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Modified Reference Point Index (mRPI) and a decision tree for deriving uncertainty factors: A practical approach to cumulative risk assessment of food contaminant mixtures. Vejdovszky Katharina,Mihats Daniela,Griesbacher Antonia,Wolf Josef,Steinwider Johann,Lueckl Johannes,Jank Bernhard,Kopacka Ian,Rauscher-Gabernig Elke Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Risk assessment of chemical mixtures remains a challenging task in all areas of food and consumer safety. So far, no general method has been developed that is best suited to several subject areas (e.g. food contaminants, additives and supplements, plant protection products). Especially for mixtures of food contaminants sophisticated methods are typically not applicable due to a general lack of complete toxicological data sets. We developed a new approach, the modified Reference Point Index (mRPI), that combines the advantages of the Hazard Index and the Reference Point Index. Furthermore, we developed a decision tree for the determination of specific uncertainty factors that makes the mRPI an easy to use method for cumulative risk assessment even in a data poor field such as food contaminants. To further characterise the estimated cumulative risks, the Maximum Cumulative Ratio (MCR) was adapted to be applied on the mRPI, and the modified Maximum Cumulative Ratio (mMCR) was established to identify whether the risks are dominated by a single substance. We present two case studies assessing the nephrotoxic and neurotoxic risks for the Austrian population originating from food contaminant mixtures. Calculations could not rule out potential cumulative risks, yet, they seemed to be dominated by single substances. 10.1016/j.fct.2019.110812
Refined reference doses and new procedures for phthalate mixture risk assessment focused on male developmental toxicity. Kortenkamp Andreas,Koch Holger M International journal of hygiene and environmental health New procedures for phthalate mixture risk assessments (MRAs) focused on male developmental toxicity (anti-androgenicity) are overdue. Previous efforts suffer from several shortcomings: There is a lack of consistency in terms of the phthalates entered into the assessments, and in the choice of tolerable intakes. Many of these values do not reflect new evidence about low dose male developmental effects. Nearly all previous mixture risk assessments have focused solely on phthalates, with no regard for exposures to other chemicals that also induce male developmental toxicity, leading to underestimations of risks. Here, we address these weaknesses and inconsistencies by proposing criteria for the selection of phthalates for MRA based on structure-activity relationships. We suggest new reference doses for phthalates for use in MRA, as follows: DBP 6.7 μg/kg/d, DIBP 100 μg/kg/d, BBP 10 μg/kg/d, DEHP 10 μg/kg/d, DINP 59 μg/kg/d. We conclude that the fixation on the Hazard Index (HI) = 1 as signalling acceptable combined phthalate exposures is misguided as it ignores co-exposure to other anti-androgenic chemicals that also contribute to male developmental risks. Until more comprehensive assessments of phthalates in combination with other anti-androgens become feasible, we propose the use of a HI of 0.1-0.2 as a benchmark for interpreting phthalate mixture risk assessments. 10.1016/j.ijheh.2019.113428
Physiologically based kinetic (PBK) modelling and human biomonitoring data for mixture risk assessment. Pletz Julia,Blakeman Samantha,Paini Alicia,Parissis Nikolaos,Worth Andrew,Andersson Anna-Maria,Frederiksen Hanne,Sakhi Amrit K,Thomsen Cathrine,Bopp Stephanie K Environment international 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. 10.1016/j.envint.2020.105978
Examining the feasibility of mixture risk assessment: A case study using a tiered approach with data of 67 pesticides from the Joint FAO/WHO Meeting on Pesticide Residues (JMPR). Evans Richard M,Scholze Martin,Kortenkamp Andreas Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association The way in which mixture risk assessment (MRA) should be included in chemical risk assessment is a current topic of debate. We used data from 67 recent pesticide evaluations to build a case study using Hazard Index calculations to form risk estimates in a tiered MRA approach in line with a Framework proposed by WHO/IPCS. The case study is used to illustrate the approach and to add detail to the existing Framework, and includes many more chemicals than previous case studies. A low-tier MRA identified risk as being greater than acceptable, but refining risk estimates in higher tiers was not possible due to data requirements not being readily met. Our analysis identifies data requirements, which typically expand dramatically in higher tiers, as being the likely cause for an MRA to fail in many realistic cases. This forms a major obstacle to routine implementation of MRA and shows the need for systematic generation and collection of toxicological data. In low tiers, hazard quotient inspection identifies chemicals that contribute most to the HI value and thus require attention if further refinement is needed. Implementing MRA requires consensus on issues such as scope setting, criteria for performing refinement, and decision criteria for actions. 10.1016/j.fct.2015.08.015
Identification of component-based approach for prediction of joint chemical mixture toxicity risk assessment with respect to human health: A critical review. Kumari Minashree,Kumar Arun Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Toxicity risk assessment of chemical mixture possesses huge challenges due to limited evidence on toxicity of compounds, the infinite number of chemical combinations makes the problem even more difficult. Normally, prediction of joint mixture toxicity depends on toxicological data of constituent compounds, although lack of information on dose-response of chemical mixture raises serious concerns on human health. Component-based approaches mainly use dose-addition or response-addition method to assess mixture toxicity risk exposure. Several models based on theoretical concepts of concentration/dose addition and independent/response action were also developed but these models do not address chemical interactions in mixture, and were mostly used to assess ecological risk exposure with limited or no information on human health risk assessment. This paper reviews available models to predict joint toxicity of chemical mixtures, and most applicable one to address human health risk exposure was identified. United States Environmental Protection Agency (US EPA) weight-of-evidence hazard index (HI) based approach seems to be most appropriate to predict joint toxicity of chemical mixtures, and applicability of model is explained using emerging contaminants as an example. The review also identified challenges in implementing the interaction-based EPA approach and highlighted the need for necessary future research actions. 10.1016/j.fct.2020.111458
Mixture risk assessment due to ingestion of arsenic, copper, and zinc from milkfish farmed in contaminated coastal areas. Lin Yi-Jun,Ling Min-Pei,Chen Szu-Chieh,Chen Wei-Yu,Hsieh Nan-Hung,Cheng Yi-Hsien,You Shu-Han,Chou Wei-Chun,Lin Ming-Chao,Liao Chung-Min Environmental science and pollution research international Human health risks associated with the consumption of metal-contaminated fish over extended periods have become a concern particularly in Taiwan, where fish is consumed on a large scale. This study applied the interaction-based hazard index (HI) to assess the mixture health risks for fishers and non-fishers who consume the arsenic (As), copper (Cu), and zinc (Zn) contaminated milkfish from As-contaminated coastal areas in Taiwan, taking into account joint toxic actions and potential toxic interactions. We showed that the interactions of As-Zn and Cu-Zn were antagonistic, whereas As-Cu interaction was additive. We found that HI estimates without interactions considered were 1.3-1.6 times higher than interactive HIs. Probability distributions of HI estimates for non-fishers were less than 1, whereas all 97.5%-tile HI estimates for fishers were >1. Analytical results revealed that the level of inorganic As in milkfish was the main contributor to HIs, indicating a health risk posed to consumers of fish farmed in As-contaminated areas. However, we found that Zn supplementation could significantly decrease As-induced risk of hematological effect by activating a Zn-dependent enzyme. In order to improve the accuracy of health risk due to exposure to multiple metals, further toxicological data, regular environmental monitoring, dietary survey, and refinement approaches for interactive risk assessment are warranted. 10.1007/s11356-017-8982-9
Cancer Risk Assessment of Airborne PAHs Based on in Vitro Mixture Potency Factors. Dreij Kristian,Mattsson Åse,Jarvis Ian W H,Lim Hwanmi,Hurkmans Jennie,Gustafsson Johan,Bergvall Christoffer,Westerholm Roger,Johansson Christer,Stenius Ulla Environmental science & technology Complex mixtures of polycyclic aromatic hydrocarbons (PAHs) are common environmental pollutants associated with adverse human health effects including cancer. However, the risk of exposure to mixtures is difficult to estimate, and risk assessment by whole mixture potency evaluations has been suggested. To facilitate this, reliable in vitro based testing systems are necessary. Here, we investigated if activation of DNA damage signaling in vitro could be an endpoint for developing whole mixture potency factors (MPFs) for airborne PAHs. Activation of DNA damage signaling was assessed by phosphorylation of Chk1 and H2AX using Western blotting. To validate the in vitro approach, potency factors were determined for seven individual PAHs which were in very good agreement with established potency factors based on cancer data in vivo. Applying the method using Stockholm air PAH samples indicated MPFs with orders of magnitude higher carcinogenic potency than predicted by established in vivo-based potency factors. Applying the MPFs in cancer risk assessment suggested that 45.4 (6% of all) cancer cases per year in Stockholm are due to airborne PAHs. Applying established models resulted in <1 cancer case per year, which is far from expected levels. We conclude that our in vitro based approach for establishing MPFs could be a novel method to assess whole mixture samples of airborne PAHs to improve health risk assessment. 10.1021/acs.est.7b02963
State of the art in the application of QSAR techniques for predicting mixture toxicity in environmental risk assessment. Kim J,Kim S SAR and QSAR in environmental research The focus of regulatory chemical risk assessment has been mainly placed on single chemicals rather than mixtures. However, living organisms and the environment might be exposed to mixtures of chemicals. Many scientific studies have revealed that mixture toxicity can arise from the combined effects of components present at levels below their individual no-effect concentrations. Predictive approaches will be essential for estimating mixture toxicity, as the number of possible mixtures is extremely large. Although predictive models are virtually indispensable for estimating mixture toxicity for both scientific and regulatory purposes, risk assessors encounter substantial difficulties in using conventional models, mainly due to the lack of information on the modes of toxic action of the mixture constituents. Alternative models that use different information instead of the modes of action thus need to be developed. The objective of this study is to investigate the state of the art in predictive models based on quantitative structure-activity relationship techniques for estimating the toxicity of mixture components, and to identify future challenges hindering more reliable mixture risk assessment for environmental risk assessment. Alternative models need to be developed not only to overcome the limitations of conventional models, but also to improve their performance. 10.1080/1062936X.2014.984627
Should the scope of human mixture risk assessment span legislative/regulatory silos for chemicals? Evans Richard M,Martin Olwenn V,Faust Michael,Kortenkamp Andreas The Science of the total environment Current chemicals regulation operates almost exclusively on a chemical-by-chemical basis, however there is concern that this approach may not be sufficiently protective if two or more chemicals have the same toxic effect. Humans are indisputably exposed to more than one chemical at a time, for example to the multiple chemicals found in food, air and drinking water, and in household and consumer products, and in cosmetics. Assessment of cumulative risk to human health and/or the environment from multiple chemicals and routes can be done in a mixture risk assessment (MRA). Whilst there is a broad consensus on the basic science of mixture toxicology, the path to regulatory implementation of MRA within chemical risk assessment is less clear. In this discussion piece we pose an open question: should the scope of human MRA cross legislative remits or 'silos'? We define silos as, for instance, legislation that defines risk assessment practice for a subset of chemicals, usually on the basis of substance/product, media or process orientation. Currently any form of legal mandate for human MRA in the EU is limited to only a few pieces of legislation. We describe two lines of evidence, illustrated with selected examples, that are particularly pertinent to this question: 1) evidence that mixture effects have been shown for chemicals regulated in different silos and 2) evidence that humans are co-exposed to chemicals from different silos. We substantiate the position that, because there is no reason why chemicals allocated to specific regulatory silos would have non-overlapping risk profiles, then there is also no reason to expect that MRA limited only to chemicals within one silo can fully capture the risk that may be present to human consumers. Finally, we discuss possible options for implementation of MRA and we hope to prompt wider discussion of this issue. 10.1016/j.scitotenv.2015.10.162
The MCRA toolbox of models and data to support chemical mixture risk assessment. van der Voet Hilko,Kruisselbrink Johannes W,de Boer Waldo J,van Lenthe Marco S,van den Heuvel J J B Hans,Crépet Amélie,Kennedy Marc C,Zilliacus Johanna,Beronius Anna,Tebby Cleo,Brochot Céline,Luckert Claudia,Lampen Alfonso,Rorije Emiel,Sprong Corinne,van Klaveren Jacob D Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association A model and data toolbox is presented to assess risks from combined exposure to multiple chemicals using probabilistic methods. The Monte Carlo Risk Assessment (MCRA) toolbox, also known as the EuroMix toolbox, has more than 40 modules addressing all areas of risk assessment, and includes a data repository with data collected in the EuroMix project. This paper gives an introduction to the toolbox and illustrates its use with examples from the EuroMix project. The toolbox can be used for hazard identification, hazard characterisation, exposure assessment and risk characterisation. Examples for hazard identification are selection of substances relevant for a specific adverse outcome based on adverse outcome pathways and QSAR models. Examples for hazard characterisation are calculation of benchmark doses and relative potency factors with uncertainty from dose response data, and use of kinetic models to perform in vitro to in vivo extrapolation. Examples for exposure assessment are assessing cumulative exposure at external or internal level, where the latter option is needed when dietary and non-dietary routes have to be aggregated. Finally, risk characterisation is illustrated by calculation and display of the margin of exposure for single substances and for the cumulation, including uncertainties derived from exposure and hazard characterisation estimates. 10.1016/j.fct.2020.111185
Chemical Mixture Calculator - A novel tool for mixture risk assessment. Boberg Julie,Bredsdorff Lea,Petersen Annette,Löbl Nathalie,Jensen Bodil Hamborg,Vinggaard Anne Marie,Nielsen Elsa Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Humans are continuously exposed to complex chemical mixtures from foods and the environment. Experimental models in vivo and in vitro have increased our knowledge on how we can predict mixture effects. To accommodate a need for tools for efficient mixture risk assessment across different chemical classes and exposure sources, we have developed fit-for-purpose criteria for grouping of chemicals and a web-based tool for mixture risk assessment. The Chemical Mixture Calculator (available at www.chemicalmixturecalculator.dk) can be used for mixture risk assessment or identification of main drivers of risk. The underlying database includes hazard and exposure estimates for more than 200 chemicals in foods and environment. We present a range of cumulative assessment groups for effects on haematological system, kidney, liver, nervous system, developmental and reproductive system, and thyroid. These cumulative assessment groups are useful for grouping of chemicals at several levels of refinement depending on the question addressed. We present a mixture risk assessment case for phthalates, evaluated with and without contributions from other chemicals with similar effects. This case study shows the usefulness of the tool as a starting point for mixture risk assessment by the risk assessor, and emphasizes that solid scientific insight regarding underlying assumptions and uncertainties is crucial for result interpretation. 10.1016/j.fct.2021.112167
A Novel Approach to Chemical Mixture Risk Assessment-Linking Data from Population-Based Epidemiology and Experimental Animal Tests. Bornehag Carl-Gustaf,Kitraki Efthymia,Stamatakis Antonios,Panagiotidou Emily,Rudén Christina,Shu Huan,Lindh Christian,Ruegg Joelle,Gennings Chris Risk analysis : an official publication of the Society for Risk Analysis Humans are continuously exposed to chemicals with suspected or proven endocrine disrupting chemicals (EDCs). Risk management of EDCs presents a major unmet challenge because the available data for adverse health effects are generated by examining one compound at a time, whereas real-life exposures are to mixtures of chemicals. In this work, we integrate epidemiological and experimental evidence toward a whole mixture strategy for risk assessment. To illustrate, we conduct the following four steps in a case study: (1) identification of single EDCs ("bad actors")-measured in prenatal blood/urine in the SELMA study-that are associated with a shorter anogenital distance (AGD) in baby boys; (2) definition and construction of a "typical" mixture consisting of the "bad actors" identified in Step 1; (3) experimentally testing this mixture in an in vivo animal model to estimate a dose-response relationship and determine a point of departure (i.e., reference dose [RfD]) associated with an adverse health outcome; and (4) use a statistical measure of "sufficient similarity" to compare the experimental RfD (from Step 3) to the exposure measured in the human population and generate a "similar mixture risk indicator" (SMRI). The objective of this exercise is to generate a proof of concept for the systematic integration of epidemiological and experimental evidence with mixture risk assessment strategies. Using a whole mixture approach, we could find a higher rate of pregnant women under risk (13%) when comparing with the data from more traditional models of additivity (3%), or a compound-by-compound strategy (1.6%). 10.1111/risa.13323
Grouping of endocrine disrupting chemicals for mixture risk assessment - Evidence from a rat study. Christiansen Sofie,Axelstad Marta,Scholze Martin,Johansson Hanna K L,Hass Ulla,Mandrup Karen,Frandsen Henrik Lauritz,Frederiksen Hanne,Isling Louise Krag,Boberg Julie Environment international Exposure to mixtures of endocrine disrupting chemicals may contribute to the rising incidence of hormone-related diseases in humans. Real-life mixtures are complex, comprised of chemicals with mixed modes of action, and essential knowledge is often lacking on how to group such chemicals into cumulative assessment groups, which is an essential prerequisite to conduct a chemical mixture risk assessment. We investigated if mixtures of chemicals with diverse endocrine modes of action can cause mixture effects on hormone sensitive endpoints in developing and adult rat offspring after perinatal exposure. Wistar rats were exposed during pregnancy and lactation simultaneously to either bisphenol A and butylparaben (Emix), diethylhexyl phthalate and procymidone (Amix), or a mixture of all four substances (Totalmix). In male offspring, the anogenital distance was significantly reduced and nipple retention increased in animals exposed to Amix and Totalmix, and the mixture effects were well approximated by the dose addition model. The combination of Amix and Emix responded with more marked changes on these and other endocrine-sensitive endpoints than each binary mixture on its own. Sperm counts were reduced by all exposures. These experimental outcomes suggest that the grouping of chemicals for mixture risk assessment should be based on common health outcomes rather than only similar modes or mechanisms of action. Mechanistic-based approaches such as the concept of Adverse Outcome Pathway (AOP) can provide important guidance if both the information on shared target tissues and the information on shared mode/mechanism of action are taken into account. 10.1016/j.envint.2020.105870
Probabilistic Integrated Human Mixture Risk Assessment of Multiple Metals Through Seafood Consumption. Lin Yi-Jun,Lin Pinpin Risk analysis : an official publication of the Society for Risk Analysis Inorganic arsenic (iAs), cadmium (Cd), lead (Pb), and methylmercury (MeHg) are toxic metals that cause substantial health concern and are present in various seafood items. This study linked probabilistic risk assessment to the interactive hazard index (HI ) approach to assess the human mixture risk posed by the dietary intake of iAs, Cd, Pb, and MeHg from seafood for different age populations, and joint toxic actions and toxic interactions among metals were also considered in the assessment. We found that, in combination, an iAs-Cd-Pb-MeHg mixture synergistically causes neurological toxicity. Furthermore, an iAs-Cd-Pb mixture antagonistically causes renal and hematological effects and additively causes cardiovascular effect. Our results demonstrated that if toxic interactions are not considered, the health risk may be overestimated or underestimated. The 50th percentile HI estimates in all age populations for neurological, renal, cardiovascular, and hematological effects were lower than 1; however, the 97.5th percentile HI estimates might exceed 1. In particular, toddlers and preschoolers had the highest neurological risk, with 0.16 and 0.19 probabilities, respectively, of neurological HI exceeding 1. Saltwater fish consumption was the principal contributor to the health risk. We suggest that regular monitoring of metal levels in seafood, more precise dietary surveys, further toxicological data, and risk-benefit analysis of seafood consumption are warranted to improve the accuracy of human mixture risk assessment and determine optimal consumption. 10.1111/risa.13183