NYMC Faculty Publications

Consensus Diagnoses and Mode of Action for the Formation of Gastric Tumors in Rats Treated With the Chloroacetanilide Herbicides Alachlor and Butachlor

Author Type(s)

Faculty

DOI

10.1177/0192623313484106

Journal Title

Toxicologic Pathology

First Page

386

Last Page

402

Document Type

Article

Publication Date

1-1-2014

Department

Pathology, Microbiology and Immunology

Keywords

Acetamides, Acetanilides, Animals, Carcinogenesis, Female, Herbicides, Male, Rats, Rats, Long-Evans, Rats, Sprague-Dawley, Stomach, Stomach Neoplasms

Disciplines

Medicine and Health Sciences

Abstract

A panel of pathologists (Panel) was formed to evaluate the pathogenesis and human relevance of tumors that developed in the fundic region of rat stomachs in carcinogenicity and mechanistic studies with alachlor and butachlor. The Panel evaluated stomach sections stained with hematoxylin and eosin, neuron-specific enolase, and chromogranin A to determine the presence and relative proportion of enterochromaffin-like (ECL) cells in the tumors and concluded all tumors were derived from ECL cells. Biochemical and pathological data demonstrated the tumor formation involved a nongenotoxic threshold mode of action (MOA) initially characterized by profound atrophy of the glandular fundic mucosa that affected gastric glands, but not surface epithelium. This resulted in a substantial loss of parietal cells and a compensatory mucosal cell proliferation. The loss of parietal cells caused a marked increase in gastric pH (hypochlorhydria), leading to sustained and profound hypergastrinemia. The mucosal atrophy, together with the increased gastrin, stimulated cell growth in one or more ECL cell populations, resulting in neoplasia. ECL cell autocrine and paracrine effects led to dedifferentiation of ECL cell tumors. The Panel concluded the tumors develop via a threshold-dependent nongenotoxic MOA, under conditions not relevant to humans.

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