MALIGNANT MELANOMA IN CHILDREN

Background. While significant risk factors for malignant melanoma may initially develop or are first seen in childhood, the actual occurrence of this neoplasm in prepubertal children is uncommon. Methods. A retrospective study of malignant melanoma in Puerto Ricans up to 16 years of age occurring from 1973 to 1990 was carried out by identifying those cases in the Puerto Rico Cancer Registry. Results. A total of seven cases were found consisting of three boys and four girls with ages ranging from 22 months to 16 years and comprising 0.94% of the total melanomas. In three of the seven cases, there was a history of a previously existent small congenital melanocytic nevus on the area. Three cases were Clark's level I, two level II, and in two cases with proved metastatic disease, Clark's level of invasion were not reported. Those cases with Clark's level I and II had a 100% 5-year survival. Conclusions. Although rare, malignant melanoma in children can be as aggressive as in adults. Among the known factors predisposing to malignant melanoma, three out of seven cases developed within a small congenital nevus, two of which occurred during the first decade of life. Due to the rarity of this event in our population, it appears unreasonable to excise all small congenital nevi during the first decade of life. Even for those who advocate excision of all small congenital nevi, the evidence at present suggests that such small nevi very rarely undergo malignant change before puberty and therefore a policy of observation in childhood and offering excision around the time of puberty is perfectly logical.     

A Multicenter Experience with a Bipolar Tined Polyurethane Ventricular Lead

A multicenter study was undertaken to determine the failure rate of a specific polyurethane bipolar tined pacing lead, the Medtronic 4012 pacing lead. Six centers in the United States and Canada implanted 1,190 Medtronic 4012 pacing leads. The study was designed to determine the probability and clinical manifestations of lead failure. Only failures compatible with an insulation problem were included. The probability of a 4012 lead failure by Kaplan-Meier analysis was 20.9% at 6 years after implantation. Failures were manifested as sensing abnormalities, failure to capture, early battery depletion, and significant decrease in measured impedance compared with the previous impedance measurements. Of the 95 definite lead failures, 16 (16.8%) were associated with symptoms similar to those experienced before pacemaker placement. The observed failure rate is unacceptable, and strong consideration should be given to replacing the 4012 pacing lead in pacemaker-dependent patients and closely monitoring nondependent patients.     

A 90-Day Chloroform Inhalation Study in Female and Male B6C3F1 Mice: Implications for Cancer Risk Assessment

High doses of chloroform induced liver cancer in male and femaleB6C3F₁ mice when administered by gavage, kidney cancer in maleOsborne-Mendel rats when given by gavage or in the drinkingwater, and kidney cancer in male BDF₁ mice when administeredby inhalation. The weight of evidence indicates that chloroformis acting through a nongenotoxic-cytotoxic mode of action. Thepresent study was designed to investigate the dose-responserelationships for chloroform-induced lesions and regenerativecell proliferation in B6C3F₁ mice as the basis for formulationof a biologically based risk assessment for inhaled chloroform.Different groups of female and male B6C3F₁ mice were exposedto atmospheric concentrations of 0, 0.3, 2, 10, 30, and 90 ppmchloroform 6 hr/day, 7 days/week for exposure periods of 4 daysor 3, 6, or 13 consecutive weeks. Some additional exposure groupswere exposed for 5 days/week for 13 weeks or were exposed for6 weeks and then examined at 13 weeks. Bromodeoxyuridine wasadministered via osmotic pumps implanted 3.5 days prior to necropsy,and the labeling index (LI, percentage of nuclei in S-phase)was evaluated iminunohistochemically from histological sections.Complete necropsy and microscopic evaluation revealed treatment-induceddose- and time-dependent lesions only in the livers and nasalpassages of the female and male mice and in the kidneys of themale mice. Large, sustained increases in the liver LI were seenin the 90-ppm groups at all time points. The female mice weremost sensitive, with a no-observed-adverse-effect level (NOAEL)for induced hepatic cell proliferation of 10 ppm. The hepaticLI in the 5 days/week groups were about half of those seen inthe 7 days/week groups and had returned to the normal baselinein the 6-week recovery groups. Induced renal histologic changesand regenerative cell proliferation were seen in the male miceat 30 and 90 ppm with 7 days/week exposures and also at 10 ppmwith the 5 days/week regimen. Nasal lesions were transient andconfined to mice exposed to 10, 30, or 90 ppm for 4 days. Ina previous cancer bioassay, a gavage dose of 477 mg/kg/day produced a 95% liver tumor incidence in female B6C3F₁ mice. Thisgavage dose is equivalent to a daily 6 hr/day inhalation exposureof approximately 80 ppm, based on the observed induced increasesin the LI as an internal dosimeter. The United States EnviromnentalProtection Agency currently uses the linearized multistage modelapplied to the mouse liver tumor data from the chloroform gavagestudy to estimate a virtually safe dose (VSD) as a one in amillion increased lifetime risk of cancer. The resulting valueis an airborne exposure concentration of 0.000008 ppm. Assumingthat chloroform-induced female mouse liver cancer is secondaryto events associated with necrosis and regenerative cell proliferation,then no increases in liver cancer in female mice would be predictedat the NOAEL of 10 ppm or below based on the results reportedhere. Applying an uncertainty factor of 1000 yields an estimateof a VSD at 0.01 ppm. This estimate relies on inhalation dataand is more consistent with the mode of action of chloroform.     

Developmental Exposure to Aroclor 1254 Produces Low-Frequency Alterations in Adult Rat Brainstem Auditory Evoked Responses

Developmental exposure of Long—Evans rats to 0, 1, 4,or 8 mg/kg/day Aroclor 1254 (A1254) from Gestational Day 6 throughPostnatal Day 21 produces an elevated behavioral threshold fora 1-kHz tone. Brahistem auditory evoked responses (BAERs) wereassessed in a subset of these animals (about 1 year old) usingfiltered clicks at 1 (65 and 80 dB SPL), 4 (60 and 80 dB SPL),16 (40 and 80 dB SPL), and 32 (40 and 80 dB SPL) kHz. Aroclor1254 decreased BAER amplitudes at 1 and 4 kHz, but not at 16or 32 kHz. A dose-related decrease in the baseline-to-peak P_1Aamplitude was observed for the 1-kHz (80-dB) stimulus. Dosesof 1, 4, or 8 mg/kg/day A1254 decreased the peak-to-peak amplitudeof both P_1AN₁ and P_1BN₁ for a 1-kHz (80-dB) stimulus. Dosesof 4 and 8 mg/kg/day A1254 decreased the peak-to-peak amplitudeof N₁P₂ and P₂N₂ for a 4-kHz (60-dB) or 1-kHz (80-dB) stimulus.At 8 mg/kg/day, A1254 also increased the latency of peak P₄at 1 kHz (65 dB). The decreases in peak P_1A amplitudes are consistentwith a dysfunction of the cochlea and/or auditory nerve. Together,the data confirm that developmental exposure of rats to A1254produces a permanent low- to mid-frequency auditory dysfunctionand suggest a cochlear and/or auditory nerve site of action.     

How useful are verbal autopsies to estimate childhood causes of death?

Verbal autopsies (VAs) are widely used to describe causes ofdeath in individuals who die outside hospital or clinic settings.However, they have received surprisingly little validation.The technique assumes that diseases which cause death can bereadily distinguished from one another by distinct syndromes,and that these can be reported accurately by lay respondents.This paper describes the potential problems of syndrome definitionand the likely biases introduced through poor recognition andrecall by bereaved relatives; how these may be tested; and finally,what can be done where the VA proves unable to identify causeof death.     

Histopathology of Acute Toxic Response in Rats and Mice Exposed to Methyl Chloride by Inhalation

Histopathology of Acute Toxic Response in Rats and Mice Exposedto Methyl Chloride by Inhalation. Morgan, K.T., Swenberg, J.A.,Hamm, T.E., Jr., Wolkowski-Tyl, R. and Phelps, M. (1982). Fundam.Appl. Toxicol. 2:293-299. Both sexes of one strain of rat (F344),two strains of mice (C3H and C57BL/6) and the cross (B6C3F1)of these 2 strains of mice were exposed by inhalation to methylchloride for 6 hours per day for up to 12 days. Methyl chlorideconcentrations in air were 0, 500, 1000, or 2000 ppm for mice,and 0, 2000, 3500 or 5000 ppm for rats. All male B6C3F1 miceexposed to 2000 ppm were dead or moribund by day 2, and allmale and female mice in the remaining 2000 ppm groups were moribundby day 5. Prior to death many of these mice exhibited ataxia,and hematuria with the latter occurring mainly in females. Treatmentassociated lesions in mice included hepatocellular degenerationand necrosis, degeneration and necrosis of proximal convolutedtubules and/or basophilic tubules in the renal cortex, and focalareas of necrosis of the internal granular layer of the cerebellum.Brain lesions were most severe in female C57BL/6 mice, whilehepatocellular degeneration was most severe in male C57BL/6and B6C3F1 strains. Approximately 50% of the male and femalerats exposed to 5000 ppm were killed in extremis on day 5. Theprincipal clinical signs, which were confined to the 5000 and3500 ppm groups, included severe diarrhea, incoordination ofthe fore-limbs, and in a small number of animals, hind limbparalysis and convulsions. In rats, lesions were observed inthe liver, kidney and brain which resembled those seen in micebut were generally less severe. Lesions observed in tissuesexamined only in rats included vacuolar degeneration of thezona fasciculata of the adrenal glands and degenerative changesin the seminiferous tubules and epididymis. Rats appeared torespond in a similar manner to mice but were more resistantto methyl chloride toxicity. These findings demonstrate species,strain and sex differences in susceptibility to methyl chloride.