griem, C Goebel, H Scheffler. 2003. Proposal for a risk assessment methodology for skin sensitization based on sensitization potency data. Regulatory Toxicology and Pharmacology 38:269-290.

J Hilton, R Dearman, P Harvey, P Evans, D Basketter, I Kimber. 1998. Estimation of the relative skin sensitizing potency using the local lymph node assay: a comparison of formaldehyde with glutaraldehyde. American Journal of Contact Dermatitis 9:29-33.

I Jowsey, D Basketter, C Westmoreland, I Kimber. 2006. A future approach to measuring relative skin sensitising potency: a proposal. Journal of Applied Toxicology 26:341-350.

I Kimber, D Basketter, M Butler, A Gamer, J Garrigue, G Gerberick, et al. 2003. Classification of contact allergens according to potency: proposals. Food and Chemical Toxicology 41:1799-1809.

I Kimber, D Basketter, K Berthold, M Butler, J Garrigue, L Lea, C Newsome, R Roggeband, W Steiling, G Stropp, S Waterman, C Wiemann. 2001. Skin sensitization testing in potency and risk assessment. Toxicological Sciences 59:198-208.

I Kimber, G Gerberick, D Basketter. 1999. Thresholds in contact sensitization: theoretical considerations and practical applications. Food and Chemical Toxicology 37:553-560.

I Kimber, D Basketter. 1997. Contact sensitization: a new approach to risk assessment. Human and Ecological Risk Assessment (HERA) 3:385-395.

I Kimber, J Hilton, R Dearman, G Gerberick, C Ryan, D Basketter, E Scholes, R House, A Guy, G Ladics, S Loveless. 1995. An international evaluation of the murine local lymph node assay and comparison of modified procedures. Toxicology 103:63-73.

I Kimber, R Dearman. 1991. Investigation of lymph node cell proliferation as a possible immunological correlate of contact sensitizing potential. Food and Chemical Toxicology 29:125–129.

J Lalko, A Api. 2006. Investigation of the dermal sensitization potential of various essential oils in the local lymph node assay. Food and Chemical Toxicology 44:739-746.

L Lea, V Warbrick, R Dearman, P Harvey, I Kimber, D Basketter. 1999. The impact of vehicle on assessment of relative skin sensitisation potency of 1,4-dihydroquinone in the local lymph node assay. American Journal of Contact Dermatitis 10:213–218.

S Loveless, G Ladics, G Gerberick, C Ryan, D Basketter, E Scholes, R House, J Hilton, R Dearman, I Kimber. 1996. Further evaluation of the local lymph node assay in the final phase of an international collaborative trial. Toxicology 108:141-152.

H McGarry. 2007. The murine local lymph node assay: Regulatory and potency considerations under REACH. Toxicology 238:71–89.

G Patlewicz, D Basketter, C Smith, S Hotchkiss, D Roberts. 2001. Skin sensitisation structure activity relationships for aldehydes. Contact Dermatitis 44:331-336.

C Ryan, J Chaney, P Kern, R Dearman, I Kimber, D Basketter, G Gerberick. 2007. Extrapolating local lymph node assay EC3 values to estimate relative sensitizing potency. Journal of Toxicology: Cutaneous and Ocular Toxicology 26:135-45.

C Ryan, G Gerberick, L Cruse, D Basketter, L Lea, L Blaikie, R Dearman, E Warbrick, I Kimber. 2000. Activity of human contact allergens in the murine local lymph node assay. Contact Dermatitis 43:95-102.

E Schlede, W Aberer, T Fuchs, I Gerner, H Lessmann, T Maurer, et al. 2003. Chemical substances and contact allergy - 244 Substances ranked according to allergenic potency. Toxicology 193:219-259.

K Schneider, Z Akkan. 2004. Quantitative relationship between the local lymph node assay and human skin sensitization assays. Regulatory Toxicology and Pharmacology 39:245-255.

E Warbrick, R Dearman, L Lea, D Basketter, I Kimber. 1999. Local lymph node assay responses to paraphenylenediamine: intra- and inter-laboratory evaluations. Journal of Applied Toxicology 19:255-260.

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Non-Radioactive LLNA Methods

P Azam, J Peiffer, J Ourlin , P Bonnet, M Tissier, L Vian, et al. 2005. Qualitative and quantitative evaluation of a local lymph node assay based on ex vivo interleukin-2 production. Toxicology 206:285-298.

G Gerberick, L Cruse, C Ryan. 1999. Local lymph node assay: differentiating allergic and irritant responses using flow cytometry. Methods: A Companion to Methods in Enzymology 19:48-55.

V Hans-Werner, A Jurgen. 2005. The local lymph node assay being too sensitive? Archives of Toxicology 79:721-728.

T Hariya, M Hatao, H Ichikawa. 1999. Development of a non-radioactive endpoint in a modified local lymph node assay. Food and Chemical Toxicology 37:87-93.

M Hatao, T Hariya, Y Katsumura, S Kato. 1995. A modification of the local lymph node assay for contact allergenicity screening: measurement of interleukin-2 as an alternative to radioisotope-dependent proliferation assay. Toxicology 98:15-22.

N Humphreys, R Dearman, I Kimber. 2003. Assessment of cumulative allergen-activated lymph node cell proliferation using flow cytometry. Toxicological Sciences 73:80-89.

U Kuhn, U Lempertz, J Knop, D Becker. 1995. A new method for phenotyping proliferating cell nuclear antigen positive cells using flow cytometry: implications for analysis of the immune response in vivo. Journal of Immunological Methods 179:215-222.

J Lee, J Park, S Park, H Kim, H Oh. 2002. A nonradioisotopic endpoint for measurement of lymph node cell proliferation in a murine allergic contact dermatitis model, using bromodeoxyuridine immunohistochemistry. Journal of Pharmacological and Toxicological Methods 48(1):53-61.

A Suda, M Yamashita, M Tabei, K Taguchi, H Vohr, N Tsutsui, et al. 2002. Local lymph node assay with non-radioisotope alternative endpoints. Journal of Toxicological Sciences 27:205-218.

M Takeyoshi, S Noda, K Yamasaki, I Kimber. 2006. Advantage of using CBA/N strain mice in a non-radioisotopic modification of the local lymph node assay. Journal of Applied Toxicology 26:5-9.

M Takeyoshi, M Sawaki, K Yamasaki, I Kimber. 2003. Assessment of statistic analysis in non-radioisotopic local lymph node assay (non-RI-LLNA) with α-hexylcinnamic aldehyde as an example. Toxicology 191:259-263.

M Takeyoshi, K Yamasaki, Y Yakabe, M Takatsuki, I Kimber. 2001. Development of non-radio isotopic endpoint of murine local lymph node assay based on 5-bromo-2'-deoxyuridine (BrdU) incorporation. Toxicology Letters 119:203-208.

G Ehling, M Hecht, A Heusener, J Huesler, A Gamer, H van Loveren, T Maurer, K Riecke, L Ullmann, P Ulrich, R Vandebriel, H Vohr. 2005. An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: first round. Toxicology 212:60-68.

G Ehling, M Hecht, A Heusener, J Huesler, A Gamer, H van Loveren, T Maurer, K Riecke, L Ullmann, P Ulrich, R Vandebriel, H Vohr. 2005. An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: 2nd round. Toxicology. 212:69-79.

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LLNA Use in Testing of Mixtures, Formulations, Metals or Aqueous Solutions

F Andersen. 2005. Final report on the safety assessment of potassium silicate, sodium metasilicate, and sodium silicate. International Journal of Toxicology 24(SUPPL. 1):103-117.

D Basketter, L Lea, K Cooper, C Ryan, G Gerberick, R Dearman, et al. 1999. Identification of metal allergens in the local lymph node assay. American Journal of Contact Dermatitis 10:207-212.

F Clottens, A Breyssens, H De Raeve, M Demedts, B Nemery. 1996. Assessment of the ear swelling test and the local lymph node assay in hamsters. Journal of Pharmacological and Toxicological Methods 35:167-172.

T Hariya, M Hatao, H Ichikawa. 1999. Development of a non-radioactive endpoint in a modified local lymph node assay. Food and Chemical Toxicology 37:87-93.

J Hostynek, H Maibach. 2004. Copper hypersensitivity: dermatologic aspects. Dermatologic therapy 17:328-333.

--- 2003. Copper Hypersensitivity: Dermatologic aspects - an overview. Reviews on Environmental Health 18:153-183.

Y Ikarashi, M Kaniwa, T Tsuchiya. 2002. Sensitization potential of gold sodium thiosulfate in mice and guinea pigs. Biomaterials 23:4907-4914.

Y Ikarashi, Y Tsukamoto, T Tsuchiya, A Nakamura. 1993. Influence of irritants on lymph node cell proliferation and the detection of contact sensitivity to metal salts in the murine local lymph node assay. Contact Dermatitis 29:128-132.

Y Ikarashi, T Tsuchiya, A Nakamura. 1993. A sensitive mouse lymph node assay with two application phases for detection of contact allergens. Archives of Toxicology 67:629-636.

---. 1993. Evaluation of contact sensitivity of rubber chemicals using the murine local lymph node assay. Contact Dermatitis 28:77-80.

Y Ikarashi, K Ohno, T Tsuchiya, A Nakamura. 1992. Differences of draining lymph node cell proliferation among mice, rats and guinea pigs following exposure to metal allergens. Toxicology 76:283-292.

Y Ikarashi, T Tsuchiya, A Nakamura. 1992. Detection of contact sensitivity of metal salts using the murine local lymph node assay. Toxicology Letters 62:53-61.

I Kimber, A Bentley, J Hilton. 1990. Contact sensitization of mice to nickel sulphate and potassium dichromate. Contact Dermatitis 23:325-330.

J Lalko, A Api. 2006. Investigation of the dermal sensitization potential of various essential oils in the local lymph node assay. Food and Chemical Toxicology 44:739-746.

C Mandervelt, F Clottens, M Demedts, B Nemery. 1997. Assessment of the sensitization potential of five metal salts in the murine local lymph node assay. Toxicology 120:65-73.

A Nakamura, Y Kanazawa, H Sato, T Tsuchiya, Y Ikarashi, W De Jong, et al. 2003. Evaluation of allergic potential of rubber products: comparison of sample preparation methods for the testing of polymeric medical devices. Journal of Toxicology - Cutaneous and Ocular Toxicology 22:169-185.

C Ryan, L Cruse, R Skinner, R Dearman, I Kimber, G Gerberick. 2002. Examination of a vehicle for use with water soluble materials in the murine local lymph node assay. Food and Chemical Toxicology 40:1719-1725.

D Sailstad, J Tepper, D Doerfler, M Qasim, M Selgrade. 1994. Evaluation of an azo and two anthraquinone dyes for allergic potential. Fundamental and Applied Toxicology 23:569-577.

M Skold, A Karlberg, M Matura, A Borje. 2006. The fragrance chemical beta-caryophyllene - air oxidation and skin sensitization. Food and Chemical Toxicology 44:538-545.

M Skold, A Borje, E Harambasic, A Karlberg. 2004. Contact allergens formed on air exposure of linalool. Identification and quantification of primary and secondary oxidation products and the effect on skin sensitization. Chemical Research in Toxicology 17:1697-1705.

S Tinkle, J Antonini, B Rich, J Roberts, R Salmen, K DePree, et al. 2003. Skin as a route of exposure and sensitization in chronic beryllium disease. Environmental Health Perspectives 111:1202-1208.

T Yamano, M Shimizu, T Noda. 2006. Allergenicity and cross-reactivity of naphthenic acid and its metallic salts in experimental animals. Contact Dermatitis 54:25-28.

NTP is located at the National Institute of Environmental Health Sciences, part of the National Institutes of Health.