Interpretation Of Toxicity Studies Research Articles

Toxicokinetic Model Development for the Insensitive Munitions Component 3-Nitro-1,2,4-Triazol-5-One.

3-Nitro-1,2,4-triazol-5-one (NTO) is a component of insensitive munitions that are potential replacements for conventional explosives. Toxicokinetic data can aid in the interpretation of toxicity studies and interspecies extrapolation, but only limited data on the toxicokinetics and metabolism of NTO are available. To supplement these limited data, further in vivo studies of NTO in rats were conducted and blood concentrations were measured, tissue distribution of NTO was estimated using an in silico method, and physiologically based pharmacokinetic models of the disposition of NTO in rats and macaques were developed and extrapolated to humans. The model predictions can be used to extrapolate from designated points of departure identified from rat toxicology studies to provide a scientific basis for estimates of acceptable human exposure levels for NTO.

Quantitative structure-activity relationships for cellular uptake of surface-modified nanoparticles.

Quantitative structure-activity relationships (QSARs) were developed, for cellular uptake of nanoparticles (NPs) of the same iron oxide core but with different surface-modifying organic molecules, based on linear and non-linear (epsilon support vector regression (ε-SVR)). A linear QSAR provided high prediction accuracy of R2=0.751 (coefficient of determination) using 11 descriptors selected from an initial pool of 184 descriptors calculated for the NP surfacemodifying molecules, while a ε-SVR based QSAR with only 6 descriptors improved prediction accuracy to R2=0.806. The linear and ε-SVR based QSARs both demonstrated good robustness and well spanned applicability domains. It is suggested that the approach of evaluating pertinent descriptors and their significance, via QSAR analysis, to cellular NP uptake could support planning and interpretation of toxicity studies as well as provide guidance for the tailor-design NPs with respect to targeted cellular uptake for various applications.

Prediction of nanoparticles-cell association based on corona proteins and physicochemical properties

Cellular association of nanoparticles (NPs) in biological fluids is affected by proteins adsorbed onto the NP surface, forming a "protein corona", thereby impacting cellular bioactivity. Here we investigate, based on an extensive gold NPs protein corona dataset, the relationships between NP-cell association and protein corona fingerprints (PCFs) as well as NP physicochemical properties. Accordingly, quantitative structure-activity relationships (QSARs) were developed based on both linear and non-linear support vector regression (SVR) models making use of a sequential forward floating selection of descriptors. The SVR model with only 6 serum proteins and zeta potential had higher accuracy (R(2) = 0.895) relative to the linear model (R(2) = 0.850) with 11 PCFs. Considering the initial pool of 148 descriptors, the APOB, A1AT, ANT3, and PLMN serum proteins along with NP zeta potential were identified as most significant to correlating NP-cell association. The present study suggests that QSARs exploration of NP-cell association data, considering the role of both NP protein corona and physicochemical properties, can support the planning and interpretation of toxicity studies and guide the design of NPs for biomedical applications.

The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Incorporation of pharmacokinetic studies describing absorption, distribution, metabolism, and excretion is an essential tool for improving the design and interpretation of toxicity studies and their application for safety assessment. A tiered approach is described in which basic pharmacokinetic studies, similar to those for pharmaceuticals, are conducted for regulatory submission. Subsequent tiers provide additional information in an iterative manner, depending on pharmacokinetic properties, toxicity study results, and the intended uses of the compound.

Use of Pharmacokinetic Data Under the FDA's Redbook II Guidelines for Direct Food Additives

Experience with food additive petitions submited after publication of the Food and Drug Administration's Redbook I (U. S. FDA, 1982) guide lines indicated a number of areas in which improvements were needed, and advances in toxicol-ogy testing during the last decade required additional rev is ions. In March 1993, the FDA's Center for Food Safety and Applied Nutrition (CFSAN) distributed copies of a draft of Redbook II for public comment. Since that time, revisions have been made based on comments received on the initial draft. This article describes the rationale for Redbook II guidance on the design of pharm acoki-netic studies and discusses some common problems the FDA has encountered in reviewing pharmacokine tic data submitted as part of food additive petitions. Points emphasized are that (1) pharmaco kinetic information is needed for the interpretation of toxicity studies and is most use ful when conducted before major toxicity studies, (2) the use of whole-body autoradiography is encouraged as a means to select tissues of interest, and as a substitute for dissection and tis-sue sampling, (3) kinetic and mechanistic studies conducted with blood compo-nents, tissue slices, hepatocytes, and othercell types in vitro ofien provide more useful information on the fate of chemicals in specific tissues than information extracted from whole-animal studies. The intention of th e new guide lines for pharmaco kinetic studies is to increase the information content of data gathered and to encourage the use of pharmaco kinetic models and results in the selection of doses for subchronic, chronic, and developmental toxicity studies.