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PCBs and Liver Cancer in Humans This is not a complete list of all liver cancer research involving PCBs.  For more, visit the TOXNET database operated by the National Library of Medicine (the source of these abstracts).  Keep in mind that not all liver cancer studies are equal in quality or size.  Some have been published in peer-reviewed journals, while others were simply presented at conferences or other less formal venues.  Some studies may involve only some of the 209 kinds of PCBs.   In addition, this list includes only human liver cancer studies.  It does not include many dozens of controlled animal studies which together prove that PCBs cause liver cancer in animals.   Study #1 liver cancer research found a statistically significant excess in deaths from liver cancer (primary and unspecified), gall bladder and biliary tract most excess deaths occurred in women A retrospective cohort mortality study of 2,588 workers exposed to polychlorinated biphenyls (PCBs) in two plants manufacturing electrical capacitors was reported in 1981. The study was conducted primarily to examine the risk of cancer mortality associated with exposure to PCBs. Based on animal data, liver cancer was the disease of most interest. Due to the small number of deaths and a relatively short observation period, the study was considered inconclusive. This study has been updated by adding 7 yr of observation. The number of deaths in the study cohort has increased from 163 to 295. Mortality from all causes was found to be lower than expected (295 observed vs. 318 expected deaths) as well as mortality from all cancers (62 observed vs. 80 expected deaths). A statistically significant excess in deaths was observed in the disease category that includes cancer of the liver (primary and unspecified), gall bladder, and biliary tract (5 observed vs. 1.9 expected; p less than .05). Most of this excess was observed in women employed in one plant. Due to the small number of deaths and the variability of specific cause of death within this category, it remains difficult to interpret these findings in regard to PCB exposure. (Brown, 1987) Study #2 within 4 years, 12 of 2061 PCB poisoned Taiwanese died fromhepatoma (liver cancer), liver cirrhosis or liver diseases with hepatomegaly --- half of all deaths An outbreak of polychlorinated biphenyl (PCB) poisoning from the consumption of contaminated rice oil, covering four counties in central Taiwan, was investigated. There were 1843 cases by the end of 1980. The highest frequency of incidence occurred during the period from March to July 1979. The severity of clinical manifestations varied. Most patients showed symptoms of mild or moderate severity. The major age group affected was between 11 and 20 years old. Most of the victims were students and factory workers. The amount of PCB intake in each victim was estimated to be 0.7 to 1.84 g and the latent period from the time of intake to the onset of clinical manifestations was approximately 3 to 4 months. The patients' blood PCB concentrations ranged from 3 ppb to 1156 ppb; 44.27% of 613 patients had levels of 51 to 100 ppb and 27.6% PCB blood levels over 100 ppb. In the course of 3.5 years, 2061 persons were determined to be PCB poisoning victims. Now, except for a few severe cases, their skin symptoms are very much improved. Thirty-nine babies showing hyperpigmentation were born from PCB-poisoned mothers. The fatality rate was high: eight of them died. Another 24 deaths were reported among the PCB-poisoned group, almost half of them (12) from hepatoma, liver cirrhosis or liver diseases with hepatomegaly. (Hsu et al, 1985) Study #3 2 of 12 autopsied Japanese PCB victims showed liver cancer Autopsy findings of 12 patients with yusho including 2 stillborn babies are reported. Characteristic pathological changes were acne-like eruptions and cutaneous pigmentation with histological features of follicular hyperkeratosis, dilated hair follicles, and an increase of melanin pigment of the epidermis. In addition to the skin lesions, multiplication of the duct epithelium of the esophageal gland was found in 6 patients. Unusual multiple small foci of myocardial necrosis and fibrosis with basophilic myofibrillar degeneration were found in one patient, suggesting a relation to PCB exposure. Five cases with carcinomas (two involving the liver, two the lung, and one the esophagus) were also found, but their causal relationship with PCB was not certain. Nine cases showed the characteristic gas chromatographic pattern of yusho, but two cases had the same one as that of healthy controls. (Kikuchi, 1984) Study #4 2 cases of liver and bile duct cancer Mortality and cancer incidence were investigated among 242 male capacitor manufacturing workers, exposed to polychlorinated biphenyls (PCBs) for at least six months between 1965 and 1978. Mortality and cancer incidence were followed from 1965 to 1991. There was a significantly increased mortality from cardiovascular diseases among those employed for at least five years in high-exposed jobs, with a latency of 20 years. There were two cases of cancer of the liver and bile ducts, which previously has been associated with PCB exposure, both in epidemiological and animal experimental studies. No data on smoking habits were available. The study supports some previous findings of an increased risk of cancer of the liver and bile ducts after exposure to PCBs. The reason for the excess of cardiovascular deaths in the high-exposure group is not known and deserves evaluation in future studies. (Gustavsson et al, 1997) Study #5 overall cancer mortality was greater than expected in male Japanese PCB poisoning victims liver cancer risk was consistently high in both men and women during the entire 16-year observation period.  even after a 9-year latent period, the risk of liver cancer in males was significant close structural similarity of furans to dioxins especially 2,3,7,8-T4CDD which is a proven animal carcinogen, raises concern as to the potential carcinogenicity of furans nonneoplastic hepatotoxic effects (primarily fatty metamorphosis and necrosis) were concentration-related PCBs as the components of the furans may also have been responsible for the statistically significant liver cancers  In the atmosphere, dibenzofuran has the potential to undergo direct photolysis, which is due to UV absorption >290 nm, and it may react with photochemically generated hydroxyl radicals (estimated vapor phase ty2 is ? hours). (U.S. EPA, 1982, 1986a). Since part of the dibenzofuran emitted to the atmosphere may exist in the particulate form, this part may, as a constituent of coke dust, grate ash, fly ash, flame soots, etc., transport over long distances because the particulate sorbed compound is less likely to undergo chemical reaction than the compound in the vapor state (U.S. EPA, 1982; Ligocki et al., 1985). In water and soil systems, microbial degradation appears to be the dominant degradation mechanism of polynuclear aromatic compounds (Sims and Overcash, 1983). In aqueous systems, dibenzofuran should bioaccumulate moderately in aquatic organism and adsorb to suspended solids and sediments (Lu et al., 1978, U.S. EPA, 1982; Bjoerseth et al., 1979). In the sorbed state the compound is likely to be persistent (Bjoerseth et al., 1979). Estimated Koc values ranging from 1230-9940 indicate that dibenzofuran should strongly adsorb to soil; however, dibenzofuran has been detected in a shallow aquifer under a creosote facility (Bedient et al., 1984). Pertinent data regarding human exposure to dibenzofuran could not be located in the available literature. Animal. Close structural similarity of PCDFs to PCDDs, especially 2,3,7,8-T4CDD which is a proven animal carcinogen, raises concern as to the potential carcinogenicity of 2,3,7,8-T4CDF. However, no animal carcinogenicity bioassay data on PCDFs are currently available in the literature. The NCI (1979) conducted 2-year dibenzo-p-dioxin feeding studies using rats and mice. This compound is structurally similar to dibenzofuran. Rats and mice of both sexes received 0, 5000, or 10,000 ppm; survivors were sacrificed after 100-117 weeks (rats) or 91-97 weeks (mice) for histological analysis. Administration of the high concentration accelerated mortality rate in female rats due to treatment. Nonneoplastic hepatotoxic effects (primarily fatty metamorphosis and necrosis) were concentration-related in rats and female mice. There were also slight treatment- related increases in renal lesions, including renal tubular dilutations (female rats) and interstitial inflammation (female mice). The U.S. EPA (1986c) noted that the biological activity of various chlorinated dibenzofurans varies greatly, so that risk assessment by analogy to any of these more widely studied compounds would not be recommended. Human. A? et al. (1984) recently completed a 16-year cohort mortality study of 1086 Yusho victims in Japan. The 581 males and 505 females sustained a total of 70 deaths (42 males vs. 45.81 expected and 28 females vs. 31.3 expected). These data are based upon Japanese national death rates over age 40 through October 31, 1983. In this population, for persons over 40 years of age overall cancer mortality was greater than expected in men but no difference in women. In male Yusho victims 19 cancer deaths occurred vs. 11.50 expected and in female Yusho victims 7 cancer deaths occurred vs. 7.20 expected. However, by organ site, the risk of liver cancer was consistently found to be high in both men and women during the entire 16-year observation period. Even after a 9-year latent period, the risk of liver cancer in males was significant (observed = 5, expected = 0.75, p<0.01). As a result of an in-depth review of this study, it has been suggested by CAG (U.S. EPA, 1986c) that a case could be made that PCBs as the components of the PCDFs that caused the Yusho incident in Japan may also have been responsible for the statistically significant liver cancers seen in these victims. Dibenzofuran should be classified as an EPA Group D (U.S. EPA, 1986b) or an IARC Group 3 chemical. These categories are for compounds in which evidence of animal carcinogenicity is inadequate or limited and there are no human data. Pertinent guidelines and standards, including EPA ambient air quality criteria, drinking water standards, EPA or FAO/WHO ADIs (currently RfDs), EPA or FDA tolerances for new agricultural commodities or foods, SNARLs, HAs, DWELs, and ACGIH, NIOSH or OSHA occupational exposure limits could not be located in the available literature. The U.S. EPA (1975) determined an odor threshold of 120 ug/2 for dibenzofuran. The U.S. EPA (1982) recommended that this level be considered an ambient water criteria, based exclusively on organoleptic properties. (EPA Working Group, 1987) Study #6 study 1 ---five liver and biliary cancer deaths observed in workers, where 1.9 would have been expected (4 out of 5 were female).  study 2 --- among male workers, cancers of the gastrointestinal tract (including liver cancer) were significantly increased (6 observed, 2.2 expected).  study 3 --- almost five-fold significantly elevated risk of primary liver cancer in Yusho PCB victims (Japan) available studies suggest an association between cancer and exposure to PCBs. increased risk from hepatobiliary (liver or bile duct) cancer emerged consistently in different studies. Ultrasonic and tumour marker examination of two series of 79 and 125 patients with 'Yusho' disease in 1983 and 1984, respectively, did not reveal any case of hepatic-cell carcinoma Because the numbers were small, dose-response relationships could not be evaluated, and the role of compounds other than PCBs could not be excluded, the evidence was considered to be limited A. Evidence for carcinogenicity to humans (limited) Information on the possible carcinogenic risk of human exposure to polychlorinated biphenyls (PCBs) comes from studies of occupational populations and of populations exposed to the compounds accidentally. PCB mixtures may be contaminated with polychlorinated dibenzofurans and polychlorinated dibenzodioxins (see, e.g, p. 350). A slight increase in the incidence of cancer, particularly melanoma of the skin, was reported in a small group of men exposed to Aroclor 1254, a mixture of PCBs. In a study of over 2500 US workers exposed to a similar mixture of PCBs during the manufacture of electrical capacitors, five deaths due to cancer of the liver and biliary passages were observed, where as 1.9 would have been expected. This increase was sustained mainly by female workers in one of the two plants in the study (four of the five deaths), and all five workers had first been employed before the early 1950s. Another study of workers in a capacitor plant was conducted in Italy. Exposure in the early years of production (until 1964) was to PCB mixtures containing 54% chlorine (mainly Aroclor 1254 and Pyralene 1476), which were later replaced by mixtures containing 42% chlorine (mainly Pyralene 3010 and 3011). Early results showed a significant excess of all cancers among male workers, which was due mainly to cancers of the digestive system and of the lymphatic and haematopoietic tissues. Among female workers, a slight increase in mortality from cancer of the lymphatic and haematopoietic tissues was reported. The study was later enlarged and extended to include 2100 workers and to cover the period 1946-1982. Both male and female workers exhibited significantly increased cancer mortality in comparison with rates for the local population (14 observed, 7.6 expected; and 12 and 5.3, respectively, for men and women). Among male workers, cancers of the gastrointestinal tract (two stomach, two pancreas, one liver and one biliary passages) taken together were significantly increased (6 observed, 2.2 expected). Female workers showed a significant increase in deaths from haematological neoplasms (4 observed, 1.1 expected). In Sweden, among 142 male workers employed between 1965 and 1978 in a capacitor manufacturing plant when PCB mixtures containing up to 42% chlorine had been used, no significant excess of cancer deaths was noted. Cancer incidence was also examined: the number of cases observed corresponded well to that expected. One individual in a subgroup with higher exposure developed two relatively rare tumours, both of which occurred ten years after the start of exposure: a slow-growing mesenchymal tumour (desmoid) and a malignant lymphoma. After contamination of cooking oil with a mixture of PCBs (Kanechlor 400) in Japan in 1968, a large population was intoxicated ('Yusho' disease). An early report on mortality from 1963-1983 showed a significantly increased risk of all cancers, and an almost five-fold significantly elevated risk of primary liver cancer. The edible rice oil had also been contaminated by polychlorinated quaterphenyls and polychlorinated dibenzofurans. Dose response relationships were not clarified. A further comprehensive study of 887 male 'Yusho' patients showed statistically significantly increased mortality from all malignancies (33 observed, 15.5 expected), from liver cancer (9 observed, 1.6 expected) and from lung cancer (8 observed, 2.5 expected). Use of local rather than national rates in calculating expected number of deaths decreased the observed:expected ratio for liver cancer from 5.6 to 3.9, which was still statistically significant. A closer look at the geographical distribution of liver cancer cases did not allow exclusion of factors other than PCB poisoning as a possible explanation for this finding. For the 874 female patients examined, none of the noted observed:expected ratios was significant. In a series of ten autopsies of 'Yusho' patients, two adenocarcinomas of the liver were found, with no indication of a direct association with exposure to PCBs. Ultrasonic and tumour marker examination of two series of 79 and 125 patients with 'Yusho' disease in 1983 and 1984, respectively, did not reveal any case of hepatic-cell carcinoma. Two studies of the PCB content of fat tissues and cancer occurrence were available. An association was suggested between PCB concentrations in subcutaneous abdominal adipose tissue and the occurrence of cancers of the stomach, colon, pancreas, ovaries and prostate. No indication emerged of a relationship between PCB content in extractable breast fat tissue and the occurrence of breast cancer. The available studies suggest an association between cancer and exposure to PCBs. The increased risk from hepatobiliary cancer emerged consistently in different studies. Since, however, the numbers were small, dose-response relationships could not be evaluated, and the role of compounds other than PCBs could not be excluded, the evidence was considered to be limited. B. Evidence for carcinogenicity to animals (sufficient) Certain PCBs (particularly with greater than 50% chlorination) produced benign and malignant liver neoplasms in mice and rats after their oral administration. Oral administration of Aroclor 1254 to rats yielded hepatocellular adenomas and carcinomas as well as intestinal metaplasia and a low, statistically nonsignificant incidence of stomach adenocarcinomas. PCBs were inadequately tested in mice for induction of skin tumours. In several studies, oral or intraperitoneal administration of PCBs enhanced the incidences of preneoplastic lesions and of neoplasms of the liver induced in rats by N-nitrosodiethylamine or 2-acetylaminofluorene. In one study, intragastric administration of PCBs to mice increased the incidence of lung tumours induced by intraperitoneal administration of N-nitrosodimethylamine. C. Other relevant data No data were available on the genetic and related effects of PCBs in humans. Dominant lethal effects were not induced in rats administered PCBs orally, but were produced in rats nursed by females that had received PCBs orally. PCBs did not induce chromosomal aberrations in bone-marrow cells or spermatagonia of rats treated in vivo; micronuclei were not induced in bone-marrow cells of mice in one study, while equivocal results were obtained in a second study in which the PCBs were administered in corn oil. They did not transform Syrian hamster embryo cells in vitro. PCBs induced DNA strand breaks and unscheduled DNA synthesis in rat hepatocytes in vitro. Neither chromosomal breakage nor aneuploidy was induced in Drosophila. PCB mixtures did not induce SOS repair and were not mutagenic to bacteria. 2,2',5,5'-Tetrachlorobiphenyl induced DNA strand breaks in mouse cells in vitro. 2,4,5,2',4',5'-Hexachlorobiphenyl but not 3,4,5,3',4',5'-hexachlorobiphenyl inhibited intercellular communication in Chinese hamster V79 cells. Purified 2,4,2',4'-, 2,5,2',5'- and 3,4,3',4'-tetrachloro- and 2,4,6,2',4',6'-hexachlorobiphenyl were not mutagenic to bacteria. (IARC, 1987) Study #7 patient mortality due to malignant neoplasms suggested an excess of cancer induced deaths. both PCBs and furans are well known toxic agents to the liver with severe necrosis expected and the risk of cancer possible. liver function tests failed to reveal any serious liver lesions in the patients systemic dysfunctions included liver enzyme induction and abnormal lipid metabolism At a polychlorinated-biphenyl (1336363) (PCB) conference, some of the recent findings concerning Yusho, the rice oil disease, were discussed. Analysis of Yusho, first detected in 1968, has been limited and has produced varying results. Yusho oil has been determined to contain a high level of polychlorinated-dibenzofurans (PCDFs). The PCDF levels were especially high when the oil was contaminated with PCB as a heat transfer medium. Although PCB levels in adipose tissue in earlier cases were quite high, recent decedents did not exhibit the same characteristic. Blood PCB levels in recently afflicted patients also approach the normal range, a finding contrary to earlier studies. One of the most dominant objective signs in the incipient stage of Yusho was the markedly increased serum triglyceride concentration. Both PCB and PCDF are well known toxic agents to the liver with severe necrosis expected and the risk of cancer possible. However, liver function tests failed to reveal any serious liver lesions in the patients. Children born to mothers with Yusho were also afflicted prenatally, via the placenta, and postnatally, through breast milk. Patient mortality due to malignant neoplasms suggested an excess of cancer induced deaths. Systemic dysfunctions noted were retarded growth, neuroendocrine disturbances, phenomenon of enzyme induction, respiratory ailments, and abnormal lipid metabolism. Acneform eruption and pigmentation, as cutaneomucosal lesions, and ocular symptoms were identified as outstanding local symptoms. (Kuratsune et al, 1976) Study #8 increased incidence of cancer of the liver and of the biliary tract toxicity is probably mediated through interaction with the Ah receptor, and they are potent inducers of certain cytochrome enzymes typical toxic effects of PCBs, such as tumour promotion, are caused by PCB congeners in all of these three classes PCB congeners are metabolized to yield hydroxy- and methyl sulphone metabolites epidemiological studies of occupationally-exposed workers have indicated an increased incidence of cancer of the liver and of the biliary tract Introduction: The risk assessment from exposure to PCBs presents problems which are more complicated than are usually encountered when dealing with a group of compounds. Indeed, it is certainly much more complicated than the earlier risk assessment of dioxins (Ahlborg el al. 1988). The PCBs constitute a series of 209 individual congeners, varying in the number and sites of chlorine substitution. The biological effects caused by the various congeners differ, not only in potency but also qualitatively. Our knowledge of the mechanisms of toxicity indicates that some of the PCB congeners act by the same mechanisms as the chlorinated dioxins, i.e. the toxicity is probably mediated through interaction with the Ah receptor, and they are potent inducers of certain cytochrome enzymes. Other PCB congeners presumably act by different mechanisms and are potent inducers of a different set of cytochromes. In addition, there are PCB congeners which are intermediate in this respect, i.e. they elicit a mixed spectrum of enzyme induction. Some typical toxic effects of PCBs, such as tumour promotion, are caused by PCB congeners in all of these three classes, but the underlying mechanisms involved are probably different. Our knowledge of possible interactions between the various groups of PCBs is still very limited. Almost all animal studies with PCB mixtures have been performed using commercially-available PCBs. Due to differences between individual congeners, with regards to resistance to degradation and metabolism, the composition of a commercial mixture is different from the composition of the mixtures which humans will be exposed to, especially from food. A further complication in the risk assessment is the fact that many PCB congeners are metabolized to yield hydroxy- and methyl sulphone metabolites. The available data on the possible biological and toxicological effects of these metabolites are, however, very limited and preclude consideration of these metabolites in the present risk assessment. The risk assessment of PCBs has been approached in two different ways. Assessing the risk from the exposure to mixtures of PCBs utilizing data from human studies and experimental animal studies. The various end-points which can be used for such an assessment are immunotoxicity in animals, cancer in humans and animals, and developmental/behavioural effects in humans and animals. Assessing the risk from exposure to individual PCB congeners. In this ease, only data from animal studies are at present available for evaluation. Furthermore, the present data-base will only allow for this exercise to be performed on congeners acting through the same mechanisms as the chlorinated dioxins. Mixtures of PCBs: The critical endpoints for risk assessment of PCBs arc identified as cancer, immunotoxic and behavioural effects. Cancer: Positive, long-term bioassays in the rat have all been performed with one dose level, 100 ppm, of either of two commercial mixtures (Aroclor 1260 or Clophen A60), roughly corresponding to 5 mg/kg b.w. and day. An increased frequency of liver tumours is reported in several strains. Due to the lack of dose-response data from animal bioassays, it is presently impossible to perform any quantitative risk evaluation, including the establishment of a no observed adverse effect level (NOAEL). Discrepancies between the commercial mixtures and environmental exposures, with regards to congener composition, also imply that the predictive value of these studies is limited with respect to judgement of the risks from environmental exposure. However, intake estimates for humans indicate that non-occupational exposure in men is several orders of magnitude lower than the tested carcinogenic dose of the commercial mixtures. A few epidemiological studies of occupationally-exposed workers have indicated an increased incidence of cancer of the liver and of the biliary tract. However, in all of these studies the exposure occurred to commercial PCB mixtures, the compositions of which clearly differ [note: are probably less carcinogenic than,] from those of PCBs in food. In addition, the PCB mixtures were contaminated to various extents with other chlorinated compounds, especially polychlorinated dibenzofurans (PCDFs), which might have contributed to the observed effects. Taken together with the lack of good exposure measurements, it is not possible to use these qualitative data for the present risk assessment. Immunotoxicity: Long-term, low-level exposure to one commercial mixture (Aroclor 1254) has been shown to produce moderate, but statistically significant, effects on certain immunological parameters in Rhesus monkeys. The significance to health of these findings is difficult to evaluate since it is not known how they are related to functional impairment of the immune system. Behavioural effects: Hyperactivity and impaired learning ability have been reported for Rhesus monkey infants exposed to Aroclors 1248 and 1016 in utero and during lactation. The congener patterns of these mixtures are quite different from those seen in most biological samples, including fish and human milk. It is thus difficult to utilize the data on these monkeys directly for the present risk assessment. However, supportive data are available from studies in rats, mice and quails. Behavioural effects similar to those seen in monkeys have also been reported for human infants whose mothers were exposed to PCBs through the intake of contaminated fish in Michigan, U.S.A. The effects recorded in infants were slight, but should still be regarded as adverse. However, the study is not fully conclusive from an epidemiological point of view. Thus, a causal relationship between PCB and the effects is not proven due to some potentially important confounding factors. On the other hand, a causal relationship is definitely possible. Furthermore, supportive evidence comes from a similar study performed in North Carolina, U.S.A. Although there are great uncertainties involved, a lowest observed effect level (LOEL) for slight neurotoxic effects in infants from exposed mothers can be calculated to be in the range 0.014 - 0.9 ug/kg b.w./day. This can be compared with an estimated intake in Nordic countries of around 0.2 ,ug/kg b.w./day. People with a higher than average fish intake may have considerably higher intake of PCB. Dioxin-like PCB congeners: Several non- and mono-ortho-substituted PCB congeners induces effects similar to those caused by chlorinated dioxins and dibenzofurans. In common with that established for chlorinated dioxins and dibenzofurans, the toxicity of such PCB congeners can be expressed in terms of TCDD-equivalency factors (TEFs), i.e. expressed as a fraction of the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For the calculations performed in this document, data mainly from in vivo studies have been utilized. However, it should be noted that the derived TEFs are still based on acute effects at relatively high doses. Applying such TEFs to samples of fish and human milk demonstrates that the contribution from PCBs to large total dioxin-like toxicity is very important. Thus, in fish the contribution from PCBs is at the same level as that from dioxins and dibenzofurans although, so far, only non-ortho congeners have been analyzed. In human milk, the total contribution from non-ortho and mono-ortho substituted congeners is higher than that from dioxins and dibenzofurans. However, not all of the mono-ortho-substituted PCB congeners have yet been an (incomplete abstract) (Ahlborg et al, 1992) Study #9 it appears that any level of PCB exposure may be injurious to human health. the most consistent tissue modification has been a marked hypertrophy of the liver. tumors in patients who inadvertently consumed PCBs in 1968 included one or more occurrences of liver cancer The general toxic effects and the carcinogenic potential of the polychlorinated biphenyls (1336363) (PCBs) were reviewed. Low level exposure of primates to PCBs has caused widespread deleterious effects that persist indefinitely. General effects of the PCBs in man and in nonhuman primate experimental animals were discussed. In man, the effects have included fatigue, headaches, digestive disorders, menstrual disturbances, and hyperpigmentation in infants born to mothers exposed to PCBs. In experimental animals, the most consistent tissue modification has been a marked hypertrophy of the liver. Biochemical implications of the PCBs as possible carcinogens were discussed in terms of several metabolites and their association with cellular macromolecules. Morphological changes and tumor development associated with chronic feeding of PCBs to rodents and monkeys were described, including neoplastic liver nodules, liver adenofibrosis, hepatocellular carcinomas, and hyperplastic and metaplastic alterations of the stomach. Preliminary observations on the association of PCBs and tumor development in man were reviewed. Tumors in patients who inadvertently consumed PCBs in 1968 have included one or more occurrences of stomach, liver, lung, and breast cancers, malignant melanomas, and a malignant lymphoma. The author concludes that although there is only suggestive evidence that persons exposed to PCBs have a higher incidence of cancer, the data that have been obtained in lower animals warrant concern in man, and that until a better understanding of the potential danger of low level, long term exposure is established, it appears that any level of exposure may be injurious to human health. (Allen et al, 1977) Study #10 human mortality studies provide strong evidence that PCBs produce cancer of the liver, biliary tract, and gallbladder induction of liver enzymes have been consistently observed in humans Occupational exposure to polychlorinated-biphenyls (1336363) (PCBs) and the carcinogenic potential of PCBs were reviewed. Studies in laboratory animals were reviewed. These have shown that chronic exposure to PCBs containing 40 to 60 percent chlorine induces precancerous lesions in the liver such as neoplastic nodules or altered foci in mice and rats. The incidence of the lesions was strongly correlated with the degree of chlorination. Long term exposure to aroclor-1260 (11096825) and Kanechlor-500 (61788338) produced a high incidence of hepatocellular carcinomas in rats and mice, respectively. PCBs also produced lymphomas and leukemias. PCBs have shown promotional ability in rats and mice. Human morbidity studies have shown that human exposure to PCBs commonly results in skin abnormalities such as acneform eruptions and folliculitis. Induction of liver enzymes and elevation of serum triglycerides and cholesterol concentrations have been consistently observed. Human mortality studies have provided strong evidence that PCBs produce cancer of the liver, biliary tract, and gallbladder and suggestive evidence that PCBs increase the risk of cancer of the lymphatic and hematopoietic systems. A discussion of PCB use and sources of occupational exposure in Ontario was included as an appendix. (Industrial Disease Standards Panel, 1987) Study #11 No conclusive evidence of human liver cancer resulting from occupational exposure to PCBs has been obtained. [An occupational PCB liver cancer study was published the same year by Brown, see above.] PCBs impaired liver function in humans Human health effects of polychlorinated-biphenyls (1336363) (PCBs) and polybrominated-biphenyls (59536651) (PBBs) were reviewed. Studies have indicated that PCBs are ubiquitous and very persistent in the environment, resulting in widespread human exposure. Most human PCB exposure in the United States resulted from eating fish from contaminated waters. PBBs do not occur in the environment to any significant extent because they have less commercial use than PCBs. PBBs and PCBs accumulate preferentially in adipose tissue. In laboratory animal studies, PCBs generally affected reproduction, exerted immunotoxic effects, and induced liver tumors in rodents. Epidemiological studies showed that serum PCB concentrations were positively associated with serum triglyceride and cholesterol concentrations. Occupational exposure resulted in chloracne, pruritus, and eye, nose, and throat irritation. PCBs affect the liver by inducing the mixed function oxidase system. No conclusive evidence of human liver cancer resulting from occupational exposure to PCBs has been obtained. [This evidence was provided by an occupational PCB liver cancer study was published the same year by Brown, see above.] Poisoning incidents resulting from PCB contamination of rice-oil were described. The rice oil contained both PCBs and polychlorinated dibenzofurans (PCDFs) and caused chloracne, skin pigmentation, impaired liver function, and compromised immune system function. Widespread, low level exposure occurred to individuals living in the lower Michigan peninsula after a commercial PBB mixture was inadvertently mixed with cattle feed. Symptoms in exposed persons did not correlate well with PBB body burden. In laboratory animals, PBBs caused effects similar to those of PCBs. Teratogenicity, thymus atrophy, and hepatocellular carcinomas have been observed. The author concludes that acute poisoning outbreaks have occurred only after exposure to a combination of PCBs and PCDFs. Exposures to PCBs or PBBs alone have caused only minor acute effects. No significant chronic health effects have been causally associated with PCB or PBB exposure. (Kimbrough, 1987) Study #12 several occupational studies show cancer mortality rates for exposed workers were significantly elevated for cancers of the liver, biliary tract and gallbladder PCB exposure is rarely limited to a single congener, therefore, the review dealt with the effects of complex mixtures of PCBs, possibly containing dioxins and furans A review of human morbidity and mortality studies on the effects of polychlorinated biphenyls (PCBs), as well as experimental animal studies, was presented. Since PCB exposure was rarely limited to a single congener, the review dealt with the effects of complex mixtures of PCBs, possibly containing polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). Abnormal dermatological symptoms, such as chloracne, were considered clinical signs of occupational exposure to PCBs. Other commonly reported symptoms, including burning sensations in the eyes or skin and rashes, were concurrent with exposure while chloracne persisted for years. Findings of elevation of the liver enzymes gamma-glutamyltranspeptidase (GGTP) and serum glutamic-oxaloacetic transaminase (SGOT), and serum triglycerides and cholesterol levels were cited. The elevation of diastolic blood pressure with increased serum PCB levels in the general population was discussed. Studies of infants born to PCB exposed mothers showed lower birth weights, psychomotor development and poorer short term memory. Chronic animal studies using PCBs uncontaminated with PCDFs were described, demonstrating the production of precancerous lesions. The incidence of the lesions was directly related to the degree of PCB chlorination. Studies in rats and mice found hepatocellular carcinomas produced by exposure to Aroclor-1260 (11096825), Aroclor-1254 (11097691) and Kanechlor-500 (37317412). Significant increases in lymphomas and leukemias with PCB exposure were also reported. Based on the presented evidence, PCBs were considered animal carcinogens, acting as promoting agents. The ability of PCBs to alter the metabolism of other carcinogens was discussed. Several studies of human mortality following PCB exposure were discussed in which cancer mortality rates for exposed workers were significantly elevated for cancers of the liver, biliary tract and gallbladder, and for skin melanoma. (Nicholson et al, 1994) Study #13 for practical purposes, PCBs should be regarded as if they were carcinogenic to humans almost without exception, PCBs contain various levels of Furans as contaminants Five polychlorinated biphenyl mixtures have been tested in mice and/or rats only by oral administration. Kanechlor 500 and Aroclor 1254 are carcinogenic in mice, and Aroclor 1260 is carcinogenic in rats; all induced benign and malignant liver-cell tumours. In an experiment in rats of only one year's duration, Kanechlor 500, 400 and 300 induced liver lesions described as multiple hyperplastic nodules. Human exposure to small amounts of polychlorinated biphenyls is widespread as a result of environmental contamination and the high stability of these compounds. They are commonly found in human tissues. Unusually high levels of exposure to polychlorinated biphenyls have occurred among workers manufacturing or using them and in Japanese who consumed rice oil accidentally contaminated with Kanechlor 400. The latter showed acute and chronic toxic effects. An apparent excess of malignant melanoma has been reported in workers exposed to Aroclor 1254. No melanomas were reported in 9 persons who died from cancer among the 1200 Japanese heavily exposed to Kanechlor 400, but these deaths all occurred within 5 1/2 years of first exposure. Neither the workers exposed occupationally nor the Japanese were exposed solely to polychlorinated biphenyls. There is experimental evidence of a carcinogenic effect of some polychlorinated biphenyls in rodents. The epidemiological data provide suggestive evidence of a relationship between exposure to polychlorinated biphenyls and the development of malignant melanoma. Efforts should be made to obtain both confirmatory experimental and epidemiological evidence; in particular, continuing follow-up of survivors of the Yusho episode is necessary. In the meantime, for practical purposes, polychlorinated biphenyls should be regarded as if they were carcinogenic to humans.Almost without exception, polychlorinated biphenyls contain various levels of polychlorinated dibenzofurans as contaminants, and the polychlorinated biphenyls responsible for the Yusho episode in Japan were found to contain an unusually high level of polychlorinated dibenzofurans. It is not known if and to what extent polychlorinated dibenzofurans play a role in the observed carcinogenic effects of polychlorinated biphenyls. (IARC, 1978) Study #14 epidemiologic studies have suggested that exposure to PCBs can cause liver cancer PCBs are metabolized and excreted primarily through the liver and kidneys The toxicity of polychlorinated biphenyls (PCBs) was discussed. The uses of PCBs were summarized. The historical background leading to the discovery that PCBs were a serious environmental contaminant was outlined. Laboratory animal studies of PCB toxicity were reviewed. These have shown that PCBs induce the hepatic cytochrome-P-450 isozyme system and amino-N-demethylase, and aniline-hydroxylase activities. Prolonged dietary exposure to high doses of aroclor-1254 (11097691) and aroclor-1260 (11096825) have caused liver cancer in rodents. Industrial and environmental poisoning by PCBs was considered. Induction of chloracne by industrial and environmental PCB exposures was discussed. The Yusho poisoning incident was described. The use of serum PCB concentrations as markers of PCB exposure was considered. Alterations in immune function induced by PCB exposure were discussed. Studies of PCB metabolism in experimental animals were reviewed. These have shown that PCBs accumulate in the body fat and lipotropic organs such as the adrenals, brain, skin, and liver. Ingested PCBs are metabolized and excreted primarily through the hepatobiliary system and kidneys. The carcinogenic risk of PCBs for humans was discussed. Epidemiologic studies have suggested that exposure to PCBs can cause liver and colorectal cancer and possibly cancers at other sites. It was noted that although it is not possible to extrapolate the results of animal studies to human exposure, PCBs can be classified as category-I carcinogens. Treatment for PCB poisoning was discussed. (Lemesh, 1992) Study #15 Several epidemiologic studies of both occupational PCB exposure and accidental PCB intoxication suggest PCBs might be a potent carcinogen in the liver PCBs which induce the enzyme P-450 may promote tumors by inhibiting intercellular communication and/or by stimulating cell proliferation. Furans are attracted to cells in the liver and lungs. Furans induce necrosis (cell death) and epoxide formation to their target cells, which might result in carcinogenesis of liver and lungs. PCBs are compounds whose physical/chemical properties led to their wide spread commercial use. The persistence and stability of PCBs have resulted in a world wide distribution. PCDFs, ones of PCB derivatives, are primary causal agents of mass food poisoning, called Yusho in Japan and Yu-Cheng in Taiwan. Several epidemiologic studies on the carcinogenicity of PCBs in both occupational exposure and accidental intoxication suggest that PCBs might be a potent carcinogen in liver and lung. Many investigators reported that PCBs induced hepatocellular carcinoma in rat and mice. Although either mutagenic or genotoxic effects of PCBs are not definite, their tumor promoting effects have been repeatedly demonstrated in the liver. The effects of PCBs as tumor promoter in the lung have also been reported. PCB congeners that efficaciously promote carcinogenesis increase cytochrome P-450-dependent monooxygenases, which are abundant both in bronchiolar Clara cells and in hepatocytes. PCB congeners which are inducers of P-450 may be active as tumor promoter by inhibiting intercellular communication and/or by stimulating cell proliferation. Furan derivatives like PCDFs have high affinity to bronchiolar Clara cells and hepatocytes. PCDFs induce necrosis and epoxide formation to their target cells, which might result in carcinogenesis of liver and lung. (Nakanishi et al, 1991) Study #16 certain PCBs are evaluated by the World Health Organization, and classified with dioxins [which they have declared as known human carcinogens] In 1990, WHO recommended the TDI (Tolerable Daily Intake) of 10 pg/kg bw/day for dioxin. Since then, industrialized countries have set TDIs or exposure limits based on their own evaluation of the exposure levels and the toxicity of dioxin. In Japan, the MHW announced 10 pg TCDD/kg bw/day as the temporary TDI in 1996. WHO reevaluated the TDI in May 1998 and announced the TDI in the range of 1-4 pg TEQ/kg bw/day including coplanar PCBs, which will definitely have a big impact all over the world. Moreover, dioxins, as endocrine disrupting chemicals, are reviewed on their hazards on health and the mechanism of actions. (Article includes keyword: Hepatoma) (Kurokawa et al, 1998) Study #17 PCB contribution to cancer risk may only now start to appear, due to long human cancer latency and the nature of tumor promotion PCBs promote liver tumors by triggering the early appearance of tumors which have been initiated but would normally lay dormant and appear only in old age --- ie: cancers occur at younger ages Liver tumors required a "start-up" chemical before PCBs could promote the tumors, in this case nitrosames (a common byproduct of meat preservatives) were used Polychlorinated biphenyls (PCB), which are tumor promoters, have been found in human tissues for decades. Their contribution to cancer risk may only now start to appear, due to long human cancer latency and the nature of tumor promotion. Epidemiological associations have been seen between PCB exposure or tissue content and cancer at several sites. In rodents, tumor promotion by PCBs has been little studied in tissues other than liver. Previously, in an experiment modeling infant carcinogen exposure following PCBs received in milk, lung and liver tumors, initiated neonatally in mice by the environmental nitrosamine N-nitrosodimethylamine (NDMA), were promoted by later treatment with Aroclor 1254. The present study was undertaken to confirm and characterize the effects of Aroclor 1254 on tumor number, latency, size and malignancy. Male Swiss mice were given NDMA on postnatal day 4 and Aroclor 1254 (250 mg/kg) on day 8, and killed at intervals. Eight PCB congeners were quantified in the carcasses. Incidences of mice with NDMA-initiated lung tumors at 28 weeks of age were increased 2.5-fold by PCBs. Multiplicities of lung tumors were enhanced four-fold by PCBs at 28 and 52 weeks. By 72 weeks tumor numbers were similar in the NDMA-only and NDMA-PCB groups. Liver tumors first occurred in significant numbers at 52 weeks and only in mice receiving both NDMA and PCBs. As for the lung, at 72 weeks the incidence was high in both the NDMA-only and NDMA-PCB groups. Sizes of tumors and liver carcinoma incidence were not altered by PCB treatment. Carcass analysis revealed a significant positive association between lung tumor numbers at 28 weeks and relative percentage of 2,2',4,4',5-pentachlorobiphenyl, with no other correlations. The results confirm that PCBs promote lung as well as liver tumors, by triggering the early appearance of latent initiated tumors otherwise presenting in old age. (Anderson et al, 1994) Study #18 dioxin (TCDD) is known to cause hepatocellular carcinomas (liver cancers) (certain PCBs are dioxin-like) Studies involving polychlorinated biphenyls (PCBs) are reviewed. PCBs are a class of halogenated aromatic compounds, including halogenated biphenyls, naphthalenes, dibenzodioxides, and dibenzofurans. PCBs persist in the environment and are retained in tissue because they are lipid soluble. They affect reproduction, suppress the immune system, cause tumors in laboratory rodents, cause hepatic porphyria, and cause chick edema in chickens. Cell mediated immunity is impaired by PCB, although the degree of impairment is determined by the type of isomers present. PCBs are not teratogenic, but they are fetotoxic, producing cleft palates, subcutaneous edema, and hemorrhage. PCBs are passed to mammalian offspring in the milk. 2,3,7,8-Tetrachloro-dibenzo-p-dioxin (TCDD) is known to cause hepatocellular carcinomas and squamous carcinomas of the oropharynx and lungs. Subcutaneous sarcomas and tumors of the thyroid are also noted. The primary source of PCB exposure to the general United States population is fish from contaminated water. Serum cholesterol levels in humans are directly proportional to PCB levels. The concentration of PCB in human milk is particularly high. There is no clear evidence of harm to humans from PCB, but research is inconclusive. The author concludes that PCB may be a cancer promoter, but additional studies on exposed human cohorts, such as fishermen, must be done before any conclusions about the effects of PCB on humans can be reached. (Kimbrough, 1985) Study #19 PCBs are associated with hepatocellular carcinomas (liver cancers) in humans PCBs have tumor promoter effects The hazardous and toxicological aspects of polychlorinated biphenyls (PCBs) and other polyhalogenated hydrocarbons were reviewed. PCBs were manufactured in the United States under the trade name Aroclor from 1929 to 1977. Under the Toxic Substances Control Act, Congress banned further manufacture and limited distribution beyond 1979. Discussion of the absorption, metabolism and excretion of PCBs included the role of the cytochrome-P450 enzymes in the liver, lung, and small intestine of animals and humans, excretion products, serum levels in occupationally exposed persons, and the half lives of various isomers. Health effects in animals and humans including tumorigenicity (especially hepatocellular carcinomas), tumor promoter effects, chloracne, serum lipid alterations, reproductive effects in women, and epidemiologic studies were discussed. PCBs were not mutagenic. Polybrominated biphenyls (PBBs) are similar to PCBs, but have not been widespread environmental contaminants. Although various health effects including neurobehavioral alterations were reported, no human clinical illnesses were causally linked with PBB with certainty. The information available on the health effects and pharmacokinetics of chlorinated benzenes (CBs) was limited to isolated case reports. While some connection between CBs and liver and kidney carcinomas, and adrenal and parathyroid adenomas was evident in laboratory animals, no epidemiologic association with cancer was established for humans. The major known human health effect was the development of porphyria cutanea tarda. (Shields et al, 1992) Study #20 liver cancers in rats were used to extrapolate human cancer risks in 1984 Limited human data are available suggesting a relationship between PCB exposure and cancer. In vitro mutagenicity evaluations have been primarily negative. PCBs have been shown to be carcinogenic in rats and mice when administered orally. Using data for hepatocellular carcinoma and neoplastic nodules in female rats, a carcinogenic potency (q1*) of 4.34 (mg/kg/day)E-2 has been estimated for oral exposure of humans to PCBs. Data were inadequate to develop a quantitative estimate for the inhalation route. (EPA Working Group, 1984) Study #21 several studies have demonstrated the carcinogenic potential of PCB mixtures. Results of several animal bioassays have demonstrated the carcinogenic potential of polychlorinated biphenyl (PCB) mixtures. Although PCBs are no longer manufactured, cancer risk assessment for PCBs remains an important issue because of continued potential human exposure from many sources. The existing cancer risk estimate for PCBs used by the U.S. EPA is based on liver tumors observed in female Sprague-Dawley rats in a lifetime bioassay. Liver cancer has been observed in other long-term bioassays as well. In this case study, experimental designs and biological characteristics of the data from these studies were evaluated to determine whether a combination of the data sets is scientifically reasonable. A statistical analysis of the data sets based on likelihood ratio theory was used to assess the compatibility of individual data sets to a common multistage dose-response model. The results from these biological and statistical assessments suggest that at least two data sets could be combined to derive a quantitative risk estimate for PCBs. Increased confidence in the quantitative estimate would result from such combination because more data are being used to assess the dose-response relationship. (Vater et al, 1995) Study #22 PCBs ingested with food may play a role in inducing primary cancer of the liver subliminal quantities of potential hepatocarcinogens may play a synergistic role with high fat diets simultaneous smoking and alcohol intake may have a co-carcinogenic role Among the many substances ingested with food which may play a role in inducing primary cancer of the liver are PCBs and organochlorine pesticides (including DDT, aldrin, dieldrin, heptachlor and chlordane). DDT repeatedly administered po was found to produce liver cancer in mice and rats after 2.5 yr. DDTs true carcinogenic effect on humans may be underrated since the effects of its long persistence in the environment remains to be assessed. Residues of the herbicides amitrole and di-allate present in treated crops were found to be hepatocarcinogenic for mice and rats following po and sc administration. Subliminal quantities of potential hepatocarcinogens may play a synergistic role with high fat diets; in the genesis of intestinal, prostate, orophageal and esophageal cancers. (Darnis et al, 1980) Study #23 PCB damage may not be contingent on binding to the aromatic halogenated hydrocarbon (AHH) receptor non-coplaner PCB congeners are not necessarily wholly responsible for the liver carcinogen properties of PCBs Human teratocarcinoma cells in culture were used to study the ability of various chemicals to inhibit cell to cell communication. The chemicals studied included Firemaster-BP-6 (59536651) (FM), a mixture of polybrominated-biphenyls (PBB), and the congeners 2,2',4,4',5,5'-hexabromobiphenyl (67774327) (245-HBB), 3,3',4,4',5,5'-hexabromobiphenyl (345-HBB), and 3,3',4,4'-tetrabromobiphenyl (34-TBB). Cell to cell communication was inhibited by FM and 245-HBB with little effect on cell survival. A high degree of cytotoxicity was noted with 345-HBB but no interruption of cell to cell communication was noted. Moderate cytotoxicity was evident with 34-TBB, but no cell to cell communication was blocked. It is suggested that adverse consequences can result from exposure to some polyhalogenated biphenyls which are not contingent upon their binding to the aromatic halogenated hydrocarbon receptor. Thus, noncoplaner congeners are not necessarily wholly responsible for the hepatocarcinogenic properties of polychlorinated-biphenyl and PBB mixtures. The authors further suggest that perhaps a metabolite of 34-TBB might be active in inhibiting metabolic cooperation. The lower toxicity of 34-TBB relative to that of 345-HBB indicates to the authors that some metabolism of this congener does occur in these cells. (Kavanagh et al, 1987) Study #24 certain PCBs have toxicities in human tissues comparable to dioxin genetic susceptibilities in humans may be similar to those reported among mouse strains Aryl hydrocarbon hydroxylase (AHH)-inducing potency of eight polychlorinated dibenzofuran (PCDF) isomers, 3,4,5,3',4',5'-hexachlorobiphenyl (HCB) and 2,3,7,8-tetrachlorodibenzo-p-dioxon (TCDD) in two inbred mouse strains (AHH responsive and nonresponsive mouse strains) and eight human lymphoblastoid cell lines (four males and four females) was investigated to evaluate their relative toxic potency. In AHH nonresponsive DBA mouse strain, only TCDD induced hepatic AHH activity at a dose of 30 micrograms/kg, while in AHH responsive C57 mouse strain, six PCDF isomers besides TCDD could enhance the enzyme activity significantly. 2,3,7,8-Tetrachlorodibenzofuran (2,3,7,8-TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1,2,3,7,8-PCDF) and 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PCDF) showed the highest AHH inducing activity among the PCDF isomers tested. In contrast with the results obtained from the mouse experiments, in human lymphoblastoid cells, 2,3,4,7,8-PCDF, 1,2,3,4,6,7-hexachlorodibenzofuran (1,2,3,4,6,7-HCDF) and 1,2,3,7,8-hexachlorodibenzofuran (1,2,3,4,7,8-HCDF) elicited the highest AHH induction and were as potent AHH inducers as TCDD. These observations suggest that toxicities of 2,3,4,7,8-PCDF, 1,2,3,4,6,7-HCDF and 1,2,3,4,7,8-HCDF in human tissues may be comparable to that of TCDD. It was also observed that in both male and female human cell lines, the degree of AHH inducibilities of these compounds were roughly parallel to that of 3-methylcholanthrene, possibly indicating that genetic susceptibility among human population to the toxic compounds are also present similar to those reported among mouse strains. (Nagayama et al, 1985) Study #25 review article Polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) are compounds whose physical/chemical properties led to their widespread commercial use. Although their production has been banned or severely limited in most countries since the 1970s, the persistence and stability of these compounds have resulted in a worldwide distribution, especially of PCBs. PBB contamination is limited principally to the state of Michigan, where a series of tragic errors eventually resulted in the accumulation of residues in livestock and the general human population. Long-term exposure to PCBs and PBBs in animals has been associated with the induction of neoplastic nodules in the liver and in some cases hepatocellular carcinoma. This review discusses the role of PCBs and PBBs in the process of carcinogenesis. The mutagenicity/genotoxicity of these compounds, as well as their initiation/promotion potential is discussed. The epidemiology of PCB and PBB exposure is reported along with an estimation of the risk of cancer to humans. Finally, possible molecular mechanisms of action are suggested for polyhalogenated biphenyls in cancer development. (Silberhorn et al, 1990) Study #26 certain genetic characteristics in fish are very similar to human genes, and may mark a susceptibility for liver cancer when exposed to PCBs Ras gene activation in a naturally exposed feral fish population may prove to be a particularly sensitive genetic marker of malignancy. The aim of this study was to relate our current knowledge of polychlorinated biphenyl (PCB) bioactivation and polycyclic aromatic hydrocarbon (PAH)-induced DNA damage to ras gene activation in liver tumors from dragonets exposed to these environmental carcinogens. We identified a member of the ras gene family in the marine fish dragonet (Callionymus lyra). The first two exons of this new sequence showed a very high degree of homology with the human ras genes (81-86%) at the nucleic acid level and perfect homology at the amino-acid level. In a pilot study, we collected dragonets from the Seine estuary, an area highly contaminated with PAHs and PCBs. An increase in DNA adducts and an accumulation of ortho- and non-ortho-substituted chlorobiphenyls (CB-77, CB-126, and CB-169) were observed in the livers, a finding that correlates well with the levels of PAHs and PCBs in the sediment. Although liver neoplasia was uncommon, a codon 11 mutation was found in two fish with liver cell hyperplasia, suggesting a possible correlation between hepatic precancerous lesions and ras gene activation in dragonets. (Vincent et al, 1998) Study #27 certain PCBs have an estrogenic (hormonal) effect on human liver cancer cells [which may stimulate tumor growth] together, several types of PCBs have additive estrogenic effects The estrogenic activity of 2',4',6'-trichloro-4-biphenylol (HO-PCB3), 2',3',4',5'-tetrachloro-4-biphenylol (HO-PCB4), and an equimolar mixture of both compounds (HO-PCB3/HO-PCB4) was investigated in the 21-day-old B6C3F1 mouse uterus, MCF-7 and MDA-MB-231 human breast cancer cells, HepG2 cells, and in a yeast-based reporter gene assay. Treatment of the animals with 17beta-estradiol (E2) (0.02 microg/kg/day x3) resulted in increased uterine wet weight, peroxidase activity and progesterone receptor binding. Treatment with 18, 73, 183 or 366 micromol/kg (x3) doses of HO-PCB3, HO-PCB4, or HO-PCB3/HO-PCB4 (equimolar) caused a dose-dependent increase in estrogenic activity; a maximal-induced response was not observed at any dose and the activity of the mixture was additive. Binding of E2, HO-PCB3, HO-PCB4, and HO-PCB3/HO-PCB4 to the mouse uterine estrogen receptor (ER) was determined in a competitive binding assay using [3H]E2 as the radioligand. The IC50 values were 1.1 x 10(-8), 3.4 x 10(-6), 9.9 x 10(-7), and 4.25 x 10(-6) m, respectively. HO-PCB3 and HO-PCB4 maximally induced MCF-7 cell proliferation, rat creatine kinase, and human complement C3 (C3-LUC) reporter gene activity at concentrations of 10(-5) to 10(-6) m, and these compounds were 10(3) to 10(4) less potent than E2. The HO-PCB3/HO-PCB4 mixture was active at the high concentration (10(-5) m) and was additive for these responses. HO-PCB3 and HO-PCB4 also exhibited estrogenic activity in human HepG2 cells cotransfected with C3-LUC and an ER expression plasmid, and the estrogenic activity of the HO-PCB mixture was additive. Similar results were obtained in yeast transformed with the human ER and a double estrogen responsive element upstream of the beta-gal reporter gene. The effects of variable ER expression on the potential synergistic interactions of HO-PCB3/HO-PCB4 were investigated in HepG2 cells cotransfected with C3-LUC (405 ng/well) and variable amounts of ER expression plasmid (270, 27, 2.7, or 0.27 ng/well). The results show that as ER levels decreased, the magnitude of the induction response by E2, HO-PCB3, HO-PCB4, and HO-PCB3/HO-PCB4 also decreased. However, the activities of the HO-PCB mixture were additive at high and low levels of ER. Similar results were obtained in MDA-MB-231 cells cotransfected with C3-LUC and variable amounts of ER expression plasmid. The results of this study demonstrate that for several estrogen-responsive assays in the mouse uterus; MCF-7, HepG2, and MDA-MBA-231 human cancer cells; and a yeast based-reporter gene assay, both HO-PCB3 and HO-PCB4 exhibited estrogenic activity. The estrogenic activity of an equimolar mixture of these compounds was additive at high and low levels of ER expression. (Ramamoorthy et al, 1997) Go to: Upcoming Research, Studies without Abstracts, Links and References   Back to top Back to Human Health Risks Back to Fox River Watch To Site Index