Investigation of the DNA Adducts Formed in B6C3F1 Mice Treated with Benzene: Implications for Molecular Dosimetry

Bodell, William J.; Pathak, Deena N.; Lévay, György; Ye, Qiuping; Pongracz, Krisztina

doi:10.2307/3433162

Cited by 8 publications

(8 citation statements)

References 21 publications

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“…Benzene yielded mixed results in genotoxicity test systems (International Agency for Research on Cancer, 2000b), with the exception of bone marrow. DNA binding was either absent or extremely low in several tissues in rats (Reddy et al, 1989), although binding was reported under extreme conditions (twice-daily treatment for 1 to 7 days with 440 mg/kg benzene) (Bodell et al, 1996). A scheme for the biotransformation of benzene based upon (Snyder and Hedli, 1996) is shown in Figure 19.…”

Section: Human Effects Of Rodent Nasal Cytotoxinsmentioning

confidence: 99%

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

2006

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Toxicity and carcinogenicity in the mucosa of the nasal passages in rodents has been produced by a variety of organic chemicals which are systemically distributed. In this review, 14 such chemicals or classes were identified that produced rodent nasal cytotoxicity, but not carcinogenicity, and 11 were identified that produced nasal carcinogenicity. Most chemicals that affect the nasal mucosa were either concentrated in that tissue or readily activated there, or both. All chemicals with effects in the nasal mucosa that were DNA-reactive, were also carcinogenic, if adequately tested. None of the rodent nasal cytotoxins has been identified as a human systemic nasal toxin. This may reflect the lesser biotransformation activity of human nasal mucosa compared to rodent and the much lower levels of human exposures. None of the rodent carcinogens lacking DNA reactivity has been identified as a nasal carcinogen or other cancer hazard to humans. Some DNA-reactive rodent carcinogens that affect the nasal mucosa, as well as other tissues, have been associated with cancer at various sites in humans, but not the nasal cavity. Thus, findings in only the rodent nasal mucosa do not necessarily predict either a toxic or carcinogenic hazard to that tissue in humans.

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Section: Human Effects Of Rodent Nasal Cytotoxinsmentioning

confidence: 99%

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

2006

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“…39 Through their inhibitory action on topoisomerase II, binding to other DNA-associated proteins and formation of DNA adducts, phenol and hydroquinone cause double-strand breaks and chromosome breakage. 40,41 This has been shown in vitro to lead to deletions and translocations commonly found in leukemia, including del(5q) and del(7q). 38 Again, workers exposed to benzene have been shown to have higher levels of del(5q), del(7q) and translocation (8;21) in their blood cells.…”

Section: Figurementioning

confidence: 99%

Hypothesis: Phenol and hydroquinone derived mainly from diet and gastrointestinal flora activity are causal factors in leukemia

et al. 2001

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High background levels of phenol and hydroquinone are present in the blood and urine of virtually all individuals, but vary widely. Phenol and hydroquinone have been strongly implicated in producing leukemia associated with benzene exposure, because they reproduce the hematotoxicity of benzene, cause DNA and chromosomal damage found in leukemia, inhibit topoisomerase II, and alter hematopoiesis and clonal selection. The widely varying background levels of phenol and hydroquinone in control individuals stem mainly from direct dietary ingestion, catabolism of tyrosine and other substrates by gut bacteria, ingestion of arbutin-containing foods, cigarette smoking, and the use of some over-the-counter medicines. We hypothesize that these background sources of phenol and hydroquinone and associated adducts play a causal role in producing some forms of de novo leukemia in the general population. This hypothesis is consistent with recent epidemiological findings associating leukemia with diets rich in meat and protein, the use of antibiotics (which change gastrointestinal flora make-up), lack of breastfeeding, and low activity of NAD(P)H quinone oxidoreductase which detoxifies quinones derived from phenol and hydroquinone and protects against benzene hematotoxicity. An attractive feature of our hypothesis is that it may explain why many people who have no known occupational exposures or significant smoking history develop leukemia. The hypothesis predicts that susceptibility to the disease would be related to diet, medicinal intake, genetics and gut-flora composition. The latter two of these are largely beyond our control, and thus dietary modification and reduced use of medicines that elevate phenol levels may be the best intervention strategies for lowering leukemia risk. Leukemia (2001) 15, 10-20.

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“…DNA damage, formation of DNA adducts, chromosomal aberrations such as aneuploidy, increased formation of micronuclei and sister chromatid exchanges) of benzene and its metabolites (namely HQ, 1,4-BQ, 1,2,4-BT and catechol) is the most reported key event observed in the identified in vitro studies Bodell et al, 1996;Chung et al, 2002;Hedli et al, 1996;Ishihama et al, 2008;Levay & Bodell, 1992;Levay et al, 1993;Lindsey et al, 2005;Lindsey et al, 2004;Mondrala & Eastmond, 2010;Oikawa et al, 2001;Pandey et al, 2009;Pasquini et al, 2003;Thys et al, 2015;Winn, 2003;Zhang et al, 1993;Zhang et al, 1994;Zhang et al, 1998). Then it is followed by oxidative stress as an early key event associated with benzene and its metabolites (Badham & Winn, 2010a;Goldman et al, 1999;Ishihama et al, 2008;Kolachana et al, 1993;Li & Trush, 1993;Nishikawa et al, 2012;Oikawa et al, 2001;Ruiz-Ramos et al, 2005;Wan & Winn, 2007;Wiemels & Smith, 1999;Zhang et al, 1993).…”

Section: Supporting Publications 2016: En-955 129mentioning

confidence: 99%

“…not immortalised) cells Bodell et al, 1996;Chung et al, 2002;Irons et al, 1992;Levay et al, 1993;Thys et al, 2015;Zhang et al, 1998).…”

Section: Supporting Publications 2016: En-955 129mentioning

confidence: 99%

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

Choi¹,

Polcher²,

Joas³

2016

EFSA Supporting Publications

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This report presents the outcomes of a systematic review (SR) identifying the mechanisms and chemicals involved in the pathogenesis of Parkinson's disease (PD) and childhood leukaemia (CL). This work serves as a basis for defining and mapping the causal linkages between a molecular initiating event (MIE) and a final adverse outcome (AO) that are relevant for the development of a prototype adverse outcome pathway (AOP) for assessing risk factors for PD and CL. Search for literature from 1990 to present was conducted using Web of Science, PubMed and TOXNET, and relevant references were selected using established inclusion/exclusion criteria and ranked using a set of quality control factors.For PD, 7,384 individual references were identified to be relevant for PD pathogenesis and chemicals associated with PD. Dopaminergic neurodegeneration in the substantia nigra leading to locomotor deficits was identified as the AO in PD. Other identified key events in PD pathogenesis include mitochondrial dysfunction, cellular accumulation of alpha-synuclein and oxidative stress. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone and paraquat are some chemicals identified to be associated with PD pathogenesis.For CL, 1,988 individual references were identified to be relevant for CL pathogenesis and chemicals associated with CL. Chromosomal translocation, genetic damage/mutation and hyperdiploidy are considered as driving forces of CL. Except for infant leukaemia, CL pathogenesis requires a 'two-hit' model with an initiating event occurring in utero followed by a secondary hit potentially occurring after birth. Potential MIEs leading to these driving mechanisms include aberrant DNA topoisomerase II activity and erroneous DNA repair. Epigenetics appears to also play an influential role in CL pathogenesis. Benzene, bioflavonoids and organophosphates are some chemicals identified to be implicated in CL pathogenesis.The challenges of developing AOPs for these two diseases and the data gaps identified from the outcomes of this SR are also elaborated in this report. The present document has been produced and adopted by the bodies identified above as authors. This task has been carried out exclusively by the authors in the context of a contract between the European Food Safety Authority and the authors, awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors. KEY WORDSSystematic Review, Parkinson Disease, Childhood Leukaemia, Pathogenesis, Chemicals, Pesticides, Adverse Outcome Pathway SUMMARYThe aim of this project was to perform a systematic review (SR) to collect relevant publications related to the mechanisms involved in the pathogenesis of Parkinson's disease (PD)...

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Investigation of the DNA Adducts Formed in B6C3F1 Mice Treated with Benzene: Implications for Molecular Dosimetry

Cited by 8 publications

References 21 publications

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

Hypothesis: Phenol and hydroquinone derived mainly from diet and gastrointestinal flora activity are causal factors in leukemia

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

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