Archives of toxicology. Supplement. = Archiv fur Toxikologie. Supplement最新文献

Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin. Over 4000 different flavonoids have been described, and they are categorized into flavonols, flavones, catechins, flavanones, anthocyanidins, and isoflavonoids. Flavonoids have a variety of biological effects in numerous mammalian cell systems, as well as in vivo. Recently much attention has been paid to their antioxidant properties and to their inhibitory role in various stages of tumour development in animal studies. Quercetin, the major representative of the flavonol subclass, is a strong antioxidant, and prevents oxidation of low density lipoproteins in vitro. Oxidized low density lipoproteins are atherogenic, and are considered to be a crucial intermediate in the formation of atherosclerotic plaques. This agrees with observations in epidemiological studies that the intake of flavonols and flavones was inversely associated with subsequent coronary heart disease. However, no effects of flavonols on cancer were found in these studies. The extent of absorption of flavonoids is an important unsolved problem in judging their many alleged health effects. Flavonoids present in foods were considered non-absorbable because they are bound to sugars as beta-glycosides. Only free flavonoids without a sugar molecule, the so-called aglycones were thought to be able to pass through the gut wall. Hydrolysis only occurs in the colon by microorganisms, which at the same time degrade flavonoids. We performed a study to quantify absorption of various dietary forms of quercetin. To our surprise, the quercetin glycosides from onions were absorbed far better than the pure aglycone. Subsequent pharmacokinetic studies with dietary quercetin glycosides showed marked differences in absorption rate and bioavailability. Absorbed quercetin was eliminated only slowly from the blood. The metabolism of flavonoids has been studied frequently in various animals, but very few data in humans are available. Two major sites of flavonoid metabolism are the liver and the colonic flora. There is evidence for O-methylation, sulfation and glucuronidation of hydroxyl groups in the liver. Bacterial ring fission of flavonoids occurs in the colon. The subsequent degradation products, phenolic acids, can be absorbed and are found in urine of animals. Quantitative data on metabolism are scarce.

It is clear that members of the Cytochrome P450 supergene family are responsible for the majority of activations of procarcinogens to ultimate carcinogens in the body. These procarcinogens include the food mutagens (heterocyclic amines), pesticides, polycyclic aromatic hydrocarbons and nitrosamines. The Cyp P450 profile in a cell can indicate the capacity of that cell to form reactive metabolites. Furthermore, environmental factors, through their action on P450s, influence the fate of procarcinogens in a cell. This is because different isoforms of P450 are regulated differently by ethanol, diet and environmental inducers, have different substrate specificities and different propensity to be inhibited or activated by dietary components. Cyp P450 (through steroid inactivation), can also influence sensitivity of cells to hormones. Age and hormone related regulation of P450 isoforms such as 1A1, 2B1 and 2A3 in the breast suggest that in situ activation of carcinogens and hormone inactivation can occur in the breast. In the brain and endometrium most of the #P450 isoforms remain to be identified.

Promotion of animal welfare is an underlying and laudable goal for toxicologists and there is good reason to adopt practical, focused, investigative approaches towards this aim. Pharmaceutical regulatory toxicology can be subdivided into the areas of systemic (target organ), reproductive, genetic and topical toxicology, as well as immunotoxicology and oncology. These areas can be assessed for prioritisation as to where adoption of measures to promote any or all of the 3 Rs (reduction, replacement, refinement) would lead to the most tangible benefit for animals. These measures can range, for example, from replacement of animal experimentation with alternative in vitro techniques, to adoption of regulatory protocols that reduce the number of animals required. This paper is confined to consideration of in vitro technology in terms of reducing/replacing laboratory animal use, and a suggested list of criteria for prioritisation is potential for:- Regulatory acceptability Reducing development cost Reducing animal numbers Promoting welfare aspects Elucidating toxic mechanisms Usefulness in compound selection Advancing the science of toxicology Clear messages emerge from such an analysis which could influence prioritisation of the application of in vitro toxicology from the standpoints of animal welfare, feasibility and resources.

The traditional, but little used, way of assessing effects of the interaction between known chemicals is to use factorial experimental designs. Such designs allow one to test for less than additive (antagonistic) and greater than additive (synergistic) effects. Whilst synergism can be demonstrated in such experiments the concentrations at which synergistic effects occur are extremely high and are unlikely to occur in nature. Recently developed techniques allow one to measure directly the effects of combined stressors in the field. These biological effect techniques range from tests on individual organisms to tests on communities. At the biochemical level the tests can indicate that the organism has been exposed to certain groups of chemicals (for example cytochrome P-450 enzymes responding to PAHs or metallothioneins responding to heavy metals). At the community level of organisation there are highly sensitive statistical techniques that indicate clearly the combined effect of stressors. The effects of oil exploration and production on benthic communities in the North Sea can be linked to concentrations of chemicals. However, such relationships are correlative and do not necessarily indicate cause and effect. Experiments are needed to test the hypotheses generated concerning the interactive effects of chemicals on the benthic species. The statistical analyses do, however, show which species have been affected and their relative sensitivity to chemical and physical disturbances. Such species are preferable to the traditional "laboratory weeds" usually utilised. A strategy for risk assessment is needed that combines an experimental protocol for making predictions, from laboratory experiments, of likely effects to be found in the field. This should be combined with field monitoring that allows one to detect changes that were not predicted. At present most monitoring designs cannot adequately detect trends. This is due to concentration on Type-I statistical errors rather than properly considering Type-II errors. By concentrating on Type-II errors one can design monitoring programmes that are able to detect trends with a given degree of precision. There are also strong ethical grounds for a change to giving more emphasis to Type-II errors.