Chronic Toxicity Data Research Articles

Aquatic test organisms and methods useful for assessment of chronic toxicity of chemicals

Literature data on the toxicity of chemicals to fish, a daphnid, and a mammal were reviewed to form a basis for efficiently determining chronic no-effect levels for many chemicals as may be required by law. The principal measurements used in statistically determining chronic no-effect levels for chemicals are the acute LC 50, the maximum acceptable toxicant concentration (MATC), and the application factor (AF). Equations for these measurements were developed to help in predictive calculation of AFs, MATCs and LC 50's for combinations of related and unrelated organisms (fish and Daphnia) and chemicals. None of these methods are entirely reliable but are useful for early assessment of chronic toxicity to determine whether extensive testing appears necessary. The degree of predictability increases with the use of shortened or short-life-cycle chronic toxicity data.

Potent carcinogenicity of nitrosodiethanolamine in rats.

Nitrosodiethanolamine is found in synthetic cutting oils and in many cosmetic preparations and is probably the N-nitroso compound to which human exposure is greatest. It is formed by reaction of the commonly used amines diethanolamine and triethanolamine with nitrosating agents. An assessment of the possible risk in human exposure to nitrosodiethanolamine must be based on sound chronic toxicity data. A previously published chronic test of this compound in rats has shown it to induce liver tumours after very high oral doses, and tumours of the nasal cavity after administration of high repeated doses to Syrian hamsters by subcutaneous injection. To improve our understanding of the carcinogenic potency of nitrosodiethanolamine, we undertook a more extensive study, in which the compound was administered at concentrations ranging from 3,900 to 31,250 parts per million (p.p.m.) in drinking water, to groups of rats for about 6 months. We report here that when the animals were killed, all bore hepatocellular carcinomas, many of which metastasized at the higher doses, indicating that nitrosodiethanolamine is a carcinogen of considerable potency in the rat. However, it is inactive or very weakly active in short-term tests, such as the Salmonella mutagenesis test developed by Ames.

Correlations Between Daphnia magna and Fathead Minnow (Pimephales promelas) Chronic Toxicity Values for Several Classes of Test Substances

Chronic toxicity values were developed for Daphnia magna with six surfactants and a detergent builder, each selected on the basis of previously existing chronic fish test data. Predictive correlations were examined for testing end points between 21-d Daphnia chronics and 1-yr fish chronics to provide a short-term alternative chronic test species while developing toxicity data for an intermediate trophic level species. For the detergent materials tested, a strong correlation (r = 0.98) exists between Daphnia and fish no-effect concentrations. A replacement term, NOEC (no observed effect concentration), is suggested to clarify interpretive ambiguities associated with the definition of the MATC (maximum acceptable toxicant concentration) value. Additional chronic toxicity data from the current literature for these two test species and several test substances representing metals, polychlorinated biphenyl isomers, and pesticide formulations were similarly compared. A correlation analysis demonstrated an overall Pearson correlation coefficient of 0.79 for these data. Although significant outliers were evident from this correlation, these differences may be due primarily to differences in modes of toxic action of these test substances. The relatively short life cycle and 21-d duration of the test, small water volumes, ease in handling, high fecundity, and good correlation of 21-d chronic data with chronic fish toxicity data make Daphnia chronic tests an attractive alternative to the conduct of longer term fish tests. Key words: Daphnia, Pimephales promelas, toxicity tests, chronic, mortality, surfactants, metals, pesticides

Some suggested approaches to the analysis of chronic toxicity and chronic drug adminitration data

This paper discusses several methods for analyzing data emanating from chronic toxicity and safety-efficacy studies in which repeated measurements are obtained on the same subjects at regular intervals throughout a prolonged period of drug administration. The procedures recommended are described in some detail, and a completely worked example is given. In view of the general availability of high-speed data processing facilities, the routine application, where appropriate, of these or similar methods of analysis should significantly reduce the amount of experimentation necessary to detect various treatment effects over time.

A method for the determination of pentachlorophenol in human urine in picogram quantities

Pentachlorophenol (PCP), together with its salts, is used as a contact herbicide and defoliant, as a control against microbiological attack in the manufacture of cellulosic products, adhesives, and paints, as a fermentation inhibitor for non-edible materials, and as a control against termites, powder post beetles, and other wood-boring insects (1, 2, 3). This pesticide can be harmful to humans, especially to the occupationally exposed worker, and acute toxicity problems have occurred with the use of PCP formulations primarily through carelessness or failure to observe the manufacturers’ precautionary instructions for its use (4, 5, 6). No chronic toxicity data of any consequence exist on the human individual that may have been exposed to PCP over a long period of time, either through occupational use or through occasional use in the home to control insect infestation. Any effort to establish a relationship between long-term exposure of the individual to this pesticide and any apparent adverse physiological effects will necessitate the acquisition of analytical data on PCP residues in the human system.

Methodology for Determining Toxicity of Pesticides to Wild Vertebrates

The use of chemical agents for controlling unwanted or injurious forms of plants and animals necessarily results in the introduction of more or less toxic substances into wildlife habitats, with the concomitant possibility that wild birds, mammals and fish may come into direct contact with the toxicants or ingest them with their food. The effects of such environmental contamination may be expected to be proportional to, or be affected by: (a) The toxicity of the compound or formulation, as measured by the quantities (mg/kg; ppm in food or water) which will cause death through acute or chronic poisoning, or which will impair vital functions, such as growth or reproduction. (b) Rate at which the toxicant is applied, in weight per unit area or volume, and the size of the area treated, i.e. the concentration and total number of toxic equivalents in the environment. (c) Persistence of the basic chemical or its toxic degradation products in soil, water, plants and animal tissues, and the extent to which residues may accumulate or be concentrated in animal tissues or successive elements of food chains. (d) Biochemical or pharmacological properties of the toxicant, including rates and pathways of absorption, physiological mechanisms affected, nature and toxicity of metabolites or degradation products and the extent to which the toxicant potentiates or is potentiated by other pesticides which may be present in the environment. Data on chemical and physical properties and toxicity to conventional laboratory animals (rats, mice, dogs, etc.) are required in the United States for the registration of pesticides and for the development of criteria for the use of these materials. However, these criteria usually are established for the protection of man and his economic interests, and they are not necessarily adequate for eliminating or minimizing hazards to fish and wildlife. There are marked differences between species in susceptibility to various toxicants, and in the degree to which they may be exposed to a pesticide under the conditions of use. Appraisal or deliniation of pesticide-wildlife relationships requires extension of test schedules to include representative species of wild vertebrates, and in some cases, aquatic invertebrates. The nature and extent of tests required, and the species to be utilized as test subjects, will vary according to the properties of the toxicants and their patterns of use. Data on acute toxicities to mammals and birds are needed for all compounds, mixtures or formulations. If the use involves direct application to or possible inadvertent contamination of aquatic areas, tests should be conducted on representative species of fish. Data on effects of prolonged or repeated exposures are needed for persistent materials or those which are applied several times per season. The chronic toxicity data might include information on quantities causing death, effects of sublethal exposure on growth, reproduction or other functions, and on the maximum 'no effect' levels. Protocols for acute toxicity tests on wild vertebrates have been developed by the Fish

Oral toxicities of lauric acid and certain lauric acid derivatives

Subacute toxicity data for lauric acid and sorbitan monclaurate (Span 20) and chronic toxicity data for lauric acid glycerides (S-1062) and polyoxyethylene-20 monolaurate (G-2129) in rats have been presented. Sorbitan monolaurate tested at 25, 20, and 15% levels for 23 weeks caused significant growth depression beginning at the lowest dietary level and significant increase in mortality at the 25% level. There was progressive enlargement of the common bile duct with each increase in dosage, and gangrene of the tail at all feeding levels, with a greater number of rats affected at the 25% dosage. Histologically, liver damage was pronounced and lung changes were present. Polyoxyethylene-20 monolaurate tested at 25, 10, 5, and 2% levels for two years caused growth retardation in male rats at the 25% level. Mortality data showed no significant differences from the controls. There was a progressive increase in incidence of liver cysts and distention of the cecum as the dosage increased. Feeding of lauric acid glycerides at 25% of the diet for two years caused only minor histological changes in the liver. In a group of 5 rats, not microscopically examined, feeding of lauric acid at 10% of the diet for 18 weeks had no deleterious effect.

Diphenylacetyl-l,3-Indandione as a Potent Hypoprothrombinemic Agent

Out of a group of compounds, including bishydroxycoumarin, ethyl biscoumacetate, and 17 analogues of indandione, tested in rabbits, 2-diphenylacetyl 1,3-indandione (U-1363) demonstrated the greatest hypoprothrombinemic potency. The prothrombinopenic response of rabbits to acute and chronic doses of U-1363 are reported. Histopathologic observations are reported for rabbits that were given U-1363 daily for several weeks. Acute and chronic toxicity data are reported for U.1363. Vit. K1, but not a water-soluble vit. K analogue. Is an antidote to the hypoprothrombinemia produced by U-1363.

A pharmacological study of dl-desoxyephedrine hydrochloride

The LD50 (intraperitoneal) of dl-desoxyephedrine hydrochloride for rats and mice was determined to be 54.48 and 61.16 mg./Kg., respectively. The oral LD50 for mice was 143 mg./Kg. Chronic toxicity data following intraperitoneal injections in rats are reported. Effects of the drug on the isolated uteri and on the isolated ileum of both mice and guinea pigs were determined. The drug counteracted both pilocarpine and barium spasm of the intestine of these animals. Body temperature was elevated by small doses of dl-desoxyephedrine. The compound usually stimulated respiration and caused hypotension in anesthetized rabbits. In dogs the pressor effect was only about 1/500 that of epinephrine.

The Evaluation of Drugs in Experimental Leishmaniasis

SummaryA method of evaluating drugs proposed for use in leishmaniasis is described, in which experimentally infected Chinese hamsters are used. The procedure adopted is an extension of known laboratory methods, and emphasizes the importance of dealing with drugs of known composition, on which acute and chronic toxicity data are available or determined. Normal and infected animals are used and careful and frequent observations are made on treated and control groups of at least 30 animals each, including tissue studies of drug and disease effects.