Exposure to heavy metals and red blood cell parameters in children: a systematic review of observational studies

© 2022 Capitão, Martins, Santos, Bicho, Szigeti, Katsonouri, Bocca, Ruggieri, Wasowicz, Tolonen and Virgolino. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: Mechanistic studies show that heavy metals interfere with the hematopoietic system by inhibiting key enzymes, which could lead to anemia. However, the link between children’s exposure and red blood cell (RBC) parameters has been inconsistent. We aimed to summarize evidence on human studies exploring the association between exposure to lead, mercury, cadmium, arsenic, and chromium VI and RBC parameters in children. Methods: Following the PRISMA guidelines, we searched PubMed, Scopus, and Web of Science databases for studies published between January 2010 and April 2022. Eligible papers included human observational studies that directly assessed exposure (internal dose) to the heavy metals under study and RBC parameters in participants aged ≤18 years. We excluded studies using hospital-based samples. Study quality was assessed using the National Institutes of Health’s Quality Assessment Tools for Cohort and Cross-Sectional Studies. We synthesized the evidence using vote counting based on the direction of the relationship. Results: Out of 6,652 retrieved papers, we included a total of 38 (33 assessing lead, four mercury, two cadmium, and two arsenic; chromium VI was not assessed in any included paper). More than half of the studies were conducted in Asia. We found evidence of a positive relationship between lead concentration and hemoglobin (proportion of studies reporting negative relationships = 0.750; 95% Confidence Interval (CI) 0.583, 0.874) and mean corpuscular hemoglobin (0.875; 95% CI 0.546, 0.986), and a positive relationship with red cell distribution width (0.000; 95%CI 0.000, 0.379). When considering only good-quality studies (24% of the Pb studies), only the relationship with hemoglobin levels remained (0.875; 95% CI: 0.546, 0.986). Conclusion: We found evidence of a negative relationship between lead concentration and hemoglobin and mean corpuscular hemoglobin and of a positive relationship with red cell distribution width in children. We also identified a need to conduct more studies in European countries. Future studies should use standardized practices and make eorts to increase study quality, namely by conducting comprehensive longitudinal studies. Our findings support the need to take further actions to limit heavy metal exposure during childhood.This work was developed under the HBM4EU initiative, funded by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 733032.info:eu-repo/semantics/publishedVersio

Dietary acrylamide exposure and risk of site-specific cancer: a systematic review and dose-response meta-analysis of epidemiological studies

Copyright © 2022 Filippini, Halldorsson, Capitão, Martins, Giannakou, Hogervorst, Vinceti, Åkesson, Leander, Katsonouri, Santos, Virgolino and Laguzzi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Diet is a main source of acrylamide exposure to humans. Existing observational data on the relationship between dietary exposure to acrylamide and risk of cancer are inconsistent. We performed a systematic review and dose-response meta-analysis of epidemiological studies evaluating the association between dietary acrylamide exposure and several site-specific cancer. A systematic literature search was conducted in PubMed, Scopus, and Web of Science databases until March 7, 2022. Studies were eligible if they were carried out in non-occupationally exposed adults, assessed dietary acrylamide exposure (µg/day) and reported risk estimates of cancer incidence (all but gynecological cancers). Using a random-effects model, we performed a metaanalysis of site-specific cancer risk comparing the highest vs. lowest category of dietary acrylamide exposure. We also carried out a one-stage dose-response metaanalysis assessing the shape of the association. Out of 1,994 papers screened, 31 were eligible (total of 16 studies), which included 1,151,189 participants in total, out of whom 48,175 developed cancer during the median follow-up period of 14.9 years (range 7.3–33.9). The mean estimated dose of dietary acrylamide across studies was 23 µg/day. Pooled analysis showed no association between the highest vs. lowest dietary acrylamide exposure and each site-specific cancer investigated, with no evidence of thresholds in the dose-response meta-analysis. There were also no associations between dietary acrylamide exposure and the risk of cancers when stratifying by smoking status, except for increased risk of lung cancer in smokers. In conclusion, high dietary acrylamide exposure was not associated with an increased risk of site-specific non-gynecological cancer.This work was supported by the European Union Horizon-2020 Research and Innovation Programme under grant agreement No. 733032 HBM4EU.info:eu-repo/semantics/publishedVersio

Consultation on a sustainable HBM initiative in Europe - Deliverable Report D6.3 WP6 Sustainability and Capacity building.

This deliverable was produced under Task 6.3 of Work Package 6 on “Longer-term needs and expectations of stakeholders (2021-2030)”. The aim of this task was to gather information on the needs and expectations of both the National Hubs (NH) and a broad range of stakeholders regarding a long-term Human Biomonitoring (HBM) programme for Europe, to be establish in follow up to the current project, HBM4EU. Firstly and with a focus on options for financing a future initiative, information was collected on a range of available funding mechanisms at national, regional and international level. In terms of national funding, the results presented rely on responses to a survey with the NH. Unfortunately, the response from NHs was very limited, and as such the report only captures funding mechanisms from a limited number of countries, including Portugal, Spain, France, Germany and Cyprus. In order to gain insight into the status of the National Hubs and their capacities for HBM, a survey was conducted. The results provide an overview of the current situation across the NHs with regards to a range of aspects, including the level of activity of the NH, status of political support, availability of funding, ongoing HBM studies and willingness to align studies with HBM4EU. The results suggest that HBM4EU has raised the political profile of HBM in partner countries. Regarding ongoing HBM studies, only six countries have national HBM programmes, with most countries having only hot spot studies. Despite this, there was support for the alignment of studies to achieve European geographical coverage. Regarding funding, access to European funding is seen as important to leverage funds at national level. A second survey was targeted at a wide range of stakeholders, aiming to better understand their expectations for a long-term sustainable HBM initiative. The survey was followed by a workshop, where a more limited number of stakeholders had the opportunity to discuss the survey results and address such aspects as the scope of a future initiative, how to achieve financial sustainability, how to involve and how a future initiative might contribute to chemical policies. Concerning the needs and expectations of stakeholders, there is a strong interest in and support for a future HBM initiative at European level. The involvement of a European Union (EU) institution as part of a future steering committee was seen as crucial. According to this stakeholders’ consultation, the initiative should focus on protecting human health and the environment in Europe from hazardous chemical exposures by producing harmonised, high quality, transparent and inclusive data for effective risk assessment and management.HBM4EU - Grant agreement 733032 HORIZON 2020 Programmeinfo:eu-repo/semantics/publishedVersio

Scoping Review-The Association between Asthma and Environmental Chemicals

Asthma is one of the most common chronic diseases worldwide affecting all age groups from children to the elderly. In addition to other factors such as smoking, air pollution and atopy, some environmental chemicals are shown or suspected to increase the risk of asthma, exacerbate asthma symptoms and cause other respiratory symptoms. In this scoping review, we report environmental chemicals, prioritized for investigation in the European Human Biomonitoring Initiative (HBM4EU), which are associated or possibly associated with asthma. The substance groups considered to cause asthma through specific sensitization include: diisocyanates, hexavalent chromium Cr(VI) and possibly p-phenylenediamine (p-PDA). In epidemiological studies, polyaromatic hydrocarbons (PAHs) and organophosphate insecticides are associated with asthma, and phthalates, per- and polyfluoroalkyl substances (PFASs), pyrethroid insecticides, mercury, cadmium, arsenic and lead are only potentially associated with asthma. As a conclusion, exposure to PAHs and some pesticides are associated with increased risk of asthma. Diisocyanates and Cr(VI) cause asthma with specific sensitization. For many environmental chemicals, current studies have provided contradicting results in relation to increased risk of asthma. Therefore, more research about exposure to environmental chemicals and risk of asthma is needed.Peer reviewe

Coordination of chemical analyses under the European Human Biomonitoring Initiative (HBM4EU): Concepts, procedures and lessons learnt

The European Human Biomonitoring Initiative (HBM4EU) ran from 2017 to 2022 with the aim of advancing and harmonizing human biomonitoring in Europe. More than 40,000 analyses were performed on human samples in different human biomonitoring studies in HBM4EU, addressing the chemical exposure of the general population, temporal developments, occupational exposure and a public health intervention on mercury in populations with high fish consumption. The analyses covered 15 priority groups of organic chemicals and metals and were carried out by a network of laboratories meeting the requirements of a comprehensive quality assurance and control system. The coordination of the chemical analyses included establishing contacts between sample owners and qualified laboratories and monitoring the progress of the chemical analyses during the analytical phase, also addressing status and consequences of Covid-19 measures. Other challenges were related to the novelty and complexity of HBM4EU, including administrative and financial matters and implementation of standardized procedures. Many individual contacts were necessary in the initial phase of HBM4EU. However, there is a potential to develop more streamlined and standardized communication and coordination in the analytical phase of a consolidated European HBM programme.This study was part of the HBM4EU project receiving funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 733032. The co-funding of the HBM4EU partner countries is gratefully acknowledged. The authors thank all sample owners and qualified laboratories for the excellent collaboration. The authors also acknowledge the HBM4EU partners in charge of upstream (WP7, WP8) and downstream (WP10) processes for the smooth connections with the analytical phase.S

WP6 - Sustainability and Capacity building

This report aims to provide a revision on the national needs (T6.1), the funding mechanisms (T6.2) and the long-term sustainability of HBM4EU (T6.3). Therefore, this report is divided in the three above-mentioned sections, for which the different tasks within work package 6 (WP 6) provided input. Concerning national needs, a survey is conducted annually by the national hub (NH) coordinator to monitor and evaluate the progress and development of all National Hubs involved in HBM4EU. With 2020 being the fourth year of the HBM4EU project, the survey followed many of the questions of previous years. Most NHs are satisfied with their current HBM4EU involvement, but have expressed their concerns regarding the communication, funding and lack of direct involvement. The follow-up to HBM4EU, PARC, was mentioned and the necessary involvement of all countries as well as the importance of communication between NHs and National Hub Contact Points (NHCPs) was highlighted. Inclusivity of smaller countries seems to be a problem through both lack of funding and adequate tasks. Regarding funding mechanisms, the initial list of financing mechanisms in the HBM and environmental health area at national and international level was updated and is available on the HBM4EU website under the “Funding Opportunities” tab. This intends to be an inventory that can be used not only by the HBM4EU consortium but by the entire scientific community to provide an overview of existing funding sources. It comprises of a set of targeted strategies for identification and dissemination of funding which are explained in further detail in section 6 Funding mechanisms. A systematic literature review was also undertaken to understand what the primary funding source of projects in HBM was. The results are not available yet. As part of T6.3 on the long-term sustainability, a citizen survey was developed together with T4.1 – mapping of needs. This survey was initially used for focus groups to better understand their awareness and concerns of chemical exposure and Human Biomonitoring. It was updated to harvest more EU-wide results including chemical exposure during the COVID-19 pandemic. The survey took place between September 2020 and February 2021 and the results were organised to cover the same regions as the aligned studies to allow for the organisation of results in a similar way for coherence. In order to produce a short report summarising the outcome of the survey, the questions were grouped for quicker analysis. The majority of the respondents considers HBM a tool that produces important results on human exposure to chemicals and that it should be performed more often and in a more coordinated way. This was a non-representative survey and future work should focus on wider dissemination in other population groups and on understanding how perceptions change over time. The survey’s answers were also distributed to the NHs, so they can produce internal communication briefs on their own data for further dissemination.HORIZON2020 Programme Contract No. 733032 HBM4EU.info:eu-repo/semantics/publishedVersio

A Comprehensive Review

Funding: This project has received funding from the European Unions’ Horizon 2020 research and innovation Programme under grant agreement No 733032. HBM4EU.Polycyclic aromatic hydrocarbons (PAHs) are among the chemicals with proven impact on workers' health. The use of human biomonitoring (HBM) to assess occupational exposure to PAHs has become more common in recent years, but the data generated need an overall view to make them more usable by regulators and policymakers. This comprehensive review, developed under the Human Biomonitoring for Europe (HBM4EU) Initiative, was based on the literature available from 2008-2022, aiming to present and discuss the information on occupational exposure to PAHs, in order to identify the strengths and limitations of exposure and effect biomarkers and the knowledge needs for regulation in the workplace. The most frequently used exposure biomarker is urinary 1-hydroxypyrene (1-OH-PYR), a metabolite of pyrene. As effect biomarkers, those based on the measurement of oxidative stress (urinary 8-oxo-dG adducts) and genotoxicity (blood DNA strand-breaks) are the most common. Overall, a need to advance new harmonized approaches both in data and sample collection and in the use of appropriate biomarkers in occupational studies to obtain reliable and comparable data on PAH exposure in different industrial sectors, was noted. Moreover, the use of effect biomarkers can assist to identify work environments or activities of high risk, thus enabling preventive risk mitigation and management measures.publishersversionpublishe

HBM4EU-MOM: Prenatal methylmercury-exposure control in five countries through suitable dietary advice for pregnancy – Study design and characteristics of participants

Background: Seafood is a major source of vital nutrients for optimal fetal growth, but at the same time is the main source of exposure to methylmercury (MeHg), an established neurodevelopmental toxicant. Pregnant women must be provided with dietary advice so as to include safely fish in their diet for nutrition and mercury control. The aim of this work is to present the design of a multicentre randomized control trial (RCT), which combines human biomonitoring (HBM) with dietary interventions using seafood consumption advice to pregnant women for MeHg control, and to collect information about other possible sources of exposure to mercury. It also presents the materials developed for the implementation of the study and the characteristics of the study participants, which were self-reported in the first trimester of pregnancy. Methods: The "HBM4EU-MOM" RCT was performed in the frame of the European Human Biomonitoring Initiative (HBM4EU) in five coastal, high fish-consuming European countries (Cyprus, Greece, Spain, Portugal and Iceland). According to the study design, pregnant women (≥120/country, ≤20 weeks gestational age) provided a hair sample for total mercury assessment (THg) and personal information relevant to the study (e.g., lifestyle, pregnancy status, diet before and during the pregnancy, information on seafood and factors related to possible non-dietary exposures to mercury) during the first trimester of pregnancy. After sampling, participants were randomly assigned to "control" (habitual practices) or "intervention" (received the harmonized HBM4EU-MOM dietary advice for fish consumption during the pregnancy and were encouraged to follow it). Around child delivery, participants provided a second hair sample and completed another tailored questionnaire. Results: A total of 654 women aged 18-45 years were recruited in 2021 in the five countries, primarily through their health-care providers. The pre-pregnancy BMI of the participants ranged from underweight to obese, but was on average within the healthy range. For 73% of the women, the pregnancy was planned. 26% of the women were active smokers before the pregnancy and 8% continued to smoke during the pregnancy, while 33% were passive smokers before pregnancy and 23% remained passively exposed during the pregnancy. 53% of the women self-reported making dietary changes for their pregnancy, with 74% of these women reporting making the changes upon learning of their pregnancy. Of the 43% who did not change their diet for the pregnancy, 74% reported that their diet was already balanced, 6% found it difficult to make changes and 2% were unsure of what changes to make. Seafood consumption did not change significantly before and during the first trimester of pregnancy (overall average ∼8 times per month), with the highest frequency reported in Portugal (≥15 times per month), followed by Spain (≥7 times per month). During the first-trimester of pregnancy, 89% of the Portuguese women, 85% of the Spanish women and 90%) were unaware of safe procedures for handling spillage from broken thermometers and energy-saving lamps, though >22% experienced such an incident (>1 year ago). 26% of the women had dental amalgams. ∼1% had amalgams placed and ∼2% had amalgams removed during peri-pregnancy. 28% had their hair dyed in the past 3 months and 40% had body tattoos. 8% engaged with gardening involving fertilizers/pesticides and 19% with hobbies involving paints/pigments/dyes. Conclusions: The study design materials were fit for the purposes of harmonization and quality-assurance. The harmonized information collected from pregnant women suggests that it is important to raise the awareness of women of reproductive age and pregnant women about how to safely include fish in their diet and to empower them to make proper decisions for nutrition and control of MeHg, as well as other chemical exposures.We acknowledge funding for HBM4EU from the European Union’s Horizon 2020 research and innovation program under grant agreement #733032 and the national governments of the participating countries. This publication reflects only the authors’ views, and the European Commission is not responsible for any use that may be made of the in formation it contains.info:eu-repo/semantics/publishedVersio

Application of human biomonitoring to assess occupational exposure to polycyclic aromatic hydrocarbons in Europe: a literature review

Os hidrocarbonetos aromáticos policíclicos (HAPs) são produtos químicos com impacto em saúde ocupacional, pelo que a avaliação da exposição humana através de estudos de biomonitorização tem aumentado nos últimos anos. No entanto, os dados obtidos são ainda insuficientes para os reguladores e decisores políticos. Este trabalho, no contexto da Iniciativa Europeia em Biomonitorização Humana (HBM4EU), descreve uma revisão da literatura sobre a exposição ocupacional aos HAPs na Europa, entre 2008 e 2022, com o objetivo de identificar as vantagens e limitações dos vários biomarcadores de exposição e /ou de efeito, bem como o conhecimento em falta para melhorar a regulamentação. Os resultados da análise dos 42 artigos elegíveis para inclusão nesta revisão demonstram que o biomarcador de exposição mais utilizado é o 1-hidroxipireno urinário, sendo os biomarcadores de efeito mais comuns, biomarcadores de stresse oxidativo e genotoxicidade. Globalmente, verificou-se a necessidade de desenvolver novas abordagens de recolha de dados e amostras, bem como a seleção apropriada de biomarcadores de forma a obter dados fiáveis e comparáveis em diferentes setores industriais. Além disso, a aplicação de biomarcadores de efeito contribui para a identificação de ambientes de trabalho ou atividades de alto risco, possibilitando medidas de mitigação e gestão de risco.Polycyclic aromatic hydrocarbons (PAHs) are chemicals with impact on occupational health, therefore the assessment of human exposure using biomonitoring has increased in recent years. However, the data obtained are still insufficient to be useful to regulators and policy makers. This work, in the context of the Human Biomonitoring for Europe Initiative (HBM4EU), describes a review of the literature on occupational exposure to PAHs in Europe, between 2008 and 2022, with the aim of identifying the advantages and limitations of the various biomarkers of exposure and/or effect, as well as the missing knowledge to improve regulation in occupational settings. The results of the analysis of the 42 articles eligible for inclusion in this review demonstrate that the most used biomarker of exposure is urinary 1-hydroxypyrene, with the most common biomarkers of effect being the measurement of oxidative stress and genotoxicity. Overall, it was noted the need to develop new approaches to samples and data collection, as well as the appropriate selection of biomarkers in order to obtain reliable and comparable data in different industrial sectors. In addition, the application of effect biomarkers contributes to the identification of high-risk work environments or activities, enabling measures of risk mitigation and management.Este estudo recebeu financiamento do programa de investigação e inovação Horizonte 2020 da União Europeia sob o acordo de subvenção n.º 733032 e recebeu cofinanciamento das organizações dos autores.info:eu-repo/semantics/publishedVersio

HBM4EU-MOM: Prenatal methylmercury-exposure control in five countries through suitable dietary advice for pregnancy - Study design and characteristics of participants

Background: Seafood is a major source of vital nutrients for optimal fetal growth, but at the same time is the main source of exposure to methylmercury (MeHg), an established neurodevelopmental toxicant. Pregnant women must be provided with dietary advice so as to include safely fish in their diet for nutrition and mercury control. The aim of this work is to present the design of a multicentre randomized control trial (RCT), which combines human biomonitoring (HBM) with dietary interventions using seafood consumption advice to pregnant women for MeHg control, and to collect information about other possible sources of exposure to mercury. It also presents the materials developed for the implementation of the study and the characteristics of the study participants, which were self-reported in the first trimester of pregnancy. Methods: The "HBM4EU-MOM" RCT was performed in the frame of the European Human Biomonitoring Initiative (HBM4EU) in five coastal, high fish-consuming European countries (Cyprus, Greece, Spain, Portugal and Iceland). According to the study design, pregnant women (≥120/country, ≤20 weeks gestational age) provided a hair sample for total mercury assessment (THg) and personal information relevant to the study (e.g., lifestyle, pregnancy status, diet before and during the pregnancy, information on seafood and factors related to possible non-dietary exposures to mercury) during the first trimester of pregnancy. After sampling, participants were randomly assigned to "control" (habitual practices) or "intervention" (received the harmonized HBM4EU-MOM dietary advice for fish consumption during the pregnancy and were encouraged to follow it). Around child delivery, participants provided a second hair sample and completed another tailored questionnaire. Results: A total of 654 women aged 18-45 years were recruited in 2021 in the five countries, primarily through their health-care providers. The pre-pregnancy BMI of the participants ranged from underweight to obese, but was on average within the healthy range. For 73% of the women, the pregnancy was planned. 26% of the women were active smokers before the pregnancy and 8% continued to smoke during the pregnancy, while 33% were passive smokers before pregnancy and 23% remained passively exposed during the pregnancy. 53% of the women self-reported making dietary changes for their pregnancy, with 74% of these women reporting making the changes upon learning of their pregnancy. Of the 43% who did not change their diet for the pregnancy, 74% reported that their diet was already balanced, 6% found it difficult to make changes and 2% were unsure of what changes to make. Seafood consumption did not change significantly before and during the first trimester of pregnancy (overall average ∼8 times per month), with the highest frequency reported in Portugal (≥15 times per month), followed by Spain (≥7 times per month). During the first-trimester of pregnancy, 89% of the Portuguese women, 85% of the Spanish women and 90%) were unaware of safe procedures for handling spillage from broken thermometers and energy-saving lamps, though >22% experienced such an incident (>1 year ago). 26% of the women had dental amalgams. ∼1% had amalgams placed and ∼2% had amalgams removed during peri-pregnancy. 28% had their hair dyed in the past 3 months and 40% had body tattoos. 8% engaged with gardening involving fertilizers/pesticides and 19% with hobbies involving paints/pigments/dyes. Conclusions: The study design materials were fit for the purposes of harmonization and quality-assurance. The harmonized information collected from pregnant women suggests that it is important to raise the awareness of women of reproductive age and pregnant women about how to safely include fish in their diet and to empower them to make proper decisions for nutrition and control of MeHg, as well as other chemical exposures.We acknowledge funding for HBM4EU from the European Union’s Horizon 2020 research and innovation program under grant agreement #733032 and the national governments of the participating countries. This publication reflects only the authors’ views, and the European Commission is not responsible for any use that may be made of the information it contains.S