Current Opinion in Toxicology最新文献

The possible risk that exposure to chemicals leads to disruption of the thyroid hormone (TH) system in humans and animals can be assessed through biomonitoring of chemicals for which TH system disruption has been demonstrated in animal studies. In addition, epidemiological studies may establish a relationship between exposure to chemicals and adverse outcomes on the thyroid hormone system. However, such studies are often limited to single chemicals or classes of chemicals, and do not account for the complex mixtures to which humans and animals are exposed, consisting of multiple chemicals that in combination may affect similar or different endpoints in the TH system. The use of in vivo, and in vitro studies using complex extracts coming from real-life samples is necessary to unravel the specific effects that chemical mixtures inflict on the TH system. In addition, approaches such as effect-directed analysis that combine bioassays with integrated chemical analysis allow the identification of mixture risk drivers avoiding the loss of chemicals due to excessive sample processing.

Morphogenesis of the blood-brain barrier (BBB) is a complex process linked to neovascularization of the embryonic neural tube. This selective transport interface forms between vascular-neural compartments during organogenesis and dysregulation has been linked to neuroinflammation and neurodevelopmental defects. One emerging concept is that microglial cells play a central role in this neurovascular patterning, yet despite an extensive literature base, many gaps still exist in understanding how this resident immunological sentinel cell type interacts with chemical exposure at critical stages of neurodevelopment. The goals of this short review were to: (i) synopsize current understanding of microglial function during BBB morphogenesis; (ii) review potential disruption of microglial function linked to drug/chemical exposure during pregnancy; and (iii) present a working computational model for predictive toxicology of BBB dysmorphogenesis.

The Hazard Index (HI) was developed as a quantitative tool for characterizing noncancer risks from combined exposures. HI, and related approaches, dominate assessments of such risks. Despite this dominance, HI has limitations: the widespread lack of data required to use the tool; the inability to deal with synergy and potentiation; and the inability to quantitatively predict the probability of specific adverse effects. This article provides a review of recent advancements in toxicology and exposure science and their implications for HI. The new findings illuminate aspects of the HI and reduce the limitations of using the tool.

In this opinion, we provide a brief overview of three main approaches for assessing effects of chemical mixtures on human health, such as experimental or theoretical component-based or whole mixture studies. We compare the purposes, pros, and cons of the approaches and highlight the recent advances within the field that focus on “real-life” exposures for risk-assessing chemical mixtures. Whole mixture studies combined with effect-directed analysis have been used mostly within ecotoxicology and less so within human toxicology, opening the potential for the determination of mixture drivers in human tissues. Concerning the implementation of mixture risk assessment in legislation, we discuss whether a data-driven factor, for example, a mixture driver factor for each chemical or chemical class could be useful when deriving the toxicologically acceptable limit.

Traditional teratological protocols in mammals are mandatory for pharmaceutical and chemical product registration, but require hundreds of animals and are complex and money/time-consuming. Among alternative methods, low vertebrate (the teleost zebrafish and the amphibian Xenopus) whole embryo developmental toxicological tests appear evolutionary closer to humans than invertebrates and produce more useful data for human health extrapolation. At least during early stages, in fact, all vertebrate embryos share, from both morphological and molecular point of view, developmental pathways. By consequence similar toxicological responses of embryos to toxicant are expected. Advantages and disadvantages of these two alternative whole organism tests are briefly reviewed.

Endocrine-disrupting chemicals (EDCs) can cause reproductive toxicity in both humans and animals. To study this reproductive toxicity, extensive efforts have been made to determine the mode of action (MoA) of EDCs of interest, which typically act in complex chemical settings. Recently, notable progress has been made in computational tools in this field, owing to their high reliability, efficiency, and accessibility. The adverse outcome pathway (AOP) network is one of the most representative tools for investigating all possible pathways of reproductive toxicity caused by EDCs in a complex environment. In this review, we aimed to provide a guide for the implementation of an AOP network for evaluating EDC-induced reproductive toxicity. Specifically, we introduce the principles for establishing an AOP network, present widely used software and toolboxes for constructing an AOP network, and discuss a few successful cases of reproductive toxicity induced by EDCs using the AOP network. Future development of a quantitative AOP network is proposed.

A high level of protection of human health including pre- and postnatal development is a main objective of Regulation (EC) No 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP). Identifying developmental toxicants is crucial for protecting human embryos, foetuses and children from exposure to chemicals that adversely affect their normal development. This objective requires the intrinsic developmental toxic properties of substances to be investigated in adequately designed studies that are fit for this purpose. In this article, we address dose levels, administration route and species as an inadequate selection of these critical study parameters that reduces the usefulness of new studies and may hamper the identification of substances as developmental toxicants.

Outsourcing of preclinical developmental and reproductive toxicology testing (DART) is accelerating, but the availability of experienced, well-qualified individuals responsible for DART is diminishing. Current DART training at all levels is anemic. We identify four requisite training areas including hands-on technical skills, scientific knowledge, management, and oral/written communications. We suggest that comprehensive training could be accomplished through DART-targeted certificate programs or post-baccalaureate curricula designed and funded by the combined efforts of industry consortia, contract research organizations, government, and academia. Graduates of such training would be better able to serve as DART technicians, study directors, study monitors or regulatory scientists.

Boric acid and sodium borates are classified as toxic to reproduction under category 1B, with the hazard statement of H360FD in the EU-CLP regulation. This classification has triggered occupational epidemiology studies on boron (B) in countries with high boron reserves, especially in China and Türkiye. The highest mean total daily B exposure (DBE) levels in mining areas or processing plants of China and Türkiye were 41.2 and 47.17 mg/day respectively. Despite these reported high exposure levels in occupational settings, B-mediated reproductive effects have not been observed. The highest mean blood-boron concentrations (BBC) reported for the B exposed workers in these countries, are still much lower than the BBC corresponding to the NOAEL for reproductive effects in rats. The current epidemiological studies have proven that it will not be possible to reach the critical BBC in humans for the reproductive and developmental effects, especially in daily life.