Proposal for a risk assessment methodology for skin sensitization based on sensitization potency data

Griem, Peter; Goebel, Carsten; Scheffler, Heike

doi:10.1016/j.yrtph.2003.07.001

Cited by 116 publications

(74 citation statements)

References 84 publications

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“…In view of these properties also in the skin, a prolonged presence of formaldehyde can be expected after exposure. Our results on the EC3 value (0.96%) of formaldehyde are on the same order of magnitude as previously published (EC3 of 0.54% and 0.65%, Griem et al, 2003;Basketter et al, 2005a). For the formaldehyde donors investigated, we did not reach a stimulation index of 3 in the dose-response experiments (Table 1).…”

Section: Exposure To Chemicalsupporting

confidence: 90%

“…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%

“…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). Extrapolation factors might be incorporated for interspecies, intraspecies, and exposure variations as discussed by Felter et al (2002) and Griem et al (2003).…”

Section: Introductionmentioning

confidence: 99%

“…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). Extrapolation factors might be incorporated for interspecies, intraspecies, and exposure variations as discussed by Felter et al (2002) and Griem et al (2003). Such approaches open the possibility for risk assessment of individual chemicals for sensitization which is currently not performed at the regulatory level.…”

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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Section: Exposure To Chemicalsupporting

confidence: 90%

Section: Exposure To Chemicalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…429;OECD, 2002) as a stand-alone test for skin sensitization. One of the merits of the LLNA is that it provides quantitative information on the sensitization potency of a test chemical in the form of an EC3 value (i.e., the estimated concentration required to induce a 3-fold increase in lymph node cell proliferation), which can be used for the risk assessment of finished products containing that chemical (Gerberick et al, 2001;Griem et al, 2003;Api and Vey, 2008). The LLNA is currently the first-choice method for assessing sensitization potency (Angers-Loustau et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Utility of murine dendritic cell line DC2.4 for <i>in vitro </i>assay of skin-sensitization potential

Shiraishi

Ido

Hiromori

et al. 2017

Fundam. Toxicol. Sci.

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-Animal tests, such as the local lymph node assay (LLNA), are the gold standard for assaying skin-sensitizing potential. However, because of concerns about animal welfare, extensive research has been conducted on the use of various cell lines, such as human leukemia cells, for in vitro assays of skin-sensitizing potential, but such assays have not replaced animal tests as stand-alone assays. Because Langerhans cells-a type of dendritic cell-are the main antigen-presenting cells in the epidermis and because they play a central role in the induction of allergic skin disorders, these cells may be useful for skin-sensitizing-potential assays. Here, we investigated the utility of the murine dendritic cell line DC2.4 for in vitro assay of the skin-sensitization potential of 2,4-dinitrochlorobenzene (DNCB), 2-mercaptobenzothiazole (MBT), and α-hexyl cinnamaldehyde (HCA), which are categorized as extremely, moderately, and weakly sensitizing, respectively, on the basis of LLNA results. DC2.4 cell viability decreased dose-dependently with increasing concentration upon treatment with each of the compounds for 24 hr; the DNCB, MBT, and HCA concentrations that resulted in 75% cell viability were 6.07, 120.14, and 118.70 μg/mL, respectively. At nontoxic concentrations (concentrations less than the 75% cell viability concentrations), these compounds dose-dependently upregulated the expression of both CD86 and CD54 on the surface of DC2.4 cells. Their potency decreased in the order DNCB > MBT > HCA, which agrees with the order indicated by the LLNA. These results suggest that DC2.4 cells may be a viable replacement for human leukemia cells in in vitro assays of skin-sensitization potential.

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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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Proposal for a risk assessment methodology for skin sensitization based on sensitization potency data

Cited by 116 publications

References 84 publications

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

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

Utility of murine dendritic cell line DC2.4 for <i>in vitro </i>assay of skin-sensitization potential

Dermal Toxicology of Cosmetics and Body‐Care Products

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