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PubMed1976

Laboratory diagnosis of botulism complicated by pyridostigmine treatment of the patient. A method for selectively removing interfering substances from clinical specimens.

In August 1974, a case of botulism occurred; home-canned potatoes and peas containing Clostridium botulinum, type A, were strongly incriminated as the vehicle of transmission. C. botulinum, type A, was isolated from a stool specimen of the patient, but the mouse neutralization test for botulinal toxin could not be completed because the stool extract contained a highly toxic, heat-stable substance that rapidly killed mice. Historical and laboratory evidence indicated that the substance was pyridostigmine bromide, a low-molecular-weight drug with which the patient had been treated after her disease was misdiagnosed as myasthenia gravis. A generally applicable method employing dialysis by which toxic SUBSTANCED of low molecular weigth could be selectively removed from specimens without diminishing the potency of botulinal toxin contained in them was developed. Dialysis rendered a pyridostigmine solution, a stool extract from the patient with botulism, and a stool extract from a person taking pyridostigmine virtually nontoxic to mice. Dialysis did not significantly alter the toxicity to mice of crude botulinal toxin; it selectively eliminated all or almost all pyridostigmine toxicity from a pyridostigmine-botulinal toxin mixture without altering the toxicity of the botulinal toxin.

Animals↗
PubMed2003

Tea catechin synergies in inhibition of cancer cell proliferation and of a cancer specific cell surface oxidase (ECTO-NOX).

The anticancer properties of tea catechins are most frequently attributed to the principal catechin (-)-epigallocatechin-3-gallate (EGCg). Efficacy was evaluated using growth of cultured HeLa cells and inhibition of the enzymatic activity of a putative cell surface tea target enzyme, a cancer-associated cell surface-located NADH oxidase (ECTO-NOX) designated tNOX. The amounts of EGCg required to inhibit by both criteria was reduced 10 times by combination with inactive catechins such as (-)-epicatechin (EC), (-)-epigallocatechin (EGC) or (-)-epicatechin-3-gallate (ECG). Various synthetic mixtures based on purified catechins and decaffeinated tea extracts treated enzymatically to reduce the ester bond-containing catechins varying in EGCg content from 0.065 to 40% were of comparable efficacy to decaffeinated green tea extracts as long as EGCg was present and the ratio of total catechins to EGCg + EGC was about 1.5. Such mixtures appear to offer potential cancer protection and therapeutic advantages over those of EGCg alone through lowered toxicity of the mixture to normal cells and for more efficient blood delivery of orally-administered catechins to a tumour site.

Antineoplastic Agents↗
PubMed2001

Predictions of sediment toxicity using consensus-based freshwater sediment quality guidelines.

The objectives of this study were to compare approaches for evaluating the combined effects of chemical mixtures on the toxicity in field-collected sediments and to evaluate the ability of consensus-based probable effect concentrations (PECs) to predict toxicity in a freshwater database on both a national and regional geographic basis. A database was developed from 92 published reports, which included a total of 1,657 samples with high-quality matching sediment toxicity and chemistry data from across North America. The database was comprised primarily of 10- to 14-day or 28- to 42-day toxicity tests with the amphipod Hyalella azteca (designated as the HA10 or HA28 tests) and 10- to 14-day toxicity tests with the midges Chironomus tentans or C. riparius (designated as the CS10 test). Mean PEC quotients were calculated to provide an overall measure of chemical contamination and to support an evaluation of the combined effects of multiple contaminants in sediments. There was an overall increase in the incidence of toxicity with an increase in the mean quotients in all three tests. A consistent increase in the toxicity in all three tests occurred at a mean quotient > 0.5, however, the overall incidence of toxicity was greater in the HA28 test compared to the short-term tests. The longer-term tests, in which survival and growth are measured, tend to be more sensitive than the shorter-term tests, with acute to chronic ratios on the order of six indicated for H. azteca. Different patterns were observed among the various procedures used to calculate mean quotients. For example, in the HA28 test, a relatively abrupt increase in toxicity was associated with elevated polychlorinated biphenyls (PCBs) alone or with elevated polycyclic aromatic hydrocarbons (PAHs) alone, compared to the pattern of a gradual increase in toxicity observed with quotients calculated using a combination of metals, PAHs, and PCBs. These analyses indicate that the different patterns in toxicity may be the result of unique chemical signals associated with individual contaminants in samples. Though mean quotients can be used to classify samples as toxic or nontoxic, individual quotients might be useful in helping identify substances that may be causing or substantially contributing to the observed toxicity. An increase in the incidence of toxicity was observed with increasing mean quotients within most of the regions, basins, and areas in North America for all three toxicity tests. The results of these analyses indicate that the consensus-based PECs can be used to reliably predict toxicity of sediments on both a regional and national basis.

Animals↗
PubMed2003

Evaluation of fish early life-stage toxicity models of chronic embryonic exposures to complex polycyclic aromatic hydrocarbon mixtures.

Polycyclic aromatic hydrocarbons (PAHs) can cause a variety of effects in early life-stages of fish that have been chronically exposed as embryos, including mortality, deformities, and edemas. Mechanistic models of the chronic toxicity of complex mixtures of PAHs in fish have not been reported, with the exception of a previously untested model based on the lipids of fish as the site of action and toxicity caused through a narcosis mechanism. Four mechanism-based models of the chronic toxicity of embryonic exposures to complex mixtures of petrogenic PAHs in two species of fish, Pacific herring and pink salmon, were evaluated using a toxic-units approach: narcosis, aryl hydrocarbon receptor (AhR) agonism, alkyl phenanthrene toxicity, and combined toxicity. Alkyl phenanthrenes were the predominant PAH constituent determining early life-stage toxicity in both herring and salmon. The alkyl phenanthrene model had 67 to 80% accuracy in predicting the absence or presence of significant early life-stage toxicity, compared with a 40 to 50% accuracy and general underprediction of toxicity with the narcosis model. PAHs with high relative AhR affinity did not appear to contribute substantially to the observed early life-stage toxicity because of low concentrations of the most potent AhR agonists. Narcosis appeared to primarily contribute to embryo mortality and to be predominantly controlled by the concentration of naphthalenes. Except for the highest PAH exposure to herring, the primary toxic unit contribution to the combined toxicity model was alkyl phenanthrene toxicity to both herring and salmon. We recommend the continued use of total PAHs as a metric of exposure until mechanistic models have been further evaluated.

Animals↗
PubMed2002

Application of biologically based computer modeling to simple or complex mixtures.

The complexity and the astronomic number of possible chemical mixtures preclude any systematic experimental assessment of toxicology of all potentially troublesome chemical mixtures. Thus, the use of computer modeling and mechanistic toxicology for the development of a predictive tool is a promising approach to deal with chemical mixtures. In the past 15 years or so, physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling has been applied to the toxicologic interactions of chemical mixtures. This approach is promising for relatively simple chemical mixtures; the most complicated chemical mixtures studied so far using this approach contained five or fewer component chemicals. In this presentation we provide some examples of the utility of PBPK/PD modeling for toxicologic interactions in chemical mixtures. The probability of developing predictive tools for simple mixtures using PBPK/PD modeling is high. Unfortunately, relatively few attempts have been made to develop paradigms to consider the risks posed by very complex chemical mixtures such as gasoline, diesel, tobacco smoke, etc. However, recent collaboration between scientists at Colorado State University and engineers at Rutgers University attempting to use reaction network modeling has created hope for the possible development of a modeling approach with the potential of predicting the outcome of toxicology of complex chemical mixtures. We discuss the applications of reaction network modeling in the context of petroleum refining and its potential for elucidating toxic interactions with mixtures.

Computer Simulation↗
PubMed1993

Toxicological approaches to complex mixtures.

This paper reviews the role of toxicological studies in understanding the health effects of environmental exposures to mixtures. The approach taken is to review mixtures that have received the greatest emphasis from toxicology; major mixtures research programs; the toxicologist's view of mixtures and approaches to their study; and the complementary roles of toxicological, clinical, and epidemiological studies. Studies of tobacco smoke, engine exhaust, combustion products, and air pollutants comprise most of the past research on mixtures. Because of their great experimental control over subjects, exposures, and endpoints, toxicologists tend to consider a wider range of toxic interactions among mixture components and sequential exposures than is practical for human studies. The three fundamental experimental approaches used by toxicologists are integrative (studying the mixture as a whole), dissective (dissecting a mixture to determine causative constituents), and synthetic (studying interactions between agents in simple combinations). Toxicology provides information on potential hazards, mechanisms by which mixture constituents interact to cause effects, and exposure dose-effect relationships; but extrapolation from laboratory data to quantitative human health risks is problematic. Toxicological, clinical, and epidemiological approaches are complementary but are seldom coordinated. Fostering synergistic interactions among the disciplines in studying the risks from mixtures could be advantageous.

Air Pollutants↗
PubMed1993

Chemical interaction: enhancement and inhibition of clastogenicity.

Most environmental exposures involve concurrent or sequential exposure to multiple chemicals in air, water, and food. Interactive effects in carcinogenesis have been described for certain combinations of agents. They are described in terms of enhancement or inhibition of carcinogenesis. Enhancement effects have been documented for cigarette smoking in combination with exposure to asbestos, radon, alcohol, or other exposures. A variety of inhibitors of carcinogenesis have also been described. They are classified into agents preventing formation of carcinogens; blocking agents; and suppressing agents. Assessment of risk from exposure to multiple agents can be derived either from epidemiological studies in relation to actual exposure or from laboratory studies after controlled exposure to different agents. Prediction of how toxic components of mixtures will interact should be based on an understanding of the mechanisms of such interactions. Compounds may interact chemically, yielding new toxic components or causing a change in the biological availability of the existing components or metabolites. In humans, great individual variability in response is to be expected because of genetic heterogeneity or acquired host susceptibility factors. Interaction is thus a key component in the risk assessment process. In this paper, the definition of interaction and the theoretical basis for different types of interaction in cancer causation are reviewed. Epidemiological and experimental studies showing interactive effects of two chemical carcinogens are also presented.

Antimutagenic Agents↗
PubMed2001

Toxicity and bioaccumulation of DDT in freshwater amphipods in exposures to spiked sediments.

The amphipods Hyalella azteca and Diporeia spp. were exposed to sediments dosed with dichlorodiphenyltrichloroethane (DDT), and the toxicity and toxicokinetics were determined. The toxicity was evaluated with the equilibrium partitioning (EqP) and critical body residue approaches. The DDT in the sediments degraded during the equilibration period prior to organism exposure. Thus, the toxicity using EqP pore-water toxic units (TUs) was evaluated for DDT and its degradation product, dichlorodiphenyldichloroethane (DDD), as the ratio of the predicted interstitial water concentration divided by the water-only LC50 values. The sum of TUs (sum(TU)) was assumed to best represent the toxicity of the mixture. For H. azteca, the 10-d LC50 was 0.98 and 0.33 sum(TU) for two experiments. For Diporeia spp., no toxicity was found in the first experiment with up to 3 sum(TU) predicted in the interstitial water. However, in the second experiment, the 28-d LC50 was 0.67 sum(TU). These data suggest that the EqP approach approximately predicts the toxicity for the combination of DDT and DDD in sediment, provided a toxic unit approach is employed. The critical body residue approach also used TUs because DDT is biotransformed by H. azteca and because of the dual exposure to DDT and DDD. Because biotransformation was only determined in the second experiment, the critical body residue approach could only be evaluated for that case. The TUs were calculated as the ratio of the concentration in the live amphipods divided by the respective LR50 (residue concentration required to produce 50% mortality) values. The LR50 was 1.1 sum(TU) for H. azteca for the 10-d exposure and 0.53 for Diporeia spp. after a 28-d exposure. Thus, this approach was also quite successful in predicting the toxicity. The accumulation and loss rates for H. azteca were much greater than for Diporeia spp. Thus, 10-d exposures represent steady-state conditions for H. azteca, while even at 28-d, the Diporeia spp. are not at steady state.

Animals↗
PubMed1984

The joint action of malathion and IBP against malathion-resistant and -susceptible strains of Anopheles stephensi.

Malathion resistance in an Anopheles stephensi strain from Pakistan is dependent on a single gene, which results in increased degradation of malathion to the monocarboxylic acid. Mixtures of malathion and the fungicide IBP (O, O-bis(1-methylethyl) S-phenylmethyl phosphorothioate) were tested against this resistant strain and a laboratory susceptible strain. The mixtures were more toxic to both the resistant and susceptible insects than either IBP or malathion alone. The high degree of synergism with the mixtures against the susceptible strain would not be expected if IBP were simply competing with malathion for a common carboxylesterase detoxification enzyme. The reason for the high degree of synergism in the susceptible strain is unknown.

Anopheles↗
PubMed1995

Toxicity of antibiotics and antifungals on cultured human corneal cells: effect of mixing, exposure and concentration.

Toxic effects of topical drugs may be masked by manifestations of the disease they cure. The toxicity of drug mixtures has not been thoroughly studied. We therefore investigated cytopathic effects on primary cultures of human corneal cells of six topical antimicrobials singly and in combinations of any two, to determine the combined toxicity ranking and the interaction between duration of exposure and concentration. Preconfluent cultures were exposed to fixed dilutions of single drugs, or to equal-dilution mixtures of two drugs, for 7 and 14 days. Diminishing concentrations of single drugs were applied sequentially to cultures for 14 days. The number of metabolically competent cells was assessed by measuring hexosaminidase and total protein. Toxic effects depended on substance, concentration and exposure. The scale of toxicity determined for single drugs after 7 days of exposure was: gentamicin > econazole > or = methicillin > or = clotrimazole > or = miconazole > or = chloramphenicol. After 14 days this order changed: in particular chloramphenicol showed a highly increased toxicity. The order of diminishing effects was: gentamicin > chloramphenicol > or = methicillin > miconazole > econazole > clotrimazole. A clear reduction in cytopathic effects was observed when drug concentration was decreased progressively only in cultures treated with gentamicin or methicillin. All drug combinations were more toxic than their components at equal dilution. Combinations containing chloramphenicol ranked most toxic overall, those containing econazole least. A tapering off combination regime did not improve cell survival. These in vitro toxicity data complement clinical studies and suggest ways in which topical drugs can be chosen to minimise toxic effects to corneal surface.

Anti-Bacterial Agents↗
PubMed2006

The role of the aryl hydrocarbon receptor pathway in mediating synergistic developmental toxicity of polycyclic aromatic hydrocarbons to zebrafish.

Planar halogenated aromatic hydrocarbons (pHAHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), show strong binding affinity for the aryl hydrocarbon receptor (AHR) and are potent inducers of cytochrome P4501A (CYP1A). It is widely accepted that dioxin toxicity is largely AHR mediated; however, the role of CYP1A activity in causing that toxicity is less clear. Another class of AHR agonists of increasing concern because of their known toxicity and ubiquity in the environment is the polycyclic aromatic hydrocarbons (PAHs). Like dioxin, some PAHs also cause toxicity to early life stages of vertebrates. Symptoms include increased cardiovascular dysfunction, pericardial and yolk sac edemas, subcutaneous hemorrhages, craniofacial deformities, reduced growth, and increased mortality rates. Although developmental effects are comparable between these two types of AHR agonists, the roles of both the AHR and CYP1A activity in PAH toxicity are unknown. As observed in previous studies with killifish (Fundulus heteroclitus), we demonstrate here that coexposure of zebrafish (Danio rerio) embryos to the PAH-type AHR agonist beta-naphthoflavone (BNF) and the CYP1A inhibitor alpha-naphthoflavone (ANF) significantly enhanced toxicity above that observed for single-compound exposures. In order to elucidate the role of the AHR pathway in mediating synergistic toxicity of PAH mixtures to early life stages, we used a morpholino approach to knock down expression of zebrafish AHR2 and CYP1A proteins during development. We observed that while knock down of AHR2 reduces cardiac toxicity of BNF combined with ANF to zebrafish embryos, CYP1A knockdown markedly enhanced toxicity of BNF alone and BNF + ANF coexposures. These data support earlier chemical inducer/inhibitor studies and also suggest that mechanisms underlying developmental toxicity of PAH-type AHR agonists are different from those of pHAHs. Identifying the pathways involved in PAH toxicity will provide for more robust, mechanistic-based tools for risk assessment of single compounds and complex environmental mixtures.

Animals↗
PubMed2003

Loss of pre-B and IgM(+) B cells in the bone marrow after exposure to a mixture of herbicides.

This study determined alterations to bone marrow B-cell populations after in vivo exposure to a mixture containing the herbicides 3,4-dichloropropionanilide (propanil) and 2,4-dichlorophenoxyacetic acid (2,4-D) and compared them to the effects of exposure to the individual herbicides. Propanil and 2,4-D are postemergent herbicides that are sold commercially as a mixture. The individual herbicides or the mixture containing propanil and 2,4-D were administered intraperitoneally to C57Bl/6 female mice at doses from 50 to 200 mg herbicide/kg body weight. The mixtures were given in a 1:1 ratio. Flow cytometric analysis was performed to quantitate bone marrow B-cell populations at 1, 2, 7, and 14d posttreatment. Mixture treatment decreased pre-B and immunoglobulin (Ig) M(+) B-cell populations at all doses by 2 d postexposure. The cell populations were still decreased at 7d posttreatment. In contrast, exposure to the individual herbicides only caused decreases in the pre-B and IgM(+) B-cell populations 7d after exposure to the high doses. Previous studies have demonstrated that corticosterone levels are increased by exposure to propanil. Therefore, the glucocorticoid hormone, corticosterone, was investigated as a possible mediator of cell loss in the bone marrow. Treatment with the glucocorticoid receptor antagonist, RU 486, however, did not prevent cell loss in the bone marrow of mice exposed to the mixture of propanil and 2,4-D. This study demonstrates that pre-B and IgM(+) B-cell populations are decreased after exposure to propanil, 2,4-D, or the mixture containing propanil and 2,4-D. Exposure to the mixture had greater toxic effects than the individual herbicides on bone marrow pre-B and IgM(+) B-cell populations, emphasizing the need to study mixture interactions.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1994

Phototoxicology. 2. Near-ultraviolet light enhancement of Microtox assays of trinitrotoluene and aminodinitrotoluenes.

Coexposure of 2,4,6-trinitrotoluene (TNT), 2-amino-4,6-dinitrotoluene (2A), or 4-amino-2,6-dinitrotoluene (4A) to near-ultraviolet (nuv) light (lambda max-354 nm) significantly enhanced their toxicity toward Photobacterium phosphoreum (Microtox bioassay) during 30 min but not 15 min. Based on the slopes of the dose-response lines, the nuv coexposure and dark toxic mechanisms of action for TNT, 2A, and 4A appeared to be similar. nuv coexposure of binary mixtures significantly enhanced (supraadditivity) the toxicity of these compounds to P. phosphoreum. Under normal laboratory lighting, the toxicity of TNT + 2A and 2A + 4A mixtures were supraadditive but the toxicity of TNT + 4A mixtures could be explained by simple addition. Supporting these conclusions, the response curves of alpha-terthienyl, a compound known not to require nuv for toxicity, were similar in the dark and with nuv coexposure. In contrast, angelicin and psoralen, compounds known to require nuv coexposure to damage DNA, gave response curves having different slopes in the dark and with nuv coexposure. The nuv coexposure Microtox assay was able to detect and quantify phototoxicity in psoralen, angelicin, alpha-terthienyl, anthracene, TNT, and aminodinitrotoluenes.

Aniline Compounds↗
PubMedDate not supplied

Limitations of the toxic equivalency factor approach for risk assessment of TCDD and related compounds.

Halogenated aromatic hydrocarbons (HAHs), such as polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs), are industrial compounds or by-products that have been widely identified as environmental contaminants. Hazard and risk assessment of complex HAH mixtures have utilized a toxic equivalency factor (TEF) approach, where the toxic equivalents (TEQs) of any mixture are equal to the sum of the concentration of individual (i) congeners times their potencies (TEFi) relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, TEF = 1.0). TEQ = sigma [PCDDi] x TEFi + sigma [PCDFi] x TEFi + sigma [PCBi] x TEFi. The TEQ (or TCDD equivalents) can be readily calculated from analytical data and provides an estimate of the toxicity of any mixture containing HAHs. Several in vivo and in vitro studies with some PCDD/PCDF and PCB mixtures have demonstrated correlations between experimentally determined and calculated TEQs. However, results of several studies have also shown that for specific responses, the TEQ for some HAH mixtures are non-additive. For example, PCB mixtures and individual PCB congeners such as 2,2',4,4',5,5'-hexachlorobiphenyl inhibit toxic and biochemical responses induced by TCDD and related compounds. Another problem associated with hazard and risk assessment of background exposure to HAHs is the relative contribution of trace levels of HAHs (exodioxins) compared to relatively high exposure to naturally occurring aryl hydrocarbon receptor (AhR) agonists, which act through the same mechanistic pathway.

Benzofurans↗
PubMed1990

The cytotoxic effects of cadmium chloride and mercuric chloride mixtures in rat primary hepatocyte cultures.

The toxic effects of Cd and Hg mixtures were studied using primary monolayer cultures of rat hepatocytes. Cytotoxicity was assessed by measuring the release of lactic dehydrogenase from the cells. Cytotoxic and non-cytotoxic metal levels were used. At the higher exposure concentrations (0.2 micrograms Cd.ml-1 and 2.0 micrograms Hg.ml-1), Cd was very toxic to hepatocytes whereas Hg was only marginally toxic. The combination of Cd and Hg was more toxic than predicted by summation of the individual metal toxicities. The incorporation of [35S]cysteine into protein of the cytosol and insoluble cell fraction was increased in response to Cd or Hg exposure and was directly related to cell 35S accumulation. Combinations of Cd and Hg significantly increased the proportion of total 35S which was incorporated in cell protein, an effect that was attributed to the accumulation of protein in the insoluble cell fraction. Cd uptake by hepatocytes was related to exposure concentration but was lower when Hg was also present in the incubation medium. Gel chromatography of the cytosol from Cd-exposed cells showed 3 Cd containing fractions which corresponded to the elution positions of high Mr proteins, metallothionein (MT) and low Mr molecules. When hepatocytes were exposed to Hg in combination with Cd, the MT-like fraction was no longer evident and Cd in the low Mr fraction was greatly reduced. Regardless of the presence or absence of Cd in the exposure medium, 98% of cytosol Hg in Hg-exposed cells was found to elute after the low Mr fraction, at a position equivalent to inorganic salts. This indicates that the enhanced cytotoxicity of Cd and Hg may be related to a decrease in the MT-like protein in the cytosol and not due to a direct competitive binding interaction in relation to the protein.

Animals↗
PubMed2004

QSAR-based toxicity classification and prediction for single and mixed aromatic compounds.

Quantitative structure-activity relationships (QSARs) based on the octanol/water partition coefficient were employed to predict acute toxicities of 36 substituted aromatic compounds and their mixtures. In this study, the model developed by Verhaar et al. was modified and used to calculate octano/water partition coefficients of chemical mixtures. To validate the model, acute toxicities of these chemicals were measured to Vibrio fischeri in terms of EC50. The results indicated that the obtained QSAR models could be used to predict toxicities of samples consi sting of these substituted aromatic compounds, individually or in combinations. The obtained equations were proved to be robust enough by using the leave-one-out test method. By classifying these chemicals into two groups, polar and non-polar, the toxicities of chemical mixtures within each group can be predicted accurately from their calculated partition coefficients.

Environmental Pollutants↗
PubMed1998

Role of tissue repair in toxicologic interactions among hepatotoxic organics.

It is widely recognized that exposure to combinations or mixtures of chemicals may result in highly exaggerated toxicity even though individual chemicals might not be toxic at low doses. Chemical mixtures may also cause additive or less than additive toxicity. From the perspective of public health, highly exaggerated toxicity is of significant concern. Assessment of risk from exposure to chemical mixtures requires knowledge of the underlying mechanisms. Previous studies from this laboratory have shown that nontoxic doses of chlordecone (10 ppm, 15 days) and carbon tetrachloride (CCl4) (100 microliters/kg) interact at the biologic interface, resulting in potentiated liver injury and 67-fold amplification of CCl4 lethality. In contrast, although interaction between phenobarbital and CCl4 leads to even higher injury, animal survival is unaffected because of highly stimulated compensatory tissue repair. A wide variety of additional experimental evidence confirms the central role of stimulated tissue repair as a decisive determinant of the final outcome of liver injury inflicted by hepatotoxicants. These findings led us to propose a two-stage model of toxicity. In this model, tissue injury is inflicted in stage one by the well-described mechanisms of toxicity, whereas in stage two the ultimate toxic outcome is determined by whether timely and sufficient tissue repair response accompanies this injury. In an attempt to validate this model, dose-response relationships for injury and tissue repair as opposing responses have been developed for model hepatotoxicants. Results of these studies suggest that tissue repair increases in a dose-dependent manner, restraining injury up to a threshold dose, whereupon it is inhibited, allowing an unrestrained progression of injury. These findings indicate that tissue repair is a quantifiable response to toxic injury and that inclusion of this response in risk assessment may help in fine-tuning prediction of toxicity outcomes.

Animals↗
PubMed2000

Interacting effects of toxicants and organic matter on the midge Chironomus riparius in polluted river water.

Toxicants and organic matter in river water have contrasting impacts on macrofauna. Through manipulations of both factors, their interactive effects on organisms were evaluated. This way, an attempt was made to clarify the presence or absence of pollution-"tolerant" and -"sensitive" species in rivers affected by mixed sources of pollution. Under controlled conditions, larval growth of the "tolerant" midge Chironomus riparius was measured in different types of river water containing varying levels of particles (obtained by selective filtration) and toxicants (either complex mixtures or metals). Exposure of first-instar larvae to water from the polluted rivers Meuse and Dommel revealed that growth was less inhibited by toxicant levels in river water than expected based on laboratory toxicity tests. Factors present in polluted river water stimulated growth of midges to such an extent that inhibiting effects of high toxicant concentrations were neutralized, and at low toxicant levels, were overcompensated for. It was found that particulate matter has great potential to reduce inhibiting effects of toxicants on C. riparius, not (only) by reducing the bioavailability of toxicants, but by serving as a supplementary, superior food source. The success of the "pollution-tolerant" midge was not explained by tolerance of this species to toxicants, but by its ability to take advantage of coinciding organic enrichment. It is hypothesized that the extent to which beneficial effects of organic compounds on organisms occur is species specific.

Animals↗