Bioavailability bound residue

This nonextractable radioactivity was probably the result of covalent binding of the furazolidone intermediates to endogenous macromolecules. The bioavailability of these bound tissue residues from the above pig residue depletion study was determined by feeding rats lyophilized samples of liver and muscle tissues from animals sacrificed at 0 and 45 days after the last treatment (132). Results showed that the fraction of the bound residues bioavailable to rats was in the range 16-41%. The toxicological impact of these bioavailable bound residues has not been yet determined. 

It is questionable whether or not the value obtained by bioassays or the sequestration value can be used to define contaminant-bound residues. Ageing-sequestration relationships in the subsurface, as determined through bioavailability, may provide an... 

The residue profile of cefquinome in beef calves intramuscularly treated with the drug has been studied (86). The data were reminiscent of those form other cephalosporins and indicated that cefquinome was rapidly cleared, with detectable levels of significance seen at injection site, kidney, and liver tissues. However, the residues remaining after 12 h at the injection site, kidney, and liver were not antimicrobially active and/or bioavailable and no parent drug could be detected 80-100% of these residues were bound residues. 

The US Food and Drug Administration (FDA) has recently proposed an approach to the safety assessment of bound residues derived from carcinogenic drugs thought to be both scientifically valid and reasonably capable of being accomplished (20, 21). This approach is based on the data collected from a combination of both in vitro and in vivo tests in the areas of the bioavailability and toxicological potential of bound residues, the reversibility of adduct formation, and the mechanism of bound residue formation. 

Another subject of scientific debate is still the bioavailability and toxicity of bound residues (2). Data on this particular topic are sparse but tend to suggest the absence of hazardous effects of bound residues rather than the contrary. Answers that remain to be provided on this subject concern the relevance of these toxicological effects and, if the effects are viable, the best and most reliable method by which they can be measured and evaluated for a specific compound. As long as these questions are not answered satisfactorily, any attempt to address them can only be considered as a shot in the dark and a potential waste of finance and time. The industry is prepared to perform any additional safety evaluation as long as the answers are reasonable and can result in a greater guarantee of protection for the consumer. 

Kloskowski, R., Ftihr, F., and Mittelstaedt, W. (1986a). Formation of bound residues of [benzene ring-U-14C]- anilazine and [triazine-U-14C]-anilazine inparabraunerde (Alfisol soil) and their availibility to maize. In Quantification, Nature, and Bioavailability of Bound 14C-Pesticide Residues in Soil, Plants, and Food. Int. Atomic Energy Agency, Vienna, 65-70. 

When significant quantities of residues remain at the skin site, the conventional approach is to include these residues in the percentage of absorbed dose. Eor instance, as part of the North American Free Trade Agreement (NAFTA) Technical Working Group on Pesticides, there was agreement that bound skin residues are considered absorbed when the bioavailability of residues cannot be determined (NAFTA, 2000). This approach is considered conservative as it is unlikely that all... 

In conclusion, toxic chlorinated phenol intermediates formed during the chemical, photochemical and/or enzymatic degradation of chlorophenoxyalkanoic compounds would temporarily be detoxified when they are incorporated into the humic acid, since their bioavailability and movement into terrestrial and aquatic ecosystems would be greatly reduced. However, the knowledge of the potential toxicity problems which these bound-residues could give rise to in the environment is still very limited. Xenobiotic chemicals incorporated into humic polymers are not really removed from the ecosystem and they may maintain their identity and toxic properties for unknown time spans, eventually causing time-delayed pollution problems, if and when they will be released from humic substances. 

Other assumptions and variables may also be involved in determining MRLs, including safety factors used in establishing ADIs, withdrawal times, the contribution of bound residues, and the bioavailability of residues. 

The following factors were considered in estimating the MRLs the ADI the parent drug is a suitable residue marker and is 2.4% of the total residues all the residues in muscle and fat are equivalent to the parent drug 50% of the residues in liver are bound and 15% of these bound residues are bioavailable the residues in kidney are qualitatively similar to those in liver it is assumed that all bioavailable residues in liver and kidney are equivalent to the parent drug and the residues are similar in cattle, sheep, and pigs. 

Xenobiotics are frequently metabolized in plants by mechanisms that lead to the incorporation or inclusion of the xenobiotic into biological polymers or tissue residues that are not soluble in commonly used nonreactive solvents. These residues are frequently refered to as bound, insoluble, or nonextractable residues (2 ). Bound residues in plants have most commonly been detected in plant tissues treated with radloactlvely-labeled pesticides. These residues were an important topic of a symposium held in Vail, Colo, in 1975 (17) they have been discussed in mauiy more recent papers (11,154-1577"and they were discussed at a symposium at the l88th ACS National Meeting, 1984 "Non-extractable Pesticide Residues Characteristics, Bioavailability and Toxicological Significance". 

Although the globally distributed DDT is a very well investigated xenobiotic regarding the environmental occurrence and behaviour, detailed information about the fate of DDT in the bound residues fraction is very limited. Already in 1977 Lichtenstein et al. (1977) reported the formation of bound 14C-labelled DDT on agricultural soil accompanied by a drastically reduced insecticidal activity of the associated proportion. Also recent studies confirmed the decrease of DDT toxicity with time after application to soils as a result of less bioavailibility due the incorporation into the non-extractable particulate matter (Robertson and Alexander 1998). For a better understanding of the processes leading to these observations more information is required about the incorporation of DDT residues into the non-extractable particulate matter not only of soils but also of particulate matter within the aquatic environment. 

Specific problems are raised by bound residues. After an animal has been treated with a medicine, its residues are present in plasma and tissues as parent drug and metabolite or metabolites. The residues may be present as free drug and/or metabolites or as covalently bound residues. This then raises the question of the degree of bioavailability of these bound residues and their biological activity (47,48). In most cases, this question has no simple answers. Of course a drug may be metabolized to carbon dioxide and hence bicarbonate ion or some other simple precursor of normal endogenous biochemicals. If these arise from a radiolabelled portion of the molecule, measurements of residues simply as incorporated radiolabel will... 

Efforts to enhance the recovery of drug-related residue from livers of treated cattle are currently in progress. If these efforts are unsuccessful, and the review of the toxicology data indicates that the safe concentration of total residue is reached at a later time period, then it will be necessary to conduct a relative bioavailability study to assess the percentage of bound residue which is not bioavailable. 

Regarding the persistence of bound residues, as compared to the parent compound and other metabolites, and their high bioavailibility when fed to rats (63), special attention was paid to their identity and possible toxic properties. In particular the possible presence of reversible protein-bound metabolites in tissues of treated animals was hypothesized to imply a possible health-risk for the consumer (63). The issue of bound-residues of furazolidone and other drugs has long been one of the most controversial and difficult problems in the field of residue toxicology (64, 65). 

Limited bio availability may lead to unexpected persistence of transformation products in soil and sediment, and longer persistence could lead to accumulation of residues. Whether bound pesticide residues in soils are occluded or may remain bioavailable in the long term in the environment is still an ongoing debate [33]. Generally, soil-bound chemicals are not considered bioavailable prior to desorption [41]. However, some evidence suggests that bound residues can be bioavailable or at least that desorption is not a requisite for biodegradation. Bioavailability is considerably lower from bound residues than from freshly treated soil. It has been suggested that the uptake ratio of chemicals and their transformation products from bound residues compared to those from freshly treated soils was about 1 5 [42]. 

The bioavailability of the radiolabeled bound residues of (XVI) and (XVII) is being investigated following oral administration to bile duct-cannulated rats. The outcomes of these studies are still being analyzed and only initial results are presented. Experiments were conducted in accordance with the UK Home Office regulations for animal welfare. 

Pesticide Metabolism, Conjugate, Bound Residue, Bioavailability... 

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