Current Opinion in Toxicology最新文献

In this article, we review recent research in the application of PBPK modeling to chemical mixtures, focusing on the previous three years. The scope of the review included both isozyme-specific modeling of drug–drug interactions and modeling of complex environmental mixtures. Recent pharmaceutical-related modeling efforts continue to advance the state of the art for predicting both pharmacokinetic and pharmacodynamic interactions. In contrast, recent studies on modeling of environmental mixtures have often assumed that the human exposures are too low to drive metabolic interactions, and evaluations of complex mixtures have shifted focus to assessing the potential for PD interactions. Future progress in this area is hindered by the fact that the available PBPK platforms for modeling drug–drug interactions are not designed to support interaction modeling for more than two compounds. While this limitation may not be of concern for pharmaceuticals, it severely limits potential applications to environmental mixtures. Widespread application of PBPK interaction modeling to complex mixtures will require the development of user-friendly, web-based applications that allow individuals from a wide variety of disciplines to exercise the models. The Open Systems Pharmacology suite (PK-Sim and Mobi) may provide a useful platform for this purpose.

Health consequences of exposure to arsenic, a major environmental pollutant, is diverse ranging from metabolic to respiratory diseases. Exposure to arsenic during pregnancy is the most critical window, since the rapidly developing fetus is most vulnerable to the toxic insult. Experimental and epidemiological studies indicate that arsenic disrupts immunological balance and impairs immune function. However, knowledge on impact of prenatal arsenic exposure on cellular immunity in humans is limited. Findings from longitudinal/birth-cohort studies indicate that impairing T cell-mediated immunity may be one pathway through which prenatal arsenic exposure contributes to long-term adverse health effects. This review summarizes the current research on the effects of in utero arsenic exposure on T cell development, their functional competence and discusses their importance in understanding the mechanisms of immunotoxicity, the challenges and future directions.

Polycyclic aromatic hydrocarbons (PAHs) are a class of organic compounds produced by a variety of petrogenic and pyrogenic sources. PAHs inherently occur in the environment in complex mixtures. The early life-stage zebrafish model is a valuable tool for high-throughput screening (HTS) for toxicity of complex chemical mixtures due to its rapid development, high fecundity, and superb sensitivity to chemical insult. Zebrafish are amenable to exposure to surrogate mixtures as well as extracts of environmental samples and effect-directed analysis. In addition to its utility to HTS, the zebrafish has proven an excellent model for assessing chemical modes of action and identifying molecular initiating and other key events in an Adverse Outcome Pathway framework. Traditional methods of assessing PAH mixture toxicity prioritize carcinogenic potential and lack consideration of non-carcinogenic modes of action, assuming a similar molecular initiating event for all PAHs. Recent work in zebrafish has made it clear that while PAHs belong to the same chemical class, their modes of action can be divergent. Future research should use zebrafish to better classify PAHs by their bioactivity and modes of action to better understand mixture hazards.

This paper advocates a human-based holistic approach to chemical safety assessment, based on an in silico description of human biology, the derivation of the adverse outcome pathway network from that description, its translation into batteries of in vitro and in silico assays to monitor critical key events in the pathway network, and the integration of the results by modern computational tools to predict health effects. Several ongoing international research projects are described which take on this challenge aiming at providing proofs of principle for the feasibility of this approach. This advance is supported by successes in the application of computational approaches, such as machine learning in clinical diagnostics and treatment.

Pesticides are increasingly recognized to induce or accelerate the development of neurodegenerative diseases, which pose an increasing health burden to society. Pesticides in general, and (mixtures of) specific active substances in particular, have been associated with neurodegenerative diseases such as Parkinson's disease, both epidemiologically and experimentally. Current regulatory guidelines for safety assessment cannot fully capture neurodegenerative effects of chemical substances, primarily due to a lack of dedicated histopathological markers and functional behaviour parameters in both standard- and specific neurotoxicity studies. Given the widespread use of pesticides and societal burden of neurodegenerative diseases, there is an urgent need for improvements. Here we propose a tiered approach consisting of 1) short term adaptations to current guideline studies and 2) long term transition of chemical safety assessment to a strategy based on human biology using in vitro and in silico methods.

The field of antisense oligonucleotide (ASO)-based therapies have been making strides in precision medicine due to their potent therapeutic application. Early successes in treating some genetic diseases are now attributed to an emerging class of antisense drugs. After two decades, the US Food and Drug Administration (FDA) has approved a considerable number of ASO drugs, primarily to treat rare diseases with optimal therapeutic outcomes. However, safety is one of the biggest challenges to the therapeutic utility of ASO drugs. Due to patients' and health care practitioners' urgent demands for medicines for untreatable conditions, many ASO drugs have been approved. However, a complete understanding of the mechanisms of adverse drug reactions (ADRs) and toxicities of ASOs still need to be resolved. The range of ADRs is unique to a specific drug, while few ADRs are common to a section of drugs as a whole. Nephrotoxicity is an important concern that needs to be addressed considering the clinical translation of any drug candidates ranging from small molecules to ASO-based drugs. This article encompasses what is known about the nephrotoxicity of ASO drugs, the potential mechanisms of action(s), and recommendations for future investigations on the safety of ASO drugs.

The increasing consumption of drugs of abuse represents a global public health concern. Kidneys are especially vulnerable to the toxic effects of these substances, as these organs are involved in their filtration, concentration and metabolism to potentially toxic metabolites. Distinct clinical manifestations known to precede acute and chronic kidney injury (e.g., rhabdomyolysis, vasoconstriction, decreased estimated glomerular filtration rate) have been reported for different drugs of abuse (e.g., cannabinoids, cocaine, opioids, substituted phenethylamines). However, the underlying mechanisms remain poorly understood. As such, we herein review the most recent updates on the nephrotoxicity associated with drugs of abuse, as understanding their nephrotoxic profile assumes major relevance to improve risk assessment and therapeutic responses to drug-related complications.

Drug-induced acute kidney injury (AKI), especially from exposure to antibiotics, has a high prevalence secondary to their frequent prescription. Typically, drug-induced AKI results from acute tubular necrosis or acute interstitial nephritis. While some risk factors for the development of AKI in individuals treated with antibiotics are modifiable, others such as concomitant drug therapies to treat comorbidities, age, and pre-existing chronic kidney disease are not modifiable. As such, there is an urgent need to identify strategies to reduce the risk of AKI in individuals requiring antibiotic therapy. Natural products, especially those rich in active constituents possessing antioxidant properties are an attractive option to mitigate AKI risk. Given that mitochondrial dysfunction precedes AKI and natural products can restore mitochondrial health and counter the oxidative stress secondary to mitochondrial damage investigating their utility warrants further attention. The following review summarizes the available preclinical and clinical evidence that provides a foundation for future study.