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

Cohen, Samuel M.; Gordon, Elliot B.; Singh, Phirtu; Arce, Gail Theall; Nyska, Abraham

doi:10.3109/10408441003742903

Cited by 42 publications

(39 citation statements)

References 45 publications

(74 reference statements)

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“…This has been surmised based on findings that erythrocytes express high levels of the SLC4A1 anion transporter and readily take up Cr(VI) (Cohen et al , 1993; Markovich, 2001). The SLC4A1 protein product, anion exchanger 1 (AE1, also known as band 3), is inhibited by stilbene disulfonates (Cohen et al , 1993; Little et al , 1996; Markovich, 2001). These inhibitors have also been shown to reduce Cr(VI) uptake into cells in vitro ; however, the inhibitors are not specific to AE1 (Kudrycki et al , 1990).…”

Section: Application Of Moa and Human Relevance Frameworkmentioning

confidence: 99%

Application of the U.S. EPA Mode of Action Framework for Purposes of Guiding Future Research: A Case Study Involving the Oral Carcinogenicity of Hexavalent Chromium

Thompson

Haws

Harris

et al. 2010

Toxicological Sciences

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Mode of action (MOA) analysis provides a systematic description of key events leading to adverse health effects in animal bioassays for the purpose of informing human health risk assessment. Uncertainties and data gaps identified in the MOA analysis may also be used to guide future research to improve understanding of the MOAs underlying a specific toxic response and foster development of toxicokinetic and toxicodynamic models. An MOA analysis, consistent with approaches outlined in the MOA Framework as described in the Guidelines for Carcinogen Risk Assessment, was conducted to evaluate small intestinal tumors observed in mice chronically exposed to relatively high concentrations of hexavalent chromium (Cr(VI)) in drinking water. Based on review of the literature, key events in the MOA are hypothesized to include saturation of the reductive capacity of the upper gastrointestinal tract, absorption of Cr(VI) into the intestinal epithelium, oxidative stress and inflammation, cell proliferation, direct and/or indirect DNA modification, and mutagenesis. Although available data generally support the plausibility of these key events, several unresolved questions and data gaps were identified, highlighting the need for obtaining critical toxicokinetic and toxicodynamic data in the target tissue and in the low-dose range. Experimental assays that can address these data gaps are discussed along with strategies for comparisons between responsive and nonresponsive tissues and species. This analysis provides a practical application of MOA Framework guidance and is instructive for the design of studies to improve upon the information available for quantitative risk assessment.

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Section: Application Of Moa and Human Relevance Frameworkmentioning

confidence: 99%

Application of the U.S. EPA Mode of Action Framework for Purposes of Guiding Future Research: A Case Study Involving the Oral Carcinogenicity of Hexavalent Chromium

Thompson

Haws

Harris

et al. 2010

Toxicological Sciences

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“…As with tumors, the incidence of diffuse epithelial hyperplasia was highest in the proximal SI (duodenum) and lowest in the distal intestine (ileum). Diffuse epithelial hyperplasia is a non‐neoplastic lesion that, under chronic wounding, can lead to increased stem cell proliferation, which can promote transformation and carcinogenesis (Cohen & Ellwein, 1990; Cohen, Gordon, Singh, Arce, & Nyska, 2010; Tomasetti & Vogelstein, 2015). Because Cr(VI) flux through intestinal sections well describes the tumor response in the SI, and hyperplasia is a critical preceding event to tumor formation, intestinal flux was used to model hyperplasia incidence from the NTP (2008) 2 year bioassay.…”

Section: Resultsmentioning

confidence: 99%

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin‐of‐exposure values for hexavalent chromium

Thompson

Kirman²,

Hays³

et al. 2017

J of Applied Toxicology

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The current US Environmental Protection Agency (EPA) reference dose (RfD) for oral exposure to chromium, 0.003 mg kg−1 day−1, is based on a no‐observable‐adverse‐effect‐level from a 1958 bioassay of rats exposed to ≤25 ppm hexavalent chromium [Cr(VI)] in drinking water. EPA characterizes the confidence in this RfD as “low.” A more recent cancer bioassay indicates that Cr(VI) in drinking water is carcinogenic to mice at ≥30 ppm. To assess whether the existing RfD is health protective, neoplastic and non‐neoplastic lesions from the 2 year cancer bioassay were modeled in a three‐step process. First, a rodent physiological‐based pharmacokinetic (PBPK) model was used to estimate internal dose metrics relevant to each lesion. Second, benchmark dose modeling was conducted on each lesion using the internal dose metrics. Third, a human PBPK model was used to estimate the daily mg kg−1 dose that would produce the same internal dose metric in both normal and susceptible humans. Mechanistic research into the mode of action for Cr(VI)‐induced intestinal tumors in mice supports a threshold mechanism involving intestinal wounding and chronic regenerative hyperplasia. As such, an RfD was developed using incidence data for the precursor lesion diffuse epithelial hyperplasia. This RfD was compared to RfDs for other non‐cancer endpoints; all RfD values ranged 0.003–0.02 mg kg−1 day−1. The lowest of these values is identical to EPA's existing RfD value. Although the RfD value remains 0.003 mg kg−1 day−1, the confidence is greatly improved due to the use of a 2‐year bioassay, mechanistic data, PBPK models and benchmark dose modeling.

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“…Exposure to captan dust (a risk predominantly limited to agricultural workers) causes skin, eye and respiratory tract inflammation [33]; dietary Captan exposure produced reproductive anomalies in Drosophila [34]. The specific targets for Captan toxicity are unknown but the compound reacts readily with thiols to form thiophosgene, a compound that is known to cause gastrointestinal lesions and malignancies [35]. Captan inhibits Hs PBGS with an IC 50 of 3.0 ± 0.3 μM, and is also an effective hexamer stabilizer, shifting the oligomeric equilibrium to 72.3 ± 0.3% at 2 mM Captan (Table 1, Fig.…”

Section: Resultsmentioning

confidence: 99%

Environmental Contaminants Perturb Fragile Protein Assemblies and Inhibit Normal Protein Function

Lawrence¹,

Selwood²,

Jaffe³

2013

CCB

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The molecular mechanisms whereby small molecules that contaminate our environment cause physiological effects are largely unknown, in terms of both targets and mechanisms. The essential human enzyme porphobilinogen synthase (HsPBGS, a.k.a. 5-aminolevulinate dehydratase, ALAD) functions in heme biosynthesis. HsPBGS catalytic activity is regulated allosterically via an equilibrium of inactive hexamers and active octamers, and we have shown that certain drugs and drug-like small molecules can inhibit HsPBGS in vitro by stabilizing the hexamer. Here we address whether components of the National Toxicology Program library of environmental contaminants can stabilize the HsPBGS hexamer and inhibit activity in vitro. Native polyacrylamide gel electrophoresis was used to screen the library (1,408 compounds) for components that alter the oligomeric distribution of HsPBGS. Freshly purchased samples of 37 preliminary hits were used to confirm the electrophoretic results and to determine the dose-dependence of the perturbation of oligomeric distribution. Seventeen compounds were identified which alter the oligomeric distribution toward the hexamer and also inhibit HsPBGS catalytic activity, including the most potent HsPBGS inhibitor yet characterized (Mutagen X, IC50 = 1.4 μM). PBGS dysfunction is associated with the inborn error of metabolism know as ALAD porphyria and with lead poisoning. The identified hexamer-stabilizing inhibitors could potentiate these diseases. Allosteric regulation of activity via an equilibrium of alternate oligomers has been proposed for many proteins. Based on the precedent set herein, perturbation of these oligomeric equilibria by small molecules (such as environmental contaminants) can be considered as a mechanism of toxicity.

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

Cited by 42 publications

References 45 publications

Application of the U.S. EPA Mode of Action Framework for Purposes of Guiding Future Research: A Case Study Involving the Oral Carcinogenicity of Hexavalent Chromium

Application of the U.S. EPA Mode of Action Framework for Purposes of Guiding Future Research: A Case Study Involving the Oral Carcinogenicity of Hexavalent Chromium

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin‐of‐exposure values for hexavalent chromium

Environmental Contaminants Perturb Fragile Protein Assemblies and Inhibit Normal Protein Function

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