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Title: A revised model of ex-vivo reduction of hexavalent chromium in human and rodent gastric juices

Abstract

Chronic oral exposure to hexavalent chromium (Cr-VI) in drinking water has been shown to induce tumors in the mouse gastrointestinal (GI) tract and rat oral cavity. The same is not true for trivalent chromium (Cr-III). Thus reduction of Cr-VI to Cr-III in gastric juices is considered a protective mechanism, and it has been suggested that the difference between the rate of reduction among mice, rats, and humans could explain or predict differences in sensitivity to Cr-VI. We evaluated previously published models of gastric reduction and believe that they do not fully describe the data on reduction as a function of Cr-VI concentration, time, and (in humans) pH. The previous models are parsimonious in assuming only a single reducing agent in rodents and describing pH-dependence using a simple function. We present a revised model that assumes three pools of reducing agents in rats and mice with pH-dependence based on known speciation chemistry. While the revised model uses more fitted parameters than the original model, they are adequately identifiable given the available data, and the fit of the revised model to the full range of data is shown to be significantly improved. Hence the revised model should provide better predictions of Cr-VImore » reduction when integrated into a corresponding PBPK model. - Highlights: • Hexavalent chromium (Cr-VI) reduction in gastric juices is a key detoxifying step. • pH-dependent Cr-VI reduction rates are explained using known chemical speciation. • Reduction in rodents appears to involve multiple pools of electron donors. • Reduction appears to continue after 60 min, although more slowly than initial rates.« less

Authors:
;
Publication Date:
OSTI Identifier:
22439882
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 280; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BINDING ENERGY; CHEMISTRY; CHROMIUM; CONCENTRATION RATIO; DRINKING WATER; FORECASTING; HUMAN POPULATIONS; MICE; NEOPLASMS; ORAL CAVITY; PH VALUE; RATS; REDUCING AGENTS; REDUCTION; SENSITIVITY; VALENCE

Citation Formats

Schlosser, Paul M., E-mail: schlosser.paul@epa.gov, and Sasso, Alan F.. A revised model of ex-vivo reduction of hexavalent chromium in human and rodent gastric juices. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.08.010.
Schlosser, Paul M., E-mail: schlosser.paul@epa.gov, & Sasso, Alan F.. A revised model of ex-vivo reduction of hexavalent chromium in human and rodent gastric juices. United States. doi:10.1016/J.TAAP.2014.08.010.
Schlosser, Paul M., E-mail: schlosser.paul@epa.gov, and Sasso, Alan F.. 2014. "A revised model of ex-vivo reduction of hexavalent chromium in human and rodent gastric juices". United States. doi:10.1016/J.TAAP.2014.08.010.
@article{osti_22439882,
title = {A revised model of ex-vivo reduction of hexavalent chromium in human and rodent gastric juices},
author = {Schlosser, Paul M., E-mail: schlosser.paul@epa.gov and Sasso, Alan F.},
abstractNote = {Chronic oral exposure to hexavalent chromium (Cr-VI) in drinking water has been shown to induce tumors in the mouse gastrointestinal (GI) tract and rat oral cavity. The same is not true for trivalent chromium (Cr-III). Thus reduction of Cr-VI to Cr-III in gastric juices is considered a protective mechanism, and it has been suggested that the difference between the rate of reduction among mice, rats, and humans could explain or predict differences in sensitivity to Cr-VI. We evaluated previously published models of gastric reduction and believe that they do not fully describe the data on reduction as a function of Cr-VI concentration, time, and (in humans) pH. The previous models are parsimonious in assuming only a single reducing agent in rodents and describing pH-dependence using a simple function. We present a revised model that assumes three pools of reducing agents in rats and mice with pH-dependence based on known speciation chemistry. While the revised model uses more fitted parameters than the original model, they are adequately identifiable given the available data, and the fit of the revised model to the full range of data is shown to be significantly improved. Hence the revised model should provide better predictions of Cr-VI reduction when integrated into a corresponding PBPK model. - Highlights: • Hexavalent chromium (Cr-VI) reduction in gastric juices is a key detoxifying step. • pH-dependent Cr-VI reduction rates are explained using known chemical speciation. • Reduction in rodents appears to involve multiple pools of electron donors. • Reduction appears to continue after 60 min, although more slowly than initial rates.},
doi = {10.1016/J.TAAP.2014.08.010},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 280,
place = {United States},
year = 2014,
month =
}
  • In vivo and in vitro systems were used to evaluate hexavalent chromium toxicity to alveolar macrophages. Rat alveolar macrophages were exposed to 2 ..mu..g calcium chromate (CaCrO/sub 4/, insoluble) or 2 ..mu..g chromium trioxide (CrO/sub 3/, soluble) in live animals, in vivo, and in tissue culture, in vitro, collected by lavage from the lung. Chemiluminescence and oxygen consumption were measured as indicators of toxicity. Trypan blue dye exclusion was used to determine macrophage viability. In vivo exposure of the macrophage to either chromium compound showed no toxic effects at a 2-..mu..g dose. Macrophages exposed in tissue culture, however, had valuesmore » significantly different from controls. The untreated controls for both exposure methods were compared to evaluate differences resulting from methods alone.« less
  • The in vivo toxic effects of hexavalent chromium (20 mg/liter) on hemolymph glucose, tissue glycogen, total free sugars, and active and total phosphorylases of an edible, freshwater crab Barytelphusa guerini were studied. In a 15-day exposure span followed by a 15-day postexposure recovery, the time-course alterations in these constituent segments of the glycogen metabolism indicate an inconsistent depletion in metabolite levels and elevated enzyme activities during exposure period as well as hyperglycemia. An insignificant recovery was observed in these parameters on the 15th day of the postexposure phase.
  • Hexavalent chromium (Cr6) is a drinking water contaminant that has been detected in most of the water systems throughout the United States. In 2-year drinking water bioassays, the National Toxicology Program (NTP) found clear evidence of carcinogenic activity in male and female rats and mice. Because reduction of Cr6 to trivalent chromium (Cr3) is an important detoxifying step in the gastrointestinal (GI) tract prior to systemic absorption, models have been developed to estimate the extent of reduction in humans and animals. The objective of this work was to use a revised model of ex vivo Cr6 reduction kinetics in gastricmore » juice to analyze the potential reduction kinetics under in vivo conditions for mice, rats and humans. A published physiologically-based pharmacokinetic (PBPK) model was adapted to incorporate the new reduction model. This paper focuses on the toxicokinetics of Cr6 in the stomach compartment, where most of the extracellular Cr6 reduction is believed to occur in humans. Within the range of doses administered by the NTP bioassays, neither the original nor revised models predict saturation of stomach reducing capacity to occur in vivo if applying default parameters. However, both models still indicate that mice exhibit the lowest extent of reduction in the stomach, meaning that a higher percentage of the Cr6 dose may escape stomach reduction in that species. Similarly, both models predict that humans exhibit the highest extent of reduction at low doses. - Highlights: • We outline a new in vivo model for hexavalent chromium reduction in the stomach. • We examine in vivo reduction for mice, rats, and humans under varying conditions. • Species differences in toxicokinetics may explain susceptibility. • We show that a simplified stomach reduction model is adequate for extrapolation. • Internal dose uncertainties still exist.« less
  • Desulfovibrio vulgaris Hildenborough is a well-studiedsulfate reducer that can reduce heavy metals and radionuclides [e.g.,Cr(VI) and U(VI)]. Cultures grown in a defined medium had a lag period ofapproximately 30 h when exposed to 0.05 mM Cr(VI). Substrate analysesrevealed that although Cr(VI) was reduced within the first 5 h, growthwas not observed for an additional 20 h. The growth lag could beexplained by a decline in cell viability; however, during this time smallamounts of lactate were still utilized without sulfate reduction oracetate formation. Approximately 40 h after Cr exposure (0.05 mM),sulfate reduction occurred concurrently with the accumulation of acetate.Similar amounts ofmore » hydrogen were produced by Cr-exposed cells compared tocontrol cells, and lactate was not converted to glycogen duringnon-growth conditions. D. vulgaris cells treated with a reducing agentand then exposed to Cr(VI) still experienced a growth lag, but theaddition of ascorbate at the time of Cr(VI) addition prevented the lagperiod. In addition, cells grown on pyruvate displayed more tolerance toCr(VI) compared to lactate-grown cells. These results indicated that D.vulgaris utilized lactate during Cr(VI) exposure without the reduction ofsulfate or production of acetate, and that ascorbate and pyruvate couldprotect D. vulgaris cells from Cr(VI)/Cr(III) toxicity.« less