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ToxSci Advance Access originally published online on August 28, 2006
Toxicological Sciences 2006 94(1):108-117; doi:10.1093/toxsci/kfl094
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Published by Oxford University Press 2006.

Inconsistencies between Cytokine Profiles, Antibody Responses, and Respiratory Hyperresponsiveness following Dermal Exposure to Isocyanates

MaryJaneK Selgrade*,1, Elizabeth H. Boykin*, Najwa Haykal-Coates*, Michael R. Woolhiser{dagger}, Connie Wiescinski{dagger}, Debora L. Andrews*, Aimen K. Farraj*, Donald L. Doerfler* and Stephen H. Gavett*

* National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711 {dagger} The Dow Chemical Company, Midland, Michigan 48674

Received July 14, 2006; accepted August 23, 2006

Cytokine profiling of local lymph node responses has been proposed as a simple test to identify chemicals, such as low molecular weight diisocyanates, that pose a significant risk of occupational asthma. Previously, we reported cytokine messenger RNA (mRNA) profiles for dinitrochlorobenzene (DNCB) and six isocyanates: toluene diisocyanate, diphenylmethane-4,4'-diisocyanate, dicyclohexylmethane-4,4'-diisocyanate, isophorone diisocyanate, p-tolyl(mono)isocyanate, and meta-tetramethylene xylene diisocyanate. The present study was conducted to test the hypothesis that relative differences in the cytokine profile are predictive of relative differences in total serum immunoglobulin (Ig) E and respiratory responses to methacholine (Mch) following dermal exposure to the chemicals. After a preliminary experiment to determine an exposure regimen sufficient to achieve responses to Mch following dermal diisocyanate exposure, BALB/c mice received nine dermal exposures over a period of 28 days to one of six isocyanates, DNCB, or vehicle. Mice were then challenged with increasing doses of Mch and responsiveness was assessed using whole-body plethysmography. Serum antibody responses and cytokine mRNA profiles in the draining lymph node were also assessed. In separate experiments, cytokine protein assays were performed after five dermal exposures over a 14-day period. The response pattern for interleukin (IL)-4, IL-10, and IL-13 for the different isocyanates was highly reproducible as determined by RNAse protection assay, reverse transcription–PCR, or cytokine protein levels. However, the relative differences in T-helper cytokine profiles were not predictive of relative differences in either total serum IgE or respiratory responses to Mch following dermal exposure. The data suggest that the cytokine profiling approach needs to be further developed and refined before adoption and that other approaches to hazard identification should be pursued as well. Based on the weight of evidence from all the assays performed, it appears that all six isocyanates tested have some potential to cause respiratory hypersensitivity following dermal exposure.

Key Words: isocyanates; hypersensitivity; occupational asthma; cytokineprofiling.


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A. K. Farraj, E. Boykin, N. Haykal-Coates, S. H. Gavett, D. Doerfler, and M. Selgrade
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