Applying the adverse outcome pathway concept for assessing non-monotonic dose responses: biphasic effect of bis(2-ethylhexyl) phthalate (DEHP) on testosterone levels.

Male reproduction is one of the primary health endpoints identified in rodent studies for some phthalates, such as DEHP (Bis(2-ethylhexyl) phthalate), DBP (Dibutyl phthalate), and BBP (Benzyl butyl phthalate). The reduction in testosterone level was used as an intermediate key event for grouping some phthalates and to establish a reference point for risk assessment. Phthalates, and specifically DEHP, are one of the chemicals for which the greatest number of non-monotonic dose responses (NMDRs) are observed. These NMDRs cover different endpoints and situations, often including testosterone levels. The presence of NMDR has been the subject of some debate within the area of chemical risk assessment, which is traditionally anchored around driving health-based guidance values for apical endpoints that typically follow a clear monotonic dose-response. The consequence of NMDR for chemical risk assessment has recently received considerable attention amongst regulatory agencies, which confirmed its relevance particularly for receptor-mediated effects. The present review explores the relationship between DEHP exposure and testosterone levels, investigating the biological plausibility of the observed NMDRs. The Adverse Outcome Pathway (AOP) concept is applied to integrate NMDRs into Key Event Relationships (KERs) for exploring a mechanistic understanding of initial key events and possibly associated reproductive and non-reproductive adverse outcomes.

[Implementation of a new gene therapy in ophthalmology: Regulatory and organizational issues]. / Mise en place d'une nouvelle thérapie génique en ophtalmologie : aspects réglementaires et organisationnels.

Voretigene neparvovec (VN) is the first gene therapy in ophthalmology for patients with RPE65-mediated hereditary retinal dystrophy. It has recently obtained European market approval, which is subject to strict regulatory and organizational conditions for its use. Here, we analyze the main studies supporting the authorization of this new therapy and describe the necessary steps to take at a hospital level for optimal administration to patients following current regulations.

[Retrospective cohort study of rituximab biosimilar (Rixathon®) adverse events in adult hematology and pediatric nephrology]. / Etude de cohorte rétrospective sur les effets indésirables du biosimilaire du rituximab (Rixathon®) en hématologie adulte et néphrologie pédiatrique.

The purpose of this study was to describe rituximab biosimilar safety in adult hematology and pediatric nephrology units. Adverse events were classified using the Common Terminology Criteria for Adverse Events (CTCAE) classification. Fifty adult patients were enrolled for a total of 126 cures and 11 pediatric patients for a total of 24 biosimilar cures. Among adults, three infusion-related reactions of biosimilar occurred : a bronchospasm, a reaction at the injection site and emesis. Among children, infusion-related reactions were: a bronchospasm, an injection site reaction, an emesis, and diarrhea. For adults, the most common adverse events included neutropenia (13.5 %) with 9 severe grade 3/4 cases, anemia (8.7 %), grade 1 thrombocytopenia (6.3 %), asthenia (2.4 %), infection (2.4 %), and chills (1.6 %). For children, a case of severe grade 4 neutropenia, a fever and conjunctivitis were observed. Results of this study show a confident safety profile of rituximab biosimilar in adults and children in «real life¼.

L'objectif de ce travail est de décrire les effets indésirables du biosimilaire du rituximab en «vie réelle¼ dans les services d'Hématologie adulte et de Néphrologie pédiatrique. Les effets indésirables ont été codés selon la classification des «Common Terminology Criteria for Adverse Events¼ (CTCAE). Cinquante patients adultes ont été inclus pour un total de 126 cures et 11 enfants pour un total de 24 cures de biosimilaire. Chez l'adulte, des réactions liées à la perfusion du biosimilaire ont été caractérisées par un bronchospasme avec frissons, une réaction au point d'injection et un cas de vomissements. Chez les enfants, les réactions liées à la perfusion étaient similaires avec un bronchospasme, une réaction au point d'injection, un cas de vomissements, et un cas de selles liquides. Chez les adultes, les effets indésirables les plus fréquents étaient la neutropénie (13,5 %), une anémie (8,7 %), une thrombopénie de grade 1 (6,3 %), une asthénie (2,4 %), une infection (2,4 %). Chez les enfants, un cas de neutropénie de grade 4, une fièvre et une conjonctivite ont été enregistrés. Le profil d'effets indésirables du biosimilaire du rituximab chez les adultes et les enfants est rassurant.

Risk analysis in pediatric inpatients.

The complexity and vulnerability of the pediatric population make them unique to risk management. Risk analysis is particularly demanding here and requires comprehensive identification of hazardous situations. Few data are published on methods to prevent medication errors in pediatric inpatients, reducing the possibility for healthcare institutions to prioritize the actions to take. This paper summarizes the proactive risk analysis methods described in the literature, the failures identified, and the corrective actions applied to reduce the risks in pediatrics.

Oral pentobarbital suspension for children sedation during MR imaging.

OBJECTIVES: The efficacy and safety of an oral pentobarbital suspension for sedation during pediatric MR imaging were assessed. METHODS: Data were recorded from October 2016 to January 2017. The exact dose of oral pentobarbital suspension was given for each child with an oral syringe. Parameters recorded included the patient's age and weight, the time required to sedate, the duration of sedation, the time required to discharge, and quality of MR imaging. The adverse effects were recorded. RESULTS: Oral pentobarbital suspension was administered to 81 children aged from 8 months to 8 years at a dose of 5mg/kg of body weight. The mean time required to sedate was 30±21min, a mean time of sedation of 47±23min, and a mean time to discharge of 77±32min. Sedation occurred a satisfied quality of MR imaging in 67% of patients. The failure of examination was essentially due to bad taste of the drug suspension. The overall success rate of sedation in patients less than 12 months was 100%. For ages 1 to 3 years, the success rate decreased to 76% and for ages 4 to 8 years, it decreased to 42%. CONCLUSIONS: Oral pentobarbital suspension used in MR imaging demonstrated its high rate of successful sedation in infants less than 12 months with no adverse effects during the study period.

Simultaneous determination of methanol, acetaldehyde, acetone, and ethanol in human blood by gas chromatography with flame ionization detection.

BACKGROUND: Methanol, acetaldehyde, acetone, and ethanol, which are commonly used as biomarkers of several diseases, in acute intoxications, and forensic settings, can be detected and quantified in biological fluids. Gas chromatography (GC)-mass spectrometry techniques are complex, require highly trained personnel and expensive materials. Gas chromatographic determinations of ethanol, methanol, and acetone have been reported in one study with suboptimal accuracy. Our objective was to improve the assessment of these compounds in human blood using GC with flame ionization detection. METHODS: An amount of 50 µl of blood was diluted with 300 µl of sterile water, 40 µl of 10% sodium tungstate, and 20 µl of 1% sulphuric acid. After centrifugation, 1 µl of the supernatant was injected into the gas chromatograph. We used a dimethylpolysiloxane capillary column of 30 m × 0.25 mm × 0.25 µm. RESULTS: We observed linear correlations from 7.5 to 240 mg/l for methanol, acetaldehyde, and acetone and from 75 to 2400 mg/l for ethanol. Precision at concentrations 15, 60, and 120 mg/l for methanol, acetaldehyde, and acetone and 150, 600, and 1200 mg/ml for ethanol were 0.8-6.9%. Ranges of accuracy were 94.7-98.9% for methanol, 91.2-97.4% for acetaldehyde, 96.1-98.7% for acetone, and 105.5-111.6% for ethanol. Limits of detection were 0.80 mg/l for methanol, 0.61 mg/l for acetaldehyde, 0.58 mg/l for acetone, and 0.53 mg/l for ethanol. CONCLUSION: This method is suitable for routine clinical and forensic practices.

Preliminary risk analysis applied to the transmission of Creutzfeldt-Jakob disease.

Transmissible spongiform encephalopathy (TSE) is a degenerative disease of the central nervous system. As yet, there is no human screening test and no effective treatment. This disease is invariably fatal. General preventive measures are therefore essential. The objective of this study is to analyze and address on a prioritized basis the risks relating to the transmission of Creutzfeldt-Jakob disease during surgical operations by means of a preliminary risk analysis (PRA). The PRA produces 63 scenarios with maximum risk relating to operational and legal dangers. The study recommends a number of courses of action, such as training and internal controls, in order to reduce the risks identified. A procedure has been drawn up and assessed for each action. This PRA makes it possible to target and significantly reduce the potential dangers for transmission of Creutzfeldt-Jakob disease through the use of medical instruments.

Map of risks for the implementation of radio-frequency identification: application of ancillaries in the University Hospital Jean Verdier.

Ancillaries are surgical instruments, such as orthopedical instruments set for reconstruction of knee (a mounting arm...) used to implant or extract prosthesis. Their management involves the departments of sterilization and surgery as well as the suppliers. Such a long circuit exposes the instruments to potential risk hazards like a lack of traceability as the suspicion of Creutzfeldt-Jakob. In order to reduce the risk of errors we will propose the implementation of radio-frequency identification (RFID) to trace the ancillaries during each step of the supply chain. The objective of our study is to analyze and to map the risks associated with RFID implementation. A preliminary analysis of risks (APR) is conducted to map out the hazards for the implementation of RFID. The APR identifies 162 scenarios with a maximum risk connected to environment and technology. To reduce the risks identified, 22 courses of action are proposed, such as audits, training, and internal controls. For each action, a procedure has been designed and evaluated. This preliminary analysis of risks allows targeting the potential dangers for the RFID implementation applied to ancillaries and reduces them significantly.

Association between folate, vitamin B(6) and vitamin B(12) intake and depression in the SUN cohort study.

BACKGROUND: An association between low blood levels of folate, vitamins B(6) and B(12) and a higher prevalence of depressive symptoms has been reported in several epidemiological studies. The present study aimed to assess the association between folate, vitamins B(6) and B(12) intake and depresion prevalence in the SUN cohort study. METHODS: The study comprised a cross-sectional analysis of 9670 participants. A validated semi-quantitative food frequency questionnaire was used to ascertain vitamin intake. The association between the baseline intake of folate, vitamins B(6) and B(12) categorised in quintiles and the prevalence of depression was assessed. The analyses were repeated after stratifying by smoking habits, alcohol intake, physical activity and personality traits. RESULTS: Among women, odds ratios (OR) [95% confidence interval (CI)] for the third to fifth quintile for vitamin B(12) intake were 0.58 (0.41-0.84), 0.56 (0.38-0.82) and 0.68 (0.45-1.04), respectively. Among those men with a low level of anxiety and current smokers, a significant positive association between low folate intake and the prevalence of depression was found. The OR (95% CI) for the first quintile of intake was 2.85 (1.49-5.45) and 2.18 (1.08-4.38), respectively, compared to the upper quintiles of intake (Q2-Q5) considered as a group. CONCLUSION: Low folate intake was associated with depression among currently smoking men and men with low anxiety levels. Low intake of vitamin B(12) was associated with depression among women. No significant associations were found for vitamin B(6) intake.

Data requirements for risk assessment of furan in food.

Furan is an organic, volatile compound used in various chemical-manufacturing industries. Headspace gas chromatography is the analytical method of choice for obtaining reliable results on its occurrence. The presence of furan in some food items has been known since the late 1970s, but a US Food and Drug Administration (FDA) survey published in 2004 revealed the occurrence of furan in a broad variety of canned and jarred foods, including baby food, that undergo heat treatment. Furan is carcinogenic in rats and mice, showing a dose-dependent increase in hepatocellular adenomas and carcinomas. In rats, a dose-dependent increase of mononuclear leukaemia is evident and a very high incidence of cholangiocarcinomas of the liver, even at the lowest dose tested. There is evidence to indicate that furan-induced carcinogenicity is probably attributable to a genotoxic mechanism. However, chronic toxicity with secondary cell proliferation may indirectly amplify the tumour response. From the available data, there is a relative small difference between possible human exposure and the doses in experimental animals required to produce carcinogenic effects. However, reliable risk assessment requires further data on both toxicity and exposure. The European Food Safety Authority's (EFSA) Scientific Panel on Contaminants in the Food Chain (CONTAM) recommended these studies as part of a reliable risk assessment of furan in food.

Evaluation of certain food additives and contaminants.

This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food additives, including flavouring agents, with a view to recommending acceptable daily intakes (ADIs) and to preparing specifications for identity and purity. The Committee also evaluated the risk posed by two food contaminants, with the aim of advising on risk management options for the purpose of public health protection. The first part of the report contains a general discussion of the principles governing the toxicological evaluation and assessment of intake of food additives (in particular flavouring agents) and contaminants. A summary follows of the Committee's evaluations of technical, toxicological and intake data for certain food additives (acidified sodium chlorite, asparaginase from Aspergillus oryzae expressed in Aspergillus oryzae, carrageenan and processed Eucheuma seaweed, cyclotetraglucose and cyclotetraglucose syrup, isoamylase from Pseudomonas amyloderamosa, magnesium sulfate, phospholipase A1 from Fusarium venenatum expressed in Aspergillus oryzae, sodium iron(III) ethylenediaminetetraacetic acid (EDTA) and steviol glycosides); eight groups of related flavouring agents (linear and branched-chain aliphatic, unsaturated, unconjugated alcohols, aldehydes, acids and related esters; aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances; simple aliphatic and aromatic sulfides and thiols; aliphatic acyclic dials, trials and related substances; aliphatic acetals; sulfur-containing heterocyclic compounds; aliphatic and aromatic amines and amides; and aliphatic alicyclic linear alpha, beta -unsaturated di- and trienals and related alcohols, acids and esters); and two food contaminants (aflatoxin and ochratoxin A). Specifications for the following food additives were revised: maltol and ethyl maltol, nisin preparation, pectins, polyvinyl alcohol, and sucrose esters of fatty acids. Specifications for the following flavouring agents were revised: maltol and ethyl maltol, maltyl isobutyrate, 3-acetyl-2,5-dimethylfuran and 2,4,5-trimethyl-delta-oxazoline (Nos 1482, 1506 and 1559), and monomenthyl glutarate (No. 1414), as well as the method of assay for the sodium salts of certain flavouring agents. Annexed to the report are tables summarizing the Committee's recommendations for intakes and toxicological evaluations of the food additives and contaminants considered.

Risk assessment of substances that are both genotoxic and carcinogenic report of an International Conference organized by EFSA and WHO with support of ILSI Europe.

The European Food Safety Authority (EFSA) and the World Health Organization (WHO), with the support of the International Life Sciences Institute, European Branch (ILSI Europe), organized an international conference on 16-18 November 2005 to discuss how regulatory and advisory bodies evaluate the potential risks of the presence in food of substances that are both genotoxic and carcinogenic. The objectives of the conference were to discuss the possible approaches for risk assessment of such substances, how the approaches may be interpreted and whether they meet the needs of risk managers. ALARA (as low as reasonably achievable) provides advice based solely on hazard identification and does not take into account either potency or human exposure. The use of quantitative low-dose extrapolation of dose-response data from an animal bioassay raises numerous scientific uncertainties related to the selection of mathematical models and extrapolation down to levels of human exposure. There was consensus that the margin of exposure (MOE) was the preferred approach because it is based on the available animal dose-response data, without extrapolation, and on human exposures. The MOE can be used for prioritisation of risk management actions but the conference recognised that it is difficult to interpret it in terms of health risk.

Approaches to the risk assessment of genotoxic carcinogens in food: a critical appraisal.

The present paper examines the particular difficulties presented by low levels of food-borne DNA-reactive genotoxic carcinogens, some of which may be difficult to eliminate completely from the diet, and proposes a structured approach for the evaluation of such compounds. While the ALARA approach is widely applicable to all substances in food that are both carcinogenic and genotoxic, it does not take carcinogenic potency into account and, therefore, does not permit prioritisation based on potential risk or concern. In the absence of carcinogenicity dose-response data, an assessment based on comparison with an appropriate threshold of toxicological concern may be possible. When carcinogenicity data from animal bioassays are available, a useful analysis is achieved by the calculation of margins of exposure (MOEs), which can be used to compare animal potency data with human exposure scenarios. Two reference points on the dose-response relationship that can be used for MOE calculation were examined; the T25 value, which is derived from linear extrapolation, and the BMDL10, which is derived from mathematical modelling of the dose-response data. The above approaches were applied to selected food-borne genotoxic carcinogens. The proposed approach is applicable to all substances in food that are DNA-reactive genotoxic carcinogens and enables the formulation of appropriate semi-quantitative advice to risk managers.

Oxidative stress related DNA adducts in the liver of female rats fed with sunflower-, rapeseed-, olive- or coconut oil supplemented diets.

Both animal and epidemiological studies support an effect of fatty acid composition in the diet on cancer development, in particular on colon cancer. We investigated the modulating effect of supplementation of the diet of female F344 rats with sunflower-, rapeseed-, olive-, or coconut oil on the formation of the promutagenic, exocyclic DNA adducts in the liver, an organ where major metabolism of fatty acids takes place. 1,N(6)-ethenodeoxyadenosine (etheno-dA), 3,N(4)-ethenodeoxycytidine (etheno-dC) and 1,N(2)-propandodeoxyguanosine from 4-hydroxy-2-nonenal (HNE-dGp) were determined as markers for DNA-damage derived from lipid peroxidation products and markers for oxidative stress. 8-Oxo-deoxyguanosine (8-Oxo-dG) was also measured as direct oxidative stress marker. The body weight of the rats was not influenced by the four diets containing the different vegetable oils during the 4-week feeding period. Highest adduct levels of etheno-dC (430 +/- 181 adducts/10(9) parent bases), HNE-dGp (617 +/- 96 adducts/10(9) parent bases) and 8-Oxo-dG (37,400 +/- 12,200 adducts/10(9) parent bases) were seen in rats on sunflower oil diet (highest linoleic acid content). Highest adducts levels of etheno-dA (133 +/- 113 adducts/10(9) parent bases) were found in coconut oil diet (lowest content of linoleic acid). Weakly positive correlations between linoleic acid content in the four diet groups were only observed for levels of HNE-dGp and 8-Oxo-dG. Neither the diet based on olive oil (which contains mainly oleic acid) nor the diet based on rapeseed oil (containing alpha-linolenic acid) exerted any significant protective effect against oxidative DNA damage. Our results indicate that a high linoleic acid diet may contribute to oxidative stress in the liver of female rats leading to a marginal increase in oxidative DNA-damage.

Psicopatología asociada a la homosexualidad / Psychopathology related to homosexuality

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[Drug interactions in an elderly population. Prospective assessment of their frequency and seriousness among 56 patients]. / Interactions médicamenteuses dans une population âgée.

OBJECTIVE: To assess the nature and the number of potential adverse drug interactions by analysis of outpatient prescriptions for elderly patients, of medications taken during the week before hospitalization in a general surgery department. METHOD: The study of 56 patients older than 65 years was conducted from November 2002 through February 2003. The outpatient prescriptions corresponding to medications taken during the 7 days before admission were analyzed by a pharmacy resident, who used data-processing tools and databases. RESULTS: Most patients (83%) knew the reason for their prescription. Thirteen (28%) reported using over-the-counter medication. Only 89% of the patients reported complete compliance with the prescription. The average age of the patients was 72.1 +/- 6.3 years and the median was 71 years [65-91]; 43% were women and 57% men. The 257 lines of prescriptions analyzed averaged 5.7 +/- 2.6 drugs (range: 2-10) per prescription. The average number of possible interactions was 3.1 +/- 2.8 per prescription for a total of 89 listed potential interactions. The levels observed were 3 warnings (3%), 37 precautions (42%) and 49 possible adverse interactions (55%). No contraindication was noted. The drugs mentioned most often were benzodiazepines, diuretics, conversion enzyme inhibitors, angiotensin II inhibitors, and beta-blockers. The potential risks most often found were hypotension, depression of the central nervous system, hypoglycemia and acute renal failure. The drug interactions were mainly due to the accumulation of the effects of separate drug classes. Deterioration in renal function was often noted as plasma concentration of the second drug increased. DISCUSSION: This exploratory study shows the reality of the iatrogenic risk for elderly patients. This analysis of outpatient prescriptions is consistent with findings in the literature. Analysis of interactions is conducted on a pairwise basis. It is thus difficult to envisage the consequences of the association of 5 or more drugs in patients with complex illnesses and diminished physiological and metabolic capacity. Patient files kept by the pharmacist could provide information about individual combinations ofthe prescription and over-the-counter drugs.

Stability of doxorubicin combined with Radioselectan, a contrast agent, for chemoembolization.

OBJECTIVE: To assess the stability of doxorubicin combined with Radioselectan. METHODS: Solutions of doxorubicin 5 mg/mL were prepared from commercially available 50 mg powder with 10 mL of Radioselectan. They were stored in glass syringes at 4, 25 and 45 degrees C. The concentrations of doxorubicin were determined using a stability-indicating high-performance liquid chromatography method. The initial and final pHs of solutions were compared. The times (t90) needed for doxorubicin to fall to 90% of its initial concentration were calculated by a linear regression analysis. RESULTS: The t90 [95% confidence limits] were 79 [75-83], 56 [53-59] and 22 [21-23] hours for the solutions stored at 4, 25 and 40 degrees C respectively. The initial pH of the solutions stored at 4, 25 and 40 degrees C were 6.52, 6.50 and 6.51 respectively. The final pH of solutions stored at 25 and 40 degrees C decreased significantly by 0.3 and 0.9 respectively. No change of pH solution stored at 4 degrees C was observed. CONCLUSION: Doxorubicin combined with Radioselectan stored at room temperature is stable for 48 h.

Human exposure and internal dose assessments of acrylamide in food.

This review provides a framework contributing to the risk assessment of acrylamide in food. It is based on the outcome of the ILSI Europe FOSIE process, a risk assessment framework for chemicals in foods and adds to the overall framework by focusing especially on exposure assessment and internal dose assessment of acrylamide in food. Since the finding that acrylamide is formed in food during heat processing and preparation of food, much effort has been (and still is being) put into understanding its mechanism of formation, on developing analytical methods and determination of levels in food, and on evaluation of its toxicity and potential toxicity and potential human health consequences. Although several exposure estimations have been proposed, a systematic review of key information relevant to exposure assessment is currently lacking. The European and North American branches of the International Life Sciences Institute, ILSI, discussed critical aspects of exposure assessment, parameters influencing the outcome of exposure assessment and summarised data relevant to the acrylamide exposure assessment to aid the risk characterisation process. This paper reviews the data on acrylamide levels in food including its formation and analytical methods, the determination of human consumption patterns, dietary intake of the general population, estimation of maximum intake levels and identification of groups of potentially high intakes. Possible options and consequences of mitigation efforts to reduce exposure are discussed. Furthermore the association of intake levels with biomarkers of exposure and internal dose, considering aspects of bioavailability, is reviewed, and a physiologically-based toxicokinetic (PBTK) model is described that provides a good description of the kinetics of acrylamide in the rat. Each of the sections concludes with a summary of remaining gaps and uncertainties.

[Drug administration to paediatric inpatient]. / L'administration des médicaments à l'enfant hospitalisé.

OBJECTIVE: Available commercial drugs in France are often unsuitable for children. The aim of this study was, for every medicinal form orally or parenterally administered, to identify and to quantify difficulties met by the nurses administering drugs to paediatric inpatients and to propose solutions to main identified problems. MATERIAL AND METHOD: The study was realized in 14 hospitals by direct observation. The observer, provided with a questionnaire, followed during a time slot of at least 2 h for one or several nurses and raised all the oral or injectable administrations. RESULTS: One thousand and nine hundred forty-six observations were performed. The children were 12.6 +/- 17 months old, and weighed 8.5 +/- 9.4 kg. Injectable drugs: half of the observations showed a posology and a mode of dilution not corresponding to the summary of product characteristics. Eight percent of orally administered drugs were injectable drugs. In 35.5% of cases, administered amount was lower than the quarter of the present quantity in the therapeutic unity. The rest of the therapeutic unity was thrown (77.2% of cases). Liquid oral forms: liquid oral forms were ready for use regarding 83.8% of cases. The medicine was readministered to the same patient (23.5%), and/or administered to other patients (80.0%). Capsules: 66.9% of the administered capsules were prepared by the hospital pharmacies. The pharmacies organized with an unit dose drug dispensing system produced significantly more preparations than those working by global distribution (P < 0.0001). In 58.4% of cases, the administered capsule was an off-label drug. Tablets: 46% of drug administration concerned a tablet without pediatric indication. 46.7% of tablets were cut, 74% were crushed. Bags: in 35.2% of observations, the bag was not administered in its entirety. CONCLUSION: Our study confirms the unsuitability of drugs to paediatric inpatients, the necessity of recommendations of good practices in the administration of drugs to paediatric inpatients, and proposes corrective actions.