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PubMed2005

Arsenite-induced aryl hydrocarbon receptor nuclear translocation results in additive induction of phase I genes and synergistic induction of phase II genes.

Complex mixtures of carcinogenic metalloids, such as arsenic, and polycyclic aromatic hydrocarbons or halogenated aromatic hydrocarbons are common environmental contaminants. The biological consequences of exposure to these mixtures are unpredictable and, although the health effects of individual chemicals may be known, the toxicity of environmental mixtures is largely unexplored. Arsenic, not a potent mutagen by itself, is co-mutagenic with many DNA-damaging agents. Mixtures of arsenite plus benzo[a]pyrene (B[a]P) augment B[a]P mutagenicity, suggesting that arsenite might uncouple expression of phase I and II genes responsible for detoxification. We have studied the effects of arsenite exposure on the activation of the aryl hydrocarbon receptor (AHR) and its subsequent role in gene transactivation. Treatment of mouse Hepa-1 cells with arsenite induces AHR nuclear translocation and binding to the Cyp1a1 gene promoter with the same efficiency as tetrachlorodibenzo-p-dioxin (TCDD), the most potent ligand of the AHR; however, TCDD and B[a]P are an order of magnitude more potent than arsenite in up-regulating Cyp1a1 transcription. Global profiling analyses of cells treated with arsenite plus B[a]P indicate that several phase I and II detoxification genes are in some cases additively and in others synergistically deregulated by the mixtures. Real-time reverse transcription-polymerase chain reaction analyses of mouse embryonic fibroblasts showed that the mixtures had an additive effect on the mRNA levels of Cyp1b1, a prototypical phase I detoxification gene, and an AHR-dependent synergistic effect on the corresponding levels of Nqo1, a prototypical phase II gene. We conclude that exposure to arsenite/B[a]P mixtures causes regulatory changes in the expression of detoxification genes that ultimately affect the metabolic activation and disposition of toxicants.

Active Transport, Cell Nucleus↗

PubMed1997

Inhibition of toxic activities of Bothrops asper venom and other crotalid snake venoms by a novel neutralizing mixture.

The majority of snake bites in Central America are caused by Bothrops asper, whose venom induce complex local effects such as myonecrosis, edema and especially hemorrhage. These effects are only partially neutralized by the clinically used antivenom, even when administered rapidly after envenomation. Recently we screened 49 substances for antihemorrhagic activity and found that a mixture composed of CaNa2, EDTA, a B. asper serum fraction (natural antidote), and the currently used horse polyvalent antiserum is highly effective in the neutralization of local and systemic hemorrhage developing after B. asper envenomation (Borkow et al., Toxicon 35, 865-877, 1997). In the present study we screened the best six antihemorrhagic compounds for their capacity to neutralize the lethal activity in mice and the proteolytic, hemolytic, and antiattachment activities in vitro of the venom. The compounds tested included the currently used horse antivenom, rabbit antiserum against whole B. asper venom or against heated venom, B. asper and Natrix tessellata serum fractions, and CaNa2 EDTA. The constituents of the antihemorrhagic mixture were also the best inhibitors of the other examined toxic activities. Importantly, the mixture effectively neutralized toxic activities of an additional nine venoms from snakes abundant in Central America. This work suggests that the polyvalent antivenom used in Central America could be enriched with a B. asper serum fraction producing a more effective antivenom. In addition, the local application of CaNa2 EDTA to neutralize hemorrhagic toxins, immediately after a snake bite, may provide rapid inhibition of local damage caused by the venoms.

Animals↗

PubMed2005

Trehalose differentially inhibits aggregation and neurotoxicity of beta-amyloid 40 and 42.

A key event in Alzheimer's disease (AD) pathogenesis is the conversion of the peptide beta-amyloid (Abeta) from its soluble monomeric form into various aggregated morphologies in the brain. Preventing aggregation of Abeta is being actively pursued as a primary therapeutic strategy for treating AD. Trehalose, a simple disaccharide, has been shown to be effective in preventing the deactivation of numerous proteins and in protecting cells against stress. Here, we show that trehalose is also effective in inhibiting aggregation of Abeta and reducing its cytotoxicity, although it shows differential effects toward Abeta40 and Abeta42. When co-incubated with Abeta40, trehalose inhibits formation of both fibrillar and oligomeric morphologies as determined by fluorescence staining and atomic force microscopy (AFM). However, when co-incubated with Abeta42, trehalose inhibits formation only of the fibrillar morphology, with significant oligomeric formation still present. When aggregated mixtures were incubated with SH-SY5Y cells, trehalose was shown to reduce the toxicity of Abeta40 mixtures, but not Abeta42. These results provide additional evidence that aggregation of Abeta into soluble oligomeric forms is a pathological step in AD and that Abeta42 in particular is more susceptible to forming these toxic oligomers than Abeta40. These results also suggest that the use of trehalose, a highly soluble, low-priced sugar, as part of a potential therapeutic cocktail to control Abeta peptide aggregation and toxicity warrants further study.

Alzheimer Disease↗

PubMed2002

Thyroid toxicity due to subchronic exposure to a complex mixture of 16 organochlorines, lead, and cadmium.

The human population in the industrialized world is ubiquitously exposed to complex mixtures of persistent pollutants that contaminate food, water, and air. A large number of these contaminants have been shown to cause significant toxicity to the hypothalamic-pituitary-thyroid (HPT) axis in laboratory animal studies, through a variety of mechanisms, although these effects occur at levels of exposure greatly in excess of common human exposure. While many of the mechanisms of thyroid toxicity of these substances are potentially complementary, little is known of the degree of interaction of common persistent contaminants on responses of the HPT axis. To investigate the potential effects of a complex, environmentally relevant mixture on the HPT axis, sexually mature male rats were administered a mixture of 16 common organochlorines (dichlorodiphenoxytrichloroethane [DDT], p,p'-dichlorodiphenoxydichloroethylene [p,p'-DDE], hexachlorobenzene [HCB], tetrachlorodibenzo-p-dioxin [TCDD], polychlorinated biphenyls [PCBs], methoxychlor, endosulfan, heptachlor, hexachlorocyclohexane, dieldrin, aldrin, mirex, and several chlorinated benzenes, and metal contaminants [lead, cadmium]). The doses of the mixture that were administered were related to minimum risk levels or tolerable daily intakes of these substances, as derived by risk assessment with the 1x, 10x, 100x, and 1000x groups receiving mixture components at doses equivalent to 1x, 10x, 100x, or 1000x the minimum risk level (or tolerable daily intake, reference dose), respectively. After 70 daily treatments by gavage, endpoints related to circulating thyroid hormone (serum thyroxine [T(4)], triiodothyronine [T(3)], thyroid stimulating hormone [TSH], and serum T(3) uptake [T(3)-up]), thyroid gland histomorphology (thyroid follicle cross sectional area, epithelial height, follicle roundness or aspect ratio, colloid/epithelial ratio) and hepatic metabolism of thyroid hormone (UDP-glucuronyl transferase [UGT] and outer-ring deiodinase [ORD]) were assessed. All examined endpoints were significantly altered by the mixture albeit with great variability between endpoints in the sensitivity. While most endpoints examined did not show significant changes at mixture doses below 1000x, 2 endpoints, TSH and hepatic outer ring deiodinase activity, were significantly increased and decreased, respectively, by 1x dose and showed dose-related increases in severity with increasing dose. Median thyroid follicle cross sectional area was also increased by the lowest dose of the mixture but decreased with subsequent increases in dose until, at the highest dose, this parameter was significantly reduced relative to control. The relative sensitivity of endpoints of thyroid function in detecting toxicity of the mixture was TSH = ORD = median follicle area >> T(3) > all other endpoints. These results demonstrate that low doses of ubiquitous environmental contaminants can alter HPT physiology in sexually mature males.

Animals↗

PubMed2007

Deciding which chemical mixtures risk assessment methods work best for what mixtures.

The most commonly used chemical mixtures risk assessment methods involve simple notions of additivity and toxicological similarity. Newer methods are emerging in response to the complexities of chemical mixture exposures and effects. Factors based on both science and policy drive decisions regarding whether to conduct a chemical mixtures risk assessment and, if so, which methods to employ. Scientific considerations are based on positive evidence of joint toxic action, elevated human exposure conditions or the potential for significant impacts on human health. Policy issues include legislative drivers that may mandate action even though adequate toxicity data on a specific mixture may not be available and risk assessment goals that impact the choice of risk assessment method to obtain the amount of health protection desired. This paper discusses three important concepts used to choose among available approaches for conducting a chemical mixtures risk assessment: (1) additive joint toxic action of mixture components; (2) toxicological interactions of mixture components; and (3) chemical composition of complex mixtures. It is proposed that scientific support for basic assumptions used in chemical mixtures risk assessment should be developed by expert panels, risk assessment methods experts, and laboratory toxicologists. This is imperative to further develop and refine quantitative methods and provide guidance on their appropriate applications. Risk assessors need scientific support for chemical mixtures risk assessment methods in the form of toxicological data on joint toxic action for high priority mixtures, statistical methods for analyzing dose-response for mixtures, and toxicological and statistical criteria for determining sufficient similarity of complex mixtures.

Algorithms↗

PubMed1990

[Local anesthetic mixtures in various regional anesthesia procedures].

The use of local anaesthetic mixtures in regional anaesthesia has been discussed controversially. This assumption led us to conduct an inquiry on anaesthesiologist opinion on local anaesthetic mixtures. The study was performed on 131 anaesthesiologists answering a questionnaire. It was asked how often and how many procedures of regional anaesthesia were performed, whether local anaesthetic mixtures were used or not, and what were the most common mixtures. Other questions were in what kind of regional anaesthesia mixtures were applied, and which causes led to the use of local anaesthetic mixtures. Local anaesthetic mixtures were used by 70.2% of the anaesthesiologists who responded. Generally, however, parent components were preferred (88.3%). The types of regional anaesthesia in which mixtures were applied, were blockades of plexus brachialis (50.4%), spinal anaesthesia (29.0%), and epidural anaesthesia (28.4%). Locally applied anaesthetic mixtures - in 40.5% a mixture of bupivacaine and prilocaine and in 38.2% a mixture of bupivacaine and mepivacaine - were used in 58.0% because of their short latency and their long duration. In 27.5% the reply was that the anaesthesiologists used such combinations since in these the maximal doses of the parent components were not exceeded. In 22.9% it was argued that mixtures were less toxic than the parent components. On the other hand, the application of local anaesthetic mixtures was rejected because of their unpredictable effect (33.6%), and also to avoid local anaesthetic interactions (13.7%). The results of the inquiry demonstrate that the use of local anaesthetic mixtures in regional anaesthesia is common practice. However, mixing local anaesthetics may produce unpredictable interactions. We conclude that mixtures of local anaesthetics should be used only in exceptional cases.

Anesthesia, Conduction↗

PubMed1980

Acid hydrolysis of military standard formulations of diazinon.

Acid hydrolysis is a means of disposal of diazinon, O,O-diethyl-O-(2-isopropyl-4-methyl-6-pyrimidinyl)-phosphorothioate. Procedures were developed for the hydrolysis of three military standard diazinon formulations (47.5% emulsifiable concentrate, 2% dust and 0.5% oil solution). The kinetics of hydrolysis at four temperatures were obtained for each formulation in order to predict the half-life of diazinon between 5 degrees and 50 degrees C. The toxicities of the reaction mixtures were evaluated by aquatic bioassay with bluegill sunfish (Lepomis macrochirus). When the hydrolysis of a formulation had reduced the diazinon concentration by greater than 99.9%, there was less than 50% reduction in the toxicity of the reaction mixture to bluegill sunfish. Analysis of reaction mixtures showed that the toxic component was O,O,O,O-tetraethyldithiopyrophosphate (Sulfotepp), which was present in all diazinon formulations.

Animals↗

PubMed1982

The relative toxicity of metal salts to immune hemolysis in a mixture of antibody-secreting spleen cells, sheep red blood cells and complement.

The relative toxicity of metal salts was examined using a mixture of antibody-secreting spleen cells, sheep red blood cells and complement. The amount of immune hemolysis in the mixture was reduced by mercuric chloride, methylmercuric chloride and nickel chloride at concentrations of 14 microM or more, by sodium selenite and zinc chloride at 140 microM or more, and by sodium selenate, cadmium chloride, cadmium acetate, chromic chloride and beryllium chloride at 1400 microM. On the other hand, the amount of immune hemolysis was increased by both cadmium chloride anc cadmium acetate at concentrations of 14 and 140 microM. Mercuric chloride, methylmercuric chloride and nickel chloride were assumed to inhibit the antibody secretion of antibody-forming spleen cells.

Animals↗

PubMed2006

Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae.

The toxicity of SSRIs to algae/phytoplankton was investigated using the US EPA ECOSAR, acute single-species growth inhibition assays, species sensitivity distributions (SSDs), and an outdoor microcosm mixture experiment. Worst-case ECOSAR estimates of SSRI toxicity to algae ranged from 0.73 to 13.08 mg/L. Sertraline was the most toxic SSRI tested in single-species growth inhibition assays followed by fluoxetine and fluvoxamine with worst-case 96-h IC10s of 4.6, 31.3, and 1662 microg/L, respectively. HC5s of 2.4, 3.6, and 1100 microg/L were estimated, respectively, for sertraline, fluoxetine, and fluvoxamine toxicity to algae-using SSDs. Microcosm phytoplankton structural endpoints were more sensitive than functional endpoints in the short term. However, in the long term, structural endpoints were resilient and functional endpoints remained impacted even after a period of recovery. The worst-case EC10 determined from the outdoor microcosm mixture toxicity to phytoplankton communities was 15.2 nM. Although SSRIs are toxic to algae, hazard quotients using worst-case PECs represent a margin of safety of 20 to phytoplankton. Although SSRIs do not appear to pose a hazard to primary production, this assessment is not protective of higher aquatic organisms and further research into the chronic toxicity to low levels of SSRIs to higher-level aquatic species is recommended.

Biomass↗

PubMed1986

In vitro synergism between hybrid immunotoxins and chemotherapeutic drugs: relevance to immunotherapy of prostate carcinoma.

Cultured prostate carcinoma cells incubated in the presence of a novel hybrid immunotoxin and ricin A chain exhibited synergy with the chemotherapeutic drugs vinblastine, methotrexate, and bleomycin. No cooperative effect was noted with adriamycin. Under conditions where individual components of immunotoxin or chemotherapeutic drug mixtures were nontoxic or minimally toxic the immunotoxin-drug mixture exhibited marked impact on 14C amino acid incorporation into prostate carcinoma cells. Analysis of drug-treated cells by flow cytometry indicated that cells exposed to vinblastine and bleomycin bound hybrid immunotoxin antibody to a greater extent than cells not exposed to these drugs. Adriamycin did not exhibit synergistic cytotoxicity with hybrid immunotoxin. Also, adriamycin did not enhance antibody binding as evaluated by flow cytometry. The fact that hybrid monoclonal antibody-ricin A chain (HIT-RAC) conjugates inhibited uptake of 14C amino acids 3 to 10-fold within 48 h of incubation with target cells and that this inhibition was further increased 2 to 3-fold in conjunction with three out of four chemotherapeutic drugs tested may be attributed to the unique cytotoxicity imposed by the hybrid immunotoxins. The RAC moiety is not chemically coupled to antibody but instead occupies one of the antigen-combining sites of the molecule. In this manner, RAC is closely juxtaposed to the cell membrane of the target cell and is anchored in this position via binding of the remaining antigen-combining site to p40 prostate restricted antigen.

Antibodies, Monoclonal↗

PubMed1994

Review of the safety assessment of polychlorinated biphenyls (PCBs) with particular reference to reproductive toxicity.

1. The methods used to evaluate the toxicological effects of PCBs in animals have been reviewed. 2. The data show that Toxic Equivalency Factors (TEFs) could be developed to assess the potential toxicity of PCB mixtures for certain specific target organ effects (such as the liver and immune system) but would be inappropriate for other effects (e.g. thyroid function and neurochemical effects). More data on a wider range of individual PCB congeners and a method for systematically balancing toxicodynamic and toxicokinetic data are required before the TEF approach can be fully evaluated. 3. With the exception of the teratogenic effects seen in mice and the anti-oestrogenic effects reported in in vitro studies, there are insufficient data on individual PCB congeners to evaluate the structure-activity relationships for the effects of PCBs on reproduction. The data also show that individual PCBs may have opposing effects on a particular aspect of reproduction (for example individual PCB congeners may have either oestrogenic or anti-oestrogenic effects). Studies with individual PCB congeners have shown both enhancement and antagonism of the teratogenic effects of 2, 3, 7, 8-tetrachloro dibenzo-p-dioxin (TCDD) in the mouse. It is not possible to use TEFs to evaluate the reproductive effects of PCBs. 4. The mechanism(s) responsible for the effects of PCBs on postnatal neurobehavioural development in rodents and monkeys have not been elucidated. At least two groups of PCBs which might be responsible for the observed effects have been identified in this review, one affecting the dopaminergic system and the other group affecting thyroid hormone levels. Considerably more research would be required before the TEF approach could be applied to the effects of PCBs on postnatal neurobehavioural development. This would include research on an appropriate animal model to determine whether the critical toxicological mechanism is mediated through the Ah receptor. 5. The reproductive toxicity of complex PCB mixtures such as those found in foods will depend on the identifies and relative proportions of individual PCB congeners in the mixture. It is not possible to give an accurate estimate of a NOAEL or LOAEL from the reproduction studies using commercial PCB mixtures which could be readily applied to the safety assessment of PCBs present as contaminants in food. 6. It is concluded that the data presented in this paper support the hypothesis that there is no satisfactory method derived from the available studies in laboratory animals for evaluating the potential risk of adverse effects on reproduction posed by contamination of foods with PCBs.

Adrenal Glands↗

PubMed2003

Toxicity of chemical components of fine particles inhaled by aged rats: effects of concentration.

This study tested the hypothesis that exposure to mixtures containing fine particles and ozone (O3) would cause pulmonary injury and decrements in functions of immunological cells in exposed rats (22-24 months old) in a dose-dependent manner. Rats were exposed to high and low concentrations of ammonium bisulfate and elemental carbon and to 0.2 ppm O3. Control groups were exposed to purified air or O3 alone. The biological end points measured included histopathological markers of lung injury, bronchoalveolar lung fluid proteins, and measures of the function of the lung's innate immunological defenses (macrophage antigen-directed phagocytosis and respiratory burst activity). Exposure to O3 alone at 0.2 ppm did not result in significant changes in any of the measured end points. Exposures to the particle mixtures plus O3 produced statistically significant changes consistent with adverse effects. The low-concentration mixture produced effects that were statistically significant compared to purified air but, with the exception of macrophage Fc receptor binding, exposure to the high-concentration mixture did not. The effects of the low- and high-concentration mixtures were not significantly different. The study supports previous work that indicated that particle + O3 mixtures were more toxic than O3 alone.

Aerosols↗

PubMed2004

Evaluation of toxic equivalency factors for induction of cytochromes P450 CYP1A1 and CYP1A2 enzyme activity by dioxin-like compounds.

The toxic equivalency factor (TEF) method has been used to characterize the toxicity of human mixtures of dioxin-like compounds and is being considered for use with other classes of potentially toxic agents. TEFs are estimated by examining the relative potencies of the various congeners for a series of biological and toxicological effects. In this paper, we consider changes in activity for two enzymes, cytochrome P450 1A1 (CYP1A1)-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activity, resulting from exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) or a mixture of these agents. The ratio of median effective dose (ED50) is one way to estimate the relative potencies, especially for gene expression and protein endpoints. ED50's were estimated with a nonlinear regression model in which dose-related changes in mean responses are described by a Hill function. ED50's along with other model parameters were estimated by fitting this model to a given data set. Significant differences in estimated model parameters were tested by likelihood ratio methods. The estimated parameters indicated that congener-specific dose-response shapes were significantly different, that additivity failed for these congeners, and that the ratios of ED50's did not predict the response seen for the mixture. These results indicate that for some biological responses, the use of a single relative potency factor (RPF) is not appropriate for the comparison of the dose response behavior of different dioxin-like congeners.

Animals↗

PubMed1977

[Studies on antiarrhythmic effects and toxicity of quinidine and dihydroquinidine as well as defined mixtures of both in rats (author's transl)].

The antiarrhythmic and acute toxic actions of quinidine (Q) and dihydroquinidine (DHQ) were investigated in experiments in rats. 1. No significant difference was found between Q and DHQ with regard to the doses necessary to suppress electrically induced ventricular fibrillation in the heart (p greater than 0.05). 2. On oral administration, pure DHQ was slightly less toxic than pure Q. This difference is significant (p less than 0.05). It may be explained by a lower absorption rate of DHQ in the rat. Addition of 15 or 30% DHQ to Q did not produce any significant difference in the acute toxic doses (LD50) in comparison with pure Q (p greater than 0.05). 4. The results of a published clinical study showed that the antiarrhythmic actions of pure Q and "commercial" Q are the same with regard to quality, potency and duration. The frequency of side-effects after adminstration of the two alkaloids also did not differ. 5. Limitation or reduction of the DHQ content of pharmaceutical quality quinidine below a technically practicable level does not seem to be justified from a medical point of view from the results of the animal experiments presented and from the clinical study mentioned.

Administration, Oral↗

PubMed1991

Study of the separate and combined effects of the non-planar 2,5,2',5'- and the planar 3,4,3',4'-tetrachlorobiphenyl in liver and lymphocytes in vivo.

Polychlorinated biphenyls (PCBs) are a group of industrial chemicals that are widely distributed in the environment. Because these compounds occur as mixtures, studies of their possible interactive effects are essential for an understanding of the mechanism of the toxicity of these mixtures. For the determination of a possible interaction of the effects in vivo of 2,5,2',5'-tetrachlorobiphenyl (TCB) and 3,4,3',4'-TCB, rats were exposed to a single dose of diethylnitrosamine (DEN) and subsequently to 0.1 p.p.m. 3,4,3',4'-TCB and/or 10 p.p.m. 2,5,2',5'-TCB in the feed for 1 year. The two major targets of PCB toxicity, the liver and the peripheral blood, were examined after these treatments. TCB treatment after DEN exposure caused a predominance of increased placental glutathione S-transferase (PGST) and deficiencies of ATPase as preneoplastic markers in focal hepatic lesions. When 0.05% phenobarbital (PB) was administered after DEN exposure, the distribution of markers in altered hepatic foci (AHF) was essentially equal for increased PGST and gamma-glutamyltranspeptidase (GGT) and for ATPase deficiency. Many of these AHF also exhibited increased P450 b/e expression. Our results demonstrated that the two PCB congeners interacted in vivo to produce an increase in AHF that were PGST positive and ATPase negative. PGST-positive and ATPase-negative AHF correlated best with focal areas of P450 b/e expression. The combination of the two PCBs caused a greater than additive decrease in the total number of lymphocytes and antibody-producing B-cells. Also the thymocyte-dependent T-helper cells isolated from the animals receiving the combination of TCBs demonstrated a morphologically abnormal subpopulation. The results indicate that the interaction of 2,5,2',5'-TCB and 3,4,3',4'-TCB in vivo induced much greater toxicity and mutagenicity in peripheral lymphocytes and hepatocytes than treatment with either congener alone.

Animals↗

PubMed1992

[Effects of combined action of heavy metal salts and phenol on energetics of isolated rat liver mitochondria].

Experiments were carried out to investigate effects of heavy metal salts and phenol both alone and in different combinations on respiration rate and coupling of respiration and oxidative phosphorylation by rat liver mitochondria. Oxygen consumption measurements were obtained using a Clark electrode and lactate plus glutamate as substrates. It is shown that a 50% decrease of the respiratory rate was achieved in less concentrations of substances in the mixture compared with the effects of the individual substances. For respiratory control recovery by EDTA titration more amounts of complexion for model mixtures was necessary. The results evidence synergism of the substances responsible for a considerable increase in toxicity. Mitochondrial test-systems are suggested for rapid prognosis of toxicity of multicomponent mixtures of substances.

Animals↗

PubMed2002

Modes of action in ecotoxicology: their role in body burdens, species sensitivity, QSARs, and mixture effects.

In contrast to the general research attitude in the basic sciences, environmental sciences are often goal-driven and should provide the scientific basis for risk assessment procedures, cleanup, and precautionary measures and finally provide a decision support for policy and management. Hence, the prominent role of mechanistic studies in ecotoxicology is not only to understand the impact of pollutants on living organisms but also to deduce general principles for the categorization and assessment of effects. The goal of this review is, therefore, not to provide an exhaustive coverage of modes of toxic action and their underlying biochemical mechanisms but rather to discuss critically the application of this knowledge in ecotoxicological risk assessment. Knowing the mechanism or, at least the mode of toxic action is indispensable for developing descriptive and predictive models in ecotoxicology. This review seeks to show the crucial role of target sites, interactions with the target site(s), and mechanisms for an adequate and efficient ecotoxicological risk assessment. Emphasis in the discussion is on target effect concentrations (or target occupancy), species selectivity and species sensitivity, time perspective of effect studies, Quantitative Structure-Activity Relationships (QSAR), and mixture toxicity. A particular focus of this review is on multiple mechanisms. Although the illustrative examples were mainly taken from studies in aquatic ecotoxicology, the proposed conceptual approach is also in principle applicable and even particularly useful for soil and sediment systems. Recommendations for further research and developments include the use of internal effect concentrations and target site concentrations in site-specific risk assessment and as a mixture toxicity parameter as well as general considerations for the derivation of mechanistically meaningful QSAR and other predictive models.

Body Burden↗

PubMed1950

The sterilization of bacteriological media and other fluids with ethylene oxide.

Ethylene oxide is an effective sterilizing agent for bacteriological broths, milk, and serum. A short time after it has exerted its sterilizing effect, the treated fluids again become capable of supporting bacterial growth. Ethylene oxide has been shown to destroy a number of aerobic Gram-positive and Gram-negative organisms, aerobic and anaerobic spore-forming bacilli, fungi, and vaccinia virus. No organisms have been encountered which withstand its action. The quantity of ethylene oxide necessary for sterilization depends to some degree on the character of the medium sterilized. None of the materials tested required more than 1 volume per cent of liquid ethylene oxide. Ethylene oxide is highly reactive chemically, and its reactions with many of the components of complex biological fluids cannot be fully anticipated. Regardless of the chemical changes produced, ethylene oxide did not permanently alter the essential qualities of the growth factors in broth and milk which are required by fastidious organisms such as group A streptococci and others. However, its effect on the biological activity of any particular organic compound should be assayed before it can be assumed not to have a deleterious effect. The sterilization of media by ethylene oxide is accompanied by a rise in pH. Fluids which have a relatively high initial pH may require adjustment with sterile acid to return them to the optimal pH for bacterial growth. A mixture of ethylene oxide and broth was toxic to mice for 6 hours after admixture. Toxicity disappeared on incubating the mixture longer, and no residual toxicity could be demonstrated after 6 hours, even on repeated intraperitoneal inoculations. As a means of sterilizing bacteriological media and other biological fluids, ethylene oxide deserves consideration when heat and filtration cannot be used.

Animals↗