Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals

Mortelmans, Kristien; Haworth, Steve; Lawlor, Timothy E.; Speck, William T.; Tainer, Beth; Zeiger, Errol

doi:10.1002/em.2860080803

Cited by 75 publications

(75 citation statements)

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“…Our findings are consistent with the accumulating evidence that MPH does not induce genetic damage in vitro or in vivo (Mortelmans et al, 1986; Teo et al, 2003; Suter et al, 2006, Walitza et al, 2007; Manganatha et al, 2008; Witt et al, 2008b; Walitza et al, 2009; Morris et al, 2009). …”

Section: Discussionsupporting

confidence: 93%

“…Exposure to MPH is widespread, with annual prescriptions in the United States alone exceeding five million. The overall safety profile of MPH has been favorable (Biederman et al, 2006), and in terms of its genotoxicity, results from a variety of standard genetic toxicity assays have provided little evidence that treatment with MPH poses a hazard (Mortelmans et al, 1986; NTP, 1995; Teo et al, 2003; Suter et al, 2006). In 2005, however, a report of chromosomal damage in ADHD children following 3 months of treatment with MPH (El Zein et al, 2005) prompted a number of follow-up studies designed to clarify the genotoxic potential of MPH in humans (Suter et al 2006; Walitza et al, 2007; Manjanatha et al, 2008; Witt et al, 2008b; Walitza et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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No increases in biomarkers of genetic damage or pathological changes in heart and brain tissues in male rats administered methylphenidate hydrochloride (Ritalin) for 28 days

Witt

Malarkey

Hobbs

et al. 2009

Environ and Mol Mutagen

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Following a 2005 report of chromosomal damage in children with attention deficit/hyperactivity disorder (ADHD) who were treated with the commonly prescribed medication methylphenidate (MPH), numerous studies have been conducted to clarify the risk for MPH-induced genetic damage. Although most of these studies reported no changes in genetic damage endpoints associated with exposure to MPH, one recent study (Andreazza et al. 2007) reported an increase in DNA damage detected by the Comet assay in blood and brain cells of Wistar rats treated by intraperitoneal injection with 1, 2, or 10 mg/kg MPH; no increases in micronucleated lymphocyte frequencies were observed in these rats. To clarify these findings, we treated adult male Wistar Han rats with 0, 2, 10, or 25 mg/kg MPH by gavage once daily for 28 consecutive days and measured micronucleated reticulocyte (MN-RET) frequencies in blood, and DNA damage in blood, brain, and liver cells 4 hr after final dosing. Flow cytometric evaluation of blood revealed no significant increases in MN-RET. Comet assay evaluations of blood leukocytes and cells of the liver, as well as of the striatum, hippocampus, and frontal cortex of the brain showed no increases in DNA damage in MPH-treated rats in any of the three treatment groups. Thus, the previously reported observations of DNA damage in blood and brain tissue of rats exposed to MPH for 28 days were not confirmed in this study. Additionally, no histopathological changes in brain or heart, or elevated serum biomarkers of cardiac injury were observed in these MPH-exposed rats.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

No increases in biomarkers of genetic damage or pathological changes in heart and brain tissues in male rats administered methylphenidate hydrochloride (Ritalin) for 28 days

Witt

Malarkey

Hobbs

et al. 2009

Environ and Mol Mutagen

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“…Genotoxicity tests with furan have given mixed results, with many studies providing negative data [2,20,23–26]. However, furan exposure is associated with unique Hras1 mutations in liver tumors [27,28], strengthening support for at least a partial genotoxic mechanism for furan’s carcinogenic properties.…”

Section: Introductionmentioning

confidence: 99%

“…However, the chemical reactivity of BDA complicates the proposed link between furan metabolism and a genotoxic event in the cell. In many test systems, furan was activated extracellularly [2,23]. Given the reactivity of BDA with protein nucleophiles, it is possible that insufficient quantities of the metabolite generated extracellularly were able to reach nuclear DNA to form mutagenic adducts.…”

Section: Introductionmentioning

confidence: 99%

Mutagenicity of furan in female Big Blue B6C3F1 mice

Terrell

Huynh

Grill

et al. 2014

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Furan is an abundant food and environmental contaminant that is a potent liver carcinogen in rodent models. To determine if furan is genotoxic in vivo, female B6C3F1 Big Blue transgenic mice were treated with 15 mg/kg bw furan by gavage 5 days a week for 6 weeks, or once weekly for 3 weeks. Liver cII trans-gene mutation-frequency and mutation spectra were determined. Furan did not increase the mutation frequency under either treatment condition. In the 6-week treatment regimen, there was a change in the cII transgene mutation-spectrum, with the fraction of GC to AT transitions significantly reduced. The only other significant change was an increase in GC to CG transversions; these represented a minor contribution to the overall mutation spectrum. A much larger furan-dependent shift was observed in the 3-week study. There was a significant increase in transversion mutations, predominantly GC to TA transversions as well as smaller non-significant changes in GC to CG and AT to TA transversions. To determine if these mutations were caused by cis-2-butene-1,4-dial (BDA), a reactive metabolite of furan, the mutagenic activity and the mutation spectrum of BDA was determined in vitro, in Big Blue mouse embryonic fibroblasts. This compound did not increase the cII gene mutation-frequency but caused a substantial increase in AT to CG transversions. This increase, however, lost statistical significance when adjusted for multiple comparisons. Together, these findings suggest that BDA may not be directly responsible for the in-vivo effects of furan on mutational spectra. Histopathological analysis of livers from furan-treated mice revealed that furan induced multifocal, hepatocellular necrosis admixed with reactive leukocytes and pigment-laden Kupffer cells, enhanced oval-cell hyperplasia, and increased hepatocyte mitoses, some of which were atypical. An indirect mechanism of genotoxicity is proposed in which chronic toxicity followed by inflammation and secondary cell proliferation triggers cancer development in furan-exposed rodents.

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“…In responding to these points, El-Zein et al16 emphasized that their pilot study required replication and expansion to more conclusively define the genotoxic potential of MPH in humans. The reported observations of cytogenetic damage in children were unexpected because, before the El-Zein et al12 report, there had been no clear evidence for MPH-induced genetic damage in standard mutation and chromosome damage studies conducted in bacterial and animal test systems in vitro or in vivo 17–20. More recent studies, prompted by the El-Zein et al12 report, have shown no evidence for MPH-induced CA in human lymphocytes in vitro or MN in mouse erythrocytes after a single 250 mg/kg oral dose of MPH 21.…”

mentioning

confidence: 99%

Methylphenidate and Amphetamine Do Not Induce Cytogenetic Damage in Lymphocytes of Children With ADHD

Witt

Shelby

Itchon-Ramos

et al. 2008

Journal of the American Academy of Child & Adolescent Psych

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Objective-In response to previously published findings of methylphenidate-induced chromosomal changes in children, this study was designed to determine whether methylphenidateor amphetamine-based drugs induce chromosomal damage (structural aberrations, micronuclei, and sister chromatid exchanges) in peripheral blood lymphocytes of children with attention-deficit/ hyperactivity disorder after 3 months of continuous treatment.Method-Stimulant drug-naïve subjects, 6 to 12 years of age, in good overall health, and judged to be appropriate candidates for stimulant therapy based on rigorously diagnosed ADHD using DSM-IV criteria, were randomized into two open-label treatment groups (methylphenidate or mixed amphetamine salts). Each subject provided a blood sample before initiation of treatment and after 3 months of treatment. Pretreatment and posttreatment frequencies of chromosomal aberrations, micronuclei, and sister chromatid exchanges were determined for each subject.Results-Sixty-three subjects enrolled in the study; 47 subjects completed the full 3 months of treatment, 25 in the methylphenidate group and 22 in the amphetamine group. No significant treatment-related increases were observed in any of the three measures of cytogenetic damage in the 47 subjects who completed treatment or the 16 subjects who did not. Conclusions-Earlier findings of methylphenidate-induced chromosomal changes in childrenwere not replicated in this study. These results add to the accumulating evidence that therapeutic levels of methylphenidate do not induce cytogenetic damage in humans. Furthermore, our results indicate that amphetamine-based products do not pose a risk for cytogenetic damage in children. Although the use of these products has been associated with a number of manageable adverse effects (appetite suppression, insomnia, nervousness, headache, and dry mouth) and concern has been raised over potential adverse cardiovascular effects, their overall safety profiles are good. [7][8][9][10][11] However, the safety of MPH was abruptly challenged in 2005 by a report of increased frequencies of sister chromatid exchanges (SCE; indicative of DNA damage), structural chromosomal aberrations (CA), and micronuclei (MN; biomarkers of numerical and structural chromosomal changes) in lymphocytes of 12 pediatric patients with ADHD after 3 months of MPH-based drug therapy. 12 That study raised concern among members of the medical community and families of children with ADHD receiving MPH-based therapy because increased frequencies of CAs and micronuclei in peripheral blood lymphocytes are associated with an increased risk of cancer. 13,14 However, questions were raised regarding the study design and some of the reported findings, including the small sample size (12 children), a lack of critical details on blood sample processing and slide scoring, and the complete absence of SCE recorded in 6 of the 11 children analyzed for this endpoint. 15 The absence of SCE was especially troubling because such an observation has never been repor...

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Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals

Cited by 75 publications

References 0 publications

No increases in biomarkers of genetic damage or pathological changes in heart and brain tissues in male rats administered methylphenidate hydrochloride (Ritalin) for 28 days

No increases in biomarkers of genetic damage or pathological changes in heart and brain tissues in male rats administered methylphenidate hydrochloride (Ritalin) for 28 days

Mutagenicity of furan in female Big Blue B6C3F1 mice

Methylphenidate and Amphetamine Do Not Induce Cytogenetic Damage in Lymphocytes of Children With ADHD

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