Subchronic exposure to diisocyanates increases guinea pig tracheal smooth muscle responses to acetylcholine.
OBJECTIVE
In order to study the threshold concentrations of isocyanates (IC) for induction of lung disorders, constrictive responses of tracheal smooth muscles to acetylcholine (ACH) in guinea pigs with and without diisocyanate [toluene diisocyanate (TDI), hexamethylene diisocyanate (HDI) and diphenylmethane diisocyanate (MDI)] exposure were investigated.


METHODS
An IC-induced increase in smooth muscle responsiveness was studied by measuring cumulative ACH dose responses (10(-10) to 10(-4) M ACH). Basal ACH dose-response curves, measured twice in intervals of 1 h using tracheal preparations of 11 guinea pigs previously not exposed to IC, were reproducible.


RESULTS
Subchronic in vivo exposures to TDI, HDI, and MDI atmospheres of 10 and 20 parts per billion (ppb) on 5 consecutive days led to significantly (p < 0.05) increased ACH responsiveness of tracheal smooth muscle, whereas concentrations of 2.5 and 5 ppb were not effective. Exposure to HDI atmospheres of 10 ppb for 1, 2, 4, or 8 weeks resulted in a time-dependent increase in ACH responses (p < 0.05) of guinea pig tracheal smooth muscle. Increased tracheal muscle responses to ACH were transient since tracheal preparations from animals exposed to 10 and 20 ppb MDI for 4 weeks and with an exposure-free interval of 8 weeks before preparation did not show enlarged ACH responses, which were present in preparations at the end of the exposure period (p < 0.05). Exposure to low IC concentrations as present in workplaces cause increased ACH responsiveness of guinea pig tracheal smooth muscle. The increased responsiveness of the airways seems to be largely reversible, since normal responses were found after 8 weeks of IC avoidance.


CONCLUSIONS
Reversibility of IC-induced airway hyperresponsiveness is of great occupational and preventive medical importance. Workers with acquired airway hyperresponsiveness might escape lung damage if the changes are detected in an early stage before alterations in lung function are in a chronic stage.
Marek
W
W
Research Institute for Diagnosis and Treatment of Early Lung Cancer, Ruhr University of Bochum, Germany. Wolfgang.Marek@ruhr-uni-bochum.de
Potthast
J
J
Marczynski
B
B
Mensing
T
T
Baur
X
X
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D046508:Culture Techniques; D003485:Cyanates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D017953:Isocyanates / Q000494:pharmacology*; D008171:Lung Diseases / Q000139:chemically induced; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D012016:Reference Values; D014051:Toluene 2,4-Diisocyanate / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects* / Q000502:physiology; D001559:Benzhydryl Compounds
D000109:Acetylcholine; D003485:Cyanates; D017953:Isocyanates; D014051:Toluene 2,4-Diisocyanate; C015262:1,6-hexamethylene diisocyanate; C005969:4,4'-diphenylmethane diisocyanate; D001559:Benzhydryl Compounds