Validity of methods to predict the respiratory sensitizing potential of chemicals: A study with a piperidinyl chlorotriazine derivative that caused an outbreak of occupational asthma.
A piperidinyl chlorotriazine (PCT) derivative, used as a plastic UV-stabilizer, caused an outbreak of occupational asthma. We verified, in BALB/c mice, the sensitizing potential of PCT in comparison to a known respiratory sensitizer (toluene diisocyanate [TDI]) and a known dermal sensitizer (oxazolone), using three different methods in order to evaluate the validity of current models of sensitization. These included the local lymph node assay (LLNA) and the mouse IgE test. In addition, respiratory hyper-reactivity was assessed following a novel protocol involving dermal sensitization (20 microl of a 3% solution on each ear for three days) and intranasal challenge (0.1% or 1%, 10 microl per nostril on day 10), followed, after 24 h, by a methacholine challenge (using whole-body plethysmography), bronchoalveolar lavage, and histology. PCT was also used for structure-activity relationship (SAR) models for (respiratory) sensitization. High concentrations of PCT (10 and 20%) resulted in significant responses in the local lymph node assay (LLNA; stimulation indices (SI) of 2.7 +/- 0.9 and 3.2 +/- 0.6, respectively). The mouse IgE test was positive with 20% PCT only. Methacholine responsiveness was increased only in previously sensitized mice receiving a challenge with TDI or PCT. However, there was no evidence for pulmonary inflammation. The SAR studies indicated that PCT could be a respiratory sensitizer. Based on an approved test protocol such as the LLNA and the mouse IgE test, PCT proved to be a weak sensitizer when compared to TDI and oxazolone. However, in a protocol involving an intranasal challenge, PCT appeared to be a respiratory sensitizer of similar potency to TDI.
D000276:Adjuvants, Immunologic; D000279:Administration, Cutaneous; D000485:Allergens / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001249:Asthma / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D018893:Bronchoalveolar Lavage; D017449:Dermatitis, Allergic Contact / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007073:Immunoglobulin E / Q000097:blood; D023441:Local Lymph Node Assay; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016273:Occupational Exposure / Q000009:adverse effects*; D010081:Oxazolone / Q000008:administration & dosage / Q000633:toxicity; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D011237:Predictive Value of Tests; D013329:Structure-Activity Relationship; D014051:Toluene 2,4-Diisocyanate / Q000008:administration & dosage / Q000633:toxicity; D014227:Triazines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*
D000276:Adjuvants, Immunologic; D000485:Allergens; D010880:Piperidines; D014227:Triazines; C488303:piperidinyl chlorotriazine derivative; D016210:Methacholine Chloride; D010081:Oxazolone; D014051:Toluene 2,4-Diisocyanate; D007073:Immunoglobulin E