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PubMed1998

Subchronic/chronic toxicity of a mixture of four chlorinated dibenzo-p-dioxins in rats. I. Design, general observations, hematology,and liver concentrations.

Groups of 20 male and 20 female rats were administered five different doses of a mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentaCDD (PCDD), 1,2,3,4,7,8-hexaCDD (HxCDD), and 1,2,3,4,6,7,8-heptaCDD (HpCDD). Doses were selected based on relative potency factors derived from acute toxicity data and a previous subchronic study with HpCDD. The mixture was constituted such that each of the congeners contributed one fourth to total toxic equivalency. Total doses were divided into four daily loading doses and six biweekly maintenance doses. The highest total dose for males was 17.5 microg/kg of TCDD, 87.5 microg/kg of PCDD, 350 microg/kg of HxCDD, and 2500 microg/kg of HpCDD. Positive controls were administered PCDD (350 microg/kg) or HxCDD (1400 microg/kg). Females were given 1.5 times lower doses than males. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest provided with an off-dose period of another 13 weeks. Liver concentrations as determined by GC-MS reflected the doses administered. Body weight gain was dose-dependently reduced throughout the study. Mortality rates at the end of the off-dose period were 80 and 60% for the two highest dosages (mixture) in males and 70 and 10% for females. Clinical signs and necropsy findings suggested that the cause of death was related to wasting, hemorrhage, and anemia. Prothrombin times were prolonged and platelet counts were decreased in some rats receiving high doses. This study provides in vivo support for the validity of the assumption of additive toxicity of CDDs as currently used in the toxicity equivalency factor approach to assess the toxicity of mixtures of CDDs.

Administration, Oral↗
PubMed1997

Induction of micronuclei in cultured human lymphocytes with the mixture of highly toxic organochlorine compounds retained in human body.

In this study, we investigated the effect of mixture of the organochlorine compounds, which very resembled their contamination profile of healthy Japanese people in its composition, on the induction of micronuclei 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 observed a fairly good dose-response relationship between the concentration of the mixture and the induction of micronuclei. In particular, we found that 50% effective concentration of the mixture of the organochlorine chemicals was considered only about 7 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 5 times more than that in the presence of ANF. Based on these results, the mixture was regarded as extremely genotoxic. Our human bodies, however, have already been contaminated with a variety of chemicals including PCDDs, PCDFs and Co-PCBs and accordingly one of the most important problems to be solved is a further comprehensive genotoxicity and health consequences due to these chemicals to the descendants.

Adult↗
PubMed2003

Acute and subacute toxicities of the saponin mixture isolated from Schefflera leucantha Viguier.

Acute toxicity of the bronchodilator saponin mixture isolated from Schefflera leucantha Viguier leaves was investigated in comparison with the methanol and the water extract of this plant. Oral doses of 5000 mg/kg of the methanol extract, the water extract and the saponin mixture did not produce mortality or significant changes in the general behavior and gross appearance of internal organs of rats. Subacute toxicity of the saponin mixture was evaluated with the dose of 1000 mg/kg, orally for 14 days. An extra group (satellite group) was given saponin mixture and kept for a further 14 days after treatment. All animals did not show signs of toxicity during the experimental period. Liver weights of the saponin-treated and the satellite male groups were higher whereas testis weight were lower than those of the control group which received distilled water. However, the histological examination of various organs revealed that there were no differences between the control and the treated rats. BUN, Cr, AST, ALT and ALP levels increased in saponin-receiving rats. It is possible that the saponin mixture directly impacts on the liver and the kidney functions.

Animals↗
PubMed1992

Comparative toxicity of four chlorinated dibenzo-p-dioxins (CDDs) and their mixture. Part I: Acute toxicity and toxic equivalency factors (TEFs).

There is presently no scientifically proven method to assess the toxicity of environmental samples containing complex mixtures of chlorinated dibenzo-p-dioxins (CDDs) of known composition. Their risk assessment is currently based on the interim concept of toxicity equivalency factors (TEFs), with the unproven assumption that all interactions of CDDs are additive. To address this problem we conducted acute toxicity studies with four different CDDs, viz 2,3,7,8-tetrachlorodibenzo-p-dioxin (tetra-CDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (penta-CDD), 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (hexa-CDD) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (hepta-CDD), all containing chlorine substituents in the crucial 2,3,7,8-positions. The homologues, dissolved in corn oil/acetone, were administered to groups of five male Sprague Dawley rats at several doses (at least three) by gastric intubation. The obtained mortality data were employed to calculate the LD20,50 and 80 for each homologue. These data were subsequently used to prepare equipotent doses (expected mortality of 20, 50 and 80%) of a mixture containing all four homologues, each of them contributing one fourth of the toxicity, under the assumption of additive toxicity. The obtained LD50 value and (TEF) was for tetra-CDD 43 micrograms/kg (1), penta-CDD 206 micrograms/kg (0.2) hexa-CDD 887 micrograms/kg (0.05) and hepta-CDD 6325 micrograms/kg (0.007), respectively. The dose-response to the mixture confirmed the hypothesis of strict additivity in the acute toxicity of the four CDD homologues.

Animals↗
PubMed1975

[Effect of polarizing mixture on the toxicity and cardiotonic effect of strophanthin].

Experiments on doves and frogs with a biological valorization of Strophantin reveale a decreasing biological activity of the glycoside under the effect of a polarizing mixture by 54.2% and 28.5%, respectively. The LD50 test in mice also demonstrated a 50% decrease of Strophantin toxicity. Electrocardiographic studies conducted in mice and rats (with a fractionated administration of the glycoside) showed that the polarizing mixture decelerates the development of a negative chronotropic action of Strophantin, and in the presence of toxic doses of the glycoside it weakens its effect upon the excitability and conductivity of the myocardium. In experiments with rabbits and recording of their left ventricular pressure a decreasing cardiotonic effect of Strophantin under the effect of the polarizing mixture was also established, both in the intact animals, and in those with an experimentally induced myocardial infarction. The weakening of the cardiotonic effect and of the toxicity of Strophantin is interpreted in terms of the anatagonistic effects of the glycoside and insulin on the system "catecholamines -- cyclic 3,5 -- AMP", as well as in terms of their effect on the bioenergetics of the myocardium and the dynamics of the content of intracellular potassium.

Animals↗
PubMed2005

Influence of acid volatile sulfides and simultaneously extracted metals on the bioavailability and toxicity of a mixture of sediment-associated Cd, Ni, and Zn to polychaetes Neanthes arenaceodentata.

Laboratory microcosm experiments were conducted to investigate the influence of acid volatile sulfides (AVS) and simultaneously extracted metals (SEM) in sediments on the bioavailability and toxicity of Cd, Ni, and Zn in sediments to polychaete worms Neanthes arenaceodentata. Cohorts of juvenile N. arenaceodentata were exposed to sediments spiked with metal mixtures containing Cd, Ni, and Zn (0.5-15 micromol x g(-1) of total SEM) with Low- (approximately 1 micromol x g(-1)), Medium- (approximately 5 micromol x g(-1)), and High-AVS concentrations (approximately 10 micromol x g(-1)) for 20 days to determine mortality, growth rate, and metal bioaccumulation. Tissue Cd and Zn concentrations at the end of the exposure were significantly higher in sediments with the low-AVS concentration at a given SEM concentration due to the increased dissolved metal concentrations in overlying water (OW). However, tissue Ni concentrations were not related to dissolved Ni in the OW. AVS concentrations also influenced the toxicity of metals to the worms. Significant mortality was observed only at the highest SEM treatments at Low-AVS series. Most individuals survived at the highest SEM treatments at Medium- and High-AVS series. Similarly, the growth rates of worms were reduced in treatments having higher molar differences between SEM and AVS ([SEM-AVS]). Overall, the bioavailability and toxicity of metals in sediments was not well predicted by sediment metal concentrations only, but considering the influence of geochemical factors (AVS) on the metal bioavailability improved the prediction of toxicity. Also, the relationship between tissue metal concentration and toxicity was used to determine which contaminant was most responsible for the observed toxicity of the metal mixture.

Animals↗
PubMed2005

A comparison of the lethal and sublethal toxicity of organic chemical mixtures to the fathead minnow (Pimephales promelas).

The joint toxic effects of known binary and multiple organic chemical mixtures to the fathead minnow (Pimephales promelas) were defined at both the 96-h 50% lethal effect concentration (LC50) and sublethal (32-d growth) response levels for toxicants with a narcosis I, narcosis II, or uncoupler of oxidative phosphoralation mode of toxic action. Experiments were designed to define the degree of additive joint toxicity for mixtures of specific xenobiotics that are believed to act through a similar or different primary mode of toxic action. Our results support the general conclusion that concentration addition is expected for the joint toxicity of similarly acting toxicants. When chemicals were thought to act by a dissimilar mechanism, the combined effects we observed at both of the response levels tested were less than predicted by concentration addition, but usually more toxic than that predicted by the independent action/response addition model. It was demonstrated in multichemical mixtures that several toxicants can act together in a nearly additive fashion to produce effects even when they are present at concentrations below their individual no-observed-effect concentration. Concentration-response relationships for test chemicals at both the lethal and sublethal responses were defined for each of the three modes of toxic action studied. When normalized for potency, it was observed that one relationship could be defined to predict lethality to juvenile fathead minnows when exposed to individual chemicals with either a narcosis I, narcosis II, or uncoupler mode of toxic action. These sublethal relationships were similar for the narcosis I and narcosis II test chemicals, but a steeper response was observed for tests conducted with uncouplers.

1-Octanol↗
PubMed1997

Subacute toxicity of a mixture of nine chemicals in rats: detecting interactive effects with a fractionated two-level factorial design.

The present study was intended (1) to find out whether simultaneous administration of nine chemicals at a concentration equal to the "no-observed-adverse-effect level" (NOAEL) for each of them would result in a NOAEL for the combination and (2) to test the usefulness of fractionated factorial models to detect possible interactions between chemicals in the mixture. A 4-week oral/inhalatory study in male Wistar rats was performed in which the toxicity (clinical chemistry, hematology, biochemistry, and pathology) of combinations of the nine compounds was examined. The study comprised 20 groups, 4 groups in the main part (n = 8) and 16 groups in the satellite part (n = 5). In the main study, the rats were simultaneously exposed to mixtures of all nine chemicals [dichloromethane, formaldehyde, aspirin, di(2-ethylhexyl)phthalate, cadmium chloride, stannous chloride, butyl hydroxyanisol, loperamide, and spermine] at concentrations equal to the "minimum-observed-adverse-effect level" (MOAEL), NOAEL, or 1/3NOAEL. In the satellite study the rats were simultaneously exposed to combinations of maximally five compounds at their MOAEL. These combinations jointly comprise a two-level factorial design with nine factors (=9 chemicals) in 16 experimental groups (1/32 fraction of a complete study). In the main part many effects on hematology and clinical chemistry were encountered at the MOAEL. In addition, rats of the MOAEL group showed hyperplasia of the transitional epithelium and/or squamous metaplasia of the respiratory epithelium in the nose. Only very few adverse effects were encountered in the NOAEL group. For most of the end points chosen, the factorial analysis revealed main effects of the individual compounds and interactions (cases of nonadditivity) between the compounds. Despite all restrictions and pitfalls that are associated with the use of fractionated factorial designs, the present study shows the usefulness of this type of factorial design to study the joint adverse effects of defined chemical mixtures at effect levels. It was concluded that simultaneous exposure to these nine chemicals does not constitute an evidently increased hazard compared to exposure to each of the chemicals separately, provided the exposure level of each chemical in the mixture is at most similar to or lower than its own NOAEL.

Administration, Inhalation↗
PubMed1989

Development and validation of in vitro induction assays for toxic halogenated aromatic mixtures: a review.

Halogenated aromatic industrial compounds, typified by the polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) have been identified as residues in almost every component of the global ecosystem. Risk assessment of the complex mixtures of halogenated aromatics found in environmental samples is complicated by analytical problems and the lack of toxicological information on individual compounds and mixtures. Research in our laboratory has focused on the development and vadidation of the in vitro aryl hydrocarbon hydroxylase (AHH) induction assay in rat hepatoma H-4-II E cells in culture for quantitating individual toxic halogenated aryl hydrocarbons and their mixtures. For several PCB, PCDD, PCDF congeners, their mixed bromo/chloro analogs and reconstituted mixtures there was an excellent linear correlation between their -log ED50 values for AHH induction in rat hepatoma cells and their -log ED50 values for in vivo hepatic microsomal AHH induction, inhibition of body weight gain and thymic atrophy in the rat. It has also been shown for selected compounds that there was a good correlation between their in vitro AHH induction potencies and their effects in guinea pigs (AHH induction, inhibition of body weight gain) and mice (immunotoxicity). This assay system has been utilized to quantitative the "2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents" present in extracts from diverse sources including fly ash from a municipal incinerator and pyrolyzed brominated flame retardants which contain a complex mixture of halogenated dibenzo-p-dioxins and dibenzofurans.

Animals↗
PubMed1977

Central-nervous-system toxicity of local anesthetic mixtures in monkeys.

The central-nervous-system toxicities of local anesthetic mixtures consisting of lidocaine and etidocaine or lidocaine and tetracaine, administered intravenously to four healthy, non-medicated rhesus monkeys, were evaluated. Toxicities were compared by determining seizure dosages for each drug alone and then in a lidocaine-etidocaine-tetracaine mixture. Arterial plasma levels of lidocaine and etidocaine at which electrical seizure activity occurred also were measured when the drugs were administered alone and in combination. The seizure dosages and arterial plasma levels for the drug mixtures studied were equal to the sums of the dosages and thresholds for individual constituents of the mixtures. Under the conditions of this investigation local anesthetic toxicity was additive. (Key words: Anesthetics, local, lidocaine; Anesthetics, local, etidocaine; Anesthetics, local, tetracaine; Brain, seizure thresholds; Toxicity, convulsions.)

Acid-Base Equilibrium↗
PubMed1978

Acute toxicity of phosphate ester mixtures to invertebrates and fish.

The acute toxicity of three commercial phosphate ester mixtures (hydraulic fluids) was tested against two invertebrates and four fishes. Pydraul 50E was more toxic than Houghtosafe 1120 in static and flow-through tests; Pydraul 115E was the least toxic. In flow-through tests these phosphate esters were less acutely toxic than PCB's. However, sublethal reactions to the phosphates suggest a need for chronic toxicity studies.

Animals↗
PubMed2004

Pesticide mixtures potentiate the toxicity in murine thymocytes.

The immunotoxic risks of multiple pesticide exposure were evaluated. C57BL/6 mouse thymocytes were exposed to lindane, malathion, and permethrin, either separately or in mixtures of two pesticides, in vitro. These pesticide exposures caused both apoptotic and necrotic cell death in thymocytes as evaluated by flow cytometric analysis in combination with 7-aminoactinomycin-D (7-AAD), Annexin-V/propidium iodide (PI) staining assays and lactate dehydrogenase release assays. When cells exposed to mixtures of two pesticides, a significantly greater than additive interaction was observed in both apoptotic and necrotic populations of cells. The gel electrophoresis of DNA of cells showed DNA ladder formation with limited genomic DNA and increased laddering in mixture exposures. Based on these findings, it is suggested that these pesticides are potent immunotoxicants, in vitro, and that the mechanism of cytotoxicity observed upon exposure to these pesticides may, at least in part, be due to induction of apoptosis. We also provided evidence that induction of drug metabolizing mixed function oxidase system with lindane may, in part, be responsible for the potentiation of cytotoxicity in the combined exposures. As more information is obtained on the potential immunotoxic effects of pesticides, further insights will be gained for the risk assessment of these environmental pollutants.

Animals↗
PubMed2005

Light as a confounding factor for toxicity assessment of complex contaminated sediments.

Polycyclic aromatic hydrocarbons (PAHs) are contaminants often found in sediments. Their relevant contribution to toxic effects induced by environmental samples has been demonstrated using effect-directed analysis (EDA). Toxicity of PAHs previously has been reported to depend on light conditions. The aim of this study was to analyze the influence of simulated sunlight, in comparison to standard algal growth light, on the toxicity of samples, in which PAHs were identified as major toxicants using EDA. Additionally, toxicity of identified toxicants and mixtures of these compounds were assessed. It can be shown that the samples, the PAH compounds, and the created mixtures exhibit photoenhanced toxicity. The combined effects of the mixtures can be predicted using the model of concentration addition. This is surprising because different modes of action have been reported to contribute to phototoxicity of the identified toxicants. For the confirmation step in EDA, the toxicity assessment under simulated sunlight reveals that less of the samples' toxicity can be explained by the identified compounds, compared to the assessment conducted under standard growth light. Finally, the relevance of light conditions in the toxicity assessment is demonstrated for eight out of 13 transect samples of sediment extracts from river Elbe, Germany.

Confounding Factors, Epidemiologic↗
PubMedDate not supplied

Genetic toxicity of a mixture of fifteen pesticides commonly found in the Italian diet.

To determine the toxicological effects of complex mixtures of pesticides, we obtained data on 100 pesticide residues in common foods of central Italy. Fifteen pesticides were more regularly detected at higher levels (dithiocarbamates, benomyl/carbendazim, thiabendazole, diphenylamine, chlorthalonil, procymidone, fenarimol, chlorpropham, vinchlozolin, methidathion, chlorpyriphos-ethyl, parathion-methyl, parathion, chlorfenviphos, pirimiphos-ethyl). Using itemized data on daily food consumption in Italy, we calculated that the average exposure for an adult subject was 716 micrograms/day, ranging from 148 micrograms of dithiocarbamates to 1 microgram of pirimiphos-ethyl. We made a mixture of these 15 pesticides at concentrations proportional to the ratio determined in foods and tested it with the Salmonella-microsome assay, with and without metabolic activation with PCB-induced rat liver S9. No mutagenic activity was observed at concentrations up to 500 micrograms/plate. We also tested the same mixture at concentrations ranging from 0.1 to 20 micrograms/ml on human lymphocytes in vitro, and observed a slight but statistically significant increase in sister-chromatid exchanges at 1 microgram/ml. We also administered the mixture in corn oil by gavage to Wistar rats at doses of 1, 10, and 100 micrograms/kg. After 24 hr the ratio between bone marrow polychromatic and normochromatic lymphocytes (a sign of cellular toxicity) was decreased by the exposure, but we did not observe a significant increase in the frequency of micronuclei. We conclude that the pesticide mixture did not have appreciable genotoxic activity in the assays used.

Adult↗
PubMed2005

Ecotoxicity quantitative structure-activity relationships for alcohol ethoxylate mixtures based on substance-specific toxicity predictions.

Traditionally, ecotoxicity quantitative structure-activity relationships (QSARs) for alcohol ethoxylate (AE) surfactants have been developed by assigning the measured ecotoxicity for commercial products to the average structures (alkyl chain length and ethoxylate chain length) of these materials. Acute Daphnia magna toxicity tests for binary mixtures indicate that mixtures are more toxic than the individual AE substances corresponding with their average structures (due to the nonlinear relation of toxicity with structure). Consequently, the ecotoxicity value (expressed as effects concentration) attributed to the average structures that are used to develop the existing QSARs is expected to be too low. A new QSAR technique for complex substances, which interprets the mixture toxicity with regard to the "ethoxymers" distribution (i.e., the individual AE components) rather than the average structure, was developed. This new technique was then applied to develop new AE ecotoxicity QSARs for invertebrates, fish, and mesocosms. Despite the higher complexity, the fit and accuracy of the new QSARs are at least as good as those for the existing QSARs based on the same data set. As expected from typical ethoxymer distributions of commercial AEs, the new QSAR generally predicts less toxicity than the QSARs based on average structure.

Alcohols↗
PubMed1997

Predicting the toxicity of complex mixtures using artificial neural networks.

Industrial and municipal wastewaters constitute major sources of contamination of the aquatic compartment and represent a threat to aquatic life. Artificial neural networks based on three different learning paradigms were studied as a means of predicting acute toxicity to trout (5 days exposure to wastewaters) using input data from two simple microbiotests requiring only 5 or 15 min of incubation. These microbiotests were 1) the chemoluminescent peroxidase (Cl-Per) assay, which can detect radical scavengers and enzyme-inhibiting substances, and 2) the luminescent bacteria toxicity test (Microtox), in which reduction of light emission by bacteria during exposure is taken as a measure of toxicity. The responses obtained with the trout bioassay, the Cl-Per and the Microtox test were analyzed through statistical correlation (Pearson product-moment correlation), unsupervised learning by a self-organizing network, and assisted learning by the backpropagation and the Boltzmann machine (probabilistic) paradigms. No significant correlation (p < 0.05) was found between the responses obtained with either the Cl-Per assay (p = 0.121) or the Microtox (p = 0.061) microbiotest and those resulting from the trout bioassay. The self-organizing network was able to identify by itself a maximum of five classes that were more or less relevant for predicting toxicity to fish: class 1 contained 2 samples that were toxic to fish, class 2 contained 2/3 samples that were toxic, class 3 showed 6/8 samples that were non toxic, class 4 contained 5/6 samples that were non-toxic and class 5 comprised one sample that was toxic. Supervised learning with backpropagation analysis yielded two kinds of networks that hold potential. The first one was able to predict the actual toxic wastewater concentration with an overall performance of 65% when fed fresh data, while the second one, which was designed to differentiate between toxic and non-toxic effluents, exhibited a much better performance (90%). However, the probabilistic network also proved to be a very good predictive model for toxicity to fish, with an overall performance of 90%. Although more data are needed, the network based on the backpropagation paradigm seems to be a better predictor or classifier of trout toxicity when used with the Cl-Per and the Microtox microbiotests.

Algorithms↗
PubMed1996

Developmental toxicity of Exell, a surfactant mixture, in rats and rabbits.

A surfactant mixture (C.A.S No. 104559-06-2), is used in combination with foliar-acting herbicides to improve herbicidal performance by increasing plant uptake. It was administered by gavage as an aqueous solution to groups of 25 assumed pregnant Crl:CD BR rats from days 7-16 of gestation at daily dosage levels of 0, 3, 8, 20 or 50 mg/kg body weight. The dams were euthanized on Day 22 of gestation and the offspring were weighed and examined for external, visceral, and skeletal alterations. The surfactant mixture was maternally toxic at levels of 20 mg/kg/day and above as evidenced by reduced maternal weight gain and by an increased incidence of lung noise (wheezing and/or rattling) and sneezing. In addition, maternal food consumption was reduced in the high dosage group. There was no evidence of developmental toxicity at any dosage level. In the rabbit study, groups of 20 artificially inseminated adult Hra:(NZW)SPF rabbits were similarly dosed from Days 6-18 of gestation at daily dosage levels of 0, 12, 35, or 100 mg/kg body weight. The dose were euthanized on Day 29 of gestation and the offspring were weighed and examined for external, visceral, and skeletal alterations. Dosages of 35 and 100 mg/kg/day resulted in reduced maternal body weight gain, food consumption and fetal body weight. Thus, in the rat, the maternal and developmental no-observed-adverse-effect levels (NOAELs) were 8 mg/kg/day and greater than 50 mg/kg/day, respectively. In the rabbit, the maternal and developmental NOAELs were 12 mg/kg/day. This surfactant mixture was, therefore, not demonstrated to be uniquely toxic to either the rat or rabbit conceptus.

Abnormalities, Drug-Induced↗
PubMed2006

Bile fluorescence, heme oxygenase induction, and increased biliverdin excretion by mixtures of environmental toxicants.

The measurement of bile fluorescence has become a popular biomarker to demonstrate the exposure of fish to polycyclic aromatic hydrocarbons. Conflicting data has been published on how to normalize bile fluorescence. To investigate if normalization to biliverdin is a suitable method, experiments were performed to study the mechanisms related to biliverdin excretion in fish. In two separate experiments channel catfish (Ictalurus punctatus) were dosed with mixtures of benzo[a]pyrene with cadmium, chlorinated phenols or borneol. The results showed linear relationships between bile protein and biliverdin for each treatment group, but the slope of this relationship was significantly increased when fish received more chemical stress. Thus, under increasing toxicant stress, more biliverdin was excreted per amount of protein. To investigate if the increased biliverdin excretion was related to increased heme degradation, enzymatic activity of heme oxygenase (HO) was measured in liver homogenates of the dosed fish. The fish dosed with chemical mixtures had a significantly higher HO activity than the control fish, and in both experiments a significant correlation was observed between HO activity and biliverdin concentration in the bile. It is concluded that mixtures of environmental pollutants can induce HO activity and that this chemical stress leads to increased biliverdin excretion. The elucidation of this mechanistic pathway warrants that bile fluorescence should not be expressed per biliverdin absorption, and that expression per bile protein would be a more reliable method.

Animals↗