Olfactory mucosal toxicity screening and multivariate QSAR modeling for chlorinated benzene derivatives.
The olfactory mucosa (OM) is an important target for metabolism-dependent toxicity of drugs and chemicals. Several OM toxicants share a 2,6-dichlorinated benzene structure. The herbicides dichlobenil (2,6-dichlorobenzonitrile) and chlorthiamide (2,6-dichlorothiobenzamide) and the environmental dichlobenil metabolite 2,6-dichlorobenzamide all induce toxicity in the OM following covalent binding in the Bowman's glands. In addition, we have shown that 2,6-dichlorophenyl methylsulfone targets the Bowman's glands and is probably the most potent OM toxicant so far described. These findings suggest that the 2,6-positioning of chlorines in combination with an electron-withdrawing group in the primary position of the benzene ring is an arrangement that facilitates OM toxicity. This study examined the physicochemical characteristics of the 2,6-dichlorinated OM toxicants. A number of 2,6-dichlorinated benzene derivatives with various types of substituents in primary position were tested for OM toxicity in mice. In addition, some other 2,6- and 2,5-substituted benzene derivatives were examined. Two novel OM toxicants, 2,6-dichlorobenzaldehyde oxime and 2,6-dichloronitrobenzene, were identified. By the use of partial least squares projection to latent structures with discriminant analysis (PLS-DA) a preliminary quantitative structure-activity relationship (QSAR) model was built also using reported OM toxicity data. Physicochemical properties positively correlated with olfactory mucosal toxicity were identified as molecular dipolar momentum and the electronic properties of the substituent. Inversely correlated descriptors were variables describing the hydrophobicity, electronic properties of the molecule such as electron affinity and the electronic charge on the primary carbon. In conclusion, this preliminary PLS-DA model shows that a 2,6-dichlorinated benzene derivative with a large, polar, and strong electron-withdrawing substituent in the primary position has the potential of being a potent OM toxicant in mice.
Carlsson
Carina
C
Department of Environmental Toxicology, Uppsala University, Norbyvägen 18A, 75236 Uppsala, Sweden.
Harju
Mikael
M
Bahrami
Fariba
F
Cantillana
Tatiana
T
Tysklind
Mats
M
Brandt
Ingvar
I
D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000473:pathology; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis
D001555:Benzene Derivatives; D006843:Hydrocarbons, Chlorinated