Aneuploidy: a report of an ECETOC task force.

Aneuploidy plays a significant role in adverse human health conditions including birth defects, pregnancy wastage and cancer. Although there is clear evidence of chemically induced aneuploidy in experimental systems, to date there are insufficient data to determine with certainty if chemically induced aneuploidy contributes to human disease. However, since there is no reason to assume that chemically induced aneuploidy will not occur in human beings, it is prudent to address the aneugenic potential of chemicals in the safety assessment process. A wide range of methods has been described for the detection of chemically induced aneuploidy including subcellular systems, tests with fungi, plants and Drosophila as well as in vitro mammalian systems and in vivo mammalian somatic and germ cell assays. However, none of these methods is sufficiently validated or widely used in routine screening. Underlying the efforts to develop aneuploidy-specific assays is the presumption that current genetic toxicology tests do not detected chemicals that have aneuploidy-inducing potential. To address this, we have critically evaluated data from standard genetic toxicology assays for 16 known or suspected aneugens. The conclusions from the review are listed below. 1. At present there are only nine chemicals that can be classified as definitive aneugens, as determined by positive results in in vivo rodent assays. 2. As expected, the majority of definitive and suspected aneugens are negative in the bacterial mutation assay. 3. The majority of definitive aneugens evaluated induce polyploidy in vitro. With few exception, they also induced structural chromosome aberrations in vitro. 4. All of the definitive aneugens that have been sufficiently tested induce micronuclei in rodent bone marrow cells in vivo. A number of these chemicals also induced structural chromosome aberrations in vivo. 5. There is no evidence for a unique germ cell aneugen, that is a chemical that induces aneuploidy in germ cells and not in somatic cells. Furthermore, an analysis of several databases indicates the proportion of chemicals which induce polyploidy and not chromosome aberrations in vitro is low. Based on these conclusions, the following recommendations are made: for screening purposes, a standard genotoxicity test battery (including an in vitro cytogenetic assay with an assessment of polyploidy and clastogenicity at the same harvest time) should be performed; in the absence of polyploidy induction in vitro no further evaluation of aneuploidy-inducing potential is needed; if polyploidy is observed, in vitro follow-up testing to investigate further the aneuploidy-inducing potential should be conducted; such follow-up testing will generally start with the conduct of a standard in vivo somatic cell micronucleus assay; if the in vivo somatic cell micronucleus assay is negative, with adequate evidence of exposure of the bone marrow to the test compound, no further testing of aneuploidy-inducing potential is needed; if the in vivo somatic cell micronucleus assay is positive, further information on mechanisms of micronucleus induction can be obtained by using kinetochore/centromeric staining in vitro and/or in vivo; an assessment of potential germ cell aneuploidy activity may then be considered; aneuploidy induction which does not involve the direct interaction of a chemical or its metabolite(s) with DNA is expected to have a threshold. This must be considered in the risk assessment of such chemicals; this is not addressed by current risk assessment guidelines.

B mode ultrasonography--spectrum of paediatric ocular disease.

BACKGROUND: Despite having appropriate sonographic equipment available many radiologists remain unfamiliar with B mode sonography of the eye. OBJECTIVE: This article reviews the advantages and disadvantages of B mode sonography of the paediatric eye. We illustrate the spectrum of eye abnormalities occurring in paediatric practice and the sonographic appearance of clinical entities for which sonography is appropriate. MATERIALS AND METHOD: We reviewed our experience of eye sonography within a paediatric radiology department over 8 years. A total of 212 sonographic examinations were performed on 206 eyes in 103 children, aged from 3 days to 16 years (mean 4.6 years). RESULTS: Sonography was well tolerated by the children, was a very useful imaging modality and was the only diagnostic imaging modality required in 94%. Supplementary computed tomography (CT) was performed in ten of 206 eyes (5%) and magnetic resonance imaging (MR) was performed in two of 206 eyes (1%). CONCLUSIONS: B mode sonography is a very useful imaging modality for suspected ocular or orbital pathology in children and is often the appropriate first line investigation following clinical evaluation. Radiologists familiar with sonography of the eye can provide valuable support to their ophthalmology colleagues.

Pediatric musculoskeletal computed radiography.

BACKGROUND: In conventional radiography, a film-screen system serves as the X-ray detector and the film also functions as an archival and display medium. Unlike film-screen radiography, these functions are uncoupled in computed radiography (CR). CR uses conventional radiographic equipment to expose an image on a storage phosphor plate instead of a film-screen combination. OBJECTIVE: To review the basic concepts of CR and to provide a background for discussion of specific musculoskeletal applications of CR in children. MATERIALS AND METHODS: Various aspects of musculoskeletal CR in children are presented based on our 4 years' experience and a review of the literature. RESULTS: A greater amount of scatter capture occurs with storage phosphor CR than with a film-screen system in the 70- to 120-kVp range. This is attributed to a lower K-absorption edge of barium in the barium fluorohalide (BaFBr) compound used in the imaging plate. A significant reduction of scatter to primary radiation, improvement in bony trabecular sharpness, and improvement in line pair resolution can be achieved in pediatric musculoskeletal imaging using an air gap without an increase in the skin entrance dose as compared to the non-grid table top technique. With CR, in addition to proper radiographic exposure technique, one needs to preprogram and select the optimal processing technique for each anatomic region, projection and age group of the child. CONCLUSION: The main advantages of CR in pediatric musculoskeletal imaging consist of a reduction in radiation dose for many applications, improved contrast resolution, near elimination of repeat radiographs related to exposure errors, and digital processing capabilities for image enhancement, storage, retrieval, display and transmission. The current limitations of CR include the moderately high start-up cost, the long learning curve to produce optimal films, and the reduced spatial resolution.

Splanchnic artery pseudo-aneurysms secondary to blunt abdominal trauma in children.

Traumatic splanchnic artery pseudo-aneurysms are uncommon; only two cases have been reported among the pediatric population. The authors describe their experience with four patients in whom splanchnic artery pseudoaneurysms developed after blunt abdominal trauma. Splenic artery pseudo-aneurysms were found in a 6-year-old boy and an 8-year-old girl after blunt splenic injuries. In both cases, spontaneous thrombosis of the pseudo-aneurysms occurred after a period of observation. Hepatic artery pseudoaneurysms were found in a 7-year-old boy and a 10-year-old girl after major liver lacerations. The boy had successful angiographic embolization of the lesion, but the girl required direct ligation of the pseudo-aneurysm after nearly exsanguinating from acute hemorrhage. All four children have recovered completely, with no long-term sequelae. Traumatic splanchnic artery pseudo-aneurysms are potentially life-threatening complications that can occur after blunt abdominal trauma. The investigation and management of these lesions must be individualized according to the clinical scenario.

Skin irritation: Reference chemicals data bank.

A list of 176 chemicals, all of high or consistent purity and stable on storage, has been developed using available comprehensive in vivo rabbit skin irritation data. No new in vivo testing was conducted to qualify a chemical for inclusion in the list. The chemicals were tested undiluted in in vivo studies, apart from those chemicals where high concentrations could be expected to cause severe effects. The in vivo data were generated in studies carried out since 1981 according to OECD Test Guideline 404 and following the principles of Good Laboratory Practice. The data were obtained from tests normally using at least three rabbits evaluated at the same time, involving application of 0.5 g or 0.5ml to the flank under semi-occlusive patches for 4 hr, and in which observations were made at least 24, 48 and 72 hr after removal of the patch. The chemicals represent a range of chemical classes [acids, acrylates/methacrylates, alcohols, aldehydes, alkalis, amines, brominated derivatives, chlorinated solvents, esters, ethers, fatty acids and mixtures, fragrance oils, halogenated aromatics, hydrocarbons (unsaturated), inorganics, ketones, nitrites, phenolic derivatives, S-containing compounds, soaps/surfactants, triglycerides] and different degrees of irritancy. They are ranked for skin irritation potential on the basis of a 'primary irritation index'. These chemicals could be used in validation tests of promising alternatives to the in vivo rabbit skin irritation/corrosion test. This is an essential step in the progression to regulatory acceptance of alternative procedures.

Voiding cystourethrography in children with urinary tract infection: the frequency of vesicoureteric reflux is independent of the specialty of the physician requesting the study.

OBJECTIVE: The purpose of this study was to determine if the frequency of vesicoureteric reflux on voiding cystourethrography in children with a history of urinary tract infection varies according to the specialty of the physician requesting the examination. MATERIALS AND METHODS: The study included 309 children (192 girls, 117 boys) with a history of urinary tract infection who had their first voiding cystourethrogram. The median age at first voiding cystourethrogram in boys was 12 months; in girls, it was 48 months. The reports of these examinations were retrospectively reviewed, and the presence of vesicoureteric reflux was recorded. The age and sex distribution of children referred for voiding cystourethrography by pediatric urologists and nephrologists (subspecialists) was compared with the age and sex distribution of children referred by pediatricians, family practitioners, and adult urologists (other clinicians). The rate of detection of vesicoureteric reflux was calculated according to age and sex. Ages studied were younger than 1 year, younger than 2 years, 2-4 years, and 5 years or older. The frequency of vesicoureteric reflux in children referred by subspecialists was compared with the frequency in children referred by other clinicians, allowing for the age and sex of the children. RESULTS: The sex distribution of children referred for voiding cystourethrography was similar for subspecialists and other clinicians. More children younger than 2 years old were referred by other clinicians than by subspecialists. Vesicoureteric reflux was found in 30% of boys and 29% of girls. The frequency of reflux in boys did not change with age. The frequency of reflux in girls 5 years or older (15%) was less than in younger girls. We found no significant difference between the rates of reflux in boys and girls within the age groups examined. The overall rate of detection of reflux in patients referred by subspecialists (30%) was almost the same as that in patients referred by other clinicians (29%). We also found no difference in the frequency of reflux in children referred by subspecialists compared with children referred by other clinicians after allowing for the age and sex of the children. CONCLUSION: In children with a history of urinary tract infection, the rate of detection of vesicoureteric reflux on voiding cystourethrography is independent of the specialty of the physician requesting the examination.

Polypropylene production and colorectal cancer: a review of the epidemiological evidence.

Polypropylene has been produced for over 35 years and has a wide variety of applications including industrial uses, food packaging and many domestic uses. As a high-molecular-weight polymer, polypropylene is considered chemically inert with little or no physiological or toxicological effects. Nevertheless, early epidemiological studies of polypropylene production workers and carpet manufacturing employees who use polypropylene reported a significant excess of colorectal cancer. In one study, five of the seven cases were diagnosed within a five-month period, and in the other study, five cases were diagnosed within an 18-month period. Recent updates of these two study populations have found no continuation of the excess of colorectal cancer, thereby indicating that the earlier observations on these two groups reflected the chance nature of a time-space cluster. Moreover, investigations of polypropylene production workers in the United States, Germany, Australia and the United Kingdom found no association with colorectal cancer. When the results of all studies of polypropylene production workers are pooled, the summary risk ratio for colorectal cancer is 1.37 (95% confidence interval 0.83-2.11). Taken together, the epidemiological evidence and the absence of toxicological data do not support a causal association between polypropylene and colorectal cancer.

Pathology considerations for, and subsequent risk assessment of, chemicals identified as immunosuppressive in routine toxicology.

Several proposals have been made with the aim of assisting in the early identification of chemicals with immunotoxic potential. The Organisation for Economic Cooperation and Development is now likely to incorporate enhanced immunopathology into the test guideline for the 28-day rat study, which may be regarded as a Tier I investigation. However, no guidelines have yet been proposed either for how the new data generated will be evaluated, or for how a subsequent risk assessment will be made. In this paper, considerations for the immunopathological assessment of the thymus, spleen, lymph nodes and bone marrow are described, together with comments on haematological and organ weight changes that may be associated with immunotoxicity. Their interpretation will depend on the doses at which changes are manifest, the quantity and quality of the effects observed and the presence and severity of other forms of toxicity. Lastly, risk assessment and the approach to Tier II testing in immunotoxicity is discussed. It is concluded that much of this work must be on a case-by-case basis, but should not in principle differ from the approach adopted for any other type of toxicity identified ina 28-day study.

The identification of chemicals with sensitizing or immunosuppressive properties in routine toxicology.

In the context of this paper, immunotoxicity is taken to encompass immunosuppression/immunopotentiation and allergy. Over the last 10 to 15 years, well characterized methods for the assessment of altered immune competence have been reported. This has led to proposals for tiered testing schemes. This review examines the suitability of immunotoxicity parameters for inclusion in routine 28-day studies and comments on methods that have been proposed for incorporation within the guidelines issued by the US FDA and US EPA and OECD. It is recommended that the existing OECD Guideline 407 is modified to incorporate total and differential blood cell counts, spleen and thymus weight and histopathology, and draining and distal lymph node histopathology for Tier I level testing. Data so generated will provide a reliable and accurate means of identifying at an early stage potential immunotoxic effects. Tier II testing should be carried out on a case by case basis and only assuming positive results are obtained at Tier I. An increasingly sophisticated understanding of the nature of immune responses to chemical allergens has facilitated the design of novel predictive methods for the identification of sensitizing activity. Opportunities which arise from these new developments in allergy testing such as the local lymph node assay, mouse ear swelling test, and the mouse IgE test should be monitored closely.

Comparison of stimulable phosphor technology and conventional screen-film technology in pediatric scoliosis.

One hundred consecutive patients being investigated for scoliosis were studied using a double cassette containing a conventional film screen and a stimulable phosphor plate. The images were separated, randomised and scored thrice by three radiologists for anatomic structure visualisation. The exposure to the plate and film and repeat rate were measured. Scoliosis angles were comparable on both sets of images, however, visualisation of vertebrae, vertebral end plates, pedicles, spinous processes and other structures were significantly improved (p < 0.0001). Intra- and inter-observer reliability was high with good intraclass correlation. There was a 40% potential exposure reduction, and retakes were decreased from 3 to 0%. We conclude that stimulable phosphor images give better anatomic structure visualisation with potential radiation exposure reduction and lower repeat rate.

Prepubertal ovarian cyst formation: 5 years' experience.

OBJECTIVE: To document the frequency of ovarian cyst formation in the prepubertal female and to report on the clinical implications of these cysts. METHODS: We evaluated cases from a retrospective chart review of prepubertal females with ovarian cysts. RESULTS: Over a 5-year period, 1818 ultrasound studies were completed in prepubertal females, from which 99 patients were identified as having ovarian cysts. The majority (82 of 99, 83%) were small, unilocular cysts averaging 2-3 mm in diameter. The incidence of these small cysts ranged at 2-5% in females between birth and age 8. Large ovarian cysts (ie, greater than 2 cm in diameter) are rare in young girls over age 2, with most occurring within the first year of life. Of the 17 large ovarian cysts, two presented with torsion and both were complex on ultrasound examination. Five (29%) of the large ovarian cysts were treated conservatively and demonstrated regression on follow-up; these were unilocular cysts. Although functioning cysts resulting in precocious pseudopuberty are expected to be rare, we identified five cases (5%) in our series. CONCLUSIONS: Small, unilocular ovarian cysts less than 1 cm in diameter are found in prepubertal females with a frequency of 2-5% and are clinically insignificant. Ovarian cysts greater than 2 cm are rare. Unilocular ovarian cysts less than 5 cm may be followed conservatively with ultrasound surveillance until regression, without a major risk of torsion. Ovarian cysts associated with precocious pseudopuberty are generally larger than 2 cm and may be recurrent.

Long term survival of an infant with sirenomelia.

We report on a 3-month-old infant whose sirenomelia was diagnosed prenatally. The infant is neurologically normal and has "fusion" of the lower limbs with associated renal dysplasia, imperforate anus, pelvic and sacral "dysplasia," and genital abnormalities. In addition she has a preauricular skin tag and rib fusion. The infant's anomalies are compatible with life and surgical separation of the lower limbs is planned.

Hypersensitivity reaction to single contrast barium meal studies in children.

We report two children who developed hypersensitivity reactions of varying severity following barium meal examination, the more severe of which was associated with documented severe food allergy. For children with this risk factor, contrast studies should be performed only where facilities and personnel are available for immediate resuscitation of all sizes of child. For children such as these, consideration should be given to the use of pure barium sulphate.