Toxicokinetics

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, ...

Cosmetic ingredients derived from Achillea millefolium function in cosmetics as skin-conditioning agents-miscellaneous, skin-conditioning agents-humectants, and fragrance ingredients. The Cosmetic Ingredient Review Expert Panel (Panel) reviewed relevant animal and human data to determine their safety in cosmetics and raised concerns about cosmetics containing linalool, thujone, quercetin, hydroquinone, or α-peroxyachifolid. Because final product formulations may contain multiple botanicals, each containing similar constituents of concern, formulators are advised to be aware of these components and to avoid reaching levels that may be hazardous to consumers. Additionally, industry was advised to use good manufacturing practices to limit impurities. The Panel concluded that achillea millefolium extract, achillea millefolium flower extract, and achillea millefolium flower/leaf/stem extract are safe in the present practices of use and concentration in cosmetics when formulated to be non...

This document provide details on the concepts of TOXICOKINETICS/ PHARMACOKINETICS (ADME) of drugs, toxins, and toxicants administered into the human. This document also convey in-depth information relative to absorption, metabolism, distribution, and excretion of substances from the human body.

Silver nanoparticles (Ag NPs) have been used in numerous consumer products and may enter the soil through the land application of biosolids. However, little is known about the relationship between Ag NP exposure and their bioavailability for soil organisms. This study aims at comparing the uptake and elimination kinetics of Ag upon exposures to different Ag forms (NPs and ionic Ag (as AgNO3)) in the isopod Porcellionides pruinosus. Isopods were exposed to contaminated Lufa 2.2 soil or alder leaves as food. Uptake and elimination rate constants for soil exposure did not significantly differ between Ag NPs and ionic Ag at 30 and 60 mg Ag/kg. For dietary exposure, the uptake rate constant was up to 5 times higher for Ag NPs than for AgNO3, but this was related to feeding activity and exposure concentrations, while no difference in the elimination rate constants was found. When comparing both routes, dietary exposure resulted in lower Ag uptake rate constants but elimination rate consta...

The intraspecies uncertainty factor (UF(HH)=10x) is used in the determination of the reference dose or reference concentration and accounts for the pharmacokinetic and pharmacodynamic heterogeneity within the human population. The Food Quality Protection Act of 1996 mandated the use of an additional uncertainty factor (UF(HC)=10x) to take into account potential pre- and postnatal toxicity and lack of completeness of the data with respect to exposure and toxicity to children. There is no conclusive experimental or theoretical justification to support or refute the magnitude of the UF(HH) and UF(HC) nor any conclusive evidence to suggest that a factor of 100 is needed to account for intrahuman variability. This study presents a new chemical-specific method for estimating the pharmacokinetic (PK) component of the interspecies uncertainty factor (UF(HH-PK) and UF(HC-PK)) for volatile organic compounds (VOCs). The approach utilizes validated physiological-based pharmacokinetic (PBPK) mod...

Reports of environmental and human health impacts of per- and polyfluoroalkyl substances (PFAS) have greatly increased in the peer-reviewed literature. The goals of this review are to assess the state of the science regarding toxicological effects of PFAS, and to develop strategies for advancing knowledge on the health effects of this large family of chemicals. Currently, much of the toxicity data available for PFAS are for a handful of chemicals, primarily legacy PFAS such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Epidemiological studies have revealed associations between exposure to specific PFAS and a variety of health effects, including altered immune and thyroid function, liver disease, lipid and insulin dysregulation, kidney disease, adverse reproductive and developmental outcomes, and cancer. Concordance with experimental animal data exists for many of these effects. However, information on modes of action and adverse outcome pathways must be expanded, and profound differences in PFAS toxicokinetic properties must be considered in understanding differences in responses between sexes and among species and life stages. With many health effects noted for a relative few example compounds, and hundreds of other PFAS in commerce lacking toxicity data, more contemporary and high throughput approaches such as read across, molecular dynamics, and protein modeling are proposed to accelerate the development of toxicity information on emerging and legacy PFAS, individually and as mixtures. Additionally, an appropriate degree of precaution, given what is already known from the PFAS examples noted here, may be needed to protect human health. This article is protected by copyright. All rights reserved.

Tracer kinetic studies of amino acid metabolism during periods of high amino acid intake should allow insights into adaptive or maladaptive regulatory mechanisms controlling amino acid catabolic or disposal events before clinically evident effects. The principles of amino acid tracer kinetics have been well defined, but their application to establishing upper safe intake levels has been essentially nonexistent. Similarly, the pharmacology field has well-established disciplines of toxicokinetics (the relationship of toxicant dose and delivery to its site of action) and toxicodynamics (the relationship of toxicant at its site of action and downstream functional consequences), but these principles have not been transferred to the field of amino acid metabolism. In this context, a theoretical framework is presented for tracer kinetic experiments to help establish upper tolerable levels of amino acid infusion and/or ingestion. In addition, experiments to couple specific amino acid intake...

Selenium (Se) is an essential element that can be harmful for wildlife. However, its toxicity in poikilothermic amniotes, including turtles, remains poorly investigated. The present study aims at identifying selenium toxicokinetics and toxicity in juvenile slider turtles (age: 7 months), Trachemys scripta, dietary exposed to selenium, as selenomethionine SeMet, for eight weeks. Non-destructive tissues (i.e. carapace, scutes, skin and blood) were further tested for their suitability to predict selenium levels in target tissues (i.e. kidney, liver and muscle) for conservation perspective. 130 juvenile yellow-bellied slider turtles were assigned in three groups of 42 individuals each (i.e. control, SeMet1 and SeMet2). These groups were subjected to a feeding trial including an eight-week supplementation period SP 8 and a following 4-week elimination period EP 4 . During the SP8, turtles fed on diet containing 1.1 ± 0.04, 22.1 ± 1.0 and 45.0 ± 2.0 µg g(-1) of selenium (control, SeMet1 a...

Dodecylbenzene sulfonate (DBS) is a component of linear alkylbenzene sulfonate (LAS), an anionic surfactant, mainly used in household detergents. Due to the large quantity of DBS in use, there is concern over adverse environmental effects. This work examined the toxicokinetics and toxicity of the 2-phenyl isomer of dodecylbenzene sulfonate in 4-d, 10-d, and partial life-cycle tests on the midge, Chironomus riparius, exposed to aqueous solutions. Toxicokinetics were determined in 10-d uptake and 5-d elimination tests. The toxicokinetics were based on parent compound concentration in water and yielded an uptake coefficient (ku) of 17.5 (14.87-20.20) ml/g/h, an elimination rate constant (ke) of 0.073 (0.062-0.085) per h, a bioconcentration factor (BCF) of 56 to 240, and a half-life (t 1/2) of 9.5 (8.0-11.0) h. Biotransformation measurements did not reveal evidence for DBS metabolism. Thus, body residues, determined in the toxicity study, represent parent compound. In toxicity tests, 4-...