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H Hagenmaier

Publications and source records attributed to H Hagenmaier.

At least 19 recordsLinked to original sources
PubMed2001

Kinetics and inductive potency of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (H7CDD) in rats.

The kinetic properties and the inductive potency of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (H7CDD) were studied in Wistar rats following subcutaneous (s.c.) injections. For assessing the dose-response, rats were treated with a single dose of 3. 10 or 30 microg H7CDD/kg body wt. Tissue concentrations and enzyme induction were measured 1, 2, and 3 weeks after treatment, and in the 30 microg/kg group additionally after 6, 20 and 57 weeks. Tissue concentrations increased dose-dependently from 3 to 30 microg/kg. Concentrations in liver were always higher than in adipose tissue, the concentration ratio: liver/adipose tissue varied between 32 and 67. The activity of (ethoxyresorufin O-deethylase) (EROD) in liver microsomes was clearly induced by H7CDD, reaching maximal induction three weeks after treatment. (3-fold at 3 microg/kg, 5-fold at 10 microg/kg and nearly 30-fold at 30 microg/kg). For assessing the time dependency, tissue levels and hepatic enzyme induction were monitored over a period of 57 weeks after a single s.c.-injection of 30 microg H7CDD/kg body wt. Hepatic concentrations of the congener remained rather constant from the 2nd to the 20th week after treatment (280 ng/g and 319 ng/g, respectively). In contrast, concentrations in adipose tissue and thymus increased 2-fold during this period, and 20 weeks after injection reached a maximum of 11 ng/g and 3 ng/g, respectively. Thereafter, the concentrations decreased and tissue levels of 91 ng/g (liver), 3 ng/g (adipose tissue) and 2 ng/g (thymus) were detected 57 weeks after treatment. The elimination half-life (t 1/2) calculated from our data was 140 days in liver and 130 days in adipose tissue. The reasonable explanation for the increase in tissue concentrations of H7CDD up to 20 weeks after treatment is the slow release of this congener from the subcutaneous injection site. Induction of hepatic EROD activity always closely followed changes in the hepatic concentrations of H7CDD, reaching a maximum 3 weeks after treatment and remaining at this level until the 20th week. Correlation analysis of hepatic H7CDD concentrations versus the extent of EROD induction indicated a linear relationship in a double-logarithmic plot. When compared with TCDD, the hepatic monooxygenase-inducing potency of H7CDD within the low dose range was found in the rat to be 170 to 440-times lower than that of TCDD. Measurement of 14C-caffeine demethylation, using a 14CO2 breath test, revealed a similar time course in vivo when compared with the microsomal EROD activity ex vivo.

Animals↗
PubMed2001

PCBs and their putative effects on polecat (Mustela putorius) populations in Central Europe.

In Europe polecat populations are declining for unknown reasons during the last decades. Data on the river otter, another mustelid predator, indicate that PCB levels are high enough in some populations to interfere with the reproduction of this aquatic species. Since the diet of the polecats consists to a large amount of aquatic prey (amphibians) it appears reasonable to assume that PCBs ingested with the prey are a factor in the decline of polecats. To test this assumption PCB residues in amphibians and in adipose tissue and liver of polecats from Southwest Germany were quantified and the results were compared with literature data on the reproductive toxicity of PCBs in feral mink. According to the current data total PCB levels in polecats (adipose tissue, mean 1244 ng/g lipids; liver, mean 1677 ng/g lipids) and their prey (frogs, mean 9279 ng/kg fresh weight; toads, 4948 ng/kg fresh weight) are comparatively low. Using the toxic equivalent approach, it was calculated that polecats could feed exclusively on amphibians without consuming a harmful amount of PCBs. Therefore, PCBs cannot be an agent currently affecting polecat populations in Central Europe. Other environmental factors like habitat destruction or road accidents are more likely to have a negative impact on polecat populations.

Adipose Tissue↗
PubMed2001

Phenolic xenoestrogens in surface water, sediments, and sewage sludge from Baden-Württemberg, south-west Germany.

Nine structurally different phenolic chemicals, which have been reported to mimic estrogen effects, were determined in various aquatic environmental compartments. Twenty-three water samples from five streams and rivers showed levels up to 458 ng/l for 4-nonylphenol (4NP), 189 ng/l for 4-t-octylphenol (4tOP), 272 ng/l for bisphenol A (BPA) and 47 ng/l for 2-hydroxybiphenyl (2OHBiP). Elevated levels of these compounds in a stream with a high load of effluents of sewage treatment plants (STPs), compared to a brook free of sewage, identified STPs as major sources. With a similar order, 4NP (10-259 micrograms/kg dry matter), 4tOP (< 0.5-8 micrograms/kg), BPA (< 0.5-15 micrograms/kg), and 2OHBiP (2-69 micrograms/kg) were also detected regularly in riverine sediment (n = 11). Levels in sewage sludge were one order of magnitude higher than in sediments. 4-Hydroxybiphenyl and 4-chloro-3-methylphenol were found predominantly in sludge and sediment in the lower ppb range.

Estrogens, Non-Steroidal↗
PubMed2000

PCDD/PCDF emissions from small firing systems in households.

This report presents results of emission measurements of polychlorinated dibenzo-p-dioxins (PCDD) and polychlorinated dibenzofurans (PCDF) in the flue gas of seven oil, nine gas, and two wood firing systems under laboratory conditions. The burn rate of the combustion was in the range of the rated useful heat output. Two additional test series varied the amount of combustion air and thus the heat output. The PCDD/PCDF emissions for oil- and gas-fired boilers are in the range of 0.0020-0.0142 ng I-TEQ/m3 (referring to 3% O2 in the dry flue gas). No correlation between the combustion technique and the PCDD/PCDF emissions could be established. In the tests with the wood-fired furnaces PCDD/PCDF concentrations in the flue gas ranging from 0.014 to 0.076 ng I-TEQ/m3 (referring to 13% O2 in the dry flue gas) were found. A significant correlation between the firing rate of the heating insert and the measured PCDD/PCDF concentrations was found. On examination of three typical 2,3,7,8-CDD/CDF congener profiles, a comparable pattern could be observed with natural gas and light fuel oil. The congener distribution for wood combustion is considerably different.

Benzofurans↗
PubMed1999

Development of a sensitive E-screen assay for quantitative analysis of estrogenic activity in municipal sewage plant effluents.

A simplified proliferation test with human estrogen receptor-positive MCF-7 breast cancer cells (E-screen assay) was optimized and validated for the sensitive quantitative determination of total estrogenic activity in effluent samples from municipal sewage plants. After solid phase extraction of 1 l sewage on either 0.2 g polystyrene copolymer (ENV+) or 1 g RP-C18 material and removal of the solvent, analysis of the extracts in the E-screen assay could be performed without any clean-up step. This was even possible with untreated sewage. Parallel extraction of four sewage samples on both different solid phase materials gave comparable quantitative results in the E-screen. A blank sample did not induce cell proliferation. As additive behaviour of the estrogenic response of single compounds was proven for two different mixtures each containing three xenoestrogens, total estrogenic activity in the sewage samples, expressed as 17 beta-estradiol equivalent concentration (EEQ), could be calculated comparing the EC50 values of the samples with those of the positive control 17 beta-estradiol. The detection limit of the E-screen method was 0.05 pmol EEQ/l (0.014 ng EEQ/l), the limit of quantification 0.25-0.5 pmol EEQ/l (0.07-0.14 ng EEQ/l). In total, extracts of nine effluent and one influent sample from five different municipal sewage plants in South Germany were analyzed in the E-screen. All samples strongly induced cell proliferation in a dose-dependent manner which was completely inhibited by coincubation with 5 nM of the estrogen receptor-antagonist ICI 182,780. The proliferative effect relative to the positive control 17 beta-estradiol (RPE) was between 30 and 101%. 17 beta-Estradiol equivalent concentrations were between 2.5 and 25 ng/l indicating a significant input of estrogenic substances via sewage treatment plants into rivers.

Biological Assay↗
PubMed1999

Mechanism of the formation of polychlorinated dibenzo-p-dioxins and dibenzofurans from chlorophenols in gas phase reactions

The pyrolysis of chlorinated phenates at a temperature of about 280 degrees C results in the formation of definite chlorinated dibenzodioxin (PCDD) congeners [1-3]. It is shown that in gas phase reactions chlorophenols react in the presence of oxygen above 340 degrees C not only to PCDD but also to chlorinated dibenzofurans (PCDF). The mechanism of this reaction of chlorophenols to PCDD and PCDF was elucidated. In a first step phenoxyradicals are formed which are capable of forming PCDDs and PCDFs. This is confirmed by the oxygen dependency of the reaction. In an argon atmosphere no dimerization of chlorophenols could be observed at 420 degrees C. By the identification of intermediates and by analyzing the PCDF isomers formed from individual chlorophenols the reaction pathway is elucidated. As intermediates in the formation of PCDFs polychlorinated dihydroxybiphenyls (DOHB) were identified. These are most likely formed by the dimerization of two phenoxy radicals at the hydrogen substituted carbons in ortho-positions under simultaneous movement of the hydrogen atoms to the phenolic oxygen PCDDs are formed in the gas phase via ortho-phenoxyphenols (POP) analogous to the pyrolysis of phenates, but due to the radical mechanism in the first condensation step to POPs not only a chlorine atom is capable for substitution but also the hydrogen atoms. The formation of the DOHBs and their condensation to PCDFs and hydroxylated PCDFs as well as the ratio of PCDD to PCDF formed show a strong dependency on the reaction temperature, the substitution pattern of the chlorophenols and the oxygen concentration.

Journal Article↗
PubMed1999

Effects of single polychlorinated biphenyls on the morphology of cultured rat tubuli seminiferi.

The effects of single polychlorinated biphenyls (PCB) on isolated tubuli seminiferi of the rat were studied. Freshly isolated rat tubuli seminiferi were prepared according to their transillumination pattern, i.e. dark or pale. Tubuli seminiferi with the dark pattern included stages II to VIII and tubuli with the pale pattern represented stages IX to XIV and stage I of the seminiferous cycle. Afterwards, tubuli seminiferi were exposed to single polychlorinated biphenyls for 5 or 24 h in vitro. PCB 126, PCB 77, and PCB 118 were used in final parts per billion (p.p.b.) concentrations as determined by quantitative PCB analysis. Eventually, the specimens were plastic embedded, cut into semithin sections, stained, and morphology was evaluated by light microscopy. Single PCB congeners induced morphological alterations in cultivated rat tubuli seminiferi in a time- and stage-dependent manner. Effects comprised loosened intercellular contacts between germ cells and Sertoli cells as well as cellular fragmentation in the layer of round spermatids. Early spermiogenesis seems particularly susceptible to single PCB congeners in concentration of background magnitude. The target cell has still to be discovered.

Animals↗
PubMed1998

The olfactory system as a portal of entry for airborne polychlorinated biphenyls (PCBs) to the brain?

Ferrets, mammalian carnivores, kept in an indoor enclosure were continuously exposed to low concentrations of polychlorinated biphenyls (PCBs) in the ambient air for 5 years. After that time PCB concentrations were quantified in the olfactory bulbs and in the remaining brain, adipose tissue and liver. The results revealed unexpectedly high PCB concentrations in the olfactory bulbs, surpassing those in the remaining brain and the peripheral tissues. The PCB congener pattern in the olfactory bulbs resembled that found in the ambient air and the less chlorinated volatile PCBs were found in higher concentrations. We, therefore, assume that airborne PCBs enter directly via the olfactory system and are transported through the axons to the olfactory bulbs where they accumulate.

Air Pollutants↗
PubMed1998

Elimination kinetics and toxicity of 2,3,7,8-tetrachlorothianthren, a thio analogue of 2,3,7,8-TCDD.

In comparison to the polychlorinated dibenzo-p-dioxins (PCDD) informations on their thio analogues the polychlorinated thianthrens (PCTA) are very limited. In this study we investigated the kinetics and toxicity of 2,3,7,8-tetrachlorothianthren (TCTA), the analogue of the most toxic PCDD congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It was found that TCTA is rapidly eliminated in mouse liver homogenate fortified with an NADPH-regenerating system suggesting rapid metabolic degradation by liver monooxygenases. Furthermore, TCTA was rapidly eliminated from mouse liver and whole body. In accordance with this rapid elimination, a weekly dosage of 1mg TCTA per kg body weight (i.p.) over six weeks did not result in weight loss or other signs of overt toxicity in male mice. In rat hepatocytes in primary culture, TCTA was active as inducer of dioxin receptor-regulated cytochrome P4501A1 activity measured as 7-ethoxyresorufin O-deethylase (EROD). The relative inducing potency was about 0.0001 in comparison to TCDD. In spite of this molecular effects, the rapid elimination both in vitro and in vivo argues against a consideration of a TCDD equivalency factor for TCTA.

Animals↗
PubMed1998

Dioxin-like PCBs in the environment-human exposure and the significance of sources.

Dioxin-like PCBs represent an important component of the Sigma-TEQ in many environmental media. Specifically, in animal produce and in fish PCBs dominate the Sigma-TEQ ingested by humans. This in turn leads to high background body burdens in humans with PCB-TEQ greater than that associated with PCDD/Fs. High fish consumers are apparently subject to elevated TEQ exposure from dioxin-like PCBs. This has important implications for exposure assessment studies which have previously only been concerned with PCDDs and PCDFs. Unlike PCDD/Fs, dioxin-like PCBs are not controlled within the food chain. Sources and pathways of exposure are poorly defined. Aroclor formulations and their subsequent usage are considered to be the most important sources in terms of human exposure to some TEF-rated congeners, notably PCB-118, PCB-156 and part of PCB-126. Emissions from combustion sources contribute additional PCB-126. More research is needed to place these compounds in an integrated risk evaluation framework.

Dioxins↗
PubMed1997

Synthesis and analysis of mixed chlorinated-fluorinated dibenzo-p-dioxins and dibenzofurans and assessment of formation and occurrence of the fluorinated and chlorinated-fluorinated dibenzo-p-dioxins and dibenzofurans.

Various mixtures of chlorinated-fluorinated dibenzodioxins (PCFDD), dibenzofurans (PCFDF) and biphenyls (PCFB) were synthesized. For trace analysis, we compared the behavior of PCFDD/PCFDF and chlorinated congeners in extraction, enrichment and clean-up steps. To establish GC/MS analysis, various columns were tested, temperature programs were optimized and for MS-identification specific masses were selected from the mass spectra. To evaluate the possibility of formation of these compounds in thermal processes, samples from the aluminum-producing industry and products of pyrolysis of chlorofluoro- hydrocarbons (FCKW) on a laboratory scale were analyzed. At present, the most important potential sources of fluorinated or mixed chlorinated-fluorinated dioxins, furans and biphenyls - combustion processes and large scale chemical production - do not cause significant environmental contamination at least in the areas considered. However, in a sample of filter dust from the refining process of aluminum using freon 12 we found high amounts (4.5 g/kg !) of chlorinated and chlorinated-fluorinated aromatic compounds including chlorinated-fluorinated dibenzofurans and biphenyls. Since the FCKW ban in Europe, this procedure was modified in 1992, replacing freon 12 by a mixture of chlorine and argon. The PFDD/PFDF concentration in the fluorophenols was between 0.45 and 120 micrograms/kg. The fluorobenzenes analyzed contained between 15 and 70 mg/kg fluorinated biphenyls.

Benzofurans↗
PubMed1997

Metabolic degradation, inducing potency, and metabolites of fluorinated and chlorinated-fluorinated dibenzodioxins and dibenzofurans.

The metabolic degradation of fluorinated, chlorinated-fluorinated and chlorinated congeners was measured in liver homogenate of NMRI mice. While in the time period between 0 and 240 min no degradation of the 2,3,7,8-TCDD/TCDF could be detected, for all fluorinated congeners a perceptible degradation was found, even for the 2,3,7,8-TFDD. Stepwise chlorination of the 2,3,7,8-fluorinated congeners leads to a decrease of the degradation rate. In the EROD test, the exchange of chloro- with fluorosubstituents in the 2,3,7,8-TCDF leads to a decrease of induction potency. 3,7-Dichloro-2,8-difluorodibenzofuran was about 1/1000th as potent as 2,3,7,8-TCDF, while 2,3,7,8-TFDF was complete inactive. Comparison of the metabolic rates of different TCDD with those of the analogous TFDD demonstrates that the order of enzymatic degradation of different TCDD and the analogous TFDD is identical. The TFDD are degraded slightly faster than the corresponding TCDD. Surprisingly 1,4,6,9-TXDD showed the second slowest metabolic rate of the fluorinated and chlorinated TXDD after 2,3,7,8-TXDD although none of the 2,3,7,8-positions were substituted. Judging from 2,3,7,8-TFDD and 1,7-dichloro-2,8-difluorodibenzofuran the metabolic pathway of fluorinated and chlorinated-fluorinated congeners seem to be comparable to the chlorinated congeners.

Animals↗
PubMed1997

Occurrence of non-ortho, mono-ortho and di-ortho substituted PCB congeners in polecats, stone martens and badgers from the state of Baden-Württemberg, Germany.

The concentrations of non-ortho, mono-ortho and di-ortho substituted PCB congeners in tissues of three European mustelid species--polecat, stone marten and badger--were determined. Median congener concentrations are comparable in the three species and are lower than in previous studies on polecats. In all samples PCB-126 contributes most to the TCDD-TEQ; it occurs in considerably higher concentrations in polecats. Additionally, amphibs, the main prey of polecats, were analysed. The total PCB intake of polecats feeding solely on amphibs would be below a critical level, considering the NOAEL for the reproduction of mink, a closely related species.

Adipose Tissue↗
PubMed1997

Dioxinlike components in incinerator fly ash: a comparison between chemical analysis data and results from a cell culture bioassay.

Potent polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxinlike polychlorinated biphenyls (PCBs) are among the most relevant toxic emissions from incinerators. Induction of cytochrome P450 1A1-catalyzed 7-ethoxyresorufin O-deethylase (EROD) activity in mammalian cell culture (EROD bioassay) is thought to be a selective and sensitive parameter used for the quantification of dioxinlike compounds. Fly ash extracts from municipal waste incinerators (MWI), a crematorium, wood combustors, and a noble metal recycling facility were analyzed in the EROD bioassay using rat hepatocytes in primary culture. Fractions containing 2,3,7,8-substituted PCDDs/PCDFs, dioxinlike PCBs, and 16 major polycyclic aromatic hydrocarbons (PAHs) were isolated from the extract and analyzed by gas chromatography-mass spectrometry (GC-MS) and by the EROD bioassay. It was found that with MWI samples the bioassay of the extract resulted in a two- to fivefold higher estimate of TCDD equivalents (TEQ) than the chemical analysis of PCDDs/PCDFs and PCBs. However, the outcome of both methods was significantly correlated, making the bioassay useful as a rough estimate for the sum of potent PCDDs/PCDFs and dioxinlike PCBs in extracts from MWI fly ash samples and in a fly ash sample from a crematorium. In noble metal recycling facility and wood combustor samples, higher amounts of PAHs were found, contributing to more pronounced differences between the results of both methods. The remaining unexplained inducing potency in fly ash samples probably results from additional dioxinlike components including certain PAHs not analyzed in this study. The hypothesis that emissions from MWI of hitherto unidentified dioxinlike compounds are higher by orders of magnitude than emissions of potent PCDDs/PCDFs and dioxinlike PCBs could not be confirmed. We found no indication for a marked synergistic interaction of dioxinlike fly ash components in the bioassay.

Air Pollutants↗
PubMed1996

Tissue distribution after a single subcutaneous administration of 2,3,7,8-tetrabromodibenzo-p-dioxin in comparison with toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Wistar rats.

Tissue concentrations of 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) and induction of ethoxyresorufin O-deethylase (EROD) were determined in female Wistar rats following a single subcutaneous (s.c.) injection of TBDD. Two sets of experiments were performed in order to study (a) the time course after a single s.c. administration of 600 ng TBDD/kg body wt up to 78 days, and (b) the dose-response seven days after a single s.c. injection of different doses of TBDD (3 to 3,000 ng/kg body wt). The results obtained on toxicokinetics and enzyme induction were compared with those following a single s.c. administration of 300 ng/kg body wt 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Three days after the injection, approximately 93% of TBDD and 90% of TCDD had been absorbed. Fourteen days after s.c. injection less than 1% of the administered dose of both substances remained at the injection site. Three days after a single s.c. injection of 600 ng TBDD/kg body wt and 300 ng TCDD/kg body wt, the maximum tissue concentrations in the liver amounted to (M +/- S.D.) 5.7 +/- 0.8 and 4.7 +/- 0.9 ng/g wet weight, respectively. In adipose tissue, the peak concentration was 3.2 +/- 0.2 ng/g wet weight for TBDD on day 14, and 0.8 +/- 0.1 ng/g for TCDD on day 7. Throughout the study, the concentration ratio in the TCDD-treated group was always at least twice as high as that in the TBDD-treated group. The elimination half-life (t1/2) of TBDD and of TCDD in the liver was 13.3 and 13.6 days, respectively. In the adipose tissue the t1/2 of TCDD was 24.5 days but no reliable t1/2 could be calculated for TBDD (t1/2 = 39.4 days with a 95% confidence interval of 25.9 to 82.4 days). Tissue content of TBDD and TCDD in liver and adipose tissue increased dose-dependently, and the linear regression in a double-logarithmic plot showed a straight line. Time course of the induction of hepatic EROD activity after treatment with 600 ng TBDD/kg body wt was almost identical with that observed following a single dose of 300 ng TCDD/kg body wt. The induction of hepatic EROD activity was linearly correlated in a double-logarithmic plot to the hepatic concentrations of the congeners (both TBDD and TCDD). The slopes of the dose-response curves after administration of TBDD and TCDD were almost parallel for tissue concentrations ranging from 0.1 to 30 ng/g wet weight.

Absorption↗
PubMed1995

Polyfluorinated dibenzodioxins and dibenzofurans--synthesis, analysis, formation and toxicology.

The 75 congeners of the polyfluorinated dibenzodioxins (PFDDs) and about half of the 135 polyfluorinated dibenzofurans (PFDFs) have been synthesized by pyrolysis of fluorophenols and fluorobenzenes. The individual congeners were characterized by GC/MS. 2,3,7,8-TFDD was also characterized by 1H-, 13C- and 19F-NMR spectroscopy. The retention behaviour of PFDDs and PFDFs during gaschromatographic separation is entirely different from that of PCDDs/PCDFs or PBDDs/PBDFs. The PFDDs/PFDFs elute earlier than the PCDDs/PCDFs and the order of the elution is not governed by the degree of substitution, O8FDD eluting e.g. much earlier than the M1FDDs. A preliminary toxicological evaluation of 2,3,7,8-TFDD was carried out. The elimination of 2,3,7,8-TFDD from mice after a single i.p. injection is biphasic with a very rapid elimination half-life of 5 minutes and a slower phase of 165 minutes. This means a dramatically reduced half-life compared to 2,3,7,8-TCDD with 8.5 d. In liver the TFDD level reaches a maximum 30 minutes after injection and also declined in a biphasic manner. In rat hepatocytes a primary culture induction of CYP4501A1-catalyzed EROD activity could be demonstrated, indicating that 2,3,7,8-TFDD activates the dioxin receptor. In rat hepatocyte cultures similar EC50 values were found for 2,3,7,8-TCDD and 2,3,7,8-TFDD. So far no de novo synthesis of PFDD/PFDF could be detected under conditions were PCDDs/PCDFs are formed. Also, formation of PFDDs/PFDFs could not be detected during thermal treatment of fluorotrichloromethane or Teflon.

Animals↗
PubMed1994

Promotion of preneoplastic foci in rat liver with 2,3,7,8-tetrachlorodibenzo-p-dioxin, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin and a defined mixture of 49 polychlorinated dibenzo-p-dioxins.

In a two-stage initiation-promotion experiment the hypothesis was investigated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents (TE), calculated from data of CYP1A induction in hepatocytes in primary culture, or international TCDD equivalents (ITE) are useful for evaluating the tumor-promoting potency of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) and of a defined mixture (M2) of 49 polychlorinated dibenzo-p-dioxins (PCDDs) in comparison with TCDD. Therefore, female Wistar rats were treated with an initiating dose of N-nitrosomorpholine, and subsequently received daily doses of 2, 20 and 200 ng TCDD/kg or equivalent doses of HpCDD or M2, based on TE values. After a promotion phase of 13 weeks, hepatic PCDD levels, CYP1A activity and the relative hepatic volume of adenosinetriphosphatase-negative or glutathione S-transferase P-positive preneoplastic foci were determined. After logarithmic transformation, linear PCDD level-response relationships were obtained for induction of CYP1A activity with TCDD, HpCDD or M2. Based on TE values, inducing potencies of both HpCDD and M2 were over-estimated at higher doses, whereas induction was approximately equivalent at the lowest dose. The best fit of PCDD level-response relationships of relative hepatic volumes of preneoplastic lesions was achieved using a four-parameter logistic model. Significantly different functions were calculated for promotion with TCDD or HpCDD. It is concluded that (i) different PCDD level-response relationships exist for the induction of hepatic CYP1A activity and the promotion of preneoplastic liver foci, and (ii) that TE or ITE factors provide only a rough estimate of the tumor-promoting potency of a PCDD mixture but may overestimate the risk from exposure to higher-chlorinated 2,3,7,8-substituted congeners such as HpCDD.

Animals↗