Japanese Journal of Clinical Oncology 33:259-270 (2003)
© 2003 Foundation for Promotion of Cancer Research
Carcinogenesis and Its Modification by Environmental Endocrine Disruptors: In Vivo Experimental and Epidemiological Findings
1 Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, Tokyo and 2 Asian Pacific Organization for Cancer Prevention Editorial Office, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCLASSES OF ENDOCRINE MODULATORSCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Although a great deal of concern has been raised about the hazard potential of endocrine disruptors present in the environment, the in vivo data available from both experimental and epidemiological studies suggest that the majority of those agents do not pose a risk with regard to cancer development. Indeed, naturally occurring examples such as isoflavonoids even appear to exert protective effects. Only for xenobiotics such as 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), polychlorinated biphenyls (PCBs) and tetrachloro-p-dioxin (TCDD) and special cases of phenols and phthalates is there unequivocal evidence of carcinogenicity and this appears to be directly linked to their toxicity. Thus, careful in vivo assessment is required before drawing any conclusions regarding agents capable of affecting the mammalian endocrine system.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCLASSES OF ENDOCRINE MODULATORSCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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It has long been known that plant constituents may be hormonally active and in the 1940s much attention was paid to compounds such as thiourea, which was found to disrupt thyroid function in rodents. Therefore, the recent ‘chemophobia’ (1) regarding endocrine disruptors in the environment is not a new phenomenon and thus demands for restrictions need to be based on strong evidence of harm. The present review concentrates on the epidemiological findings and experimental data relevant to carcinogenesis, the latter primarily gained from in vivo studies in rodents. Reference will be made to in vitro results only where appropriate to discuss possible mechanisms of action.
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CLASSES OF ENDOCRINE MODULATORS |
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TOPABSTRACTINTRODUCTIONCLASSES OF ENDOCRINE MODULATORSCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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The classes of endocrine modulators covered here are generally as reviewed by Nilsson (1) (see Table 1). Others might also be considered, although some of them are extreme. For example, if electric lighting as currently employed contributes to ‘circadian disruption’, it may be an important cause of ‘endocrine disruption’ and thereby might pose some risk to breast cancer in industrialized societies (2).
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A: Xenobiotics Mimicking or Antagonizing Sex Hormones (Fig. 1)
Chlorinated Compounds
The potential carcinogenic risk to humans of xenobiotic chlorinated compounds, particularly pesticides and related substances which may act as endocrine disruptors, has been covered in great detail by a number of IARC workshops (3–8). The overall conclusions drawn were that TCDD is an unequivocal human carcinogen (class 1), whereas PCBs and DDT belong to class 2B (possibly carcinogenic to humans) (see Table 1).
1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT)
The evidence from in vivo animal experiments for the organochlorine pesticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) is unequivocal, pointing to complete carcinogenicity in the rodent liver, which is also the target for its toxicity (3,6,8). However, there is evidence for a dose threshold and exceedingly low doses may even act in a hormetic fashion, inhibiting development of the lesions (9,10). The situation with regard to epidemiological data, however, is less clear and with industrial exposure the findings are also equivocal. Although several early descriptive studies and a cohort study identified a strong positive association with breast cancer risk and adipose or blood levels of its metabolite dichlorodiphenyldichloroethylene (DDE), most of the more recent case–control and nested case–control studies have not supported such an association (11). For example, in the USA no association was found between adipose tissue levels of DDE/DDT and breast cancer risk (12). It has been proposed that their hydroxylated metabolites should in fact be used for assessment (13), but this has been questioned (14). Their serum levels also demonstrated no link in Mexico, although the possibility of higher levels of exposure playing a role could not be excluded (15). Results from Vietnam also suggest that recent and past exposure to DDT do not play an important role in the etiology of breast cancer among women living in a country with a tropical climate where it is commonly used as an insecticide for mosquitoes (16). Cross-European studies similarly did not provide any evidence (17). For other organs the picture is somewhat different. In Egypt, for example, colorectal cancer patients demonstrated higher serum organochlorine levels than controls (18). Significantly high biliary DDT concentrations further suggest that this pesticide might be associated with carcinogenesis in the gallbladder (19). Also in pancreatic cancer patients in the USA, elevated odds ratios were observed for self-reported exposure to DDT and other organochlorine pesticides, although statistical significance was not established (20). However, no long-term carcinogenic effects were found in non-human primates, despite fatty changes in the liver (21). It should be borne in mind that in animal experiments the possibility of a paradoxical hormetic effect or protection at very low doses has been suggested (9).
Polychlorinated biphenyls (PCBs)
PCBs, complete carcinogens and promoters in the rodent liver (5), affect both cellular proliferation and apoptosis (22). They may act as promoters in the mouse lung (23) and may be associated with accumulation of iron in Kupffer cells and elevated proliferation of hepatocytes in the rat liver (24). There is evidence that neonatal exposure to high doses of organochlorines could favor the development of MNU-induced mammary lesions, but it is also reported to delay the development of palpable tumors in the rat (25).
Given the findings in laboratory animals and indications from industrial exposure in humans, although varied, PCBs have been classified as class 2B agents (5). However, the largest cohort of male and female production workers so far studied cast doubt on any important human health effects of PCBs (26), because of the lack of significant elevations in the site-specific cancer mortality. Therefore, reassessment may be appropriate. Recent examination of plasma data indicated that exposure to dioxin-like PCBs increases the breast cancer risk, although the authors offered an alternative explanation based on the differences between cases and controls regarding metabolic pathways involved in the biotransformation of both mono-ortho-PCBs and estrogens (27). However, many PCBs may be more strongly associated with tumors of poor prognosis (28). No significant differences were observed in 8-hydroxydeoxyguanine (8-OhdG) levels in cancerous versus non-cancerous human tissues and no correlation was demonstrated between the organochlorines and levels of 8-OhdG. Hence the data do not support the hypothesis that oxidative DNA damage caused by exposure to those agents is an important risk factor in breast cancer (29). Combined evidence does not support any definite association of breast cancer risk with plasma/serum concentrations of PCBs or DDE. Moreover, the exposure to these compounds, as measured in adult women, was considered unlikely to explain the high rates of breast cancer experienced in the northeastern USA (30). Nor did the results from a large-scale nurses study support the hypothesis that exposure to PCBs (or DDT) increases the risk of breast cancer (31). A similar conclusion can be drawn from Norwegian data for serum organochlorine levels (32). In one study looking at both US whites and African-Americans, however, a positive link was demonstrated for the latter (33). Furthermore, a study in Spain showed a particular PCB (n-28) in breast fat to be significantly associated with cancer risk (34). However, in Sweden no link was found between serum organochlorines and endometrial cancer risk (35). This may be of particular interest because the endometrium is more sensitive than the breast to estrogenic stimulation.
Tetrachloro-p-dioxin (TCDD)
In mice and rats, TCDD is a complete hepatocarcinogen, which also causes follicular cell adenomas of the thyroid gland, squamous cell carcinomas of the nasal cavity and fibrosarcomas in different sites (8). Hence the data including tumor causation in rats, mice and hamsters are unequivocal, although a role for non-specific toxicity has been proposed (36). In fact, TCDD is a highly toxic agent and data from human populations are less convincing. The strongest epidemiological evidence is for all sites combined rather than any particular organ or tissue, as shown in a German cohort study, for example (37). While serum levels appeared to be correlated with an increased risk of all cancers and breast cancer and there was a non-significant link with endometriosis after the Soweso incident (38–40), this was not the case with an American epidemiological exercise (41).
Phenols and Phthalates
Butylated hydroxyanisole (BHA)
In rodents, BHA is a forestomach carcinogen, but with a dose threshold pointing to an epigenetic mode of action (42) dependent on proliferation (43). Assessment of the reversibility of the lesion further led to the conclusion that the tumors induced by BHA are most unlikely to be relevant to humans exposed to the agent at much lower levels (44). Furthermore, in The Netherlands an epidemiological cohort study showed no link with stomach cancer risk (45). While promotion potential has also been reported for the urinary bladder (46), BHA has been found to act as an inhibitor of lung carcinogenesis in A/J mice (47) and rats (48), of hepatocarcinogenesis in rats (49) and of pancreatic carcinogenesis in Syrian hamsters (50).
Triazines
While one study suggested a link between agricultural exposure to atrazine and non-Hodgkin’s lymphomas (51), the epidemiological evidence regarding triazines points to a null association for breast cancer across all exposure indices and an inverse association with ovarian cancer (52). In farm workers, no general links were apparent. However, for Hispanic males the following correlations were observed: leukemia and atrazine (r = 0.40), leukemia and 2,4-dichlorophenoxyacetic acid (r = 0.41), leukemia and captan (r = 0.46), brain cancer and atrazine (r = 0.54) and testicular cancer and atrazine (r = 0.41). For black males, prostate cancer and atrazine have also been demonstrated to have a significant relationship (r = 0.67) (53). Atrazine contamination levels [range 50–649 ng/l in drinking water, maximum acceptable concentration (MAC) = 60 000 ng/l] were positively associated (P < 0.05) with stomach cancer incidence and negatively associated with colon cancer incidence in another study (54). However, an earlier review of the literature, a pooled analysis of three of the case–control studies and the combined analysis of two retrospective follow-up studies did not demonstrate such types of dose–response or induction time patterns that would be expected if triazines were in fact causal factors (55).
When Fischer F344/LATI rats of both sexes were given atrazine in the diet at concentrations of 0, 375 and 750 p.p.m. for 126 weeks, in the high-dose male group were found a significantly increased number of combined leukemias/lymphomas and also a higher incidence of mammary tumors, together with uterine carcinomas in a dose-dependent manner (56). However, in other investigations mammary tumor was only noted to develop in SD and not F344 rats, which was observed only at or above the threshold dose (the maximum tolerated dose) that interferes with normal estrous cycling, promoting prolonged exposure to endogenous estrogen (57). SD rats exhibiting persistent estrus also have a prolonged elevation of estrogen secretion. Therefore, it is proposed that the triazine-associated mammary tumor response is promoted by the test animal’s own estrogen from ovarian follicles that fail to ovulate, because gonadotropin surge sufficiency is blocked by the high-dose herbicide (58). It has further been hypothesized that, because reproductive senescence in SD rats is fundamentally different from menopause in women, the animal response to dosing in addition to the enormous dosing level required would establish a safety margin of very low risk to human health based on this mode of action.
Regarding other findings reported, it should be noted that a significant increase in lymphomas was observed with chronic treatment of Swiss albino mice (59). Chloro-s-triazine herbicides [cyanazine (CZ), atrazine (AZ), simazine (SZ)] increase mammary tumors in Crl:CD BR rats but not in F344 rats or in mice, but this was mediated through a prolactin mechanism not relevant to humans (60).
Alkylphenols
In a study after dimethylbenz[a]anthracene (DMBA) initiation in SD rats, ovarian tumor development was significantly suppressed by 4-nonylphenol (61), although the same chemical caused an increase in the multiplicity of mammary tumors in female transgenic rats bearing copies of the human c-Ha-ras proto-oncogene with its own promoter region (62). Bisphenol A, an antagonist of PPAR gamma, induces apoptosis of tumor cells, although the mechanism was unclear (63). It also significantly inhibited rapid mammary cancer induction after DMBA-initiation model in human H-ras transgenic rats (64). No effects of bisphenol A or methoxychlor were found either on dihydroxydi-n-propylnitrosamine-initiated thyroid carcinogenesis (65) or of the n-octylphenol in the prostate after dimethylaminobiphenyl initiation (66). However, in adult Donryu rats, N-ethyl-N'-nitro-N-nitrosoguanidine-initiated endometrial carcinogenesis was promoted by high-dose exposure, possibly owing to uterotrophic effects (67).
Di(2-ethylhexyl) phthalate (DEHP)
DEHP, a peroxisome proliferator, has been listed by the International Agency for Research on Cancer (IARC) as a possible or reasonably anticipated human carcinogen, because it induces dose-related increases in liver tumors in both sexes of rats and mice (68). Since DEHP also exerts other biological effects that occur independently of peroxisome proliferation (e.g. morphological cell transformation and decreased levels of gap junction intercellular communication), it is possible that some of these responses may also contribute to the carcinogenicity of this chemical. Because proliferation of peroxisomes has not been established as an obligatory step in the carcinogenicity of DEHP, the contention should be viewed as a still unvalidated hypothesis that DEHP poses no carcinogenic risk to humans because of the species difference in the peroxisome proliferation (69). However, no short-term effects were evident in cynomolgus monkeys (70) and on application of the new US EPA Risk Assessment Guidelines, it was concluded that the hepatocarcinogenic response of rodents to DEHP is not relevant to human cancer risk at any anticipated exposure level (71). They considered that DEHP should be classified as an unlikely human carcinogen with the margin of exposure (MOE) approach to risk assessment. Inhibition of pancreatic carcinogenesis has been shown in hamsters (72), but there was no effect in the rat urinary bladder (73).
Tin Compounds
Tributyltin (TBT)
It was reported that when several cohorts of mice bearing cancers were continuously dosed with 2,2'-bipyridyldibutyltin dichloride, 1,10-phenanthrolinedibutyltin and histidinedibutyltin at 1 and 10 p.p.m. in drinking water, tumor growth rates were significantly reduced (74). Tributyltin fluoride (TBTF) was ineffective when applied dermally over the tumor site, using dimethyl sulfoxide (DMSO) as the carrier. Variation in thymus and spleen weight between controls and tin-exposed mice indicates a lymphatic involvement. Analysis of mouse tissue for total tin content showed high tin concentrations in the thymus and spleen (74). Tributyrin has been shown to be cytostatic to tumor cells by inducing differentiation and apoptosis and the compound is a potent inducer of ICAM-1, LFA-3 and Fas on target cells, corresponding to an increase in FasL expression by IL-2/IL-12 on the effector cells (75).
B: Natural Compounds Mimicking or Antagonizing Sex Hormones
Isoflavonoids (Glucoside Conjugates)
Genistein or daidzein
Incidences of breast and prostate cancer are relatively low in China and Japan where relatively high amounts of soy products are consumed, and this has led to a suggestion of their protective effects (76,77). In fact, there is now a very large body of evidence, from both epidemiological and experimental animals studies in vivo, pointing to the inhibitory potential of soy products against cancer development in many organ sites (see Tables 2 and 3). The overwhelming conclusion from both in vivo and in vitro data is that soy products or constituents such as genistein or daidzein can act as cancer-preventive agents in the mammary gland and possibly also in the endometrium, ovary, prostate and stomach, through both hormone-related and non-hormone-related mechanisms (78, 79). There are also data supporting their protective effects in the colon, liver, thyroid, skin and lung, with very few reports of promotion or toxicity.
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Mycoestrogens
Zearalenone (from Fusarium species)
Previous surveys of fungal contamination of corn in China have detected fumonisins, which are mycotoxins produced by Fusarium moniliforme. However, the findings of Groves et al. (151) do not support the hypothesis that mycotoxin contamination increases the risk of gastric cancer among those who consume fermented Chinese pancakes. In carcinogenicity studies, zearalenone caused an increased incidence of HCCs in female mice and pituitary tumors in both sexes of mice but no lesions in rats, evidence difficult to permit the drawing of any definite conclusions (152). Prepubertal exposure to zearalenone reduces DMBA mammary tumorigenesis (114).
Saponin glycosides (from ginseng)
In a recent review, Yun (153) summarized the epidemiological evidence of cancer chemopreventive benefits from consumption of ginseng. Chemistry and cancer-preventing activities of ginseng saponins and some related triterpenoid compounds have also been reviewed in detail by Shibata (154). The ocotillol-type saponin, of which majonoside-R2 (MR2) obtained from the rhizome and root of Panax vietnamensis (Vietnamese ginseng) is an active constituent, exhibited potent anti-tumor-promoting activity in the two-stage mouse hepatic tumor model, where N-nitrosodiethylamine (DEN) and phenobarbital (PB) were used as the initiator and the promoter, respectively. Furthermore, MR2 exhibited remarkable post-initiation inhibitory effects on induction of skin cancer in mouse by nitric oxide (NO) donor–12-O-tetradecanoylphorbol-13-acetate (TPA) or peroxynitrite–TPA (155). In another study, dietary intake of soya saponins significantly reduced the incidence of aberrant crypt foci after initiation with azoxymethane (156).
Lignans
Enterolactone, a phytoestrogen belonging to the class of lignans, is produced by the intestinal microflora from precursors in plant foods. An inverse association between serum enterolactone level and risk of breast cancer was seen among both premenopausal and postmenopausal women in Finland (157), with no evidence of protection against prostate cancer (158). In a comparison study of males from Hong Kong, the UK and Portugal, the last two countries had by far the greatest levels of enterolactone in the prostate fluid (159).
Continuous exposure, particularly to purified lignans, results in differentiation of the rat mammary gland (160). Dietary supplementation with flaxseed or its lignan secoisol ariciresinol diglycoside (SDG) has reduced DMBA-induced mammary tumor size and number in rats (161,162). The anticancer effect of flaxseed and SDG may be related, in part, to the increased ß-glucuronidase activity (163) and/or reduction in plasma IGF-I (164).
Another lignan, hydroxymatairesinol (HMR), showed a strong chemopreventive effect on intestinal tumor development in adenomatous polyposis coli multiple intestinal neoplasia (Apc) (Min) mice, with normalization of ß-catenin levels in the adenoma tissue. This indicates that HMR mediates its chemopreventive effect through the Apc–ß-catenin pathway (165). In another study, anti-promotional effects of arctiin, a lignan with antiestrogenic action against 17-ß-thinylestradiol (EE) and 2-acetylaminofluorene (2-AAF), were examined using a medium-term liver bioassay based on the induction of glutathione S-transferase placental form (GST-P) positive foci in rat liver, where a reduction in the 2-AAF case was observed (166). Two lignans, asarinin and xanthoxylol, isolated from the radix of Asiasarum heterotropoides var. mandshuricum from a kampo prescription, Shouseiryu-to, exhibited remarkable inhibitory effects on the two-stage genesis of mouse skin and pulmonary tumors (167).
C: Substances Affecting Thyroid Function
PCBs and Goitrogens
PCBs, with a significant impact on the thyroid, have already been reviewed above. With regard to other agents, Son et al. (149,150) and Takagi et al. (65) have conducted a number of studies. Isoflavones and nonylphenol were generally found to be without effects. Propylthiouracil was found to promote thyroid tumorigenesis induced by N-bis(2-hydroxypropyl) nitrosamine in rats (168). Thyroid dysfunction (induced by thyroidectomy or administration of thyroxin and methylthiouracil) during the postnatal period after transplacental initiation with N-methyl-N-nitrosourea (MNU) resulted mainly in inhibition of tumors of the nervous system and kidney in rats of two subsequent generations, but thyroid carcinogenesis was again increased (169). Another thyroid hormone-disrupting agent, 3-amino-1,2,4-triazole, was also found to have tumorigenic and promoting effects (170,171), although inhibition was evident in the liver in another experiment (172). Thyrotropic agents were in fact the subject of the recent IARC Monograph (173).
D: Modulators Causing Mineral Corticosteroid Imbalance
Glycyrrhizic Acid (from liquorice)
Data on the effects of glycyrrhizic acid in vivo are relatively limited, although this agent has been used to treat chronic viral hepatitis in Japan for many years, long-term exposure to which was aimed at preventing liver cirrhosis and hepatocellular carcinoma development (174). A review of the effects of liquorice on cancer (175) pointed to its anti-inflammatory, antivirus, antiulcer and anticarcinogenesis effects and to the need for further research into its potential chemopreventive applications. Glycyrrhizic acid is in fact an inhibitor of lipoxygenase and cyclooxygenase, inhibits protein kinase C and downregulates the epidermal growth factor receptor. Inhibition of N-acetyltransferase activity and DNA–2-aminofluorene adducts by glycyrrhizic acid in human colon tumor cells has also been reported (176). In mouse, chronic oral feeding of glycyrrhizin in drinking water reduced skin tumor-initiating activity of DMBA and also the binding of topically applied [3H]benzo[a]pyrene and [3H]DMBA to epidermal DNA (177). Furthermore, concomitant intramuscular administration of glycyrrhizin inhibited diethylnitrosamine induction of HCCs in BALB/c mice, with the possible involvement of modulation of cell proliferation and apoptosis as underlying mechanisms (178). Furthermore, a long-term tumorigenicity study in B6C3F1 mice did not yield any evidence of chronic toxicity or carcinogenic potential (179).
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONCLASSES OF ENDOCRINE MODULATORSCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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It is evident from the above that the class of endocrine disruptor compounds in fact comprises many different types, with differing mechanisms of action. Whereas those which cause toxicity, generally in the liver, can be unequivocally classified as carcinogens, this is not the case for any of the other classes. Indeed most of the compounds which can interfere with estrogen actions exert beneficial effects, at least with regard to neoplasia. The relative dearth of in vivo studies, in clear contrast to the abundant data from in vitro studies, suggests that a change in research strategies might be warranted if the real impact of endocrine disruptors in the environment on human disease is to be accurately defined.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONCLASSES OF ENDOCRINE MODULATORSCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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This study was supported by a Grant-in Aid for the Second Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare, a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, a Grant-in-Aid for Scientific Research (KAKENHI) on Priority Areas from the Ministry of Education, Science, Sports and Culture of Japan and a Grant-in Aid for the Long-range Research Initiative from the Japan Chemical Industry Association (CC05-01). During the drafting of this paper, Malcolm A. Moore and Chuel Kyu Kim were the recipients of Foreign Research Fellowships and Katsumi Fukamachi of a Research Residency from the Foundation for Promotion of Cancer Research Program for Invitation of Foreign Researchers.
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FOOTNOTES |
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+ For reprints and all correspondence: Hiroyuki Tsuda, Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: htsuda{at}gan2.ncc.go.jp
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Received February 25, 2003; accepted April 19, 2003
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