A long-term follow-up study was carried out to assess ototoxicity in children who had been treated for a malignant tumour with "standard dose" cisplatin (60-100 mg/m2 per course), and were at least 2 years from stopping treatment. The median age at diagnosis was 2 years 2 months (range 1 month to 13.5 years). On the basis of hearing assessment by pure-tone audiometry, a practical grading system of hearing loss from 0 to 4 is proposed. Moderate to severe high-frequency hearing loss (grade 2-4) was found in half the children and 10 require appropriate hearing aids. The risk of developing ototoxicity increased significantly with the cumulative cisplatin dose (P = 0.027), although there was considerable individual susceptibility. Serial follow-up testing, to a median of 4 years after completion of cisplatin treatment, showed no recovery of hearing in any of these children. We suggest careful monitoring of young children by a consultant audiological physician throughout treatment with cisplatin, particularly when doses of 400 mg/m2 and over have been reached. Alternative chemotherapy should be discussed if grade 2 ototoxicity develops.

No abstract

Chronic exposure to manganese (Mn) produces a spectrum of cognitive and behavioral deficits associated with a neurodegenerative disorder resembling Parkinson's disease. The effects of high-dose exposure to Mn in occupational cohorts and in adult rodent models of the disease are well described but much less is known about the behavioral and neurochemical effects of Mn in the developing brain. We therefore exposed C57Bl/6 mice to Mn by intragastric gavage as juveniles, adults, or both, postulating that mice exposed as juveniles and then again as adults would exhibit greater neurological and neurochemical dysfunction than mice not preexposed as juveniles. Age- and sex-dependent vulnerability to changes in locomotor function was detected, with juvenile male mice displaying the greatest sensitivity, characterized by a selective increase in novelty-seeking and hyperactive behaviors. Adult male mice preexposed as juveniles had a decrease in total movement and novelty-seeking behavior, and no behavioral changes were detected in female mice. Striatal dopamine levels were increased in juvenile mice but were decreased in adult preexposed as juveniles. Levels of Mn, Fe, and Cu were determined by inductively coupled plasma-mass spectrometry, with the greatest accumulation of Mn detected in juvenile mice in the striatum, substantia nigra (SN), and cortex. Only modest changes in Fe and Cu were detected in Mn-treated mice, primarily in the SN. These results reveal that developing mice are more sensitive to Mn than adult animals and that Mn exposure during development enhances behavioral and neurochemical dysfunction relative to adult animals without juvenile exposure.