Governance of advanced materials: Shaping a safe and sustainable future.

The past few decades of managing the uncertain risks associated with nanomaterials have provided valuable insights (knowledge gaps, tools, methods, etc.) that are equally important to promote safe and sustainable development and use of advanced materials. Based on these insights, the current paper proposes several actions to optimize the risk and sustainability governance of advanced materials. We emphasise the importance of establishing a European approach for risk and sustainability governance of advanced materials as soon as possible to keep up with the pace of innovation and to manage uncertainty among regulators, industry, SMEs and the public, regarding potential risks and impacts of advanced materials. Coordination of safe and sustainable advanced material research efforts, and data management according to the Findable, Accessible, Interoperable and Reusable (FAIR) principles will enhance the generation of regulatory-relevant knowledge. This knowledge is crucial to identify whether current regulatory standardised and harmonised test methods are adequate to assess advanced materials. At the same time, there is urgent need for responsible innovation beyond regulatory compliance which can be promoted through the Safe and Sustainable Innovation Approach. that combines the Safe and Sustainable by Design concept with Regulatory Preparedness, supported by a trusted environment. We further recommend consolidating all efforts and networks related to the risk and sustainability governance of advanced materials in a single, easy-to-use digital portal. Given the anticipated complexity and tremendous efforts required, we identified the need of establishing an organisational structure dedicated to aligning the fast technological developments in advanced materials with proper risk and sustainability governance. Involvement of multiple stakeholders in a trusted environment ensures a coordinated effort towards the safe and sustainable development, production, and use of advanced materials. The existing infrastructures and network of experts involved in the governance of nanomaterials would form a solid foundation for such an organisational structure.

PACEMweb: a tool for aggregate consumer exposure assessment.

BACKGROUND: To ascertain the safe use of chemicals that are used in multiple consumer products, the aggregate human exposure, arising from combined use of multiple consumer products needs to be assessed. OBJECTIVE: In this work the Probabilistic Aggregate Consumer Exposure Model (PACEM) is presented and discussed. PACEM is implemented in the publicly available web tool, PACEMweb, for aggregate consumer exposure assessment. METHODS: PACEM uses a person-oriented simulation method that is based on realistic product usage information obtained in surveys from several European countries. PACEM evaluates aggregate exposure in a population considering individual use and co-use patterns as well as variation in product composition. Product usage data is included on personal care products (PCPs) and household cleaning products (HCPs). RESULTS: PACEM has been implemented in a web tool that supports broad use in research as well as regulatory risk assessment. PACEM has been evaluated in a number of applications, testing and illustrating the advantage of the person-oriented modeling method. Also, PACEM assessments have been evaluated by comparing its results with biomonitoring information. SIGNIFICANCE: PACEM enables the assessment of realistic aggregate exposure to chemicals in consumer products. It provides detailed insight into the distribution of exposure in a population as well as products that contribute the most to exposure. This allows for better informed decision making in the risk management of chemicals. IMPACT: Realistic assessment of the total, aggregate exposure of consumers to chemicals in consumer products is necessary to guarantee the safe use of chemicals in these products. PACEMweb provides, for the first time, a publicly available tool to assist in realistic aggregate exposure assessment of consumers to chemicals in consumer products.

APROBA-Plus: A probabilistic tool to evaluate and express uncertainty in hazard characterization and exposure assessment of substances.

To facilitate the application of probabilistic risk assessment, the WHO released the APROBA tool. This tool applies lognormal uncertainty distributions to the different aspects of the hazard characterization, resulting in a probabilistic health-based guidance value. The current paper describes an extension, APROBA-Plus, which combines the output from the probabilistic hazard characterization with the probabilistic exposure to rapidly characterize risk and its uncertainty. The uncertainty in exposure is graphically compared with the uncertainty in the target human dose, i.e. the dose that complies with the specified protection goals. APROBA-Plus is applied to several case studies, resulting in distinct outcomes and illustrating that APROBA-Plus could serve as a standard extension of routine risk assessments. By visualizing the uncertainties, APROBA-Plus provides a more transparent and informative outcome than the more usual deterministic approaches, so that risk managers can make better informed decisions. For example, APROBA-Plus can help in deciding whether risk-reducing measures are warranted or that a refined risk assessment would first be needed. If the latter, the tool can be used to prioritize possible refinements. APROBA-Plus may also be used to rank substances into different risk categories, based on potential health risks without being compromised by different levels of conservatism that may be associated with point estimates of risk.

Direct and Air-Mediated Transfer of Labeled SVOCs from Indoor Sources to Dust.

Two small-scale field studies were conducted to investigate the transfer of substances from products into dust due to direct and air-mediated transfer. The project focused on semivolatile organic compounds (SVOCs), which are frequently found in and re-emitted from dust. For the field studies, four artificial products containing deuterium-labeled SVOCs (eight phthalates and adipates) were installed in residential indoor environments. Two plastic products were installed vertically to investigate substance transfer due to evaporation into air. One plastic product and a carpet were installed horizontally to investigate the direct transfer from source to dust. A pyrethroid was intentionally released by spraying a commercial spray. Dust samples were collected from the floor, elevated surfaces in the room and the surfaces of the horizontally installed products. We observed that the dust concentrations of substances exclusively transferred via air were similar at different collection sites, but the concentrations of chemicals present in horizontal products were up to 3 orders of magnitude higher in dust deposited on the source. We conclude that direct transfer from source into dust substantially increases the final SVOC concentration in dust in contact with the source, regardless of the vapor pressure of investigated SVOCs, and may lead to larger human exposure.

Tracking SVOCs' Transfer from Products to Indoor Air and Settled Dust with Deuterium-Labeled Substances.

Semivolatile organic compounds (SVOCs) can be released from products and distributed in the indoor environment, including air and dust. However, the mechanisms and the extent of substance transfer into air and dust are not well understood. Therefore, in a small-scale field study the transfer of nine SVOCs was investigated: Four artificial consumer products were doped with eight deuterium-labeled plasticizers (phthalates and adipates) and installed in five homes to investigate the emission processes of evaporation, abrasion, and direct transfer. Intentional release was studied with a commercial spray containing a pyrethroid. During the 12 week study, indoor air and settled dust samples were collected and analyzed. On the basis of our measurement results, we conclude that the octanol-air partitioning coefficient Koa is a major determinant for the substance transfer into either air or dust: A high Koa implies that the substance is more likely to be found in dust than in air. The emission process also plays a role: For spraying, we found higher dust and air concentrations than for evaporation. In contrast, apartment parameters like air exchange rate or temperature had just a minor influence. Another important mechanistic finding was that although transfer from product to dust currently is postulated to be mostly mediated by air, direct transport from product to dust on the product surface was also observed.

The probabilistic aggregate consumer exposure model (PACEM): validation and comparison to a lower-tier assessment for the cyclic siloxane D5.

Current practice of chemical risk assessment for consumer product ingredients still rarely exercises the aggregation of multi-source exposure. However, focusing on a single dominant source/pathway combination may lead to a significant underestimation of the risk for substances present in numerous consumer products, which often are used simultaneously. Moreover, in most cases complex multi-route exposure scenarios also need to be accounted for. This paper introduces and evaluates the performance of the Probabilistic Aggregate Consumer Exposure Model (PACEM) applied in the context of a tiered approach to exposure assessment for ingredients in cosmetics and personal care products (C&PCPs) using decamethylcyclopentasiloxane (D5) as a worked example. It is demonstrated that PACEM predicts a more realistic, but still conservative aggregate exposure within the Dutch adult population when compared to a deterministic point estimate obtained in a lower tier screening assessment. An overall validation of PACEM is performed by quantitatively relating and comparing its estimates to currently available human biomonitoring and environmental sampling data. Moderate (by maximum one order of magnitude) overestimation of exposure is observed due to a justified conservatism built into the model structure, resulting in the tool being suitable for risk assessment.

Exploring the uncertainties in cancer risk assessment using the integrated probabilistic risk assessment (IPRA) approach.

Current methods for cancer risk assessment result in single values, without any quantitative information on the uncertainties in these values. Therefore, single risk values could easily be overinterpreted. In this study, we discuss a full probabilistic cancer risk assessment approach in which all the generally recognized uncertainties in both exposure and hazard assessment are quantitatively characterized and probabilistically evaluated, resulting in a confidence interval for the final risk estimate. The methodology is applied to three example chemicals (aflatoxin, N-nitrosodimethylamine, and methyleugenol). These examples illustrate that the uncertainty in a cancer risk estimate may be huge, making single value estimates of cancer risk meaningless. Further, a risk based on linear extrapolation tends to be lower than the upper 95% confidence limit of a probabilistic risk estimate, and in that sense it is not conservative. Our conceptual analysis showed that there are two possible basic approaches for cancer risk assessment, depending on the interpretation of the dose-incidence data measured in animals. However, it remains unclear which of the two interpretations is the more adequate one, adding an additional uncertainty to the already huge confidence intervals for cancer risk estimates.

Variability of bioaccessibility results using seventeen different methods on a standard reference material, NIST 2710.

Bioaccessibility is a measurement of a substance's solubility in the human gastro-intestinal system, and is often used in the risk assessment of soils. The present study was designed to determine the variability among laboratories using different methods to measure the bioaccessibility of 24 inorganic contaminants in one standardized soil sample, the standard reference material NIST 2710. Fourteen laboratories used a total of 17 bioaccessibility extraction methods. The variability between methods was assessed by calculating the reproducibility relative standard deviations (RSDs), where reproducibility is the sum of within-laboratory and between-laboratory variability. Whereas within-laboratory repeatability was usually better than (<) 15% for most elements, reproducibility RSDs were much higher, indicating more variability, although for many elements they were comparable to typical uncertainties (e.g., 30% in commercial laboratories). For five trace elements of interest, reproducibility RSDs were: arsenic (As), 22-44%; cadmium (Cd), 11-41%; Cu, 15-30%; lead (Pb), 45-83%; and Zn, 18-56%. Only one method variable, pH, was found to correlate significantly with bioaccessibility for aluminum (Al), Cd, copper (Cu), manganese (Mn), Pb and zinc (Zn) but other method variables could not be examined systematically because of the study design. When bioaccessibility results were directly compared with bioavailability results for As (swine and mouse) and Pb (swine), four methods returned results within uncertainty ranges for both elements: two that were defined as simpler (gastric phase only, limited chemicals) and two were more complex (gastric + intestinal phases, with a mixture of chemicals).

Usage patterns of personal care products: important factors for exposure assessment.

Complete information regarding the use of personal care products (PCPs) by consumers is limited, but such information is crucial for realistic consumer exposure assessment. To fill this gap, a database was created with person-oriented information regarding usage patterns and circumstances of use for 32 different PCPs. Out of 2700 potential participants from the Netherlands, 516 men and women completed a digital questionnaire. The prevalence of use varied by gender, age, level of education and skin type. A high frequency of use was observed for some products (e.g. lip care products), while toothpaste, deodorant and day cream were generally used once or twice a day. The frequency of use for other PCPs varied over a wide range. The amounts of use varied largely between and within different product groups. Body lotion, sunscreen and after sun lotion were often applied on adjacent body parts. The majority of PCPs were applied in the morning, but some products, such as night cream and after sun, were predominantly applied in the evening or night. As expected, the participants used several PCPs simultaneously. The database yields important personalized exposure factors which can be used in aggregate consumer exposure assessment for substances that are components of PCPs.

Risk assessment of N-nitrosodimethylamine formed endogenously after fish-with-vegetable meals.

The consumption of fish and nitrate-rich vegetables may lead to the formation of the genotoxic carcinogen N-nitrosodimethylamine (NDMA) in the stomach. To assess human cancer risk associated with this formation, a dynamic in vitro gastrointestinal model was used to simulate NDMA formation in the stomach after a fish + vegetable meal. The experimental results were combined with statistical modeling of Dutch food consumption data resulting in predicted exposures to endogenously formed NDMA in the population. The 95th percentile of the long-term exposure distribution was around 4 ng/kg-bw in young children and 0.4 ng/kg-bw in adults. By comparing this exposure with the Benchmark Dose Lower bound (BMDL) 10 for liver cancer in a chronic carcinogenicity study, a chronic margin of exposure (MOE) was calculated of 7000 and 73,000 for young children and adults. Furthermore, the long-term exposure distribution was combined with a dose-response analysis of the liver cancer incidence data to obtain a cancer risk distribution for the human population. The 95th percentile of that distribution was 6 x 10(-6) extra risk for 5-year-old children and 8 x 10(-7) for adults. The liver cancer data allowed for the analysis of the relationship between tumor incidence and time to tumor. For an extra risk of 10(-6), the decrease in time to tumor was conservatively estimated at 3.8 min in the rat, equivalent to 0.1 days in humans. We also combined acute exposure estimates with the BMDL10 from an acute carcinogenicity study for NDMA, resulting in an acute MOE of 110,000. We conclude that the combined consumption of fish and nitrate-rich vegetables appears to lead to marginal increases of additional cancer risk.

Comparison of two models for the estimation of usual intake addressing zero consumption and non-normality.

Various models exist for estimating the usual intake distribution from dietary intake data. In this paper, we compare two of these models, the Iowa State University Foods (ISUF) model and the betabinomial-normal (BBN) model and apply them to three different datasets. Intake data are obtained by aggregating over multiple food products and are often non-normal. The ISUF and BBN model both address non-normality. While the two models have similar structures, they show some differences. The ISUF model includes an additional spline transformation for improving the normality of the intake amount distribution, while the BBN model includes the possibility of addressing covariates, such as age or sex. Our analyses showed that for two of the example datasets both models produced similar estimates of the higher percentiles of the usual intake distribution. However, for the third dataset, where the intake amount distribution appear to be multimodal, both models produced different percentile estimates.

Dietary exposure to dioxins and dioxin-like PCBs in The Netherlands anno 2004.

In this study, representative occurrence data for PCDD/Fs and dioxin-like PCBs in food were obtained and used to estimate dietary exposure of the Dutch population. Food composite samples were analyzed as well as single fish and vegetables samples. Total dioxin concentrations in animal products ranged from 0.05 pg TEQ/g product in poultry to 2.5 pg TEQ/g product (using TEF(2006)) in fish (shrimp), with 0.12pg TEQ/g product being the lowest concentrations measured in fish (tuna). In vegetable products, concentrations ranged from 0.00002 pg TEQ/g product (white kale) to 0.19 pg TEQ/g (oils and fats). A long-term dietary exposure distribution was calculated using Monte Carlo Risk Assessment software. The lower bound median exposure of the Dutch population to PCDD/Fs and dioxin-like PCBs was estimated at 0.8 pg WHO-TEQ/kgbw/d, half of which were dioxin-like PCBs. Dairy was the main source (38%) due to its high consumption. Time-trend analysis shows that the exposure to dioxins has further decreased by 35% over the past five years. This is due to lower levels of dioxin-like compounds in most of the foods, mainly influenced by lower levels in meat and milk. The use of the new TEFs gives an exposure reduction of 10% with respect to TEF(1998). Still, 4% of the Dutch population exceeds the exposure limit of 14 pg/kgbw/week as set by the EU.

Framework for intake simulation of functional ingredients.

OBJECTIVE: To create a general framework for the simulation of intakes from mandatory or voluntary fortification, which will make outcomes of simulation studies more comparable and give insight on uncertainties. DESIGN: A general framework was developed based on methods used in already published case studies of mandatory fortification. The framework was extended to be suitable for the simulation of voluntary fortification. Case studies of folic acid fortification were used to illustrate the general framework. RESULTS: The developed framework consists of six steps. First, the definition of the fortification strategy (step 1), followed by the identification of potential carrier products (step 2), and the definition of fortification levels or ranges (step 3). Thereafter, virtual food/supplement composition data are created (step 4) and food/supplement consumption data are required (step 5). Finally, the intake of the functional ingredient from functional foods, other foods and dietary supplements is calculated during the simulation resulting in total habitual intake distributions (step 6). CONCLUSIONS: Simulation of both mandatory and voluntary folic acid fortification in The Netherlands showed that the general framework is applicable. Also with incomplete data or data from different sources, the (habitual) intake distributions can be estimated using assumptions, statistical procedures or probabilistic modelling approaches. It is important that the simulation procedure is described well, so that an insight on uncertainties and knowledge gaps to be filled is given.

Dietary intake and risk evaluation of polybrominated diphenyl ethers in The Netherlands.

The current study aims at estimating the dietary intake of PBDEs in the Netherlands and evaluating the resultant risk. Dietary intake was estimated using results of PBDE analyses in Dutch food products from 2003/2004 and consumption data of the third Dutch National Food Consumption Survey (1997/1998). Assuming that non-detects represent levels of half the detection limit, the median long-term intake of the Dutch population of the sum of five major PBDEs (namely PBDEs 47, 99, 100, 153+154) is 0.79 ng/kg body weight bw/day (P97.5: 1.62 ng/kg bw/day). When non-detects are considered as zeros the values are 0.53 (median) and 1.34 (P97.5) ng/kg bw/day. Environmental concentrations of PBDEs in Europe are expected to decline in the near future because of the ban on penta- and octaBDE technical products. However, it will take at least a decade before this will result in lower PBDE concentrations in food products. Hence, a regular monitoring program for PBDEs is recommended. A risk evaluation at the most sensitive endpoints of BDE 99 carried out in this paper indicates that, although the long-term exposure to BDE 99 is well below the human exposure threshold level for neurodevelopmental toxicity, it may be close to that for reproductive toxicity.

A simple steady-state model for carry-over of aflatoxins from feed to cow's milk.

A simple steady-state model is derived from two kinetic one-compartment models for the disposition of aflatoxin B1 (AFB1) and aflatoxin M1 (AFM1) in the lactating cow. The model relates daily intake of AFB1 in feed of dairy cattle and the cow's lactation status to resulting concentrations of AFM1 in milk. Moreover, assuming a linear relationship between the cow's lactation status and feed intake, the model relates daily milk production and AFB1 concentration in total feed to AFM1 levels in milk. The model explains similar experimental outcomes from different investigations into carry-over of aflatoxins from feed to milk. Although it is difficult to set a permanent limit for AFB1 in feed, the European Union (EU) limit of 5 microg AFB1 kg(-1) concentrate has proved, thus far, to be an appropriate level in preventing the EU limit of 0.05 microg AFM1 kg(-1) milk being exceeded.

Dry deposition of atmospheric polycyclic aromatic hydrocarbons in three Plantago species.

The concentrations of polycyclic aromatic hydrocarbons (PAHs) in the leaf wax of three Plantago species were determined weekly for 3 weeks. The almost glabrous, free-standing leaves of Plantago major and the sparsely hairy Plantago lanceolata leaves were more heavily contaminated with low molecular weight (MW) PAHs (MW < 228) than the densely hairy, partly overlapping Plantago media leaves. This may be caused by the lower canopy roughness (higher aerodynamic resistance), the higher amount of leaf hairs (higher boundary resistance), and/or the higher leaf overlap (smaller accessible leaf area) of P. media. On the other hand, PAHs with MW ≥ 252 tended to show higher concentrations in P. media than in the other two species. This is likely caused by the dense layer of hairs on P. media leaves, which can efficiently intercept the largely particle-bound high MW PAHs. When the PAH concentrations were normalized to projected leaf surface area, the differences between P. media and the other two species became significant (p < 0.05) for the high MW PAHs, while the differences for the low MW PAHs decreased. Although the differences in PAH concentrations between species are relatively small (factor 2-5), this study clearly shows that plant architecture and leaf hairs influence the dry deposition of PAHs.