New approach methodologies (NAMs): identifying and overcoming hurdles to accelerated adoption.

New approach methodologies (NAMs) can deliver improved chemical safety assessment through the provision of more protective and/or relevant models that have a reduced reliance on animals. Despite the widely acknowledged benefits offered by NAMs, there continue to be barriers that prevent or limit their application for decision-making in chemical safety assessment. These include barriers related to real and perceived scientific, technical, legislative and economic issues, as well as cultural and societal obstacles that may relate to inertia, familiarity, and comfort with established methods, and perceptions around regulatory expectations and acceptance. This article focuses on chemical safety science, exposure, hazard, and risk assessment, and explores the nature of these barriers and how they can be overcome to drive the wider exploitation and acceptance of NAMs. Short-, mid- and longer-term goals are outlined that embrace the opportunities provided by NAMs to deliver improved protection of human health and environmental security as part of a new paradigm that incorporates exposure science and a culture that promotes the use of protective toxicological risk assessments.

From worst-case to reality - Case studies illustrating tiered refinement of consumer exposure to cosmetic ingredients.

Consumer exposure to cosmetic ingredients is estimated in a tiered manner. Simple Tier1 deterministic aggregate exposure modelling generates a worst case estimate of exposure. Tier1 assumes that a consumer uses all cosmetic products concomitantly daily, at maximum frequency, and products always contain the ingredient at the maximum allowed % w/w concentration. Refining exposure assessment from worst case to more realistic estimates uses evidence from surveys of actual use levels of ingredients and Tier2 probabilistic models, where distributions of consumer use data can be applied. In Tier2+ modelling, occurrence data provides evidence of products on the market actually containing the ingredient. Three case studies are presented using this tiered approach to illustrate progressive refinement. The scale of refinements from Tier1 to Tier2+ modelling for the ingredients, propyl paraben, benzoic acid and DMDM hydantoin were: 0.492 to 0.026; 1.93 to 0.042 and 1.61 to 0.027 mg/kg/day exposure dose. For propyl paraben, moving from Tier1 to Tier2+ represents a refinement from 49-fold to 3-fold overestimate of exposure when compared to a maximum estimate of 0.01 mg/kg/day exposure seen in human studies. Such refinements from worst case to realistic levels of exposure estimation can be critical in the demonstration of consumer safety.

Risk assessment in the 21st century: where are we heading?

Reliance on animal tests for chemical safety assessment is increasingly being challenged, not only because of ethical reasons, but also because they procrastinate regulatory decisions and because of concerns over the transferability of results to humans. New approach methodologies (NAMs) need to be fit for purpose and new thinking is required to reconsider chemical legislation, validation of NAMs and opportunities to move away from animal tests. This article summarizes the presentations from a symposium at the 2022 Annual Congress of the British Toxicology Society on the topic of the future of chemical risk assessment in the 21st century. The symposium included three case-studies where NAMs have been used in safety assessments. The first case illustrated how read-across augmented with some in vitro tests could be used reliably to perform the risk assessment of analogues lacking data. The second case showed how specific bioactivity assays could identify an NAM point of departure (PoD) and how this could be translated through physiologically based kinetic modelling in an in vivo PoD for the risk assessment. The third case showed how adverse-outcome pathway (AOP) information, including molecular-initiating event and key events with their underlying data, established for certain chemicals could be used to produce an in silico model that is able to associate chemical features of an unstudied substance with specific AOPs or AOP networks. The manuscript presents the discussions that took place regarding the limitations and benefits of these new approaches, and what are the barriers and the opportunities for their increased use in regulatory decision making.

Read-across and new approach methodologies applied in a 10-step framework for cosmetics safety assessment - A case study with parabens.

Parabens are esters of para-hydroxybenzoic acid that have been used as preservatives in many types of products for decades including agrochemicals, pharmaceuticals, food and cosmetics. This illustrative case study with propylparaben (PP) demonstrates a 10-step read-across (RAX) framework in practice. It aims at establishing a proof-of-concept for the value added by new approach methodologies (NAMs) in read-across (RAX) for use in a next-generation risk assessment (NGRA) in order to assess consumer safety after exposure to PP-containing cosmetics. In addition to structural and physico-chemical properties, in silico information, toxicogenomics, in vitro toxicodynamic, toxicokinetic data from PBK models, and bioactivity data are used to provide evidence of the chemical and biological similarity of PP and analogues and to establish potency trends for observed effects in vitro. The chemical category under consideration is short (C1-C4) linear chain n-alkyl parabens: methylparaben, ethylparaben, propylparaben and butylparaben. The goal of this case study is to illustrate how a practical framework for RAX can be used to fill a hypothetical data gap for reproductive toxicity of the target chemical PP.

A 10-step framework for use of read-across (RAX) in next generation risk assessment (NGRA) for cosmetics safety assessment.

This paper presents a 10-step read-across (RAX) framework for use in cases where a threshold of toxicological concern (TTC) approach to cosmetics safety assessment is not possible. RAX builds on established approaches that have existed for more than two decades using chemical properties and in silico toxicology predictions, by further substantiating hypotheses on toxicological similarity of substances, and integrating new approach methodologies (NAM) in the biological and kinetic domains. NAM include new types of data on biological observations from, for example, in vitro assays, toxicogenomics, metabolomics, receptor binding screens and uses physiologically-based kinetic (PBK) modelling to inform about systemic exposure. NAM data can help to substantiate a mode/mechanism of action (MoA), and if similar chemicals can be shown to work by a similar MoA, a next generation risk assessment (NGRA) may be performed with acceptable confidence for a data-poor target substance with no or inadequate safety data, based on RAX approaches using data-rich analogue(s), and taking account of potency or kinetic/dynamic differences.

New framework for a non-animal approach adequately assures the safety of cosmetic ingredients - A case study on caffeine.

This case study on the model substance caffeine demonstrates the viability of a 10-step read-across (RAX) framework in practice. New approach methodologies (NAM), including RAX and physiologically-based kinetic (PBK) modelling were used to assess the consumer safety of caffeine. Appropriate animal systemic toxicity data were used from the most relevant RAX analogue while assuming that no suitable animal toxicity data were available for caffeine. Based on structural similarities, three primary metabolites of the target chemical caffeine (theophylline, theobromine and paraxanthine) were selected as its most relevant analogues, to estimate a point of departure in order to support a next generation risk assessment (NGRA). On the basis of the pivotal mode of action (MOA) of caffeine and other methylxanthines, theophylline appeared to be the most potent and suitable analogue. A worst-case aggregate exposure assessment determined consumer exposure to caffeine from different sources, such as cosmetics and food/drinks. Using a PBK model to estimate human blood concentrations following exposure to caffeine, an acceptable Margin of Internal Exposure (MOIE) of 27-fold was derived on the basis of a RAX using theophylline animal data, which suggests that the NGRA approach for caffeine is sufficiently conservative to protect human health.

Aggregate exposure modelling of vitamin A from cosmetic products, diet and food supplements.

Realism is important in estimating consumer exposure to a substance, especially when accounting for exposure from multiple sources. Humans are exposed to vitamin A from food, dietary supplements and cosmetics products. A probabilistic aggregate exposure model was developed for estimating exposure distributions to vitamin A (as retinol equivalents) in pre-/post-menopausal, and menopausal women in European and US populations. Data from large dietary surveys were used, together with realistic and extreme case scenarios of cosmetics product use (including occurrence data for vitamin A presence in 17 cosmetic products). Results of absorbed exposure estimates were expressed as µg/kg bw/day by incorporating dermal and oral bioavailability data. The mean and 95th percentile (P95) aggregate exposures were below the EU Tolerable Upper Intake Limit (3000 µg/day; 45 µg/kg/day internal exposure dose (IED)), providing positive assurances of safety. The major source of vitamin A exposure is the diet, with cosmetics providing only a small fraction of total exposure (2-5% at P95). In addition to providing a realistic assessment of total vitamin A exposure, this work provides a case study on how to approach future complex aggregate exposure questions.

Assessment of Dermal Absorption of Aluminum from a Representative Antiperspirant Formulation Using a 26 Al Microtracer Approach.

A clinical pharmacokinetic study was performed in 12 healthy women to evaluate systemic exposure to aluminum following topical application of a representative antiperspirant formulation under real-life use conditions. A simple roll-on formulation containing an extremely rare isotope of aluminum (26 Al) chlorohydrate (ACH) was prepared to commercial specifications. A 26 Al radio-microtracer was used to distinguish dosed aluminum from natural background, using accelerated mass spectroscopy. The 26 Al citrate was administered intravenously (i.v.) to estimate fraction absorbed (Fabs ) following topical delivery. In blood samples after i.v. administration, 26 Al was readily detected (mean area under the curve (AUC) = 1,273 ± 466 hours×fg/mL). Conversely, all blood samples following topical application were below the lower limit of quantitation (LLOQ; 0.12 fg/mL), except two samples (0.13 and 0.14 fg/mL); a maximal AUC was based on LLOQs. The aluminum was above the LLOQ (61 ag/mL) in 31% of urine samples. From the urinary excretion data, a conservative estimated range for dermal Fabs of 0.002-0.06% was calculated, with a mean estimate of 0.0094%.