Derivation of noncancer reference values for acrylonitrile.

Dose-response assessments were conducted for the noncancer effects of acrylonitrile (AN) for the purposes of deriving subchronic and chronic oral reference dose (RfD) and inhalation reference concentration (RfC) values. Based upon an evaluation of available toxicity data, the irritation and neurological effects of AN were determined to be appropriate bases for deriving reference values. A PBPK model, which describes the toxicokinetics of AN and its metabolite 2-cyanoethylene oxide (CEO) in both rats and humans, was used to assess the dose-response data in terms of an internal dose measure for the oral RfD values, but could not be used in deriving the inhalation RfC values. Benchmark dose (BMD) methods were used to derive all reference values. Where sufficient information was available, data-derived uncertainty factors were applied to the points of departure determined by BMD methods. From this assessment, subchronic and chronic oral RfD values of 0.5 and 0.05 mg/kg/day, respectively, were derived. Similarly, subchronic and chronic inhalation RfC values of 0.1 and 0.06 mg/m(3), respectively, were derived. Confidence in the reference values derived for AN was considered to be medium to high, based upon a consideration of the confidence in the key studies, the toxicity database, dosimetry, and dose-response modeling.

Neurochemical alterations induced by manganese chloride in neonatal rats.

Male rats were exposed to manganese at doses of 1, 10, and 20 microg/g body weight/day from birth to day 24 post-partum. Animals were weighed and examined daily. The animals showed no visible signs of toxicity and exhibited normal weight gain. On day 25 the animals were killed by decapitation and the hypothalamic area and corpus striatum were removed and analyzed for several neurochemical components. Chronic manganese administration (10 and 20 microg/g) caused a significant reduction in the concentration of endogenous dopamine in the hypothalamic area. The concentration of endogenous norepinephrine in the hypothalamic area was unaffected at all levels of manganese administration. The depletion of dopamine induced by alpha-methyl-p-tyrosine was less in the hypothalamic area of chronic manganese-treated rats suggesting that dopamine turnover was reduced. No significant changes in neurochemical components occurred in the corpus striatum. Manganese at a dose of 20 microg/g caused a significant decrease in hypothalamic tyrosine hydroxylase activity and a significant increase in hypothalamic monoamine oxidase activity. The dosing regimen of 10 and 20 microg/g caused a significant elevation in tissue levels of manganese in both the hypothalamic area and corpus striatum. The results of this study indicate that minor alterations in the manganese content of the developing rat brain can lead to neurochemical alterations in specific brain regions.

An investigation into the effects of manganese and other divalent cations on tyrosine hydroxylase activity.

The activity of tyrosine hydroxylase (TH) was measured in homogenates of hypothalamic tissue and corpus striatum obtained from 24 day old rats. The addition of manganese to the preparations had no direct effect on TH activity in either brain region. Similarly, the addition of calcium, magnesium and lead at concentrations of 1.0 mM did not affect TH activity. Cadmium and zinc (1.0 mM) significantly reduced TH activity in both the hypothalamic area and corpus striatum. Iron (1.0 mM) significantly stimulated TH activity in the corpus striatum but did not affect TH activity in the hypothalamic area. At conentrations of 1.0 mM, neither disodium ethylenediamine tetra-acetic acid (EDTA) nor ethylene glycol bis (beta-amino-ethyl ether)-N,N'-tetraacetic acid (ECTA) affected directly TH activity in either brain region. Cyclic adenosine 3',5'-monophosphate (cAMP) at a concentration of 1.0 mM did not affect TH activity in either the hypothalamic area or corpus striatum. Results from these in vitro studies show clearly that manganese does not inhibit directly TH activity and that manganese does not compete with other physiologically important divalent cations to cause the reduction in TH activity seen in vivo after chronic exposure.

Optimal technique to diagnose primary ciliary dyskinesia.

OBJECTIVE: To develop a cost-effective protocol for diagnosing primary ciliary dyskinesia (PCD). STUDY DESIGN: Retrospective chart review in a tertiary care academic medical center. METHODS: A review of the electron microscopy logbook identified all patients who had a suspected diagnosis of PCD. Biopsy of respiratory tract mucosa was performed using a cytology brush or a cup forceps in the outpatient clinic or operating room (OR). Outcome measures were to determine the diagnostic adequacy of cytological evaluation compared with tissue biopsy and to determine whether an adequate nasal mucosa sample can be collected in the outpatient clinic setting as compared with the OR and the use of general anesthesia RESULTS: Twenty-seven patients underwent 31 biopsies. Fifteen specimens were collected with a cup forceps, and 16 with a cytology brush. The sampling sites were nasal mucosa in 28 cases and trachea in the rest. Twelve specimens (39%) were collected in the clinic; the rest were obtained in the OR in conjunction with another procedure. Neither method of specimen collection nor mode of anesthesia made a significant difference in the probability of obtaining an adequate specimen. Ten samples were nondiagnostic: cytological evaluation, 31% (n = 16); tissue biopsy, 27% (n = 15); clinic, 42% (n = 12); and OR, 31% (n = 16). The cost of evaluating ciliary motion at our institution was $150, with an additional charge of $1,297 for electron microscopic evaluation. The nonprofessional fee for an outpatient nasal biopsy was $98; in the OR the cost of anesthesia supplies, surgical suite, recovery room, and day-surgery bed was at least $1,860. CONCLUSION: Our results suggest that the optimal method for diagnosis of PCD is in the outpatient clinic with specimen collection by means of either a cup forceps or a cytology brush.

Long-term airway sequelae in a pediatric burn population.

All admissions to the Shriner's Burn Institute in Galveston over a 5-year period were reviewed. One hundred of 1,092 patients admitted (9.2%) required airway support (endotracheal intubation or tracheostomy) for more than 24 hours. All clinical variables relating to general presentation and airway care were tabulated. Children who required open airway operations for resolution of acquired airway defects were analyzed separately. No predictive factors could be identified. Guidelines for optimal airway management in the burned child are reviewed.

Bronchoscopy and laryngoscopy findings as indications for tracheotomy in the burned child.

OBJECTIVE: To determine possible indications for tracheotomy in the burned child based on bronchoscopic and laryngoscopic findings. DESIGN AND SETTING: A retrospective case study of all patients admitted to a tertiary children's burn center. PARTICIPANTS: All children admitted with burn inhalation injury between 1990 and 1995 (n = 211). INTERVENTION: All patients underwent laryngoscopy and bronchoscopy and 19 underwent tracheotomy, with 5 tracheotomy tubes placed emergently. MAIN OUTCOME MEASURES: Observations during laryngoscopy and bronchoscopy included erythema, edema, carbonaceous material, ulcerations, and bronchial mucous casts. The supraglottis, glottis, and subglottis were analyzed separately, when possible. Any sepsis resulting from tracheotomy was determined. Complications, such as glottic webs, subglottic stenosis, and tracheomalacia, were noted. RESULTS: Indications for tracheotomy included 6 for airway obstruction, 6 for prolonged intubation, 6 for pulmonary cleansing, and 1 for endotracheal tube complications (subglottic stenosis). When examined by bronchoscopy and laryngoscopy, 17 of 19 children had significant airway edema, 10 had carbonaceous material in the airway, and 3 had ulcerations in the airway. CONCLUSIONS: Tracheotomy is indicated in the burned child when significant airway edema is present. Failure to place a tracheotomy tube in these cases leads to a high incidence of immediate tracheotomies (26%). There was no evidence of clinically significant infection attributable to tracheotomy. The number of airway complications due to tracheotomy was no higher than from endotracheal intubation.

Meta-analysis of pediatric tympanoplasty.

OBJECTIVE: To determine which preoperative conditions or surgical techniques may influence the success of tympanoplasty in the pediatric population. DATA SOURCES: A MEDLINE search of the English-language literature from 1966 to May 1997 was conducted using the search terms pediatric or child and tympanoplasty or myringoplasty. STUDY SELECTION: Articles that provided age-specific data on tympanoplasty or myringoplasty were included. Of the original 651 studies retrieved, 30 were accepted for inclusion. The principal reason for exclusion was inability to separate adult and pediatric results in series that combined both patient populations. DATA EXTRACTION: Success was defined as an intact tympanic membrane for the purpose of this review. Data were tabulated by consensus of 2 reviewers. DATA SYNTHESIS: The effect of surgical technique, prior adenoidectomy, presence of active infection, size of perforation, status of the contralateral ear, age, and eustachian tube function on healing of the tympanic membrane after surgery was assessed. Only those studies providing data on a given parameter of interest could be included when comparing each variable. Weighted means were compared and subjected to sensitivity analysis. Simple linear regression analysis was used to assess the effect of age on outcome. CONCLUSIONS: Greater success in healing of the tympanic membrane following tympanoplasty in children is seen with advancing age. None of the other parameters studied was shown to be a significant predictor of success. Guidelines for reporting results of tympanoplasty are presented.

Subchronic nose-only inhalation study of propylene glycol in Sprague-Dawley rats.

Groups of nineteen Sprague-Dawley rats of each sex were exposed by a nose-only inhalation to 0.0, 0.16, 1.0 or 2.2 mg propylene glycol/litre air, for 6 hr/day, 5 days/wk for 90 days. There were no significant differences in respiratory rates, minute volumes or tidal volumes between any of the groups during aerosol exposure. The uniformity of respiratory parameters between dose groups implied that the delivered doses were proportional to the exposure concentrations. The mean terminal body weights were not significantly different from controls for any group of male animals. The mean body weights of the females exposed to 2.2 mg/litre were significantly less than those of female controls from day 50 onwards. This effect, in female rats, was consistent with a decrease in feed consumption for the high-exposure female rats beginning on study day 43. Statistically significant differences between the treated and control groups in certain haematological parameters, serum enzyme activities, other serum chemistry parameters and organ weights did not show clear dose relationships. There was a significant increase in the number of goblet cells or an increase in the mucin content of the existing goblet cells in the nasal passages of the medium- and high-exposure animals. Exposure to the above concentrations of propylene glycol caused nasal haemorrhage and ocular discharge in a high proportion of animals, possibly as a result of dehydration of the nares and eyes.

Near-fatal complication of tracheal T-tube use.

Stenosis of the larynx and trachea is an unfortunate sequel to many thermal injuries. Numerous surgical techniques have been developed for correction of such problems, many involving use of a tracheal T-tube. We report a serious complication attributed to the use of such a tube. Factors contributing to this complication are analyzed and methods for avoiding similar near-catastrophes discussed.

Sandifer syndrome: a cause of torticollis in infancy.

A case of Sandifer syndrome is presented. It is similar to previously reported cases. The diagnosis may be overlooked if symptoms are mild. Neurologic disorders are often suspected. Infants or children with torticollis, dystonic posturing or atypical seizures should be evaluated for Sandifer syndrome, Exhaustive and expensive neurologic examinations may be unnecessary. Early diagnosis allows prompt treatment and resolution of the problem. Medical management is usually successful.

Popliteal pterygium syndrome.

A syndrome of popliteal pterygium, cleft lip-palate, lower lip pits, eyelid adhesions, genito-urinary anomalies and digital anomalies is presented as the Popliteal pterygium syndrome. The hereditary pattern appears to be an autosomal dominant trait with incomplete penetrance and variable expressivity. The pediatric otolaryngologist should be alert to this syndrome and will be consulted for airway and feeding problems as well as speech and hearing management. Because of the wide variability of expression of popliteal pterygium syndrome, careful physical evaluation of available family members should be made in sporadic cases to confirm the diagnosis in those presenting with minor manifestations and to discover less severely affected relatives of those full expression. Appropriate genetic counseling can then be given to these families.

Establishment of normal values of nasal choanal size in children: comparison of nasal choanal size in children with and without symptoms of nasal obstruction.

Twenty-eight pediatric patients between the ages of 2 and 13 years underwent intraoperative measurement of the nasal choanae using an instrument custom designed for this purpose by the Pilling Surgical Instrument Company. Additional data points recorded included age, surgical procedure, and the presence or absence of nasal obstructive symptoms which was determined by carefully questioning parents or guardians. Results were analyzed using linear regression, analysis of variance, and logistic regression. Data supported the following conclusions: (1) a linear relationship exists between age and average choanal size with the choanae enlarging at a rate of 0.208 +/- 0.09 mm per year (P < 0.03, r2 = 0.16); (2) there is no significant difference between the average choanal size in children with and without nasal obstructive symptoms; (3) the size of the posterior choanal air space cannot be used to accurately predict the presence or absence of nasal obstructive symptoms in children between the ages of 2 and 13 years.

Stridor in the infant and child. Assessment, treatment.

The health care team caring for the child with stridor must be familiar with congenital abnormalities of the airway and airway problems resulting from infections and foreign bodies and their typical presentation and endoscopic findings. Teamwork and communication are the keys to safe diagnosis and management of these children.

Cancer dose--response assessment for acrylonitrile based upon rodent brain tumor incidence: use of epidemiologic, mechanistic, and pharmacokinetic support for nonlinearity.

A cancer dose-response assessment was conducted for acrylonitrile (AN) using updated information on mechanism of action, epidemiology, toxicity, and pharmacokinetics. Although more than 10 chronic bioassays indicate that AN produces multiple tumors in rats and mice, a number of large, well-conducted epidemiology studies provide no evidence of a causal association between AN exposure and cancer mortality of any type. The epidemiological data include early industry exposures that are far higher than occur today and that approach or exceed levels found to be tumorigenic in animals. Despite the absence of positive findings in the epidemiology data, a dose-response assessment was conducted for AN based on brain tumors in rats. Mechanistic studies implicate the involvement of oxidative stress in rat brain due to a metabolite (2-cyanoethylene oxide or CEO, cyanide), but do not conclusively rule out a potential role for the direct genotoxicity of CEO. A PBPK model was used to predict internal doses (peak CEO in brain) for 12 data sets, which were pooled together to provide a consistent characterization of the dose-response relationship for brain tumor incidence in the rat. The internal dose corresponding to a 5% increase in extra risk (ED 05=0.017 mg/L brain) and its lower confidence limit (LED 05=0.014 mg/L brain) was used as the point of departure. The weight-of-evidence supports the use of a nonlinear extrapolation for the cancer dose-response assessment. A quantitative comparison of the epidemiology exposure-response data (lung and brain cancer mortality) to the rat brain tumor data in terms of internal dose adds to the confidence in the nonlinear extrapolation. Uncertainty factors of 200 and 220 (for the oral and inhalation routes, respectively) were applied to the LED 05 to account for interspecies variation, intraspecies variation, and the severity of the response measure. Accordingly, oral doses below 0.009 mg/kg-day and air concentrations below 0.1mg/m(3) are not expected to pose an appreciable risk to human populations exposed to AN.

Central catecholaminergic lesions in the developing rat: effects of cardiac noradrenaline levels, turnover and release.

1. The role of the central nervous system in regulating cardiac sympathetic tone was examined in developing rats with neonatal central catecholaminergic lesions produced by intracisternal 6-hydroxydopamine treatment. 2. Lesioned animals showed a persistent deficit in both cardiac noradrenaline levels and spontaneous turnover rate as evaluated by alpha-methyl-p-tyrosine treatment. 3. Despite these deficits, tyramine was fully capable of releasing cardiac noradrenaline and short-term centrally-mediated release also could be elicited by exposure to cold or by swimming exercise. 4. The alterations in cardiac noradrenaline content produced by the central lesions may result from long-term reductions in sympathetic tone which do not necessarily compromise short-term response capabilities of the sympathetic system.

Parathion toxicity in perinatal rats born to spontaneously hypertensive dams.

Placental transfer and fetal toxicity of pesticides have been documented in normotensive rats but no reports appear in the literature regarding the susceptibility of spontaneously hypertensive (SHR) perinates to pesticide challenge. This report describes the effects of prolonged parathion exposure to perinatal rats born to hypertensive dams. Ninety day old, spontaneously hypertensive (WKY strain) male and female rats were bred and vaginal plugs were used to determine that copulation had occurred. Parathion (0.01, 0.10 and 1.00 mg/kg) suspended in peanut oil was administered daily to the dam via oral intubation from day one of gestation to day fifteen of lactation, a total of thirty-seven days. On day twenty-four post partum the perinates were examined. Male and female SHR perinates exhibited a significant reduction in plasma cholinesterase at the 1.00 mg/kg dose level. Changes in relative organ weights, hematological parameters and serum enzymes were found. Heart rate was significantly reduced at the 0.01 mg/kg and 0.10 mg/kg dose levels. The results of this study indicate that exposure of SHR dams to parathion during gestation and lactation resulted in toxicological effects in the perinate basically similar to those seen in normotensive perinates.

Horner's syndrome caused by intra-oral trauma.

A 7-year-old boy developed a Horner's syndrome after falling on a stick that penetrated his peritonsillar soft palate. He did not suffer from any major vascular injury, and pharmacologic testing indicated a preganglionic lesion. We review previously reported cases of oculosympathetic paresis caused by surgical and nonsurgical intra-oral trauma. Because of the proximity between sympathetic and vascular structures in the lateral and parapharyngeal space, Horner's syndrome in the setting of intra-oral trauma should prompt evaluation of the internal carotid artery. Magnetic resonance imaging may be a reasonable noninvasive method for this investigation.

Development of alpha-noradrenergic and Dopaminergic receptor systems depends on maturation of their presynaptic nerve terminals in the rat brain.

To study the relationship between ontogeny of rat brain catecholamine nerve terminals and the receptor systems for the catecholamine transmitters, the developmental patterns of synaptosomal uptake mechanisms were compared with those of alpha-noradrenergic and dopaminergic receptor-mediated effects. Uptakes of [(3)H]dopamine or [(3)H]norepinephrine into dopaminergic and noradrenergic nerve terminals were low during the 1st week postpartum and increased rapidly during the 2nd week. A similar pattern was obtained for ontogeny of dopaminergic receptor binding sites, as evaluated by [(3)H]domperidone binding. Stimulation of incorporation of (33)P(i) into brain phospholipids (elicited by intracisternal injection of dopamine), which is mediated by dopaminergic receptors, was shown to be highly correlated with the maturation of both receptor binding sites and presynaptic nerve terminal uptake. A similar result was seen with norepinephrine, in that the synaptosomal uptake mechanism and norepinephrine-induced stimulation (33)P(i) incorporation into phospholipids, an alpha-noradrenergic effect, developed in a parallel fashion. To test the hypothesis that development of the receptor systems is linked to nerve terminal ontogeny, presynaptic nerve terminals were destroyed in neonates by intracisternal administration of 6-hydroxydopamine. The lesions prevented the maturational increase in the number of dopamine receptor binding sites and produced a defect in development of the dopamine- and norepinephrine-induced stimulation of (33)P(i) incorporation. The results suggest that ontogeny of both dopaminergic and alpha-noradrenergic receptor systems depend upon development of the presynaptic nerve terminals containing the transmitters.

The pharmacological activity of the fatty acid conjugate 11-palmitoyloxy-delta 9-tetrahydrocannabinol.

A long-retained cannabinoid metabolite has been detected in rat tissue after intravenous administration of delta 9-tetrahydrocannabinol (THC) and has been identified as a fatty acid conjugate of psychoactive 11-hydroxy-delta 9-tetrahydrocannabinol (11-OH-delta 9-THC) and palmitic acid. The objective of these studies was to determine if this compound, 11-palmitoyloxy-delta 9-tetrahydrocannabinol (11-palm-delta 9-THC) is pharmacologically active. Intravenously injected 11-palm-delta 9-THC decreased thermal sensitivity and induced catalepsy in rats, responses similar to those produced by 11-OH-delta 9-THC, but less pronounced and more delayed. To further characterize the response, animals were intracisternally injected with 11-OH-delta 9-THC or 11-palm-delta 9-THC. Catalepsy and decreased thermal sensitivity were seen in the 11-OH-delta 9-THC and 11-palm-delta 9-THC groups, and again, 11-OH-delta 9-THC appeared to be the more potent of the two cannabinoids. In contrast to the intravenous study, 11-palm-delta 9-THC-induced effects were seen soon after treatment and appeared to be fully developed by the first test time (15 min). The intracisternal results suggest that 11-palm-delta 9-THC itself is active; however, since it is known that the fatty acid conjugate is hydrolyzed in vivo to 11-OH-delta 9-THC in the rat, the possibility remains that the effects of 11-palm-delta 9-THC are due to metabolic conversion to 11-OH-delta 9-THC.