Fighting Antimicrobial Resistance and Healthcare-Associated Infections in EU-JAMRAI: The One-Health Response from Italy.

INTRODUCTION: Antimicrobial resistance (AMR) is a serious health threat, and it has high priority among the European public health agenda. The development and implementation of the National Action Plans (NAPs) with a One-Health perspective to fight AMR was supported in 2017 by the European Union (EU) through a Joint Action on Antimicrobial Resistance and Healthcare Associated Infections (EU-JAMRAI). The Italian National Institute of Health (Istituto Superiore di Sanità), supported by the University of Udine, and the University of Foggia were among the 44 partners involved. This paper describes the results of EU-JAMRAI relevant to Italy and its impact on national policies. METHODS: The activities involved national and international experts who worked in groups, either in virtual or face-to-face meetings. Country-to-country visits were organized to assess and compare the national strategies to counteract AMR and to exchange best practices. In addition, qualitative research methods, particularly focus groups (FGs) and structured interviews, were carried out to collect information and opinions from the experts. RESULTS: The Italian team of experts from the Ministry of Health and the University of Foggia visited the Netherlands and hosted the Polish expert team in Italy. In two FG, stakeholders' opinions from different organizations were collected and analyzed to identify critical areas and provide recommendations to ensure implementation of the NAP and effective One-Health integration. In addition, attitudes of medical professionals toward antimicrobial stewardship were evaluated in a medium/large Italian hospital. Strengths were identified in the multidisciplinary approach and the hospital management's proactive involvement. As for the veterinary sector, Italy was among the 10 EU countries that did not have any national AMR surveillance in place for animal bacterial pathogens. Consequently, a European surveillance system was proposed with the adhesion of Italy. Regarding research and innovation to fight AMR and healthcare-associated infection, Italy worked with the other European partners to identify national research gaps and opportunities. As a result, recommendations were issued to the authorities to promote research and innovation with a One-Health approach. CONCLUSIONS: The Italian participation in the EU JAMRAI provided experience and examples to the Italian government for implementing the NAP and planning the roadmap to fight AMR and helped point out the system's criticalities. It also supported the promotion of the One-Health integrated vision that was included in the updated NAP.

Urinary Bisphenol-A (BPA) and Bis(2-ethylhexyl)phthalate (DEHP) metabolite concentrations in children with obesity: A case-control study.

Introduction Obesity is a worldwide public health problem. Experimental animal and in vitro studies suggest that the exposure to BPA and phthalates are associated to a higher risk of obesity. Objective To determine urinary excretion of bisphenol A and phthalates in obese and normal weight children. Methods A case-control study was conducted in 122 children. Sixty-six obese children 36 girls (mean age 8.41±1.27 years) and 30 boys (mean age 8.51 ± 1.33 years), and 56 normal weight children, 27 girls (mean age 7.64 ± 1.49 years) and 29 boys (mean age 7.77 ± 1.56 years) were studied. Urinary BPA and Bis(2-ethylhexyl) phthalate (DEHP) metabolites (MEHP, MEHHP and MEOHP) were measured respectively by gas chromatography and high-performance liquid chromatography. Individual determinants of exposure were evaluated through "ad hoc" questionnaires. Results BPA and DEHP metabolites were detectable in obese and normal weight children. Obese girls showed significantly higher BPA concentrations in comparison with normal weight girls (means 10.77, 95% CI 7.02-16.53 vs 5.50, 95% CI 3.93-7.71 µg/g creatinine, respectively, p< 0.02). The first step of DEHP metabolic rate was significantly higher in obese girls compared with controls (p<0.05). DEHP metabolites correlated significantly with leptin concentrations in obese girls (p< 0.03). A higher risk of obesity was found in children with BPA levels above the median values with the habit to eat food packaged (OR=11.09, 95% CI=1.28-95.78). Conclusions These findings show that a higher exposure to BPA is associated with the risk of obesity in girls. Further studies are needed to unveil the cause-effect relationship.

Ecological and environmental factors affecting the risk of tick-borne encephalitis in Europe, 2017 to 2021.

BackgroundTick-borne encephalitis (TBE) is a disease which can lead to severe neurological symptoms, caused by the TBE virus (TBEV). The natural transmission cycle occurs in foci and involves ticks as vectors and several key hosts that act as reservoirs and amplifiers of the infection spread. Recently, the incidence of TBE in Europe has been rising in both endemic and new regions.AimIn this study we want to provide comprehensive understanding of the main ecological and environmental factors that affect TBE spread across Europe.MethodsWe searched available literature on covariates linked with the circulation of TBEV in Europe. We then assessed the best predictors for TBE incidence in 11 European countries by means of statistical regression, using data on human infections provided by the European Surveillance System (TESSy), averaged between 2017 and 2021.ResultsWe retrieved data from 62 full-text articles and identified 31 different covariates associated with TBE occurrence. Finally, we selected eight variables from the best model, including factors linked to vegetation cover, climate, and the presence of tick hosts.DiscussionThe existing literature is heterogeneous, both in study design and covariate types. Here, we summarised and statistically validated the covariates affecting the variability of TBEV across Europe. The analysis of the factors enhancing disease emergence is a fundamental step towards the identification of potential hotspots of viral circulation. Hence, our results can support modelling efforts to estimate the risk of TBEV infections and help decision-makers implement surveillance and prevention campaigns.

The use of aminopenicillins in animals within the EU, emergence of resistance in bacteria of animal and human origin and its possible impact on animal and human health.

Aminopenicillins have been widely used for decades for the treatment of various infections in animals and humans in European countries. Following this extensive use, acquired resistance has emerged among human and animal pathogens and commensal bacteria. Aminopenicillins are important first-line treatment options in both humans and animals, but are also among limited therapies for infections with enterococci and Listeria spp. in humans in some settings. Therefore, there is a need to assess the impact of the use of these antimicrobials in animals on public and animal health. The most important mechanisms of resistance to aminopenicillins are the ß-lactamase enzymes. Similar resistance genes have been detected in bacteria of human and animal origin, and molecular studies suggest that transmission of resistant bacteria or resistance genes occurs between animals and humans. Due to the complexity of epidemiology and the near ubiquity of many aminopenicillin resistance determinants, the direction of transfer is difficult to ascertain, except for major zoonotic pathogens. It is therefore challenging to estimate to what extent the use of aminopenicillins in animals could create negative health consequences to humans at the population level. Based on the extent of use of aminopenicillins in humans, it seems probable that the major resistance selection pressure in human pathogens in European countries is due to human consumption. It is evident that veterinary use of these antimicrobials increases the selection pressure towards resistance in animals and loss of efficacy will at minimum jeopardize animal health and welfare.

One Health challenges and actions: Integration of gender considerations to reduce risks at the human-animal-environmental interface.

The human-animal-environment interface is where the emergence of new infectious diseases can occur as a result of many complex reasons, including its alteration due to intensive farming and agriculture, increased human encroachment into wildlife habitats, international travel networks, and urbanization. The One Health approach to zoonoses is a holistic approach that considers environmental sustainability, animal health, and human health together. Gender-specific social and domestic roles can modulate (increase or decrease) an individual's risk of exposure to various hazards, including infectious diseases and zoonoses. The two scenarios presented here, one on avian influenza and the other on leptospirosis, clearly highlight the influence of gender, demonstrating that women's roles at the human-animal-environment interface are not the same as men's. Integrating the gender aspect into cross-sectoral interventions defined according to the One Health perspective could help reduce the risks of exposure to infections for humans and animals and the possible consequent economic losses. We suggest supplementing the One Health perspective with a gender analysis to study the influence of social norms, activities and risk behavior on exposure to infections, chemical pollution and the consequences of climate change.

Gender gap reduction and the one health benefits.

Several factors including gender, age groups, cultures and social conditions may affect significantly the risk of diseases and their clinical evolution. Unfortunately, little research has been carried out on these aspects and, consequently few guidelines or interventions have been implemented. In particular, gender is considered a main determinant of inequalities in living conditions, access to health services and, thus, in health protection. Focusing on the gender gap, we propose an ecological approach to find relationships between quantitative indicators of the gender gap dimension, the environmental performance index and the life expectancy at birth as summary of human health index in 155 countries. We speculated on the consequences of wider gender gaps to the population and environmental health. We further explore these relationships considering gender gap and environmental aspect subindexes, to identify determinants that should be addressed to maximize the One Health effect. We found that the gender gap in educational attainment followed by the political empowerment were strongly correlated with life expectancy, environmental health, and ecosystem vitality. Addressing gender issues, particularly the education attainment and political empowerment, can provide positive impact beyond the social dimension and the population health, and gender should be component of the One Health approach. We recommend gender targeted interventions that integrate these aspects into One Health national policies.

An annotated dataset for event-based surveillance of antimicrobial resistance.

This paper presents an annotated dataset used in the MOOD Antimicrobial Resistance (AMR) hackathon, hosted in Montpellier, June 2022. The collected data concerns unstructured data from news items, scientific publications and national or international reports, collected from four event-based surveillance (EBS) Systems, i.e. ProMED, PADI-web, HealthMap and MedISys. Data was annotated by relevance for epidemic intelligence (EI) purposes with the help of AMR experts and an annotation guideline. Extracted data were intended to include relevant events on the emergence and spread of AMR such as reports on AMR trends, discovery of new drug-bug resistances, or new AMR genes in human, animal or environmental reservoirs. This dataset can be used to train or evaluate classification approaches to automatically identify written text on AMR events across the different reservoirs and sectors of One Health (i.e. human, animal, food, environmental sources, such as soil and waste water) in unstructured data (e.g. news, tweets) and classify these events by relevance for EI purposes.

Exposure to Endocrine Disruptors (Di(2-Ethylhexyl)phthalate (DEHP) and Bisphenol A (BPA)) in Women from Different Residing Areas in Italy: Data from the LIFE PERSUADED Project.

Phthalates and bisphenol A (BPA) are plasticizers used in many industrial products that can act as endocrine disruptors and lead to metabolic diseases. During the LIFE PERSUADED project, we measured the urinary concentrations of BPA and Di(2-ethylhexyl)phthalate (DEHP) metabolites in 900 Italian women representative of the Italian female adult population (living in the north, centre, and south of Italy in both rural and urban areas). The whole cohort was exposed to DEHP and BPA with measurable levels above limit of detection in more than 99% and 95% of the samples, respectively. The exposure patterns differed for the two chemicals in the three macro-areas with the highest urinary levels for DEHP in south compared to central and northern Italy and for BPA in northern compared to central and southern Italy. BPA levels were higher in women living in urban areas, whereas no difference between areas was observed for DEHP. The estimated daily intake of BPA was 0.11 µg/kg per day, about 36-fold below the current temporary tolerable daily intake of 4 µg/kg per day established by the EFSA in 2015. The analysis of cumulative exposure showed a positive correlation between DEHP and BPA. Further, the reduction of exposure to DEHP and BPA, through specific legislative measures, is necessary to limit the harmfulness of these substances.

Characteristics of COVID-19 cases in Italy from a sex/gender perspective.

INTRODUCTION: Coronavirus disease 19 (COVID-19) is an infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). To date, few data on clinical features and risk factors for disease severity and death by gender are available. AIM: The current study aims to describe from a sex/gender perspective the characteristics of the SARS-CoV-2 cases occurred in the Italian population from February 2020 until October 2021. METHOD AND RESULTS: We used routinely collected data retrieved from the Italian National Surveillance System. The highest number of cases occurred among women between 40 and 59 years, followed by men in the same age groups. The proportion of deaths due to COVID-19 was higher in men (56.46%) compared to women (43.54%). Most of the observed deaths occurred in the elderly. Considering the age groups, the clinical outcomes differed between women and men in particular in cases over 80 years of age; with serious or critical conditions more frequent in men than in women. CONCLUSIONS: Our data clearly demonstrate a similar number of cases in women and men, but with more severe disease and outcome in men, thus confirming the importance to analyse the impact of sex and gender in new and emerging diseases.

Where we are in the fight against Antimicrobial Resistance and Healthcare-Associated Infections. The opinion of the stakeholders of the European Joint Action on Antimicrobial Resistance and Healthcare-Associated Infections (EU-JAMRAI).

During the second European Joint Action on Antimicrobial Resistance (AMR) and Healthcare-Associated Infections (HCI) (EU-JAMRAI) annual meeting, the Evaluation Team elicited stakeholders' opinions regarding the implementation of the National Strategies and Action Plans to fight AMR and HCI, the One Health integration and the EU-JAMRAI support to the national and EU authorities in two Focus Groups. This qualitative exercise contributed to identify criticalities and possible improvements in aspects such as political priorities, legislation/legal requirements, human and financial resources, and supervision in many health sectors to ensure effective implementation of the action plans. Stakeholders pointed out at the different speed of EU member states, in particular concerning the One Health integration in the plans. Finally, the Stakeholders strongly asked the EU-JAMRAI to reinforce the integration and dissemination of the best practices and results, to help policymakers at national and European levels in defining and implementing harmonized policies and actions against AMR and HCI.

Review and Analysis of National Monitoring Systems for Antimicrobial Resistance in Animal Bacterial Pathogens in Europe: A Basis for the Development of the European Antimicrobial Resistance Surveillance Network in Veterinary Medicine (EARS-Vet).

The monitoring of antimicrobial resistance (AMR) in bacterial pathogens of animals is not currently coordinated at European level. To fill this gap, experts of the European Union Joint Action on Antimicrobial Resistance and Healthcare Associated Infections (EU-JAMRAI) recommended building the European Antimicrobial Resistance Surveillance network in Veterinary medicine (EARS-Vet). In this study, we (i) identified national monitoring systems for AMR in bacterial pathogens of animals (both companion and food-producing) among 27 countries affiliated to EU-JAMRAI, (ii) described their structures and operations, and (iii) analyzed their respective strengths, weaknesses, opportunities and threats (SWOT). Twelve countries reported having at least one national monitoring system in place, representing an opportunity to launch EARS-Vet, but highlighting important gaps in AMR data generation in Europe. In total, 15 national monitoring systems from 11 countries were described and analyzed. They displayed diverse structures and operations, but most of them shared common weaknesses (e.g., data management and representativeness) and common threats (e.g., economic vulnerability and data access), which could be addressed collectively under EARS-Vet. This work generated useful information to countries planning to build or improve their system, by learning from others' experience. It also enabled to advance on a pragmatic harmonization strategy: EARS-Vet shall follow the European Committee on Antimicrobial Susceptibility Testing (EUCAST) standards, collect quantitative data and interpret AMR data using epidemiological cut-off values.

Defining the scope of the European Antimicrobial Resistance Surveillance network in Veterinary medicine (EARS-Vet): a bottom-up and One Health approach.

BACKGROUND: Building the European Antimicrobial Resistance Surveillance network in Veterinary medicine (EARS-Vet) was proposed to strengthen the European One Health antimicrobial resistance (AMR) surveillance approach. OBJECTIVES: To define the combinations of animal species/production types/age categories/bacterial species/specimens/antimicrobials to be monitored in EARS-Vet. METHODS: The EARS-Vet scope was defined by consensus between 26 European experts. Decisions were guided by a survey of the combinations that are relevant and feasible to monitor in diseased animals in 13 European countries (bottom-up approach). Experts also considered the One Health approach and the need for EARS-Vet to complement existing European AMR monitoring systems coordinated by the ECDC and the European Food Safety Authority (EFSA). RESULTS: EARS-Vet plans to monitor AMR in six animal species [cattle, swine, chickens (broilers and laying hens), turkeys, cats and dogs], for 11 bacterial species (Escherichia coli, Klebsiella pneumoniae, Mannheimia haemolytica, Pasteurella multocida, Actinobacillus pleuropneumoniae, Staphylococcus aureus, Staphylococcus pseudintermedius, Staphylococcus hyicus, Streptococcus uberis, Streptococcus dysgalactiae and Streptococcus suis). Relevant antimicrobials for their treatment were selected (e.g. tetracyclines) and complemented with antimicrobials of more specific public health interest (e.g. carbapenems). Molecular data detecting the presence of ESBLs, AmpC cephalosporinases and methicillin resistance shall be collected too. CONCLUSIONS: A preliminary EARS-Vet scope was defined, with the potential to fill important AMR monitoring gaps in the animal sector in Europe. It should be reviewed and expanded as the epidemiology of AMR changes, more countries participate and national monitoring capacities improve.

A Strong Evidence Outbreak of Salmonella Enteritidis in Central Italy Linked to the Consumption of Contaminated Raw Sheep Milk Cheese.

Salmonellosis is the second most commonly reported gastrointestinal infection in humans after campylobacteriosis, and an important cause of foodborne outbreaks in the EU/EEA. The vast majority (72.4%) of the salmonellosis foodborne outbreaks reported in EU in 2019 were caused by Salmonella Enteritidis, even if their total number due to this serovar decreased. In spring 2020, a foodborne outbreak of S. Enteritidis occurred in the Marche region (Central Italy), involving 85 people. The common exposure source was a cheese, pecorino "primo sale", produced with raw sheep milk. The cheese batches were produced by two local dairies, with a livestock production facility, also including a sheep farm, being part of one dairy. Bacteriological analysis of samples collected allowed the detection of S. Enteritidis in animal faeces, environmental samples, raw-milk bulk tanks and milk taken from single animals. These data confirm that, despite the scarce scientific evidence, S. Enteritidis can infect sheep and be shed into the animals' milk. Hence, this is a real risk for public health when unpasteurized milk is used in production of such cheese. The present paper describes the results of the investigations conducted to clarify this outbreak.

Italian Children Exposure to Bisphenol A: Biomonitoring Data from the LIFE PERSUADED Project.

A human biomonitoring (HBM) study on bisphenol A (BPA) in Italian children and adolescents was performed within the LIFE PERSUADED project, considering the residing areas, sex and age. The median urinary BPA level was 7.02 µg/L, with children living in the South of Italy or in urban areas having higher levels than those residing in the North or in rural areas. Children aged 4-6 years had higher BPA levels than those aged 7-10 and 11-14 years, but no differences were detected between sexes. The exposure in Italian children was higher compared to children from other countries, but lower than the HBM guidance value (135 µg/L). The estimated daily intake was 0.17 µg/kg body weight (bw) per day, about 24-fold below the temporary Tolerable Daily Intake of 4 µg/kg bw per day established by the European Food Safety Authority. However, this threshold was exceeded in 1.44% of the enrolled children, raising concern about the overall exposure of Italian young population.

Predicting respiratory failure in patients infected by SARS-CoV-2 by admission sex-specific biomarkers.

BACKGROUND: Several biomarkers have been identified to predict the outcome of COVID-19 severity, but few data are available regarding sex differences in their predictive role. Aim of this study was to identify sex-specific biomarkers of severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19. METHODS: Plasma levels of sex hormones (testosterone and 17ß-estradiol), sex-hormone dependent circulating molecules (ACE2 and Angiotensin1-7) and other known biomarkers for COVID-19 severity were measured in male and female COVID-19 patients at admission to hospital. The association of plasma biomarker levels with ARDS severity at admission and with the occurrence of respiratory deterioration during hospitalization was analysed in aggregated and sex disaggregated form. RESULTS: Our data show that some biomarkers could be predictive both for males and female patients and others only for one sex. Angiotensin1-7 plasma levels and neutrophil count predicted the outcome of ARDS only in females, whereas testosterone plasma levels and lymphocytes counts only in males. CONCLUSIONS: Sex is a biological variable affecting the choice of the correct biomarker that might predict worsening of COVID-19 to severe respiratory failure. The definition of sex specific biomarkers can be useful to alert patients to be safely discharged versus those who need respiratory monitoring.

Community waterborne outbreak linked to a firefighting response during the COVID-19 emergency.

BACKGROUND: On 6 March 2020, a big fire in a village forced the firefighters to draw water simultaneously from many sources, including the Adige river. From 9 March, an increasing number of inhabitants reported gastrointestinal symptoms. We describe the outbreak and the challenges linked to the concurrent COVID-19 spread. METHODS: Residents with enteric symptoms and their relatives were interviewed and samples from some of the patients and public water pipelines were tested for enteric pathogens with microbiological and molecular methods. RESULTS: By 20 March, 182 people reported symptoms and 131 met the case definition. Norovirus GI/GII and other pathogens were found in human and water samples. CONCLUSIONS: Contamination of the public water network with sewage-contaminated river water through the firefighters pressurized water tank was the suspected source of the outbreak. The investigation was partly hampered due to the SARS-CoV-2 emergency. Control measures included avoiding tap water, alternative water supplies and chlorination of public water.

Microbiological survey and occurrence of bacterial foodborne pathogens in raw and ready-to-eat green leafy vegetables marketed in Tehran, Iran.

Fresh leafy (FL) and ready-to-eat (RTE) vegetables are recognized as an important source of foodborne disease outbreaks worldwide. Currently, there are no data available for the prevalnce of bacterial foodborne pathogens (FBPs) in raw vegetables consumed in Iran. Here, we evalated the presence of common bacterial FBPs among 366 samples of raw vegetables including 274 FL and 92 RTE collected from 21 districts of Tehran. The presence of FBPs were screened using conventional microbiological culture methods and real-time PCR assays. Overall, a higher rate of bacterial contamination was detected in FL compared to RTE samples using both detection methods. The results obtained by microbiological methods showed that Staphylococcus aureus (134/366, 36.6%), followed by Escherichia coli (85/366, 23.2%) and Clostridium perfringens (66/366, 18%) were detetcted as the most prevalent pathogens in this study. Vibrio cholerae was not detected in any of the samples either by microbiological methods or by the real-time PCR assays. There was a noticeable reduction in the proportion of Campylobacter positive samples using conventional microbiological methods (3.5%) compared to the real-time PCR assay (20.7%). The proportion of FL and RTE positive samples obtained by conventional microbiological methods was significantly different (P < 0.05) for C. perfringens, Campylobacter spp. and S. aureus. The proportion of positive samples in FL and RTE vegetables obtained by the real-time PCR assays was significantly different (P < 0.05) for C. perfringens, S. aureus, Helicobacter pylori and STEC/EHEC, the last one was found more frequently in RTE than in FL samples. Our findings indicated a contamination of FL and RTE vegetables in Iran with a range of well-known and emerging FBPs. Positivity and the distribution of bacterial species from the current data indicated different contamination sources, and overall a lack of effective decontamination steps during the production chain. Moreover, further information about the quality of the water, the hygiene measures implemented during the processing, storage and marketing are required to better identify the critical points and define the proper measures.

How can we manage the COVID-19 infodemics? A case study targeted to health workers in Italy.

INTRODUCTION: The Istituto Superiore di Sanità (ISS) has been asked for rapid technical and scientific advice to the State and Regions during Sars-CoV-2 pandemic preparedness. METHODS: An ad hoc Working Group on Scientific Literature updates (WG SL) was set up at ISS (March-May 2020) to screen pre-prints and peer reviewed papers from arXiv, medRxiv, bioRxiv, and Pubmed to provide a real time knowledge and empirical evidence addressed to health-workers. RESULTS: The WG SL screened a total of 4,568 pre-prints and 15,590 peer reviewed papers, delivered as daily summary report of pre-print selection for ISS President activity in the National Scientific Technical Committee framework and a weekly open access publication (COVID Contents) on peer-reviewed papers of interest for health professionals, monitored by a satisfaction questionnaire. CONCLUSIONS: Promoting heath literacy, with a cross-cutting approach is a powerful heritage of Public Health Institutes and a proven effective non pharmacological intervention.

The challenging task to select Salmonella target serovars in poultry: the Italian point of view.

According to the European Food Safety Authority (EFSA) and European Centre for Disease Prevention and Control (ECDC) annual report, human salmonellosis is mostly related to consumption of contaminated poultry products. Since 2003 in Europe, the Salmonella serovars considered relevant for human health and subject to control in breeding hens of Gallus gallus are: S. Enteritidis, S. Typhimurium (including the monophasic variant), S. Infantis, S. Hadar and S. Virchow. Herein, we investigated the Italian epidemiological situation from 2016 to 2018, comparing Salmonella serovar distributions in humans and poultry, in order to identify the target Salmonella serovars that, if controlled, would potentially have the largest public health impact in Italy. The results showed that control of S. Virchow and S. Hadar does no longer seem to be a priority in Italy and that S. Napoli and S. Derby, which are not included in the group of EU target serovars, are among the most frequent serovars isolated from humans in Italy. While S. Derby has its main reservoir in pigs, S. Napoli does not have a specific reservoir. However, because this serovar is frequently isolated from breeding poultry flocks and is characterised by causing severe human illness, it is a potential target Salmonella serovar in breeding hens of Gallus gallus in Italy.

Toxicological Assessment of Oral Co-Exposure to Bisphenol A (BPA) and Bis(2-ethylhexyl) Phthalate (DEHP) in Juvenile Rats at Environmentally Relevant Dose Levels: Evaluation of the Synergic, Additive or Antagonistic Effects.

BACKGROUND: The general population (including children) is exposed to chemical mixtures. Plasticizers such as Bisphenol A (BPA) and Phthalates (mainly Bis(2-ethylhexyl) phthalate-DEHP) are widespread contaminants classified as endocrine disrupters which share some toxicological profiles and coexist in food and environment. METHODS: To identify hazards of DEHP and BPA mixtures, the juvenile toxicity test-where rodents are in peripubertal phase of development, resembling childhood-was selected using exposure data from biomonitoring study in children. Biological activity and potential enhanced and/or reduced toxicological effects of mixtures due to common mechanisms were studied, considering endpoints of metabolic, endocrine and reproductive systems. The degree of synergy or antagonism was evaluated by synergy score calculation, using present data and results from the single compound individually administered. RESULTS: In metabolic system, synergic interaction predominates in female and additive in male rats; in the reproductive and endocrine systems, the co-exposure of BPA and DEHP showed interactions mainly of antagonism type. CONCLUSIONS: The present approach allows to evaluate, for all the endpoints considered, the type of interaction between contaminants relevant for human health. Although the mode of action and biological activities of the mixtures are not completely addressed, it can be of paramount usefulness to support a more reliable risk assessment.