title: Dermal exposure to 3-amino-5-mercapto-1,2,4-triazole (AMT) induces sensitization and airway hyperreactivity in BALB/c mice.
abstract: A cluster of occupational asthma (OA) cases associated with occupational exposure to 3-amino-5-mercapto-1,2,4-triazole (AMT) and N-(2,6-difluorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonamide (DE498) in a herbicide producing plant was previously reported by the National Institute for Occupational Safety and Health. Due to the limited toxicological data available for these chemicals, murine studies were undertaken to evaluate the toxicity and sensitization potential of these two agents. No signs of systemic toxicity as evaluated by body and selected organ weights or irritancy were observed following dermal exposure to concentrations up to 25% (w/v) AMT in BALB/c mice. DE498 tested negative for sensitization potential in both the TOPKAT QSAR model and in vivo in the Local Lymph Node Assay (LLNA), while AMT tested positive in both TOPKAT QSAR and the LLNA. Evaluation of the potential for AMT to induce contact hypersensitivity using the MEST yielded negative results. Cytokine evaluation and phenotypic analysis of draining lymph node (DLN) cells demonstrated an increase in IL-4 and IgE+B220+ cells 4 and 10 days post initial exposure, respectively. Following dermal exposure 7 days a week for 35 days, animals exposed to up to 25% AMT demonstrated a dose-dependent elevation in total serum IgE and an increase in airway hyperreactivity upon methacholine challenge. Following intratracheal challenge with AMT, pulmonary histopathology revealed a dose-dependent suppurative and histiocytic alveolitis in these animals. These studies indicate that DE498 does not induce sensitization following dermal exposure; however, AMT was identified as a sensitizer with the potential to induce airway hyperreactivity.
authors.affiliation: National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Klink
authors.forename: B J
authors.initials: BJ
authors.lastname: Meade
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D007073:Immunoglobulin E / Q000097:blood; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008954:Models, Biological; D016273:Occupational Exposure; D010641:Phenotype; D011743:Pyrimidines / Q000008:administration & dosage / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D012333:RNA, Messenger / Q000096:biosynthesis; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000633:toxicity; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: C488155:3-amino-5-mercapto-1,2,4-triazole; D016207:Cytokines; D011743:Pyrimidines; D012333:RNA, Messenger; D013449:Sulfonamides; D014230:Triazoles; D015847:Interleukin-4; D007073:Immunoglobulin E; C472634:N-(2,6-difluorophenyl)-5-methyl(1,2,4)-triazol(1,5-a)pyrimidine-2-sulfonamide