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.

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.

Procedures for health risk assessment in Europe.

This report compares cancer classification systems, health risk assessment approaches, and procedures used for establishing occupational exposure limits (OELs), in various European countries and scientific organizations. The objectives were to highlight and compare key aspects of these processes and to identify the basis for differences in cancer classifications and OELs between various scientific organizations and countries. Differences in cancer classification exist in part due to differences in the ultimate purpose of classification and to the relative importance of different types of data (i.e., animal vs human data, mechanistic data, and data from benign vs malignant tumors). In general, the groups surveyed tend to agree on classification of chemicals with good evidence of carcinogenicity in humans, and agree less on classification of chemicals with positive evidence in animals and inadequate or limited evidence in humans. Most entities surveyed distinguish between genotoxic and nongenotoxic chemicals when conducting risk assessments. Although the risk assessment approach used for nongenotoxic chemicals is fairly similar among groups, risk assessment approaches for genotoxic carcinogens vary widely. In addition to risk assessment approaches, other factors which can affect OELs include selection of the critical effect, use of health-based vs technology-based exposure limits, and consideration of technological feasibility and socioeconomic factors.

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.

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.

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.

Respiratory syncytial virus induces selective production of the chemokine RANTES by upper airway epithelial cells.

The presence of histamine and eosinophil cationic protein in nasopharyngeal secretions of infants with respiratory syncytial virus (RSV)-induced bronchiolitis implies the activation of basophil and eosinophil leukocytes, but the specific mechanism of their recruitment has not been elucidated. Chemokines are potent and selective leukocyte chemotactic molecules that are also expressed by airway epithelial cells. Therefore, the pattern of chemokines produced in response to RSV infection was investigated in primary cultures of human nose- and adenoid-derived epithelial cells. Interleukin-8, growth-related peptide-alpha, and monocyte chemotactic protein-1 were constitutively released by uninfected epithelial cells and were not further enhanced by infection with RSV. RANTES (regulated upon activation, normal T cell-expressed and -secreted), which was present in negligible concentrations in uninfected cultures, was strongly induced by RSV infection, in a dose- and time-dependent manner. Through the release of RANTES, epithelial cells may control the selective concentration and activation of basophils and eosinophils in RSV-infected airway mucosa.

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.

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.

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.

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.

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.

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.

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.

Prechronic toxicity of o-benzyl-p-chlorophenol in rats and mice.

o-Benzyl-p-chlorophenol (BCP) is a major household and industrial germicide. Its prechronic toxicity was evaluated in male and female F344 rats and B6C3F1 mice. Treatment was by gavage in corn oil. BCP was slightly toxic after acute oral exposure, with high mortality at 4000 and 2000 mg/kg in rats and mice. Exposure to 12 oral doses of BCP at 1000, 500, 250, 125, 62.5, or 0 mg/kg body wt resulted in dose-related cecal dilatation and nephrosis in both rats and mice. Doses for the subchronic studies were based on the results of the 2-week studies. Ten animals were treated per dose per sex. Rats received 480, 240, 120, 60, 30, or 0 mg BCP/kg. Mice were treated with 1000, 800, 650, 500, or 0 mg BCP/kg. Animals were dosed 5 days per week for 13 weeks. Clinical signs related to dosing included urogenital staining in rats and rough/oily haircoats in mice. No effects on growth rate were seen in rats, but growth was retarded at the higher doses used in mice. Kidney weights increased in rats, and liver weights increased in mice. A decrease in thymus weight accompanied by a depletion in thymic lymphocytes (rats) or thymic necrosis (mice) occurred only in a high-dose animals. In both species, the kidney was the major target organ. In rats, there was an increase in incidence and severity of nephropathy and renal tubule regeneration. The lesions in mice primarily involved the renal cortex and included necrosis, casts, chronic inflammation, and regeneration of the renal tubules. No effects of BCP exposure in rats were seen in a broad spectrum of hematology or urinalysis parameters. Minor decreases in blood urea nitrogen, creatinine, and alanine amino transferase were detected in male and female rats. There were no biologically significant neurobehavioral effects in rats or immunotoxic effects in mice due to exposure to BCP. Thus, the kidney is the major target organ for BCP.

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.