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As part of the Stage III Pig-a multilaboratory validation trial, we examined the induction of CD59-negative reticulocytes and total red blood cells (RET(CD59-) and RBC(CD59-) , respectively) in male Sprague Dawley(®) rats treated with 4-nitroquinoline-1-oxide (4NQO), for 28 consecutive days by oral gavage, at doses of 1.25, 2.50, 3.75, 5.00, and 7.50 mg kg(-1) day(-1) (the high dose group was sacrificed on Day 15 due to excessive morbidity/mortality). Animals also were evaluated for: micronucleated reticulocytes (mnRET) by flow cytometry; DNA damage in peripheral blood, liver, and stomach using the Comet assay; and chromosome aberrations (CAb) in peripheral blood lymphocytes (PBL). All endpoints were analyzed at two or more timepoints where possible. Mortality, body and organ weights, food consumption, and clinical pathology also were evaluated, and demonstrated that the maximum tolerated dose was achieved at 5.00 mg kg(-1) day(-1) . The largest increases observed for the genetic toxicology endpoints (fold-increase compared to control, where significant; all at 5.00 mg kg(-1) day(-1) on Day 29) were: RET(CD59-) (21X), RBC(CD59-) (9.0X), and mnRET (2.0X). In contrast, no significant increases were observed for the CAb or Comet response, in any tissue analyzed, at any timepoint. Because 4NQO is a well known mutagen, clastogen, and carcinogen, the lack of response for these latter endpoints was unexpected. These results emphasize the extreme care that must betaken in dose and endpoint selection when incorporating genotoxicity endpoints into routine toxicity studies as has been recommended or is under consideration by various regulatory and industrial bodies.

No abstract

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...