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Subtle effects of low-dose exposure to environmental toxicants may be altered or masked by an inappropriate choice of anaesthesia prior to manipulation or termination of experimental animals. This study was designed to investigate effects of various anaesthetics and terminal procedures on neurotransmitters from male Sprague-Dawley rats. Significant changes in neurotransmitters were observed in the caudate nucleus, nucleus accumbens, hippocampus and substantia nigra but not the frontal cortex upon exposure to isoflurane, an Equithesin-like mixture or carbon dioxide relative to control animals that were decapitated without anaesthesia. Terminal use of any of these three anaesthetics also masked or altered some of the changes induced by exposure to Aroclor 1254. These results suggest that it is critical to avoid anaesthetizing experimental animals and that decapitation is the preferred method for euthanasia when conducting neurochemical studies.

The subchronic toxicity of chloral hydrate, a disinfection byproduct, was studied in rats following 13 weeks of drinking water exposure. Male (262 +/- 10 g) and female (190 +/- 8 g) Sprague-Dawley rats, ten animals per group, were administered chloral hydrate via drinking water at 0.2, 2, 20 and 200 ppm. Control animals received distilled water only. Gross and microscopic examinations, serum chemistry, hematology, biochemical analysis, neurogenic amine analysis and serum trichloroacetic acid (TCA) analysis were performed at the end of the treatment period. Bronchoalveolar fluids were collected at necropsy and urine specimens were collected at weeks 2, 6 and 12 for biochemical analysis. No treatment-related changes in food and water intakes or body weight gains were observed. There were no significant changes in the weights of major organs. Except for a mild degree of vacuolation within the myelin sheath of the optic nerves in the highest dose males, there were no notable histological changes in the tissues examined. Statistically significant treatment-related effects were biochemical in nature, with the most pronounced being increased liver catalase activity in male rats starting at 2 ppm. Liver aldehyde dehydrogenase (ALDH) was significantly depressed, whereas liver aniline hydroxylase activity was significantly elevated in both males and females receiving the highest dose. A dose-related increase in serum TCA was detected in both males and females starting at 2 ppm. An in vitro study of liver ALDH confirmed that chloral hydrate was a potent inhibitor, with an IC(50) of 8 micro M, whereas TCA was weakly inhibitory and trichloroethanol was without effect. Analysis of brain biogenic amines was conducted on a limited number (n = 5) of male rats in the control and high dose groups, and no significant treatment-related changes were detected. Taking into account the effect on the myelin sheath of male rats and the effects on liver ALDH and aniline hydroxylase of both males and females at the highest dose level, the no-observed-effect level (NOEL) was determined to be 20 ppm or 1.89 mg kg(-1) day(-1) in males and 2.53 mg kg(-1) day(-1) in females. This NOEL is ca. 1000-fold higher than the highest concentration of chloral hydrate reported in the municipal water supply.

The biochemical and toxicological effects of chloral hydrate were investigated. Four groups (n = 7 per group) of male Sprague-Dawley rats (161-170 g) were administered chloral hydrate in drinking water at concentrations of 20, 200 or 2000 ppm for 7 days. The control group received phosphate-buffered water only. There were no treatment-related changes in the body weight gains, relative weights of major organs or haematological parameters. Trichloroacetic acid was significantly (P < 0.05) elevated in the serum of high-dose animals (7.75 +/- 5.14 mg dl(-1), mean +/- SD). In the high-dose animals there was a 36% increase in protein level in the liver homogenates but not in the corresponding 9000 g supernatants. Concurrently, there was a threefold increase in the activity of the hepatic peroxisomal enzyme palmitoyl CoA oxidase (PCO). A prominent change was the dose-related suppression in hepatic aldehyde dehydrogenase (ALDH) activity observed in all treatment groups, with the decrease ranging from 15% at 20 ppm to 68% at 2000 ppm. There were no significant decreases in the activity of hepatic enzymes ethoxyresorufin O-deethylase (EROD), benzyloxyresorufin O-dealkylase (BROD) and UDP-glucuronosyl-transferase (UDPGT). In the high-dose group there was a 30% increase in hepatic glutathione-S transferase (GST) activity, accompanied by a 13% increase in glutathione (GSH). Significant effects on lipids were observed in the liver of the high-dose animals, with a 15% decrease in hepatic cholesterol and triglyceride levels. There were no treatment-related changes in serum chemistry parameters, including cholesterol and triglyceride levels. Although in vitro assays showed chloral hydrate to be an inhibitor of serum pseudocholinesterase activity, with a 50% inhibition concentration (ic(50)( of approximately 0.7 mM at 5 mM butyrylthiocholine, no decrease in serum pseudocholinesterase activity was found in the treated animals. It was concluded that the liver is the target organ for chloral hydrate, with suppression of ALDH as the most sensitive endpoint followed by alteration in the GSH level and GST activity. Changes observed in the high-dose animals, such as increased peroxisomal PCO activity in the liver and perturbation of lipid homeostasis in the liver and blood, were likely to be associated with trichloracetic acid, the major metabolite of chloral hydrate.

The toxicity of 2,3,3',4,4'-pentachlorobiphenyl (PCB 105) was investigated in Sprague-Dawley rats following dietary exposure to this substance at levels of 0, 0.05, 0.5, 5 or 50 ppm for 13 weeks. Growth rate and food consumption were not affected and no clinical signs of toxicity were observed. Increased incidences of enlarged, fatty liver and decreased thymic weight were observed in the highest-dose groups of both genders; these groups also had elevated hepatic microsomal ethoxyresorufin deethylase activity and uroporphyrin. Significant increases in serum cholesterol and hepatic pentoxyresorufin dealkylase activity were observed in the highest-dose males and two highest-dose females. By contrast, liver UDP-glucuronosyl transferase activity was elevated in the two highest-dose males and the highest-dose females. Urinary ascorbic acid excretion was increased in the highest-dose males. While the amount of vitamin A was decreased dose-dependently, starting at 0.5 ppm in the liver of both sexes and in the lung of the females, the level in the kidney of the highest-dose group was increased. Administration of PCB 105 resulted in decreased dopamine in the caudate nucleus region of the brain in males and homovanillic acid in caudate nucleus and nucleus accumbens of females. Increased 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were observed in the substantia nigra region of both sexes, with most of the increases being seen in highest-dose females. Anemia, characterized by decreased hemoglobin, hematocrit and red cell indices, occurred in the highest-dose group, as did eosinophilia. Treatment with PCB 105 caused dose-dependent histopathological changes in the liver and thyroid. Thymic changes were observed in the highest-dose males and two highest-dose females. Tissue residue data showed a dose-dependent accumulation of this congener in fat, liver and spleen, kidney and brain. Based on these data the no-observable-effect level of PCB 105 was judged to be 0.05 ppm or 3.9 microg kg(-1) body wt. day(-1) in males and 4.2 microg kg(-1) body wt. day(-1) in females.

The subchronic toxicity of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) was investigated in rats after 13 weeks of dietary exposure. Groups of 10 male and 10 female rats were administered PCB 153 in their diet at levels of 0.05, 0.50, 5.0 or 50 ppm for 13 weeks. The control groups received the diet containing 4% corn oil. Growth rate and dietary consumption were not affected by treatment. Clinical signs of toxicity were not observed. Enlarged, fatty liver was observed in treated animals at necropsy, but most were confined to the two highest dose groups. Increased hepatic microsomal ethoxyresorufin-O-deethylase, aminopyrine-N-demethylase and aniline hydroxylase activities occurred in high-dose groups of both sexes, with increased ethoxyresorufin-O-deethylase activity being observed starting at 0.05 ppm in females and at 0.5 ppm in males. Treatment-related reduction in hepatic and pulmonary vitamin A was seen in the highest dose group of both sexes. Changes in brain biogenic amines and intermediate products were observed mainly in females; these included decreased dopamine and 5-hydroxytryptamine concentrations in the frontal cortex region, and dihydroxyphenylacetic acid in the caudate nucleus region at 5.0 and 50 ppm. Female rats appeared to be more sensitive to the neurotoxic effects of PCB 153 than males. Dose-dependent histological changes were observed in the thyroid and liver of rats of both sexes and significant changes occurred at 5.0 and 50 ppm. Based on these data, the no-observable-adverse-effect level (NOAEL) of PCB 153 was judged to be 0.5 ppm in the diet or 34 micrograms kg-1 body wt. day-1.

The present study was conducted as part of a larger project to determine the toxicity of dermally applied coal coprocessing products. Groups of male and female rats were administered, dermally, heavy gas oil II (HGOII) at 8.7, 20.8, 50.0 and 120 mg kg(-1) body wt, day(-1) for 91 days. A coal liquefaction product was given as positive control at 120 mg kg(-1) body wt. day(-1). Saline was used on control animals. At termination, the blood and bone marrow were taken from the animals and subjected to hematological examination. Dose-dependent hematological effects were seen in peripheral blood in HGOII-treated animals and consisted of significantly reduced hemoglobin, hematocrit, red cell count and platelet count. Mean corpuscular volume was increased, along with mean corpuscular hemoglobin, at the highest dose level. Red cell protoporphyrin, total iron and total iron binding capacity were also significantly elevated at this dose level. Morphological analysis of blood showed increases in polychromatic red cells, schizocytes, Howell-Jolly bodies, injured cells, hypersegmented neutrophils and shift platelets primarily at the highest dose level. In addition, there was notable anisocytosis, microcytosis and macrocytosis. Quantitative bone marrow evaluation revealed a significant reduction in the myeloid/erythroid ratio for the three highest treatment levels of HGOII. These data indicate that the effect of HGOII on the hemopoietic system is a treatment-related, partially compensated, hemolytic anemia. The apparent reduction in myelopoiesis may be compensated for by a concurrent increase in marrow volume.

Repeated exposure to coal liquefaction products produces a broad range of systemic effects. Among these, growth suppression, anaemia, leucocytosis and other haematological disorders are most prominent. Bone marrow, liver and kidney are the target organs affected by treatment. The effects are more severe with heavy distillates and male rats are more sensitive than females. Other changes included increased serum transaminases, alkaline phosphatase and cholesterol. Depending on the route of administration, the skin or lung may also be affected. Inhalation exposure produces the most severe changes, and oral exposure the least. Distillates containing N-PAHs and sulphur-containing PAHs are also more biologically active. Teratological effects were only observed if animals were exposed to the heavy distillate. Similarly, heavy distillates have mutagenic or carcinogenic properties. Teratological effects, as well as mutagenicity and carcinogenicity, of the coal liquefaction distillates seem to be linked to their PAH content, especially the N-PAHs. From the data presented in this review, it should become evident that the potential effects of coal liquefaction products on human health could be severe, especially with long-term exposure. Limited information exists on the occupational effects to coal liquefaction materials because most of the work to date has been with pilot plants. Careful and good judgement is required in order to extrapolate data from pilot plants to commercial-scale production. Experience in health effects of workers in the petroleum industry and coke-oven operations can serve as a guide for the implementation of industrial hygiene programmes for coal liquefaction operations. These programmes include engineering controls, health education, personal monitoring and hygienic practices, medical surveillance and long-term epidemiology studies, and they should be implemented to make coal liquefaction a healthy and environmentally sustainable industry.