Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-01
2004-04-13
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S460000, C570S211000
Reexamination Certificate
active
06720431
ABSTRACT:
FIELD OF THE INVENTION
This invention relates, in general, to analytical systems for separating and detecting polyhalogenated diaromatic hydrocarbons.
BACKGROUND OF THE INVENTION
Polyhalogenated diaromatic hydrocarbons (PHDHs) are a diverse group of widespread environmental contaminants that include polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), polychlorinated dibenzo-p-dioxins (PCDDs), polybrominated biphenyls (PBBs), polybrominated dibenzofurans (PBDFs), polybrominated dibenzo-p-dioxins (PBDDs), and other subclasses of PHDHs. See, e.g., Giesy et al, Chapter 9, pp. 249-307,
Dioxins and Health
(ed., A. Schechter, Plenum Press, New York, 1994). Of the PHDHs, the chlorinated compounds or polychlorinated diaromatic hydrocarbons (PCDHs) have been most widely studied. However, the environmental and health impacts of other PHDH compounds, such as polybrominated diaromatic hydrocarbons and mixed brominated/chlorinated diaromatic hydrocarbons are increasingly being recognized.
Many PHDHs are lipophilic and resistant to degradation, and have been detected in soil, sediment, and water. Moreover, many PHDHs have been found to concentrate and accordingly amplify their effect in the food chain. See, e.g., Giesy et al. (1994a), supra; Tanabe et al.,
Environmental Pollution
47, 147-163 (1987); Giesy et al,
Environmental Science and Technology,
28, 128A-135A (1994b); Webster et al., Chapter 1, pp. 1-6,
Dioxins and Health
(ed., A. Schechter, Plenum Press, New York, 1994). Exposure to and bioaccumulation of PHDHs have been observed to produce a variety of deleterious species- and tissue-specific effects, including tumor promotion, birth defects, hepatotoxicity, immunotoxicity, dermal toxicity, alterations in endocrine homeostasis, undesirable induction of numerous enzymes (including cytochrome P450 1A1), and death. See e.g., Giesy et al., 1994b, supra, Poland et al.,
Ann. Rev. Pharmacol. Toxicol.
22, 517-542 (1982); Safe,
Critical Reviews in Toxicology
24, 87-149 (1994); DeVito & Birnbaum, in
Dioxins and Health,
pp. 139-162 (ed., A. Schechter, Plenum Press, New York, 1994)
Known techniques for detection and quantification of PHDHs generally involve costly and time-consuming traditional instrumental analysis methods, such as gas chromatography separation (GC) and mass spectrometry (MS). These methods generally involve extensive sample processing before quantification and analysis. See, e.g., United States Environmental Protection Agency (EPA) Method 1613 (40 C.F.R. Part 136) and EPO Method 8290 (40 C.F.R. Part 261). High resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS) processing generally requires an extraction of the sample to be analyzed, then treatment of the resulting extract with acid and base compounds, followed by sequential separations (usually by chromatography techniques) on silica gel columns impregnated with, e.g., sulfuric acid, neutral alumina, silica gel and activated carbon; This multiple-step processing of sample extracts usually yields an extract sufficiently free of interfering compounds to yield a congener-specific quantification of many, but not all, toxic PHDHs using HRGC/HRMS detection.
A significant disadvantage of the HRGC/HRMS technique is that, in general, only polychlorinated compounds (e.g., PCDHs) can be quantified by the method. For example, analytical techniques for detecting/quantifying polybrominated compounds and mixed brominated/chlorinated compounds are currently very costly and their standards not well-established. Unfortunately, it is now thought that polybrominated or mixed polybrominated/polychlorinated compounds are as toxic or even more toxic than corresponding chlorinated isomers. There accordingly remains a need for systems and methods that can determine and quantify toxic compounds not detectable by the HRGC/HRMS methods, such as toxic polybrominated or mixed polybrominated/polychlorinated diaromatic hydrocarbons.
Moreover, although HRGC/HRMS analysis allows detection and quantification of mixtures of known PCDH isomers and congeners, the method generally does not provide any information about the biological and/or toxicological effects of these complex mixtures. These mixtures, under certain environmental conditions, may theoretically contain up to or even more than 210 different PCBs, 135 different PCDFs, and 75 different PCDD isomers and congeners, each of which have vastly different chemical, physical, and toxicological properties. See Safe, 1994, supra, and Safe,
Critical Reviews in Toxicology
21, 51-88 (1990).
Accordingly, accurate prediction of the biological/toxic activity of complex PCDH mixtures using HRGC/HRMS is difficult. Consequently, the toxicological potency of a complex mixture of PCDH chemicals is generally assessed by the toxic equivalent factor (TEF) approach, in which the concentration of individual compounds present in the PCDH mixture are multiplied by their specific TEF, and the sum of the values expressed as toxic equivalents (TEQs). See Safe, 1994, supra; Safe, 1990, supra; and Ahlborg et al.,
European J. of Pharmacol and Environmental Toxicology
228, 179-199 (1992).
It is generally thought that many effects of PHDDs, PHDFs, and dioxin-like PHBs proceed through the action of the aryl hydrocarbon receptor (AhR), a cytosolic protein that binds these compounds with high affinity (Safe 1990, supra; S. Safe,
Environ. Health Perspect.
100, 259-268 (1992); Safe 1994, supra; L. S. Birnbaum,
Environ. Health Perspect.
102, Suppl. 9, 157-167 (1994); M. S. Denison and S. Heath-Pagliuso,
Bulletin of Environmental Contamination and Toxicology
61, 557-568 (1998); M. S. Denison et al., “The Ah receptor signal transduction pathway,” in Denison, M. S., Helferich, (Eds.),
Xenobiotics, receptors and gene expression
(Taylor and Francis, Philadelphia, pp. 3-33, 1998a). The occurrence of this common mechanism supports the continued use of the TEF concept.
PCDDs and PCDFs with chlorine substitutions in the 2-,3-,7-, and 8-positions exhibit the highest affinity binding to the AhR and the strongest toxic effects, with increasing chlorination generally reducing potency. The toxic potencies of the different congeners relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), the most toxic dioxin, are indicated by their corresponding toxic equivalency factors (TEFs). Over the past decade, a number of different TEF schemes have been proposed. See e.g., U. G. Ahlborg,
Chemosphere
28, 1049-1067 (1994); M. Van den Berg et al.,
Environ. Health Perspect.
103, 775-792 (1998); S. Safe,
Teratogenesis, Carcinogenesis and Mutagenesis
17, 285-304 (1997-98). The most recent consensus TEFs for humans, fish and wildlife risk assessment were derived at a WHO/IPCS (World Health Organization/International Programme on Chemical Safety) meeting held in Stockholm, Sweden on Jun. 15-18, 1997. See Van den Berg et al., 1998, supra, and M. Van den Berg,
Food Add. Contam.
17, 347-358 (2000). TEFs have been assigned to seven PCDDs, ten PCDFs and twelve PCBs, and range from 0.00001 to 1, reflecting a pronounced variability in toxicity.
Hazard and risk assessments of chemicals carried out by regulatory agencies have primarily addressed the toxicities of individual compounds, whereas humans and wildlife are exposed to complex mixtures of toxic compounds (Safe, 1998, supra). In addition to PCDDs, PCDFs, and dioxin-like PCBs, a number of other compounds exert AhR-agonist activity. In 1998, the international WHO committee agreed that other halogenated chemicals meet the criteria for inclusion in the TEF concept, but maintained that insufficient environmental and toxicological data were available to establish TEF values for these compounds (Van den Berg et al., 1998, supra). A few examples of these compounds, detailed further below, are brominated and mixed chloro/bromo-substituted analogues of PCDDs, PCDFs and PCBs, halogenated naphthalenes, halogenated diphenyl ethers, halogenated azo- and azoxybenzenes and polycyclic aromatic hydrocarbons (PAHs). See, e.g., G. Sundstrom et al.,
Chemospher
Chu Michael D.
Clark George C.
Myers Bigel & Sibley Sajovec, PA
Seaman D. Margaret
Xenobiotic Detection Systems International, Inc.
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