Biologically Based, Quantitative Risk Assessment of Neurotoxicants

The need for biologically based, quantitative risk assessmentprocedures for noncancer endpoints such as neurotoxicity hasbeen discussed in reports by the United States Congress (Officeof Technology Assessment, OTA), National Research Council (NRC),and a federal coordinating council. According to OTA, currentattention and resources allocated to health risk assessmentresearch are inadequate and not commensurate with its impacton public health and the economy. Methods to include continuousrather than dichotomous data for neurotoxicity endpoints, biomarkersof exposure and effects, and pharmacokinetic and mechanisticdata have been proposed for neurotoxicity risk assessment butrequire further review and validation before acceptance. Thepurpose of this symposium was to examine procedures to enhancethe risk assessment process for neurotoxicants and to discusstechniques to make the process more quantitative. Accordingly,a review of the currently used safety factor risk assessmentapproach for neurotoxicants is provided along with specificexamples of how this process may be enhanced with the use ofthe benchmark dose approach. The importance of including physiologicallybased pharmacokinetic data in the risk assessment process andspecific examples of this approach is presented for neurotoxicants.The role of biomarkers of exposure and effect and mechanisticinformation in the risk assessment process are also addressed.Finally, quantitative approaches with the use of continuousneurotoxicity data are demonstrated and the outcomes comparedto those generated by currently used risk assessment procedures.     

Reliability of the peabody developmental gross motor scale in children with cerebral palsy

The test/retest, intrarater, and interrater reliability of the Peabody Development Gross Motor Scale (PDGMS) was assessed in 12 children with mild or moderate cerebral palsy. A baseline test was administered, scored, and videotaped by one rater and rescored from the videotape by a second independent rater. In order to minimize the effect of developmental maturation, test/retest correlation coefficients of the tests were performed two weeks apart. The intraclass correlation coefficients ranged from 0.82 to 0.98. For interrater reliability, testing following the same protocol was repeated at 2 weeks, 3 and 6 months. Interrater correlation coefficients (r) ranged from 0.89 to 0.98. Interrater correlation coefficients (ICC) from scoring and later rescoring ten videotapes with the closest and furthest interrater agreement ranged from 0.88 to 0.99. The balance and locomotor skill categories were most responsive for assessing gross motor function in this population. These data support the use of the PDGMS as an assessment tool for children with cerebral palsy and the reliability of videotaping assessments.     

Epigenetic changes in the early stage of silica-induced cell transformation

The increasing use of nanomaterials in numerous domains has led to growing concern about their potential toxicological properties, and the potential risk to human health posed by silica nanoparticles remains under debate. Recent studies proposed that these particles could alter gene expression through the modulation of epigenetic marks, and the possible relationship between particle exposure and these mechanisms could represent a critical factor in carcinogenicity. In this study, using the Bhas 42 cell model, we compare the effects of exposure to two transforming particles, a pyrogenic amorphous silica nanoparticle NM-203 to those of the crystalline silica particle Min-U-Sil^® 5. Short-term treatment by Min-U-Sil^® 5 decreased global DNA methylation and increased the expression of the two de novo DNMTs, DNMT3a and DNMT3b. NM-203 treatment affected neither the expression of these enzymes nor DNA methylation. Moreover, modified global histone H4 acetylation status and HDAC protein levels were observed only in the Min-U-Sil^® 5-treated cells. Finally, both types of particle treatment induced strong c-Myc expression in the early stage of cell transformation and this correlated with enrichment in RNA polymerase II as well as histone active marks on its promoter. Lastly, almost all parameters that were modulated in the early stage were restored in transformed cells suggesting their involvement mainly in the first steps of cell transformation.     

Improvement of bone scintigraphy by quantitative evaluation compared with X-ray studies and iliac crest biopsy in malignant disease

Bone marrow biopsy of the iliac crest was performed on 268 patients (124; 144). Of these patients 206 had haematological systemic disorders (HSD) or carcinoma and suspected bone involvement, which was confirmed by biopsy on 66 patients.Bone biopsy was performed not longer than 3 weeks after X-ray examination and bone scintigraphy which, combined, had already raised the suspicion of skeletal involvement in 55% of the 66 patients with skeletal involvement diagnosed by biopsy. Additional quantitative evaluation of the bone scans using bone to soft tissue ratios was able to increase the overall accuracy to 67% in that group.Additional quantitative assessment of the scan yielded considerably more effective bone scintigraphy, particularly in cases with visually normal patterns. Available equipment should therefore be used in scintigraphic bone imaging on a routine basis.It was shown that the various methods of examination, i.e. X-ray, biopsy and scintigraphy with both visual and quantitative evaluation provide their own individual values for the final diagnosis. Therefore, if one of the methods shows a negative result, bone involvement is not excluded and the others should be used for confirmation.     

Fluid control mechanisms after exercise dehydration

Summary Since the osmocontrol- (osmolality), the renin-angiotensin- (PRA), and the volume control- (central venous pressure, CVP) systems are involved in the maintainance of the salt-water balance, we investigated the pattern of these parameters in the recovery period after exercise dehydration in 13 well trained long-distance runners.On average, after exercise the athletes had lost 3.1% of their body weight (BW). After eating and drinking the BW was still 1.3% below control value, indicative of continuing deficits. Plasma osmolality increased, however, from an average value of 286–290 mosmol/kg after exercise as well as postprandially, but the change was not significant. PRA-Levels rose significantly from 0.167–0.599 ng/ml·h after exercise and decreased to 0.333 ng/ml·h postprandially.CVP was significantly altered after exercise (–3.5 cm H₂O) as well as postprandially (–2.4 cm H₂O).The results suggest that the salt-water balance is maintained by the interplay of all the three systems. In conflicting situations, however, as when intercompartmental water- and solute-shifts take place during the recovery period, the volume control system triggered off by the CVP is the dominant corrective response to the prevailing deficits.Supported by the Bundesinstitut für Sportwissenschaften, Köln     

Effects of Difloxacin on the Metabolism of Glycosaminoglycans and Collagen in Organ Cultures of Articular Cartilage

Fluoroquinolones, including difloxacin, are potent antibacterialcompounds which, as a side effect, cause lesions in articular-epiphysealcartilage complexes (AECC) of growing animals. To evaluate theeffects of difloxacin on the structure of AECC and the metabolismof sulfated glycosaminoglycans (GAG) and collagen, explantsof AECC were obtained from 18 healthy, 3-month-old Beagle dogsand cultured in medium which either had no difloxacin or hadthe drug at one of three concentrations (40, 80, or 160 µg/ml).Rates of synthesis of GAG and collagen were reduced by concentrationsof difloxacin that were at or above 80 µg/ml. The rateof synthesis of total protein, however, was reduced only atthe highest dose level. Catabolism of GAG and collagen was unaffectedby the treatment. The principal ultrastructural changes in affectedchondrocytes were distension of rough endoplasmic reticulumwith electron-dense material that was probably protein, andvacuolation of cytoplasm. Structural changes were not observedin the extracellular matrix. It, therefore, appeared plausiblethat difloxacin affected chondrocytes by interfering with secretionof the matrix components, GAG and collagen.     

Characterization of immunoglobulin and T-cell receptor gene patterns in B-cell precursor acute lymphoblastic leukemia of childhood

Immunoglobulin (Ig) and T-cell receptor (TCR) genes were examined in the lymphoblasts of 70 children with immunophenotypically defined B-cell precursor acute lymphoblastic leukemia (ALL). The most frequent genes to rearrange were Ig heavy (H) chain (93%) and TCR delta (79%), followed by TCR gamma (49%), Ig kappa and/or lambda light (L) chain (46%), TCR alpha (46%), and TCR beta (29%). Thus, despite their putative "B-cell precursor" lineage, these leukemias manifest a remarkably high incidence of TCR gene rearrangements. While certain patterns predominate, there is considerable heterogeneity in Ig and TCR genotypes in this disease. No significant associations were found between Ig and TCR genotype and commonly used prognostic factors including age, sex, race, WBC, French-American-British (FAB) subtype, or cytogenetics. However, the lymphoblasts of three of six patients who failed to achieve initial remission had germline patterns of every Ig and TCR gene, a genotype not observed in the leukemic cells from any of the 64 patients who achieved complete remission (p2 = .0007). This study suggests that particular Ig and TCR genotypes may be of clinical relevance in childhood B-cell precursor ALL. The finding of rearranged TCR genes in a large proportion of cases raises fundamental questions about early lineage commitment and lymphocyte differentiation along B-cell and T-cell pathways.     

MRI of female genital and pelvic organs during sexual arousal

We utilized contrast enhanced magnetic resonance imaging (MRI) to delineate the anatomy of the female genital and pelvic organs during sexual arousal. Eleven healthy pre-menopausal women and eight healthy post-menopausal women underwent MRI of the pelvis while watching an erotic video. A 1.5 Tesla MR system was used to produce T1-weighted images following administration of MS-325, a gadolinium-based blood pool contrast agent. Selected structural dimensions and enhancement were measured prior to and during sexual arousal. In both pre- and post-menopausal subjects, vestibular bulb and labia minora width increased with arousal. Enhancement measurements increased in the bulb, labia minora and clitoris in both pre- and post-menopausal subjects, and in the vagina in pre-menopausal subjects. There were no marked changes in size or enhancement of the labia majora, urethra, cervix, or rectum during sexual arousal in pre- or post-menopausal subjects. Using MRI, we observed specific changes in the female genitalia and pelvic organs with sexual arousal, in both pre- and post-menopausal women. MRI can potentially provide detailed anatomical information in the assessment of female sexual function, particularly with regard to changes in blood flow.     

Impact of a fast free-breathing 3-T abdominal MRI protocol on improving scan time and image quality for pediatric patients with tuberous sclerosis complex

Pediatric Radiology - Magnetic resonance imaging (MRI) of the abdomen can be especially challenging in pediatric patients because of image quality degradation from respiratory motion. Abdominal MR...