Threshold for classification as a skin sensitizer in the local lymph node assay: a statistical evaluation

Basketter, David A.; Lea, Linda J.; Cooper, Karen J.; Stocks, Janice; Dickens, Andrea; Pate, Ian; Dearman, Rebecca J.; Kimber, Ian

doi:10.1016/s0278-6915(99)00112-x

Cited by 108 publications

(72 citation statements)

References 17 publications

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“…A LR QSAR model with ten 4D-fingerprint terms is obtained using the stepwise procedure on VS_USMAX: (22) Although the cross-validation accuracy of eq. (22) is 81.8%, its Hosmer-Lemeshow goodnessof-fit statistic is 24.003, and the corresponding p-value is 0.002 indicating this model doesn't fit the data very well.…”

Section: Logistic Regression (Lr)mentioning

confidence: 99%

“…It provides a standardized continuous scale suitable for quantitative assessment of skin sensitization. 22 The extent of sensitization is quantified from a measurement of the cellular proliferation induced in the lymph nodes draining the site of chemical application. The response data are usually represented by a stimulation index (SI) that compares the proliferation for each test material to that from a vehicle control.…”

Section: Introductionmentioning

confidence: 99%

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4D-Fingerprint Categorical QSAR Models for Skin Sensitization Based on the Classification of Local Lymph Node Assay Measures

Tseng

Pan

et al. 2006

Chem. Res. Toxicol.

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Currently, the only validated methods to identify skin sensitization effects are in vivo models, such as the Local Lymph Node Assay (LLNA) and guinea pig studies. There is a tremendous need, in particular due to novel legislation, to develop animal alternatives, eg. Quantitative Structure-Activity Relationship (QSAR) models. Here, QSAR models for skin sensitization using LLNA data have been constructed. The descriptors used to generate these models are derived from the 4D-molecular similarity paradigm and are referred to as universal 4D-fingerprints. A training set of 132 structurally diverse compounds and a test set of 15 structurally diverse compounds were used in this study. The statistical methodologies used to build the models are logistic regression (LR), and partial least square coupled logistic regression (PLS-LR), which prove to be effective tools for studying skin sensitization measures expressed in the two categorical terms of sensitizer and non-sensitizer. QSAR models with low values of the Hosmer-Lemeshow goodness-of-fit statistic, , are significant and predictive. For the training set, the cross-validated prediction accuracy of the logistic regression models ranges from 77.3% to 78.0%, while that of PLS-logistic regression models ranges from 87.1% to 89.4%. For the test set, the prediction accuracy of logistic regression models ranges from 80.0%-86.7%, while that of PLS-logistic regression models ranges from 73.3%-80.0%. The QSAR models are made up of 4D-fingerprints related to aromatic atoms, hydrogen bond acceptors and negatively partially charged atoms.

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Section: Logistic Regression (Lr)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

4D-Fingerprint Categorical QSAR Models for Skin Sensitization Based on the Classification of Local Lymph Node Assay Measures

Tseng

Pan

et al. 2006

Chem. Res. Toxicol.

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“…When a chemical induces a stimulation index (SI) of 3 or higher it is considered a sensitizer. This figure was empirically determined by comparing the murine results with knowledge of human sensitizers (Kimber and Basketter, 1992), and later confirmed by statistical analysis (Basketter et al, 1999a) and an independent evaluation process (Haneke et al, 2001).…”

Section: Introductionmentioning

confidence: 91%

“…In order to investigate the effects of such an accumulation, the induction of cellular proliferation in draining lymph nodes was compared after short and repeated prolonged exposure to formaldehyde releasers. We used the stimulation index of 3 as a benchmark response as this value is used as cutoff to conclude sensitizing ability (Kimber and Basketter, 1992;Basketter et al, 1999a;Haneke et al, 2001) and, in addition, can be used to compare potency of various chemicals (Van Och et al, 2000;De Jong et al, 2002b;Kimber et al, 2003;Basketter et al, 2005a).…”

Section: Exposure To Chemicalmentioning

confidence: 99%

“…Using the EC3 value (the effective concentration inducing a threefold increase in lymph node cell proliferation compared to 240 DE JONG ET AL. controls, SI = 3), various chemicals can be compared with each other for their sensitizing potency, and a ranking order can be determined (Basketter et al, 1999a(Basketter et al, , 1999b(Basketter et al, , 2005aVan Och et al, 2000;De Jong et al, 2002b). Based on such ranking, chemicals might be classified according to their potency in various categories instead of the two categories currently used-sensitizer and non-sensitizer (Dearman et al, 1999;Kimber et al, 2003;Schneider and Akkam, 2004;Basketter et al, 2005a).…”

Section: Introductionmentioning

confidence: 99%

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Effect of Prolonged Repeated Exposure to Formaldehyde Donors with Doses Below the EC3 Value on Draining Lymph Node Responses

Jong

Klerk

Beek

et al. 2007

Journal of Immunotoxicology

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In the Local Lymph Node Assay (LLNA), a stimulation index of 3 (SI = 3) is established as a threshold value for hazard identification of sensitization. The corresponding EC3 value, the effective concentration inducing a threefold increase compared to controls, can possibly predict threshold levels for sensitization in humans. Exposure to a dose below the threshold dose would not result in an induction of an immune response. Each repeated contact would be considered and viewed as a new contact and as long as the dose is below the threshold there will be no response, even after repeated exposures. However, repeated exposure may result in local accumulation eventually resulting in a dose that induces a response above the threshold for immunization. We investigated lymph node responses after short and prolonged exposure to formaldehyde donors, chemicals that are highly reactive with proteins and may thus persist in the skin. The studies were performed with formaldehyde and formaldehyde releasers (formaldehyde, paraformaldehyde, Quaternium-15, 2-Chloro-N-(hydroxymethyl)acetamide, and hexamethylenetetramine), at concentrations that induce a SI = 2, i.e., below the threshold for hazard identification. For all test chemicals investigated enhanced lymph node responses were obtained when comparing long-term prolonged exposure to short-term exposure, while three of five chemicals induced responses above SI = 3. Our results show that repeated and prolonged exposure to doses below the EC3 value can induce reactions above the SI = 3, the hazard identification threshold for sensitization in mice. So, when discussing the possible use of the EC3 as benchmark for risk assessment, one should consider duration of exposure and the possibility of local accumulation of the chemical under investigation.

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Local lymph node assay: use in hazard and risk assessment

1999

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The murine local lymph node assay (LLNA) was developed as an alternative method for the identification of chemicals that have the ability to cause skin sensitization and allergic contact dermatitis. The assay now has been evaluated extensively in the context of both national and international inter‐laboratory collaborative trials and has been the subject of detailed comparisons with guinea pig test methods and human skin sensitization data. On the basis of these evaluations the LLNA has been endorsed recently by the US Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) as a stand‐alone method for skin sensitization testing. The assay offers a number of important benefits compared with conventional guinea pig test methods, among these being provision of an objective and quantitative endpoint. Moreover, the LLNA provides advantages in the context of animal welfare; compared with guinea pig tests, fewer animals are required and these animals are subject to less trauma. It is important now that the validation status of the LLNA is recognized and the method applied widely so that these advantages may be realized. Hazard identification represents only the first step in the risk assessment process. A full toxicological evaluation of skin sensitization activity requires an understanding of relative potency. Guinea pig methods do not lend themselves readily to assessment of potency, and interest recently has focused on the utility of the LLNA for this purpose. Contained within this review article are brief descriptions of the history of the LLNA and the immunobiological basis for the method, together with detailed accounts of the conduct and interpretation of the assay. Procedural modifications to, and alternative endpoints for, the LLNA are considered also. Finally, the current regulatory status of the LLNA is summarized and the application of the method for the purposes of defining relative potency and developing risk assessments is reviewed. Copyright © 1999 John Wiley & Sons, Ltd.

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Threshold for classification as a skin sensitizer in the local lymph node assay: a statistical evaluation

Cited by 108 publications

References 17 publications

4D-Fingerprint Categorical QSAR Models for Skin Sensitization Based on the Classification of Local Lymph Node Assay Measures

4D-Fingerprint Categorical QSAR Models for Skin Sensitization Based on the Classification of Local Lymph Node Assay Measures

Effect of Prolonged Repeated Exposure to Formaldehyde Donors with Doses Below the EC3 Value on Draining Lymph Node Responses

Local lymph node assay: use in hazard and risk assessment

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