Toxicological concern

Rubbers. Plasticizers have been used in mbber processing and formulations for many years (8), although phthaHc and adipic esters have found Htde use since cheaper alternatives, eg, heavy petroleum oils, coal tars, and other predominandy hydrocarbon products, are available for many types of mbber. Esters, eg, DOA, DOP, and DOS, can be used with latex mbber to produce large reductions in T. It has been noted (9) that the more polar elastomers such as nitrile mbber and chloroprene are insufficiendy compatible with hydrocarbons and requite a more specialized type of plasticizer, eg, a phthalate or adipate ester. Approximately 50% of nitrile mbber used in Western Europe is plasticized at 10—15 phr (a total of 5000—6000 t/yr), and 25% of chloroprene at ca 10 phr (ca 2000 t/yr) is plasticized. Usage in other elastomers is very low although may increase due to toxicological concerns over polynuclear aromatic compounds (9). 

NADA methods should be capable of reliably measuring an analyte (i.e., the marker residue) that has a defined quantifative relationship to the total residues of toxicological concern in the tissues of interest, namely the target tissue and muscle. The target tissue is generally the last tissue in which total residues deplete to the permitted maximum safe concentration. When the marker residue is at the tolerance, a defined unique concentration, the total residues have depleted to the respectively established safe concentrations in the target tissue and muscle. 

The platform includes different decision trees for the following endpoints the estimation of Threshold of Toxicological Concern (TTC), aquatic modes of action [44], skin and eye irritation and corrosion, mutagenicity and carcinogenicity [45], in vivo micronucleus assay, identification of Michael Acceptors and biodegradation potential [46]. 

Immunotoxicity testing in rodents exposed to industrial and/or environmental chemicals, has been recognized as an important toxicological concern for over 25 years. Early immunotoxicity testing relied primarily on the mouse, due to the plethora of immune structure and function research performed by immunologists to better understand the human immune system. As such, the mouse has been the most employed rodent for immunotoxicity testing. Immune system function assays employed in screening for immunotoxicity were developed in adult mice. These same immune function assays have served to help identify toxicant induced immunosuppression in the rat. 

BARLOW, S. M., KOZIANOWSKI, G., WURTZEN, G. and SCHLATTER, J. 2001. Threshold of toxicology concern for chemical substances present in the diet. Food Chem. Toxicol. 39 893-905. 

SCF ADI Acceptable Daily Intake allocated by the Scientific Committee on Food, formerly known as the Scientific Committee for Food. (The SCF has often considered and then adopted JECFA ADI values.) Numbers in this column are the numerical ADI in mg per kg body weight, (mg/kg b.w.) expressed as 0—X, because 0 mg/kg b.w. is also acceptable NS = Not specified. This implies that the no-effect level and conditions of use have been assessed to be such as to cause no toxicological concern. It does not mean that no ADI could be allocated, because of, for instance, lack of submitted evidence. 

An estimate for the lowest level of toxicological concern for human exposure to a chemical is developed by dividing the appropriate NOAEL by the uncertainty factor. Historically, this estimate has been termed the acceptable daily intake (or ADI) although it has been replaced by what EPA calls the reference dose (or RfD). Both ADIs and RfDs are expressed in terms of the amount of chemical exposure per amount of body weight per day. 

Nony et al. 1980 Zwimer-Baier and Neumann 1994). Some of the methods have been shown to be suitable for the determination of the aeetylated metabolites (Bowman and Nony 1981 Nony and Bowman 1980 Nony et al. 1980). The methods of Bimer et al. (1990), Joppieh-Kuhn et al. (1997), and Zwimer-Baier and Neumann (1994) permit the analysis of hemoglobin adduets of 3,3 -diehlorobenzidine and its monoacetyl metabolite. Limits of deteetion for 3,3 -diehlorobenzidine in mine and semm were reported to be as low as 1 to 5 ppb (Bowman and Rushing 1981 Hoffman and Sehmidt 1993 Roberts and Rossano 1982), with detectable concentrations of the aeetylated metabolites somewhat higher. Most of these studies were performed with samples from rats the methods should be tested to determine if they are applieable to samples of human origin. In addition, the levels of these biomarkers associated with exposures to 3,3 -dichlorobenzidine of toxicological concern should be defined in order to increase their utility. 

Nitrosamines have been of significant interest since they were discovered to be DBFs in 2002 [42, 43]. Their structures are shown in Fig. 3. A-Nitrosodi-methylamine (NDMA) is a probable human carcinogen, and there are toxicological concerns regarding other nitrosamines. NDMA was initially discovered in chlorinated drinking waters from Ontario, Canada [44], and has since been found in other locations [42, 43, 45]. The detection of NDMA in drinking water is largely due to improved analytical techniques that have allowed its determination at low... 

To ensure compliance with the withdrawal period, an assay is needed to monitor total residues in the edible tissues. Because it is impractical to develop assays for each residue in each of the edible tissues, the concept of a marker residue and a target tissue is introduced. The marker residue is a selected analyte whose level in a particular tissue has a known relationship to the level of the total residue of toxicological concern in all edible tissues. Therefore, it can be taken as a measure of the total residue of interest in the target animal. The information obtained from studies of the depletion of the radiolabeled total residue can be used to calculate a level of the marker residue that must not be exceeded in a selected tissue (the target tissue) if the total residue of toxicological concern in the edible tissues of the target animal is not to exceed its safe concentration. 

Finally, the concept of hormesis (Section 4.12), threshold of toxicological concern (Section 4.13), and probabilistic methods for effect assessment (Section 4.14) will be briefly addressed. 

Human Exposure Threshold of Toxicological Concern (TTC) Values... 

Barlow, S. 2005. Threshold of Toxicological Concern (TTC). A tool for assessing substances of unknown toxicity present at low levels in the diet. ILSI Europe Concise Monograph Series. Europe, Bmssels, Belgium ILSI. http //europe.ilsi.org/publications/Monographs/ThreshoIdToxicoIogicaIConcem.htm Barnes, D., G. Daston, J. Evans, et al. 1995. Benchmark dose workshop Criteria for use of a benchmark dose to estimate a reference dose. Regul. Toxicol. Pharmacol. 21 296-306. 

Kroes, R., C. Galli, 1. Munro, et al. 2000. Threshold pf toxicological concern for chemical substances in the diet A practical tool for assessing the need for toxicity testing. Food Chem. Toxicol. 38 255-312. 

Kroes, R., A. Renwick, M. Cheeseman, et al. 2004. Structure-hased thresholds of toxicological concern (TTC) Guidance for application to substances present at low levels in the diet. Food Chem. Toxicol. 42 65-83. 

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