New Approach Methodologies (NAMs) for ad hoc human health risk assessment of food and non-food products - Proceedings of a workshop.

RIVM convened a workshop on the use of New Approach Methodologies (NAMs) for the ad hoc human health risk assessment of food and non-food products. Central to the workshop were two case studies of marketed products with a potential health concern: the botanical Tabernanthe iboga which is used to facilitate mental or spiritual insight or to (illegally) treat drug addiction and is associated with cardiotoxicity, and dermal creams containing female sex hormones, intended for use by perimenopausal women to reduce menopause symptoms without medical supervision. The workshop participants recognized that data from NAM approaches added valuable information for the ad hoc risk assessment of these products, although the available approaches were inadequate to derive health-based guidance values. Recommendations were provided on how to further enhance and implement NAM approaches in regulatory risk assessment, specifying both scientific and technical aspects as well as stakeholder engagement aspects.

Towards an animal-free human health assessment: starting from the current regulatory needs.

Societal concern for animal welfare and scientific concerns about the predictive power of animal models for the human situation are driving forces for the development of animal-free approaches for the safety testing of chemicals. A paradigm shift towards an assessment of human health risks that is fully based on non-animal approaches is not foreseen within the next decades. To accelerate the use of non-animal innovations (e.g. in vitro experiments, in silico methods etc) in the EU, it has multiple advantages to simultaneously work towards a new risk assessment paradigm and to aim their development at better meeting the current regulatory needs. To achieve this, a multi-stakeholder collaboration is needed already in the development phase of animal-free innovations, where regulators can inform on the regulatory needs and the criteria for acceptance. As a first step, the present paper discusses what basic information is needed within the context of four areas of chemical safety assessment in the EU: 1) classification, labelling and packaging, 2) the derivation of health-based guidance values and product limits, 3) risk assessments of exposure situations of concern and 4) addressing specific topics of societal concern. Further agreements on the level of detail and uncertainty, robustness, predictive value, reproducibility and validation are a prerequisite to develop tools that can be trusted and that will be legally binding.

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).

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.

Assessment of the risk of respiratory sensitization from fragrance allergens released by air fresheners.

Consumers using air fresheners are exposed to the emitted ingredients, including fragrances, via the respiratory tract. Several fragrances are known skin sensitizers, but it is unknown whether inhalation exposure to these chemicals can induce respiratory sensitization. Effects on the immune system were assessed by testing a selection of five fragrance allergens in the respiratory local lymph node assay (LLNA). The probability and extent of exposure were assessed by measuring concentrations of the 24 known fragrance allergens in 109 air fresheners. It was shown that the most frequently used fragrances in air fresheners were D-limonene and linalool. In the respiratory LLNA, these fragrances were negative. Of the other tested chemicals, only isoeugenol induced a statistically significant increase in cell proliferation. Consumer exposure was assessed in more detail for D-limonene, linalool, and isoeugenol by using exposure modeling tools. It was shown that the most frequently used fragrances in air fresheners, D-limonene, and linalool gave rise to a higher consumer exposure compared with isoeugenol. To evaluate whether the consumer exposure to these fragrances is low or high, these levels were compared with measured air concentrations of diisocyanates, known human respiratory sensitizers. This comparison showed that consumer exposure from air fresheners to D-limonene, linalool, and isoeugenol is considerably lower than occupational exposure to diisocyanates. By combing this knowledge on sensitizing potency with the much lower exposure compared to diisocyanates it seems highly unlikely that isoeugenol can induce respiratory sensitization in consumers using air fresheners.

Identifying important life stages for monitoring and assessing risks from exposures to environmental contaminants: results of a World Health Organization review.

In this paper, we summarize exposure-related issues to consider in determining the most appropriate age ranges and life stages for risk assessment. We then propose a harmonized set of age bins for monitoring and assessing risks from exposures to chemicals for global use. The focus is on preconception through adolescence, though the approach should be applicable to additional life stages. A two-tiered set of early life age groups is recommended. The first tier involves the adoption of guidance similar to the childhood age groups recommended by the U.S. Environmental Protection Agency, whereas the second tier consolidates some of those age groups to reduce the burden of developing age-specific exposure factors for different regions. While there is no single "correct" means of choosing a common set of age groups to use internationally in assessing early life exposure and risk, use of a set of defined age groups is recommended to facilitate comparisons of potential exposures and risks around the globe, the collection of data and analyses of aggregate exposure and cumulative risk. Application of these age groups for robust assessment of exposure and risk for specific populations will require region-specific exposure factors as well as local environmental monitoring data.

Results of a cosmetovigilance survey in The Netherlands.

BACKGROUND: Cosmetic products contribute considerably to the incidence of contact dermatitis. In response to a resolution of the Council of Europe, the National Institute for Public Health and the Environment (RIVM) in The Netherlands set up a pilot project to report undesirable effects attributed to cosmetic products. OBJECTIVES: To provide an overview of undesirable effects attributed to cosmetic products and to identify the ingredients involved. The information could contribute to the assessment of whether current EU legislation on cosmetics provides adequate protection. PATIENTS/METHODS: General practitioners, dermatologists and consumers in The Netherlands completed questionnaires on reported undesirable effects of cosmetics. Dermatologists also carried out patch tests and, where necessary, tests with specific batch ingredients of the associated cosmetic product. A website and a public awareness campaign were launched to encourage consumers to report undesirable effects. RESULTS: Between July 2009 and May 2011, the RIVM received more than 1600 reports. Severe undesirable effects were claimed in 1-4% of the cases. The most frequently reported cosmetic products were make-up and moisturisers, and the most frequently identified allergens were isothiazolinones and fragrance ingredients. Three patients tested positive for co-polymers/cross-polymers. CONCLUSIONS: Further investigations are recommended on the prevalence of isothiazolinone-induced allergic contact dermatitis and the allergenic potential of co-polymers/cross-polymers.

A structured approach to Exposure Based Waiving of human health endpoints under REACH developed in the OSIRIS project.

Exposure Based Waiving (EBW) is one of the options in REACH when there is insufficient hazard data on a specific endpoint. Rules for adaptation of test requirements are specified and a general option for EBW is given via Appendix XI of REACH, allowing waiving of repeated dose toxicity studies, reproductive toxicity studies and carcinogenicity studies under a number of conditions if exposure is very low. A decision tree is described that was developed in the European project OSIRIS (Optimised Strategies for Risk Assessment of Industrial Chemicals through Integration of Non-Test and Test Information) to help decide in what cases EBW can be justified. The decision tree uses specific criteria as well as more general questions. For the latter, guidance on interpretation and resulting conclusions is provided. Criteria and guidance are partly based on an expert elicitation process. Among the specific criteria a number of proposed Thresholds of Toxicological Concern are used. The decision tree, expanded with specific parts on absorption, distribution, metabolism and excretion that are not described in this paper, is implemented in the OSIRIS webtool on integrated testing strategies.

Respiratory sensitization: advances in assessing the risk of respiratory inflammation and irritation.

Respiratory sensitization provides a case study for a new approach to chemical safety evaluation, as the prevalence of respiratory sensitization has increased considerably over the last decades, but animal and/or human experimental/predictive models are not currently available. Therefore, the goal of a working group was to design a road map to develop an ASAT approach for respiratory sensitisers. This approach should aim at (i) creating a database on respiratory functional biology and toxicology, (ii) applying data analyses to understand the multi-dimensional sensitization response, and how this predisposes to respiratory inflammation and irritation, and (iii) building a systems model out of these analyses, adding pharmacokinetic-pharmacodynamic modeling to predict respiratory responses to low levels of sensitisers. To this end, the best way forward would be to follow an integrated testing approach. Experimental research should be targeted to (i) QSAR-type approaches to relate potential as a respiratory sensitizer to its chemical structure, (ii) in vitro models and (iii) in vitro-in vivo extrapolation/validation.

Exposure-based waiving under REACH.

Within the REACH framework, but also within OECD, there is understanding that for reasons of animal welfare, costs and logistics, it is important to limit the number of tests to be conducted. Exposure-based waiving (EBW) is a potentially important element in testing strategies. This publication describes criteria for exposure-based waiving as foreseen in the REACH regulation and gives more detail to the REACH requirements for exposure-based waiving The principle behind any EBW is that there are situations when human or environmental exposures are so low or infrequent that there is a very low probability that the acquisition of additional effect information may lead to an improvement in the ability to manage risk. EBW therefore is risk-based and needs thorough knowledge on exposure as well as on effects criteria. Both elements are discussed: exposure models are analysed and the uncertainty in their predictions discussed as well as no-effect criteria such as the threshold of toxicological concern. Examples of EBW are provided for environmental, consumer and worker exposure. REACH only allows EBW in a limited number of cases with constraints on tonnage levels, types of tests to be waived and the need for a thorough ES and exposure assessment throughout the life cycle of a chemical and for all human exposure routes and environmental pathways. EBW will only be considered a real option by industry if a cost-benefit analysis shows an advantage, which may heavily depend on the weighing factor one applies for the non-use of experimental animals.

Risk management measures for chemicals in consumer products: documentation, assessment, and communication across the supply chain.

This paper analyzes the way risk management measures (RMMs) for consumer products have been used to date in authority and industry risk assessments. A working concept for consumer product RMMs is developed, aimed at controlling, limiting or avoiding exposures, and helping to insure the safe use (or handling) of a substance as part of a consumer product. Particular focus is placed on new requirements introduced by REACH (registration, evaluation, and authorization of chemicals). A RMMs categorization approach is also developed, dividing consumer product RMMs into those that are product integrated and those that are communicated to consumers. For each of these categories, RMMs for normal use, accidental use or misuse need to be distinguished. The level of detail for documenting, assessing and communicating RMMs across supply chains can vary, depending on the type of the assessment (tiered approach). Information on RMMs was collected from published sources to demonstrate that a taxonomical approach using standard descriptors for RMMs libraries is needed for effective information exchange across supply chains.

Consumer product in vitro digestion model: Bioaccessibility of contaminants and its application in risk assessment.

This paper describes the applicability of in vitro digestion models as a tool for consumer products in (ad hoc) risk assessment. In current risk assessment, oral bioavailability from a specific product is considered to be equal to bioavailability found in toxicity studies in which contaminants are usually ingested via liquids or food matrices. To become bioavailable, contaminants must first be released from the product during the digestion process (i.e. become bioaccessible). Contaminants in consumer products may be less bioaccessible than contaminants in liquid or food. Therefore, the actual risk after oral exposure could be overestimated. This paper describes the applicability of a simple, reliable, fast and relatively inexpensive in vitro method for determining the bioaccessibility of a contaminant from a consumer product. Different models, representing sucking and/or swallowing were developed. The experimental design of each model can be adjusted to the appropriate exposure scenarios as determined by the risk assessor. Several contaminated consumer products were tested in the various models. Although relevant in vivo data are scare, we succeeded to preliminary validate the model for one case. This case showed good correlation and never underestimated the bioavailability. However, validation check needs to be continued.