Search PubMed⌕ Search

Biomedical subjects

A Brouwer

Publications and source records attributed to A Brouwer.

At least 73 records · Page 4Linked to original sources
PubMed1995

Species-specific antagonism of Ah receptor action by 2,2',5,5'-tetrachloro- and 2,2',3,3'4,4'-hexachlorobiphenyl.

Using recombinant cell lines showing Ah receptor-controlled expression of a luciferase reporter gene, the interaction of di-ortho-substitute polychlorinated biphenyls (PCBs) with Ah receptor agonists was studied. In the recombinant Hepa1c1c7 mouse hepatoma (H1L1.1c7) cells strong antagonistic interaction of 2,2',5,5'-tetrachlorobiphenyl (PCB52) with luciferase expression induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3',4,4'-tetrachlorobiphenyl (PCB77) was observed, and similarly, between 2,2',3,3',4,4'-hexachlorobiphenyl (PCB128) and PCB77. Accordingly, PCB52 was found to inhibit ethoxyresorufin-O-deethylase (EROD) induction by PCB77 in wild-type Hepa1c1c7 cells. In contrast, the antagonistic effect of PCB52 on TCDD-induced luciferase expression was only minor in recombinant guinea pig GPC16 colon adenocarcinoma (G16L1.1c8) and human HepG2 hepatoma (HG2L1.1c3) cells, and intermediate in recombinant H4IIE rat hepatoma (H4L1.1c4) cells. Gel retardation studies using a 32 P-labelled dioxin responsive element (DRE)-containing oligonucleotide, and ligand binding studies using [3H]TCDD, demonstrated that the species-specific antagonistic activity of PCB52 on Ah receptor-controlled luciferase expression is due to inhibition of Ah receptor ligand and DNA binding. We conclude, that Ah-mediated luciferase expression provides a useful tool to study the species specificity of Ah receptor (ant)agonists.

Animals↗
PubMed1995

Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants.

A scientific evaluation was made of functional aspects of developmental toxicity of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in experimental animals and in human infants. Persistent neurobehavioral, reproductive and endocrine alterations were observed in experimental animals, following in utero and lactational exposure to PCBs, PCDDs and PCDFs. The lowest observable adverse effect levels (LOAELs) for developmental neurobehavioral and reproduction endpoints, based on body burden of TCDD-toxic equivalents (TEQs) in animals, are within the range of current background human body burdens. Relatively subtle adverse effects on neurobehavioral development and thyroid hormone alterations have also been observed in infants and children exposed to background levels. Exclusive use of the toxic equivalency factor (TEF) approach may underestimate the risk of neurodevelopmental effects, because both Ah receptor dependent and independent mechanisms may be involved in these effects. The use of marker congeners and/or bioassays based on Ah receptor mediated mechanisms are rapid, low cost pre-screening alternatives for expensive and time consuming gas chromatographic-mass spectrometric analysis.

Animals↗
PubMed1995

Subchronic effects of 2,3,7,8-TCDD or PCBs on thyroid hormone metabolism: use in risk assessment.

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), or 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156) on thyroid hormone metabolism were studied in 13-week feeding studies in female Sprague-Dawley rats. The diets were supplemented with the compounds tested at concentrations ranging from 0.2 to 20 micrograms/kg diet for TCDD, 7 to 180 micrograms/kg diet for PCB 126, or 1.2 to 12 mg/kg diet for PCB 156, respectively. Significant correlations were found for all three compounds between reductions in plasma total thyroxine (TT4) levels and inductions of the microsomal phase II enzyme UDP-glucuronosyltransferase by using T4 as a substrate (T4UGT). Furthermore, the coinduction of certain phase I and II isozymes, i.c., cytochrome P450 1A1 (CYP1A1) and UGT1A1, by these compounds, clearly suggests the involvement of an Ah receptor-mediated mechanism in the disturbance of thyroid hormone metabolism by these polyhalogenated aromatic compounds. These results provide a mechanistic base for the use of certain effects on thyroid hormone metabolism by polyhalogenated aromatic compounds in risk assessment. By using these effects, potencies of PCB 126 and PCB 156 relative to TCDD ranged from 0.008 to 0.1 for PCB 126, and from 0.00007 to 0.004 for PCB 156, respectively. These values correspond very well with relative potencies of PCB 126 and PCB 156 by using some other well-known Ah receptor-mediated toxic and biochemical parameters.

Animals↗
PubMed1995

Metabolism and biochemical effects of 3,3',4,4'-tetrachlorobiphenyl in pregnant and fetal rats.

The metabolism and distribution of a single oral dose of 25 mumol 14C-labelled 3,3',4,4'-tetrachlorobiphenyl (14C-TCB) were investigated in pregnant female Wistar rats and their fetuses. TCB was administered on day 13 of gestation and the elimination was followed for 7 days. Non-pregnant rats were treated similarly for comparison. Fecal elimination of 14C-TCB derived radioactivity was significantly lower in pregnant rats than in non-pregnant rats. The major metabolite found in adult liver and plasma, placental tissue, whole fetuses and fetal plasma was 3,3',4',5-tetrachloro-4-biphenylol (4-OH-TCB). Tissue levels (liver, abdominal fat, skin, skeletal muscle, kidney and plasma) of 14C-TCB-derived radioactivity declined by 65-85% over a 7-day period following administration in the adult animals. However, 14C-TCB-derived radioactivity accumulated more than 100-fold in the fetuses over the same time period, and GC/MS analysis revealed that the fetal accumulation in radioactivity was due primarily to 4-OH-TCB, and not the parent compound. On day 20 of gestation, concentrations of 4-OH-TCB were 14 times greater in fetal plasma than maternal plasma. Treatment with 14C-TCB significantly reduced plasma thyroxine levels by at least 28% up to 7 days after administration in non-pregnant animals and up to 4 days after administration in pregnant rats (31% decrease). By 7 days after administration plasma thyroxine levels had returned to control levels in the TCB-treated pregnant rats. However, fetal plasma thyroxine levels were significantly decreased by 35% in fetuses from 14C-TCB-treated dams 7 days after TCB administration. Hepatic microsomal ethoxyresorufin-O-deethylase (EROD) activity was significantly induced in TCB-treated dams relative to controls at 4 and 7 days after administration, while no EROD activity was detected in hepatic microsomes from control or TCB treated fetal rats at day 20 of gestation. These data suggest that hydroxylated metabolites of polychlorinated biphenyls may play a role in the development toxicity of these compounds.

Animals↗
PubMed1995

Fetal, neonatal, and long-term alterations in hepatic retinoid levels following maternal polychlorinated biphenyl exposure in rats.

This study was undertaken to investigate the effects of perinatal polychlorinated biphenyl (PCB; Aroclor 1254) exposure on hepatic and plasma retinoid levels in fetal rats, their dams, and neonatal and adult offspring. Pregnant Wistar rats were treated with 0, 5, or 25 mg Aroclor 1254/kg body wt from Days 10 to 16 of gestation. Hepatic retinoid (retinol, retinyl palmitate, and retinyl stearate) levels were determined in fetuses and dams from Day 20 of gestation, in male and female neonates 21 days postpartum, and in young adult offspring 90 days after birth. Retinol levels were determined in fetal and maternal plasma (Gestation Day 20) and plasma from the offspring 21 and 90 days after birth. Maternal and fetal plasma retinol levels were decreased by 35 and 38% on Day 20 of gestation following exposure to the highest dose of Aroclor 1254. Male, but not female, neonatal plasma retinol levels were significantly decreased (23%) in the high-dose group. No effects of PCB treatment were seen on plasma retinol levels in the offspring 90 days after birth. Only slight reductions in fetal and maternal hepatic retinol and retinyl palmitate concentrations were observed after prenatal PCB exposure. Male neonatal hepatic retinyl palmitate levels were reduced by 25 and 50% in the 5 and 25-mg Aroclor 1254/kg dose groups, respectively, while female neonatal hepatic retinyl palmitate levels were significantly reduced only in the high-dose group. Ninety days after birth, male hepatic retinyl palmitate levels were only slightly reduced in the highest dose group; however, hepatic retinol concentrations were significantly reduced by 50% in both PCB treatment groups. Female adult offspring exhibited significant reductions in hepatic retinyl palmitate levels (25%) in both PCB treatment groups, while hepatic retinol levels exhibited an unusual increase of more than 100% of controls in the low-dose group, while levels in the high-dose group were similar to controls. This study demonstrates that even a relatively low maternal dose of Aroclor 1254 results in long-term alterations in retinoid status of the offspring in the rat.

Animals↗
PubMed1995

Subchronic dose-response study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats.

Toxic and biochemical potencies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied in a 13-week feeding study in female Sprague-Dawley rats. The diets were supplemented with 0, 0.2, 0.4, 0.7, 5, or 20 micrograms TCDD/kg diet. The estimated daily intakes were calculated to be 0, 14, 26, 47, 320, or 1024 ng TCDD/kg body wt/day. At the end of the study, TCDD concentrations were measured in liver and adipose tissue. The lowest estimated daily intake that caused an increase in liver weight was 320 ng TCDD/kg/day, while an intake of 47 ng TCDD/kg/day resulted in a decrease in plasma thyroid hormone concentrations and a decrease in body weight gain. Decreases in relative thymus weights, loss of hepatic retinoids, and induction of CYP1A1 and CYP1A2 activities were already found at 14 ng/kg/day, the lowest dose used. Therefore, 95% confidence limits for the no-effect levels (CNELs) were calculated from the corresponding dose-response relationships by using sigmoidal curve fittings (Hill, Weibull, and a Logistic model) and a probability level of p < 0.05. For increases in CYP1A1 and CYP1A2 activities, the right critical values for the CNELs ranged from 0.7 to 4 ng TCDD/kg/day (Hill and Weibull). Based on hepatic TCDD residue levels, these right critical values for the CNELs ranged from 0.06 to 0.4 ng TCDD/g liver (wet weight) (Hill and Weibull). The CNELs in this study agree very well with the no-observed-adverse-effects levels as reported before in chronic, carcinogenicity, and reproductive studies with rats and TCDD, i.e., 1 ng/kg/day.

Animals↗
PubMed1995

Interactive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and retinoids on proliferation and differentiation in cultured human keratinocytes: quantification of cross-linked envelope formation.

Dioxins are potent inducers of chloracne in humans. This skin aberration can be interpreted as an altered differentiation pattern of acinar sebaceous base cells and a change in the rate of terminal differentiation of the keratinocytes. We measured this rate induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in primary cultures of human keratinocytes. As parameters for differentiation, we quantified the 35S-methionine incorporation into cross-linked envelopes (revealing the total CLE biomass), as well as the number of microscopically visible CLEs. It was shown that TCDD is a very potent inducer of both CLE biomass and number with a half-maximal effect concentration (EC50) of 1.4 nM. CLE biomass was maximally increased 10-fold and the number of cells in culture producing a CLE was increased from 15% in control cultures to maximally 75% of the cells in TCDD-treated cultures. Both effects were Ca(2+)-dependent and increased with elevated cell density, being optimal in post-confluent cultures. Retinoic acid dose-dependently decreased the effect of 10(-8) M TCDD, 10(-6) M having a nearly complete antagonistic action. This interaction of retinoic acid with TCDD-induced differentiation was non-competitive. Retinol was equally potent as an antagonist of the TCDD-induced elevation of CLE formation as compared with retinoic acid. Retinyl palmitate and etretinate were not very effective as TCDD antagonists. Supplementation of hydrocortisone suppressed the TCDD-induced keratinocyte differentiation. It was concluded that CLE biomass quantification provides a reliable and sensitive parameter for keratinocyte differentiation. In this in vitro system it is shown that TCDD strongly induces a switch from proliferation to terminal differentiation and that this effect can be antagonized effectively by retinoic acid and retinol.

Adult↗
PubMed1995

Short term fasting does not aggravate immunosuppression in harbour seals (Phoca vitulina) with high body burdens of organochlorines.

Two groups of 11 harbour seals (Phoca vitulina) with different body burdens of organochlorines were subjected to an experimental 15-day fasting period, during which they lost an average 16.5% of their body weights. Blood levels of the most persistent organochlorines showed an approximate twofold increase, while levels of aryl hydrocarbon receptor-binding organochlorines remained largely unaffected. Few differences in immunological parameters were observed between the two dietary groups. Numbers of circulating lymphocytes dropped to about 65% of the initial values and NK cell activity showed a slight increase in both groups. Mitogen- and antigen-induced lymphoproliferative responses of the Baltic group of seals remained within normal ranges. These results suggest that relatively short-term fasting periods do not present an additional immunotoxicological risk to seals with high body burdens of organochlorines.

Adipose Tissue↗
PubMed1995

Expression patterns of the paired-related homeobox genes MHox/Prx1 and S8/Prx2 suggest roles in development of the heart and the forebrain.

Prx1 and Prx2 (previously called MHox and S8, respectively) are the members of a small subfamily of vertebrate homeobox genes expressed during embryogenesis from gastrulation onwards. We directly compared the expression domains of the Prx genes in detail in mouse and in addition some aspects of these patterns in chicken. In addition to the superficially similar expression patterns of Prx1 and Prx2 in cranial mesenchyme, limb buds, axial mesoderm, and branchial arches and their derivatives, we detect major differences at many sites particularly in heart and brain. Our analysis indicated in several cases a correlation with regions developing into connective tissues. From at least day 8.5, Prx-1 expression was observed in the heart, initially in the endocardial cushions and later in the developing semilunar and atrioventricular valves. Prx2 develops early on a diffuse myocardial expression pattern and is later higher expressed in the ventricular septum and in particular in the ductus arteriosus. Prx2 is never expressed in the brain, whereas Prx1 is expressed, from at least day 9.5 onwards, in a unique distinct domain in the ventral part of the hypothalamus, as well as in a broader region of the telencephalon.

Amino Acid Sequence↗
PubMed1995

Production of eicosanoids and cytokines by Kupffer cells from young and old rats stimulated by endotoxin.

1. The clinicopathological features of endotoxaemia have been ascribed to cytotoxic mediators such as tumour necrosis factor, interleukins and eicosanoids. Macrophages, particularly Kupffer cells, are an important source of these mediators. Mortality from endotoxaemia is highly age related. 2. These studies focus on the role of hepatic Kupffer cells in the increased sensitivity of old rats to bacterial endotoxins. Possible age-related changes in the production of eicosanoids and induction of gene expression and secretion of interleukin 1, tumour necrosis factor and interleukin 6 were investigated in Kupffer cells derived from both young and old animals. 3. Basal production of biological response modifiers was low in cells of both young and old rats. Lipopolysaccharide stimulated production of the same types of monokines as described for other types of macrophages, although the pattern was specific for Kupffer cells. 4. Eicosanoids, predominantly prostaglandin D2 and prostaglandin F2 alpha, were produced mainly during the first hour after exposure to lipopolysaccharide. Endotoxin stimulated synthesis of mRNAs of interleukin 1, interleukin 6 and tumour necrosis factor alpha resulting in increased secretion of these cytokines into the medium. 5. Kupffer cells from both young and aged animals appear to be exquisitely sensitive to endotoxin in respect of expression of mRNA for both interleukin 1 alpha and interleukin 1 beta and less sensitive with respect to interleukin 6 and tumour necrosis factor alpha gene expression. At relatively high lipopolysaccharide concentrations interleukin 6 was secreted in particularly large amounts. 6. The effects of ageing on any of these responses of Kupffer cells were minimal.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1995

Beta-carotene (provitamin A) decreases the severity of CCl4-induced hepatic inflammation and fibrosis in rats.

Earlier data from experiments in rats have shown that administration of retinyl esters (vitamin A) strongly influences the effects of CCl4 on the liver. The accumulation of collagen was inhibited, but an increase in CCl4-toxicity with high mortality was observed. The present study was conducted to examine the effects of beta-carotene (provitamin A) on CCl4-related general and hepatic toxicity in rats. Oral administration of beta-carotene during CCl4-treatment resulted, biochemically, in a significantly lower increase in the hydroxyproline liver content and, histopathologically, in less severe liver fibrosis as compared with the liver of rats not treated with beta-carotene. The study also showed that beta-carotene administration could prevent the long-term loss of retinoids from the CCl4-injured liver. No significant toxic effects of beta-carotene, as previously found with retinyl esters (vitamin A), were observed. This experimental study suggests that beta-carotene has the therapeutic potential to decrease the severity of liver fibrosis without marked toxicity.

Animals↗
PubMed1995

beta-Naphthoflavone- and self-induced metabolism of 3,3',4,4'-tetrachlorobiphenyl in hepatic microsomes of the male, pregnant female and foetal rat.

1. The in vitro metabolism of 3,3',4,4'-tetrachloro-[14C]-biphenyl ([14C]-TCB) by hepatic microsomes from the Wistar rat was investigated with liver microsomes from the male, pregnant female and foetus. 2. Three hydroxylated metabolites (4-OH-3,3',4,5'-tetrachlorobiphenyl, 5-OH-3,3',4,4'-tetrachlorobiphenyl, and 6-OH-3,3',4,4'-tetrachlorobiphenyl) were identified by hplc and gc-ms after incubations of liver microsomes from the beta-naphthoflavone-pretreated male rat and TCB-treated pregnant rat. No metabolites of [14C]-TCB were found after incubation with foetal liver microsomes from dams pretreated with [14C]-TCB. The results indicate that the in vivo accumulation of 4-OH-tetraCB in the foetal compartment is probably due to transplacental transport rather than the formation of this metabolite in the foetus. 3. Pretreatment of the male rat with beta-naphthoflavone substantially induced the formation of hydroxylated metabolites, but pretreatment with phenobarbital and dexamethasone was without effect. Based on in vitro incubations of liver microsomes from the beta-naphthoflavone pretreated male rat, an apparent Km and Vmax of 4.5 microM and 240 pmol/mg protein/min respectively was determined for the metabolism of [14C]-TCB. The formation of phenolic metabolites of [14C]-TCB was most likely dependent on P4501A induction.

Animals↗
PubMed1995

The influence of dietary restriction on the metabolism of theophylline and antipyrine in the ageing female BN/BiRij rat.

The influence of ageing and dietary restriction (DR) on the in vivo activities of different P450 enzymes was studied longitudinally in female BN/BiRij rats. For this purpose, antipyrine (AP) and theophylline (TH) were used as substrates. The metabolic clearances of AP (CIm AP) and TH (CIm TH) were used as indicators for P450 enzyme activities in vivo. Therefore, we also included the assessment of the clearances of formation of three AP metabolites, i.e., 3-hydroxymethylantipyrine (CI-->HMA), 4-hydroxyantipyrine (CI-->OHA) and norantipyrine (CI-->NORA). Ninety, 50 and 10% survival times were prolonged significantly in DR rats. In control animals, the contribution to the metabolism of AP in the formation of HMA, OHA and NORA, expressed as percentage of the dose, decreased with ageing, indicating that other pathways compensate for this decrease. Only a significant decrease in the metabolism to OHA was observed in DR animals. CI-->HMA, CI-->OHA and CI-->NORA showed an age-related decrease in the control rats, whereas in the DR rats an age-related decrease was observed for CI-->HMA and CI-->OHA. The results of the present study suggest that the decrease in the activities of the P450 enzymes involved in the formation of HMA, OHA and NORA have a later onset in the DR rats. In conclusion, DR not only has a strong positive influence on the health and life span of the rats, but also results in a delayed onset of the decrease in activity of certain P450 enzymes.

Aging↗
PubMed1994

Different competition of thyroxine binding to transthyretin and thyroxine-binding globulin by hydroxy-PCBs, PCDDs and PCDFs.

In an earlier study several hydroxylated polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) competitively displaced [125I]thyroxine (T4) from transthyretin with different potencies. Transthyretin is the major T4 transport protein in plasma of rodents. In man, however, thyroxine-binding globulin transports most of the T4 in blood. In this study, hydroxylated PCBs, PCDDs and PCDFs were tested in an in vitro competitive binding assay, using purified human thyroxine-binding globulin and [125I]T4 as the displaceable radioligand. None of the tested hydroxylated PCBs, PCDDs and PCDFs inhibited [125I]T4 binding to thyroxine-binding globulin. In addition, some T4 derived compounds, e.g., tyrosine, mono-iodotyrosine, di-iodotyrosine and tri-iodophenol were tested on both transthyretin and thyroxine-binding globulin to investigate possible differences in structural characteristics determining T4 binding to thyroxine-binding globulin and transthyretin. The T4 derived compounds also did not inhibit [125I]T4 binding to thyroxine-binding globulin as tested in the in vitro assay. However, tri-iodophenol and to a lesser extent di-iodotyrosine inhibited [125I]T4-transthyretin binding. These results indicate a marked difference in T4 binding to thyroxine-binding globulin or transthyretin. The hydroxylated PCBs, PCDDs and PCDFs can inhibit T4 binding to transthyretin, but not to thyroxine-binding globulin, and thus may cause different effects in rodents and man.

Benzofurans↗
PubMed1994

In vitro metabolism of 3,3',4,4'-tetrachlorobiphenyl in relation to ethoxyresorufin-O-deethylase activity in liver microsomes of some wildlife species and rat.

A qualitative study was performed of the capacity of hepatic microsomes of several wildlife species to metabolize 3,3',4,4'-tetrachlorobiphenyl (TCB). Hepatic microsomes of species environmentally exposed to polychlorinated biphenyls (PCBs): harbour porpoise (Phocoena phocoena), harbour seal (Phoca vitulina), common tern (Sterna hirundo), and hepatic microsomes from species experimentally exposed to PCBs: eider duck (Somateria mollissima), rainbow trout (Salmo gairdneri), flounder (Platichthys flesus), and Wistar rat, were incubated with 14C-labelled TCB ([14C]TCB). The mammals and birds were able to metabolize TCB at a rate that correlated with their ethoxyresorufin-O-deethylase (EROD) activity. No [14C]TCB metabolism was observed in the fish, despite elevated EROD activity in the trout. HPLC analysis of diisopropylether extracts of the microsomal incubations indicated the presence of 4-OH-, 5-OH-, and 6-OH-tetrachlorobiphenyl metabolites and a yet unidentified metabolite. The ratio of the different hydroxy metabolites formed varied for the various species.

Animals↗
PubMed1994

Morphological characterization of scavenger receptor-mediated processing of modified lipoproteins by rat liver endothelial cells.

Scavenger receptor-mediated processing by rat liver endothelial cells in vivo is studied by using acetylated and oxidized low-density lipoproteins (LDL) as ligands. The cellular localization of acetylated LDL (Ac-LDL) is visualized by both immunohistochemistry and silver enhancement of ultrasmall gold particles conjugated to Ac-LDL. Scavenger receptor-mediated internalization by the endothelial cells only involves coated vesicle formation. Subsequently, three stages of processing are noticed, as represented by (i) large electron lucent vesicles, with ligand in close association to the membrane, (ii) relatively electron-lucent structures, with Ac-LDL dispersed over the vesicular lumen, while tubular membrane extensions did not contain ligand, and (iii) electron-dense vesicles in which the nondegradable gold particles of the conjugate accumulate, while the immunoreactivity for Ac-LDL is low. Addition of chloroquine, an inhibitor of lysosomal degradation, demonstrated that the relatively electron-lucent and electron-dense structures represent subsequent stages of the lysosomal pathway of Ac-LDL, which was also verified by detection of the lysosomal enzyme cathepsin D. Evaluation of the processing of Ac-LDL and oxidized LDL, labeled with different fluorochromes, demonstrated that both ligands follow apparently the same intracellular pathway in the liver endothelial cells, since the fluorescent probes are predominantly localized in the same structures. It is concluded that the scavenger receptor-mediated processing of modified LDL by rat liver endothelial cells involves four morphologically distinguishable stages which represent a highly effective catabolic route, sustaining the important role of the liver endothelial cells in the protection against circulating atherogenic lipoproteins.

Animals↗
PubMed1994

Toxic potency of 2,3,3',4,4',5-hexachlorobiphenyl relative to and in combination with 2,3,7,8-tetrachlorodibenzo-p-dioxin in a subchronic feeding study in the rat.

Interactive effects on toxicity and biochemical parameters were studied between 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a 13-week feeding study of female Sprague-Dawley rats. The diets were supplemented with PCB 156 (1.2, 6, or 12 mg/kg), with TCDD (5 micrograms/kg), or with combinations of both compounds. Estimated daily intake of 365 micrograms/kg body wt/day (6 mg/kg diet group) of PCB 156 caused a decrease in body weight gain, thymic atrophy, liver enlargement, a loss in hepatic retinoids, induction of CYP2B activity, and a decrease in plasma thyroxine concentrations. At an estimated daily intake of 81 micrograms PCB 156/kg body wt/day CYP1A1 and CYP1A2 activities were induced. Compared to a simultaneous subchronic feeding study with TCDD a toxic equivalency factor (TEF) between 0.00004 and 0.001 was estimated for PCB 156 with respect to the mentioned effects. Antagonistic effects were found between TCDD and PCB 156 for CYP2B activity and hepatic retinol levels. These effects concurred with a PCB 156 dose-dependent decrease in hepatic TCDD levels. Hepatic PCB 156 levels were found to be increased at the 1.2-mg PCB 156/kg dose group in coadministration with TCDD. In conclusion, at least part of the antagonistic effects between PCB 156 and TCDD observed have a toxico-kinetic base. Furthermore, the magnitude of the antagonistic effects may be neglected in comparison with the uncertainty in the TEF value. Therefore, the interactive effects found between PCB 156 and TCDD may have no implications for the additivity of the TEF concept.

Animals↗