Acute Toxicity Experiments Research Articles

Urinary taurine as a non-invasive marker of aflatoxin B 1-induced hepatotoxicity: success and failure

The usefulness of urinary taurine as a non-invasive measure of hepatotoxicity of aflatoxin B 1 (AFB 1) was evaluated: changes in urinary taurine were characterized in a dose-response, acute toxicity experiment and in two sub-chronic, low dose exposure experiments. Urine of young, male, F344 rats was collected for 4 days prior to, and for 3 days after, the treatment with AFB 1. Rats received a single p.o. dose of 0, 0.25, 0.5, 1, 2 or 3 mg AFB 1/kg body wt. A transient increase in urinary taurine was noted with doses of 1, 2 or 3 mg AFB 1/kg. In two sub-chronic exposure experiments, rats were gavaged with 25 μg AFB 1/day for 5 successive days per week for 1 or 2 weeks (approximately 0.25 mg/kg/day). In the first experiment, only a transient increase in urinary taurine during 5 successive doses of AFB 1 was observed, while in the second experiment, urinary taurine rose continuously during the 2 weeks of the AFB 1 treatment. An explanation for these differing results is not obvious. Urinary taurine appeared to be a useful, non-invasive marker when hepatotoxicity was extensive. Unfortunately, at the low doses of AFB 1 (0.25–0.5 mg/kg) as used in carcinogenesis experiments (10 doses of 25 μg/rat), urinary taurine appeared to be an insensitive measure of hepatic damage.

Effect of sediment on growth and acute ammonia toxicity for the school prawn, Metapenaeus macleayi (Haswell)

The effects of sediment on growth, survival, food conversion efficiency and acute ammonia toxicity were determined for the school prawn, Metapenaeus macleayi, a species which normally buries in sediment during the day. Survival of prawns in 70-litre acrylic aquaria was high (90–100%) regardless of the absence of sediment (bare plastic) or the type of sediment (mud, fine sand or coarse sand) or whether the prawns were confined in mesh cages. Growth (weight gain) and food conversion efficiency for confined prawns were significantly lower than for non-confined prawns in aquaria with or without sediment. Prawns grew 11–22% faster in aquaria with sediment than in aquaria without sediment although the type of sediment had no effect on growth. In a 96-h acute toxicity experiment, mortality of prawns increased with increasing ammonia concentration and, at a concentration of 31 5–32 mg total ammonia-N (TAN)/I, was higher in aquaria without sediment (30.0 ± 5.8%; mean ± s.e., n = 3) than in those with sediment (6.7 ± 6.7%). Emergence of prawns from the sediment was affected by time of day and ammonia concentration. During the day, emergence increased from 7.3 to 79.2% with increasing ammonia concentration (< 0.05 to 52.8 mg TAN/1), but most prawns were emergent during the night regardless of ammonia concentrations. In aquaria without prawns, ammonia concentrations and pH were always lower in water extracted from the sediment than in the water column. The effects of different arrangements of sediment, filtration and aeration on ammonia concentrations in aquaria are described in relation to conducting and interpreting ammonia toxicity experiments with prawns.

Effect of ambient oxygen concentration upon the acute toxicity of chlorophenols and heavy metals to the groundwater copepod Parastenocaris germanica (crustacea)

Acute static toxicity experiments have been performed under normoxic and hypoxic conditions. The test animals used were adults of the groundwater-adapted copepod Parastenocaris germanica. The animals originated from a sandy, gravelly phreatic aquifer of the Meuse valley in The Netherlands. Toxicants applied were pentachlorophenol, 3,4-dichlorophenol, zinc, and cadmium. The results were statistically evaluated by a log-logistic model. LC 50 and LC 5 values with 95% confidence limits were calculated. Response models of application under both oxygen conditions were compared. The influence of ambient oxygen concentration on sensitivity appeared to be very small; only in the case of pentachlorophenol were hypoxic and normoxic models slightly but significantly different. Comparisons with the sensitivity of other organisms are made and the results are discussed against the specific physiological adaptations of the organisms to groundwater conditions.

Biological activities of trimethylselenonium as influenced by arsenite

The present study was designed to evaluate three biological activities of trimethylselenonium (TMSe +): anticarcinogenicity, toxicity, and nutritional availability. These experiments were carried out in female rats both in the presence and absence of arsenite because arsenite is known to affect selenium metabolism. Supplementation with TMSe + by itself in the diet, at levels of 20, 40, or 80 ppm Se, did not offer any protection against mammary carcinogenesis induced by dimethylbenz(a)anthracene. On the other hand, the coadministration of arsenite (5 ppm As) with the two higher levels of TMSe + resulted in significant tumor suppression. In the acute toxicity experiment, rats were injected subcutaneously with 0.5 or 1 mg Se/kg, preceded 15 minutes earlier by arsenite at doses of 0.5, 1, or 2 mg As/kg. Although treatment with TMSe + or arsenite alone did not produce any sign of toxicity, a synergistic toxic effect was evident with the combination. Regarding the ability of TMSe + to restore hepatic glutathione peroxidase following selenium depletion, it was found that a dietary level of 40 ppm Se was necessary for complete recovery. The nutritional biopotency of TMSe + was not sensitive to either up- or down-regulation by arsenite under conditions where arsenite also enhanced the anticarcinogenic activity of TMSe +. The contrasting effects of arsenite on these two end points suggest that different forms of selenium are involved. It is hypothesized that arsenite might increase the production of a critical metabolite from methylated selenides. However, there is no clear evidence at the present time to suggest whether the same intermediate(s) is responsible for both anticareinogenicity and toxicity.

Effects of toxic cyanobacteria and purified toxins on the survival and feeding of a copepod and three species of Daphnia

Acute toxicity experiments with purified toxins show that four species of zooplankton differ markedly in their physiological sensitivity to cyclic peptide hepatotoxins from Microcystis aeruginosa (microcystin‐LR) and Nodularia spumigena (nodularin). The copepod Diaptomus birgei was most sensitive (48‐h LC50 for microcystin‐LR ranged from 0.45 to 1.00 µg ml‒1), Daphnia pulicaria was least sensitive (48‐h LC50, 21.4 µg ml‒1), and Daphnia hyalina (48‐h LC50, 11.6 µg ml‒1) and Daphnia pulex (48‐h LC50, 9.6 µg ml‒1) were intermediate in sensitivity.Survivorship in the presence of toxic Microcystis was strongly influenced by both physiological sensitivity and feeding behavior. Relatively good survivorship by D. pulicaria was associated with low sensitivity to purified toxin and rapid feeding inhibition in the presence of toxic cells. In contrast, very poor survivorship by D. pulex was associated with greater physiological sensitivity and nearly uninhibited feeding on toxic Microcystis. Intermediate survivorship by D. birgei was associated with food selection capabilities on the one hand and high physiological sensitivity and uninhibited feeding on the other. Our results suggest that zooplankton have evolved both physiological and behavioral adaptations which enhance their abilities to coexist with toxic cyanobacteria.

Phenylpyrazoles, a new class of pesticide: Effects on neuromuscular transmission and acetylcholine responses

AbstractPhenylpyrazoles constitute a newly developed class of chemicals with insecticidal and herbicidal properties. In acute toxicity experiments in rats, near‐lethal doses of phenylpyrazoles produce neurotoxic symptoms with an unknown mode of action. We have investigated the effects of two phenylpyrazoles, SLA4722 and SLA4685, in the frog neuromuscular junction and in the clonal muscle cell line BC3H‐1. In the frog neuromuscular junction SLA4722 at concentrations ⩾ 10−5 M caused a pronounced increase in the frequency of miniature endplate potentials (MEPPs). SLA4685 caused a similar increase but was less potent. In the clonal muscle cell line BC3H‐1, SLA4685 produced a concentration‐dependent block of the acetylcholine (ACh) response (IC50 = 2.4(±0.3) × 10−5 M). At 10−6 M a slight potentiating effect of SLA4685 on the ACh response was observed. SLA4722 was less potent in this preparation. The increased transmitter release might, at least partly, be responsible for the excitatory effects of the phenylpyrazoles in intact animals.

Lethal body burden of triphenyltin chloride in fish: Preliminary results

1. 1. Guppies exposed to several triphenyltin chloride (TPTC) concentrations in water died as soon as a body burden of 20 ± 10 nmol/g fish was reached. 2. 2. Accumulation of TPTC during exposure in acute toxicity experiments can be predicted by using the kinetic parameters of TPTC. 3. 3. The lethal body burden is two orders of magnitude lower than for narcotic organic compounds such as chlorobenzenes.

The relationship between thermodynamics and the toxicity of gadolinium complexes

The suitability of gadolinium complexes as magnetic resonance imaging contrast agents depends on a number of factors. A thermodynamic relationship to toxicity exists if one assumes that the chemotoxicity of the intact complex is minimal but that the toxicity of the components of the complex (free metal and uncomplexed ligands) is substantial. Release of Gd 3+ from the complex is responsible for the toxicity associated with gadolinium complexes; this release appears to be a consequence of Zn 2+, Cu 2+, and Ca 2+ transmetallation in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LD 50 values for four Gd complexes, all become lethally toxic when they release precisely the same quantity of Gd 3+, and by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn 2+ deficiency. Finally, this hypothesis predicts that subtle changes in formulation can further enhance the intrinsic safety of these complexes.

Effect of a metal mixture in diet on the toxicokinetics and toxicity of cadmium, mercury and manganese in rats.

The purpose of this work was to determine whether a metal mixture added to diet influences the toxicokinetics and toxicity of some elements. The metal mixture (MM) used in these experiments was ash (slag) from a coal gasification plant. The effect of this mixture (5 percent in diet) on the toxicokinetic and on the acute or subchronic toxicity of Cd, Hg, Mn was determined in rats of different ages. Rats were exposed for five weeks in toxicokinetic and six weeks in acute toxicity experiments. Sucklings were exposed through their mothers, which received the MM in diet over the pregnancy and lactation period. In toxicokinetic studies, half of the animals additionally received Cd, Hg or Mn (100, 50 or 2000 ppm, respectively) in drinking water. In subchronic experiments, six-week-old albino rats of both sexes were given MM in the diet and Cd, Hg or Mn in drinking water for 16 weeks. In toxicokinetic studies, 115mCd, 203Hg or 54Mn were administered orally or intraperitoneally to mothers and pups. Exposure to MM had no effect on the absorption, retention and organ distribution of these elements determined six days after radioisotope administration. In acute toxicity studies, exposure to MM in diet had no effect on LD50 values obtained eight days after oral administration of Cd, Hg or Mn to rats of different ages. In subchronic experiments, the effect of individual metals (Cd, Hg or Mn) was similar in animals with and without simultaneous exposure to the metal mixture (only a slight potentiation of a few health-effect parameters of cadmium was noticed in some animals). It is concluded that oral exposure to MM in the diet had almost no effect on the toxicokinetics and toxicity of Cd, Hg and Mn. This could be explained by the low level or low bioavailability of elements from MM, by the metal-metal interaction within the mixture or by the choice of health effect indicators determined. These results are presented as one of the potential approaches for studying the health effect of a metal mixture as occurring in the environment.

Acute Toxicity of Binary Mixtures of Five Cations (Cu2+, Cd2+, Zn2+, Mg2+, and K+) to the Freshwater Amphipod Gammarus lacustris (Sars): Alternative Descriptive Models

The combined results of 10 acute toxicity experiments, each testing the joint toxicity of two of the ions Cu2+, Cd2+, Zn2+, Mg2+, and K+, were examined in terms of different response surface models which could be used to make decisions about limiting toxic components in mixtures. The classical probit model for simple similar action described experimental results satisfactorily with a model R2 of 0.282; equations in which probit(p) was described directly by a linear combination of toxicant concentrations fit data significantly better, with an R2 of 0.527. Equations with more complex linear terms and appropriate weighting factors applied to the residual sums of squares yielded R2 values up to 0.931. Predicted LC50 values were midrange compared with published values. Based on the linear description of the probit response, K or Mg in combination with either of Cu, Cd, or Zn had additive effects, the combinations Cu and Cd, Cu and Zn, and Cd and Zn had more-than-additive effects, and Mg and K had less-than-additive effects. The relationships between the response surfaces, other described modes of joint action, the toxic units model, and mixture toxicity indices are discussed.

Toxicity and accumulation of cadmium in the crayfish,Orconectes virilis (Hagen)

The acute toxicity of cadmium to the crayfishOrconectes virilis was determined over a two week exposure period. Crayfish exhibited an increased sensitivity to cadmium over time; LC50 values decreased from 6.1 mg Cd/L for 96 hr to 0.70 mg Cd/L for 14 days. An incipient LC50 value of 0.06 mg Cd/L was also calculated forO. virilis. Whole animal and tissue analyses for cadmium were performed on the crayfish used in the acute toxicity experiments. Whole animal cadmium concentrations exhibited a linear relationship to exposure concentrations as did the gill and antennal glands. Cadmium tissue concentrations were from highest to lowest in the following tissues: gill > hepatopancreas > antennal gland > carapace and abdominal muscle.

Chemical and Biological Investigations of a Transformer Accident at Binghamton, NY

A transformer fire occurred in a state office building in Binghamton, NY on February 5, 1981. Particulates from inside surfaces of ceiling panels on 16 of the 17 floors had concentrations of polychlorinated dibenzofurans (PCDFs) ranging from &lt; 1 part per million (ppm) to 1200 ppm while polychlorinated biphenyl (PCB) concentrations varied from 28 ppm to 23,000 ppm. In spite of the wide variations in contaminant concentrations, complete analytical data from 11 floors showed that there was a consistent PCDF/PCB ratio (0.067 ± 0.026) and also consistent PCDF isomer group distributions (tetra-CDFs, 33 ± 5%; penta-CDFs, 40 ± 3%; hexa-CDFs, 18 ± 7%; hepta-CDFs, 6 ± 3%). It was found that the particulate samples could be successfully ranked in order of their degree of chemical contamination by an in vitro bioassay. The bioassay was based on induction of keratinization or changes in morphology in mouse epithelial cells. Animal toxicology experiments were carried out with a soot sample containing a PCDF concentration which approximated the mean value found on the ceiling particulates. The single dose oral LD values of the soot and its benzene extract equivalent, each administered to female guinea pigs in 0.75% methyl cellulose, were 410 and 327 mg/kg, respectively. These results demonstrated that the soot matrix had virtually no effect on the toxicity of the chemical contaminants in the soot. Morphological alterations in liver tissues from animals receiving the soot were found after examination by electron and light microscopy. Rabbits dermally exposed to the soot and its benzene extract at 500 mg/kg showed evidence of hypertrophy of centrilobular hepatocytes. In addition the rabbits exposed to the soot extract had a local inflammatory reaction at the site of application. In a subchronic feeding experiment carried out for 90 days with guinea pigs, the lowest effect level was found with an accumulated dose of 1.2 mg soot/kg. The observed effects included salivary gland duct metaplasia and decreased relative thymus weights. Based on the chemical analysis data and literature LD values for the more toxic 2,3,7,8-substituted polychlorinated dibenzo-p-dioxins (PCDDs) and PCDFs, it was calculated that the soot contained the equivalent of 44 ppm 2,3,7,8-tetra-CDD in terms of toxicity to guinea pigs. This was in close agreement with the value of 58 ppm derived from the acute oral toxicity experiments. Air sampling, accomplished on 8 floors in the final stages of the building cleanup, showed maximum total PCDF and 2,3,7,8-tetra-CDF concentrations of 264 and 23 pg/m, respectively.

Use of a Radiant Furnace Fire Model to Evaluate Acute Toxicity of Smoke

The design and construction of a radiant furnace are described. Acute toxicity experiments were conducted using the radiant furnace as a fire model to produce smoke from Douglas fir (D. fir), southern yellow pine (SYP), and tempered hard- board (THB). The correlation of blood carboxyhemoglobin (COHb) and mortality to irradiation time, smoke concentration, mass loss, carbon monoxide (CO) con centrations, and carbon dioxide (CO2) concentrations is reported. At 2.5 w/cm 2, toxicity was characterized by post-exposure lethality with sublethal COHb ex posure levels. LC 50's (median lethal concentrations) were 59.5 (D. fir), 66.6 (SYP), and 86.5 mg/L (THB) and the IT50's (median lethal irradiation times) were 6.8 (D. fir), 6.9 (SYP), and 9.3 minutes (THB). For 5.0 w/cm 2, most deaths occurred dur ing the 30 minute exposure and COHb levels were in a lethal range. LC50's at 5.0 w/cm2 were 101.6 (D. fir), 100.1 (SYP), and 58.1 mg/L (THB), and the IT50's were 2.7 (D. fir, SYP) and 2.6 minutes (THB). Data were compared to those produced in other combustion toxicity test methods, and the advantages of the radiant furnace with continuous sample mass-loss monitoring are discussed.

Toxicité aiguë d'un fongicide dithiocarbamate, le thirame, vis à vis de plusieurs espèces animales d'eau douce

Acute toxicity experiments (24, 48, 72 and 96 h) were carried out with an aqueous suspension of thiram (commercial powder titred at 80%). The animal sensitivity was very variable, the 24-h and 96-h LC 50 's being 0·53 ppm and 0·048 ppm ( Dugesia gonocephala, plathelminth), 1882 ppm and 61 ppm ( Asellus aquaticus, crustacean), 0·017 ppm and 0·013 ppm ( Xenopus laevis, amphibian, stage 47), 0·025 ppm and 0·021 ppm ( Xenopus, stage 53). In all cases, the LC 50 related to time can be described by the law y = ax b ; this permitted us to compare the present results with those already obtained in Lymnaea stagnalis (molluscan), Gammarus pulex (crustacean) and larvae of Cloeon dipterum (insect). The slopes of these curves indicate three types of reaction: one in the two crustaceans ( Asellus and Gammarus), one in Lymnaea and Dugesia and one in Cleon and Xenopus larvae. and one in Cloeon and Xenopus larvae. The six species studied can be classified according to increasing sensitivity as follows: Asellus, Lymnaea, Gammarus and Cloeon larvae at the same level, Dugesia and Xenopus larvae; the spectrum of thiram activity is in the range 10 pptm to 5000–6000 ppm: it is then very large. It can be concluded that thiram, a fungicide intensively used in agriculture, presents a real threat to all freshwater fauna.

Ultrastructural changes in skeletal muscle induced by colchicine.

COLCHICINE arrests mitotic division of many plant and animal cells by interfering with the formation of the mitotic spindle. 1-7 Cellular division is arrested at metaphase, bizarre and abnormal nuclear configurations occur, and the cell often dies. Colchicine also has a profound effect on nonmitotic differentiating cells. It induces the formation of cytoplasmic filaments in the interphase HeLa cells in vitro 8 and neurofibrillary tangles in tissue cultures of rat neurons. 9 Neurofibrillary change has recently been noted in the brainstem and spinal cord of rabbits after intracisternal injection of colchicine. 10 The variable effects of colchicine apparently depend on its binding to the subunit protein of microtubules. 11 Although colchicine consistently causes severe ascending paralysis in experimental animals, a thorough morphological study of skeletal muscle has not been undertaken. Ferguson 12 reported delayed paralysis of the hindlimbs in acute toxicity experiments in rats and prominent muscle atrophy in

Myopathy Associated with Chronic Colchicine Toxicity

TOXIC manifestations from the use of colchicine in the treatment or prevention of attacks of acute gouty arthritis, apart from the well known gastrointestinal effects of the drug, are rare. The administration of 2.3 to 4.0 mg. of colchicine daily for a few days to patients with inoperable malignant tumors produced gastrointestinal disturbances, depilation, bone-marrow depression and peripheral neuritis.1 In 1 case the ingestion of 15 mg., for suicidal purposes,2 caused neurologic manifestations similar to those observed in acute animal toxicity experiments.3 In the case presented below the repeated ingestion of toxic doses of colchicine was followed by the development . . .