Systemic circulation, toxicants

Fig. 3. Schematic representation showing the anatomical basis for differences in the quantitative supply of absorbed material to the Hver. By swallowing (oral route), the main fraction of the absorbed dose is transported direcdy to the Hver. FoUowing inhalation or dermal exposure, the material passes to the pulmonary circulation and thence to the systemic circulation, from which only a portion passes to the Hver. This discrepancy in the amount of absorbed material passing to the Hver may account for differences in toxicity of a material by inhalation and skin contact, compared with its toxicity by swallowing, if metaboHsm of the material in the Hver is significant in its detoxification or metaboHc activation.

In Section 21.4 tlie effects of the release of toxic vapors were considered in connection witli an accident sequence initiated by the failure of a plant programmable automatic controller. In tliis study, event tree analysis and fault tree analysis led to identification of tlie glycol cooling system circulation pumps as components meriting high priority for inspection. 

In the gut, many pathogens adhere to the gut wall and produce their toxic effect via toxins which pervade the surrounding gut wall or enter the systemic circulation. Vibrio cholerae and some enteropathic E. coli strains localize on the gut wall and produce toxins which increase vascular permeability. The end result is a hypersecretion of isotonic fluids into the gut lumen, acute diarrhoea and consequent dehydration which may be fatal in juveniles and the elderly. In all these instances, binding to epithelial cells is not essential but increases permeation ofthe toxin and prolongs the presence of the pathogen. 

Numerous factors, many of them poorly understood, are involved in the development of HE. In severe hepatic disease, systemic circulation bypasses the liver, so many of the substances normally metabolized by the liver remain in the systemic circulation and accumulate to toxic levels. In excess, these metabolic by-products, especially nitrogenous waste, cause alterations in central nervous system functioning.20... 

The metabolism of chloroform is well understood. Approximately 50% of an oral dose of 0.5 grams of chloroform was metabolized to carbon dioxide in humans (Fry et al. 1972). Metabolism was dose-dependent, decreasing with higher exposure. A first-pass effect was observed after oral exposure (Chiou 1975). Approximately 38% of the dose was converted in the liver, and < 17% was exhaled unchanged from the lungs before reaching the systemic circulation. On the basis of pharmacokinetic results obtained in rats and mice exposed to chloroform by inhalation, and of enzymatic studies in human tissues in vitro, in vivo metabolic rate constants (V, 3,C =15.7 mg/hour/kg, = 0.448 mg/L) were defined for humans (Corley et al. 1990). The metabolic activation of chloroform to its toxic intermediate, phosgene, was slower in humans than in rodents. 

Other Toxicity Concerns. Additional toxicity concerns include interference with normal metabolism and function of mucosal cells, for example, water absorption by these cells [80]. The unconjugated bile acids are known to block amino acid metabolism [81] and glucose transport [82]. There is a possibility of biotransformation of these enhancers to toxic or carcinogenic substances by hepatic monooxygenases [83]. Absorption of permeation enhancers into the systemic circulation can also cause toxicity, for example, azone [84] and hexamethylene lauramide [85] which are absorbed... 

Acetyls alley lie acid was shown to prevent cirrhosis under certain experimental conditions [125]. Naproxen and indomethacin partially protected against LPS and D-galactosamine-in-duced hepatotoxicity [126] Acetylsalicylic acid and ibuprofen were also protective in endo-toxic shock [127]. Endotoxaemia is one of the complications in cirrhotic patients [128] and is probably caused by an impaired ability of the liver to take up and detoxify gut-derived LPS [116]. The presence of portosystemic shunts in cirrhotic patients may also contribute to this spill-over of LPS into the systemic circulation [129]. NSAIDs, however, are also reported to provoke deleterious effects on renal function in cirrhosis [130], and can therefore not be used in cirrhotic patients. Cell-specific delivery of NSAIDs to SECs and/or KCs may make application of these drugs in cirrhosis feasible by circumventing the renal side-effects. 

First pass metabolism (metabohsm in the intestinal wall or by the fiver before the substance reaches the systemic circulation) can also be a cause for nontoxicity, which can be route- and species-dependent. Information about which metabohtes, and the relative quantities thereof, are formed, is important. Chemical substances are metabohzed to metabohtes, which may be toxicol-ogically more or less active than the parent compound, and the relative quantity of the metabolites may differ greatly among animal species. If it is known that toxicity is related to formation of an active metabolite, knowledge about the amount of this particular metabolite in humans and test animals is very important for the hazard assessment. If humans do not form the toxic metabohte, the hazard can be considered limited and vice versa. 

Local anesthetics are frequently coadministered with vasoconstrictor molecules such as epinephrine. Normally, they are applied or injected locally and then taken up by local blood vessels into the systemic circulation, ultimately leading to their metabolic breakdown. The co-administration of a vasoconstrictor decreases the systemic absorption of the local anesthetic, thereby increasing its effective half-life in the area of administration and decreasing the probability of systemic toxicity (i.e., cardiac toxicity) secondary to systemic distribution. 

The underlying dermis is more permeable and vascularized, but to reach the systemic circulation through the skin, the toxic compound would have to traverse several layers of cells, in contrast to the situation in, for example, the gastrointestinal tract, where only two cells may separate the compound from the bloodstream. 

Systemic effects are more likely to occur with long-acting anesthetics if an excessive dose is used, if absorption into the blood stream is accelerated for some reason, or if the drug is accidentally injected into the systemic circulation rather than into extravascular tissues.17 40 Other factors that can predispose a patient to systemic effects include the type of local anesthetic administered, as well as the route and method of administration.3 Therapists and other health care professionals should always be alert for signs of the systemic effects of local anesthetics in patients. Early symptoms of CNS toxicity include ringing/buzzing... 

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