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Per- and polyfluoroalkyl substances (PFAS) are used in various household and industrial products. In humans, positive associations were reported between PFAS, including perfluorsulfonic acid and perfluorooctanoic acid, and cholesterol, a cardiometabolic risk factor. Animal studies show the opposite. Human-centered approaches are needed to better understand the effects of PFAS mixtures on cholesterol. Here, a systems toxicology approach is described, using a gene-centered cholesterol biokinetic model. PFAS exposure-gene expression relations from published data were introduced into the model. An existing PFAS physiologically based kinetic model was augmented with lung and dermal compartments and integrated with the cholesterol model to enable exposure-effect modeling. The final model was populated with data reflecting lifetime mixture exposure from: tolerable weekly intake values; the environment; high occupational exposures (ski waxing, PFAS industry). Results indicate that low level exposures (tolerable weekly intake, environmental) did not change cholesterol. In contrast, occupational exposures clearly resulted in internal PFAS exposure and disruption of cholesterol homeostasis, largely in line with epidemiological observations. Despite model limitations (eg, dynamic range, directionality), changes in cholesterol homeostasis were predicted for ski waxers, hitherto unknown from epidemiological studies. Here, future studies involving lipid metabolism could improve risk assessment.

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BACKGROUND: Sesame is a significant food allergen causing severe and even fatal reactions. Given its increasing prevalence in western diet, sesame is listed as an allergenic food requiring labeling in the United States and EU. However, data on the population reaction doses to sesame are limited. METHODS: All sesame oral food challenges (OFCs), performed either for diagnosis or for threshold identification before the beginning of sesame oral immunotherapy (OIT) between November 2011 and July 2021 in Shamir medical center were analyzed for reaction threshold distribution. Safe-dose challenges with 90-120 min intervals were also analyzed. RESULTS: Two hundred and fifty patients underwent 338 positive OFCs, and additional 158 safe-dose OFCs were performed. The discrete and cumulative protein amounts estimated to elicit an objective reaction in 1% (ED01) of the entire cohort (n = 250) were 0.8 mg (range 0.3-6.3) and 0.7 mg (range 0.1-7.1), respectively, and those for 5% of the population (ED05) were 3.4 mg (range 1.2-20.6) and 4.5 mg (range 1.2-28.8), respectively. Safe-dose OFCs showed similar values of ED01 (0.8, 0.4-7.5 mg) and ED05 (3.4, 1.2-22.9 mg). While doses of ≤1 mg sesame protein elicited oral pruritus in 11.6% of the patients, no objective reaction was documented to this amount in any of the challenges, including safe-dose OFCs. CONCLUSIONS: This study provides data on sesame reaction threshold distribution in the largest population of allergic patients studied, with no right or left censored data, and with validation using a safe-dose OFC. It further supports the current methods for ED determination as appropriate for establishing safety precautions for the food industry.

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Lack of guidance regarding selection of food intake values for allergen risk assessment can lead to different outcomes for similar levels of allergens in food products. Several food consumption survey databases (United States, North-West Europe, and Netherlands) were analyzed to identify optimal food intake percentiles using a sensitivity analysis. Deterministic risk assessment scenarios using the 50th percentile up to the maximum intake per food group were compared with probabilistic risk assessment outcomes. The optimal intake percentile is the lowest percentile that results in a deterministic risk assessment outcome compliant with the predefined safety objective, i.e., the predefined risk of an objective allergic reaction at ED01, ED2.5, ED05 or ED10 doses of 14 allergenic foods. The P50 intake met these criteria in more than 99.9% of all 28,784 scenarios tested. The P50 is therefore recommended for deterministic allergen risk assessment and calculation of action levels for precautionary allergen labelling. In case a P50 value is not available, the mean is a good alternative, as analyses of the intake data showed that the mean generally is between the P50 and P65.

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Toxicology is moving away from animal testing towards in vitro tools to assess chemical safety. This new testing framework requires a quantitative method, i.e. kinetic modelling, which extrapolates effective concentrations in vitro to a bioequivalent human dose in vivo and which can be applied on "high throughput screening" of a wide variety of chemicals. Generic physiologically based kinetic (PBK) models help account for the role of toxicokinetics in setting human toxic exposure levels. Furthermore these models may be parameterized only on in silico QSARs and in vitro metabolism assays, thereby circumventing the use of in vivo toxicokinetics for this purpose. Though several such models exist their applicability domains have yet to be comprehensively assessed. This study extends previous evaluations of the PBK model IndusChemFate and compares it with its more complex biological complement ("TNO Model"). Both models were evaluated with a broad span of chemicals, varying regarding physicochemical properties. The results reveal that the "simpler" performed best, illustrating that IndusChemFate can be a useful first-tier for simulating toxicokinetics based on QSARs and in vitro parameters. Finally, proper quantitative in vitro to in vivo extrapolation conditions were illustrated starting with acetaminophen induced in vitro cytotoxicity in human HepaRG cells.

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With an increasing need to incorporate new approach methodologies (NAMs) in chemical risk assessment and the concomitant need to phase out animal testing, the interpretation of in vitro assay readouts for quantitative hazard characterisation becomes more important. Physiologically based kinetic (PBK) models, which simulate the fate of chemicals in tissues of the body, play an essential role in extrapolating in vitro effect concentrations to in vivo bioequivalent exposures. As PBK-based testing approaches evolve, it will become essential to standardise PBK modelling approaches towards a consensus approach that can be used in quantitative in vitro-to-in vivo extrapolation (QIVIVE) studies for regulatory chemical risk assessment based on in vitro assays. Based on results of an ECETOC expert workshop, steps are recommended that can improve regulatory adoption: (1) define context and implementation, taking into consideration model complexity for building fit-for-purpose PBK models, (2) harmonise physiological input parameters and their distribution and define criteria for quality chemical-specific parameters, especially in the absence of in vivo data, (3) apply Good Modelling Practices (GMP) to achieve transparency and design a stepwise approach for PBK model development for risk assessors, (4) evaluate model predictions using alternatives to in vivo PK data including read-across approaches, (5) use case studies to facilitate discussions between modellers and regulators of chemical risk assessment. Proof-of-concepts of generic PBK modelling approaches are published in the scientific literature at an increasing rate. Working on the previously proposed steps is, therefore, needed to gain confidence in PBK modelling approaches for regulatory use.

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Access to Eliciting Doses (ED) for allergens enables advanced food allergen risk assessment. Previously, the full ED range for 14 allergenic foods, including milk, and recommendations for their use were provided (Houben et al., 2020). Additional food challenge studies with cow's milk-allergic patients added 247 data points to the original dataset. Using the Stacked Model Averaging statistical method for interval-censored data on the 697 individual NOAELs and LOAELs for milk generated an updated full ED distribution. The ED01 and ED05, the doses at which 1% and 5% of the milk-allergic population would be predicted to experience any objective allergic reaction, were 0.3 and 3.2 mg milk protein for the discrete and 0.4 mg and 4.3 mg milk protein for the cumulative dose distribution, respectively. These values are slightly higher but remain within the 95% confidence interval of previously published EDs. We recommend using the updated EDs for future characterization of risks of exposure of milk-allergic individuals to milk protein. This paper contributes to the discussion on the Reference Dose for milk in the recent Ad hoc Joint FAO/WHO Expert Consultation on Risk Assessment of Food Allergens. It will also benefit harmonization of food allergen risk assessment and risk management globally.

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A follow-up study was performed in 12 healthy women to evaluate systemic exposure to aluminium following topical application of a representative antiperspirant formulation under real-life use conditions (part A) and to assess the local fate of topically applied aluminium by taking additional tape strips and skin biopsies (Part B). A simple roll-on formulation, containing the maximal possible radioactive dose, was prepared with [26Al] aluminium-labeled chlorohydrate (ACH). The microtracer of [26Al] was used to distinguish aluminium from the natural background, using accelerator mass spectrometry. [26Al] aluminiumcitrate was administered intravenously to estimate the dermal fraction absorbed. Despite the 25-fold increase of the topical dose compared with the previous study, only 12 blood samples gave results above the lower limit of quantitation (0.118 fg/mL). The most reliable estimates of the dermal fraction absorbed are derived from noncompartmental analysis with the urine data. By using the intravenous dose to normalize the urinary excretion to 100% bioavailability, the best estimate of the fraction absorbed of [26Al] from a topical application of [26Al]-aluminium-labeled chlorohydrate in an antiperspirant formulation was 0.00052%. Part B of the study demonstrated that the majority of the aluminium in the formulation remained associated with the external layers of the skin without penetration through the skin.

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BACKGROUND: Cow's milk (CM) is an increasingly common cause of severe allergic reactions, but there is uncertainty with respect to severity of reactions at low-level CM exposure, as well as the reproducibility of reaction thresholds. OBJECTIVE: We undertook an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges in CM to determine the rate of anaphylaxis to low-level exposures and the reproducibility of reaction thresholds. METHODS: We performed a systematic review and IPD meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarification as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodologic checklists. RESULTS: Thirty-four studies were included, representing data from over 1000 participants. The cumulative ED01 and ED05 (cumulative doses causing objective symptoms in 1% and 5% of the at-risk allergic population) were 0.3 (95% confidence interval [CI], 0.2-0.5) and 2.9 (95% CI, 1.6-5.4) mg, respectively. At meta-analysis, 4.8% (95% CI, 2.0-10.9) and 4.8% (95% CI, 0.7-27.1) of individuals reacting to ≤5 mg and ≤0.5 mg of CM protein had anaphylaxis (minimal heterogeneity, I2 = 0%). Then 110 individuals underwent repeat double-blind, placebo-controlled food challenges; the intraindividual variation in reaction threshold was limited to a ½-log change in 80% (95% CI, 65-89) of participants. Two individuals initially tolerated 5 mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis. CONCLUSIONS: About 5% of CM-allergic individuals reacting to ED01 or ED05 exposure might have anaphylaxis to that dose. This equates to 5 and 24 anaphylaxis events per 10,000 patients exposed to an ED01 or ED05 dose, respectively, in the broader CM-allergic population. Most of these anaphylactic reactions would be mild and respond to a single dose of epinephrine.

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The aim of this work was to demonstrate how human biomonitoring (HBM) data can be used to assess cancer risks for workers and the general population. Ortho-toluidine, OT (CAS 95-53-4) is an aniline derivative which is an animal and human carcinogen and may cause methemoglobinemia. OT is used as a curing agent in epoxy resins and as intermediate in producing herbicides, dyes, and rubber chemicals. A risk assessment was performed for OT by using existing HBM studies. The urinary mass-balance methodology and generic exposure reconstruction PBPK modelling were both used for the estimation of the external intake levels corresponding to observed urinary levels. The external exposures were subsequently compared to cancer risk levels obtained from the evaluation by the Scientific Committee on Occupational Exposure Limits (SCOEL). It was estimated that workers exposed to OT have a cancer risk of 60 to 90:106 in the worst-case scenario (0.9 mg/L in urine). The exposure levels and cancer risk of OT in the general population were orders of magnitude lower when compared to workers. The difference between the output of urinary mass-balance method and the general PBPK model was approximately 30%. The external exposure levels calculated based on HBM data were below the binding occupational exposure level (0.5 mg/m3) set under the EU Carcinogens and Mutagens Directive.

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The majority of intestinal in vitro screening models use cell lines that do not reflect the complexity of the human intestinal tract and hence often fail to accurately predict intestinal drug absorption. Tissue explants have intact intestinal architecture and cell type diversity, but show short viability in static conditions. Here, we present a medium throughput microphysiological system, Intestinal Explant Barrier Chip (IEBC), that creates a dynamic microfluidic microenvironment and prolongs tissue viability. Using a snap fit mechanism, we successfully incorporated human and porcine colon tissue explants and studied tissue functionality, integrity and viability for 24 hours. With a proper distinction of transcellular over paracellular transport (ratio >2), tissue functionality was good at early and late timepoints. Low leakage of FITC-dextran and preserved intracellular lactate dehydrogenase levels indicate maintained tissue integrity and viability, respectively. From a selection of low to high permeability drugs, 6 out of 7 properly ranked according to their fraction absorbed. In conclusion, the IEBC is a novel screening platform benefitting from the complexity of tissue explants and the flow in microfluidic chips.

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Associations between per- and polyfluoroalkyl substances (PFASs) and increased blood lipids have been repeatedly observed in humans, but a causal relation has been debated. Rodent studies show reverse effects, i.e. decreased blood cholesterol and triglycerides, occurring however at PFAS serum levels at least 100-fold higher than those in humans. This paper aims to present the main issues regarding the modulation of lipid homeostasis by the two most common PFASs, PFOS and PFOA, with emphasis on the underlying mechanisms relevant for humans. Overall, the apparent contrast between human and animal data may be an artifact of dose, with different molecular pathways coming into play upon exposure to PFASs at very low versus high levels. Altogether, the interpretation of existing rodent data on PFOS/PFOA-induced lipid perturbations with respect to the human situation is complex. From a mechanistic perspective, research on human liver cells shows that PFOS/PFOA activate the PPARα pathway, whereas studies on the involvement of other nuclear receptors, like PXR, are less conclusive. Other data indicate that suppression of the nuclear receptor HNF4α signaling pathway, as well as perturbations of bile acid metabolism and transport might be important cellular events that require further investigation. Future studies with human-relevant test systems would help to obtain more insight into the mechanistic pathways pertinent for humans. These studies shall be designed with a careful consideration of appropriate dosing and toxicokinetics, so as to enable biologically plausible quantitative extrapolations. Such research will increase the understanding of possible perturbed lipid homeostasis related to PFOS/ PFOA exposure and the potential implications for human health.

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National population-based food consumption surveys are used in food allergen risk assessment. It would be beneficial if food intake data is interchangeable between countries to bridge potential gaps present in national survey data, which is only possible when risk assessment outcomes for comparable food product groups between countries are fairly similar. Additionally, merged food intake data would enable risk assessments that cover scenarios for various countries, if based on the most critical situation. Therefore, we systematically compared risk assessment outcomes for a broad range of food groups based on United States and Dutch population food consumption survey data. We calculated risks for 14 allergenic foods for 9 concentrations (1-10,000 ppm) to assess comparability. Depending on the assumed allergen concentration, risk assessment outcomes for 20% (10 out of 49) food groups differed considerably. We consider the number of potentially relevant risk differences too high to conclude that food intake data from the US and The Netherlands can be used interchangeably. To allow risk assessments that cover scenarios for several countries, we recommend development and use of a food intake dataset based on the highest intake levels for each food group of the involved countries to facilitate risk management efforts and harmonization.

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To better understand the risk of exposure to food allergens, food challenge studies are designed to slowly increase the dose of an allergen delivered to allergic individuals until an objective reaction occurs. These dose-to-failure studies are used to determine acceptable intake levels and are analyzed using parametric failure time models. Though these models can provide estimates of the survival curve and risk, their parametric form may misrepresent the survival function for doses of interest. Different models that describe the data similarly may produce different dose-to-failure estimates. Motivated by predictive inference, we developed a Bayesian approach to combine survival estimates based on posterior predictive stacking, where the weights are formed to maximize posterior predictive accuracy. The approach defines a model space that is much larger than traditional parametric failure time modeling approaches. In our case, we use the approach to include random effects accounting for frailty components. The methodology is investigated in simulation, and is used to estimate allergic population eliciting doses for multiple food allergens.

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Previously, we published selected Eliciting Dose (ED) values (i.e. ED01 and ED05 values) for 14 allergenic foods, predicted to elicit objective allergic symptoms in 1% and 5%, respectively, of the allergic population (Remington et al., 2020). These ED01 and ED05 values were specifically presented and discussed in the context of establishing Reference Doses for allergen management and the calculation of Action Levels for Precautionary Allergen Labeling (PAL). In the current paper, we publish the full range of ED values for these allergenic foods and provide recommendations for their use, specifically in the context of characterizing risks of concentrations of (unintended) allergenic proteins in food products. The data provided in this publication give risk assessors access to full population ED distribution information for 14 priority allergenic foods, based on the largest threshold database worldwide. The ED distributions were established using broad international consensus regarding suitable datapoints and methods for establishing individual patient's NOAELs and LOAELs and state of the art statistical modelling. Access to these ED data enables risk assessors to use this information for state-of-the-art food allergen risk assessment. This paper contributes to a harmonization of food allergen risk assessment and risk management and PAL practices.

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Food allergy and allergen management are important global public health issues. In 2011, the first iteration of our allergen threshold database (ATDB) was established based on individual NOAELs and LOAELs from oral food challenge in roughly 1750 allergic individuals. Population minimal eliciting dose (EDp) distributions based on this dataset were published for 11 allergenic foods in 2014. Systematic data collection has continued (2011-2018) and the dataset now contains over 3400 data points. The current study provides new and updated EDp values for 14 allergenic foods and incorporates a newly developed Stacked Model Averaging statistical method for interval-censored data. ED01 and ED05 values, the doses at which 1%, and respectively 5%, of the respective allergic population would be predicted to experience any objective allergic reaction were determined. The 14 allergenic foods were cashew, celery, egg, fish, hazelnut, lupine, milk, mustard, peanut, sesame, shrimp (for crustacean shellfish), soy, walnut, and wheat. Updated ED01 estimates ranged between 0.03 mg for walnut protein and 26.2 mg for shrimp protein. ED05 estimates ranged between 0.4 mg for mustard protein and 280 mg for shrimp protein. The ED01 and ED05 values presented here are valuable in the risk assessment and subsequent risk management of allergenic foods.

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BACKGROUND: Food allergies are a significant public health issue, and the only effective management option currently available is strict avoidance of all foods containing the allergen. In view of the practical impossibility of limiting risks to zero, quantitative allergen risk assessment and management strategies are needed. OBJECTIVE: We sought to develop appropriate methods for informing population-based risk assessments and risk management programs to benefit all stakeholders but particularly patients with food allergy. METHODS: Individual thresholds for food allergens (maximum tolerable doses and minimum eliciting doses) can ideally be established through double-blind, placebo-controlled food challenges. If double-blind, placebo-controlled food challenge data are not available, data from widely used open food challenges using predefined objective criteria can also provide useful data regarding minimum eliciting doses. For more than 20 years, the Netherlands Organisation for Applied Scientific Research and the Food Allergy Research and Resource Program at the University of Nebraska-Lincoln have been collecting individual maximum tolerable doses and minimum eliciting doses that produce objective symptoms from published and unpublished clinical data to better refine knowledge regarding the sensitivity of the population to food allergens. RESULTS: In this article we provide in-depth insights into the methodology applied by the Netherlands Organisation for Applied Scientific Research and Food Allergy Research and Resource Program to derive individual maximum tolerable doses and minimum eliciting doses for objective symptoms from clinical food challenge data. More than 90 examples for determining individual allergic thresholds are presented. CONCLUSION: With the methodology presented in this article, we aim to stimulate harmonization and transparency in quantitative food allergen risk assessment and risk management programs, encouraging their wider adoption.

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Alternative and sustainable protein sources (e.g., algae, duckweed, insects) are required to produce (future) foods. However, introduction of new food sources to the market requires a thorough risk assessment of nutritional, microbial and toxicological risks and potential allergic responses. Yet, the risk assessment of allergenic potential of novel proteins is challenging. Currently, guidance for genetically modified proteins relies on a weight-of-evidence approach. Current Codex (2009) and EFSA (2010; 2017) guidance indicates that sequence identity to known allergens is acceptable for predicting the cross-reactive potential of novel proteins and resistance to pepsin digestion and glycosylation status is used for evaluating de novo allergenicity potential. Other physicochemical and biochemical protein properties, however, are not used in the current weight-of-evidence approach. In this study, we have used the Random Forest algorithm for developing an in silico model that yields a prediction of the allergenic potential of a protein based on its physicochemical and biochemical properties. The final model contains twenty-nine variables, which were all calculated using the protein sequence by means of the ProtParam software and the PSIPred Protein Sequence Analysis program. Proteins were assigned as allergenic when present in the COMPARE database. Results show a robust model performance with a sensitivity, specificity and accuracy each greater than ≥85%. As the model only requires the protein sequence for calculations, it can be easily incorporated into the existing risk assessment approach. In conclusion, the model developed in this study improves the predictability of the allergenicity of new or modified food proteins, as demonstrated for insect proteins.

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