Alachlor (2-chloro-2',6'-N(methoxymethyl)acetanilide) is a restricted-use pesticide used as a herbicide in the production of numerous crops. Alachlor (trade name Mallo) and several structurally-related chloracetanilide herbicides are used world-wide in the production of important food crops such as corn and soybeans, providing significant potential for environmental contamination and human exposure. Chronic dietary exposure to alachlor causes a variety of tumors, including adenomas and adneocarcinoams of the olfactory mucosa in rats. Preliminary data revealed that alachlor is positive in an in vitro mutagenicity assay in the presence of an olfactory mucosal S9 activating system, but non-mutagenic in the presence of an activating system prepared from the adjacent respiratory mucosa, suggesting that alachlor metabolites generated in the target tissue are mutagenic and carcinogenic. They will determine the cell type of origin of alachlor-induced olfactory mucosal tumors and characterize cellular and molecular changes associated with the progression from preneoplastic lesions to adenomas to adenocarcinomas. They will also determine the metabolic enzymes responsible for conversion of alachlor to its mutagenic metabolite(s); this information will aid in cross-species extrapolation for the risk associated with the development of alachlor-induced tumors. In addition, they will perform in vitro mutagenesis assays with alachlor and a key metabolite, 2,6-diethylaniline using human olfactory mucosal S9 as an activating system in order to validate cross-species extrapolation between rats and humans for risk assessment purposes. Finally, they will evaluate other chloracetanilide herbicides for potential mutagenicity in the olfactory mucosa in order to ensure a more complete hazard identification for this class of compounds. These studies will provide important new data on the site-specific mechanism of carcinogenesis of a widely-used class of toxicants and will aid in the refinement of risk assessment and risk management strategies for the chloracetanilide compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008799-04
Application #
6382217
Study Section
Special Emphasis Panel (ZRG4-ALTX-2 (01))
Program Officer
Packenham, Joan P
Project Start
1998-04-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
4
Fiscal Year
2001
Total Cost
$386,396
Indirect Cost
Name
University of Cincinnati
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Genter, M B; Warner, B M; Medvedovic, M et al. (2009) Comparison of rat olfactory mucosal responses to carcinogenic and non-carcinogenic chloracetanilides. Food Chem Toxicol 47:1051-7
Genter, Mary Beth (2006) Molecular biology of the nasal airways: how do we assess cellular and molecular responses in the nose? Toxicol Pathol 34:274-80
Genter, Mary Beth; Clay, Corey D; Dalton, Timothy P et al. (2006) Comparison of mouse hepatic mitochondrial versus microsomal cytochromes P450 following TCDD treatment. Biochem Biophys Res Commun 342:1375-81
Genter, Mary Beth; Warner, Blake M; Krell, Hans-Willi et al. (2005) Reduction of alachlor-induced olfactory mucosal neoplasms by the matrix metalloproteinase inhibitor Ro 28-2653. Toxicol Pathol 33:593-9
Genter, Mary Beth; Goss, Kathleen H; Groden, Joanna (2004) Strain-specific of alachlor on murine olfactory mucosal responses. Toxicol Pathol 32:719-25
Genter, Mary Beth (2004) Update on olfactory mucosal metabolic enzymes: age-related changes and N-acetyltransferase activities. J Biochem Mol Toxicol 18:239-44
Burman, Dawn M; Shertzer, Howard G; Senft, Albert P et al. (2003) Antioxidant perturbations in the olfactory mucosa of alachlor-treated rats. Biochem Pharmacol 66:1707-15
Genter, Mary Beth; Van Veldhoven, Paul P; Jegga, Anil G et al. (2003) Microarray-based discovery of highly expressed olfactory mucosal genes: potential roles in the various functions of the olfactory system. Physiol Genomics 16:67-81
Senft, Albert P; Dalton, Timothy P; Nebert, Daniel W et al. (2002) Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor. Free Radic Biol Med 33:1268-78
Genter, Mary Beth; Apparaju, Sandhya; Desai, Pankaj B (2002) Induction of olfactory mucosal and liver metabolism of lidocaine by 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Biochem Mol Toxicol 16:128-34

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