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Arce G.T.,Arce Consulting | Gordon E.B.,Elliot Gordon Consulting LLC | Cohen S.M.,University of Nebraska Medical Center | Singh P.,Raleigh America
Critical Reviews in Toxicology | Year: 2010

Folpet and captan are fungicides whose genotoxicity depends on their chemical reaction with thiols. Multiple mutagenicity tests have been conducted on these compounds due to their positive activity in vitro and their association with gastrointestinal tumors in mice. A review of the collective data shows that these compounds have in vitro mutagenic activity but are not genotoxic in vivo. This dichotomy is primarily due to the rapid degradation of folpet and captan in the presence of thiol-rich matrices typically found in vivo. Genotoxicity has not been found in the duodenum, the mouse tumor target tissue. It is concluded that folpet like captan presents an unlikely risk of genotoxic effects in humans. © 2010 Informa UK Ltd.

Cohen S.M.,University of Nebraska Medical Center | Gordon E.B.,Elliot Gordon Consulting LLC | Singh P.,Raleigh America | Arce G.T.,Arce Consulting | Nyska A.,Toxicologic Pathology Consultant
Critical Reviews in Toxicology | Year: 2010

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. © 2010 Informa UK Ltd.

Bailliard F.,Raleigh America | Spicer D.E.,3Congenital Heart Institute of Florida | Mohun T.J.,5Emeritus Founding Editor | Henry G.W.,5Emeritus Founding Editor | Anderson R.H.,Newcastle University
Cardiology in the young | Year: 2015

Although steps are being taken to produce a universally acceptable coding system for categorisation of the congenitally malformed hearts, obstacles remain in the search for consensus. One of the groups of lesions continuing to produce the greatest problems is those that permit interventricular shunting. The difficulties relate partly to the words used to describe the group itself, as those using Germanic languages describe the holes as ventricular septal defects, whereas those using Romance languages consider them to represent interventricular communications. The two terms, however, are not necessarily synonymous. Further disagreements relate to whether the lesions placed within the group should be sub-categorised on the basis of their geographical location within the ventricular mass, as opposed to the anatomic nature of their borders. In reality, attention to both the features is necessary if we are to recognise the full extent of phenotypic variability. In this review, we first review the evolution and theories of analysis naming the channels that permit interventricular shunting. We then demonstrate that embryologic techniques provide evidence that the changing morphology of the developing murine heart parallels the anatomy of the different lesions encountered in the congenitally malformed human heart. We suggest that, with attention paid to the temporal development of the normal murine heart, combined with a strict definition of the plane of separation between the right and left ventricular cavities, it will be feasible to produce a categorisation that is acceptable to all.

Gordon E.,Elliot Gordon Consulting LLC | Cohen S.M.,University of Nebraska Medical Center | Singh P.,Raleigh America | Singh P.,Syngenta
Toxicology Mechanisms and Methods | Year: 2012

Folpet, an agricultural fungicide, induces tumors in the mouse gastrointestinal tract, primarily in the duodenum. Bioassays show a threshold for tumors at ∼1000ppm dietary administration. We investigated the early histologic changes to the mouse duodenum in mice fed a diet containing 6000ppm folpet for 28 days. Reversibility of folpet-induced changes was evaluated after treatment for 28 days and a recovery period of 17 days. Macroscopic changes in the cecum (dilatation) and duodenum (roughening) were evident by day 7, continued through day 28, then returned to normal by recovery day 17. The duodenal mucosa also appeared to be thickened. Macroscopic changes to the forestomach were also evident as a rough surface or depressions; they also decreased in incidence and severity in the recovery animals. Histologic changes of the duodenum (crypt cell hyperplasia, villous hypertrophy, numerous intraepithelial lymphocytes, and elongation of epithelial columnar cells) were evident in all treated mice by day 7 and continued and increased in severity through 28 days of administration. The incidence and severity of these findings was reduced on recovery day 17, indicating reversibility. Histologic changes (epithelial hyperplasia and hyperkeratosis) of the non-glandular squamous epithelium in the forestomach occurred later than the changes to the duodenum. The incidence and severity of these changes also lessened by recovery day 17. These early histologic changes support a non-DNA reactive mode of action for folpet carcinogenicity in mice involving the key events of mucosal cytotoxicity with consequent regenerative proliferation. Exposures that are not sufficient to produce cytotoxicity would also not lead to tumor formation. © 2012 Informa Healthcare USA, Inc.

Hill T.,650 Mail Service Center | Kulz E.,650 Mail Service Center | Munoz B.,Rti International | Dorney J.R.,Raleigh America
Environmental Management | Year: 2013

Data from a probability sample were used to estimate wetland and stream mitigation success from 2007 to 2009 across North Carolina (NC). "Success" was defined as whether the mitigation site met regulatory requirements in place at the time of construction. Analytical results were weighted by both component counts and mitigation size. Overall mitigation success (including preservation) was estimated at 74 % (SE = 3 %) for wetlands and 75 % (SE = 4 %) for streams in NC. Compared to the results of previous studies, wetland mitigation success rates had increased since the mid-1990s. Differences between mitigation providers (mitigation banks, NC Ecosystem Enhancement Program's design-bid-build and full-delivery programs, NC Department of Transportation and private permittee-responsible mitigation) were generally not significant although permittee-responsible mitigation yielded higher success rates in certain circumstances. Both wetland and stream preservation showed high rates of success and the stream enhancement success rate was significantly higher than that of stream restoration. Additional statistically significant differences when mitigation size was considered included: (1) the Piedmont yielded a lower stream mitigation success rate than other areas of the state, and (2) recently constructed wetland mitigation projects demonstrated a lower success rate than those built prior to 2002. Opportunities for improvement exist in the areas of regulatory record-keeping, understanding the relationship between post-construction establishment and long-term ecological trajectories of stream and wetland restoration projects, incorporation of numeric ecological metrics into mitigation monitoring and success criteria, and adaptation of stream mitigation designs to achieve greater success in the Piedmont. © 2013 Springer Science+Business Media New York.

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