Mixture risk assessment and human biomonitoring: Lessons learnt from HBM4EU

Luijten, Mirjam; Vlaanderen, Jelle; Kortenkamp, Andreas; Antignac, Jean-Philippe; Barouki, Robert; Bil, Wieneke; Brand, Annick van den; Braver-Sewradj, Shalenie den; Klaveren, Jacob van; Mengelers, Marcel; Ottenbros, Ilse; Rantakokko, Panu; Kolossa-Gehring, Marike; Lebret, Erik

doi:10.1016/j.ijheh.2023.114135

Cited by 16 publications

(6 citation statements)

References 17 publications

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“…Additionally, EEDs have been linked to metabolic dysregulation, increased susceptibility to endocrinerelated cancers, and neurodevelopmental deficits. The cumulative effects of EEDs pose considerable risks to human health, necessitating further research and intervention strategies to mitigate their consequences (Luijten et al, 2023).…”

Section: Mixtures Of Edcs: Direct and Indirect Effects On Fertilitymentioning

confidence: 99%

Reproductive toxicity of combined effects of endocrine disruptors on human reproduction

Dutta

Sengupta

Bagchi

et al. 2023

Front. Cell Dev. Biol.

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Confluence of environmental, genetic, and lifestyle variables is responsible for deterioration of human fecundity. Endocrine disruptors or endocrine disrupting chemicals (EDCs) may be found in a variety of foods, water, air, beverages, and tobacco smoke. It has been demonstrated in experimental investigations that a wide range of endocrine disrupting chemicals have negative effects on human reproductive function. However, evidence on the reproductive consequences of human exposure to endocrine disrupting chemicals is sparse and/or conflicting in the scientific literature. The combined toxicological assessment is a practical method for assessing the hazards of cocktails of chemicals, co-existing in the environment. The current review provides a comprehensive overview of studies emphasizing the combined toxicity of endocrine disrupting chemicals on human reproduction. Endocrine disrupting chemicals interact with each other to disrupt the different endocrine axes, resulting in severe gonadal dysfunctions. Transgenerational epigenetic effects have also been induced in germ cells, mostly through DNA methylation and epimutations. Similarly, after acute or chronic exposure to endocrine disrupting chemicals combinations, increased oxidative stress (OS), elevated antioxidant enzymatic activity, disrupted reproductive cycle, and reduced steroidogenesis are often reported consequences. The article also discusses the concentration addition (CA) and independent action (IA) prediction models, which reveal the importance of various synergistic actions of endocrine disrupting chemicals mixtures. More crucially, this evidence-based study addresses the research limitations and information gaps, as well as particularly presents the future research views on combined endocrine disrupting chemicals toxicity on human reproduction.

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Section: Mixtures Of Edcs: Direct and Indirect Effects On Fertilitymentioning

confidence: 99%

Reproductive toxicity of combined effects of endocrine disruptors on human reproduction

Dutta

Sengupta

Bagchi

et al. 2023

Front. Cell Dev. Biol.

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“…In reality, we are exposed to the complex mixtures with various toxicity mechanisms. Large-scale human biomonitoring (HBM) projects, such as the US National Health and Nutrition Examination Survey (NHANES) and human biomonitoring for Europe (HBM4EU), have demonstrated significantly that exogenous chemicals and their metabolites are detected in blood, urine, and other human specimens [ 18 , 19 ]. However, a recent review of mixture toxicity data found that less than 20% of cases have tested a mixture including more than three components [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Toxicity Screening of Fifty Complex Mixtures in HepG2 Cells

Kim,

Kang,

Kim

et al. 2024

Toxics

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To develop the risk prediction technology for mixture toxicity, a reliable and extensive dataset of experimental results is required. However, most published literature only provides data on combinations containing two or three substances, resulting in a limited dataset for predicting the toxicity of complex mixtures. Complex mixtures may have different mode of actions (MoAs) due to their varied composition, posing difficulty in the prediction using conventional toxicity prediction models, such as the concentration addition (CA) and independent action (IA) models. The aim of this study was to generate an experimental dataset comprising complex mixtures. To identify the target complex mixtures, we referred to the findings of the HBM4EU project. We identified three groups of seven to ten components that were commonly detected together in human bodies, namely environmental phenols, perfluorinated compounds, and heavy metal compounds, assuming these chemicals to have different MoAs. In addition, a separate mixture was added consisting of seven organophosphate flame retardants (OPFRs), which may have similar chemical structures. All target substances were tested for cytotoxicity using HepG2 cell lines, and subsequently 50 different complex mixtures were randomly generated with equitoxic mixtures of EC10 levels. To determine the interaction effect, we calculated the model deviation ratio (MDR) by comparing the observed EC10 with the predicted EC10 from the CA model, then categorized three types of interactions: antagonism, additivity, and synergism. Dose–response curves and EC values were calculated for all complex mixtures. Out of 50 mixtures, none demonstrated synergism, while six mixtures exhibited an antagonistic effect. The remaining mixtures exhibited additivity with MDRs ranging from 0.50 to 1.34. Our experimental data have been formatted to and constructed for the database. They will be utilized for further research aimed at developing the combined CA/IA approaches to support mixture risk assessment.

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“…Nevertheless, these studies considered chemicals separately, while individuals are exposed simultaneously to a plethora of substances. Moreover, in Europe, human monitoring for several environmental chemicals in the research project HBM4EU evidenced higher levels of exposure than health based guidance values, which further highlighted concerns about effects on health of such chemical mixtures [ 22 , 38 ]. Our diet is an important vector of multiple exposure to chemicals, and food is the main source of exposure to a large set of environmental chemicals [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

Prenatal dietary exposure to mixtures of chemicals is associated with allergy or respiratory diseases in children in the ELFE nationwide cohort

Ghozal,

Kadawathagedara,

Delvert

et al. 2024

Environ Health

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Introduction Prenatal exposure to environmental chemicals may be associated with allergies later in life. We aimed to examine the association between prenatal dietary exposure to mixtures of chemicals and allergic or respiratory diseases up to age 5.5 y. Methods We included 11,638 mother-child pairs from the French “Étude Longitudinale Française depuis l’Enfance” (ELFE) cohort. Maternal dietary exposure during pregnancy to eight mixtures of chemicals was previously assessed. Allergic and respiratory diseases (eczema, food allergy, wheezing and asthma) were reported by parents between birth and age 5.5 years. Associations were evaluated with adjusted logistic regressions. Results are expressed as odds ratio (OR[95%CI]) for a variation of one SD increase in mixture pattern. Results Maternal dietary exposure to a mixture composed mainly of trace elements, furans and polycyclic aromatic hydrocarbons (PAHs) was positively associated with the risk of eczema (1.10 [1.05; 1.15]), this association was consistent across sensitivity analyses. Dietary exposure to one mixture of pesticides was positively associated with the risk of food allergy (1.10 [1.02; 1.18]), whereas the exposure to another mixture of pesticides was positively but slightly related to the risk of wheezing (1.05 [1.01; 1.08]). This last association was not found in all sensitivity analyses. Dietary exposure to a mixture composed by perfluoroalkyl acids, PAHs and trace elements was negatively associated with the risk of asthma (0.89 [0.80; 0.99]), this association was consistent across sensitivity analyses, except the complete-case analysis. Conclusion Whereas few individual chemicals were related to the risk of allergic and respiratory diseases, some consistent associations were found between prenatal dietary exposure to some mixtures of chemicals and the risk of allergic or respiratory diseases. The positive association between trace elements, furans and PAHs and the risk of eczema, and that between pesticides mixtures and food allergy need to be confirmed in other studies. Conversely, the negative association between perfluoroalkyl acids, PAHs and trace elements and the risk of asthma need to be further explored.

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Mixture risk assessment and human biomonitoring: Lessons learnt from HBM4EU

Cited by 16 publications

References 17 publications

Reproductive toxicity of combined effects of endocrine disruptors on human reproduction

Reproductive toxicity of combined effects of endocrine disruptors on human reproduction

In Vitro Toxicity Screening of Fifty Complex Mixtures in HepG2 Cells

Prenatal dietary exposure to mixtures of chemicals is associated with allergy or respiratory diseases in children in the ELFE nationwide cohort

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