Human Biomonitoring Data Research Articles

Deoxynivalenol exposure assessment through a modelling approach of food intake and biomonitoring data – A contribution to the risk assessment of an enteropathogenic mycotoxin

Deoxynivalenol (DON), an enteropathogenic mycotoxin produced by Fusarium species, is usually associated with adverse health outcomes such as gastrointestinal diseases and immunotoxicity. To estimate DON exposure of the Portuguese population at national level, a modelling approach, based on data from 94 Portuguese volunteers, was developed considering the inputs of the food consumption data generated within the National Food and Physical Activity Survey and the human biomonitoring data used to assess the exposure to DON. Ten models of association between DON urinary biomarkers and food items (pasta, cookies, biscuits, sweets, bread, rusks, nuts, oilseeds, beer, meat, milk) were established. Applying the most adequate model to the consumption data (n = 5811) of the general population, the exposure estimates of the Probable Daily Intake revealed that a fraction (0.1%) of the Portuguese population might exceed the Tolerable Daily Intake defined for DON. The analysis stratified by age revealed children (3.2%) and adolescents (6.0%) are more likely to exceed the Tolerable Daily Intake for DON. Although the unavoidable uncertainties, these results are important contributions to understand the exposure to this mycotoxin in Portugal, to assess the associated risk and the potential public health consequences.

Consideration of Regulatory Guidelines in the Analysis of Mixtures of Environmental Chemicals and Nutrients

We introduce a new class of models that include the regulatory concept of “acceptable concentration range” (ACR). These models complement current risk assessment methods by estimating regulatory guideline values using human biomonitoring data. We illustrate the strategy using prenatal concentrations from 11 environmental chemicals and two health outcomes. We determine that the published guideline values are orders of magnitude higher than those estimated using human data. The results suggest that chemical-by-chemical approaches underestimate risk by a factor that range from 1 to 100 for different chemicals. Further, we have developed a personalized nutrition index that measures the nutrient quality (i.e., “nutritiousness”) of a specified daily diet and is calculated based on quantification of dozens of macro- and micronutrients that are specific to an individual’s nutritional needs (as defined by published recommended guidelines for individual nutrient target ranges) by incorporating dietary restrictions, subject characteristics, activity level, and health behaviors. We illustrate the use of the nutrition index based on food frequency questionnaire nutrient estimates, adjusted for total calories, in evaluating the potential mitigating effect of good nutrition on environmental toxins and in evaluating dietary sources of toxic chemicals. (We gratefully acknowledge support from NIEHS: #R01ES028811)

Estimating human exposure to pyrethroids’ mixtures from biomonitoring data using physiologically based pharmacokinetic modeling

Human biomonitoring data provide evidence to exposure of environmental chemicals. Physiologically based pharmacokinetic (PBPK) modelling together with an adequate exposure scenario allows to transpose measured concentrations of chemicals or their metabolites into exposure levels, as daily intakes. In France, high levels of urinary pyrethroids metabolites have been measured in populations. Our work aims at estimating the exposure of the French ENNS cohort to mixtures of four pyrethroids (deltamethrin, permethrin, cypermethrin, and cyfluthrin) from the urinary concentrations of five pyrethroids' metabolites commonly measured in biomonitoring studies. We developed a modelling approach based on a global toxicokinetic model that accounts for the cumulative exposure to pyrethroids as some of the metabolites can be shared by several parent compounds and for human inter-individual variability in metabolism. The median of the individual daily intakes was estimated to 8.1 ng/kg bw/day for permethrin, 17.7 ng/kg bw/day for cypermethrin, 20.4 ng/kg bw/day for cyfluthrin and 34.3 ng/kg bw/day for deltamethrin leading to similar weights for the pair permethrin and cypermethrin (36%), cyfluthrin (31%) and deltamethrin (33%) to the cumulative exposure. Accounting for human variability enabled to explain some of the variations in the metabolites' levels within the cohort. The cumulative exposure was then weighted by their toxicities towards three neurotoxic effects to calculate margins of exposure (MOE). Low MOE values were always associated with high measured concentrations of metabolites in urine and the lowest MOEs were observed for the autonomic division. No risks associated with reconstructed mixtures of pyrethroids were expected for the ENNS cohort. Our approach is an asset to analyse the biomarkers of exposure to pyrethroids simultaneously and could be easily adapted to any local or national specificities in pyrethroids’ exposure or populations.

Possibilities to integrate wearable biomonitoring sensors into adaptive lighting systems

There are two trends in modern lighting: the first one is lighting intelligence and adaptability, and the other is an orientation on the biological effects of light on the human body. This article analyzes the possibilities for further development of adaptive lighting systems from human biomonitoring data integration point of view. A review of wearable medical devices, which in the future could work as sensors of an adaptive lighting system, is presented.

Multi-omics analysis reveals that co-exposure to phthalates and metals disturbs urea cycle and choline metabolism

This study aimed to evaluate the response of HepaRG cells after co-exposure to phthalates and heavy metals, using a high-dimensional biology paradigm (HDB). Liver is the main metabolism site for the majority of xenobiotics. For this reason, the HepaRG cell line was used as an in vitro model, and cells were exposed to two characteristic mixtures of phthalates and heavy metals containing phthalates (DEHP, DiNP, BBzP) and metals (lead, methylmercury, total mercury) in a concentration-dependent manner. The applied chemical mixtures were selected as the most abundant pollutants in the REPRO_PL and PHIME cohorts, which were studied using the exposome-wide approach in the frame of the EU project HEALS. These studies investigated the environmental causation of neurodevelopmental disorders in neonates and across Europe. The INTEGRA computational platform was used for the calculation of the effective concentrations of the chemicals in the liver through extrapolation from human biomonitoring data and this dose (and a ten-times higher one) was applied to the hepatocyte model. Multi-omics analysis was performed to reveal the genes, proteins, and metabolites affected by the exposure to these chemical mixtures. By extension, we could detect the perturbed metabolic pathways. The generated data were analyzed using advanced bioinformatic tools following the HEALS connectivity paradigm for multi-omics pathway analysis. Co-mapped transcriptomics and proteomics data showed that co-exposure to phthalates and heavy metals leads to perturbations of the urea cycle due to differential expression levels of arginase-1 and -2, argininosuccinate synthase, carbamoyl-phosphate synthase, ornithine carbamoyltransferase, and argininosuccinate lyase. Joint pathway analysis of proteomics and metabolomics data revealed that the detected proteins and metabolites, choline phosphate cytidylyltransferase A, phospholipase D3, group XIIA secretory phospholipase A2, α-phosphatidylcholine, and the a 1,2-diacyl-sn-glycero-3-phosphocholine, are responsible for the homeostasis of the metabolic pathways phosphatidylcholine biosynthesis I, and phospholipases metabolism. The urea, phosphatidylcholine biosynthesis I and phospholipase metabolic pathways are of particular interest since they have been identified also in human samples from the REPRO_PL and PHIME cohorts using untargeted metabolomics analysis and have been associated with impaired psychomotor development in children at the age of two. In conclusion, this study provides the mechanistic evidence that co-exposure to phthalates and metals disturb biochemical processes related to mitochondrial respiration during critical developmental stages, which are clinically linked to neurodevelopmental perturbations.

Data for characterizing human exposure to chemicals and their contribution to human diseases: IPCHEM, HBM4EU

Abstract Human exposure to chemicals can occur via different sources and routes. Understanding the (combined) exposure to chemicals is often hampered by a lack of data or difficulties in sharing data. This was recognized in the Commission Communication on Chemical Mixtures (252, 2012) and the Information Platform on Chemical Monitoring (IPCHEM) was developed. The aim of IPCHEM is to support a coordinated approach for collecting, storing, sharing and assessing data on the occurrence of chemicals and chemical mixtures in humans and the environment. IPCHEM covers four thematic areas to support a holistic approach to exposure assessment, including human biomonitoring, environmental monitoring, food and feed monitoring and indoor air and consumer products. The shared occurrence data support exposure assessment, the identification of sources and hot spots, the analysis of time trends and can also support the evaluation of the impact of regulatory measures to restrict exposure to specific chemicals. In particular, human biomonitoring data can provide insights into internal combined exposure, integrating across different exposure sources and routes. The ongoing EU funded project HBM4EU generates and uses human biomonitoring to assess human exposure to chemicals in Europe, to better understand the associated health impacts and to improve chemical risk assessment. Associations between chemical exposures and development of disease can be further supported using toxicological/mechanistic information to establish causal links. The presentation will focus on relevant types and sources of data available to support health impact assessments of chemical exposure.

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.

Physiologically based kinetic (PBK) modelling and human biomonitoring data for mixture risk assessment

Human biomonitoring (HBM) data can provide insight into co-exposure patterns resulting from exposure to multiple chemicals from various sources and over time. Therefore, such data are particularly valuable for assessing potential risks from combined exposure to multiple chemicals.One way to interpret HBM data is establishing safe levels in blood or urine, called Biomonitoring Equivalents (BE) or HBM health based guidance values (HBM-HBGV). These can be derived by converting established external reference values, such as tolerable daily intake (TDI) values. HBM-HBGV or BE values are so far agreed only for a very limited number of chemicals. These values can be established using physiologically based kinetic (PBK) modelling, usually requiring substance specific models and the collection of many input parameters which are often not available or difficult to find in the literature.The aim of this study was to investigate the suitability and limitations of generic PBK models in deriving BE values for several compounds with a view to facilitating the use of HBM data in the assessment of chemical mixtures at a screening level. The focus was on testing the methodology with two generic models, the IndusChemFate tool and High-Throughput Toxicokinetics package, for two different classes of compounds, phenols and phthalates. HBM data on Danish children and on Norwegian mothers and children were used to evaluate the quality of the predictions and to illustrate, by means of a case study, the overall approach of applying PBK models to chemical classes with HBM data in the context of chemical mixture risk assessment.Application of PBK models provides a better understanding and interpretation of HBM data. However, the study shows that establishing safety threshold levels in urine is a difficult and complex task. The approach might be more straightforward for more persistent chemicals that are analysed as parent compounds in blood but high uncertainties have to be considered around simulated metabolite concentrations in urine. Refining the models may reduce these uncertainties and improve predictions. Based on the experience gained with this study, the performance of the models for other chemicals could be investigated, to improve the accuracy of the simulations.

Assessing population exposure to phthalate plasticizers in thirteen Spanish cities through the analysis of wastewater

Phthalates are widely used plasticizers that produce endocrine-disrupting disorders. Quantifying exposure is crucial to perform risk assessments and to develop proper health measures. Herein, a wastewater-based epidemiology approach has been applied to estimate human exposure to six of the mostly used phthalates within the Spanish population. Wastewater samples were collected over four weekdays from seventeen wastewater treatment plants serving thirteen cities and ca. 6 million people (12.8 % of the Spanish population). Phthalate metabolite loads in wastewater were transformed into metabolite concentrations in urine and into daily exposure levels to the parent phthalates. Considering all the sampled sites, population-weighted overall means of the estimated concentrations in urine varied between 0.7 ng/mL and 520 ng/mL. Very high levels, compared to human biomonitoring data, were estimated for monomethyl phthalate, metabolite of dimethyl phthalate. This, together with literature data pointing to other sources of this metabolite in sewage led to its exclusion for exposure assessments. For the remaining metabolites, estimated concentrations were closer to those found in urine. Their 4-days average exposure levels ranged from 2 to 1347 μg/(day∙inh), exceeding in some sites the daily exposure thresholds set for di-i-butyl phthalate and di-n-buthyl phthalate by the European Food Safety Authority.

Burden of disease associated with dietary exposure to carcinogenic aflatoxins in Portugal using human biomonitoring approach

Human biomonitoring is an important tool to assess human exposure to chemicals, contributing to describe trends of exposure over time and to identify population groups that could be under risk. Aflatoxins are genotoxic and carcinogenic food contaminants causing hepatocellular carcinoma, the third leading cause of cancer deaths worldwide. In Portugal, scarce data are available regarding exposure to aflatoxins and no previous study used human biomonitoring data to comprehensively characterize the associated burden of disease. 24 h urine and first-morning urine paired samples were collected by 94 participants and were analyzed by liquid chromatography–tandem mass spectrometry for the quantitative determination of aflatoxins (B1, B2, G1, G2 and M1). Deterministic and probabilistic models were developed to assess the Portuguese exposure to aflatoxins and to estimate the health impact of this exposure, estimating the attributed Disability-Adjusted Life Years (DALYs). Aflatoxins were detected in a maximum of 13% (AFB1), 16% (AFB2), 1% (AFG1), 2% (AFG2) and 19% (AFM1) of the urine samples. Data obtained through the probabilistic approach revealed an estimated mean probable daily intake of 13.43 ng/kg body weight per day resulting in 0.13 extra cases of hepatocellular carcinoma, corresponding to mean annual DALYs of 172.8 for the Portuguese population (10291027 inhabitants). The present study generated for the first time and within a human biomonitoring study, reliable and crucial data to characterize the burden associated to the exposure to aflatoxins of the Portuguese population. The obtained results constitute an imperative support to risk managers in the establishment of preventive policy measures that contribute to ensure public health protection.

Food Consumption Data as a Tool to Estimate Exposure to Mycoestrogens.

Zearalenone and alternariol are mycotoxins produced by Fusarium and Alternaria species, respectively, that present estrogenic activity and consequently are classified as endocrine disruptors. To estimate the exposure of the Portuguese population to these two mycotoxins at a national level, a modelling approach, based on data from 94 Portuguese volunteers, was developed considering as inputs: i) the food consumption data generated within the National Food and Physical Activity Survey; and ii) the human biomonitoring data used to assess the exposure to the referred mycotoxins. Six models of association between mycoestrogens urinary levels (zearalenone, total zearalenone and alternariol) and food items (meat, cheese, and fresh-cheese, breakfast cereals, sweets) were established. Applying the obtained models to the consumption data (n = 5811) of the general population, the median estimates of the probable daily intake revealed that a fraction of the Portuguese population might exceed the tolerable daily intake defined for zearalenone. A reference intake value for alternariol is still lacking, thus the characterization of risk due to the exposure to this mycotoxin was not possible to perform. Although the unavoidable uncertainties, these results are important contributions to understand the exposure to endocrine disruptors in Portugal and the potential Public Health consequences.

Development, Testing, Parameterization, and Calibration of a Human Physiologically Based Pharmacokinetic Model for the Plasticizer, Hexamoll® Diisononyl-Cyclohexane-1, 2-Dicarboxylate Using In Silico, In Vitro, and Human Biomonitoring Data.

A physiologically based pharmacokinetic model for Hexamoll® diisononyl-cyclohexane-1, 2-dicarboxylate was developed to interpret the biokinetics in humans after single oral doses. The model was parameterized with in vitro and in silico derived parameters and uncertainty and sensitivity analysis was used during the model development process to assess structure, biological plausibility and behavior prior to simulation and analysis of human biological monitoring data. The model provided good simulations of the urinary excretion (Curine) of two metabolites; cyclohexane-1,2-dicarboxylic acid mono hydroxyisononyl ester (OH-MINCH) and cyclohexane-1, 2-dicarboxylic acid mono carboxyisononyl ester (cx-MINCH) from the biotransformation of mono-isononyl-cyclohexane-1, 2-dicarboxylate (MINCH), the monoester metabolite of di-isononyl-cyclohexane-1,2-dicarboxylate. However, good simulations could be obtained, with and without, a lymphatic compartment. Selection of an appropriate model structure was informed by sensitivity analysis which could identify and quantify the contribution to variability in Curine by parameters, such as, the fraction of oral dose that directly entered the lymphatic compartment and therefore by-passed the liver and the fraction of MINCH bio-transformed to cx-MINCH and OH-MINCH. By constraining these parameters within biologically plausible limits the presence of a lymphatic compartment was deemed an important component of model structure. Furthermore, the use of sensitivity analysis is important in the evaluation of uncertainty around in silico derived parameters. By quantifying their impact on model output sufficient confidence in the use of a model should be afforded. This type of approach could expand the use of physiologically based pharmacokinetic models since parameterization with in silico techniques allows for rapid model development. This in turn could assist in reducing the use of animals in toxicological evaluations by enhancing the utility of “read across” techniques.

Clarifying Temporal Trend Variability in Human Biomonitoring of Polybrominated Diphenyl Ethers through Mechanistic Modeling.

Human biomonitoring data collected from individuals of the same age sampled in different years provide within-age temporal trends, which are often employed to evaluate the effectiveness of chemical regulatory policies. For polybrominated diphenyl ethers (PBDEs), this within-age temporal trend has been observed to vary between congeners and age groups. We systematically explore the mechanisms responsible for such variability through simulating human exposure via multiple exposure pathways to PBDEs released from multiple lifecycle stages. Our simulation indicates that, after new use of PBDEs is banned, emissions to the outdoor environment from use and waste disposal outlast those to the indoor environment from the indoor use phase, leading to slower decline rates in the contamination of food items sourced from the outdoor environment than that from indoors. Compared with indoor exposure pathways, the consumption of contaminated food contributes more to the exposure (i) to more hydrophobic, recalcitrant congeners, and (ii) of adults than children, which results in slower rates of decline in the within-age temporal trend of those congeners and in adults. The within-age temporal trend is influenced to a lesser extent by the elimination of PBDEs from the human body, e.g., differences in biotransformation potential of congeners, growth dilution, and pre- and postnatal exposures by children.

Burden of disease attributable to exposure to aflatoxins in Portugal using Human biomonitoring data

Abstract Human biomonitoring (HBM) is recognized as an important tool to assess the Human exposure to chemicals, contributing to describe trends and patterns of exposure over time and to identify population groups that could be under risk. Natural chemicals as mycotoxins, fungi metabolites that produce toxic effects in humans, are important compounds that could be found in foods usually consumed worldwide in a daily basis. Mycotoxins as aflatoxins (AFTs) are genotoxic, carcinogenic and immunosuppressive compounds. Hepatocellular carcinoma (HCC) is one of their main health toxic effects and is the third leading cause of cancer deaths worldwide. In Portugal, scarce data are available regarding exposure to AFTs and none previous study used HBM data to characterize comprehensively the burden associated to this exposure. In the scope of the National Food, Nutrition, and Physical Activity Survey of the Portuguese General Population (2015-2016), 24h-urine samples from 94 participants were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS) for the simultaneous determination of AFTs (B1, B2, G1, G2, M1). A model was developed to estimate the health impact of the exposure of Portuguese population to aflatoxins, estimating the number of cases of HCC and DALYs attributed to AFTs exposure. AFTs were detected in 12.8% (AFB1), 16.0% (AFB2) and 19.1% (AFM1) of the 24h-urine samples. The estimated number of extra cases of HCC attributed to this exposure ranged from 17 to 65 cases/year; the associated DALYs for the Portuguese population ranged from 284 to 1802 years. The present study generated, for the first time and within a HBM study, reliable data regarding the exposure of the Portuguese population to AFTs. These data were crucial to characterize the health impact associated to AFTs exposure and to support risk managers to establish preventive policy measures that contribute to ensure the public health protection. Key messages Portuguese population is exposed to aflatoxins, chemical food contaminants that may be harmful (carcinogenic, immunotoxic, mutagenic, teratogenic, hepatotoxic) to humans. Human biomonitoring studies provide realistic data on internal exposure at individual level, contributing to a more accurate estimation of the burden derived from this exposure.

Evaluation of human biomonitoring data in a health risk based context: An updated analysis of population level data from the Canadian Health Measures Survey.

In order to characterize exposure of the Canadian population to environmental chemicals, a human biomonitoring component has been included in the Canadian Health Measures Survey (CHMS). This nationally-representative survey, launched in 2007 by the Government of Canada, has measured over 250 chemicals in approximately 30,000 Canadians during the last decade. The capacity to interpret these data at the population level in a health risk context is gradually improving with the development of biomonitoring screening values, such as biomonitoring equivalents (BE) and human biomonitoring (HBM) values. This study evaluates recent population level biomonitoring data from the CHMS in a health risk context using biomonitoring screening values. Nationally representative biomonitoring data for fluoride, selenium, molybdenum, arsenic, silver, thallium, cyfluthrin, 2,4-dichlorophenoxyacetic acid (2,4-D), 3-phenoxybenzoic acid (3-PBA), chlorpyrifos, deltamethrin, bisphenol A, triclosan, acrylamide, cadmium, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), bromoform, chloroform, benzene, toluene, xylene, ethylbenzene, styrene and tetrachloroethylene were screened as part as this study. For non-cancer endpoints, hazard quotients (HQs) were calculated as the ratio of population level concentrations of a specific chemical at the geometric mean and 95th percentile to the corresponding biomonitoring screening value. Cancer risks were calculated at the 5th, 25th, 50th, 75th and 95th percentiles of the population concentration using BEs based on a risk specific dose. Most of the chemicals analyzed had HQs below 1 suggesting that levels of exposure to these chemicals are not a concern at the population level. However, HQs exceeded 1 in smokers for cadmium, acrylamide and benzene, as well as in the general population for inorganic arsenic, PFOS and PFOA, 3-PBA and fluoride. Furthermore, cancer risks for inorganic arsenic, acrylamide, and benzene at most population percentiles of exposure were elevated (>10-5). Specifically, for inorganic arsenic in the general population, the HQ was 3.13 at the 95th percentile concentration and the cancer risk was 3.4 × 10-4 at the 50th percentile of population concentrations. These results suggest that the levels of exposure in the Canadian population to some of the environmental chemicals assessed might be of concern. The results of this screening exercise support the findings of previous risk assessments and ongoing efforts to reduce risks from exposure to chemicals evaluated as part of this study. Although paucity of biomonitoring screening values for several environmental contaminants may be a limitation to this approach, our assessment contributes to the prioritization of a number of chemicals measured as part of CHMS for follow-up activities such as more detailed characterization of exposure sources.

Biomarkers of Exposure in Environment-wide Association Studies – opportunities to decode the Exposome using Human Biomonitoring data

Biomarkers of Exposure in Environment-wide Association Studies – opportunities to decode the Exposome using Human Biomonitoring data

Lead toxicity with a new focus: Addressing low-level lead exposure in Canadian children.

Although acute and subacute lead toxicity requiring active treatment is rare in Canada, paediatricians need to be aware of new evidence linking lower lead levels to neurodevelopmental deficits. Health Canada has identified potential exposures occurring prenatally, in infancy and during early childhood from food and water, household dust, soil, and mouthing products that contain lead. Children with neurodevelopmental problems who live in older housing and newcomers to Canada may be at greater risk. Symptoms may be latent, subtle, and chronic. Blood assay, widely available clinically, does not confirm diagnosis unless lead exposure has been recent. Human biomonitoring data are available in the Canadian Health Measures Survey, and Health Canada has suggested that clinicians use these new reference ranges. Early detection and prevention of lead exposure are key public health objectives because effects of lead toxicity are chronic and treatment is complex.

Human biomonitoring in health risk assessment in Europe: Current practices and recommendations for the future.

Human biomonitoring (HBM) is an important tool to survey the internal exposure of humans which represents the real life chemical body burden to chemicals and/or their metabolites. It results from total exposure to chemical substances from different sources and via different routes. These substances may be regulated under different legislative frameworks on chemicals (e.g., environmental, occupational, food safety etc). In occupational health, HBM has long traditions to control the exposures at workplaces. By providing accurate data on internal exposure, HBM data can improve human health risk assessment (RA) for both the general population and workers. Although the past few years have shown good examples on the use of HBM in the RA of chemicals, there is still quite some work to be done to improve its use in a regulatory RA. Under the scope of the European Human Biomonitoring Initiative (project HBM4EU, 2017-2021), the current study reviews the state-of-the-art of HBM use in chemicals RA with a special focus in Europe, and attempts to identify hurdles and challenges faced by regulators. To gather information on the use of HBM, including the availability of guidance on how to use it in RA, the RA schemes applied by different European or international organizations were analysed. Examples of such use were identified for a few selected groups of chemicals of concern for human health. In addition, we present the results of a survey, aimed at collecting information from national regulatory risk assessors on their day-to-day RA practices, the use of HBM data, and the obstacles and challenges related to their use. The results evidenced and explained some of the current obstacles of using HBM data in RA. These included the lack of HBM guidance values or biomonitoring equivalents (BEs), limited toxicokinetic information to support the interpretation of HBM data and, in the occupational health and safety (OSH) field, the lack of legal enforcement. Therefore, to support the integration of HBM in regulatory RA, we recommend, on one hand, the elaboration of a EU level guidance on the use of HBM in RA and, on the other hand, the continuation of research efforts to integrate HBM with new RA approaches using in vitro/in silico data and Adverse Outcome Pathways (AOPs).

Steady-State Human Pharmacokinetics of Monobutyl Phthalate Predicted by Physiologically Based Pharmacokinetic Modeling Using Single-Dose Data from Humanized-Liver Mice Orally Administered with Dibutyl Phthalate.

Dibutyl phthalate (DBP) was widely used as a plasticizer but it has been recently replaced with other kinds of phthalates such as di(2-ethylhexyl)phthalate and diisononyl phthalate because of its toxicity. To evaluate the human risk of DBP, forward and reverse dosimetry was conducted using in silico simplified physiologically based pharmacokinetic (PBPK) modeling based on in vivo experimental pharmacokinetic data in humanized-liver mice (HL-mice) obtained after an oral dose of 100 mg/kg. Absorbed DBP was converted to monobutyl phthalate (MBP) and its glucuronide extensively in vivo. HL-mice had higher concentrations of MBP glucuronide in plasma than did the control mice. Concentrations of MBP glucuronide in 0-7 h accumulated urine samples from HL-mice were significantly higher than those in control mice. Similarly, in vitro MBP glucuronidation rates mediated by pooled microsomes from rat or mouse livers were lower than those mediated by human liver microsomes. Liver damage by MBP to humanized liver was detected by measuring human albumin mRNA in HL-mouse plasma. By simple PBPK modeling, in silico concentration curves in plasma, liver, or urine following virtual oral administration of DBP were created for rats, control mice, and HL-mice. A human PBPK model for MBP was established based on the HL-mouse PBPK model using allometric scaling without consideration of interspecies factors in terms of liver metabolism. Human PBPK models were used to estimate urinary and plasma concentrations of MBP and its glucuronide throughout 14 days of oral DBP administration (1.2 and 13 μg/kg/day). Reverse dosimetry PBPK modeling found that reported 50th and 95th percentile MBP urine and plasma concentrations of the general population could potentially imply exposures similar to or exceeding tolerable daily intake levels (5-10 μg/kg/day) recommended by the European and Japanese authorities. Further in-depth assessment of DBP is needed to assess the validity of assumptions made based on human biomonitoring data.

Perfluorohexanoic acid toxicity, part II: Application of human health toxicity value for risk characterization

Perfluorohexanoic acid (PFHxA) is a short-chain, six-carbon PFAA and is a primary impurity, degradant, and metabolite associated with the short-chain fluorotelomer-based chemistry used in the United States, Europe and Japan today. With the shift towards short-chain PFAA chemistry, uncertainties remain regarding human health risks associated with current exposure levels. Here, we present a critical review and assessment of data relevant to human health risk assessment to today's short-chain PFAA chemistry. Human biomonitoring surveys indicate that PFHxA is infrequently detected in the environment as well as in human serum and urine; however, human health concerns may persist in locations where PFHxA is detected. In a companion paper (Luz et al., 2019) we comprehensively evaluate the available toxicity data for PFHxA, and derive a chronic human health-based reference dose (RfD) for PFHxA of 0.25 mg/kg-day based on benchmark dose modeling of renal papillary necrosis in chronically exposed female rats. In this paper, we apply this RfD in human health-based screening levels calculations, and derive a drinking water lifetime health advisory of 1400 μg/L and a residential groundwater screening level for children of 4000 μg/L. Compared to environmental concentration data, even sites with more elevated concentrations of PFHxA in the environment are at least an order of magnitude lower than these screening levels. Available PFHxA human serum and urine biomonitoring data, used as a biomarker for general population exposure, demonstrates that the general human population exposures to PFHxA are low. Previous estimates of daily intake rates for infants exposed to PFHxA through breast milk, formula, and baby foods (Lorenzo et al., 2016) combined with the most conservative PFHxA peer-reviewed toxicity value (Luz et al., 2019) demonstrate that the margin of safety for PFHxA is high. Therefore, PFHxA and related fluorotelomer precursors currently appear to present negligible human health risk to the general population and are not likely to drive or substantially contribute to risk at sites contaminated with PFAS mixtures. PFHxA may also represent a suitable marker for the safety of fluorotelomer replacement chemistry used today.