Identification of emerging safety and sustainability issues of advanced materials: Proposal for a systematic approach.

The EU Chemicals Strategy for Sustainability is a first step to achieve the Green Deal ambition for a toxic-free environment, and ensure that chemicals are produced and used in a way that maximises their contribution to society while avoiding harm to our planet and to future generations. Advanced materials are predicted to play a pivotal role in achieving this ambition and the underlying sustainability goals, and considerable efforts are invested in designing new classes of materials. Examples of such materials are metamaterials, artificially architectured materials designed to have material properties beyond those of the individual ingredient materials, or active materials at the boundary between materials and devices (e.g., new biomedical soft materials). Such innovative advanced materials raise concern about possible future safety and sustainability issues and would benefit from appropriate risk governance that promotes innovation, while pushing for safety and sustainability. To balance these aspects, a methodology is proposed for the early-stage identification of emerging safety and sustainability issues of advanced materials. As exemplified by two case studies, the methodology aims to be of use for innovators, risk assessors, and regulators. Extension of the methodology is highlighted, as well as implementation in broader initiatives like the EU's industrial policy approach.

Insights into possibilities for grouping and read-across for nanomaterials in EU chemicals legislation.

This paper presents a comprehensive review of European Union (EU) legislation addressing the safety of chemical substances, and possibilities within each piece of legislation for applying grouping and read-across approaches for the assessment of nanomaterials (NMs). Hence, this review considers both the overarching regulation of chemical substances under REACH (Regulation (EC) No 1907/2006 on registration, evaluation, authorization, and restriction of chemicals) and CLP (Regulation (EC) No 1272/2008 on classification, labeling and packaging of substances and mixtures) and the sector-specific pieces of legislation for cosmetic, plant protection and biocidal products, and legislation addressing food, novel food, and food contact materials. The relevant supporting documents (e.g. guidance documents) regarding each piece of legislation were identified and reviewed, considering the relevant technical and scientific literature. Prospective regulatory needs for implementing grouping in the assessment of NMs were identified, and the question whether each particular piece of legislation permits the use of grouping and read-across to address information gaps was answered.

Pessary for prevention of preterm birth in twin pregnancy with short cervix: 3-year follow-up study.

OBJECTIVE: A recent randomized clinical trial (ProTWIN) showed that a cervical pessary prevented preterm birth and improved neonatal outcome in women with multiple pregnancy and cervical length (CL) < 38 mm. In this follow-up study, the long-term developmental outcome of these children was evaluated at 3 years' corrected age. METHODS: This was a follow-up study of ProTWIN, a multicenter trial conducted between 2009 and 2012 in which asymptomatic women with a multiple pregnancy were randomized to placement of a cervical pessary or no intervention. Current follow-up and analysis were limited to mothers with a mid-trimester CL < 38 mm (78 women (157 children) in the pessary group and 55 women (111 children) in the control group). At 3 years of corrected age, surviving children were invited for a Bayley Scales of Infant and Toddler Development-third edition (Bayley-III) assessment. Death after randomization or neurodevelopmental disability (Bayley-III score of ≤ 85, 1 SD below mean) rates were compared between the pessary and control groups, according to the intention-to-treat principle and using multiple imputation for missing data. Mean Bayley-III scores in surviving children were also assessed. A linear mixed-effects model was used to adjust for correlation between children of one mother. RESULTS: From the time of entry in the ProTWIN trial until follow-up at 3 years of age, a total of 27 children had died (six (5%) in the pessary vs 21 (26%) in the control group; odds ratio (OR), 0.13; 95% CI, 0.04-0.48). Bayley-III outcomes were collected for 173/241 (72%) surviving children (114 (75%) in the pessary vs 59 (66%) in the control group). The cumulative incidence of death or survival with a neurodevelopmental disability was 12 (10%) in the pessary vs 23 (29%) in the control group (OR, 0.26; 95% CI, 0.09-0.73). No statistical or clinically relevant differences were found with respect to cognitive, language and motor development among surviving children between the groups. Comparable results were found after multiple imputation. CONCLUSION: In women with twin pregnancy and a CL < 38 mm, the use of a cervical pessary strongly improved survival of the children without affecting neurodevelopment at 3 years' corrected age. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Comparative toxic and genotoxic effects of chloroacetanilides, formamidines and their degradation products on Vibrio fischeri and Chironomus riparius.

Toxic and genotoxic effects of alachlor, metolachlor, amitraz, chlordimeform, their respective environmentally stable degradation products 2,6-diethylaniline, 2-ethyl-4-methylaniline, 2,4-dimethylaniline, and two other related compounds, 3,4-dichloroaniline and aniline were compared. Acute toxicity tests with Chironomus riparius (96 h) and Vibrio fischeri (Microtox) and genotoxicity tests with a dark mutant of V. fischeri (Mutato) were carried out. Our results demonstrate that toxicity and genotoxicity of the pesticides are retained upon degradation to their alkyl-aniline metabolites. In the case of the herbicides alachlor and metolachlor, the toxicity to V. fischeri was enhanced upon degradation. Narcosis alone explains toxicity of the compounds to the midge, but not so for the bacteria suggesting a disparity in the selectivity of the test systems. All compounds showed direct genotoxicity in the Vibrio test. but amitraz and its metabolite were genotoxic at concentrations 10(3)-10(5) lower than all the other compounds. The observations indicate that stable aniline degradation products of the pesticides may contribute considerably to environmental risks of pesticides application and that genotoxic effects may arise upon degradation of pesticides.

Membrane-contaminant interaction found by 3D force field calculations.

Enthalpies of contaminant transfer from water to a 1,2-Dilauroyl-DL-phosphatidyl ethanolamine (DLPE) membrane were calculated in order to study the suitability of 3D force fields for the calculation of membrane-water partitioning constants (Kmw) and as potential descriptors for bio-concentration. A 3D DLPE membrane model was built in a MM+ force field using AM1 atomic charges. 3,5-Dichlorobiphenyl (PCB14), 4,4'-dichlorobiphenyl (PCB15), 1,1,1-trichloro-2,2-bis-(4-chlorophenyl)-ethane (PPDDT or p,p'-DDT) and 2-chloro-4-ethylamino-6-isopropylamino-s-triazine (atrazine) were inserted into apolar and polar sites and their interaction energies with the membrane were calculated by geometrical optimization (GO). Energies of hydratation were subtracted from membrane-contaminant interactions of selected sites. The resulting values for the enthalpies of transfer from water to the membrane were 4.7, -2.3, 11.5 and -9.2 kcal/mol for PCB14, PCB15, PPDDT and atrazine, respectively. In contrast to PCB15, the value of PCB14 compared favorably with the experimental values of similar membranes. PCB14, PCB15 and PPDDT had their lowest energies in the apolar sites of the membrane, whereas atrazine tended to accumulate in the polar membrane-bulk water boundary site. Potential advantages and limitations of the approach were discussed.

Phototoxicity of azaarene isomers to the marine flagellate Dunaliella tertiolecta.

Many studies have shown that narcosis or baseline toxicity of polycyclic aromatic hydrocarbons (PAHs) is strongly related to their lipophilicity. For azaarenes, such relationships have also been demonstrated, but for some compounds, deviations from these relationships have been observed, even for closely related compounds such as isomers. In the present study, the toxicity of four azaarene isomer pairs to the marine flagellate Dunaliella tertiolecta was determined. For quinoline, isoquinoline, acridine, phenanthridine, benz[a]acridine, and benz[c]acridine, the 72-h median effective concentrations for growth were 571, 464, 2.10, 14.7, 0.50, and 0.11 microM, respectively. For the five-ringed isomers dibenz[a,i]acridine and dibenz[c,h]acridine, no effects were observed at the highest concentration tested (0.1 and 0.005 microM, respectively). Growth inhibition by the two-, three-, and four-ringed isomer pairs to D. tertiolecta was well described by molecular volume and log Kow, indicating a narcotic mode of action. However, the toxicity of acridine and benz[c]acridine was much higher than that of their respective isomers, phenanthridine and benz[a]acridine, suggesting an additional specific mode of action. Based on the differences in energies between the highest occupied molecular orbital and the lowest unoccupied molecular orbital, acridine and benz[c]acridine are susceptible to ultraviolet (UV) radiation, in contrast to the other tested compounds. Because UV was present, it is therefore argued that the toxicity of both compounds was photoenhanced. Photoenhanced toxicity may increase the environmental hazard of azaarenes, indicating the importance of enlarging the present monitoring of PAHs with phototoxic N-heterocyclic PAHs and incorporating this mode of action in water-quality criteria.

Dimensionality, responsiveness and standardization of the Bech-Rafaelsen Mania Scale in the ultra-short therapy with antipsychotics in patients with severe manic episodes.

OBJECTIVE: Typical antipsychotics have their indication in the ultra-short (first week) treatment of severe episodes of mania. In this setting the Bech-Rafaelsen Mania Scale (MAS) was psychometrically compared with the Clinical Global Impression scale (CGI) to assess its ability to measure response. METHOD: Ratings on patients with marked to severe mania (n = 80) who participated in the clinical trials to evaluate the ultra-short antimanic effect of zuclopenthixol acetate were assessed. The MAS was analysed for internal validity (total score a sufficient statistic) and for external validity. RESULTS: The MAS was shown to have a high internal validity showing onset of action already after days of treatment. After 6 days of treatment 53% of the patients responded according to the MAS but only 30% according to the CGI. The difference was statistically significant. CONCLUSION: The MAS has been found to be a valid scale to measure early onset of action and response in the ultra-short antimanic treatment with typical antipsychotics.

Linkage of prostate cancer susceptibility loci to chromosome 1.

Three prostate cancer susceptibility genes have been reported to be linked to different regions on chromosome 1: HPC1 at 1q24-25, PCAP at 1q42-43, and CAPB at 1p36. Replication studies analyzing each of these regions have yielded inconsistent results. To evaluate linkage across this chromosome systematically, we performed multipoint linkage analyses with 50 microsatellite markers spanning chromosome 1 in 159 hereditary prostate cancer families (HPC), including 79 families analyzed in the original report describing HPC1 linkage. The highest lod scores for the complete dataset of 159 families were observed at 1q24-25 at which the parametric lod score assuming heterogeneity (hlod) was 2.54 (P=0.0006) with an allele sharing lod of 2.34 (P=0.001) at marker D1S413, although only weak evidence was observed in the 80 families not previously analyzed for this region (hlod=0.44, P=0.14, and allele sharing lod=0.67, P=0.08). In the complete data set, the evidence for linkage across this region was very broad, with allele sharing lod scores greater than 0.5 extending approximately 100 cM from 1p13 to 1q32, possibly indicating the presence of multiple susceptibility genes. Elsewhere on chromosome 1, some evidence of linkage was observed at 1q42-43, with a peak allele sharing lod of 0.56 (P=0.11) and hlod of 0.24 (P=0.25) at D1S235. For analysis of the CAPB locus at 1p36, we focused on six HPC families in our collection with a history of primary brain cancer; four of these families had positive linkage results at 1p36, with a peak allele sharing lod of 0.61 (P=0.09) and hlod of 0.39 (P=0.16) at D1S407 in all six families. These results are consistent with the heterogeneous nature of hereditary prostate cancer, and the existence of multiple loci on chromosome 1 for this disease.

Comparative metabolism of phenanthridine by carp (Cyprinus carpio) and midge larvae (Chironomus riparius).

Abiotic transformation of azaarenes in the environment has been analysed extensively, but metabolism is less well described. To further elucidate preliminary observations of interspecific differences in azaarene metabolism by aquatic organisms, phenanthridine biotransformation by midge larvae and carp was studied. In both experiments, 6(5H)-phenanthridinone (phenanthridone) was found as an important metabolite. The fish were clearly capable of metabolising phenanthridine, but in the midge experiment the metabolite was principally formed by bacteria growing on the food and not by the midges. Phenanthridone itself was further degraded to non-observed compounds in both experiments, due to bacteria and midges acting together in the midge experiment, and by carp in the fish experiment. Internal concentrations of phenanthridine and phenanthridone were non-detectable in the midge larvae, but concentrations of both compounds in carp organs suggested a major role of bile and liver. Since phenanthridone did not account for all phenanthridine loss, it was suggested that, apart from phenanthridone degradation, other metabolic pathways may play a role. This study clearly demonstrates the importance of interspecies differences in metabolism, which should not be neglected in risk assessment.

Linking ecological and ecotoxicological techniques to support river rehabilitation.

Human activities in river catchments interfere with natural fluxes of water and materials. Diffuse inputs and point-sources of toxicants have modified the ecological state of riverine communities considerably, and sanitation schemes are now under development for various rivers. To improve analysis, monitoring and prospecting the role of toxicants in river ecosystems a review of the available methods is undertaken. Ecotoxicological techniques are discussed in relation to basic ecological principles that are thought to regulate the functioning of communities. The response to toxicants among species is highly diverse and therefore the choice of test species (e.g. of typical riverine insects as caddisflies or mayflies) is critical, as it is the use of test-batteries. Long-term exposure may lead to developmental disturbances that may be assessed through morphometric techniques like analysis of asymmetry. Multi-generation exposure, although rarely studied, provides a useful insight into the genetic consequences of pollution. Selection for tolerant species or varieties has been experimentally assessed for smaller organisms such as insects, micro-algae, and bacteria. There is also perspective for multivariate analysis of species distribution in relation to pollutant exposure. Furthermore, a system approach to benthic ecology and sediment testing is needed. Such an approach reflects the strong linkage of ecological and ecotoxicological processes. Toxicants are transformed by biological activity; in some cases this alleviates toxicant stress, but in other cases degradation products are toxic as well. The risk of transformation to mutagenic products in the environment is indicated. The re-assessment of some of the classical ecotoxicological techniques is needed to adequately fulfil the needs of ecological recovery programs. To this purpose integration of ecotoxicological and ecological tools is needed.

Formation and identification of azaarene transformation products from aquatic invertebrate and algal metabolism.

The metabolism of two azaarenes, viz. acridine and phenanthridine, by aquatic organisms was studied in short-term and chronic laboratory tests. The identity of metabolites observed in the test waters was investigated with different analytical methods, including HPLC, GC and hyphenated LC- or GC-MS. The Zebra mussel (Dreissena polymorpha), one green alga species (Selenastrum capricornutum) and periphyton or bacteria transformed acridine into 9[10H]-acridinone. Phenanthridine was transformed into 5[6H]-phenanthridinone by midge (Chironomus riparius) larvae. The findings indicate that closely related isomers may undergo species-specific biotransformation. It was concluded that keto-metabolites are major products in the aquatic fate of benzoquinolines, which may be overlooked in the risk assessment of parent compounds. This study illustrates the typical problems with, as well as the potency of, chromatographic methods in the elucidation of metabolic routes of organic contaminants.

Dysregulation of airway cytokine expression in chronic obstructive pulmonary disease and asthma.

Cigarette smoking is the major factor responsible for chronic obstructive pulmonary disease (COPD). COPD occurs in a minority of smokers, but the host factors that modify risk of disease have not been clearly elucidated. There is significant clinical and histopathologic overlap between COPD and asthma, including the accumulation and activation of airway inflammatory cells. These two disorders are compared and contrasted. Abnormal airway inflammatory cytokine expression in these disorders is discussed.

Moclobemide versus amitriptyline in the treatment of depression: two small double-blind multicentre studies in Belgium.

Moclobemide was compared with amitriptyline for antidepressant efficacy, safety and tolerance. Two studies were conducted, both over at least 4 weeks; in the first, 8 patients were given moclobemide in doses ranging from 300 to 328 mg, and 9 patients amitriptyline in doses of 75 to 96 mg; in the second, the numbers were 13 on moclobemide and 14 on amitriptyline, and the mean doses were 294-408 mg and 95-129 mg respectively. Both studies showed the 2 treatments to be equally effective, and there were no significant differences at any point. Moclobemide appeared slightly more effective and slightly better tolerated than amitriptyline, but the numbers were too small for any valid conclusion.

A double-blind comparative study of remoxipride and haloperidol in schizophrenic and schizophreniform disorders.

The antipsychotic effect of remoxipride was compared to that of haloperidol in a randomized double-blind study with parallel group design comprising 98 patients with schizophrenia or schizophreniform disorder according to DSM-III. After a 3-7 day placebo washout period, patients received either 150-600 mg of remoxipride or 5-20 mg of haloperidol daily for 6 weeks. No significant differences in efficacy were found between the two treatments. Treatment-emergent checklist symptoms such as hypokinesia, rigidity, and tremor occurred more frequently and were more severe during haloperidol than during remoxipride treatment despite a significantly higher concurrent use of anticholinergic drugs in the haloperidol group. Haloperidol-treated patients reported greater increases in sleep and salivation than remoxipride-treated patients. Shoulder shaking and tremor were reported as occurring more frequently in the haloperidol group according to the Simpson and Angus rating scale for extrapyramidal symptoms. In summary, the two drugs seemed to be equally efficacious, though the tolerability profile favoured remoxipride.

Dirofilaria immitis: diethylcarbamazine-induced anaphylactoid reactions in infected dogs.

The immunopathogenesis of the anaphylactoid Mazzotti reactions has been studied by comparing physiologic and immunologic aspects of diethylcarbamazine-induced shock in Dirofilaria immitis infected dogs with antigen induced anaphylaxis in infected and uninfected controls. Filarial antigen, specific host IgG antibody, and C1 and C3 complement levels were quantitatively measured over time in relation to the levels of histamine and prostaglandin D2 in the blood and changes in mean blood pressure. D. immitis antigen injected into uninfected dogs having no detectable IgG antibody to D. immitis or Toxocara canis produced a rapid drop in blood pressure that paralleled a drop in C1 and C3 levels and an increase in prostaglandin D2. Antigen injected into infected dogs with IgG antibody produced a similar drop in blood pressure and complement and increase in prostaglandin D2 which differed from the uninfected group only in the slower clearance of antigen from the blood. Diethylcarbamazine alone produced no measurable changes in blood pressure or complement in uninfected hosts. Diethylcarbamazine, however, administered into skin test positive infected dogs, produced a temporally slower but quantitatively similar loss in blood pressure, drop in complement, and increase in prostaglandin D2 and histamine to that induced by antigen injection. Complement activation and immune complex formation are initiated by antigen release, and subsequent vasoactive mediator release leads to shock with prostaglandin D2 being quantitatively higher in blood than is histamine.