Assessment Of Potential Adverse Effects Research Articles

Do new cement-based mortars pose a significant threat to the aquatic environment?

Nowadays, the use of multi-functional mortars has increased significantly, with interesting applications in the sustainable construction. In the environment, the cement-based materials are subjected to leaching, so the assessment of potential adverse effects upon aquatic ecosystem is necessary. This study focuses on the evaluation of the ecotoxicological threat and of a new type of cement-based mortar (CPM-D) and its raw materials leachates. A screening risk assessment were performed by Hazard Quotient methods. The ecotoxicological effects were investigated by a test battery with bacteria, crustacean, and algae. Two different procedures, Toxicity test Battery Index (TBI) and Toxicity Classification System (TCS), to obtain a single value for toxicity rank were used. Raw materials showed the highest metal mobility and in particular, for Cu, Cd and V potential hazard was evidenced. Leachate toxicity assessment evidenced the highest effects linked to cement and glass while the mortar showed the lowest ecotoxicological risk. TBI procedure allows a finer classification of effect linked to materials with respect to TCS which is based on worst case approach. A safe by design approach taking into account the potential and the effective hazard of the raw materials and of their combinations could allow to achieve sustainable formulations for building materials.

Infant Exposure to Antituberculosis Drugs via Breast Milk and Assessment of Potential Adverse Effects in Breastfed Infants: Critical Review of Data.

Infants of mothers treated for tuberculosis might be exposed to drugs via breast milk. The existing information on the exposure of breastfed infants lacks a critical review of the published data. We aimed to evaluate the quality of the existing data on antituberculosis (anti-TB) drug concentrations in the plasma and milk as a methodologically sound basis for the potential risk of breastfeeding under therapy. We performed a systematic search in PubMed for bedaquiline, clofazimine, cycloserine/terizidone, levofloxacin, linezolid, pretomanid/pa824, pyrazinamide, streptomycin, ethambutol, rifampicin and isoniazid, supplemented with update references found in LactMed®. We calculated the external infant exposure (EID) for each drug and compared it with the recommended WHO dose for infants (relative external infant dose) and assessed their potential to elicit adverse effects in the breastfed infant. Breast milk concentration data were mainly not satisfactory to properly estimate the EID. Most of the studies suffer from limitations in the sample collection, quantity, timing and study design. Infant plasma concentrations are extremely scarce and very little data exist documenting the clinical outcome in exposed infants. Concerns for potential adverse effects in breastfed infants could be ruled out for bedaquiline, cycloserine/terizidone, linezolid and pyrazinamide. Adequate studies should be performed covering the scenario in treated mothers, breast milk and infants.

Potential influence of prenatal 2.45 GHz radiofrequency electromagnetic field exposure on Wistar albino rat testis.

An ever-increasing use of wireless devices over the last decades has forced scientists to clarify their impact on living systems. Since prenatal development is highly sensitive to numerous noxious agents, including radiation, we focused on the assessment of potential adverse effects of microwave radiation (MR) on testicular development. Pregnant Wistar albino rats (3 months old, weighing 282±8 g) were exposed to pulsed MR at a frequency of 2.45 GHz, mean power density of 2.8 mW/cm², and a specific absorption rate of 1.82 W/kg for 2 hours/day throughout pregnancy. Male offspring were no longer exposed to MR following birth. Samples of biological material were collected after reaching adulthood (75 days). In utero MR exposure caused degenerative changes in the testicular parenchyma of adult rats. The shape of the seminiferous tubules was irregular, germ cells were degenerated and often desquamated. The diameters of the seminiferous tubules and the height of the germinal epithelium were significantly decreased (both at ∗∗p<0.01), while the interstitial space was significantly increased (∗∗p<0.01) when compared to the controls. In the group of rats prenatally exposed to MR, the somatic and germ cells were rich in vacuoles and their organelles were often altered. Necrotizing cells were more frequent and empty spaces between Sertoli cells and germ cells were observed. The Leydig cells contained more lipid droplets. An increased Fluoro Jade - C and superoxide dismutase 2 positivity was detected in the rats exposed to MR. Our results confirmed adverse effects of MR on testicular development.

Preclinical in vivo Neurotoxicity Studies of Drug Candidates

Neurotoxic effects are one of the common reasons for discontinuation of preclinical and/or clinical studies. Preclinical evaluation of neurotoxic effects is complicated due to a wide range of manifestations and degrees of severity. Current experimental approaches to neurotoxicity assessment are cumbersome, laborious and not adapted enough for preclinical studies in the early stages of drug development. The aim of the study was to review existing approaches to experimental assessment of neurotoxic potential of new drugs and to discuss the need for and feasibility of developing and using integrated rapid neurotoxicity tests for early assessment of a pharmacological project’s potential. The authors reviewed scientific literature and guidance documents and analysed current approaches to chemical compound neurotoxicity assessment in laboratory animals. The paper analyses the main issues of neurotoxicity assessment for new drugs and compares Irwin tests with the functional observation battery. It analyses issues related to assessment of drugs’ effects on the development and maturation of central nervous system functions at pre- and postnatal stages. It was determined that the current practice is not sufficient for assessment of potential adverse effects on cognitive functions. The authors assessed factors affecting cognitive functions of rodents during studies. The “Acute suppression of the exploratory and orientation response” and “Extrapolation escape task” tests were proposed for validation as potential rapid tests for detection of an array of organic and functional neurotoxic disorders at early stages of preclinical studies.

Can risk be predicted? An umbrella systematic review of current risk prediction models for cardiovascular diseases, diabetes and hypertension

ObjectiveTo provide an overview of the currently available risk prediction models (RPMs) for cardiovascular diseases (CVDs), diabetes and hypertension, and to compare their effectiveness in proper recognition of patients at...

Ecotoxicology of manufactured graphene oxide nanomaterials and derivation of preliminary guideline values for freshwater environments.

The unique physical and chemical properties of graphene-based nanomaterials (GNMs) have inspired a diverse range of scientific and industrial applications. The market value of GNMs is predicted to reach $US 1.3 billion by 2023. Common to many nanomaterials, an important and unresolved question is the environmental consequences of the increases in GNMs use. The current deficiencies in studies reporting ecotoxicology data for GNMs include differences in analytical methodologies for quantification, no standardized test guidelines, differences in morphology of GNMs, the lack of Chemical Abstract Service numbers, and the quality of the reported data. The assessment of potential adverse effects on aquatic organisms typically relies on guideline values based on species sensitivity distributions (SSDs) of toxicity data. We present preliminary water quality guideline values for graphene oxide NMs in freshwaters. Data include 10 species from 7 phyla (bacteria and fungi were not included). The most sensitive organism was found to be the freshwater shrimp Palaemon pandaliformis. The derived guideline values for 99, 95, 90, and 80% species protection were 350, 600, 830, and 1300 μg/L, respectively. These results will contribute to the regulatory derivations of future water quality guideline values for graphene-based NMs. Environ Toxicol Chem 2018;37:1340-1348. © 2018 SETAC.

Fluoride gel effective at reducing caries in children.

Data Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline , Embase, CINAHL, LILACS, ProQuest Dissertations and Theses, the Web of Science Conference Proceedings, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. Randomised or quasi-randomised controlled trials comparing topically applied fluoride gel with placebo or no treatment in children up to 16 years were considered. Studies had to be at least one year in duration with a frequency of application of at least once a year with blind outcome assessment. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces in both permanent and primary teeth (D(M)FS and d(e/m)fs). At least two reviewers extracted data and assessed risk of bias. The primary measure of effect was the prevented fraction (PF). Where data could be pooled random-effects meta-analyses were conducted. Potential sources of heterogeneity were examined in random-effects meta-regression analyses. Twenty-eight trials involving 9140 children and adolescents were included. Most of the studies (20) were at high risk of bias, with eight at unclear risk of bias. Twenty-five trials (8479 participants) provided data for meta-analysis on permanent teeth, with a D(M)FS pooled prevented fraction (PF) estimate of 28% (95% CI; 19-36%; P < 0.0001; with substantial heterogeneity (P < 0.0001; I(2) = 82%); moderate quality evidence). Subgroup and metaregression analyses suggested no significant association between estimates of D(M)FS prevented fractions and the prespecified trial characteristics. However, the effect of fluoride gel varied according to the type of control group used, with D(M)FS PF on average being 17% (95% CI 3% to 31%; P = 0.018) higher in non-placebo-controlled trials (the reduction in caries was 38% (95% CI 24% to 52%; P < 0.0001, 2808 participants) for the ten trials with no treatment as control group, and 21% (95% CI 15% to 28%; P < 0.0001, 5671 participants) for the 15 placebo-controlled trials.A funnel plot of the 25 trials in the D(M)FS PF meta-analysis indicated a relationship between prevented fraction and study precision, with an apparent lack of small studies with statistically significant large effects.For primary teeth the d(e/m)fs pooled prevented fraction estimate for the three trials (1254 participants) = 20% (95%CI; 1% - 38%; P = 0.04; with no heterogeneity (P = 0.54; I(2) = 0%); low quality evidence).There was limited reporting of adverse events. Only two trials reported information on acute toxicity signs and symptoms during the application of the gel (risk difference 0.01, 95% CI -0.01 to 0.02; P = 0.36; with no heterogeneity (P = 36; I(2) = 0%); 490 participants; very low quality evidence). None of the trials reported information on tooth staining, mucosal irritation or allergic reaction. The conclusions of this updated review remain the same as those when it was first published. There is moderate quality evidence of a large caries-inhibiting effect of fluoride gel in the permanent dentition. Information concerning the caries-preventive effect of fluoride gel on the primary dentition, which also shows a large effect, is based on low quality evidence from only three placebo-controlled trials. There is little information on adverse effects or on acceptability of treatment. Future trials should include assessment of potential adverse effects.

Isolated Human Peripheral Blood Mononuclear Cell (PBMC), a Cost Effective Tool for Predicting Immunosuppressive Effects of Drugs and Xenobiotics.

The science of immunotoxicology began in the early 1970s, following the recognition of increased sensitivity to infection following exposure of test species, including monkeys, hamsters, ducks, rats, mice and guinea pigs to various xenobiotics. Reduced resistance to infectious disease was a well-documented consequence of primary and acquired immunodeficiencies, but a novel outcome of xenobiotic exposure, leading some to characterize xenobiotic-induced immunosuppression as “chemical AIDS”. Although the comparison was scientifically inappropriate, “immunotoxicity” was often thought of as synonymous with “immunosuppression” during the formative years of the discipline, although hypersensitivity, allergy, and autoimmunity were recognized as potential exposure outcomes. Assessment of potential adverse effects on the immune system is an important component of the overall evaluation of toxicity of personal care products, chemicals and drugs. Current public opinion and ethical considerations have stimulated efforts to reduce the number of animals used to test the toxicity of chemicals, drugs and personal care products. However, only limited effort has gone into developing in-vitro or in silico methods to detect immune dysfunction. This may be at least partially attributable to the sheer complexity of the immune response, although there has been sufficient progress to warrant continued investigation along these lines. A peripheral blood mononuclear cell (PBMC) is any blood cell having a round nucleus such as lymphocyte, monocyte or a macrophage. These blood cells are a critical component in the immune system to fight infection and adapt to intruders. These cells can be extracted from whole blood using ficoll, a hydrophilic polysaccharide that separates layers of blood, followed by gradient centrifugation, which will separate the blood into a top layer of plasma, followed by a lower layer of PBMCs and then a fraction of polymorphonuclear cells (such as neutrophils and eosinophils) and finally a bottom layer of erythrocytes. The polymorphonuclear cells can be further isolated by lysing the red blood cells. PBMCs are widely used in research and toxicology applications. Peripheral blood mononuclear cells (PBMC) give selective responses to the immune system and are the major cells in the human body immunity. They contain several types of cells such as lymphocytes,monocytes or macrophages. Because peripheral blood is the place where exposure to chemicals occurs,these fundamentally important PBMCs are prone to be influenced by drugsand chemicals. This is why the availability of PBMCs from peripheral bloodis very important for researchers studying toxicity of new drugs or drugs or drugs or chemical compounds. There are many Applications for PBMCs in toxicology research including:

Fluoride gels for preventing dental caries in children and adolescents.

Fluoride gels for preventing dental caries in children and adolescents.

Transcranial Magnetic Stimulation in the Treatment of Neurological Disease

Transcranial magnetic stimulation (TMS) holds great potential in the treatment of a host of neurological conditions due to its ability to focally modulate—suppress or enhance—activity in targeted cortical brain regions and modify activity across specific brain networks. Results from early trials in a number of neurological indications are presented, including stroke rehabilitation, Parkinson’s disease, tinnitus, chronic pain, migraine, and epilepsy. We emphasize both the challenges, such as the limited efficacy to date in tinnitus, as well as the opportunities, such as the use of TMS in epilepsy caused by focal/cortical lesions. However, to establish TMS as a clinically valuable neurological therapeutic intervention, a number of hurdles must be overcome, including accurate targeting of the treatment, characterization of its therapeutic benefit for specific patients/symptoms, proof of efficacy in multicenter trials that are adequately blinded and powered, proof of the durability of the effects, and assessment of potential adverse effects of cumulative dose and repeated application. [ Psychiatr Ann. 2014; 44(6):299–304.]

Modeling the contribution of toxicokinetic and toxicodynamic processes to the recovery of Gammarus pulex populations after exposure to pesticides

Because aquatic macroinvertebrates may be exposed regularly to pesticides in edge-of-the-field water bodies, an accurate assessment of potential adverse effects and subsequent population recovery is essential. Standard effect risk assessment tools are not able to fully address the complexities arising from multiple exposure patterns, nor can they properly address the population recovery process. In the present study, we developed an individual-based model of the freshwater amphipod Gammarus pulex to evaluate the consequences of exposure to 4 compounds with different modes of action on individual survival and population recovery. Effects on survival were calculated using concentration-effect relationships and the threshold damage model (TDM), which accounts for detailed processes of toxicokinetics and toxicodynamics. Delayed effects as calculated by the TDM had a significant impact on individual survival and population recovery. We also evaluated the standard assessment of effects after short-term exposures using the 96-h concentration-effect model and the TDM, which was conservative for very short-term exposure. An integration of a TKTD submodel with a population model can be used to explore the ecological relevance of ecotoxicity endpoints in different exposure environments.

Histopathology of biodegradable polymers: challenges in interpretation and the use of a novel compact MRI for biocompatibility evaluation

Toxicologic pathology is the art of assessment of potential adverse effects at the tissue level in pre‐clinical studies. In the case of biomaterials and medical devices, the toxicologic pathologists assess the safety (biocompatibility) and efficacy (conditions of the use) of the implantable materials. Proper assessment of biocompatibility of biomaterials is of utmost importance, since it helps to determine their safety after implantation in humans. Biomaterial‐related toxicity can be attributed to several factors, including for example leachable compounds from the material leading to thrombosis or carcinogenesis, or biodegradation of the material causing changes in its physical and compatibility properties. Evaluation of biocompatibility and biofunctionality involves assessment of cytotoxicity, allergic responses, irritation, inflammation and systemic and chronic toxicity. In many of these assessments, the toxicologic pathologist has an important role in determining product safety and potential toxicity. In this article, we review the special needs for proper toxicologic pathology assessment of biomaterials and degradable polymers. We review common adverse effects expected with biomaterials and describe their pathological picture and their clinical relevance. We also introduce a novel compact MR imaging technology as a tool for assessing biocompatibility and efficacy of implanted biodegradable materials, since it allows for the longitudinal imaging and quantification of inflammationin vivocaused by the device implantation, and enabling general inspection of shape, location and integrity of the devicein vivo. Since the MR imaging technique is non‐invasive, the effects of the implantable device can be monitored longitudinally in the same animal without perturbation of the pathology. Copyright © 2014 John Wiley &amp; Sons, Ltd.

Statement supplementing the environmental risk assessment conclusions and risk management recommendations on genetically modified insect‐resistant maize 59122 for cultivation in the light of new scientific information on non‐target organisms and regionally sensitive areas

Following a request from the European Food Safety Authority (EFSA), the Panel on Genetically Modified Organisms (GMO Panel) was asked to supplement its environmental risk assessment conclusions and risk management recommendations on maize 59122 for cultivation in the light of new scientific information on non-target organisms and regionally sensitive areas. Having considered additional information relevant to the assessment of potential adverse effects of maize 59122 on non-target organisms, the Panel must revise two of its previous environmental risk assessment conclusions, invalidating its earlier statement on the environmental safety of maize 59122 in its 2013 Scientific Opinion. A gap in the event-specific data on the honeybee study performed by Maggi (2001) was identified, as a result of which uncertainty over the occurrence of adverse effects on pollinators due to potential unintended changes in maize 59122 remains. Therefore, the Panel is no longer in a position to complete its assessment on the occurrence of adverse effects on pollinators. The Panel reassessed the available dataset on ladybirds, including the Califf and Ostrem (2009) study, and considers the latter study does not enable resolving the remaining scientific uncertainty on the potential toxicity of the binary Cry34Ab1/Cry35Ab1 proteins on Coccinella septempunctata or other ladybirds. In both cases, the Panel recommends that an additional laboratory study is performed prior to authorisation. The Panel considered regionally sensitive areas in its assessment, but regards it as premature to recommend specific risk management strategies for susceptible insect species potentially found within and nearby such areas owing to the inconclusive nature of the assessment of potential adverse effects of maize 59122 on non-target organisms.

Nutrient- and non-nutrient-based natural health product (NHP) use in adults with mood disorders: prevalence, characteristics and potential for exposure to adverse events.

BackgroundTo address knowledge gaps regarding natural health product (NHP) usage in mental health populations, we examined their use in adults with mood disorders, and explored the potential for adverse events.MethodsFood and NHP intake was obtained from 97 adults with mood disorders. NHP data was used to compare prevalence with population norms (British Columbia Nutrition Survey; BCNS). Bivariate and regression analyses examined factors associated with NHP use. Assessment of potential adverse effects of NHP use was based on comparing nutrient intakes from food plus supplements with the Dietary Reference Intakes and by reviewing databases for reported adverse health effects.ResultsTwo-thirds (66%; 95% CI 56 to 75) were taking at least one NHP; 58% (95% CI 47 to 68) were taking NHPs in combination with psychiatric medications. The proportion of each type of NHP used was generally higher than the BCNS (range of p’s < 0.05 to 0.0001). When intakes from food and NHP sources were combined, a small proportion exceeded any Lowest-Observed-Adverse-Effect-Levels: only for niacin (n = 17) and magnesium (n = 6), two nutrients for which the potential for adverse effects is minimal. Conversely, about 38% (95% CI 28 to 49) of the sample were taking a non-nutrient based NHP for which previous adverse events had been documented.ConclusionsThe prevalent use of NHPs in this population suggests that health care providers need to be knowledgeable about their characteristics. The efficacy and safety of NHPs in relation to mental health warrants further investigation.

Engraftment Patterns of Human Adult Mesenchymal Stem Cells Expose Electrotonic and Paracrine Proarrhythmic Mechanisms in Myocardial Cell Cultures

After intramyocardial injection, mesenchymal stem cells (MSCs) may engraft and influence host myocardium. However, engraftment rate and pattern of distribution are difficult to control in vivo, hampering assessment of potential adverse effects. In this study, the role of the engraftment patterns of MSCs on arrhythmicity in controllable in vitro models is investigated. Cocultures of 4×10(5) neonatal rat cardiomyocytes and 7% or 28% adult human MSCs (hMSCs) in diffuse or clustered distribution patterns were prepared. Electrophysiological effects were studied by optical mapping and patch-clamping. In diffuse cocultures, hMSCs dose-dependently decreased neonatal rat cardiomyocyte excitability, slowed conduction, and prolonged action potential duration until 90% repolarization (APD90). Triggered activity (14% versus 0% in controls) and increased inducibility of re-entry (53% versus 6% in controls) were observed in 28% hMSC cocultures. MSC clusters increased APD90, slowed conduction locally, and increased re-entry inducibility (23%), without increasing triggered activity. Pharmacological heterocellular electric uncoupling increased excitability and conduction velocity to 133% in 28% hMSC cocultures, but did not alter APD90. Transwell experiments showed that hMSCs dose-dependently increased APD90, APD dispersion, inducibility of re-entry and affected specific ion channel protein levels, whereas excitability was unaltered. Incubation with hMSC-derived exosomes did not increase APD in neonatal rat cardiomyocyte cultures. Adult hMSCs affect arrhythmicity of neonatal rat cardiomyocyte cultures by heterocellular coupling leading to depolarization-induced conduction slowing and by direct release of paracrine factors that negatively affect repolarization rate. The extent of these detrimental effects depends on the number and distribution pattern of hMSCs. These results suggest that caution should be urged against potential adverse effects of myocardial hMSC engraftment.

Mifepristone: is there a place in the treatment of Cushing’s disease?

The purpose was to review the use of mifepristone in the treatment of Cushing's syndrome (CS) in the context of other recently published studies. We review the use of mifepristone, as published in the recent Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome (SEISMIC). We also review the multiple case reports and case series of mifepristone use in CS. A review of other medications used in the treatment of Cushing's disease (CD), including pasireotide and cabergoline also provides context for the discussion of the role of mifepristone in the treatment of CD. The results show that the treatment of CD has been primarily surgical with medical therapy reserved for adjuvant therapy when primary treatment fails or other therapies require time for optimal efficacy. Two recent large prospective studies, using pasireotide and mifepristone provide new clinical insights to the medical treatment of CD in particular. Mifepristone has been used to treat excessive cortisol production by blocking the action of cortisol at the level of the glucocorticoid receptor. Until recently, the majority of clinical experience with mifepristone on the treatment of excess cortisol was derived from case reports and small case series. Based on the SEISMIC study, mifepristone was FDA approved for hyperglycemia associated with CS. In conclusion the role of mifepristone in the treatment of CD remains one of adjuvant therapy. Its place among other choices for medical therapy has yet to be firmly established and an evidenced-based approach toward the use of novel medications in the treatment of CD has not been made. Selection of medication depends on drug approval and availability in individual countries and requires cautious assessment of potential adverse effects, consideration of patient comorbidities, and efficacy.

Bone Mineral Density Increases in HIV-Infected Children Treated With Long-term Combination Antiretroviral Therapy

The long-term treatment of human immunodeficiency virus (HIV)-infected children with combination antiretroviral therapy (cART) requires assessment of potential adverse effects, such as osteoporosis. Longitudinal data on bone mineral density (BMD) in HIV-infected children showed that cumulative treatment with cART had a positive impact on BMD over time.

Distributions and bioconcentration characteristics of perfluorinated compounds in environmental samples collected from the west coast of Korea

As part of an ongoing study of the status and trends of contaminants in the Yellow Sea, during May of 2009, the concentrations of perfluorinated compounds (PFCs) were determined in water (n=15), sediment (n=12), soil (n=13), and biota (n=74) from estuarine and coastal areas along the west coast of Korea. Of the 12PFCs monitored, PFOS and PFOA were the most frequently detected compounds in water. Greater concentrations of PFCs were found in waters from the inner regions of sea dikes in three artificial lakes, Shihwa, Asan, and Sapgyo, than outer regions. Concentrations were also comparable in two estuarine areas, which indicated that most PFCs in coastal areas originated from industrial and local regions and river water flowing through estuaries. Concentrations of PFCs in soils and sediments were generally less than limits of quantification and were generally less than those measured in biota. Compound-specific bioaccumulation of PFBS and PFOS had the greatest BCF values in crab, while in fish it was PFOS and PFDA, and in gastropods and bivalves it was PFHxS. Distributions of BCFs for PFOS in body-parts of crab showed the greatest values in soft tissues followed by shells and then legs. Distribution among tissues and organs of fishes was more variable than those observed for crab. When compared to a similar study conducted by our group in 2008, concentrations of PFCs in water samples were significantly less in 2009. However, there was little change in bioconcentration from sediments into benthic organisms. Finally, we conducted the assessment of potential adverse effects for PFCs on aquatic life by use of current and previous reported data.

The treatment of minor depression with St. John’s Wort or citalopram: Failure to show benefit over placebo

This paper presents new data addressing two important controversies in psychiatry: the construct of Minor Depression (MinD) and the efficacy of St. John’s Wort for milder forms of depressive disorders. Data are from a three-arm, 12 week, randomized clinical trial of investigating the efficacy of St. John’s Wort (810 mg/day), citalopram (20 mg/day), or placebo for acute treatment of MinD. Due to a high placebo response on all outcome measures, neither St. John’s Wort nor citalopram separated from placebo on change in depressive symptom severity, quality of life, or well-being. However, systematic assessment of potential adverse effects (AEs) led to three important observations: (1) prior to the administration of study compound, 60% of subjects endorsed items that would be characterized as AEs once study compound was administered, (2) St. John’s Wort and citalopram were each associated with a significant number of new or worsening AEs during treatment, and (3) using a structured interview for identifying AEs at baseline and during treatment is informative. MinD was not responsive to either a conventional antidepressant or a nutraceutical, and both compounds were associated with a notable side effects burden. Other treatment approaches for MinD should be investigated.

An ecological risk assessment of Cry1F maize pollen impact to pale grass blue butterfly

The intrinsic toxicity of lepidopteran-active Bt proteins necessitates assessment of non-target risks associated with environmental release of transgenic crops expressing these proteins. Principles of ecological risk assessment provide a means for assessing non-target risks when information regarding exposure to the toxin and species-specific effects are lacking. This is shown for the case of Bt Cry1F maize release in Japan, where off-field pollen dissemination and effect on butterfly species is of concern. The specific ecological entity of concern for the assessment of the non-target impact of Cry1F maize pollen was Yamato-shijimi (pale grass blue butterfly), Pseudozizeeria maha (Kollar), a commonly occurring, susceptible species. Yamato-shijimi is widely adapted in Japan where it occurs in both rural and metropolitan settings, corresponding to the distribution and habitat of katabami (Oxalis corniculata (L.)), the larval host plant. The northern extent of Yamato-shijimi habitat lies to the south of major maize production regions in Japan, but exposure may occur elsewhere where maize and Yamato-shijimi co-occur. Screening level assessment of potential adverse effects to Yamato-shijimi in the field environment considered the probability for spatial-temporal co-occurrence of the life stages of concern (1st and 2nd instars) and the stressor (Cry1F protein expressed in maize pollen) at environmentally relevant concentrations. In the event of exposure to maize pollen, early instars of Yamato-shijimi feed exclusively on the underside of katabami leaves, which further limits the portion of the butterfly population that would be exposed. Projected levels of exposure to Cry1F pollen are below the toxicity level of concern and, thus, indicate negligible risk. Most sensitive species characterization (intergenera sensitivity) similarly shows negligible risk to other Japanese butterfly species of concern when distributed beyond the maize field or field margin.