Toxicity mechanisms

In order to understand the activity of organotinflV) in water environments (both fresh and seawater), equilibrium and speciahon studies are very important. Moreover, characterizing the structures of hydrolyzed species could be helpful to assess the toxicity mechanism. 

Some hydroxy metabolites of coplanar PCBs, such as 4-OH and 3,3 4,5 -tet-rachlorobiphenyl, act as antagonists of thyroxin (Chapter 6, Section 6.2.4). They have high affinity for the thyroxin-binding site on transthyretin (TTR) in plasma. Toxic effects include vitamin A deficiency. Biomarker assays for this toxic mechanism include percentage of thyroxin-binding sites to which rodenticide is bound, plasma levels of thyroxin, and plasma levels of vitamin A. 

Particular attention is given to the development of new mechanistic biomarker assays and bioassays that can be used as indices of the toxicity of mixtures. These biomarker assays are typically based on toxic mechanisms such as brain acetylcholinesterase inhibition, vitamin K antagonism, thyroxin antagonism, Ah-receptor-mediated toxicity, and interaction with the estrogenic receptor. They can give integrative measures of the toxicity of mixtures of compounds where the components of the mixture share the same mode of action. They can also give evidence of potentiation as well as additive toxicity. 

At the practical level, an ideal mechanistic biomarker should be simple to use, sensitive, relatively specific, stable, and usable on material that can be obtained by nondestructive sampling (e.g., blood or skin). A tall order, no doubt, and no biomarker yet developed has all of these attributes. However, the judicious use of combinations of biomarkers can overcome the shortcomings of individual assays. The main point to emphasize is that the resources so far invested in the development of biomarker technology for environmental risk assessment has been very small (cf the investment in biomarkers for use in medicine). Knowledge of toxic mechanisms of organic pollutants is already substantial (especially of pesticides), and it grows apace. The scientific basis is already there for technological advance it all comes down to a question of investment. 

The toxic mechanism of action of these various jellyfish venoms is complex. The cardiotoxic reaction seems to focus on calcium transport and is blocked by the prior or post administration of therapeutic doses of verapamil (7J). In neuronal tissue, Chrysaora venom induces large cationic selective channels which open and close spontaneously. These channels are permeable to Na , Li, K, and Cs but not and the channels are present in spite of the treatment with sodium and potassium inhibitors such as tetrodotoxin and tetraethylammonium (14). 

Baldelli RJ, Green FHY, Auer RN. 1993. Sulfide toxicity Mechanical ventilation and hypotension determine survival rate and brain necrosis. J Appl Physiol 75 1348-1353. 

Typically, ADME studies are included in the battery of tests used to characterize the toxicity of chemicals, as well as other studies designed to trace the underlying molecular and cellular events that lead to toxicity. These studies of toxic mechanisms take many forms, and are better viewed as research studies no general characterization of them will be made here, but some of the things such studies can reveal to aid understanding of risk will be mentioned at appropriate places in the remaining sections of the book. 

Before we embark on a descriptive survey of toxic and carcinogenic phenomena, the subjects of the next three chapters, it will be useful to provide a broad outline of the ways in which toxic injuries can be produced, and the ways in which they manifest themselves. This type of discussion will help to place into a unified context the descriptive material to come, and it will also aid in understanding concepts of toxic mechanisms as they relate to understanding human risk. The topic is presented in broad outline only details are far more complex than is suggested here. 

Lorenzo, A., Yuan, M., Zhang, Z., et al. (2000) Amyloid beta interacts with the amyloid precursor protein a potential toxic mechanism in Alzheimer s disease. Nat. Neurosci., 3, 460-464. 

A plethora of other effects on cell constituents from proteins to lipids to DNA is also documented in the early literature without, however, establishing any link between these reactions and the toxic consequences. Such an inability to deduce a toxic mechanism is not necessarily surprising. After all, aminoglycosides are highly aggressive drugs that kill cells and tissues, and a cell in the process of destruction will show a multitude of deranged biochemical and molecular pathways. 

Ultrastructural examination of duckweed frond (Fig. 5) and root tissues treated with 18 (100 xM) revealed membrane damage to the tonoplast after 12 hours of exposure. The samples viewed through the transmission electron microscope showed ruptured tonoplasts, free-floating organelles and loss of cytoplasm relative to control tissues. The tonoplast may be the primary target for the phytotoxic effect of 18, which represents an unusual, if not unique, toxic mechanism among phytotoxic agents. 

The oral LDso in rats was 2830mg/kg. Typical effects associated with acute lethal oral doses have included restlessness and increased respiratory rate, which appear quickly, followed shortly by tremors, convulsions, dyspnea, coma, and death. The primary toxic mechanism is the uncoupling of oxidative phosphorylation. ... 

Ivanciuc, O. (2002) Support vector machine idetification of the aquatic toxicity mechanism of organic compunds. Internet Electronic Journal of Molecular Design and BioChem Press 1, 157-1721 http //www.biochempress.com/av01 0157.html and ftp //biochempress.com/ieimd 2002 1 0157.pdf). 

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