A quantitative method for assessing the sensitizing potency of low molecular weight chemicals using a local lymph node assay: employment of a regression method that includes determination of the uncertainty margins

Och, François M.M van; Slob, Wout; Jong, Wim H. de; Vandebriel, Rob J.; Loveren, Henk Van

doi:10.1016/s0300-483x(00)00165-7

Cited by 81 publications

(39 citation statements)

References 23 publications

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“…The EC3 (effective concentration inducing a threefold increase in 3 H-thymidine incorporation in the lymph node cells of treated animals compared to vehicle-treated animals) was estimated by the benchmark approach, by fitting a nonlinear regression model to the data of all individual animals as described previously (Van Och et al, 2000;De Jong et al, 2002b;Slob, 2002). Similarly, the EC2 value, the concentration inducing a two-fold increase in lymph node proliferation, was determined.…”

Section: Discussionmentioning

confidence: 99%

“…For the chemicals, dose-response experiments were performed for determination of the EC3 value. Chemicals were administered at various concentrations dissolved in AOO and the EC3 value was then calculated as described previously (Van Och et al, 2000;De Jong et al, 2002b;Slob, 2002).…”

Section: Chemicalsmentioning

confidence: 99%

“…Cellular proliferation as an indicator for lymph node stimulation was determined as previously described (Van Och et al, 2000;De Jong et al, 2002b;Slob, 2002). In order to enhance possible low responses of weak sensitizers, animals were pretreated on the dorsum of the ears with 25 μl 1% sodium dodecyl sulfate (SDS, Merck) 1 hr before administration of the chemicals (De Jong et al, 2002a).…”

Section: Experimental Designmentioning

confidence: 99%

“…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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Section: Discussionmentioning

confidence: 99%

Section: Chemicalsmentioning

confidence: 99%

Section: Experimental Designmentioning

confidence: 99%

Section: Exposure To Chemicalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 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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Diethylamin [MAK Value Documentation in German language, 2016]

Hartwig

Arand²

2016

The MAK‐Collection for Occupational Health and Safety

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Diethylamine The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the maximum concentration at the workplace (MAK value) of 5 ml/m 3 for diethylamine, considering all toxicity endpoints. Available unpublished study reports and publications are described in detail. The critical effect of diethylamine is atrophy of the olfactory mucosa in rats and mice in a 2‐year study. Since 2014 the Commission uses an empirical approach to set MAK values for substances with critical effects on the upper respiratory tract or the eyes. A NOAEC for atrophy of the olfactory mucosa was not obtained in the 2‐year study. A benchmark concentration of 4 ml/m 3 (BMDL 05 ) as a substitute for a NOAEC is calculated from the data of the mouse, the most sensitive species. Therefore, the MAK value for diethylamine is lowered to 2 ml/m 3 . The chronic NOAEC for systemic toxicity is judged to be 16 ml/m 3 . As local effects are critical, the assignment to Peak Limitation Category I is confirmed. The excursion factor of 2 is set with a read‐across to cyclohexylamine. The momentary value is lowered to 5 ml/m 3 . Because there are no studies on developmental toxicity, the assignment to Pregnancy Risk Group D is confirmed as well. Diethylamine is not genotoxic and not carcinogenic. Skin contact may contribute significantly to systemic toxicity and diethylamine is designated with an “H” notation. Sensitization is not expected from the limited data.

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Diethylamine [MAK Value Documentation, 2016]

Hartwig

Arand²

2018

The MAK‐Collection for Occupational Health and Safety

View full text Add to dashboard Cite

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the maximum concentration at the workplace (MAK value) of diethylamine of 5 ml/m 3 , considering all toxicity endpoints. Available unpublished study reports and publications are described in detail. The critical effect of diethylamine is atrophy of the olfactory mucosa in rats and mice in a 2‐year study. Since 2014 the Commission uses an empirical approach to set MAK values for substances with critical effects on the upper respiratory tract or the eyes. In the 2‐year study no NOAEC for atrophy of the olfactory mucosa was obtained. A Benchmark concentration of 4 ml/m 3 (BMDL05) as a substitute for a NOAEC is calculated from the data of the mouse, the most sensitive species. Therefore, the MAK value for diethylamine is lowered to 2 ml/m 3 . The chronic NOAEC for systemic toxicity is judged to be 16 ml/m 3 . As local effects are critical, the assignment to Peak Limitation Category I is confirmed. The excursion factor of 2 is set with a read‐across to cyclohexylamine. The momentary value is lowered to 5 ml/m 3 . Because there are no studies on developmental toxicity, the assignment to Pregnancy Risk Group D is confirmed as well. Diethylamine is not genotoxic and not carcinogenic. Skin contact may contribute significantly to systemic toxicity and diethylamine is designated with an “H” notation. Sensitization is not expected from the limited data.

show abstract

A quantitative method for assessing the sensitizing potency of low molecular weight chemicals using a local lymph node assay: employment of a regression method that includes determination of the uncertainty margins

Cited by 81 publications

References 23 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

Diethylamin [MAK Value Documentation in German language, 2016]

Diethylamine [MAK Value Documentation, 2016]

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