Physiologically based pharmacokinetic modeling of arsenic in the mouse

A remarkable feature of the carcinogenicity of inorganic arsenic is that while human exposures to high concentrations of inorganic arsenic in drinking water are associated with increases in skin, lung, and bladder cancer, inorganic arsenic has not typically caused tumors in standard laboratory animal test protocols. Inorganic arsenic administered for periods of up to 2 yr to various strains of laboratory mice, including the Swiss CD-1, Swiss CR:NIH(S), C57Bl/6p53(+/-), and C57Bl/6p53(+/+), has not resulted in significant increases in tumor incidence. However, Ng et al. (1999) have reported a 40% tumor incidence in C57Bl/6J mice exposed to arsenic in their drinking water throughout their lifetime, with no tumors reported in controls. In order to investigate the potential role of tissue dosimetry in differential susceptibility to arsenic carcinogenicity, a physiologically based pharmacokinetic (PBPK) model for inorganic arsenic in the rat, hamster, monkey, and human (Mann et al., 1996a, 1996b) was extended to describe the kinetics in the mouse. The PBPK model was parameterized in the mouse using published data from acute exposures of B6C3F1 mice to arsenate, arsenite, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) and validated using data from acute exposures of C57Black mice. Predictions of the acute model were then compared with data from chronic exposures. There was no evidence of changes in the apparent volume of distribution or in the tissue-plasma concentration ratios between acute and chronic exposure that might support the possibility of inducible arsenite efflux. The PBPK model was also used to project tissue dosimetry in the C57Bl/6J study, in comparison with tissue levels in studies having shorter duration but higher arsenic treatment concentrations. The model evaluation indicates that pharmacokinetic factors do not provide an explanation for the difference in outcomes across the various mouse bioassays. Other possible explanations may relate to strain-specific differences, or to the different durations of dosing in each of the mouse studies, given the evidence that inorganic arsenic is likely to be active in the later stages of the carcinogenic process. [Authors]]]> eng oai:serval.unil.ch:BIB_814 2022-02-19T02:25:05Z <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_814 Shenyang apprend à gérer ses pauvres. Kernen, A info:eu-repo/semantics/article article 1997 Perspectives Chinoises, vol. 40, pp. 17-21 fre oai:serval.unil.ch:BIB_8140284AD5C8 2022-02-19T02:25:05Z openaire documents urnserval <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_8140284AD5C8 Mitochondrial respiratory states and rate info:doi:10.26124/mitofit:190001.v2 info:eu-repo/semantics/altIdentifier/doi/10.26124/mitofit:190001.v2 Gnaiger, E. Aasander Frostner, E. Abdul Karim, N. Abumrad, NA. Acuna-Castroviejo, D. Adiele, RC. Ahn, B. Ali, SS. Alton, L. Alves, MG. Amati, F. Amoedo, ND. Andreadou, I. Arago, M. Aral, C. Arandarcikaite, O. Armand, AS. Arnould, T. Avram, VF. Bailey, DM. Bajpeyi, S. Bajzikova, M. Bakker, BM. Barlow, J. Bastos Sant'Anna Silva, AC. Batterson, P. Battino, M. Bazil, J. Beard, DA. Bednarczyk, P. Bello, F. Ben-Shachar, D. Bergdahl, A. Berge, RK. Bergmeister, L. Bernardi, P. Berridge, MV. Bettinazzi, S. Bishop, D. Blier, PU. Blindheim, DF. Boardman, NT. Boetker, HE. Borchard, S. Boros, M. Borsheim, E. Borutaite, V. Botella, J. Bouillaud, F. Bouitbir, J. Boushel, RC. Bovard, J. Breton, S. Brown, DA. Brown, GC. Brown, RA. Brozinick, JT. Buettner, GR. Burtscher, J. Calabria, E. Calbet, JA. Calzia, E. Cannon, DT. Cano Sanchez, M. Canto, AC. Cardoso, LHD. Carvalho, E. Casado Pinna, M. Cassar, S. Cassina, AM. Castelo, MP. Castro, L. Cavalcanti-de-Albuquerque, JP. Cervinkova, Z. Chabi, B. Chakrabarti, L. Chakrabarti, S. Chaurasia, B. Chen, Q. Chicco, AJ. Chinopoulos, C. Chowdhury, SK. Cizmarova, B. Clementi, E. Coen, PM. Cohen, BH. Coker, RH. Collin, A. Crisostomo, L. Dahdah, N. Dalgaard, LT. Dambrova, M. Danhelovska, T. Darveau, CA. Das, AM. Dash, RK. Davidova, E. Davis, MS. De Goede, P. De Palma, C. Dembinska-Kiec, A. Detraux, D. Devaux, Y. Di Marcello, M. Dias, TR. Distefano, G. Doermann, N. Doerrier, C. Dong, L. Donnelly, C. Drahota, Z. Duarte, FV. Dubouchaud, H. Duchen, MR. Dumas, JF. Durham, WJ. Dymkowska, D. Dyrstad, SE. Dyson, A. Dzialowski, EM. Eaton, S. Ehinger, J. Elmer, E. Endlicher, R. Engin, AB. Escames, G. Ezrova, Z. Falk, MJ. Fell, DA. Ferdinandy, P. Ferko, M. Ferreira, JCB. Ferreira, R. Ferri, A. Fessel, JP. Filipovska, A. Fisar, Z. Fischer, C. Fischer, M. Fisher, G. Fisher, JJ. Ford, E. Fornaro, M. Galina, A. Galkin, A. Gallee, L. Galli, GL. Gama Perez, P. Gan, Z. Ganetzky, R. Garcia-Rivas, G. Garcia-Roves, PM. Garcia-Souza, LF. Garipi, E. Garlid, KD. Garrabou, G. Garten, A. Gastaldelli, A. Gayen, J. Genders, AJ. Genova, ML. Giovarelli, M. Goncalo Teixeira da Silva, R. Goncalves, DF. Gonzalez-Armenta, JL. Gonzalez-Freire, M. Gonzalo, H. Goodpaster, BH. Gorr, TA. Gourlay, CW. Granata, C. Grefte, S. Guarch, ME. Gueguen, N. 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Schlattner, U. Schoenfeld, P. Schots, PC. Schulz, R. Schwarzer, C. Scott, GR. Selman, C. Shabalina, IG. Sharma, P. Sharma, V. Shevchuk, I. Shirazi, R. Shiroma, JG. Siewiera, K. Silber, AM. Silva, AM. Sims, CA. Singer, D. Singh, BK. Skolik, R. Smenes, BT. Smit

Does occupational exposure to formaldehyde cause hematotoxicity and leukemia-specific chromosome changes in cultured myeloid progenitor cells?

Several cross-sectional studies of a single population of workers exposed to formaldehyde at one of two factories using or producing formaldehyde–melamine resins in China have concluded that formaldehyde exposure induces damage to hematopoietic cells that originate in the bone marrow. Moreover, the investigators interpret observed differences between groups as evidence that formaldehyde induces myeloid leukemias, although the mechanisms for inducing these diseases are not obvious and recently published scientific findings do not support causation. Our objective was to evaluate hematological parameters and aneuploidy in relation to quantitative exposure measures of formaldehyde. We obtained the study data for the original study (Zhang et al. 2010) and performed linear regression analyses. Results showed that differences in white blood cell, granulocyte, platelet, and red blood cell counts are not exposure dependent. Among formaldehyde-exposed workers, no association was observed between individual average formaldehyde exposure estimates and frequency of aneuploidy, suggested by the original study authors to be indicators of myeloid leukemia risk. © 2017 Ramboll Environ US Corporation. Published by Informa UK Limited, trading as Taylor & Francis Group

Does occupational exposure to formaldehyde cause hematotoxicity and leukemia-specific chromosome changes in cultured myeloid progenitor cells?

<p>Several cross-sectional studies of a single population of workers exposed to formaldehyde at one of two factories using or producing formaldehyde–melamine resins in China have concluded that formaldehyde exposure induces damage to hematopoietic cells that originate in the bone marrow. Moreover, the investigators interpret observed differences between groups as evidence that formaldehyde induces myeloid leukemias, although the mechanisms for inducing these diseases are not obvious and recently published scientific findings do not support causation. Our objective was to evaluate hematological parameters and aneuploidy in relation to quantitative exposure measures of formaldehyde. We obtained the study data for the original study (Zhang et al. <a href="#CIT0026" target="_blank">2010</a>) and performed linear regression analyses. Results showed that differences in white blood cell, granulocyte, platelet, and red blood cell counts are not exposure dependent. Among formaldehyde-exposed workers, no association was observed between individual average formaldehyde exposure estimates and frequency of aneuploidy, suggested by the original study authors to be indicators of myeloid leukemia risk.</p

Comparison of tissue dosimetry in the mouse following chronic exposure to arsenic compounds

Several chronic bioassays have been conducted in multiple strains of mice in which various concentrations of arsenate or arsenite were administered in the drinking water without a tumorigenic effect. However, one study (Ng et al., 1999) reported a significant increase in tumor incidence in C57Bl/6J mice exposed to arsenic in their drinking water throughout their lifetime, with no tumors reported in controls. A physiologically based pharmacokinetic model for arsenic in the mouse has previously been developed (Gentry et al., 2004) to investigate potential differences in tissue dosimetry of arsenic species across various strains of mice. Initial results indicated no significant differences in blood, liver, or urine dosimetry in B6C3F1 and C57Bl/6 mice for acute or subchronic exposure. The current work was conducted to compare model-predicted estimates of tissue dosimetry to additional kinetic information from the (C57Bl/6 x CBA)F1 and TgAc mouse. The results from the current modeling indicate that the pharmacokinetic parameters derived based on information in the B6C3F1 mouse adequately describe the measured concentrations in the blood/plasma, liver, and urine of both the (C57Bl/6 x CBA)F1 and TgAc mouse, providing further support that the differences in response observed in the chronic bioassays are not related to strain-specific differences in pharmacokinetics. One significant finding was that no increases in skin or lung concentrations of arsenic species in the (C57Bl/6 x CBA)F1 strain were observed following administration of low concentrations (0.2 or 2 mg/L) of arsenate in the drinking water, even though differences in response in the skin were reported. These data suggest that pharmacodynamic changes may be observed following exposure to arsenic compounds without an observable change in tissue dosimetry. These results provided further indirect support for the existence of inducible arsenic efflux in these tissues. <br /

A tissue dose-based comparative exposure assessment of manganese using physiologically based pharmacokinetic modeling-The importance of homeostatic control for an essential metal.

A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue manganese (Mn) concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates. Mn exposure was determined based on measured ambient air Mn concentrations and dietary data in Canada and the United States (US). Incorporating dietary and inhalation exposures into the models indicated that increases in target tissue concentrations above endogenous levels only begin to occur when humans are exposed to levels of Mn in ambient air (i.e. >10μg/m) that are far higher than those currently measured in Canada or the US. A MOS greater than three orders of magnitude was observed, indicating that current Mn air concentrations are far below concentrations that would be required to produce the target tissue Mn concentrations associated with subclinical neurological effects. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to "convert" an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, is not appropriate in the case of Mn. PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls

Risk assessments for chronic exposure of children and prospective parents to ethylbenzene (CAS No. 100-41-4)

<div><p>Potential chronic health risks for children and prospective parents exposed to ethylbenzene were evaluated in response to the Voluntary Children's Chemical Evaluation Program. Ethylbenzene exposure was found to be predominately via inhalation with recent data demonstrating continuing decreases in releases and both outdoor and indoor concentrations over the past several decades. The proportion of ethylbenzene in ambient air that is attributable to the ethylbenzene/styrene chain of commerce appears to be relatively very small, less than 0.1% based on recent relative emission estimates. Toxicity reference values were derived from the available data, with physiologically based pharmacokinetic models and benchmark dose methods used to assess dose–response relationships. An inhalation non-cancer reference concentration or RfC of 0.3 parts per million (ppm) was derived based on ototoxicity. Similarly, an oral non-cancer reference dose or RfD of 0.5 mg/kg body weight/day was derived based on liver effects. For the cancer assessment, emphasis was placed upon mode of action information. Three of four rodent tumor types were determined not to be relevant to human health. A cancer reference value of 0.48 ppm was derived based on mouse lung tumors. The risk characterization for ethylbenzene indicated that even the most highly exposed children and prospective parents are not at risk for non-cancer or cancer effects of ethylbenzene.</p></div

Considerations for refining the risk assessment process for formaldehyde: results from an interdisciplinary workshop

Anticipating the need to evaluate and integrate scientific evidence to inform new risk assessments or to update existing risk assessments, the Formaldehyde Panel of the American Chemistry Council (ACC), in collaboration with the University of North Carolina, convened a workshop: “Understanding Potential Human Health Cancer Risk - From Data Integration to Risk Evaluation” in October 2017. Twenty-four (24)invited-experts participated with expertise in epidemiology, toxicology, science integration and risk evaluation. Including members of the organizing committee, there were 29 participants. The meeting included eleven presentations encompassing an introduction and three sessions: (1)“integrating the formaldehyde science on nasal/nasopharyngeal carcinogenicity and potential for causality”; (2)“integrating the formaldehyde science on lymphohematopoietic cancer and potential for causality; and, (3)“formaldehyde research-data suitable for risk assessment”. Here we describe key points from the presentations on epidemiology, toxicology and mechanistic studies that should inform decisions about the potential carcinogenicity of formaldehyde in humans and the discussions about approaches for structuring an integrated, comprehensive risk assessment for formaldehyde. We also note challenges expected when attempting to reconcile divergent results observed from research conducted within and across different scientific disciplines - especially toxicology and epidemiology - and in integrating diverse, multi-disciplinary mechanistic evidence.</p