Pesticides and cardiotoxicity. Where do we stand?

Cardiovascular diseases are among the most significant causes of mortality in humans. Pesticides toxicity and risk for human health are controlled at a European level through a well-developed regulatory network, but cardiotoxicity is not described as a separate hazard class. Specific classification criteria should be developed within the frame of Regulation (EC) No 1272/2008 in order to classify chemicals as cardiotoxic, if applicable to avoid long-term cardiovascular complications. The aim of this study was to review the cardiac pathology and function impairment due to exposure to pesticides (i.e. organophosphates, organothiophisphates, organochlorines, carbamates, pyrethroids, dipyridyl herbicides, triazoles, triazines) based on both animal and human data. The majority of human data on cardiotoxicity of pesticides come from poisoning cases and epidemiological data. Several cardiovascular complications have been reported in animal models including electrocardiogram abnormalities, myocardial infarction, impaired systolic and diastolic performance, functional remodeling and histopathological findings, such as haemorrhage, vacuolisation, signs of apoptosis and degeneration.

The impact of HIV preexposure prophylaxis on bacterial sexually transmitted infection occurrence in MSM: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of preexposure prophylaxis (PrEP) initiation on bacterial sexually transmitted infection (STI) occurrence (overall; chlamydia; gonorrhea; syphilis), in MSM. DESIGN: Systematic review and meta-analysis. METHODS: Systematic searches were performed in PubMed, Embase, and Scopus without language restrictions until 1 February 2023. We sought studies reporting data for the estimation of incidence rate ratios (IRR), prevalence ratios or cumulative incidence ratios (the latter in equal time periods before and after PrEP initiation) regarding bacterial STI occurrence. Separate analyses were performed overall for any STI, syphilis, chlamydia and gonorrhea (overall; rectal; urethral; pharyngeal for the two latter conditions); ratios greater than unity denoted increase in STI occurrence after PrEP initiation. RESULTS: Twenty-three eligible studies with 11 776 participants (age range: 18-71 years) with a median follow-up of 12 months were included. Overall, PrEP initiation was associated with a significant increase in the occurrence of any STI (pooled effect size: 1.15, 95% confidence interval (CI): 1.04-1.26), any gonorrhea (pooled effect size: 1.17, 95% CI: 1.02-1.34), any chlamydia (pooled effect size: 1.31, 95% CI: 1.09-1.58) and rectal chlamydia (pooled effect size: 1.31, 95% CI: 1.05-1.64), whereas a borderline increase was found in urethral chlamydia (pooled effect size: 1.25, 95% CI: 0.99-1.60, P  = 0.064). Changes in pharyngeal chlamydia and site-specific gonorrhea occurrence did not reach statistical significance. Syphilis showed virtually no change after PrEP initiation (pooled effect size: 0.99, 95% CI: 0.72-1.37). CONCLUSION: These results highlight the need for more comprehensive, accessible STI testing to tackle bacterial STI infections in PrEP users.

A closed-loop audit of the prescription practice of topical antibiotics for acute infective conjunctivitis.

Objective: The implementation of guideline recommendations for antibiotics prescription for the management of patients with acute infective conjunctivitis (AIC) in primary care departments remains below par. Our objective was to assess the impact of clinical audit on adherence to evidence-based indications for prescription of antibiotic eye drops in patients diagnosed with AIC, in the setting of a primary care practice in western Greece. Methods: We conducted a retrospective audit to evaluate the current prescription practice of antibiotics for the management of AIC. Following evidence-based indications for the prescription of antibiotics in AIC through literature search, and in combination with discussion and collaboration with the primary care doctors of our department, we formulated and implemented guidelines for the management of AIC. We then performed a prospective re-audit to assess the management of patients with AIC after local implementation of the guidelines. Results: A total of 158 cases were audited in the first cycle before the introduction of the guidelines, from 15th June 2019 to 7th March 2020, and 26 cases after, from 10th March 2020 to 20th November 2020. The compliance with the guidelines regarding antibiotics prescription was significantly improved from 12.0% to 84.6% between the first and the second cycles of audit. Conclusions: In this study, with the local introduction of guidelines, clinical audit significantly improved the prescription practice of topical antibiotics in patients with AIC in a primary care department. Abbreviations: AIC = acute infective conjunctivitis.

Fixed versus Unfixed Combination of Topical Latanoprost/Timolol for Glaucoma: An Observational Study Investigating the Level of Adherence and Ocular Surface Health.

PURPOSE: To investigate the effect of fixed combination versus concomitant unfixed topical glaucoma treatment on patients' adherence and ocular surface health. PATIENTS AND METHODS: This is a 6-month, prospective, parallel-group, observational study in patients with ocular hypertension (OHT), primary open-angle glaucoma (POAG), or exfoliation glaucoma (XFG). A total of 142 patients with similar baseline characteristics were enrolled in this study. Seventy-one patients received a Latanoprost 0.005%/Timolol 0.5% fixed combination in the evening, whereas seventy-one patients received the unfixed treatment with Latanoprost 0.005% in the evening and Timolol 0.5% twice daily. The primary outcome was the adherence rate at baseline, and at the 3- and 6-month follow-up visits. The secondary outcomes included the signs of ocular surface disease (OSD) and intraocular pressure (IOP). RESULTS: The adherence of patients treated with the fixed combination was higher than the unfixed treatment at the 3-month (78.0% vs. 63.0%, p < 0.001) and at the 6-month visits (73.0% vs. 58.5%, p < 0.01). The Break-up Time, Schirmer test, and Van Bijsterveld score were worse in the unfixed group at baseline and all subsequent examinations (p < 0.05 for all comparisons). There were no differences in the mean IOP between groups at baseline, 1-, and 3-month visits. IOP appears higher in the unfixed group at 6 months (16.7 vs. 15.0 mmHg, p < 0.01). CONCLUSION: The patients with ocular hypertension and primary open-angle glaucoma treated with a fixed combination are significantly more adherent and show a healthier ocular surface than those treated with an unfixed combination. The study provides significant evidence of the benefits of fixed combination treatment.

Cardiotoxicity of Chemical Substances: An Emerging Hazard Class.

(1) Background: Human health risks and hazards from chemical substances are well regulated internationally. However, cardiotoxicity, is not defined as a stand-alone hazard and therefore there are no defined criteria for the classification of substances as cardiotoxic. Identifying and regulating substances that cause cardiovascular adverse effects would undoubtedly strengthen the national health systems. (2) Methods: To overcome the aforementioned gap, a roadmap is proposed for identifying regulatory criteria from animal studies and endorse legislation in order to classify substances as cardiotoxic. The roadmap consists of: (i) the identification of the appropriate animal species and strains; (ii) the identification of the lines of scientific evidence (e.g., histopathological, biochemical and echocardiographic indices etc.) from animal studies with relevance to humans; (iii) the statistical analysis and meta-analysis for each line of scientific evidence after exposure to well-established cardiotoxicants to humans (e.g., anthracyclines) in order to identify threshold values or range of normal and/ or altered values due to exposure; (iv) validation of the above described lines of evidence in animals exposed to other alleged cardiotoxic substances (e.g., anabolic androgen steroids (AAS) and pesticides); (v) establishment of mechanisms of action based on information of either known or alleged cardiotoxicants; and (vi) introduction of novel indices and in silico methods. (3) Results: Preliminary results in rats indicate a clear distinction from normal values to values measured in rats exposed to anthracyclines regarding left ventricle (LV) fractional shortening (FS) and LV ejection fraction (EF). A distinctive pattern is similarly observed for Creatine Kinase-Myocardial Band isoenzyme (CK-MB) and cardiac tissue glutathione (GSH). These findings are encouraging and indicate that there is room for targeted research to this end, and that these specific indices and biochemical markers should be further investigated in order to be developed to regulatory criteria. (4) Conclusions: Further research should be conducted by both the scientific and regulatory community that aims to clearly define the cardiotoxicity hazard caused by chemicals and develop a full set of scientific criteria.

Children and Parents' Awareness Regarding Potential Hazards Derived from the Use of Chemical Products in Greece.

Over the last decades, human activities prompted the high production and widespread use of household chemical products, leading to daily exposure of humans to several chemicals. The objective of this study was to investigate the frequency of chemicals' use by children and parents in Greece and estimate the level of risk awareness and understanding among them. A total of 575 parents and children were asked to answer an anonymous, closed-ended, validated, and self-administered questionnaire. One-third of the children and almost half of the parents participating in the study believed that commonly used chemical products do not pose any risk to human health or to the environment, despite the product labelling. The majority of both children (61.8%) and parents (70.6%) were informed about product safety via the product labelling. Around 20% in both groups could not differentiate between systemic toxicity and acute lethal effects depicted by pictograms on the label and milder hazards, such as skin irritation. Moreover, the information on hazard and precautionary statements appearing on the label was very poorly perceived. Therefore, as both children and parents seem not to clearly identify the hazards and risks arising from the use of everyday chemical products, targeted awareness policies should be implemented to support the safe use of household products.

[Corrigendum] What is considered cardiotoxicity of anthracyclines in animal studies.

Subsequently to the publication of this paper, the authors have realized that the name of the seventh listed author, Dimitrios Stagos, was spelt incorrectly (it appeared as 'Stagkos' in print). The corrected author list is shown above. The authors regret that the name of the seventh author on the paper was spelt incorrectly, and apologize to the readers for any inconvenience caused.[the original article was published in Oncology Reports 44: 798-818, 2020; DOI: 10.3892/or.2020.7688].

What is considered cardiotoxicity of anthracyclines in animal studies.

Anthracyclines are commonly used anticancer drugs with well­known and extensively studied cardiotoxic effects in humans. In the clinical setting guidelines for assessing cardiotoxicity are well­established with important therapeutic implications. Cardiotoxicity in terms of impairment of cardiac function is largely diagnosed by echocardiography and based on objective metrics of cardiac function. Until this day, cardiotoxicity is not an endpoint in the current general toxicology and safety pharmacology preclinical studies, although other classes of drugs apart from anthracyclines, along with everyday chemicals have been shown to manifest cardiotoxic properties. Also, in the relevant literature there are not well­established objective criteria or reference values in order to uniformly characterize cardiotoxic adverse effects in animal models. This in depth review focuses on the evaluation of two important echocardiographic indices, namely ejection fraction and fractional shortening, in the literature concerning anthracycline administration to rats as the reference laboratory animal model. The analysis of the gathered data gives promising results and solid prospects for both, defining anthracycline cardiotoxicity objective values and delineating the guidelines for assessing cardiotoxicity as a separate hazard class in animal preclinical studies for regulatory purposes.

The application of new HARD-descriptor available from the CORAL software to building up NOAEL models.

Continuous QSAR models have been developed and validated for the prediction of no-observed-adverse-effect (NOAEL) in rats, using training and test sets from the Fraunhofer RepDose® database and EFSA's Chemical Hazards Database: OpenFoodTox. This paper demonstrates that the HARD index, as an integrated attribute of SMILES, improves the prediction power of NOAEL values using the continuous QSAR models and Monte Carlo simulations. The HARD-index is a line of eleven symbols, which represents the presence, or absence of eight chemical elements (nitrogen, oxygen, sulfur, phosphorus, fluorine, chlorine, bromine, and iodine) and different kinds of chemical bonds (double bond, triple bond, and stereo chemical bond). Optimal molecular descriptors calculated with the Monte Carlo technique (maximization of correlation coefficient between the descriptor and endpoint) give satisfactory predictive models for NOAEL. Optimal molecular descriptors calculated in this way with the Monte Carlo technique (maximization of correlation coefficient between the descriptor and endpoint) give amongst the best results available in the literature. The models are built up in accordance with OECD principles.

QSAR models for predicting acute toxicity of pesticides in rainbow trout using the CORAL software and EFSA's OpenFoodTox database.

Optimal (flexible) descriptors were used to establish quantitative structure - activity relationships (QSAR) for toxicity of pesticides (n=116) towards rainbow trout. A heterogeneous set of hundreds of pesticides has been used, taken from the EFSA's chemical Hazards Database: OpenFoodTox. Optimal descriptors are preparing from simplified molecular input-line entry system (SMILES). So-called, correlation weights of different fragments of SMILES are calculating by the Monte Carlo optimization procedure where correlation coefficient between endpoint and optimal descriptor plays role of the target function. Having maximum of the correlation coefficient for the training set, one can suggest that the optimal descriptor calculated with these correlation weights can correlate with endpoint for external validation set. This approach was checked up with three different distributions into the training (≈85%) set and external validation (≈15%) set. The statistical characteristics of these models are (i) for training set correlation coefficient (r2) ranges 0.72-0.81, and root mean squared error (RMSE) ranges 0.54-1.25; (ii) for external (validation) set r2 ranges 0.74-0.84; and RMSE ranges 0.64-0.75. Computational experiments have shown that presence of chlorine, fluorine, sulfur, and aromatic fragments is promoter of increase for the toxicity.

Synthetic and Natural Nutritional Supplements: Health "Allies" or Risks to Public Health?

BACKGROUND: The modern way of life involves high stress levels, poor eating habits, lack of exercise, obesity and other detrimental health factors. Nutritional supplements (NS) are complexes of nutrients with variant activity that may infer reversal to nutrient depletion. They tend to be popular amongst social categories associated with the healthy life style, such as the elite and amateur athletes, military people and the general population. OBJECTIVE: An overview of the state of play with regard to nutritional supplements - natural and synthetic-, is important both from toxicological and commercial point of view. METHOD: From a thorough literature review on nutritional supplements, several patents of application have been identified and herewith reviewed which recommend natural vegetable extracts as food supplements for prophylaxis, therapy, protection of immune system, diabetes, oxidative stress, cancer, chronic inflammations and other health conditions. Besides, nutritional supplements of pharmacological validity and high popularity are discussed relative to their contents and group of use. RESULTS: Cases of adulteration or unintentional contamination of commercial products with abusing substances (doping substances, narcotics etc.) or toxic compounds (heavy metals, plant toxics) have shed light to the problem of causing recalls of some products by the FDA. CONCLUSION: From the safety/ quality point of view, NS lack of harmonisation and sovereign laws/ institutional controls on the market and their wide commercialization may possibly lead to risks to public health.

Clarification of some aspects related to genotoxicity assessment.

The European Commission requested EFSA to provide advice on the following: (1) the suitability of the unscheduled DNA synthesis (UDS) in vivo assay to follow-up positive results in in vitro gene mutation tests; (2) the adequacy to demonstrate target tissue exposure in in vivo studies, particularly in the mammalian erythrocyte micronucleus test; (3) the use of data in a weight-of-evidence approach to conclude on the genotoxic potential of substances and the consequent setting of health-based guidance values. The Scientific Committee concluded that the first question should be addressed in both a retrospective and a prospective way: for future assessments, it is recommended no longer performing the UDS test. For re-assessments, if the outcome of the UDS is negative, the reliability and significance of results should be carefully evaluated in a weight-of-evidence approach, before deciding whether more sensitive tests such as transgenic assay or in vivo comet assay would be needed to complete the assessment. Regarding the second question, the Scientific Committee concluded that it should be addressed in lines of evidence of bone marrow exposure: toxicity to the bone marrow in itself provides sufficient evidence to allow concluding on the validity of a negative outcome of a study. All other lines of evidence of target tissue exposure should be assessed within a weight-of-evidence approach. Regarding the third question, the Scientific Committee concluded that any available data that may assist in reducing the uncertainty in the assessment of the genotoxic potential of a substance should be taken into consideration. If the overall evaluation leaves no concerns for genotoxicity, health-based guidance values may be established. However, if concerns for genotoxicity remain, establishing health-based guidance values is not considered appropriate.

Guidance on the assessment of the biological relevance of data in scientific assessments.

EFSA requested its Scientific Committee to prepare a guidance document providing generic issues and criteria to consider biological relevance, particularly when deciding on whether an observed effect is of biological relevance, i.e. is adverse (or shows a beneficial health effect) or not. The guidance document provides a general framework for establishing the biological relevance of observations at various stages of the assessment. Biological relevance is considered at three main stages related to the process of dealing with evidence: Development of the assessment strategy. In this context, specification of agents, effects, subjects and conditions in relation to the assessment question(s): Collection and extraction of data; Appraisal and integration of the relevance of the agents, subjects, effects and conditions, i.e. reviewing dimensions of biological relevance for each data set. A decision tree is developed to assist in the collection, identification and appraisal of relevant data for a given specific assessment question to be answered.

Guidance on the use of the weight of evidence approach in scientific assessments.

EFSA requested the Scientific Committee to develop a guidance document on the use of the weight of evidence approach in scientific assessments for use in all areas under EFSA's remit. The guidance document addresses the use of weight of evidence approaches in scientific assessments using both qualitative and quantitative approaches. Several case studies covering the various areas under EFSA's remit are annexed to the guidance document to illustrate the applicability of the proposed approach. Weight of evidence assessment is defined in this guidance as a process in which evidence is integrated to determine the relative support for possible answers to a question. This document considers the weight of evidence assessment as comprising three basic steps: (1) assembling the evidence into lines of evidence of similar type, (2) weighing the evidence, (3) integrating the evidence. The present document identifies reliability, relevance and consistency as three basic considerations for weighing evidence.

24-hour intraocular pressure control with maximum medical therapy compared with surgery in patients with advanced open-angle glaucoma.

PURPOSE: The purpose of this study was to evaluate 24-hour intraocular pressure (IOP) control in patients with moderate to severe open-angle glaucoma treated by trabeculectomy and mitomycin C versus maximum tolerated medical therapy. DESIGN: Prospective observational study. PARTICIPANTS: Thirty surgical patients and 30 medically treated patients with advanced glaucoma. METHODS: Patients successfully treated with initial trabeculectomy or patients considered successfully treated on maximum tolerated medical therapy (2-4 medicines) were enrolled. We performed IOP measurements at 6 am, 10 am, 2 pm, 6 pm, 10 pm, and 2 am. Patients were matched by IOP +/- 1 mmHg at 10 am. MAIN OUTCOME MEASURES: A 24-hour IOP control. RESULTS: The surgical patients had a mean diurnal IOP of 12.1+/-2.2 versus 13.5+/-2.0 mmHg for the matched medically treated patients (P = 0.0001). The average maximum IOP for the surgical group was 13.4+/-2.3 and 16.3+/-3.2 mm Hg for the medical group (P<0.0001). The 24-hour range of IOP for the surgical group was 2.3+/-0.8 and 4.8+/-2.3 mmHg for the medical group (P<0.0001). Except at 10 am (P = 0.5), the surgical group had a statistically lower IOP at each measured time point. Eleven (37%) patients in the medically treated group, and none in the surgically treated group, had peak IOPs > or = 18 mmHg. The majority of peak IOPs (10 of 11) occurred outside of normal office hours. CONCLUSIONS: This study suggests that a well-functioning trabeculectomy provides a statistically lower mean, peak, and range of IOP for the 24-hour day than maximum tolerated medical therapy in advanced glaucoma patients.

24-hour intraocular pressures with brimonidine purite versus dorzolamide added to latanoprost in primary open-angle glaucoma subjects.

OBJECTIVE: To evaluate the 24-hour efficacy of brimonidine purite versus dorzolamide, each added to latanoprost. DESIGN: Double-masked, 2-center, prospective, crossover comparison. PARTICIPANTS: Primary open-angle glaucoma (POAG) subjects. METHODS: Subjects were randomized to brimonidine purite or dorzolamide, each given twice daily, for the first 6-week treatment period after a 6-week latanoprost run-in. Subjects began the opposite treatment for the second 6-week period after a 6-week latanoprost-only treatment between periods. Intraocular pressure (IOP) was measured at 8 am, 12 pm, 4 pm, 8 pm, 12 am, 4 am, and 8 am at each baseline and at the end of each treatment period. This study provided an 80% power that a 1.5-mmHg difference could be excluded between groups if 27 subjects completed the study. A standard deviation (SD) of 2.8 mmHg was assumed. MAIN OUTCOME MEASURES: Twenty-four-hour efficacy of intraocular pressures of brimonidine purite versus dorzolamide, each added to latanoprost. RESULTS: In 31 completed subjects, the baseline mean diurnal 24-hour IOP (+/- SD) was 19.0+/-1.7 mmHg for brimonidine purite and 19.0+/-1.6 mmHg for dorzolamide (P = 0.52). The 8 am IOP after 6 weeks of therapy was 18.4+/-2.1 mmHg for brimonidine purite and 18.9+/-1.9 mmHg for dorzolamide (P = 0.40). The mean diurnal IOP was 16.9+/-1.5 mmHg for brimonidine purite and 16.8+/-1.5 mmHg for dorzolamide (P = 0.66). Dorzolamide caused a more bitter taste (P = 0.01) than brimonidine purite. CONCLUSIONS: This study suggests that brimonidine purite and dorzolamide, added to latanoprost, have similar efficacy and safety in POAG or ocular hypertensive subjects.

Ascorbic acid concentration is reduced in the aqueous humor of patients with exfoliation syndrome.

PURPOSE: To investigate whether there is a role for ascorbic acid in the development of exfoliation syndrome (XFS). DESIGN: A case-control study was undertaken that included consecutive patients with and without XFS in whom cataract surgery was indicated. Patients with ophthalmic conditions other than XFS and conditions that may influence ascorbic acid levels were excluded. METHODS: A prospective institutional study was undertaken. A small volume of aqueous humor was aspirated at the beginning of phacoemulsification cataract surgery. Eighty aqueous samples, 40 samples from 40 eyes of 40 cataract patients with XFS and 40 samples from 40 eyes of 40 age matched cataract patients without XFS, were collected and analyzed. Ascorbic acid concentration was evaluated in the aqueous samples with a microplate assay method. RESULTS: The mean +/- SD concentration of ascorbic acid in the aqueous from patients with XFS (0.86 +/- 0.43 mM; range, 0.12 to 1.7 mM) was significantly lower than the concentration of ascorbic acid found in the aqueous of age-matched control patients (1.15 +/- 0.50 mM; range 0.42 to 3.1 mM; P =.0068). Total mean protein concentration was found to be significantly higher in the XFS group (481.1 +/- 196.8 pg/dl versus 336.3 +/- 86.4 pg/dl in the controls; P <.0001). Nevertheless, no correlation could be established between ascorbic level and protein concentration. CONCLUSIONS: A significantly reduced mean level of ascorbic acid was observed in the aqueous humor of patients with XFS. In view of the fact that ascorbic acid is a major protective factor against free radical action, a role for free radical action is possible in the pathobiology of XFS.

Efficacy of brimonidine 0.2% in controlling acute postoperative intraocular pressure elevation after phacoemulsification.

PURPOSE: To determine the efficacy of brimonidine tartrate 0.2% drops given 2 times a day in reducing intraocular pressure (IOP) spikes during the first 24 hours after phacoemulsification cataract surgery. SETTING: Department of Ophthalmology, General Hospital of Patras Agios Andreas, Patras, Greece. METHODS: In this prospective double-blind placebo-controlled study, 1 eye of 40 consecutive normotensive cataract patients having small-incision cataract surgery was randomized into 1 of 2 treatment arms. Twenty patients received a placebo (artificial tears) and 20 patients received brimonidine tartrate 0.2% drops 2 times a day the day before and the day of surgery. Diurnal IOP variation was the primary efficacy variable; IOP was measured at baseline, before surgery, and 4, 6, 12, and 24 hours postoperatively. RESULTS: The placebo group had higher IOPs at every time point after surgery. Peak elevation of IOP occurred 6 hours after surgery. The mean IOP in the placebo group (27.71 mm Hg +/- 3.75 [SD]) was statistically significantly higher than in the brimonidine group (21.45 +/- 1.32 mm Hg) (P<.001). A major IOP rise (>/=20 mm Hg above baseline IOP) occurred in 1 patient (5%) in the placebo group who required emergency hypotensive therapy. Twenty-four hours after surgery, 11 eyes (55%) in the brimonidine group and 4 eyes (20%) in the placebo group had an IOP lower than baseline. CONCLUSION: Prophylactic treatment with brimonidine tartrate 0.2% 2 times a day for 2 days was effective in reducing IOP peaks throughout the first 24 hours after phacoemulsification surgery.

Retinal complications of phakic intraocular lenses.

High myopia has always been a challenge for refractive correction. Current laser surgical techniques, however, fall short of correcting high refractive errors due to lack of predictability, regression, corneal ectasia, and introduction of high order optical aberration. Phakic intraocular lenses (IOL) have been proposed as an effective refractive surgical procedure for the correction of severe myopia, but, despite recent advances in implant material technology and design, their concept is still under clinical investigation. Most of the concern regarding the complications of phakic IOLs focuses on the anterior segment of the eye. This review examines the posterior segment complications associated with phakic IOL implantation, evaluates possible pathogenetic mechanisms and discusses posterior segment complications, prevention and management.