Effect, carcinogenic circulation

In the past, chloroform was used extensively as a surgical anesthetic, but this use was abandoned because exposure to narcotic concentrations often resulted in sudden death from effects on the heart and circulation or from severe injury to the Hver. In addition, chloroform for this and other consumer uses was harmed by FDA in 1976 with the discovery that it is carcinogenic in mice (38). When splashed into the eye, chloroform causes local pain and irritation, but serious injury is not expected. Skin contact for single, brief exposures ordinarily causes Htde or no local irritation. 

Several epidemiological studies show that fine and ultrafine (<0.1 pm) particulate matter and air pollution can pose adverse health effects including respiratory, cardiovascular, allergic, and carcinogenic diseases (Kiinzli et al., 2000 Donaldson et al., 2003 Bernstein et al., 2004). It appears also that ultrafine particles, after deposition in the lung and gain access to the pulmonary interstitium, can penetrate the systemic circulation and exert more toxicity than coarse and fine particles (Oberdorster, 2001 Bernstein et al., 2004). 

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... 

In addition to carcinogenic effects, animal studies have shown the effects of benzene exposure on the immune system. Reid et al. showed a significant decrease in splenic cell proliferation in mice exposed to benzene for 14 days. Experimental animal studies also reported reduced circulating white blood cells, as well as changes in spleen morphology and weight in various experimental animal studies. These experimental animal studies further support the observation from 1913 by Wintemits and Hirschfelder that rabbits exposed to... 

In acute, chronic, reproductive and genotoxicity studies, kojic acid was not found as a toxicant. Due to slow absorption into the circulation from human skin, it would not reach the threshold at tumor promotion and weak carcinogenicity effects were seen. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that it is safe for use in cosmetic products up to a concentration level of 1%. The available human sensitization data support the safety of kojic acid at a concentration of 2% in leave-on cosmetics, suggesting that a limit of 2% might be appropriate. In an industrial survey of current use concentrations, it is used at concentrations ranging from 0.1% to 2%. The European Commission s Scientific Committee on Consumer Products (SCCP) determined that, based on a margin of safety calculation, the use of kojic acid at a maximum concentration of 1.0% in skin care formulations poses a risk to human health due to potential systemic effects (thyroid side effects). The SCCP also found it to be a potential skin sensitizer (Burnett, 2011). 

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