Mechanisms of toxicity and

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

A number of research projects in progress are investigating the mechanism of toxicity and tumor formation of acrylonitrile. The projects are summarized in Table 2-6. 

AEGL-1 (Non-disabling) NRa NR NR NR Not recommended due to steep dose-response relationship, mechanism of toxicity, and because toxicity occurs at or below the odor threshold... 

Implications of the Food Quality Protection Act Common Mechanism of Toxicity and Cumulative Risk Assessment... 

The processes of metabolic conversion are frequently involved in the mechanisms of toxicity and carcinogenicity. 

To discover the mechanisms of toxicity and to develop effective safe antidotes for the treatment of victims. 

Apanel of in vivo biomarkers that refiects the different mechanisms of toxicity and that could be used to predict drug response in tissue would be invaluable in hepatotoxicity risk assessment. 

In vitro testing systems are most useful in two important areas. First, they are useful in screening for toxicity, particularly in cases where sufficient in vivo data exist to validate the in vitro results. Second, in vitro tests are useful to study mechanisms of toxicity, and frequently they represent the only available approach for such studies. The wide variety of in vitro systems available to the reproductive toxicologist has been reviewed extensively (e.g., ECETOC, 1989 Chapin Heindel, 1993 Heindel Chapin, 1993 OECD, 1996b Genschow et al., 2000). 

Doing this may pose a dilemma for the organic chemist, often the principle architect of a chemical but who is unlikely to have sufficient formal training in toxicology and biochemistry to interpret such literature. However, the chemist who takes the time to identify and obtain such reference materials and, perhaps with the assistance of a toxicologist, carefully reviews and analyzes the information contained therein in totality, may very well be rewarded by the elucidation of the mechanism of toxicity and be better poised to design safer analogs of chemicals in the dass. 

Calleman, C.J. 1996. The metabolism and pharmacokinetics of acrylamide Implications for mechanisms of toxicity and human risk estimation. Drug Metab. Rev. 28(4) ... 

Further information regarding endocrine effects of DEHP can be found in the following Sections 3.2.2.5 Reproductive Effects, 3.2.2.6 Developmental Effects, 3.5.2 Mechanisms of Toxicity, and 3.6 Toxicities Mediated Through the Neuroendocrine Axis. 

This group of compounds have a 4-hydroxycoumarin ring with different side-chain substituents at the 3-position. Commonly used superwarfarin anticoagulant rodentieides in this group are bromadiolone, brodifacoum, coumate-tralyl, coumafuryl, and difenacoum. Brodifacoum, difena-coum and bromadiolone are three of the most commonly used rodentieides around the world. Brodifacoum is the most frequently used rodenticide in the USA. These rodentieides share most of their physical and chemical characteristics, as well as their toxicokinetics, toxicody-namics, and mechanism of toxicity, and the medical toxicological management is the same for all superwarfarins. 

There are very few agents like the anticoagulant warfarin whose toxicity and therapeutic effects are produced by the same mechanism. In most cases beneficial and harmful effects recruit different mechanisms of action. As far as CO is concerned not only does its mechanism of toxic and physiological actions differ, but the source from where it is derived matters too. So the mechanisms of action of inhaled-and heme-generated CO also seem to differ. Since the focus of this chapter is CO toxicity, we will attempt to elaborate the mechanism of its toxicity more than the mechanism of its physiologic actions. 

Mossman B, Light W, Wei E. 1983. Asbestos mechanisms of toxicity and carcinogenicity in the respiratory tract. Annii Rev Pharmacol Toxicol 23 595-615. 

The IPRK model has been helpful in assessing many potential nephrotoxins and in revealing mechanisms of toxicity and treatment. Given the hundreds of published studies, only selected areas will be cited. It should also be noted that many of the IPRK preparations have utilized cell-free perfusion and are therefore hkely to have varying degrees of distal tubular injury. However, as already noted, this seems less of a problem where the primary interest is in vascular or proximal tubular function. 

D-Limonene causes skin sensitization however, see sections on Mechanism of Toxicity and Chronic Toxicity - Human for discussion and data useful for assessing human sensitization risks. 

Metabonomics is now recognized as an independent and widely used technique for evaluating the toxicity of drug-candidate compounds, and has been adopted by several pharmaceutical companies into their drug development protocols. It is possible to identify the target organ toxicity, derive the biochemical mechanism of toxicity, and determine the combination of... 

There is enormous variability in the extent and nature of different databases for risk assessment. For example, in some cases, the evaluation must be based on limited data in experimental animals in other cases detailed information on the mechanism of toxicity and/or toxicokinetics may be available. In some cases the risk evaluation can be based on effects data in exposed human populations however, few chemicals have been adequately studied in humans to accurately identify a safe dose directly. Therefore, scientists typically rely on existing human... 

As risk assessment scientists continue to accumulate and develop knowledge of toxicokinetics, toxicodynamics, mechanisms of toxicity, and temporal effects of critical effects for various chemicals, evaluations become increasingly more accurate and detailed. Moreover, the science behind the use of UFs has progressed considerably. Increased understanding of... 

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