Staphylococcal toxic-shock syndrome: mixture of toxins including endotoxin.
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Bacterial Toxins↗
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[Method for studying the toxicity of a mixture of the gaseous combustion products of lubricating greases].
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Animals↗
[Studies on the chronic toxicity of a mixture of lead, cadmium and iron given to white rats with drinking water].
The experiment was carried out on male white rats of own breed which were receiving for 8 months lead acetate 200 mg/l, cadmium acetate 50 mg/l and ferrous chloride 100 mg/l with drinking water. The experimental groups received lead, cadmium, lead with cadmium, and the last group received every other day alternatingly iron or lead with cadmium. The activity of selected blood enzymes, haematological indices was determined and the memory test was carried out. In all experimental groups a decrease was noted of haemoglobin level and haematocrit value, with an increase of choline esterase and reduced learning effectiveness--most pronounced in the group treated with cadmium, less evident in groups drinking water with lead or cadmium and lead, and not significant in the group receiving iron with lead and cadmium.
Acetates↗
Reproductive toxicity of commercial PCB mixtures: LOAELs and NOAELs from animal studies.
This paper reviews the developmental/reproductive toxicity of commercial polychlorinated biphenyl (PCB) mixtures in animals and reports on the "no-observable-adverse-effect levels" (NOAELs) and "lowest-observable-adverse-effect levels" (LOAELs) from these studies. Identification of the lowest effective doses for reproductive toxicity of PCB mixtures is difficult because a variety of reproductive and developmental effects have been reported in several species using different commercial mixtures. Factors to be considered include sensitivity of the end point, sensitivity of species, study quality, biological plausibility, and relevance to humans. End points affected at the lowest doses (sensitive end points) included postnatal growth, development, and function. Among species for whom sensitive end points have been evaluated, a LOAEL of 0.25 mg/kg/day was identified for rodents on the basis of developmental delays in growth and behavioral function, and a LOAEL of 0.008 mg/kg/day was identified for nonhuman primates based on postnatal skin hyperpigmentation. NOAELs were not identifiable for these sensitive end points because effects were reported at the lowest doses tested.
Animals↗
Assessment of the reproductive toxicity of a complex mixture of 25 groundwater contaminants in mice and rats.
The potential reproductive toxicity of a mixture of 25 chemicals (MIX) formulated to simulate contaminated groundwater supplies near hazardous waste dumps was evaluated in CD-1 Swiss mice and Sprague-Dawley rats using the reproductive assessment by continuous breeding protocol. Male and female mice and rats were exposed to MIX in the drinking water at concentrations of 1, 5, and 10% of a technically achievable stock solution. For mice, body weight and feed consumption were not affected by MIX but water consumption was decreased for both the 5 and 10% MIX groups in both F0 and F1 animals. For F0 mice, the number of live pups/litter was decreased at 10% MIX and the number of females/litter was decreased 10 and 17% at the mid and high MIX dose, respectively. Vaginal cytology was normal, as were testis weight and testicular spermatid head count. For F1 mice, fertility was unaffected, but there was a decreased number of female pups/litter (19%) and a decreased adjusted live pup weight at 10% MIX. At necropsy, cauda epididymal sperm concentration and spermatid head count were reduced (20%) in the presence of normal testis, epididymis, prostate, seminal vesicle, liver, and kidney/adrenal weight. Female estrous cyclicity was altered at 5 and 10% MIX with normal kidney/adrenal, uterus, and ovary/oviduct weight. For rats, F0 body weight and feed consumption were not affected by MIX but water consumption was decreased 10, 30, and 40% in the low-, medium-, and high-dose MIX groups, respectively, and 39% in the high-dose MIX F1 animals. Rat fertility was normal but there was a decreased number of male pups/litter (11%) and a decreased live pup weight (6%) at 10% MIX. Male and female (F1) pup weights were decreased on Postnatal Days 0, 4, 7, 14, and 21 (10% MIX) and remained lower through necropsy on Day 120 +/- 10. F1 fertility was normal but F2 pup weights were decreased (10% MIX). At necropsy, F1 (10% MIX) male body weight was decreased 16% and relative kidney, testis, epididymis, and prostate weights were increased in the presence of normal sperm concentration percentage motile sperm and percentage abnormal sperm. Estrous cyclicity was normal as were kidney/adrenal and ovary weight while female liver weight was reduced 14%. In summary, a "cocktail" of 25 chemicals commonly found in contaminated groundwater at or near hazardous waste sites was administered in drinking water at doses which resulted in severely decreased water consumption in both mice and rats.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Racemic mixtures: harmless or potentially toxic?
Issues involved in the development and evaluation of racemic drug mixtures are described. Administration of a racemic drug mixture is in reality administration of two drugs with distinct pharmacokinetic and pharmacodynamic properties. Compared with the active enantiomer, the inactive enantiomer in a racemic mixture often has different rates of absorption, metabolism, and excretion, as well as different affinities for tissue receptor and protein receptor binding sites. It may be an agonist or antagonist, produce adverse effects, increase efficacy, or place an undue burden on clearance mechanisms. Thus, the pharmacokinetic and pharmacodynamic properties, pharmacologic activity, and toxicity of each enantiomer in a racemic drug mixture need to be determined. When pharmacokinetics of enantiomers differ, the contribution of each enantiomer to effectiveness and toxicity and whether the mixture may be more beneficial than a single enantiomer will need to be considered before racemic mixtures are marketed.
Animals↗
Joint algal toxicity of 16 dissimilarly acting chemicals is predictable by the concept of independent action.
For a predictive assessment of the aquatic toxicity of chemical mixtures, two competing concepts are available: concentration addition and independent action. Concentration addition is generally regarded as a reasonable expectation for the joint toxicity of similarly acting substances. In the opposite case of dissimilarly acting toxicants the choice of the most appropriate concept is a controversial issue. In tests with freshwater algae we therefore studied the extreme situation of multiple exposure to chemicals with strictly different specific mechanisms of action. Concentration response analyses were performed for 16 different biocides, and for mixtures containing all 16 substances in two different concentration ratios. Observed mixture toxicity was compared with predictions, calculated from the concentration response functions of individual toxicants by alternatively applying both concepts. The assumption of independent action yielded accurate predictions, irrespective of the mixture ratio or the effect level under consideration. Moreover, results even demonstrate that dissimilarly acting chemicals can show significant joint effects, predictable by independent action, when combined in concentrations below individual NOEC values, statistically estimated to elicit insignificant individual effects of only 1%. The alternative hypothesis of concentration addition resulted in overestimation of mixture toxicity, but differences between observed and predicted effect concentrations did not exceed a factor of 3.2. This finding complies with previous studies, which indicated near concentration-additive action of mixtures of dissimilarly acting substances. Nevertheless, with the scientific objective to predict multi-component mixture toxicity with the highest possible accuracy, concentration addition obviously is no universal solution. Independent action proves to be superior where components are well known to interact specifically with different molecular target sites, and provided that reliable statistical estimates of low toxic effects of individual mixture constituents can be given. With a regulatory perspective, however, fulfilment of both conditions may be regarded as an extraordinary situation, and hence concentration addition may be defendable as a pragmatic and precautionary default assumption.
Algorithms↗
Component-based and whole-mixture techniques for addressing the toxicity of drinking-water disinfection by-product mixtures.
Chemical disinfection of water is of direct public health benefit as it results in decreased water-borne illness. The chemicals used to disinfect water react with naturally occurring organic matter, bromide, and iodide in the source water, resulting in the formation of disinfection by-products (DBPs). Despite the identification of several hundred DBPs, more than 50% of the mass of total organic halide formed during chlorination remains unidentified. The toxic contribution of the DBPs that are formed and present but not yet chemically identified, the unidentified fraction, has been largely unexplored. A better understanding of the potential for adverse human health consequences associated with exposure to the DBPs present in drinking water will be gained by integration of knowledge on the toxicity of individual DBPs; simple, defined DBP mixtures; complex, environmentally realistic DBP mixtures with partial chemical characterization; and the unidentified fraction.
Chlorine Compounds↗
Radioprotective and toxic effects of a mixture of AET and 5-methoxytryptamine in mice.
The authors studied the radioprotective efficacy and toxicity of an AET + 5-methoxytryptamine mixture and its effect on the course of respiratory exchange, using different weight ratios of the two components. The optomum was found to be 150 mg AET/kg b.w + 25 mg 5-MOT/kg b.w. This mixture gave very good protection in the supralethal exposure range and markedly prolonged its duration. The high toxicity of this mixture was abolished by the pre-administration of glutathione. Raised and longer protection was also manifested in the course of respiratory exchange, showing that an association exists between changes in energy metabolism and raised radioresistance of the organism.
5-Methoxytryptamine↗
Evaluation of the reproductive and developmental toxicity of a fluoroalkylethanol mixture.
The objective of these studies was to evaluate the reproductive and developmental toxicity of a commercial fluoroalkylethanol mixture, which is an intermediate in the production of fluorotelomers. The test substance was administered daily by gavage to Sprague-Dawley rats as a suspension in 0.5% aqueous methylcellulose. In a one-generation reproductive toxicity study, rats (20 per sex per group) were given dosages of 0, 25, 100, or 250 mg kg(-1) day(-1) for a period of 74 days prior to cohabitation, and during mating, gestation, and lactation. Body weights, feed consumption, clinical signs, gross pathology, sperm parameters, estrous cyclicity, and reproductive performance were evaluated for the P1 generation. The F1 offspring were.evaluated during the lactation period for growth and survival and given a gross pathology examination at weaning. A subset of the offspring were retained; body weights, feed consumption, clinical signs, and age at onset of vaginal opening and preputial separation were evaluated, and gross pathology was performed on postnatal day 60. In the developmental toxicity study, groups of time-mated Sprague-Dawley female rats were given the test substance as a suspension in 0.5% aqueous methylcellulose at daily dosages of 0, 50, 200, or 500 mg kg(-1) day(-1) by gavage on gestation days 6-20. During the in-life portion of the study, growth parameters and clinical observations were made. On gestation day 21, dams were euthanized, and the thoracic and abdominal viscera were examined. The uterine contents were removed and examined, and fetuses were evaluated for any alterations. In the reproduction study, litter size at birth, number of live pups per litter on day 0 and 4 of lactation, and pup weights during lactation were reduced in groups administered > or =100 mg kg(-1) day(-1). No other reproductive parameters were affected. There were no adverse reproductive effects observed at 25 mg kg(-1) day(-1). In the developmental toxicity study, reduced maternal body weight parameters, increased perineal fur staining, and increased fetal skeletal alterations were observed at 500 mg kg(-1) day(-1). There was no maternal or developmental toxicity at 50 or 200 mg kg(-1) day(-1). Under the conditions of the studies, the no-observed adverse effect levels for this mixture were 25 mg kg(-1) day(-1) for subchronic toxicity and reproductive parameters and 200 mg kg(-1) day(-1) for developmental toxicity end points. No functional reproductive or developmental effects were observed at dose levels that did not adversely affect adult animals.
Administration, Oral↗
Toxicity and phototoxicity of mixtures of highly lipophilic PAH compounds in marine sediment: can the SigmaPAH model Be extrapolated?
The additivity of toxic units was tested using sediments contaminated with mixtures of highly lipophilic (log Kow > 4.5) parent and alkylated PAHs. The direct toxicity and photoinduced toxicity of these mixtures were examined in standard 10-day sediment toxicity tests using the infaunal amphipod Rhepoxinius abronius, with mortality and the survivors' ability to rebury as endpoints. Survivors of the initial 10-day tests were then exposed for 1 h to ultraviolet (UV) radiation and the results compared to initial (10-day) endpoints. Tissue residues and lipids were measured and biota-sediment accumulation factor (BSAF) values determined. The results indicated that the bioaccumulated contaminants were not initially toxic, however, they were highly phototoxic. Although the summed toxic units of these contaminants appeared to be nonadditive, additivity was not disproved as inaccuracies in extrapolating the Kow-LC50 QSAR or insufficient exposure duration might also have accounted for the observed results. Critical body residue (CBR) estimates for R. abronius were similar while BSAF values were much larger (10x) in comparison to other studies, which used amphipods and PAHs. The phototoxicity of mixtures of contaminants were similar to the phototoxicity of single contaminants when expressed on a molar basis, which suggests that phototoxicities may be roughly additive.
Journal Article↗
Subchronic toxicity of a fluoroalkylethanol mixture in rats.
The objective of this study was to evaluate the subchronic toxicity of a commercial fluoroalkylethanol mixture, which is an intermediate in the production of fluoroorganic compounds that are used as protectants and surfactants. The test substance was administered daily by gavage to Sprague-Dawley rats as a suspension in aqueous methylcellulose. The dosages were 0, 25, 100, or 250 mg kg(-1) day(-1). A 1- and 3-month recovery period was included to evaluate the reversibility of toxic effects. No test substance-related mortality or neurotoxicity occurred. Body weights and/or nutritional parameters were significantly reduced at 100 and 250 mg kg(-1) day(-1), and these effects were reversible. Broken and absent teeth were observed in rats dosed with 250 mg kg(-1) day(-1), and microscopic tooth lesions (ameloblast degeneration/disorganization) occurred at 100 and 250 mg kg(-1) day(-1) and persisted with decreased severity throughout recovery. Decreased red cell mass parameters occurred at 90 days in the 250 mg kg(-1) day(-1) group, but red cell counts were normal thereafter during recovery. A persistent elevation of liver weights was seen in groups given > or =100 mg kg(-l) day(-1). The increased weights correlated with microscopic hepatocellular hypertrophy only in males and females administered 250 mg kg(-1) day(-1). Hepatic beta-oxidation was increased in a dose-dependent manner and persisted through 1 month of recovery at 250 mg kg(-1) day(-1). Increased kidney weights were observed at 25 (females only), 100, and 250 mg kg(-1) day(-1). These elevated weights persisted in the high dose after recovery and correlated with microscopic tubular hypertrophy (males only). Thyroid follicular hypertrophy was present at 100 and 250 mg kg(-1) day(-1) but was not present after recovery. Total fluorine in whole blood increased with continuous dosing and achieved steady state in approximately 42 days. Both plasma and urine fluoride levels were elevated in a dose-dependent manner. Under the conditions of the study, the no-observed adverse effect level for this mixture was 25 mg kg(-1) day(-1) for subchronic toxicity.
Administration, Oral↗
4-week inhalation toxicity study with a mixture of dichloroethylene and perfluorobutylethylene in rats.
Inhalation studies were conducted to determine the potential subchronic toxicity of a mixture of trans-1,2-dichloroethylene (70%), cis-1,2-dichloroethylene (5%), and perfluorobutylethylene (25%). Groups of rats were exposed to 0, 400, 2000, or 8000 ppm concentrations of the mixture vapor 6 h/day, 5 days/wk, for a total of 20 exposures. Subgroups of rats were further observed during a 1-mo recovery period. Functional observational battery (FOB) and motor activity (MA) behavioral tests were conducted prior to initiation of the exposures, during exposure wk 4, and after a 1-mo postexposure recovery period. Clinical pathology evaluations were conducted at the end of the exposure period and after a 1-mo recovery period. At the end of the 4-wk exposure period, tissues from rats were collected, histologically processed, and evaluated by light microscopy. Test substance-related, biologically significant decreased body weights and body weight gains occurred in male and female rats exposed to 8000 ppm. In addition, test substance-related, statistically significant decreases in food consumption and/or food efficiency were observed in male rats exposed to 8000 ppm. During exposures to 8000 ppm, some rats exhibited tremors and ataxia. Usually tremors and ataxia were observed within 1 h after initiation of the daily exposure period and were observed during each exposure day. Tremors were also observed during 1 exposure day in the 2000 ppm animals. In addition to the tremors and ataxia, rats exposed to 2000 ppm or 8000 ppm had a diminished and/or no alerting response to a sharp, sound stimulus during each of the daily exposure periods. These effects were transient since no clinical observations of compromised neurological function were detected when the rats were evaluated upon return to the animal room following exposure. Daily reoccurrence of this apparently acute effect in the 8000 ppm group did not produce enduring neurological changes since there were no test substance-related effects on FOB parameters or on MA conducted the day following the last exposure or during the recovery period. In addition, there were no toxicologically significant changes in hematology, clinical chemistry, or urinalysis parameters in either males or females for any exposure concentration; and there were no test substance-related gross or microscopic morphological changes in males or females administered any exposure concentration. Under the conditions of the study, the no-observed-effect level (NOEL) was 400 ppm in males and females based on clinical signs of toxicity during exposure to 2000 or 8000 ppm.
Animals↗
Toxicity of a phytosterol mixture to grayling (Thymallus thymallus) during early developmental stages.
The study concerns the toxicity of a phytosterol mixture, ultrasitosterol, consisting mainly of beta-sitosterol 75.7% and beta-sitostanol 13.0%, to grayling (Thymallus thymallus) embryos. Eyed eggs were exposed to three concentrations (1 microg/l, 10 microg/l, and 50 microg/l) of ultrasitosterol for 4 weeks. Embryos and later on hatched fry were taken for triiodothyronine (T3), thyroxine (T4), and histopathological analyses after 7, 14, 21, and 28 days of exposure. Most of the eggs (>95%) hatched during the first week of exposure, and ultrasitosterol treatment shortened hatching time significantly (p < or = 0.0001) at all exposure concentrations in comparison to the control. Ultrasitosterol did not have any significant effect on T3 or T4 levels in the embryo extracts. However, an interesting observation was that T3 levels increased in all treatments and in the control near the time of hatching. In conclusion, ultrasitosterol showed potential to affect the development of grayling embryos and fry, but further long-term exposure experiments are needed to verify these changes in more detail.
Animals↗
[Are mixtures of local anesthetics toxic as single substances? Comments on the paper by Ch. Schnorr et al.: Local anesthetic mixtures in different regional anesthesia procedures].
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Anesthetics, Local↗
Study on the toxicity of binary equitoxic mixtures of metals using the luminescent bacteria Vibrio fischeri as a biological target.
Results from two mathematical approaches to predict the toxicity of all the possible binary equitoxic mixtures of Co, Cd, Cu, Zn and Pb were compared to the observed toxicity of these mixtures to Vibrio fischeri bacteria. Combined effect of the metals was found to be antagonistic for Co-Cd, Cd-Zn, Cd-Pb and Cu-Pb, synergistic for Co-Cu and Zn-Pb and merely additive in other cases, revealing a complex pattern of possible interactions. Besides, Cd appears much less toxic to the bacterial model than to animal cells. The synergistic effect of the Co-Cu combination and the strong lowering of Pb toxicity in the presence of Cd deserve much attention when establishing environmental safety regulations.
Aliivibrio fischeri↗
Toxicity of complex chemical mixtures: acute and long-term effects on different life stages of zebrafish (Brachydanio rerio).
Acute and long-term toxicity of 3,4-dichloroaniline and lindane to zebrafish were examined in tap water and water from the Rhine River and the toxicity of the binary mixture 3,4-dichloroaniline/lindane in tap water was investigated. The acute toxicity of 3,4-dichloroaniline and lindane was not influenced by the complex matrix of river water compared with tap water. The binary mixture of 3,4-dichloroaniline and lindane demonstrated an additive effect in the acute test. The survival rate of early life stages in river water was reduced by lindane (80 micrograms/liter), whereas the effects of 3,4-dichloroaniline on survival and growth were visible but not significant. The binary mixture of 2 micrograms/liter, 3,4-dichloroaniline and 40 micrograms/liter lindane in tap water had an influence on growth on the early life stages of zebrafish.
Aniline Compounds↗
Toxicity testing of chemical mixtures: some general aspects and need of international guidelines.
The topics discussed by the Working Group on Toxicity Testing of Chemical Mixtures included the following (1) the study designs and results from two real-life exposure scenarios as additional information to the various investigations reported at the conference; (2) the need to take into consideration low-level, long-term exposure (i.e. mimicking human exposure conditions) as well as the issue of limited resources in experimental toxicology studies; (3) the importance of exploring alternative and predictive toxicology methodologies to minimize animal use and to conserve resources; (4) the realization that interactive toxicity should include the consideration of physical and biological agents in addition to chemicals. Two specific studies reported at the conference were also discussed. A number of recommendations were made concerning the planning and implementation of toxicology studies on chemical mixtures.
Animals↗