Toxicity, residue dynamics, and reproductive effects of phthalate esters in aquatic invertebrates

Aquatic invertebrates were exposed to di-n-butyl and di-2-ethylhexyl phthalate esters in water to determine toxicity, accumulation, and reproductive effects of these compounds. The acute toxicities were low and ranged from 2.1 mg/liter to greater than 32 mg/liter. Residue accumulation was rapid resulting in body residues 70-13,600 times that of the water concentration. Phthalate residues were essentially gone after 10 days in fresh water. A reproductive impairment of 60% occurred in Daphnia magna exposed continuously to 3 μg/liter of di-2-ethylhexyl phthalate.     

Studies with the schistosomicide oxamniquine (UK-4271). I. Activity in rodents and in vitro

A single oral or intramuscular dose of oxamniquine (6-hydroxymethyl-2-isopropylaminomethyl-7-nitro-1,2,3,4-tetrahydroquinoline) had potent schistosomicidal action against Schistosoma mansoni in mice and hamsters. No convincing activity was demonstrated against Chinese S. japonicum in either host, or against Nigerian S. haematobium in hamsters, although the schistosomicide hycanthone also was inactive orally against the latter.Male S. mansoni were markedly more susceptible than females in vivo but not in vitro. Against a Puerto Rican strain in mice the oral ED₅₀ and ED₉₉ values were 20 and 44 mg./kg. respectively given as a single dose, and 28·5 and 57·5 mg./kg. respectively given as 5 consecutive daily doses of 5·7 and 11·5 mg./kg.; by the intramuscular route ED₅₀ and ED₉₉ values were 18 and 42 mg./kg. respectively as single doses, and 19·5 and 37 mg./kg. respectively given as 5 consecutive daily injections of 3·9 and 7·4 mg./kg. There were strain differences in reaction to the drug. When administered orally against an East African strain in mice, oxamniquine was 2–3 times more potent than hycanthone, 5–11 times more potent than niridazole and 8–11 times more potent than lucanthone. Oral potency against Puerto Rican S. mansoni in hamsters was similar to that in mice, but intramuscular activity was considerably greater, the single dose ED₅₀ and ED₉₉ being only 6·7 and 12 mg./kg. respectively.The acute LD₅₀ in mice was 1,300 mg./kg. (oral) or more than 2,000 mg./kg. (intramuscular), and by multiple dose regimens toxic symptoms were produced only by doses greatly in excess of the curative levels. Observations in other species and safety tests in man confirmed the suitability of the compound for clinical trial.     

Considerations on Genetic and Environmental Factors That Contribute to Resistance or Sensitivity of Mammals Including Humans to Toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and Related Compounds

The marked species differences in short-term toxicity (30-day LD₅₀) of ca. 10,000 (LD₅₀: guinea pigs ca. 1 μg/kg body wt and Han/Wistar Kuopio rats more than 9600 μg/kg body wt) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the central issues of the controversies that have developed on the validity of risk assessment strategies for TCDD and related compounds. One of the most challenging issues that toxicologists face today is the identification of genes that contribute to or are responsible for increased resistance or sensitivity to TCDD and related compounds. It is assumed that most, if not all, toxic effects of TCDD are mediated more or less through the binding affinity to the Ah receptor. This hypothesis was extended and tries to explain the differences in sensitivity/resistance of animals including humans to TCDD by their total fat (lipid) content. In this respect the gene or genes which is or are responsible for obesity of mammals including humans are of great interest. An obvious linear positive logarithmic relationship between the oral 30-day LD₅₀(μg/kg) of TCDD in different species and strains of mammals and their total body fat content (TBF%) was found: log LD₅₀= 5.30 × log (TBF) − 3.22, or LD₅₀= 0.000603 × (TBF)^5.30. By means of this regression the toxicity of TCDD in mammals including humans of different age and/or body weight can be predicted if their total body fat content is known. Examples of single-gene and polygenic disease models in different mammals, such as nonobese diabetic, diabetic, viable yellow, obese, and fat mice, as well as transgenic mice, and other suitable animal models, such as fatty Zucker rats, Han/Wistar (Kuopio) rats, and minipigs, are discussed, and predicted LD₅₀values of TCDD in these animals and humans are presented.     

Dietary protein and DDT toxicity

Summary Albino rats fed for 28 days from weaning on diets containing progressively smaller percentages of casein become progressively more susceptible to the lethal effects of single toxic oral doses of DDT than are rats fed normal amounts of dietary casein (27%). When the amount of casein in the diet is increased to 81%, the LD₅₀ also declines. The clinical signs of toxicity to DDT at the range of the acute oral LD₅₀ were similar in animals of all dietary groups studied.This project was supported by a grant from the World Health Organization.     

Enhanced immune sera and vaccine: safe approach to treat scorpion envenoming

Irradiation of Androctonus australis hector venom using a dose of 2 kGy has successfully abolished toxicity without reducing its antigenic or immunogenic properties. Toxicity of irradiated antigen was abolished until 20 times of LD₅₀ of native venom. Analysis of physiopathological effects induced by native and irradiated venoms was assessed by the analysis of tissue damage, immunohistochemistry and metabolical analysis in the organs (heart, lungs and liver). Immunological response of Aah venom using native or irradiated venom showed high titers of IgG1 in the plasma of immunized animals with native venom suggesting that Th2 cells were predominantly involved in the immune response. In the other hand, irradiated venom induced high titers of IgG2, indicating a predominantly Th1 type response. A protective effect of immunized mice with irradiated venom was evaluated. Immunized mice were protected from the toxic effects of native venom doses at one, three and six months after immunization. Mice were protected against a challenge of 4 LD₅₀ doses of native venom, one month after immunization. This protective effect was improved and effective at 3 and 6 months, all immunized mice were protected respectively against 6 and 10 LD₅₀ of native venom. At the one-month time point, the protective effect of mice was associated with high levels of antibodies in the plasma of immunized mice. However, despite the persistence of higher protection levels, the antibody titers decreased in a time-dependent manner. These results suggest that additional factors other than circulating antibodies provided the long-term protective activity produced by immunization with irradiated venom.     

The possible formation of tetrachlorodibenzo-p-dioxines in the production of chloranil

Technical chloranil (III) and its precursor 2,4,6-trichlorophenol (II) were examined for the formation of tetrachlorodibenzo-p-dioxines. In the trichlorophenol two isomers were found and characterized as 1,3,6,8-and 1,3,7,9-tetrachlorodibenzo-p-dioxine. The absence of 2,3,7,8-tetrachlorodibenzo-p-dioxine was proved in all samples. The two isomers found in the primary product were synthesized as a mixture. All substances were tested for their acute oral toxicity. The mixture of the isomers of 1,3,6,8- and 1,3,7,9-tetrachlorodibenzo-p-dioxine had an LD₅₀ of more than 5000 mg/kg body wt with female rats. The technical 2,4,6-trichlorophenol had an LD₅₀ of 1365 mg/kg. The technical chloranil had an LD₅₀ of 6951 mg/kg body wt and was free of all isomers of tetrachlorodibenzo-p-dioxine.     

VALUE OF ED50 TESTING IN ASSESSING HAZARDS OF ACUTE POISONING BY CARBAMATES AND ORGANOPHOSPHATES

It is shown from the kinetics of inhibition of cholinesterase by N-methylcarbamates and organophosphates that the LD₅₀ dose is likely to be a much greater multiple of the dose causing signs of poisoning in 50% of the animals (the ED₅₀) for the carbamates than for the organophosphates. The expected difference was demonstrated by a comparison of the LD₅₀s and ED₅₀s, intravenous and intramuscular, of five carbamates (2-isopropoxyphenyl N-methylcarbamate, 3-isopropylphenyl N-methylcarbamate, 6-chloro-3,4-xylyl N-methylcarbamate, 3,4,5-trimethylphenyl N-methylcarbamate, and 3-methyl-5-isopropylphenyl N-methylcarbamate) and two organophosphorus compounds (diethyl 4-nitrophenyl phosphate and dimethyl 4-nitrophenyl phosphate). The slightest evoked tremor was chosen as the most reliable sign of poisoning from which to estimate the ED₅₀ values. Carbamates gave much greater LD₅₀/ED₅₀ ratios than organophosphorus compounds. It is likely that occupational exposure to carbamates will produce incapacitating symptoms at doses well below lethal levels.     

Toxic Properties Of Dialkylnitrosamines and Some Related Compounds

The title compounds, which have some commercial applications, are described, and their toxic action is reviewed. Most results refer to rats.

Their main acute effect is hepatic centrilobular necrosis, though lung lesions may appear. The compounds also induce tumours in liver, lung, and kidney. One, dimethylnitrosamine, has been shown to cause kidney tumours after a single dose. The necrotic and carcinogenic doses of the compounds are closely related.

The relation between structure and toxicity is discussed. Analogous formamides are much less toxic (the LD₅₀'s in rats by intraperitoneal injection of dimethyl- and diethyl-formamides are 3,800 mg./kg. and 1,740 mg./kg.) and they do not cause centrilobular necrosis or tumours.

Nitrosamines are oxidized in vivo and by liver preparations in vitro. Their toxic action is due to the release of powerful alkylating agents in the liver. They also inhibit protein synthesis and alkylate liver protein and ribonucleic acid. In all cases the effective agent appears to be a metabolite.

The possible hazard to man in the uses of these compounds is emphasized.

     

Successful Placement of Handicapped Workers

The toxicity of chlorpropham progressively increased when given orally to albino rats previously fed from weaning on purified diets containing progressively less protein. For example, the acute oral LD₅₀ ± standard error (SE) of chlorpropham was 1.20 ± 0.14 gm/kg in rats previously fed no dietary protein and 10.39 ± 1.58 in rats previously fed normal amounts (26%) of protein as casein. The type of dietary protein also affected susceptibility to chlorpropham toxicity. Rats previously fed normal amounts of dietary protein as casein were more resistant to the toxic effects of chiorpropham than were rats fed mixed “natural” proteins in the form of a standard laboratory chow. The clinicopathoiogic syndrome of toxicity to chlorpropham at the range of the LD₅₀ was essentially the same in rats of all dietary groups studied.     

Assessment of Toxicity and Potential Risk of Butene-fipronil Using Drosophila melanogaster, in Comparison to Nine Conventional Insecticides

The toxicities of butene-fipronil to Drosophila melanogaster were evaluated, in comparison to nine conventional insecticides. According to the mean LD₅₀ values of the larvae from CS, w ¹¹¹⁸ and Oregan strains, butene-fipronil, abamectin, spinosad and chlorpyrifos exhibited high levels of toxicity. Imidacloprid, α-cypermethrin and clothianidin showed middle levels of toxicity. And acephate, methomyl and acetamiprid had low levels of toxicity. To the adults, butene-fipronil, α-cypermethrin, spinosad, and chlorpyrifos were relatively more toxic, whereas acephate, methomyl, acetamiprid, imidacloprid, clothianidin and abamectin were relatively less toxic. Butene-fipronil and abamectin were more toxic to larvae. In contrast, spinosad, α-cypermethrin, and clothianidin were more toxic to adults. Moreover, the toxic risk assessment using a risk quotient value revealed that butene-fipronil was safe to D. melanogaster adults. Thus, our results suggested that butene-fipronil is harmful to D. melanogaster larvae, but it is relatively safe to the adults.     

Oral Toxicity of Fipronil Insecticide Against the Stingless Bee <Emphasis Type="Italic">Melipona scutellaris</Emphasis> (Latreille, 1811)

For a better evaluation of the model using Apis mellifera in toxicology studies with insecticides, the oral acute toxicity of the insecticide fipronil against the stingless bee Melipona scutellaris was determined. The results showed that fipronil was highly toxic to M. scutellaris, with a calculated LC₅₀ (48 h) value of 0.011 ng a.i./μL of sucrose solution and an estimated oral LD₅₀ (48 h) of 0.6 ng a.i./bee. Our results showed that M. scutellaris bee is more sensitive to fipronil than the model specie A. mellifera.     

Acute Toxicity of Ammonia,Nitrite and Nitrate to Shrimp <Emphasis Type="Italic">Litopenaeus vannamei</Emphasis> Postlarvae in Low-Salinity Water

Shrimp farming in low salinities waters is an alternative to increasing production, and counteracting disease problems in brackish and marine waters. However, in low-salinity waters, toxicity of nitrogen compounds increases, and there is no available data of its acute toxicity in shrimp postlarvae. This study determined the acute toxicity of ammonia, nitrite and nitrate in Litopenaeus vannamei postlarvae in 1 and 3 g/L salinity, as well as the safety levels. The LC₅₀ confirms that nitrite is more toxic than ammonia and nitrate in low salinity waters, and that its toxicity increases with a decrease in salinity. The safe levels estimated for salinities of 1 and 3 g/L were 0.54 and 0.81 mg/L for total ammonia–N, 0.17 and 0.25 mg/L for NO₂–N, and 5.6 and 21.5 mg/L for NO₃–N, respectively.     

Evaluation of Acute and Sub-Acute Toxicity of Aqueous Extracts of Artemisia afra Leaves on Brain,Heart and Suprarenal Glands in Swiss Albino Mice

BackgroundThe majority of population rely on traditional medicine as a source of healthcare. Artemisia afra is a plant traditionally used for its medicinal values, including treatment of malaria in many parts of the world. Currently, it is also attracting attention because of a claim that a related species, Artemisia annua, is a remedy for the COVD-19 pandemic. The aim of the present study was to investigate toxic effects of A. afra on brain, heart and suprarenal glands in mice aged 8–12 weeks and weighing 25–30g.MethodsLeaves of A.afra were collected from Bale National Park, dried under shade, crushed into powder and soaked in distilled water to yield aqueous extract for oral administration. For acute toxicity study, seven treated and one control groups, with 3 female mice each, were used. They were given a single dose of 200mg/kg, 700mg/kg, 1200mg/kg, 2200mg/kg, 3200mg/kg, 4200mg/kg or 5000mg/kg b/wt of the extract. For the sub-acute toxicity study, two treated and one control groups, with 5 female and 5 male mice each, were used. They were daily treated with 600mg/kg or 1800mg/kg b/wt of extract.ResultsLD₅₀ was found to be greater than 5000mg/kg indicating that the plant is relatively safe. In the sub-acute study, no signs of toxicity were observed in all treatment groups. On microscopic examination of the brain, heart and suprarenal glands no sign of cellular injury was observed.ConclusionThe findings of this study suggest that the leaves extract of A. afra is relatively safe in mice.     

The effects of dimethylformamide on female mongolian gerbils,Meriones unguiculatus

Summary The female Mongolian Gerbil does not appear to be highly sensitive to DMF when compared to other species. Induced liver pathology and changes in body weight were similar irrespective of the route of administration. The toxic response from a single administration, as noted by the LD₅₀, appears to be within the 3,000 to 4,000 mg/kg for IP, SC and intubated quantities. Consumption studies had the following LD₅₀ values for related toxin levels: 66,000 ppm, 3,929 mg/kg in 3 days; 34,000 ppm, 3,846 mg/kg in 6 days; 17,000 ppm, 90,206 mg/kg in 80 days and 10,000 ppm, more than 100,000 mg/kg in more than 200 days.DMF imbibed at 10,000 ppm for 30 days in drinking water failed to cause observable liver, kidney or weight changes. Higher dosage levels of DMF, as reported, did cause death and physiological changes. DMF levels causing loss of weight were also causing serious pathological changes in the liver or kidneys in the form of necrotic foci. This loss of weight was generally associated with acute toxicity.     

The acute and chronic toxicity of acetone,dimethyl formamide,and triethylene glycol toDaphnia magna (Straus)

Acute and chronic toxicity tests were performed withDaphnia magna (Straus) and three organic solvents commonly used to facilitate the solubilization of lipophilic compounds during acute toxicity tests. The 48-hr LC50 values were: acetone 39000μl/L; dimethyl formamide, 13000μl/L; triethylene glycol, 35000μl/L. Maximum acceptable toxicant concentrations determined during the chronic toxicity tests with acetone, dimethyl formamide, and triethylene glycol were between 1400 and 2800μl/L, 1200 and 2500μl/L, and 5500 and 11000μl/L, respectively. Triethylene glycol was the least toxic solvent and is recommended as the primary choice when selecting a carrier solvent. All three solvents were sufficiently low in toxicity to suggest that the recommended usage limits (500μl/L during acute toxicity tests, 100μl/L during long-term toxicity tests) are adequate for the prevention of solvent related toxicity toD. magna.     

Enantioselectivity in aquatic toxicity of synthetic pyrethroid insecticide fenvalerate

Synthetic pyrethroids (SPs) are a family of chiral insecticides with a large number of stereoisomers. Fenvalerate (FV) is one of the most potent pyrethroid insecticides, controlling a wide range of insect pests in agricultural fields, public health situations and animal houses. FV contains two chiral centers. In this study, four stereoisomers of FV were absolutely separated by high-performance liquid chromatography with a commercial chiral column, CHIRALCEL^® OJ-H, using n-hexane containing 1,2-dichloroethane and ethanol as mobile phase. Toxicity assays of each isomer and racemate of FV were performed using Daphnia magna (D. magna), zebrafish (Danio rerio) and zebrafish embryo-larval. In the acute toxicity of D. magna, significant differences were observed: the 24 h EC₅₀ of αS-2S-FV was 51 times more toxic than the αR-2R-FV, and the 48 h LC₅₀ results showed that the αS-2S-FV was 99 times more toxic than αR-2R-FV. In the toxicity assay of D. rerio, dramatic differences were also found: the LC₅₀ value of αS-2S-FV was 17, 22, 39 and 56 times more toxic than the αR-2R-FV at 24, 48, 72 and 96 h, respectively. The assays of 4-day-old zebrafish embryo-larval showed that the exposure to FV enantioselectively induced crooked body, yolk sac edema and pericardial edema and that the αS-2S-FV was 3.8 times stronger than the other isomers in 96-h mortality. The results indicate that the enantiomeric differences should be taken into consideration in assessing the ecological effects of SPs.     

Toxicity of mono- and diesters of o-phthalic esters to a crustacean, a green alga, and a bacterium

The degradation of phthalic acid diesters may lead to formation of o-phthalic acid and phthalic acid monoesters. The ecotoxic properties of the monoesters have never been systematically investigated, and concern has been raised that these degradation products may be more toxic than the diesters. Therefore, the aquatic toxicity of phthalic acid, six monoesters, and five diesters of o-phthalic acid was tested in three standardized toxicity tests using the bacteria Vibrio fischeri, the green algae Pseudokirchneriella subcapitata, and the crustacean Daphnia magna. The monoesters tested were monomethyl, monoethyl, monobutyl, monobenzyl, mono(2-ethylhexyl), and monodecyl phthalate, while the diesters tested were dimethyl, diethyl, dibutyl, butylbentyl, and di(2-ethylhexyl)phthalate, which were assumed to be below their water solubility. The median effective concentration (EC50) values for the three organisms ranged from 103 mg/L to >4.710 mg/L for phthalic acid, and corresponding values for the monoesters ranged from 2.3 mg/L (monodecyl phthalate in bacteria test) to 4,130 mg/L (monomethyl phthalate in bacteria test). Dimethyl and diethyl phthalate were found to be the least toxic of the diesters (EC50 26.2-377 mg/L), and the toxicity of the other diesters (butylbenzyl and dibutyl phthalate) ranged from 0.96 to 7.74 mg/L. In general, the phthalate monoesters (degradation products) were less toxic than the corresponding diesters (mother compounds).     

The Effects of Water Quality and Age on the Acute Toxicity of Copper to the Florida Apple Snail, Pomacea paludosa

Copper (Cu)-containing compounds have been used in Florida as fungicides, herbicides, and soil amendments, resulting in elevated Cu in the aquatic ecosystem. The Florida apple snail (Pomacea paludosa), a key species in south Florida, may be adversely affected by Cu. Water-quality parameters, such as hardness, dissolved organic carbon (DOC), pH, and alkalinity, affect metal bioavailability and toxicity in aquatic organisms; however, it is uncertain to what extent these factors affect Cu toxicity in the Florida apple snail. The research presented here characterized the acute (96-hour) toxicity of Cu in water to the Florida apple snail at various life stages and under different water-quality parameters. Cu was more toxic to juvenile than adult apple snails. There was no difference between the 96-hour LC₅₀ at pH 5.5 and 6.5; however, the 96-hour LC₅₀ values at pH 7.5 and 8.5 were greater than at lower pHs. The decrease in Cu²⁺ above pH 7, as predicted by the MINTEQ model, accounted for the pH effect. Cu toxicity decreased as DOC increased from 0.2 to 30 mg/L. Unlike other aquatic organisms, hardness had no effect on Cu toxicity to the Florida apple snail, suggesting another mechanism of toxicity. Whole-body tissue analysis indicated that the lethal body burden of 120-day-old snails exposed to Cu for 4 days was 30 mg/kg Cu dry weight. Multiple regression analysis indicated that Cu toxicity was a function of organism age, DOC, and pH.     

Interclonal Variation in the Acute and Delayed Toxicity of Cadmium to the European Prosobranch Gastropod Potamopyrgus antipodarum (Gray)

The lethal responses of three European clones—A, B, and C—of the prosobranch snail Potamopyrgus antipodarum to acute cadmium exposure were examined by the use of a conventional LC₅₀ test and a delayed toxicity test. The questions addressed were: (1) Are there differences in susceptibility (LC₅₀ values and uniformity of response) among the three European clones of P. antipodarum? (2) Are the patterns of differences in susceptibility among clones observed in the LC₅₀ test also observed for the delayed toxicity test? (3) Is there concordance in the ranking of susceptibility among clones under acute cadmium exposure and under chronic cadmium exposure? The results showed that the widths of the tolerance distribution differed among clones. Clones A and B had a steeper slope than clone C (for clone A the difference was marginally significant), which indicates that individuals from clones A and B showed a more uniform response to acute lethal cadmium stress than individuals from clone C. On the basis of the measured differences in LC₅₀ values, clone A individuals showed the highest tolerance to acute cadmium (LC₅₀ value: 1.92 mg Cd L^?1) followed by clone B (LC₅₀ value: 1.29 mg Cd L^?1) and clone C (LC₅₀ value: 0.56 mg Cd L^?1). Clone C was significantly less tolerant than clones A and B. The delayed toxicity test showed a similar pattern to the LC₅₀ test with regard to tolerance differences among clones; however, mortality continued following transfer to clean water, indicating that cadmium was lethal at much lower concentrations than indicated by the conventional LC₅₀ test. Results of the LC₅₀ test and the delayed toxicity test in the present study were in general agreement with results from chronic cadmium exposure experiments (Jensen et al.[2000]Ecol Appl[submitted]), i.e., the least susceptible clone A in the acute cadmium exposure test was also the least susceptible clone in the chronic cadmium exposure test. Based on the dramatic differences between the LC₅₀ and the cadmium exposure concentrations causing delayed toxicity, we suggest that the potential for delayed toxicity should be given greater consideration in ecotoxicity testing.