Lack of induction of nuclear aberrations by captan in mouse duodenum

Chronic exposure to high concentrations of hexavalent chromium (Cr(VI)) in drinking water causes intestinal adenomas and carcinomas in mice, but not in rats. Cr(VI) causes damage to intestinal villi and crypt hyperplasia in mice after only one week of exposure. After two years of exposure, intestinal damage and crypt hyperplasia are evident in mice (but not rats), as are intestinal tumors. Although Cr(VI) has genotoxic properties, these findings suggest that intestinal tumors in mice arise as a result of chronic mucosal injury. To better understand the mode of action (MOA) of Cr(VI) in the intestine, a 90-day drinking water study was conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in intestinal tissues. Using MOA analyses and human relevance frameworks proposed by national and international regulatory agencies, the weight of evidence supports a cytotoxic MOA with the following key events: (a) absorption of Cr(VI) from the intestinal lumen, (b) toxicity to intestinal villi, (c) crypt regenerative hyperplasia and (d) clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis. This article summarizes the data supporting each key event in the MOA, as well as data that argue against a mutagenic MOA for Cr(VI)-induced intestinal tumors.

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“…All three chemicals also fail to induce MN in intestinal crypts (Arce et al . , 2010; Chidiac & Goldberg, 1987; Harris et al . , 2012).…”

Section: Application Of the Mode Of Action Frameworkmentioning

confidence: 99%

Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans

Thompson

Proctor

Suh

et al. 2013

Critical Reviews in Toxicology

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“…For the duodenal tumors induced in mice by folpet, the mode of action involves irritation-related cytotoxicity with consequent cellular regeneration ultimately leading to the development of tumors� The critical key event involves consumption of sufficiently high levels of folpet that yield a cytotoxic concentration of folpet and its degradation product, thiophosgene� Combined, these chemicals can cause cytotoxicity in the duodenum (Table 6)� In the stomach and duodenum there is cytotoxicity from the direct reaction of folpet with cellular components containing thiol groups as well as from the highly reactive thiophosgene, a hydrolysis product of folpet, which reacts with thiols as well as other cellular constituents (see Figures 1 and 2)� Folpet itself, like captan (Wilkinson et al�, 2004), is reactive with thiol groups, which generates thiophosgene (Figure 1)� However, thiophosgene is also reactive with thiol groups (Figure 2), with a half-life of less than 1 s (0�6 s in human blood)� Thiophosgene, thus, is generated either by the reaction of folpet with thiol groups or following hydrolysis of folpet� Direct interaction of folpet with thiol groups is the primary source of the thiophosgene� The hydrolysis of folpet to thiophosgene is highly pH dependent� The reaction occurs readily at neutral to alkaline pH but significantly less at low pH� Because of their marked reactivity, folpet and thiophosgene will react rapidly with thiol groups and not reach DNA or DNA-related targets (e�g�, histones) Liu and Fishbein, 1967;Lukens, 1966;Lukens et al�, 1965;Siegel, 1971aSiegel, , 1971bBernard and Gordon, 2000)� This is highlighted by a pair of key in vivo studies that show folpet and captan do not induce genotoxicity, as evidenced by the lack of increased nuclear aberrations in the tumor target site, the duodenum (Chidiac and Goldberg, 1987;Gudi and Krsmanovic, 2001)� Thus, DNA damage is highly unlikely and not detected in studies designed to assess this effect at the target tissue in vivo (Arce et al�, 2010)�…”

Section: Key Eventsmentioning

confidence: 99%

Carcinogenic mode of action of folpet in mice and evaluation of its relevance to humans

Cohen

Gordon²,

Singh³

et al. 2010

Critical Reviews in Toxicology

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A framework has been evolving for evaluation of mode of action (MOA) of rodent toxicity and carcinogenicity findings and their relevance to humans. Folpet produces duodenal glandular tumors in mice, but is not carcinogenic in rats. A wealth of information is available regarding folpet's mode of action, providing an excellent example of how this tumor can be evaluated using this framework. Folpet reacts with thiol groups, and is rapidly hydrolyzed at pH 7. Both reactions produce thiophosgene that reacts with thiols and other functional groups. Folpet is not genotoxic in vivo. At sufficiently high, prolonged dietary doses, folpet irritates the mouse duodenum, resulting in cytotoxicity with consequent regenerative proliferation and ultimately tumor development. Forestomach lesions secondary to cytotoxicity are also induced. Dogs have stomachs similar to humans and show no evidence of gastrointestinal toxicity or tumor formation at exposure levels at least as high as rodents. The data support a MOA in mice involving cytotoxicity and regenerative proliferation. Based on MOA analysis and assessment of human relevance, folpet, like captan, another trichloromethylthio-related fungicide with similar toxic and carcinogenic effects, is not likely to be a human carcinogen at dose levels that do not cause cytotoxicity and regenerative proliferation.

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“…In vivo, results were generally negative. This included a site-specific assay that looked for nuclear aberrations in crypt cells of the duodenum, the site of origin for adenomas (Chidiac and Goldberg, 1987). The basis of the absence of mutagenicity in vivo is the rapid reaction of captan with thiols.…”

Section: Captan Is Mutagenicmentioning

confidence: 99%

Captan: Transition from ‘B2’ to ‘not likely’. How pesticide registrants affected the EPA Cancer Classification Update

Gordon¹

2007

J of Applied Toxicology

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On 24 November 2004 EPA changed the cancer classification of captan from a 'probable human carcinogen' (Category B2) to 'not likely' when used according to label directions. The new cancer classification considers captan to be a potential carcinogen at prolonged high doses that cause cytotoxicity and regenerative cell hyperplasia. These high doses of captan are many orders of magnitude above those likely to be consumed in the diet, or encountered by individuals in occupational or residential settings. This revised cancer classification reflects EPA's implementation of their new cancer guidelines. The procedures involved in the reclassification effort were agreed upon with EPA and involved an Independent Transparent Review as it related to four components that formed the basis of the original 1986 B2 classification: mouse tumors; rat tumors; mutagenicity; and structural similarity to other carcinogens. A Peer Review Panel organized and administered by Toxicology Excellence for Risk Assessment (TERA) met on 2-3 September 2003. The Panel concluded that captan acted through a non-mutagenic threshold mode of action that required prolonged irritation of the duodenal villi as the initial key event. EPA's Cancer Assessment Review Committee (CARC) met on 9 June 2004 and endorsed the Peer Review findings. EPA intended to have the FIFRA Scientific Advisory Panel (SAP) consider the basis for this reclassification but found the science was robust and judged that a SAP review was not warranted. Using the revised classification, the margin of exposure is approximately 1,200,000, supporting the 'not likely' characterization.

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Lack of induction of nuclear aberrations by captan in mouse duodenum

Cited by 22 publications

References 32 publications

Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans

Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans

Carcinogenic mode of action of folpet in mice and evaluation of its relevance to humans

Captan: Transition from ‘B2’ to ‘not likely’. How pesticide registrants affected the EPA Cancer Classification Update

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