Toxic Substances Portal

Agency for Toxic Substances and Disease Registry. 2001. Toxic Substances Portal... 

The Agency for Toxic Substances and Disease Registry, a branch of the CDC, has a Toxic Substances Portal that details important information about toxic substances and how they affect our health www.atsdr.cdc.gov/substances/index.asp. 

Skin functions as both, an important physical barrier to the absorption of toxic substances and simultaneously as a portal of entry of such substances. The stratum comeum of the epidermis is most significant in providing some degree of physical... 

In view of the fact that we have evolved in a manner in which we obtain our energy primarily by way of the gastrointestinal (GI) system, this route also became the most likely portal for the inadvertent introduction of toxic substances. Therefore, as a survival necessity, the body had to evolve a strategy for the early interception and processing of potentially lethal xenobiotic substances. Anatomically, this is accomplished by the hepatic-portal venous system, which delivers substrates absorbed from the gut directly to a succession of chemical-transforming enzyme systems located in the liver. 

The occurrence of hepatic encephalopathy (HE) is only possible under the following conditions (1.) a serious (acute or chronic) liver disease, in which the detoxification function is significantly restricted, has to be present, and/or (2.) a functional or anatomic portosystemic collateral circulation must exist — this can be placed surgically or in the form of a TIPS (72, 90) -through which the nondetoxified portal blood bypasses the liver, so that toxic substances can reach the brain. 

The large intestine extends from the ileocecal valve to the anus. It is wider than the small intestine except for the descending colon, which when empty may have the same diameter as the small intestine. Major functions of the colon are absorption of water, Na+, and other electrolytes, as well as temporary storage of excreta followed by their elimination. The colon harbors large numbers of mostly anaerobic bacteria that can cause disease if they invade tissues. These bacteria metabolize carbohydrates to lactate, short-chain fatty acids (acetate, propionate, and butyrate), and gases (CO2, CH4, and H2). Ammonia, a toxic waste product, is produced from urea and other nitrogenous compounds. Other toxic substances are also produced in the colon. Ammonia and amines (aromatic or aliphatic) are absorbed and transported to the liver via the portal blood, where the former is converted to urea (Chapter 17) and the latter is detoxified. The liver thus protects the rest of the body from toxic substances produced in the colon. Colonic bacteria can also be a source of certain vitamins (e.g., vitamin K, Chapter 36). 

The process of bile acid formation in the liver, movement to the gallbladder, and then movement to the duodenum is a pathway that can concentrate toxicants in hepatocytes. From the gallbladder where they are stored, bile acids are released into the gut to aid in the digestion of lipophobic substances. Most of the released bile acids are reabsorbed in the intestines and are returned to the liver by the hepatic portal circulation. 

European Chemicals Bureau (http //ecb.jrc.it/) and the Hazardous Substance DataBank (http //toxnet.nlm.nih.gov/). When insufficient data were available for human chronic toxicity, a prediction of the carcinogenic and mutagenic effects was performed with the OSIRIS tool, available at the Organic Chemistry Portal (http // www.organic-chemistry.org/prog/peo/). 

Another consequence of biliary excretion is that the compound comes into contact with the gut microflora. The bacteria may metabolize the compound and convert it into a more lipid soluble substance which can be reabsorbed from the intestine into the portal venous blood supply, and so return to the liver. This may lead to a cycling of the compound known as enterohepatic recirculation which may increase the toxicity (figure 3,32). If this situation occurs the plasma level profile may show peaks at various times corresponding to reabsorption rather than the smooth decline expected. If the compound is taken orally, and therefore is transported directly to the liver and is extensively excreted into the bile, it may be that none of the parent compound ever reaches the systemic circulation. Alternatively the gut microflora may metabolize the compound to a more toxic metabolite which could be reabsorbed and cause a systemic toxic effect. An example of this is afforded by the hepatocarcinogen 2,4-dinitrotoluene discussed in more detail in Chapter 5. Compounds taken orally may also come directly into contact with the gut bacteria. For example, the naturally occurring glycoside cycasin is hydrolysed to the potent carcinogen methy... 

The CNS is involved in systemic toxicity most frequently because many compounds with prominent effects elsewhere also affect the brain. Next in order of frequency of involvement in systemic toxicity are the heart and circulatory system the blood and hematopoietic system visceral organs such as liver, kidney, and lung and the skin. Muscle and bone are least often affected. With substances that have a predominantly local effect, the frequency of tissue reaction depends largely on the portal of entry (skin, GI tract, or respiratory tract). 

Distribution is the step of toxicokinetics in which a toxicant moves from the site of absorption throughout the body. The toxicant may pass cell barriers, enter the circulation system, or enter the lymphatic system. The distribution mechanism can have profound effects on the action of a toxicant. A substance absorbed through the GI tract will be transported through the portal system to the liver. Compounds absorbed through the lungs, skin, or intravenous injection, however, will immediately enter systemic circulation. These two routes are metabolically distinct, as demonstrated in the next section. 

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