Reproducible prediction of contact allergenic potency using the local lymph node assay

Basketter, David A.; Cadby, Peter A.

doi:10.1111/j.0105-1873.2004.00278.x

Cited by 41 publications

(21 citation statements)

References 22 publications

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“…2,4-Dinitrochlorobenzene is well-known strong contact sensitizer and it has been used as the positive control substance in skin sensitization studies. Isoeugenol and HCA are also well-known contact allergens and the reproducibility of the lymphocyte proliferative responses induced by these chemicals have been reported previously (Dearman et al, 1998;Basketter et al, 2004). Based on the new procedure for classification of allergen class of chemicals by the LLNA, each chemical is compared with the same concentration of a reference human contact allergen whose sensitization potency in already known.…”

Section: Discussionmentioning

confidence: 99%

“…The LLNA has the advantage of yielding a quantitative endpoint that can be used to predict the sensitization potency of chemicals (Kimber et al, 1994Basketter et al, 2001), and the EC 3 (estimated concentration of chemicals necessary to cause a threefold increase in proliferative activity) has been proposed as a parameter for classifying the chemicals according to sensitization potency (Basketter et al, 2000;Basketter and Cadby, 2004). The EC 3 values have been reported to correlate well with the sensitization potencies of human contact allergens Griem et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Novel approach for classifying chemicals according to skin sensitizing potency by non‐radioisotopic modification of the local lymph node assay

Takeyoshi

Iida

Shiraishi

et al. 2005

J of Applied Toxicology

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The murine local lymph node assay (LLNA) is currently recognized as a stand-alone sensitization test for determining the sensitizing potential of chemicals, and it has the advantage of yielding a quantitative endpoint that can be used to predict the sensitization potency of chemicals. The EC3 has been proposed as a parameter for classifying chemicals according to the sensitization potency. We previously developed a non-radioisotopic endpoint for the LLNA based on 5-bromo-2'-deoxyuridine (BrdU) incorporation (non-RI LLNA), and we are proposing a new procedure to predict the sensitization potency of chemicals based on comparisons with known human contact allergens. Nine chemicals (i.e. diphencyclopropenone, p-phenylenediamine, glutaraldehyde, cinnamicaldehyde, citral, eugenol, isopropyl myristate, propyleneglycol and hexane) categorized as human contact allergen classes 1-5 were tested by the non-RI LLNA with the following reference allergens: 2,4-dinitrochlorobenzene (DNCB) as a class 1 human contact allergen, isoeugenol as a class 2 human contact allergen and alpha-hexylcinnamic aldehyde (HCA) as a class 3 human contact allergen. Consequently, nine test chemicals were almost assigned to their correct allergen class. The results suggested that the new procedure for non-RI LLNA can provide correct sensitization potency data. Sensitization potency data are useful for evaluating the sensitization risk to humans of exposure to new chemical products. Accordingly, this approach would be an effective modification of LLNA with regard to its experimental design. Moreover, this procedure can be applied also to the standard LLNA with radioisotopes and to other modifications of the LLNA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel approach for classifying chemicals according to skin sensitizing potency by non‐radioisotopic modification of the local lymph node assay

Takeyoshi

Iida

Shiraishi

et al. 2005

J of Applied Toxicology

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“…EC3 values were highly consistent over each of 4 determinations in each laboratory. Last, the EC3 value for a moderate allergen, isoeugenol, was assessed in a single laboratory (34). The outcome of these various assessments supplemented with a small amount of additional unpublished data for 15 chemicals of widely varying skin sensitization potency has been collated in Table 1.…”

Section: Reliabilitymentioning

confidence: 99%

The local lymph node assay and the assessment of relative potency: status of validation

2007

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For the prediction of skin sensitization potential, the local lymph node assay (LLNA) is a fully validated alternative to guinea-pig tests. More recently, information from LLNA dose-response analyses has been used to assess the relative potency of skin sensitizing chemicals. These data are then deployed for risk assessment and risk management. In this commentary, the utility and validity of these relative potency measurements are reviewed. It is concluded that the LLNA does provide a valuable assessment of relative sensitizing potency in the form of the estimated concentration of a chemical required to produce a threefold stimulation of draining lymph node cell proliferation compared with concurrent controls (EC3 value) and that all reasonable validation requirements have been addressed successfully. EC3 measurements are reproducible in both intra-and interlaboratory evaluations and are stable over time. It has been shown also, by several independent groups, that EC3 values correlate closely with data on relative human skin sensitization potency. Consequently, the recommendation made here is that LLNA EC3 measurements should now be regarded as a validated method for the determination of the relative potency of skin sensitizing chemicals, a conclusion that has already been reached by a number of independent expert groups.

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“…Although the principle of this method is very close to that of the original radioisotopoic assay, the non-radioisotopic method appeared to be less sensitive than the original method (Takeyoshi et al, 2001(Takeyoshi et al, , 2003(Takeyoshi et al, , 2004. The estimated concentration of a chemical required to induce a stimulation index of 3 relative to vehicle-treated controls (EC3 value) has been proposed as an effective parameter for estimating the sensitization potency of chemicals (Basketter et al, 2000Basketter and Cadby, 2004), and in effect for comparing the sensitivities of different modifications of the LLNA. The non-radioisotopic LLNA has tended to yield lower EC3 values for particular chemicals when compared with the standard LLNA.…”

Section: Discussionmentioning

confidence: 99%

Advantage of using CBA/N strain mice in a non-radioisotopic modification of the local lymph node assay

et al. 2005

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The murine local lymph node assay (LLNA) is currently recognized as a stand-alone test method for determining the skin sensitizing potential of chemicals. It has been incorporated into the official test guidelines published by some authorities, including the OECD. To avoid the use of radioisotopes, efforts have been made recently to develop non-radioisotopic modifications of the LLNA. A non-radioisotopic modification of the LLNA was developed previously using 5-bromo-2'-deoxyuridine (BrdU) incorporation (non-RI LLNA). However, the non-RI LLNA was found to be somewhat less sensitive than the standard assay. This study reports the advantage of using mice of the CBA/N strain in the non-RI LLNA to improve the sensitivity of this method. The non-RI LLNA was performed using CBA/JN and CBA/N mice exposed to one of four confirmed skin sensitizers, 2,4-dinitrochlorobenzene (DNCB), eugenol (EG), isoeugenol (IEG) or alpha-hexylcinnamic aldehyde (HCA), and to one non-sensitizer, propylene glycol (PG). The EC3 values for DNCB, IEG, EG, HCA and PG were calculated to be 0.1%, 9.6%, 40.6%, 45.5% and >50% in CBA/JN mice and 0.08%, 1.9%, 10.7%, 20.3% and >50% in CBA/N mice, respectively. The EC3 values for DNCB, IEG, EG, HCA and PG in the standard LLNA using CBA/Ca mice and radioisotopes were reported elsewhere as being 0.08%, 1.3%, 13.0%, 8.0% and >50%, respectively. The EC3 values derived from the CBA/N mice in the non-RI LLNA were nearly equivalent to the EC3 values obtained using the standard radioisotopic LLNA with CBA/Ca mice. These data suggest that the use of CBA/N mice may provide a realistic opportunity to develop a version of the LLNA that does not have a requirement for the use of radioisotopes, but which nevertheless has sensitivity approaching, or comparable to, the standard method.

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Reproducible prediction of contact allergenic potency using the local lymph node assay

Cited by 41 publications

References 22 publications

Novel approach for classifying chemicals according to skin sensitizing potency by non‐radioisotopic modification of the local lymph node assay

Novel approach for classifying chemicals according to skin sensitizing potency by non‐radioisotopic modification of the local lymph node assay

The local lymph node assay and the assessment of relative potency: status of validation

Advantage of using CBA/N strain mice in a non-radioisotopic modification of the local lymph node assay

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