摘要:

A short objective screening technique has been developed to identify those agents that have peripheral and/or central nervous effects in small laboratory rodents (when utilized as a feature in routine testing protocols). The technique initially utilizes a series of simple quantitative and qualitative measures of various aspects of sensory and motor function. The methodology has been designed for and utilized as modular additions in a large number and variety of toxicity studies performed on industrial compounds including macrocyclic ethers, aldehydes, urethane foam catalysts, and others. It is shown to be a more sensitive early Indicator of toxicity than such classical measures as body weight or clinical chemistry in those cases (such as the macrocyclic ethers and amino proprionitrile) where the nervous or muscular system are the ultimate target organs. It is also a noninvasive and relatively inexpensive methodology. The second phase (a series of isolated tissue assays) establishes the ability to differentiate between reversible (pharmacologic) and irreversible (toxicologic) sensory‐neural responses. The development and validation of the procedure have involved its use in both acute and subchronic studies by the inhalation, oral, ip, and sc routes. As necessary, isolated tissue and biochemical assays have been done to verify mechanisms of action. In fact, decision‐tree schemes have been developed as part of the screen. These schemes allow elucidation of mechanisms of action if such is desired and statistical evaluation of the diverse data generated.

ISSN:0098-4108    

DOI:10.1080/15287398209530197

出版商:Taylor & Francis Group    

年代:1982

数据来源: Taylor

摘要:

Multiple regression is widely employed to study the contribution of components to the toxicologic effect of a mixture. Here, use is made of the fact that data obtained from standard curves of substances and from their mixtures are separable in regression analysis. Thus, under an assumption of additivity of responses, regression coefficients obtained for components in mixtures alone should be the same as for the individual substances. A t‐test is developed such that nonsignificant t values support additivity, negative significant values support antagonism, and positive significant values support synergism. The results are applied to data on the mutagenicity of binary mixtures of azaserine, 4‐nitroquinoline N‐oxide, and 9‐aminoacridine in TA 100 in the Ames assay.

ISSN:0098-4108    

DOI:10.1080/15287398209530198

出版商:Taylor & Francis Group    

年代:1982

数据来源: Taylor

摘要:

Published data on the toxicity of nitrogen dioxide (as a model compound) from five laboratory animal species were utilized to scale the relationship of dose and toxic effect to the human species. A minute volume of inspired air was used as a metabolic scaling factor, predicting a median lethality during the time of exposure of 174 ppm NO2for a 1‐h exposure for people. This work demonstrates a method of predicting effects in people when only data for laboratory animals exist. It also shows the value of planning toxicology studies that utilize several animal species, so that their data may be applied to forecasting the human condition.

ISSN:0098-4108    

DOI:10.1080/15287398209530199

出版商:Taylor & Francis Group    

年代:1982

数据来源: Taylor

摘要:

A program involving acute, subacute, and chronic toxicity as well as reproduction studies was performed to evaluate the potential toxicity of chenodeoxycholic acid in rats, hamsters, and dogs. Acute oral toxicity studies showed that there were some species differences and that female hamsters were more sensitive to toxic doses than male hamsters. Subacute and chronic studies in hamsters showed the toxicity to be limited to effects on the liver, including proliferation of intrahepatic bile ducts in portal areas with elevations of serum glutamic‐pyruvic transaminase and glutamic‐oxaloacetic transaminase. No tumorigenic effect was observed.

ISSN:0098-4108    

DOI:10.1080/15287398209530200

出版商:Taylor & Francis Group    

年代:1982

数据来源: Taylor

摘要:

Hexachlorocyclopentadiene (Hex or C‐56) is a highly reactive intermediate used in the production of some insecticides, flame retardants, and resins. The present study was conducted to evaluate the inhalation toxicity of high‐purity Hex (97.7%) in rats and monkeys to provide information on the potential hazards of accidental exposure of workers to Hex vapors. Acute, range‐finding (14‐d), and subchronic (90‐d) inhalation studies were conducted with Sprague‐Dawley rats and subchronic (90‐d) inhalation studies were conducted with cynomolgus monkeys. Both acute and range‐finding studies with rats showed a steep dose‐response curve, and male rats were more sensitive than females. In the range‐finding study with rats the threshold of toxicity for Hex was 0.11–0.5 ppm. Histopathologic examination on rats in the 0.5 ppm group revealed lesions in the olfactory and bronchiolar epithelium and inflammatory exudate in the lumens of the respiratory tract; these changes were consistent with observed impaired respiratory function, confirming the lung as the main target organ. Recovery and regression of lung lesions in rats were noted 2–3 wk after termination of exposure. In the 90‐d study, inhalation of Hex vapors at concentrations up to 0.2 ppm for 6 h/d, 5 d/wk, produced no detectable physical or clinical effect and no remarkable gross or histological alterations in rats or monkeys.

ISSN:0098-4108    

DOI:10.1080/15287398209530201

出版商:Taylor & Francis Group    

年代:1982

数据来源: Taylor

摘要:

2,5‐Hexanedione (2,5‐HD) pretreatment potentiated CHCl3‐induced hepatotoxicity. 2,5‐HD significantly increased hepatic cytochrome P‐450, NADPH cytochrome c reductase, aniline hydroxylation, p‐nitroanisole O‐demethylation, and aminopyrine N‐demethylation in both male and female mice. 2,5‐HD pretreatment potentiated CHCl3‐induced centrilobular necrosis and increased serum alanine amino transferase (ALT) activity by 20 times more than CHCl3alone. Similarly, 2,5‐HD pretreatment potentiated CDCl3‐induced hepatotoxicity as well as CCl4‐induced hepatotoxicity in male mice, but did not potentiate trichloroethylene‐, 1,1,2‐trichloroethane‐, or perchloroethylene‐induced hepatotoxicity. In female mice, 2,5‐HD pretreatment potentiated CHCl3‐ and CDCl3‐induced hepatotoxicity as well as trichloroethylene‐, 1,1,2‐trichloroethane‐, and carbon tetrachloride‐induced hepatotoxicity, but not perchloroethylene‐induced hepatotoxicity. 2,5‐HD pretreatment had no preferential effect on either CHCl3‐ or CDCl3‐induced hepatotoxicity in females. However, phenobarbital pretreatment did differentiate CHCl3‐ and CDCl3‐induced hepatotoxicity in females. 2,5‐HD‐induced potentiation of halocarbon hepatotoxicity is sex dependent.

ISSN:0098-4108    

DOI:10.1080/15287398209530202

出版商:Taylor & Francis Group    

年代:1982

数据来源: Taylor

摘要:

1,1,1‐trichloroethane was evaluated for its effects on the delayed match‐to‐sample discrimination task in juvenile baboons. Acute 4‐h exposures to 700, 1400, 1800, and 2100 ppm were conducted no more frequently than once a week. Three months later a subchronic exposure to 1200 ppm was conducted over a 7‐d period in the same animals. The effects on accuracy of responding were minimal; however, 1,1,1‐trichloroethane reduced the number of trials attempted by the animals, reduced the number of extra inconsequential responses during the delay intervals, and increased reaction times. The findings of these experiments illustrate the usefulness of the young baboon as a primate human surrogate model for testing this type of central nervous system depressant.

ISSN:0098-4108    

DOI:10.1080/15287398209530203

出版商:Taylor & Francis Group    

年代:1982

数据来源: Taylor

摘要:

Male Sprague‐Dawley rats and male B6C3F1 mice excreted 5–15% of a tracer dose of [14C]trichloroethylene as14CO2within 24 h after ip injection of a single dose in a corn‐oil vehicle. The proportion of the dose excreted as CO2was greater in mice than in rats, but increased in the rats after starvation or pretreatment with phenobarbital. As the dose was increased toward the LD50 level, the proportion excreted as14CO2decreased slightly, but this was largely due to increased loss of unchanged trichloroethylene. The excretion of14CO2was thus correlated with the expected level of microsomal metabolism of trichloroethylene to an electrophilic intermediate capable of binding to glutathione or macromolecules. Liver protein labeling was observed to be relatively high (10,000–23,000 cpm/mg in the mouse), while DNA labeling was consistently observed to be very low, not allowing identification of any adducts by high‐performance liquid chromatography (HPLC). Also, no effect on DNA fragmentation was seen by alkaline sucrose gradient centrifugation after injection of an LD50 dose of trichloroethylene. The ability of trichloroethylene to interact with DNA in vivo was thus observed to be very slight.

ISSN:0098-4108    

DOI:10.1080/15287398209530204

出版商:Taylor & Francis Group    

年代:1982

数据来源: Taylor

摘要:

The polybrominated biphenyl (PBB) constituents of Firemaster FF‐1 were determined using gas chromatography—electron capture (GC‐EC), The distribution and clearance of the major component of the mixture, 2,2’,4,4'5,5'‐hexabromobiphenyl (HxBBb), in rat whole blood and various tissues were determined at times up to 16 wk after a single dose of 10 mg/kg of Firemaster FF‐1 given orally. A three‐comparment linear mammiliary model obtained from blood data was compared to a first‐order linear n‐compartment mammiliary model derived through direct curve‐fitting to tissue and blood concentrations. It was found that most tissues analyzed naturally correspond to compartments derived through analysis of blood data alone. Comportment 1 (C1) consisted of whole blood, spleen, kidney, and heart; compartment 2 (C2) consisted of cerebral grey and white matter, cerebellum, lung, liver, and testes; and compartment 3 (C3) consisted of subcutaneous fat. Jejunum, a tissue that does not satisfy the assumptions of a mammiliary model, could not be classified. Simulations of the kinetics for varying body‐fat proportions were obtained for obese (250% average fat), average adult, and emaciated (25% average fat) rats. It was found that the half‐life predicted in emaciated rats, 60.5 d, was markedly decreased from the measured 145 d in average rats. Obese rats were predicted to have a HxBBb half‐life of 311 d. Simulations of daily dosing based on the predicted single‐dose kinetics for these rat body types showed that at the end of three wk, C1 levels in emaciated rats were 8 times higher than the predicted C1 levels in obese rats, while C2 levels were 5 times higher and C3 levels were 4 times higher. Levels in the first two compartments returned to similar levels in all three animal types within a wk following cessation of dosing. Within 49 d, C1 levels in the lean rats fell below those of the average rat. Although levels in C3 remained elevated in the lean rats for many wk, within 4.5 mo C3 levels fell below those of the average rat. These results suggest that studies of PBB toxicity in man based upon blood and fat levels should take into account not only the amount of PBB ingested but also the pattern of ingestion, the individual body types, and the time when PBB levels were measured.

ISSN:0098-4108    

DOI:10.1080/15287398209530205

出版商:Taylor & Francis Group    

年代:1982

数据来源: Taylor

摘要:

The influence of age on O3effects in the lung was studied in 8 groups of Sprague‐Dawley rats: 7, 12, and 18 d of age (neonatal) 24, 30, and 45 d of age (infant) and 60 and 90 d of age (adult). Lung weight, total lung protein and DNA contents, and a series of marker enzyme activities in lung tissue were determined. After exposure of rats from each group to 0.8 ppm (1568 μg/m3) O3continuously for 3 d, a biphasic effect was noted. The biochemical parameters, expressed per lung, In O3‐exposed rats relative to their corresponding controls decreased in the 7‐ and 12‐d‐old groups, increased or remained unchanged in the 18‐d‐old group, and increased in the 24‐ to 90‐d‐old groups. However, the increases were much greater for 60‐ to 90‐d‐old rats than for 24‐ to 30‐d‐old rats. The Increase in lung biochemical parameters is throught to occur in response to lung injury and subsequent repair processes, and greater increases in the lungs of older rats suggest that they are more responsive to O3exposure than younger rats. The decrease in lung biochemical parameters and increased mortality in 7‐ and 24‐d‐old neonatal rats suggest that they are more susceptible to O3stress than infant and adult rats.

ISSN:0098-4108    

DOI:10.1080/15287398209530206

出版商:Taylor & Francis Group    

年代:1982

数据来源: Taylor