Weight of evidence evaluation of the metabolism disrupting effects of triphenyl phosphate using an expert knowledge elicitation approach.

Identification of Endocrine-Disrupting Chemicals (EDCs) in a regulatory context requires a high level of evidence. However, lines of evidence (e.g. human, in vivo, in vitro or in silico) are heterogeneous and incomplete for quantifying evidence of the adverse effects and mechanisms involved. To date, for the regulatory appraisal of metabolism-disrupting chemicals (MDCs), no harmonised guidance to assess the weight of evidence has been developed at the EU or international level. To explore how to develop this, we applied a formal Expert Knowledge Elicitation (EKE) approach within the European GOLIATH project. EKE captures expert judgment in a quantitative manner and provides an estimate of uncertainty of the final opinion. As a proof of principle, we selected one suspected MDC -triphenyl phosphate (TPP) - based on its related adverse endpoints (obesity/adipogenicity) relevant to metabolic disruption and a putative Molecular Initiating Event (MIE): activation of peroxisome proliferator activated receptor gamma (PPARγ). We conducted a systematic literature review and assessed the quality of the lines of evidence with two independent groups of experts within GOLIATH, with the objective of categorising the metabolic disruption properties of TPP, by applying an EKE approach. Having followed the entire process separately, both groups arrived at the same conclusion, designating TPP as a "suspected MDC" with an overall quantitative agreement exceeding 85%, indicating robust reproducibility. The EKE method provides to be an important way to bring together scientists with diverse expertise and is recommended for future work in this area.

Incorporation of Fast-Elimination Chemicals in Hair Is Governed by Pharmacokinetics-Implications for Exposure Assessment.

Mechanisms governing chemicals' incorporation in hair are incompletely understood, and gaps remain to link the concentration of chemicals in hair to level of exposure and internal dose present in the body. This study assesses the relevance of hair analysis for the biomonitoring of exposure to fast-elimination compounds and investigates the role of pharmacokinetics (PK) in their incorporation in hair. Rats were administered with pesticides, bisphenols, phthalates, and DINCH over 2 months. Hairs were analyzed for 28 chemicals/metabolites to investigate correlations between their concentration in hair and the dose administered to the animals. Urine collected over 24 h after gavage was used to determine chemicals' PK and to investigate their influence on incorporation into hair by means of linear mixed models (LMMs). Eighteen chemicals presented a significant correlation between concentration in hair and level of exposure. In models combining all chemicals, agreement between concentration in hair predicted by LMM and experimental values was moderate (R2 = 0.19) but significantly increased when PK were included in the models (R2 = 0.37), and even more when chemical families were considered separately (e.g., R2 = 0.98 for pesticides). This study shows that pharmacokinetics mediate incorporation of chemicals in hair and suggests the relevance of hair for assessing exposure to fast-elimination chemicals.

How to use human biomonitoring in chemical risk assessment: Methodological aspects, recommendations, and lessons learned from HBM4EU.

One of the aims of the European Human Biomonitoring Initiative, HBM4EU, was to provide examples of and good practices for the effective use of human biomonitoring (HBM) data in human health risk assessment (RA). The need for such information is pressing, as previous research has indicated that regulatory risk assessors generally lack knowledge and experience of the use of HBM data in RA. By recognising this gap in expertise, as well as the added value of incorporating HBM data into RA, this paper aims to support the integration of HBM into regulatory RA. Based on the work of the HBM4EU, we provide examples of different approaches to including HBM in RA and in estimations of the environmental burden of disease (EBoD), the benefits and pitfalls involved, information on the important methodological aspects to consider, and recommendations on how to overcome obstacles. The examples are derived from RAs or EBoD estimations made under the HBM4EU for the following HBM4EU priority substances: acrylamide, o-toluidine of the aniline family, aprotic solvents, arsenic, bisphenols, cadmium, diisocyanates, flame retardants, hexavalent chromium [Cr(VI)], lead, mercury, mixture of per-/poly-fluorinated compounds, mixture of pesticides, mixture of phthalates, mycotoxins, polycyclic aromatic hydrocarbons (PAHs), and the UV-filter benzophenone-3. Although the RA and EBoD work presented here is not intended to have direct regulatory implications, the results can be useful for raising awareness of possibly needed policy actions, as newly generated HBM data from HBM4EU on the current exposure of the EU population has been used in many RAs and EBoD estimations.

SCCS Scientific Opinion on Acid Yellow 3 (submission II) - SCCS/1631/21.

Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on Acid Yellow 3 - C054 (CAS Number 8004-92-0, EC No 305-897-5), submission II, preliminary version of 7 May 2021, final version of 23 July 2021, SCCS/1631/21.

Editorial for the Special Issue on "Human Biomonitoring in Health Risk Assessment: Current Practices and Recommendations for the Future".

In most health risk assessment (HRA) frameworks for chemicals, the default approach for exposure assessment is to estimate the intake from different sources and different routes of exposure [...].

Proposal for reference values for the developmental effects of valproate based on human data using a benchmark dose approach.

Following accidental release of valproate into ambient air during manufacture at a French production site in 2018, concerns were raised for inhabitants of the surrounding area. As no toxicological reference value (TRV) was available, the risks could not be properly assessed. The French Agency for Food, Environmental and Occupational Health and Safety (ANSES) was mandated to determine a TRV by inhalation to be used for risk assessment. Major congenital malformations (MCMs) in offsprings of mothers exposed to valproate during pregnancy have been reported in international scientific literature. As these adverse effects were the most sensitive effect identified, they were retained as the critical effect to be used for the TRV. The data from a robust registry on MCMs established by the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) were modellized and support a strong DRR between the prevalence of MCMs in the fetus and in utero exposure. A benchmark dose (BMD) was then calculated as the dose that may trigger a 5% increase in this risk. A lower 95% confidence limit (BMD5%L95%) of 2.26 mg/kg/day, leading to an oral TRV of 0.08 mg/kg/day and a respiratory TRV of 0.26 mg.m-3 after applying an uncertainty factor of 30, was determined.

SCCS scientific opinion on Butylated hydroxytoluene (BHT) - SCCS/1636/21.

OPINION TO BE CITED AS: SCCS (Scientific Committee on Consumer Safety), scientific opinion on Butylated hydroxytoluene (BHT), preliminary version of September 27, 2021, final version of December 2, 2021, SCCS/1636/21.

Sensitization properties of acetophenone azine, a new skin sensitizer identified in textile.

BACKGROUND: Acetophenone azine (CAS no. 729-43-1) present in sports equipment (shoes, socks and shin pads) has been suspected to induce skin allergies. Twelve case reports of allergy in children and adults from Europe and North America were published between 2016 and 2021. OBJECTIVES: The objective of this study was to confirm that acetophenone azine is indeed a skin sensitizer based on in vitro/ in vivo testings derived from the Adverse Outcome Pathway (AOP) built for skin sensitization by OECD in 2012. METHODS: Acetophenone azine was tested in vitro according to the human cell line activation test (h-CLAT) and the ARE-Nrf2 Luciferase Test (KeratinoSens) and in vivo using the Local Lymph Nodes Assay (LLNA). RESULTS: Both the h-CLAT and the KeratinoSens were positive whereas the LLNA performed at 5, 2.5 and 1% (wt/vol) of acetophenone azine, was negative. CONCLUSION: Based on these results, acetophenone azine was considered as a skin sensitizer. This was recently confirmed by its classification under the CLP regulation.

Human Biomonitoring Guidance Values (HBM-GVs) for Bisphenol S and Assessment of the Risk Due to the Exposure to Bisphenols A and S, in Europe.

Within the European Joint Programme HBM4EU, Human Biomonitoring Guidance Values (HBM-GVs) were derived for several prioritised substances. In this paper, the derivation of HBM-GVs for the general population (HBM-GVGenPop) and workers (HBM-GVworker) referring to bisphenol S (BPS) is presented. For the general population, this resulted in an estimation of the total urinary concentration of BPS of 1.0 µg/L assuming a 24 h continuous exposure to BPS. For workers, the modelling was refined in order to reflect continuous exposure during the working day, leading to a total urinary concentration of BPS of 3.0 µg/L. The usefulness for risk assessment of the HBM-GVs derived for BPS and bisphenol A (BPA) is illustrated. Risk Characterisation Ratios (RCRs) were calculated leading to a clear difference between risk assessments performed for both bisphenols, with a very low RCR regarding exposure to BPA., contrary to that obtained for BPS. This may be due to the endocrine mediated endpoints selected to derive the HBM-GVs for BPS, whereas the values calculated for BPA are based on the temporary Tolerable Daily Intake (t-TDI) from EFSA set in 2015. A comparison with the revised TDI recently opened for comments by EFSA is also discussed. Regarding the occupational field, results indicate that the risk from occupational exposure to both bisphenols cannot be disregarded.

Using Human Biomonitoring Data to Support Risk Assessment of Cosmetic Ingredients-A Case Study of Benzophenone-3.

Safety assessment of UV filters for human health by the Scientific Committee on Consumer Safety (SCCS) is based on the estimation of internal dose following external (skin) application of cosmetic products, and comparison with a toxicological reference value after conversion to internal dose. Data from human biomonitoring (HBM) could be very useful in this regard, because it is based on the measurement of real-life internal exposure of the human population to a chemical. UV filters were included in the priority list of compounds to be addressed under the European Human Biomonitoring Initiative (HBM4EU), and risk assessment of benzophenone-3 (BP-3) was carried out based on HBM data. Using BP-3 as an example, this study investigated the benefits and limitations of the use of external versus internal exposure data to explore the usefulness of HBM to support the risk assessment of cosmetic ingredients. The results show that both approaches did indicate a risk to human health under certain levels of exposure. They also highlight the need for more robust exposure data on BP-3 and other cosmetic ingredients, and a standardized framework for incorporating HBM data in the risk assessment of cosmetic products.

Partitioning of Persistent Organic Pollutants between Adipose Tissue and Serum in Human Studies.

Blood is the most widely used matrix for biomonitoring of persistent organic pollutants (POPs). It is assumed that POPs are homogenously distributed within body lipids at steady state; however, the variability underlying the partitioning of POPs between fat compartments is poorly understood. Hence, the objective of this study was to review the state of the science about the relationships of POPs between adipose tissue and serum in humans. We conducted a narrative literature review of human observational studies reporting concentrations of POPs in paired samples of adipose tissue with other lipid-based compartments (e.g., serum lipids). The searches were conducted in SCOPUS and PUBMED. A meta-regression was performed to identify factors responsible for variability. All included studies reported high variability in the partition coefficients of POPs, mainly between adipose tissue and serum. The number of halogen atoms was the physicochemical variable most strongly and positively associated with the partition ratios, whereas body mass index was the main biological factor positively and significantly associated. To conclude, although this study provides a better understanding of partitioning of POPs to refine physiologically based pharmacokinetic and epidemiological models, further research is still needed to determine other key factors involved in the partitioning of POPs.

The SCCS scientific advice on the safety of nanomaterials in cosmetics.

The Cosmetic Regulation (EC) No 1223/2009 specifically covers the risk of nanomaterials used in cosmetic products. If there are concerns regarding the safety of a nanomaterial, the European Commission refers it to the SCCS for a scientific opinion. The Commission mandated the SCCS to identify the scientific basis for safety concerns that could be used as a basis for identifying and prioritising nanomaterials for safety assessment, and to revisit previous inconclusive SCCS opinions on nanomaterials to identify any concerns for potential risks to the consumer health. The SCCS Scientific Advice identified the key general aspects of nanomaterials that should raise a safety concern for a safety assessor/manager, so that the nanomaterial(s) in question could be subjected to safety assessment to establish safety to the consumer. The Advice also developed a list of the nanomaterials notified to the Commission for use in cosmetics in an order of priority for safety assessment, and revisited three previous inconclusive opinions on nanomaterials to highlight concerns over consumer safety that merited further safety assessment.

Management of Chiari type I malformation: a retrospective analysis of a series of 91 children treated surgically.

INTRODUCTION: The diagnosis of Chiari I malformation, its symptomatology, and the results of its surgical management are still discussed. We report a pediatric series of CMI without associated skull base malformations or cerebellar growth anomalies operated between 2001 and 2018. MATERIAL AND METHODS: Ninety-one children out of 146 surgically treated cases have been included in the study. Age at surgery ranged from 5 months to 17 years clinical data, and complementary examinations leading to the surgical indication have been analyzed together with the surgical outcomes. The average follow-up duration was of 4 years. The occipito-cervical decompression with duraplasty without opening the arachnoid was the procedure of election. Three quarters of patients presented with headaches, 12% with cerebellar syndrome, 13% with vertigo, 26% with nausea or vomiting, 24% with sensorimotor deficits, 11% with cranial nerve deficits, and 29% with other symptoms. Eighteen percent of patients suffered from scoliosis, 47% had an associated syrinx and 16% a ventricular dilation. RESULTS: After the treatment, the clinical symptomatology improved in about three-quarters of the patients: headache (69.4%), nausea or vomiting (66.7%), sensorimotor deficits (55.6%), and other symptoms (78.3%). Syringomyelic cavities diminished partially in size or disappeared in 58.3% of patients, remained stable in 29.2%, and worsened in 12.5%. Only one-third of children with preoperative scoliosis benefited from the surgical treatment. No clinical signs or symptoms were found to be reliable predictors of surgical success, neither the extent of the cerebellar tonsil descent. CONCLUSION: Occipito-cervical decompression allows to improve the clinical condition in the majority of children with symptomatic CMI in the absence of associated cervico-spinal junction alterations, craniosynostosis, or cerebellar growth anomalies. No clinical signs or symptoms neither radiological criterion appear to be a specific finding for the surgical indication.

Chemical prioritisation strategy in the European Human Biomonitoring Initiative (HBM4EU) - Development and results.

The European Human Biomonitoring Initiative (HBM4EU1) has established a European Union-wide human biomonitoring (HBM) programme to generate knowledge on human internal exposure to chemical pollutants and their potential health impacts in Europe, in order to support policy makers' efforts to ensure chemical safety and improve health in Europe. A prioritisation strategy was necessary to determine and meet the most important needs of both policy makers and risk assessors, as well as common national needs of participating countries and a broad range of stakeholders. This strategy consisted of three mains steps: 1) mapping of knowledge gaps identified by policy makers, 2) prioritisation of substances using a scoring system, and 3) generation of a list of priority substances reflective of the scoring, as well as of public policy priorities and available resources. For the first step, relevant ministries and agencies at EU and national levels, as well as members of the Stakeholder Forum each nominated up to 5 substances/substance groups of concern for policy-makers. These nominations were collated into a preliminary list of 48 substances/substance groups, which was subsequently shortened to a list of 23 after considering the total number of nominations each substance/substance group received and the nature of the nominating entities. For the second step, a panel of 11 experts in epidemiology, toxicology, exposure sciences, and occupational and environmental health scored each of the substances/substance groups using prioritisation criteria including hazardous properties, exposure characteristics, and societal concern. The scores were used to rank the 23 substances/substance groups. In addition, substances were categorised according to the level of current knowledge about their hazards, extent of human exposure (through the availability of HBM data), regulatory status and availability of analytical methods for biomarker measurement. Finally, in addition to the ranking and categorisation of the substances, the resources available for the project and the alignment with the policy priorities at European level were considered to produce a final priority list of 9 substances/substance groups for research activities and surveys within the framework of the HBM4EU project.

Burden of osteoporosis and costs associated with human biomonitored cadmium exposure in three European countries: France, Spain and Belgium.

Cadmium (Cd) is a toxic heavy metal widespread in the environment leading to human exposure in particular through diet (when smoking is excluded), as documented by recent human biomonitoring (HBM) surveys. Exposure to Cd at environmental low-exposure levels has been associated with adverse effects such as renal toxicity and more recently bone effects. The implication, even if limited, of Cd in the etiology of osteoporosis can be of high importance at the population level given the significant prevalence of osteoporosis and the ubiquitous and life-long exposure to Cd. Therefore, the osteoporosis cases attributable to Cd exposure was estimated in three European countries (Belgium, France and Spain), based on measured urinary Cd levels from HBM studies conducted in these countries. The targeted population was women over 55 years old, for which risk levels associated with environmental Cd exposure were available. Around 23% of the cases were attributed to Cd exposure. Moreover, in a prospective simulation approach of lifelong urinary Cd concentrations assuming different intakes scenarios, future osteoporosis attributable cases were calculated, based on urinary Cd levels measured in women aged under 55. Between 6 and 34% of the considered populations under 55 years were at risk for osteoporosis. Finally, the costs associated to the burden of osteoporosis-related fractures attributable to Cd for each country targeted in this paper were assessed, standing for a major contributing role of Cd exposure in the overall social costs related to osteoporosis. Absolute costs ranged between 0.12 (low estimate in Belgium) and 2.6 billion Euros (high estimate in France) in women currently over 55 years old and at risk for fractures. Our results support the importance of reducing exposure of the general population to Cd.

Human biomonitoring initiative (HBM4EU): Human biomonitoring guidance values (HBM-GVs) derived for bisphenol A.

The "European Human Biomonitoring Initiative" (HBM4EU) derives human biomonitoring guidance values (HBM-GVs) for the general population (HBM-GVGenPop) and/or for occupationally exposed adults (HBM-GVWorker) for several priority substances and substance groups as identified by policy makers, scientists and stakeholders at EU and national level, including bisphenol A (BPA). Human exposure to BPA is widespread and of particular concern because of its known endocrine-disrupting properties. Unlike the conjugated forms of BPA circulating in the body, free BPA is known to interact with the nuclear estrogen receptors. Because free BPA is considered to be more toxicologically active than the conjugated forms (e.g. BPA-glucuronide (BPA-G) and BPA-sulfate (BPA-S)), its measurement in blood provides the superior surrogate of the biologically effective dose. However, considering the difficulty of implementing blood sampling in large HBM cohorts, as well as the current analytical capacities complying with the quality assurance (QA)/quality control (QC) schemes, total BPA in urine (i.e. the sum of free and conjugated forms of BPA measured after an hydrolysis of phase II metabolites) was retained as the relevant exposure biomarker for BPA. HBM-GVGenPop for total BPA in urine of 230 µg/L and 135 µg/L for adults and children, respectively, were developed on the basis of toxicological data. To derive these values, the concentrations of urinary total BPA consistent with a steady-state exposure to the temporary Tolerable Daily Intake (t-TDI) of 4 µg/kg bw/day set in 2015 by the European Food Safety Authority (EFSA) were estimated. The BPA human physiologically-based pharmacokinetic (PBPK) model developed by Karrer et al. (2018) was used, assuming an oral exposure to BPA at the t-TDI level averaged over 24 h. Dermal uptake of BPA is suspected to contribute substantially to the total BPA body burden, which in comparison with the oral route, is generating a higher ratio of free BPA to total BPA in blood. Therefore, an alternative approach for calculating the HBM-GVGenPop according to the estimated relative contributions of both the oral and dermal routes to the global BPA exposure is also discussed. Regarding BPA exposure at the workplace, the steady-state concentration of urinary total BPA was estimated after a dermal uptake of BPA that would generate the same concentration of free BPA in plasma (considered as the bioactive form) as would a 24 h-averaged intake to the European Chemicals Agency (ECHA)'s oral DNEL of 8 µg BPA/kg bw/day set for workers. The predicted concentration of urinary total BPA at steady-state is equivalent to, or exceeds the 95th percentile of total BPA in urine measured in different European HBM studies conducted in the general population. Thus, no HBM-GVWorker was proposed, as the high background level of BPA coming from environmental exposure - mostly through food intake - is making the discrimination with the occupational exposure to BPA difficult.

The European Human Biomonitoring Initiative (HBM4EU): Human biomonitoring guidance values for selected phthalates and a substitute plasticizer.

Ubiquitous use of plasticizers has led to a widespread internal exposure of the European population. Until today, metabolites are detected in almost every urine sample analysed. This raised the urgent need for a toxicological interpretation of the internal exposure levels. The European Human Biomonitoring Initiative (HBM4EU) contributes substantially to the knowledge on the actual exposure of European citizens to chemicals prioritised within HBM4EU, on their potential impact on health and on the interpretation of these data to improve policy making. On that account, human biomonitoring guidance values (HBM-GVs) are derived for the general population and the occupationally exposed population agreed at HBM4EU consortium level. These values can be used to assess phthalate exposure levels measured in HBM studies in a health risk assessment context. HBM-GVs were derived for five phthalates (DEHP, DnBP, DiBP, BBzP and DPHP) and for the non-phthalate substitute Hexamoll® DINCH. For the adult general population, the HBM-GVs for the specific metabolite(s) of the respective parent compounds in urine are the following: 0.5 mg/L for the sum of 5-oxo-MEHP and 5-OH-MEHP; 0.19 mg/L for MnBP, 0.23 mg/L for MiBP; 3 mg/L for MBzP; 0.5 mg/L for the sum of oxo-MPHP and OH-MPHP and 4.5 mg/L for the sum of OH-MINCH and cx-MINCH. The present paper further specifies HBM-GVs for children and for workers.

Refinement of health-based guidance values for cadmium in the French population based on modelling.

In France, part of the population is overexposed to cadmium by the diet. In our work, we first revised the tolerable daily intake (TDI) of 0.36 µg Cd.kg bw.d.-1 proposed by the European Food Safety Authority (EFSA), derived from effects on kidneys and based on the critical urinary Cd concentration of 1.0 µg Cd.g-1 creatinine for humans. After reviewing the epidemiological data on Cd toxicity published after 2011, bone effects were selected as the critical effects. Body burden data of 0.5 µg.g-1 creatinine was chosen for the critical threshold for human urinary cadmium concentrations. To be used for the derivation of the new oral toxicological reference value, we used a modified physiologically based pharmacokinetic model (PBPK). The reverse calculation on the PBPK model gave a TDI of 0.35 µg Cd.kg bw-1.day-1. This TDI is compatible with a urinary Cd concentrations not exceeding 0.5 µg Cd.g-1 creatinine, in a 60 year-old adult, assuming that ingestion is the only source of exposure to Cd at 60 years. After implementing the PBPK model with French physiological data, Cd biological reference values as a function of age were modelled so as to remain below the revised health-based guidance values.

Human biomonitoring initiative (HBM4EU) - Strategy to derive human biomonitoring guidance values (HBM-GVs) for health risk assessment.

The European Joint Program "HBM4EU" is a joint effort of 30 countries and the European Environment Agency, co-funded under the European Commission's Horizon 2020 program, for advancing and implementing human biomonitoring (HBM) on a European scale and for providing scientific evidence for chemical policy making. One important outcome will be a Europe-wide improvement and harmonization of health risk assessment following the coordinated derivation or update of health-related guidance values referring to the internal body burden. These guidance values - named HBM guidance values or HBM-GVs - can directly be compared with HBM data. They are derived within HBM4EU for priority substances identified by the HBM4EU chemicals prioritization strategy based on existing needs to answer policy relevant questions as raised by national and EU policy makers. HBM-GVs refer to both the general population and occupationally exposed adults. Reports including the detailed reasoning for the values' proposals are subjected to a consultation process within all partner countries of the consortium to reach a broad scientific consensus on the derivation approach and on the derived values. The final HBM-GVs should be applied first within the HBM4EU project, but may also be useful for regulators and risk assessors outside this project. The subsequent adoption of derived HBM-GVs at EU-level needs to be discussed and decided within the responsible EU bodies. Nevertheless, the establishment of HBM-GVs as part of HBM4EU is already a step forward in strengthening HBM-based policy efforts for public and occupational health. The strategy for deriving HBM-GVs which is based on already existing approaches from the German HBM Commission, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) as well as from the US-based scientific consultant Summit Toxicology, the allocation of a level of confidence to the derived values, and the consultation process within the project are comprehensively described to enlighten the work accomplished under the HBM4EU initiative.