Quantitative relationship between the local lymph node assay and human skin sensitization assays

Schneider, Klaus; Akkan, Z.

doi:10.1016/j.yrtph.2004.02.002

Cited by 105 publications

(46 citation statements)

References 81 publications

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“…However, the quantitative element of this response was also noted some years ago (22). In an extensive range of publications, the method for the determination of the EC3 value having been fixed (see above), and the relationship between LLNA EC3 values and human skin sensitization potency was described (23)(24)(25)(26)(27)(28)(29)(30). These publications also served to show that the dynamic range of these measures covered some 4-5 orders of magnitude.…”

Section: Relevancementioning

confidence: 92%

“…Thus, the work that appears in the literature cannot offer the degree of accuracy in human/mouse correlations that would ideally be liked, and a degree of judgement is inevitable to help compensate for the relatively poor quality of the limited human data that are available. Hence, it has been important that many of the publications in this area have involved independent partners closely associated with the LLNA, including dermatologists, regulators, and independent scientists (24)(25)(26)(27)(28)(29)(30).…”

Section: Relevancementioning

confidence: 99%

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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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Section: Relevancementioning

confidence: 92%

Section: Relevancementioning

confidence: 99%

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

2007

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“…The EC3 value obtained in the LLNA indicates sensization ability and sensitization potency of the investigated chemicals. Although the EC3 value itself is not a threshold for immunization in mice or man, the data can be used for prediction of safe exposure levels for man (Griem et al, 2003;Schneider and Akkam, 2004;Basketter et al, 2005b). Our results demonstrate that repeated and prolonged exposure to doses below the EC3 value can induce reactions above the cutoff point for hazard identification in draining lymph nodes in mice.…”

Section: Exposure To Chemicalmentioning

confidence: 99%

“…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). For the manufacturing of consumer products, chemicals can be chosen with a high EC3 value that is indicative for a low(er) sensitizing potency.…”

Section: Introductionmentioning

confidence: 99%

“…They cannot be considered as threshold levels for induction of sensitization in mice or humans directly, but can be of value to predict such levels, based on their linear relationship with the approximate threshold determined in humans using the human repeated insult patch test (Griem et al, 2003;Schneider and Akkam, 2004;Basketter et al, 2005b). It was proposed to use the EC3 value expressed as area dose as a surrogate for determining a human no observed effect level (NOEL), and to calculate an acceptable non-sensitizing area dose (ANSAD; Griem et al, 2003), or calculating a No Expected Sensitization Induction Level (NESIL; Api et al, 2006).…”

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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Dermal Toxicology of Cosmetics and Body‐Care Products

Basketter

Lea

2009

General, Applied and Systems Toxicology

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There is a tendency in both regulatory thinking and in public perception towards the view that cosmetics are in some way different from other products. The reality of course is that they are formed from a combination of chemical ingredients, raw materials which, in fact, can be found in a very wide range of products. Consequently, the toxicology considerations which apply to other products also apply to cosmetics and body‐care products. Application of appropriate toxicological review of product ingredients and of the final formulation is key to meeting the requirement that such products do not cause harm to the consumer. Failure to undertake such a review to an adequate standard gives rise to a risk of adverse reactions. In this chapter, we set out some general thoughts on how a review of product safety generally should be approached for these types of product. Wherever possible, emphasis has been placed on the minimization and/or elimination of the need for in vivo testing.

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Quantitative relationship between the local lymph node assay and human skin sensitization assays

Cited by 105 publications

References 81 publications

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

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

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

Dermal Toxicology of Cosmetics and Body‐Care Products

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