MDR1 gene overexpression and altered degree of methylation at the promoter region in bladder cancer during chemotherapeutic treatment.

Overexpression of the multidrug resistance 1 (MDR1) gene is closely associated with the clinical outcome of hematopoietic malignancies, but the alteration of its expression during chemotherapeutic treatment and the precise mechanism underlying MDR1 gene overexpression in solid tumors remains unclear. We determined the expression and degree of methylation at the promoter of the MDR1 gene in bladder cancer. The mRNA levels of the MDR1 gene were found to be markedly enhanced, 3.5- to 5.7-fold higher in bladder cancers after chemotherapeutic treatment than those in untreated primary tumors. The MDR1 gene was overexpressed in recurrent tumors in 89% of patients who showed rerecurrence, whereas overexpression was observed in 25% of the patients without re-recurrence. A statistically significant inverse correlation existed between MDR1 expression and the methylation of 5'CpG sites at the promoter in patients with bladder cancer after chemotherapeutic treatment, with the degree of methylation at several CpG sites, rather than other specific sites, involved in this regulation. Consistent with the increase in MDR1 expression, the frequency of patients with a hypermethylated promoter decreased to 50 and 17% after intravesical and systemic chemotherapy, respectively. Thus, overexpression of the MDR1 gene might be a prognostic marker for intravesical recurrence, whereas methylation of the promoter region negatively regulates MDR1 expression and the appearance of multidrug resistance mediated by P-glycoprotein in bladder cancers.

PCB and PCDF congeners in the blood and tissues of yusho and yu-cheng patients.

Polychlorinated biphenyl (PCB) poisonings occurred in western Japan, where it is called yusho, in 1968, and in central Taiwan, where it is called yu-cheng, in 1979. The average concentrations of PCBs in the adipose tissue, liver and blood of yusho patients and in the blood of yu-cheng patients were 1.9 ppm, 0.08 ppm, 6.7 ppb and 99 ppb, respectively. Seven PCB congeners, such as 2,4,5,3',4'-pentachloro-, 2,3,4,3',4'-pentachloro-, 2,4,5,2',4',5'-hexachloro-, 2,3,4,2',4',5'-hexachloro-, 2,3,4,5,3',4'-hexachloro-, 2,3,4,5,2',4',5'-heptachloro- and 2,3,4,5,2',3',4'-heptachloro biphenyls were identified in the blood and tissues of patients with yusho and yu-cheng and controls. The concentration of 2,3,4,5,3',4'-hexachlorobiphenyl was comparatively higher in the patients than in controls. The concentrations of polychlorinated dibenzofurans (PCDFs) in the adipose tissue and liver of yusho patients were 6 to 13 ppb and 3 to 25 ppb, respectively, while no PCDFs were detected in the controls. Major PCDF congeners identified in the tissues and blood of yusho and yu-cheng patients were the 2,3,6,8-tetrachloro-, 2,3,7,8-tetrachloro-, 1,2,4,7,8-pentachloro-, 2,3,4,7,8-pentachloro- and 1,2,3,4,7,8-hexachlorodibenzofurans (DFs), of which the 2,3,4,7,8-pentachloro compound was predominant. The concentrations of methylthio-PCB in the liver, lung and adipose tissue of yusho patients were 0.1 to 0.5, 0.2 to 1.4 and 0.5 to 1.0 ppb, respectively, and those of methysulfone PCBs were 0.3 to 0.7, 1.0 to 2.5 and 0.7 to 1.0 ppb, respectively. Some of the major peaks of the PCB methylthio and methylsulfone derivatives were identical in gas chromatographic retention times with those of 4-methylthio- and 4-methylsulfone-2,5,2',5'-tetrachlorobiphenyl PCDFs, especially 2,3,4,7,8-pentachloro DF, appear to be mainly responsible in the poisonings.

Inducing potency of aryl hydrocarbon hydroxylase activity in human lymphoblastoid cells and mice by polychlorinated dibenzofuran congeners.

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.

Bunyavirus infections in North Carolina white-tailed deer (Odocoileus virginianus).

We analyzed serum from white-tailed deer (Odocoileus virginianus) collected in southeastern North Carolina in 1991 for neutralizing antibodies to six mosquito-borne bunyaviruses (Lacrosse, Jamestown Canyon, Keystone,Cache Valley, Potosi, and Tensaw), including several of public health importance. Evidence was found for all six to be locally transmitted, although greatest seroprevalence was found for Potosi, Jamestown Canyon, and Cache Valley viruses.

Aryl hydrocarbon hydroxylase activity levels in the hepatic microsomal fraction from MC- or TCDD-treated mice: a comparison between aromatic hydrocarbon responsive and non-responsive strains.

The effects of in vivo administration of polycyclic aromatic hydrocarbons on the levels of aryl hydrocarbon hydroxylase (AHH) activity in aromatic hydrocarbon (Ah) responsive and non-responsive strains of mice were studied using the hepatic microsomal fraction. Injection of 3-methylcholanthrene (MC; 42 mg/kg body wt.) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 120 micrograms/kg body wt.) into both strains produced marked enhancement of AHH activity except for MC treatment of Ah non-responsive strains. Addition of 7,8-benzoflavone (BNF) to the microsomal AHH assay mixture prepared from mice previously injected with vehicle (olive oil) alone caused an increase in activity when the mice were responsive, while BNF lowered the activity in non-responsive strains. With regard to MC-injected mice, BNF and 3-methyl-sulphonyl-4,5,3',4'-tetrachlorobiphenyl (3-MSF-TCB) decreased microsomal AHH activity in Ah-responsive mice, whereas these drugs enhanced the activity in Ah-non-responsive strains. 3-MSF-TCB also had inhibitory potency on AHH activity, but the mechanism of inhibition seems to be somewhat different from that of BNF. It may also suggest that cytochrome P-450 isozymes inhibited by BNF are different from those inhibited by 3-MSF-TCB.

An improved method for the detection of differential survival between normal and xeroderma pigmentosum lymphoblastoid cell lines in culture with 4-nitroquinoline-1-oxide.

The effects of the UV-mimetic chemical 4-nitroquinoline-1-oxide (4-NQO) upon cell lines heterozygous or homozygous for the recessive mutant xeroderma pigmentosum (XP) were investigated. Human lymphoblastoid cell lines, which were established from 4 XP homozygote patients (XPL15, XPL17, XPL19 and XPL20). 2 XP heterozygote individuals (XPPL17 and XPML17) and 58 normal individuals, were cultured in the presence of 4-NQO at doses of 0, 2, 4 and 8 x 10(-6) M. Then the total cell number was counted and the viability of the cells was measured by the dye exclusion method using trypan blue and a newly devised fluorometric method with fluorescein diacetate. Results showed that 4-NQO affected, in increasing order of impairment, the cell lines: normal less than XP heterozygote less than XP homozygote.

Polychlorinated dibenzo-p-dioxins and related compounds in breast milk of Japanese primiparas and multiparas.

We analyzed polychlorinated dibenzo-p-dioxins and related compounds in the breast milk of primiparas and multiparas, and estimated the levels transferred to newborns by breast milk in Western Japan. 2,3,7,8-TeCDD equivalents (TEQ) of the chemicals in primiparas decreased slightly from 1994 to 1996. In particular, decreases of the TEQs of total PCDDs and total coplanar PCBs were higher than that of total PCDFs. In 2,3,7,8-TeCDD, 1,2,3,7,8-PeCDD, 1,2,3,6,7,8-HxCDD, 1,2,3,7,8,9-HxCDD, 2,3,4,7,8-PeCDF, 1,2,3,6,7,8-HxCDF, 3,3',4,4',5-PeCB and 3,3',4,4',5,5'-HxCB concentrations, those in the breast milk of multiparas were significantly lower than those in the breast milk of primiparas (p < 0.05, lipid basis). Based on the assumption that newborns ingest 120 g of breast milk per kg body weight per day, the amounts converted to TEQ values were 121 pg/kg/day (primiparas) and 97.2 pg/kg/day (multiparas).

Polychlorinated dibenzo-p-dioxins and related compounds: correlations of levels in human tissues and in blood.

We investigated PCDDs and related compounds levels in human tissue and blood obtained from the general population, and the correlation factor was calculated from the findings. None of the congeners in brain, muscle and lung were correlated except for 2,3,7,8-tetrachlorodibenzo-p-dioxin and octachlorodibenzo-p-dioxin in the brain (p < 0.05). In other tissues, all congeners had relatively good correlations to those in blood (r > 0.707). These congeners detected in blood were at high concentrations in the environment and human body. Therefore, we concluded that these congener levels in the blood might be useful for estimating these congener levels in human tissue.

Polychlorinated dibenzo-p-dioxins and related compounds: the blood levels of young Japanese women.

We investigated PCDDs and related compounds in the blood of young Japanese women, approximately 20 years of age, who had not yet had children, and discussed how the TEQ level of PCDDs and related compounds in their blood may affect the next generation. Means of total TEQ levels were 0.063 pg/g for whole blood basis and 21 pg/g for lipid basis. TEQ of PCDDs, PCDFs and coplanar PCBs accounted for about 43, 34 and 23% of the total TEQ in the whole blood basis, respectively. In the lipid basis, their values were about 44, 34 and 22%, respectively. Previously, we investigated PCDDs and related compounds levels in mother's breast milk, lymphocyte subpopulation and thyroid function of their children, and found negative correlations between the TEQ level of PCDDs and related compounds and CD4+/CD8+, and/or the TEQ level of PCDDs and related compounds and the T4 level in 36 mothers and children. Of these cases, the average age was approximately 28 years. PCDDs and related compounds may be related to immunopathy, such as atopic dermatitis. The effects of PCDDs and related compounds on babies of young Japanese women are important and must be further evaluated.

Effects of highly toxic organochlorine compounds retained in human body on induction of sister chromatid exchanges in cultured human lymphocytes.

In this study, we investigated the effect of mixture of the organochlorine compounds, which very resembled their contamination of healthy Japanese people in its composition, on the induction of sister chromatid exchanges (SCEs) in human whole-blood cultures in order to clarify their genotoxicity as a whole. The following results were obtained. Regardless of the presence or absence of 7,8-benzoflavone (ANF) in the blood culture system, we could observe a fairly good dose-response relationship between the concentration of the mixture of organochlorine compounds and the induction of SCEs/cell. In particular, we found that 50% effective concentration of the mixture of the organochlorine compounds was considered to be only about 3 times greater level over the average concentration in the healthy people, namely 70ppt as 2,3,7,8-TCDD, in the absence of ANF and about 8 times more than that in the presence of ANF.

Effects of contamination level of dioxins and related chemicals on thyroid hormone and immune response systems in patients with "Yusho".

Effects of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs) on thyroid hormone and immune response systems were examined in 16 Yusho patients at about 30 years after the outbreak of the Yusho accident. Their toxic equivalent (TEQ) levels in the blood were 27.8-1048.5 pg/g fat with the median level of 222.4 pg/g fat, which was about seven times higher than that of healthy Japanese people. Even at such high blood TEQ concentrations, they seemed not to affect the serum levels of thyroid hormones, thyroid stimulating hormone (TSH), immunoglobulins (A, G and M), autoantibodies (antinuclear antibody, rheumatoid and lupus erythematosus (LE) factors), and lymphocyte subsets in the blood. However, positive rates of rheumatoid factor were considered to increase in higher blood TEQ groups. This investigation was done using rather small number of Yusho patients, so further large-scale investigations are needed to get more conclusive findings concerning their effects on thyroid hormone and immune response systems.

Effects of donor age and contamination level of dioxins and related chemicals on frequency of sister chromatid exchanges in human lymphocytes cultured in vitro.

Frequencies of sister chromatid exchanges (SCEs) of human lymphocytes in control (DMSO treated) and 7,8-benzoflavone (ANF) treated cultures were measured in 39 healthy Japanese people and examined in connection with donor age. Both the control (baseline) and ANF induced SCE rates were significantly enhanced with age and highly positive correlation was observed between them. Therefore, in vivo aging seemed to have some effects on the frequencies of SCEs in human lymphocytes cultured in vitro. Concentrations of PCDDs, PCDFs and Co-PCBs in the blood and sebum of face were determined in the same Japanese subjects. Significantly positive correlation was observed between the blood and sebum in their total TEQ levels. Hence, PCDDs, PCDFs and Co-PCBs, which have been contaminating human bodies, are considered proportionally excreted from the sebum of face or body. Their total TEQ concentrations were also meaningfully increased with donor age in the sebum of face as well as in the blood. Either the baseline or ANF induced SCE frequencies was not enhanced with the total TEQ levels in the blood. Therefore, background levels of their contamination seem not to affect the SCE rates of the lymphocytes in the control and ANF treated cultures.

Comparison between "Yusho" patients and healthy Japanese in contamination level of dioxins and related chemicals and frequency of sister chromatid exchanges.

Highly toxic organochlorine chemicals such as polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (CoPCBs) were determined in the peripheral blood and sebum from the face of 16 "Yusho" patients of about 27 yr after the outbreak of Yusho accident, and 39 healthy Japanese people. The mean total toxic equivalent (TEQ) levels of PCDDs, PCDFs and CoPCBs in the blood were still about seven times higher in Yusho patients than in healthy Japanese at the age of 45 yr and more. The sebum excretion of these chemicals seemed proportional to their blood levels in Yusho patients. These toxic chemicals, however, did not enhance frequencies of sister chromatid exchanges (SCEs) in the control and 7,8-benzoflavone (ANF) treated cultures in Yusho patients. Hence, no significant difference was observed in the mean SCE rates between the Yusho patients and general Japanese people of more than 45 yr of age. In this study, the number of Yusho patients examined is limited, so further large-scale investigations are needed to get more conclusive results concerning the genotoxic potency such as SCE induction.

Postnatal exposure to chlorinated dioxins and related chemicals on lymphocyte subsets in Japanese breast-fed infants.

Effects of postnatal exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs) on lymphocyte subpopulations were investigated in the peripheral blood of 36 breast-fed Japanese babies. As a result, estimated total intakes of these chemicals in toxic equivalent quantity (TEQ) converted into 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) equivalents from the breast milk positively and negatively correlated with the respective percentages of CD4+ and CD8+ lymphocytes in the blood of breast-fed babies. Consequently, the ratios of CD4+ to CD8+ T cells showed significant increasing tendency with the estimated total TEQ intakes. Therefore, our study suggests that exposure to background levels of the highly toxic organochlorine compounds through the breast milk influences the human neonatal immune system.

Postnatal exposure to chlorinated dioxins and related chemicals on thyroid hormone status in Japanese breast-fed infants.

Effects of postnatal exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs) on thyroid hormone status were studied in the peripheral blood of 36 breast-fed Japanese infants. Estimated total intakes of these chemicals in toxic equivalent quantity (TEQ) converted into 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) from the breast milk significantly and negatively correlated with the levels of triiodothyronine (T3) and thyroxine (T4) in the blood of breast-fed babies. Therefore, exposure to background levels of the highly toxic organochlorine chemicals through the breast milk may cause some effects on thyroid hormone status in Japanese infants.

Maternal body burden of organochlorine pesticides and dioxins.

To investigate the body burden of organochlorine pesticides and dioxins in Japanese women, 125 milk samples were collected from 41 mothers in 1994, 42 in 1995, and 42 in 1996. Of the 125 samples, 82 were from primipara mothers (first delivery) and 43 were from multipara mothers (second or later delivery). By using capillary gas chromatography with electron capture detection, beta-HCH and p,p'-DDE were detected as the major chlorine pesticides in human milk. Average levels of beta-HCH and p,p'-DDE were 475 and 368 ng/g lipid, respectively, in primipara breast milk, 314 and 259 ng/g lipid in multipara breast milk, and 420 and 330 ng/g lipid in total breast milk. Dieldrin, heptachor epoxide, oxychlordane, trans-chlordane, and cis-chlordane were detected at lower average levels of 3, 4, 34, 41, and 5 ng/g lipid, respectively. By using high-resolution gas chromatography with mass spectrometric detection, dioxins were detected in all samples. Average levels of total polychlorinated dibenzo-p-dioxin (PCDD), total polychlorinated dibenzofuran (PCDF), total PCDD + PCDF, total coplanar polychlorinatedbiphenyl (CoPCB), and total dioxin were 10.0, 7.8, 17.7, 9.9, and 27.5 TEQ (toxic equivalent) pg/g lipid, respectively, in primipara breast milk; 7.0, 5.8, 12.8, 7.3, and 20.1 TEQ pg/g lipid in multipara breast milk; and 8.9, 7.1, 16.1, 8.9, and 25.0 TEQ pg/g lipid in total breast milk. In primipara breast milk, significant correlations were found among levels of beta-HCH, p,p'-DDE, total PCDD-TEQ, total PCDF-TEQ, total CoPCB-TEQ, and total TEQ except for less correlation between p,p'-DDE and total PCDF-TEQ. Levels of these analytes also significantly increased depending on mother's age, except for total Co-PCB-TEQ. For the correlation with food habit, the only positive correlation was between total PCDF-TEQs and fish intake.

Effects of 3-methylsulphonyl-4,5,3',4',-tetrachlorobiphenyl and 7,8-benzoflavone on aryl hydrocarbon hydroxylase activities of murine hepatic microsomes prepared from inbred strains with different Ah responsiveness.

In this work, we employed three Ah nonresponsive strains of mice, AKR, DBA and DDD, and three Ah responsive ones, C57, BALB and C3H, and prepared hepatic microsomes after the treatment of 3-methylcholanthrene (MC; 42 mg/kg, once) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 20 micrograms/kg, 6 times) in order to investigate the effect of 3-methylsulphonyl-4,5,3',4'-tetrachlorobiphenyl (3-MSF-4,5,3',4'-TCB; 1.5-45 micrograms/ml) and 7,8-benzoflavone (ANF; 1.4-42 micrograms/ml) on the hepatic microsomal AHH activities and the following results were obtained. 1. In the Ah nonresponsive strains of mice, 70 and 20% of the induced AHH activities with MC and TCDD, respectively, were attributable to the basal control enzyme activity and in the Ah responsive ones, only 4.2 and 1.4% of the induced activities with the two chemicals to the untreated control one, respectively. 2. 3-MSF-4,5,3',4'-TCB and ANF enhanced or reduced the enzyme activity depending on both their concentrations and kinds of microsomes employed, namely, control-, MC- and TCDD-microsomes. ANF showed higher potency for both the activation and inhibition of the AHH activity than 3-MSF-4,5,3',4'-TCB. 3. The effects of 3-MSF-4,5,3',4'-TCB and ANF on the enzyme activity of the MC treated Ah nonresponsive mice and those of the untreated control Ah responsive animals were quite similar and their effects on the AHH activity of the TCDD treated Ah nonresponsive strains were also almost the same as those of the MC or TCDD treated Ah responsive ones.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of methylsulphonyl polychlorinated biphenyl homologues and 7,8-benzoflavone on aryl hydrocarbon hydroxylase activity.

First, we investigated the effects of eleven methylsulphonyl polychlorinated biphenyl (MSF-PCB) homologues at 1.5 micrograms/ml and 7,8-benzoflavone (ANF) at 1.4 micrograms/ml on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 15 ng/ml)-induced aryl hydrocarbon hydroxylase (AHH) activity of cultured human lymphoblastoid cells and the following results were obtained. 1) The relative AHH activity (TCDD-induced AHH activity treated with each of the MSF-PCB compounds or ANF/the enzyme activity treated with acetone, %) of the ANF-treated culture was the smallest value (about 9%). 2) Among MSF-PCB homologues, 3-MSF-4,5,3',4'- and 4-MSF-3,5,3',4'-tetrachlorobiphenyls (TCBs) showed the highest inhibition and their relative enzyme activities were about 20%. 3) In the rest of MSF-PCB compounds, the relative AHH activities were as follows: 4-MSF-3,5,3',4',5'-pentachlorobiphenyl (PenCB); 37%, 3-MSF-4,5,2',3',4'-PenCB; 50%, 3-MSF-4,5,2',3'-TCB, 3-MSF-4,5,2',3',4',5'-hexachlorobiphenyl and 3-MSF-4,5,6,2',3',4',5'-heptachlorobiphenyl; 60 to 64%, 4-MSF-2,5,2',3',4'-PenCB; 77%, 3-MSF-2,5,3',4'-TCB; 88%, 4-MSF-2,5,2',5'-TCB; 93% and 3-MSF-4,5,3',4',5'-PenCB rather enhanced the TCDD-induced enzyme activity. Second, we prepared the hepatic microsomes of BALB/c (Ah responsive) and AKR/J (Ah nonresponsive) strains of mice after the treatment of olive oil (as control), 3-methylcholanthrene (MC, 42 mg/kg, once) and TCDD (20 micrograms/kg, 6 times, once every other week) in order to examine the effects of 3-MSF-4,5,3',4'-TCB (1.5 to 45 micrograms/ml) and ANF (1.4 to 42 micrograms/ml) on the respective hepatic microsomal AHH activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency of micronuclei induced in cultured lymphocytes by highly toxic organochlorine congeners.

Our human bodies have already been contaminated with various chemicals including highly toxic organochlorine compounds such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), 2, 3, 4, 7, 8-pentachlorodibenzofuran (PenCDF) and 3, 4, 5, 3', 4'-pentachlorobiphenyl (PenCB). In this study, in order to evaluate the genotoxicity of these three chemicals, we examined their effects on the induction of micronuclei, which has frequently been utilized as indicator of biological and genetic damage due to exposure to carcinogens or mutagens, in cultured human lymphocytes in the absence or presence of alpha-naphthoflavone (ANF) and the following results were obtained. 1)4 x 10(-5) M ANF alone significantly enhanced the frequency of micronuclei and the combination of ANF and either of TCDD, PenCDF or PenCB seemed to be additive as micronuclei inducers. 2) TCDD, PenCDF and PenCB significantly increased the frequency of micronuclei with almost the same dose-dependent manner in terms of the concentration of TCDD toxic equivalent. 3) TCDD, PenCDF and PenCB were considered to be very potent inducers of micronuclei, because their values of 50% effective concentration in micronuclei enhancement were around only 10 times higher concentration than that in healthy people, namely, 70ppt as TCDD. Consequently, the respective TCDD toxic equivalency factors of 0.5 and 0.2 for PenCDF and PenCB seemed to be reasonable so far as the induction of micronuclei was employed as an indicator of their genotoxic potency.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effects of dioxin congeners on aryl hydrocarbon hydroxylase activity].

In this study, we examined the effect of 1,3,6,8-tetrachlorodibenzo-p-dioxin (1,3,6,8-TCDD), octachlorodibenzo-p-dioxin (OCDD) and 2,4,6,8-tetrachlorodibenzofuran (2,4,6,8-TCDF) on aryl hydrocarbon hydroxylase (AHH) activity in cultured human lymphoblastoid cells. These compounds are considered to be no or less toxic isomers of polychlorinated dibenzo-p-dioxins (Dioxins) and polychlorinated dibenzofurans (Dibenzofurans). At a concentration of 90 ppb, 1,3,6,8-TCDD induced the enzyme activity about 2 times over the basal (untreated) AHH activity and 2,4,6,8-TCDF reduced the basal enzyme activity by about 40%. At a concentration of 5 ppb, OCDD enhanced the basal AHH activity by about 30%. In case of simultaneous treatment of 1,3,6,8-TCDD, OCDD or 2,4,6,8-TCDF with highly toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), at a concentration of 7.5 ppb of each compound, the AHH activities induced by 1,3,6,8-TCDD plus 2,3,7,8-TCDD and OCDD plus 2,3,7,8-TCDD were about 25% and 43%, respectively, higher than that induced by 2,3,7,8-TCDD alone. On the contrary, at the same concentration, the enzyme activity treated with 2,4,6,8-TCDF plus 2,3,7,8-TCDD were about 30% less than that treated with 2,3,7,8-TCDD alone. It has been reported that the AHH inducibility of Dioxins and Dibenzofurans correlates well with their toxic potency. Hence, taking the results of this study into account, we should clarify the biological and/or health consequences of the mixed contamination of no or less toxic and highly toxic congeners of Dioxins and Dibenzofurans by animal experiments and epidemiological studies.