Screening Petrochemicals for Contact Hypersensitivity Potential: A Comparison of the Murine Local Lymph Node Assay with Guinea Pig and Human Test Data

Edwards, Deborah A; Soranno, T. M.; Amoruso, Marie A.; House, Robert V.; TUMMEY, A. C.; Trimmer, Gary W.; Thomas, Peter T.; Ribeiro, P. L.

doi:10.1006/faat.1994.1096

Cited by 26 publications

(5 citation statements)

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“…In addition, more discrete studies of specific groups of materials have been conducted using either the standard LLNA or modifications of the method. Among the chemical classes that have been analyzed are petrochemicals (72), dyes (73), biocides (34, 74–76), metal salts (77), fragrance materials and components of personal care products (36, 78), rubber chemicals (37) and chemical mutagens and rodent carcinogens (79, 80).…”

Section: Evaluation Validation and Current Regulatory Statusmentioning

confidence: 99%

The local lymph node assay: past, present and future

et al. 2002

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The local lymph node assay (LLNA) was developed originally as a method for the identification of chemicals that have the potential to cause skin sensitization and allergic contact dermatitis. The assay is based on an understanding that the acquisition of contact sensitization is associated with, and dependent upon, the stimulation by chemical allergens of lymphocyte proliferative responses in skin-draining lymph nodes. Those chemicals that provoke a defined level of lymph node cell (LNC) proliferation (a 3-fold or greater increase compared with concurrent vehicle controls) are classified as skin sensitizers. Following its original inception and development, the LLNA was the subject of both national and international interlaboratory collaborative trials, and of very detailed comparisons with other test methods and with human skin sensitization data. The assay has now been validated fully as a stand-alone test for the purposes of hazard identification. In recent years, there has been a growing interest also in the use of the LLNA to assess the potency of contact allergens and in risk assessment. There is reason to believe that the extent of skin sensitization achieved is associated with the vigour of LNC proliferation induced in draining nodes. Given this relationship, the relative potency of skin sensitizing chemicals is measured in the LLNA by derivation of an EC3 value, this being the concentration of chemical required to provoke a 3-fold increase in the proliferation of LNC compared with controls. Experience to date indicates that relative potency as determined using this approach correlates closely with what is known of the activity of skin sensitizing chemicals in humans. In this article, we review the development, evaluation and validation of the LLNA for the purposes of hazard identification, and the more recent application of the method for evaluation of potency in the context of risk assessment. In addition, we consider what new applications and modifications are currently being investigated.Key words: allergic contact dermatitis; hazard identification; local lymph node assay; lymphocyte proliferation, potency assessment; risk assessment; skin sensitization. C Blackwell Munksgaard, 2002. C Blackwell Munksgaard, 2002. Accepted for publication 28 October 2002Skin sensitization resulting in allergic contact dermatitis is an important occupational disease, and certainly the most common manifestation of chemical allergy in humans. There is a need therefore to identify the hazards and risks of allergic contact dermatitis that may be associated with exposure to chemicals at work, at home and in the environment. Conventionally, toxicological assessments of this kind are conducted (conceptually at least) in 2 phases, wherein potential hazards are first identified and then the likelihood of those hazards translating into human health risks is assessed. The latter risk assessments are predicated upon consideration of the nature of the hazard (of particular importance being an appreciation of potency) and the likel...

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Section: Evaluation Validation and Current Regulatory Statusmentioning

confidence: 99%

The local lymph node assay: past, present and future

et al. 2002

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“…but not in an aqueous solution. Using EDA (as dihydrochloride), no sensitizing effect was obvious either in water or in acetone/olive oil (49, 50).…”

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Skin sensitizing properties of the ethanolamines mono‐, di‐, and triethanolamine. Data analysis of a multicentre surveillance network (IVDK*) and review of the literature

et al. 2009

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Numerous publications address the skin sensitizing potential of the short chain alkanolamines triethanolamine (TEA), diethanolamine (DEA), monoethanolamine (MEA), which are not skin sensitizing according to animal studies. Regarding TEA, we analysed patch test data of 85 098 patients who had been tested with TEA 2.5% petrolatum by Information Network of Departments of Dermatology (IVDK) to identify particular exposures possibly associated with an elevated risk of sensitization. Altogether, 323 patients (0.4%) tested positive. The profile of patch test reactions indicates a slightly irritant potential rather than a true allergic response in many cases. Although used widely, no exposure associated with an increased risk of TEA sensitization was identified. Therefore, the risk of sensitization to TEA seems to be very low. MEA and DEA were patch tested in a much more aimed fashion in 9602 and 8791 patients, respectively when prevalence of contact allergy was 3.8% and 1.8%. MEA is the prominent allergen in metalworkers with exposure to water-based metalworking fluids (wbMWFs); DEA is probably used in cutting fluids less frequently nowadays. Chronic damage to the skin barrier resulting from wbMWF, the alkalinity of ethanolamines (increasing from TEA to MEA), and other cofactors may contribute to a notable sensitization risk.

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“…In studies that investigated the correlation between GPMT and LLNA results, where both were conducted in parallel, it was shown that the LLNA assay was capable of detecting chemicals that exhibited a strong sensitization potential in the GPMT. The moderate sensitizers were generally positive or gave equivocal results in the LLNA, whereas the weak sensitizers were not detected (5, 7).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, this test causes less animal distress than guinea‐pig tests and is of shorter duration. Since its original development, the LLNA has been the subject of extensive comparisons with guinea‐pig tests (3–6) and/or with human data (7–10). Although comparisons of LLNA data with the results of guinea‐pig tests have been presented for various classes of materials, including process intermediates, comparisons of animal with human data have not been reported for process intermediates.…”

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confidence: 99%

Use of the local lymph node assay in the evaluation of the sensitizing potential of pharmaceutical process intermediates

et al. 2003

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The murine local lymph node assay (LLNA) has recently been developed to determine the contact sensitization potential of chemicals. Since its original development, the LLNA results have been the subject of extensive comparisons with guinea pig and human data. The investigations described here were designed to explore the ability of the LLNA to identify accurately, pharmaceutical process intermediates (PIs) known to cause contact allergy in humans. To that end, 16 PIs previously tested in the guinea-pig maximization test (GPMT) were tested in the LLNA. Another PI known to be a contact sensitizer in humans was tested only in the LLNA. Cases of contact sensitization in humans were reported only for PIs that were extreme sensitizers in the GPMT and had low EC3 values (concentration of the test substance required to generate a threefold increase in lymph node cell proliferation) in the LLNA. These data provide additional evidence that the LLNA is able to discriminate skin sensitizers from chemicals that do not possess a significant skin sensitization potential and is thus a useful method for hazard identification. In addition, this method also offers important animal welfare benefits and may also be useful for risk assessment purposes.

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Screening Petrochemicals for Contact Hypersensitivity Potential: A Comparison of the Murine Local Lymph Node Assay with Guinea Pig and Human Test Data

Cited by 26 publications

References 0 publications

The local lymph node assay: past, present and future

The local lymph node assay: past, present and future

Skin sensitizing properties of the ethanolamines mono‐, di‐, and triethanolamine. Data analysis of a multicentre surveillance network (IVDK*) and review of the literature

Use of the local lymph node assay in the evaluation of the sensitizing potential of pharmaceutical process intermediates

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