Registration,Evaluation, and Authorization of Chemicals (REACH) Is but the First Step–How Far Will It Take Us? Six Further Steps to Improve the European Chemicals Legislation

Objectives

In this commentary we analyze how much data will in fact be generated within REACH.

Conclusions

We conclude that the data requirements for many end points still have not been determined but depend on prioritization criteria and waiving practices that will be decided in the years to come. We propose six important steps toward an improved REACH: a) Clarify prioritization and waiving criteria. Implement decisions to ensure that sufficient data are obtained to make first hazard assessments of as many substances and end points as possible. b) Increase data requirements. Introduce data requirements similar to those currently required for substances produced or imported in quantities of ≥ 10 metric tons/year for substances produced or imported in quantities of ≥ 1 metric tons/year. c) Develop the tests and approaches needed to satisfy the information requirements taking into account resource limitations and the aim to reduce animal testing. d) Promote substitution of high risk chemicals. Create an effective process for identifying substances of very high concern and for making the appropriate risk management decisions for these substances. e) Address the control of substances incorporated in articles. And f) acknowledge uncertainties. Systematically report lack of data and include this as a basis for risk management.     

Sensation Following Immediate Breast Reconstruction with Implants

Sensation is a neglected aspect of the outcome of breast reconstructions with implants. The aim of this prospective study was to evaluate the cutaneous somatosensory status in breasts following mastectomy and immediate reconstruction with permanent adjustable prostheses and to analyze the patients' subjective experience of the sensation. Twenty-four consecutive patients diagnosed with invasive or in situ breast carcinoma were examined preoperatively and 2 years after mastectomy and reconstruction, for assessment of perception thresholds for touch, cold, warmth, and heat pain above and below the areola. Von Frey filaments and a Peltier element-based thermode were used. The patients completed a questionnaire concerning their experienced sensation in the reconstructed breast. Using quantitative somato-sensory testing, the sensation to all the examined modalities was significantly impaired compared to preoperatively. Most affected was the area above the areola. Patients given postoperative radiotherapy (n = 9) did not differ from those without radiotherapy (n = 15) regarding any of the modalities. All patients reported reduced sensation in the reconstructed breast compared to that preoperatively. Twenty-three patients stated that the reconstructed breast felt different from the other breast; nevertheless 16 reported that the reconstructed breast felt like a real breast. The study revealed sensation impairment following mastectomy and immediate reconstruction with implants. Patients should be informed about this effect preoperatively to allow adequate expectations regarding the sensation outcome. However, two-thirds of the study patients considered that the reconstructed breast felt like a real breast, which must be one of the main purposes of a breast reconstruction.     

Calvarial bone healing under spring distension at continuous forces

The aim of the present study was to evaluate in young animals the dynamics of calvarial bone healing when exposing a bone defect to continuous forces for up to 13 weeks. Six-week-old rabbits after a sagittal suture strip craniectomy were randomized for either of the following protocols: (1) no spring was applied (n = 7); (2) a titanium-molybdenum alloy (TMA) lower-force spring was inserted across the craniectomy gap (n = 9); (3) a stainless steel (SS) higher-force spring was applied (n = 8), or (4) sham operation (n = 8). Results showed that the surgically created calvarial bone gap was after 3 weeks kept widened both when a spring of lower force (TMA) and when a spring exerting a higher force (SS) was applied. At 6 weeks, none of the rabbits of the spring-exposed (2 and 3) groups had any bone bridging the gap, while bone bridging was visible in animals of the 2 groups (1 and 4) lacking springs. Strikingly enough, in both spring-treated groups, the surgically created defect was still after 13 weeks incompletely bridged by bone, interposed by connective tissue, most evidently in those exposed to higher forces (SS). In contrast, a normal sagittal suture enclosed by lamellar bone was seen in both the sham and the strip groups. We conclude that exposing a surgically created calvarial bone defect to continuous mechanical forces delayed the bridging of the bone defect by at least 13 weeks, even if the force exerted by either spring was very low. In any case, when a higher force (SS group) was applied, the bone reunion was efficiently prevented. No side effects were recognized.     

Cerebral white matter abnormalities in 6p25 deletion syndrome

Submicroscopic deletion of the terminal part of the short arm of chromosome 6, including 6p25, leads to developmental retardation, hearing impairment, ocular dysgenesis, and dysmorphic features. We diagnosed 3 patients referred because of white matter abnormalities of unknown origin. MR imaging showed multifocal areas of abnormal signal and enlarged perivascular spaces in the cerebral white matter that were stable during follow-up. Multifocal white matter abnormalities are most commonly seen in static, nonmetabolic encephalopathies, including chromosomal abnormalities.     

Mutations of PIK3CA are rare in cutaneous melanoma

Recent studies have shown that the PIK3CA gene, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinases, is mutated in human cancers. To determine whether PIK3CA is altered in cutaneous melanoma, we screened a series of 101 melanoma metastases. We identified PIK3CA missense mutations in three metastases (3%). Interestingly, these mutations were observed only in tumours that were negative for NRAS mutations. Using immunohistochemistry, we also analysed our metastases for the expression of phosphorylated Akt. These analyses revealed a moderate to strong phosphorylated Akt expression in 78% (21 of 27) of metastases with NRAS mutations and in 73% (54 of 74) of metastases without NRAS mutations. Interestingly, the three metastases with mutations in PIK3CA all exhibited a strong expression of phosphorylated Akt. Taken together, our results show that PIK3CA is mutated in a minority of melanomas and suggest that mutations in this gene may represent an alternative mechanism of Akt activation in cutaneous melanoma.     

Bias in toxicology

The potential for bias, i.e., influences that cause results to deviate systematically from the truth is substantial both in toxicological research and in the performance of standardized toxicological testing. In this contribution, major potential sources of bias in toxicological research and testing are identified. Due to the lack of empirical studies of bias in toxicology, very little is known about its prevalence and impact. Areas to consider for such studies are pointed out, and it is suggested that such investigations should be given priority.     

Expression of cyclo-oxygenase-2 in human atherosclerotic carotid arteries.

OBJECTIVES: the preventive effect of acetylsalicylic acid in cardiovascular disease may be due to inhibition of platelet aggregation mediated by COX-1, but may in addition be due to anti-inflammatory effects by inhibition of COX-2. The objective of this study was to analyse the expression of COX-1 and COX-2 in atherosclerotic and healthy vascular walls. DESIGN: the expression COX-1 and COX-2 was analysed in biopsies from human atherosclerotic carotid arteries and from healthy mammary arteries and saphenous veins. Materials: vascular biopsies were obtained from patients undergoing carotid endarterectomy or coronary bypass surgery. METHODS: RT-PCR was used for mRNA analysis and for localization of proteins we used immunohistochemistry. RESULTS: COX-2 was found in atherosclerotic plaques: in macrophages, in some smooth muscle cells and in endothelial cells of small vessels in the lesions. In non-atherosclerotic blood vessels, COX-2 was detected in the endothelium of the vasa vasorum in the adventitia. COX-1 was found in the endothelium in healthy and in atherosclerotic vessels. CONCLUSIONS: the expression of COX-2 by inflammatory and vascular cells in atherosclerotic arteries suggests that products of this enzyme may be important in the pathogenesis of atherosclerosis.