Houdini Alert - Stomach Tumors Don't Count (forestomach that is)

Regulatory Toxicology and PharmacologyVolume 53, Issue 1, February 2009, Pages 6-15
Evaluation of potential human carcinogenicity of the synthetic monomer ethyl acrylate
Gary M. Williams, a, and Michael J. Iatropoulosa
aNew York Medical College, Department of Pathology, Chemical Safety Laboratory, Valhalla, NY 10595, USA

Abstract
Ethyl acrylate (EA) is an acrylic monomer used in the manufacture of a variety of polymers and copolymers as components of many commercially important products. Human exposure to EA occurs primarily in the workplace via inhalation or dermal contact.
In F344 rat and B6C3F1 mouse studies of EA carcinogenicity conducted by the National Toxicology Program [National Toxicology Program, NTP, 1986. Carcinogenesis Studies of Ethyl Acrylate (CAS No. 140-88-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies) (Tech. Rep. Ser. No. 259; NIH Publication No. 87-2515), Research Triangle Park, NC, USA], the only increased tumor incidences was in squamous cell papillomas and carcinomas of the forestomach, when EA was administered by gavage in corn oil at 100 or 200 mg/kg/day (high dose; HD). The neoplasms were preceded by forestomach irritation, inflammation, hyperkeratosis and hyperplasia of the forestomach mucosa. In studies in which rats and mice were exposed at comparable doses to EA in drinking water, by inhalation, or by dermal application, no neoplasms in the forestomach or in any other tissue were reported.
EA exhibited clastogenicity and related mutagenicity in vitro, but was non-genotoxic in vivo, including in the forestomach of treated rats. The in vitro clastogenicity response correlates well with cellular toxicity, mediated by non-protein sulfhydryl depletion and mitochondrial impairment. Thus, the carcinogenicity in the forestomach can be ascribed to a non-genotoxic mode of action (MOA).
The forestomach mucosal hyperplastic and even dysplastic changes, observed chronically, were reversible, provided the HD exposure was not longer than 6 months. This again supports a non-genotoxic MOA. In addition, the route and rate of EA exposure in rodents for forestomach neoplasia are irrelevant to potential human exposure, since humans do not have forestomach and are not exposed to EA by oral bolus. Thus, the weight of evidence indicates that the tumors produced in the rodent carcinogenicity studies arise from conditions that are irrelevant for human risk assessment
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BrooklynDodger(s) Comment: The Dodger(s) wonder whether ethyl acrylate is still in play at some regulatory agency, prompting this publication. Or, was this an old regulatory document taken off the shelf? RTP publishes in full text, so the Dodger(s) didn't have to track to a library to see that the review was funded by the Basic Acrylic Monomer Manufacturers, Inc; and that the authors acknowledge critical review of the manuscript by the members of the Basic Acrylic Monomers Manufacturers group. The authors cite themselves presenting secondary information to IARC. No original research by the authors was cited in the review. At the time, the manufacturers won the argument and achieved delisting. Nevertheless, the carcinogenicity of ethyl acrylate still must be disclosed on material safety data sheets.

The canonical argument is that increased tumor incidence in the forestomach achieves statistical significance at higher doses and not lower doses, and that organ pathology also increases at the higher doses where the tumors appear. For reasons the Dodger(s) will discuss elsewhere, it is to be expected that carcinogens will also cause non-tumor pathology in the organs in which they cause tumors, by the same genotoxic mechanism. It is expected that the concentration and so the toxicity and carcinogenicity of an agent will be highest at the site of contact.

The Dodger(s) note that butoxyethanol causes forestomach tumors BY INHALATION>