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ToxSci Advance Access originally published online on September 23, 2008
Toxicological Sciences 2008 106(2):423-434; doi:10.1093/toxsci/kfn199
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

The Respiratory Local Lymph Node Assay as a Tool to Study Respiratory Sensitizers

Josje H. E. Arts*,{dagger}, Wim H. de Jong{ddagger}, Jos J. van Triel*, Marcel A. Schijf*, Arja de Klerk{ddagger}, Henk van Loveren{ddagger},§ and C. Frieke Kuper*,1

* TNO Quality of Life, Zeist, the Netherlands {dagger} Akzo Nobel Technology & Engineering, Arnhem, the Netherlands {ddagger} RIVM, Bilthoven, the Netherlands § Maastricht University, Masstricht, the Netherlands

1 To whom correspondence should be addressed at TNO Quality of Life, Toxicology and Applied Pharmacology, PO Box 360, 3700 AJ Zeist, the Netherlands. Fax: +31-30-69-44-986. E-mail: frieke.kuper{at}tno.nl.

Received July 2, 2008; accepted August 29, 2008


  Abstract

The local lymph node assay (LLNA) is used to test the potential of low molecular weight (LMW) compounds to induce sensitization via the skin. In the present study, a respiratory LLNA was developed. Male BALB/c mice were exposed head/nose-only during three consecutive days for 45, 90, 180, or 360 min/day to various LMW allergens. Ear application (skin LLNA) was used as a positive control. Negative controls were exposed to the vehicle. Three days after the last exposure, proliferation was determined in the draining mandibular lymph nodes, and the respiratory tract was examined microscopically. Upon inhalation, the allergens trimellitic anhydride, phthalic anhydride, hexamethylene diisocyanate, toluene diisocyanate, isophorone diisocyanate (IPDI), dinitrochlorobenzene, and oxazolone were positive and showed stimulation indices (SIs) up to 11, whereas trimeric IPDI, formaldehyde, and methyl salicylate were negative (viz. SI < 3). All compounds, except trimeric IPDI, induced histopathological lesions predominantly in the upper respiratory tract. Exposure by inhalation is a realistic approach to test respiratory allergens. However, based on the local toxicity, the dose that can be applied is (generally) much lower than can be achieved by skin application. It is concluded that strong LMW allergens, regardless their immunological nature, besides the skin can also sensitize the body via the respiratory tract. In addition, the contact allergens were as potent as the respiratory allergens, although the potency ranking differed from that in a skin LLNA.

Key Words: sensitizers; respiratory allergy; contact allergy; LLNA; potency.


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