Toxicological Changes Research Articles

Ketoacidosis and lactic acidosis--frequent causes of death in chronic alcoholics?

In clinical medicine, severe keto- or lactic acidosis associated with vomiting, nausea, abdominal pain, tachycardia or pathological respiration, has been described in chronic alcoholics. This study reports on fatalities of chronic alcoholics where the cause of death could not be determined by thorough autopsy, histology and toxicology including determination of alcohol concentration. In a first series, acetone was determined in the blood of such chronic alcoholics (n = 24), diabetics with metabolic decompensation (n = 7), cases of hypothermia (n = 7) and controls (n = 218). Among the 24 chronic alcoholics where the cause of death was unknown, 9 cases showed very high levels of acetone (74-400 mg/l). These comprised 6 cases without additional findings and 3 cases where a second patho-mechanism such as intoxication possibly contributed to the cause of death. In a second series, the sum values according to Traub (lactate/glucose) were determined in cerebrospinal liquor of chronic alcoholics with undetermined cause of death (n = 45), diabetics (n = 6) and controls (n = 39). Among the 45 alcoholics, 17 cases showed very high sum values (294-594 mg/dl) including 8 cases where non-lethal intoxications may have contributed to the final outcome. Other causes of a ketoacidosis or lactic acidosis (e.g. diabetes) were excluded in both groups of alcoholics. Consequently, ketoacidosis and lactic acidosis can be the cause of death of chronic alcoholics in a considerable number of cases where no pathomorphological or toxicological changes are present. A scheme for medical and laboratory examination is described.

Six-month repeated oral toxicity study of NK-104 in rats.

NK-104 is a novel potent inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and has been shown to be a highly effective agent in lowering blood cholesterol. In the present study, NK-104 was orally administered to Wistar rats at a dose of 0.3, 1, 3 or 010 mg/kg for 6 months for examination of toxicity. Additional recovery groups of 8 rats each of both sexes receiving 0 and 10 mg/kg were maintained without treatment for 1 month in order to assess recovery. As a result, no toxicological changes were observed in general signs, body weight, food intake, ophthalmological examination, urinalysis, hematological and blood chemical examinations for organ weights. An autopsy revealed thickening of the forestomach mucosa in both sexes at a dose of 1 mg/kg or more. This change was microscopically recognized as hyperkeratosis and hypertrophy of the spinous layer associated with both cell infiltration of the mucosal propria and edema of sub-mucosa in the forestomach in both sexes at doses of 3 and 10 mg/kg. Forestomach changes were not observed in any cases after 1 month cessation of drug treatment. The non-toxic dose of NK-104 in the 6-month repeated oral toxicity study in rats is estimated to be 1 mg/kg/day.

Flow cytometric analysis for sperm viability and counts in rats treated with trimethylphosphate or pyridoxine.

Six-week old SD-Slc male rats were treated for 4 weeks with compounds known to induce toxicological changes in male reproductive organs (pyridoxine in saline, 500 mg/kg/day, i.p.) or sperm (trimethylphosphate in distilled water, 100 mg/kg/day, p.o.). Each sperm sample taken from the cauda epididymis was analyzed with flow cytometry for the evaluation of sperm viability and counts. Sperm motility and morphology by microscopical observation, and histopathological examination of reproductive organs were also performed for estimating the adverse effects of each compound on spermatogenesis and sperm. While a decrease in sperm motility was noted for the trimethylphosphate group, the low motile sperm was evaluated as being viable sperm, not moribund, with flow cytometry. In the pyridoxine group, microscopical observation revealed morphological changes of sperm and a decrease of motility. The present sperm analysis with flow cytometry also suggested morphological changes reflected by dot plot as well as decrease of sperm viability and counts. These results indicated that this procedure led to profound findings in the compound-treated animals, with evaluation as viable sperm, not moribund, in a low motile sperm sample, and suggesting morphological changes in the dot plot of flow cytometry.

Consequences of classical and biotechnological resistance breeding for food toxicology and allergenicity

AbstractThe first food products derived from transgenic plants that are resistant to diseases, insects or viruses are now reaching the market and there is growing public concern about problems of allergenicity and toxicological changes in such transgenic food plants. We review the modifications being carried out or envisaged in molecular resistance breeding and specifically consider the allergenic and toxicological potential of the gene products used. Several protein families that contribute to the defence mechanisms of food plants have members which are allergens or putative allergens and some of these proteins are used in molecular approaches to increase resistance. These include α‐amylase and trypsin inhibitors, lectins and pathogenesis‐related proteins. An assessment procedure to avoid the transfer of such allergens is described. The source of the transgene is of great importance for the application of immunological assays. In addition to putative changes in the allergenic potential, the toxicological implications of classical and molecular resistance breeding are discussed. Several ‘self defence’ substances made by plants are highly toxic for mammals, including humans. Examples of molecular approaches that could be of toxicological concern are given. The source of the transgene is of no relevance in assessing the toxicological aspects of foods from transgenic plants. Food safety can also be severely influenced by invading pathogens and their metabolic products. This may result in a trade‐off situation between ‘nature's pesticides’ produced by transgenic plants or varieties from traditional breeding programmes, synthetic pesticides and mycotoxins or other poisonous products of pests.

Physiological and toxicological changes in the skin resulting from the action and interaction of metal ions.

The human environment contains more than 50 metal or metalloid elements. At least 15 are recognized as trace elements, with zinc, calcium, copper, magnesium, and iron having specific roles in skin morphogenesis and function. The present review focuses on the presumed role of metal ions in the skin, their competition for carrier proteins, and membrane receptors. Evidence presented shows that the balance of trace metal ions is critical for normal skin and repair mechanisms following injury. Xenobiotic ions can impair this balance, leading to pathological change. The skin acts as an organ of elimination of excess trace metals and xenobiotic ions from the body, but mechanisms of voidance vary for different metals. Metal ions are an important cause of allergies, and evidence is presented to show that the majority of metals or metal compounds can induce allergic changes. Except for chromium and nickel, which are among the most common human allergens, animal models have provided little information. At least cadmium, thorium, lead, chromium, nickel, beryllium, and arsenic and proven or putative carcinogens in animals or humans on the basis of cytological or epidemiological evidence. However, only arsenic exhibits a clear predilection for the skin. Other metals such as gold can induce subcutaneous sarcoma following injection, but the relevance of this observation in terms of human occupational risk is discounted.

Hepatic accumulation and hepatotoxicity of luteoskyrin in mice

HPLC analysis revealed that luteoskyrin administered orally to male mice accumulated selectively in the liver, with minor distribution to the serum and kidneys. Elevation of serum GOT and GPT values was maximal 3 days after administration. In mice administered this mycotoxin intravenously, selective accumulation was also observed in the liver, and the half-life of hepatic luteoskyrin in males was significantly longer than that in females. Increment of serum transaminases was also marked in males with maximum accumulation at 24 h after administration. Histopathologically, cellular membrane damage was an early effect of luteoskyrin on cell necrosis, and these morphological changes were also marked in males. Luteoskyrin also elevated hepatic lipid peroxides, the maximum elevation being 8 h after injection; this increase was suppressed by α-tocopherol and Bi(NO 3) 3. HPLC-ECD analysis indicated that the level of 8-hydroxy-deoxyguanosine, one of the markers for hydroxy-radical-mediated modification of DNA guanine residues, was increased in hepatic DNA. These findings indicate that luteoskyrin has a high affinity for the liver, resulting in induction of lipid peroxidation, hepatocellular membrane damage, and elevation of serum transaminase activities. It is suggested that the hydroxy radicals derived from this anthraquinone contribute to these toxicological changes.

Toxicological Assessment of Zeolites

The zeolites, sometimes referred to as molecular sieves, are a large group of natural and synthetic materials. Their composition may consist of an aluminosilicate framework containing alkali or alkaline earth cations. Zeolites exhibit fibrous, cuboidal, or other crystalline morphologies. Often considered nuisance dusts, these materials may evoke pulmonary changes leading to irritation of the respiratory tract. Pulmonary inflammatory responses, particularly those caused by natural occurring zeolites, can lead to fibrosis and even mesotheliomas. Synthetic zeolite structures, usually cuboidal, produce irritation of the eyes and mucous membranes, but there is no evidence of significant pathologic changes in the lungs. Few nonpulmonary toxicologic changes are produced by either the natural or synthetic zeolites.

A 52-week chronic oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187) in dogs

A chronic oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187), a new protease-inhibiting agent, was carried out using male and female beagle dogs. FUT-187 was orally administered to the dogs at dose levels of 7.5, 15, 30 and 60 mg/kg/day for 52 weeks, followed by 5 weeks' recovery period. Results are summarized as follows: 1. In general conditions, vomiting, salivation and the passage of mucousy stools were observed in dogs given 15 mg/kg/day or more, and diarrhea was observed at 30 mg/kg/day or more. One male given 15 mg/kg/day showed transient pallidity of the oral mucosa, and another male in the same group showed apnea and abdominal breathing. In addition, one male given 30 mg/kg/day was euthanatized due to extreme weakness, as weight loss and pallid oral mucosa, and another male in the same group died after showing acute toxic symptoms such as hyperpnea, tonic convulsion and ataxic gait. 2. Weight gain was slightly suppressed in females given 60 mg/kg/day. No significant changes in food consumption were observed. 3. Hematological examination revealed no statistically significant changes. Decreases in RBC counts, Ht values and Hb concentrations, and increased reticulocyte counts were observed in one male of 15 mg/kg/day group, which also showed pallid oral mucosa, and in one male of the 30 mg/kg/day group, which was euthanatized in a moribund state. 4. Blood biochemistry revealed increased GPT activity in males given 15 and 30 mg/kg/day and females given 60 mg/kg/day, which was accompanied by sporadic increases in GOT, A1P and/or gamma-GTP activities. Males given 30 mg/kg/day or more showed decreased total protein. 5. Hepatic function testing (ICG test) showed no statistically significant changes. One female given 60 mg/kg/day showed increased accumulating concentration of ICG. 6. There were no toxicological changes in urinalysis, fecal occult blood, renal function (PSP clearance), ophthalmological and electro-cardiographic examinations. 7. In pathological examination, inflammatory cell infiltration and microgranuloma formation in liver were noted periportally or perivenularly in both sexes given 15 mg/kg/day or more (except for 30 mg/kg/day males). In the some cases, atrophy, degeneration and necrosis of hepatocytes and/or fibrosis around inflammatory cells and microgranuloma were observed. In the spleen, one male given 15 mg/kg/day and one female given 60 mg/kg/day showed increased plasma cells in the red pulp. In the case sacrificed in a moribund condition, findings in the liver and spleen similar to those in surviving cases were detected, but were more severe, and the liver showed diffuse fibrosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Interleukin-2 in liposomes: Increased intravenous potency and less pulmonary toxicity in the rat

Incorporation of interleukin-2 (IL-2) into multilamellar vesicles, IL-2 liposomes, significantly modifies the biodistribution and prolongs the clearance of the cytokine. The rat was used to evaluate and characterize subacute toxicity and short-term pathologic effects of intravenous (i.v.) IL-2 liposomes. Once daily i.v. IL-2 liposomes in doses of 0.3 × 106u/kg, 1.5 × 106u/kg, 4.0 × 106u/kg, and 20 × 106u/kg were given to rats for 15 days; control rats received i.v. empty liposomes or buffered saline. Hematologic parameters, serum chemistry, and gross pathologic and histopathologic findings were recorded. Only at the highest dose of IL-2 liposomes were effects consistently severe enough to produce weight loss, decreased food consumption, hepatitis, anemia, and death. At this dose females were more susceptible to mortality than males; only 1 of 5 females survived compared to 4 of 5 males. Peripheral blood leukocyte increases after IL-2 liposomes were mainly associated with lymphocytosis with only minor changes in neutrophils, monocytes, and eosinophils. The marrow had significant dose-related hematopathologic findings limited to decreased percentages of lymphocytes and increased myeloid:erythroid (M:E) ratio in the 20 × 106u/kg group. No increases in marrow eosinophils or eosinophilic precursors were demonstrated. The major toxic effects of IL-2 liposomes in rats were hepatic. Dose-related elevations in liver enzyme serum chemistries (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, γ-glutamyl transferase [GGT], and alkaline phosphatase) were seen. Occasional rats had evidence of bridging fibrosis in addition to centrilobular and periportal lymphocytic and eosinophilic infiltration of the liver. Pulmonary histopathology was characterized by peribronchial and perivascular lymphoid and eosinophilic infiltration with minimal or no septa1 involvement. In summary, the spectrum of pathologic and toxicologic changes in rats receiving once daily IL-2 liposomes are similar to those previously reported in rats given the free cytokine twice daily, but occur at reduced doses with less lung pathology. Thus, compared to free cytokine i.v. IL-2 liposomes in rats have increased potency and decreased pulmonary toxicity. © 1992 Wiley-Liss, Inc.

The toxicity of tetrachlorobenzyltoluenes (Ugilec 141) and polychlorobiphenyls (Aroclor 1254 and PCB-77) compared in Ah-responsive and Ah-nonresponsive mice

The toxicity of the PCB substitute Ugilec 141, a mixture of tetrachlorobenzyltoluenes (TCBTs), is compared with the toxicity of a commercial mixture of polychlorobiphenyls (Aroclor 1254) and with the model toxic PCB-congener 3,3′,4,4′,-tetrachlorobiphenyl (PCB-77) as a positive control. Alterations in liver weight, hepatic cytochrome P450 content and EROD and PROD activity, plasma thyroxin and retinol level, hepatic retinoid level and liver and thyroid pathology, have been studied in Ah-responsive and Ah-nonresponsive mice. Ugilec 141 proved to induce similar toxicological changes, qualitatively and quantitatively, to Aroclor 1254. Therefore Ugilec may pose a similar environmental and health risk as PCBs. The criteria for acceptance of new substances, like Ugilec 141, on the European market are discussed.

Pre-clinical safety evaluation of soluble glucan

Soluble glucan, a beta-1,3-linked glucopyranose biological response modifier, is effective in the therapy of experimental neoplasia, infectious diseases and immune suppression. Currently, soluble glucan is undergoing phase I clinical trials. The present study describes the pre-clinical safety evaluation of soluble glucan in mice, rats, guinea pigs and rabbits. ICR/HSD mice and Harlan Sprague-Dawley rats received a single i.v. injection of soluble glucan in doses ranging from 40 to 1000 mg/kg. Soluble glucan administration did not induce mortality, appearance or behavioral changes in mice or rats. In subsequent studies, mice and guinea pig were injected i.p. with glucan (250 mg/kg) for 7 consecutive days. ICR/HSD mice gained weight at the same rate as the saline-treated controls. In contrast, guinea pigs receiving i.p. injections of soluble glucan showed a significant ( P<0.05) 10–13% decrease in weight gain over the 79 day period. No other toxicologic, behavioral or appearance changes were noted. To examine chronic toxicity, soluble glucan was administered twice weekly for a period of 30 or 60 days to ICR/HSD mice in the dose of 40,200 or 1000 mg/kg. No deaths were observed in any group. Chronic glucan administration did not alter body weight, liver, lung or kidney weight. However, a significant splenomegaly was observed in both the 30 and 60 day study. Histopathologic examination showed no tissue alterations at 40 or 200 mg/kg. However, at 1000 mg/kg a mononuclear infiltrrate was observed in the liver. Pyrogenicity testing, employing New Zealand white rabbits, revealed that parenteral glucan administration (5 mg/kg) did not significantly alter body temperature. These data indicate that the systemic administration of soluble glucan, over a wide dose range, does not induce mortality or significant toxicity, an important consideration in preparing soluble glucan for parenteral administration to human populations.

ニジマスにおけるカドミウムの急性毒性に対するメタロチオネインの役割

Attempts were made to elucidate the protective mechanism against acute cadmium toxicity in the rainbow trout which was previously exposed to a cadmium solution at low concentration. Fish specimens weighing about 130g, which were previously kept in tap water or 0.009ppm cadmium solution for 15 days, were intraperitoneally administered with 0.75mg of cadmium per kg body weight. During pretreatment with cadmium, this metal accumulated in the liver, kidney, gill, intestine and vertebrae of the fish. Liver and kidney extract of the cadmium exposed speci-wens gave rise to two distinct peaks of metallothionein when subjected to gel chromatography. The level of metallothionein thus induced was higher in kidney than in liver. Asubsequent ad-ministration of high level of cadmium inhibited alkaline phosphatase in serum and lowered calcium levels in serum and vertebrae. On the other hand, pretreatment with cadmium prevented these toxicological changes. Kidney metallothionein was supposed to be responsible for the increased tolerance against cadmium toxicity of rainbow trout pretreated with a low level of this metal.

A subchronic dermal exposure study of diethylene glycol monomethyl ether and ethylene glycol monomethyl ether in the male guinea pig

Diethylene glycol monomethyl ether (DEGME) has been selected as a replacement anti-icing additive for ethylene glycol monomethyl ether (EGME) in Navy jet aircraft fuel. This experiment was performed to determine whether DEGME produced similar toxicity to EGME following dermal exposure. Male guinea pigs were dermally exposed to 1.00, 0.20, 0.04, or 0 (control) g/kg/day DEGME for 13 weeks, 5 days/week, 6 hr/day. Another group of animals was similarly exposed to 1.00 g/kg/day EGME. Body weights as well as testicular and splenic weights were reduced as a result of exposure to EGME. DEGME-exposed animals exhibited decreased splenic weight in the high- and mediumdose (1.00 and 0.20 g/kg/day) exposure groups only. Hematologic changes in EGME-exposed animals included mild anemia with increased erythrocytic mean corpuscular volumes and a lymphopenia with increased neutrophils. Similar hematological changes were not observed in any animals exposed to DEGME. Serum creatine kinase activity was increased in animals exposed to EGME, and serum lactate dehydrogenase activity was increased in EGME and 1.00 g/kg/day DEGME-exposed animals. In general, DEGME produced minimal toxicological changes following dermal exposure, whereas the toxicological changes observed following similar exposure to EGME were much more profound.

A Subchronic Dermal Exposure Study of Diethylene Glycol Monomethyl Ether and Ethylene Glycol Monomethyl Ether in the Male Guinea Pig

A Subchronic Dermal Exposure Study of Diethylene Glycol Monomethyl Ether and Ethylene Glycol Monomethyl Ether in the Male Guinea Pig. HOBSON, D. W., D'ADDARIO, A. P., BRUNER, R. H., AND UDDIN, D. E. (1986). Fundam. Appl. Toxicol6, 339–348. Diethylene glycol monomethyl ether (DEGME) has been selected as a replacement anti-icing additive for ethylene glycol monomethyl ether (EGME) in Navy jet aircraft fuel. This experiment was performed to determine whether DEGME produced similar toxicity to EGME following dermal exposure. Male guinea pigs were dermally exposed to 1.00, 0.20, 0.04, or 0 (control) g/kg/day EGME for 13 weeks, 5 days/week, 6 hr/day. Another group of animals was similarly exposed to 1.00 g/kg/day EGME. Body weights as well as testicular and splenic weights were reduced as a result of exposure to EGME. DEGME-exposed animals exhibited decreased splenic weight in the high- and mediumdose (1.00 and 0.20 g/kg/day) exposure groups only. Hematologic changes in EGME-exposed animals included mild anemia with increased erythrocytic mean corpuscular volumes and a lymphopenia with increased neutrophils. Similar hematological changes were not observed in any animals exposed to DEGME. Serum creatine kinase activity was increased in animals exposed to EGME, and serum lactate dehydrogenase activity was increased in EGME and 1.00 g/kg/day DEGME-exposed animals. In general, DEGME produced minimal toxicological changes following dermal exposure, whereas the toxicological changes observed following similar exposure to EGME were much more profound.

An experimental pathological study of acute Lei Gong Teng (Tripterygium wilfordii Hook) intoxication in rats.

Acute poisoning was induced in rats by single and repeated exposures to the decoction of the root bark of Lei Gong Teng. Pathologic changes in the vital organs were studied by light and electron microscopy, and histochemically. The relatively specific and consistent pathologic changes following poisoning were observed in the lymphoid organs. Varying degrees of degeneration and necrosis in the parenchymatous cells existed in the heart, liver and kidney. The mechanism of toxicological pathologic changes and the relation between clinic and pathology were approached, and we postulate that the decoction possesses cytotoxic action which is analogous to that of immunosuppressive agent.

Toxicology of chloral hydrate in the mouse.

Chloral hydrate has been found in our drinking water supplies at levels up to 5 micrograms/1. The purpose of this study was to evalute the acute and subchronic toxicology of chloral hydrate in the random-bred CD-1 mouse, to provide data for risk assessment. The acute oral LD50 of this compound was 1442 and 1265 mg/kg in male and female mice, respectively. Acute toxicity appeared to be related to depression of the central nervous system. Fourteen-day exposure by gavage in male mice at doses 1/10 and 1/100 the LD50 caused an increase in liver weight and a decrease in spleen weight at the highest dose level. Based on the data derived from 14 days of exposure, a 90-day study was performed. The compound was delivered via the drinking water; levels of the compound delivered per day were equivalent to those dosed in the 14-day study. The target organ in both sexes appeared to be the liver, with the males most affected. Male mice demonstrated a dose-related hepatomegaly accompanied by significant changes in serum chemistries and hepatic microsomal parameters. The females did not demonstrate the hepatomegaly observed in males, but did show alterations in hepatic microsomal parameters. No other significant toxicological changes were observed in either sex following 90 days of exposure.

Trihalomethanes: II. Reversibility of toxicological changes produced by chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats.

Groups of 20 male and 20 female rats were fed 0, 5, 50, 500 or 2500 ppm trihalomethanes (chloroform, bromodichloromethane, chlorodibromomethane and bromoform) in their drinking water for 90 days. Ten rats from each group were killed at this time and the remaining animals were fed tap water for a further 90 days before they were sacrificed. Suppression of growth rate was observed in male and female rats fed 2500 ppm chloroform and bromodichloromethane (BDCM) for 90 days. After the subsequent 90-day recovery period, no effects on body weight gain in either sex were apparent. Food consumption was depressed in all groups of males and females receiving 2500 ppm chloroform, chlorodibromomethane (CDBM) and BDCM for 90 days and in these same groups during the recovery period. Bromoform at 2500 ppm suppressed food consumption of male rats but this effect was not evident 90 days after cessation of exposure. Decreased lymphocyte counts were only observed in the recovery groups fed chloroform (500 ppm, male), CDBM (2500 ppm, female) and bromoform (2500 ppm, females). Histological changes in the livers and thyroids of male and female rats were qualitatively and quantitatively similar for the four trihalomethanes. These changes were mild in nature, and were not evident 90 days after cessation of exposure. These data indicate that trihalomethanes can produce biochemical hematological and histological changes but most of these were reversible when exposure had terminated.

A sensitive method for determining the nephrotoxic effects of the analgesic acetaminophen upon esterases using isoelectric focusing

AbstractIn a study of the biochemical mechanisms of renal toxicity of acetaminophen, quantitative studies of the nonspecific kidney esterases were carried out in New Zealand white female rabbits. After the administration of a sublethal dose of 2.5 g/kg acetaminophen, four animals each plus four controls were sacrificed at 24 and 48 h. subsequent isoelectric focusing of kidney homogenate supernatants over a pH range of 3.5–8.0 showed marked changes in each of the groups. Zymograms of the nonspecific esterases in each group showed a characteristic pattern which deviated greatly from control animals. A morphological and histochemical examination of kidney sections from all animals showed no pathological changes in any of the kidneys. This would indicate that abnormal biochemical changes are being manifested in the kidney long before any morphological deviations. It would seem that this group of enzymes could provide a valuable market for early toxicological changes.

Reversibility of the toxicological changes induced by photomirex and mirex

Photomirex (8-monohydromirex) is a known environmental contaminant. In a previous 28-day and 90-day study, photomirex was shown to cause a number of biochemical and histological alterations in male rats. The present study was undertaken to determine the reversibility of those changes and to compare both effects and reversibility with the parent compound mirex. Male rats were fed diets containing 0, 0.05, 0.5, 5.0 and 50 ppm photomirex and 5 ppm or 50 ppm mirex for 28 days. Ten animals/group were killed at this time and the remainder placed on clean feed. Ten animals/group were killed after another 12, 24, and 48 weeks. The lower body weight gain in animals fed 50 ppm photomirex and 50 ppm mirex observed after 28 days on the test was not evident after 12 weeks on the clean diet or thereafter. Reduced food consumption produced by these groups persisted for 12 weeks but not 24 weeks. Liver hypertrophy was observed in the 5.0-ppm and 50-ppm photomirex groups after 28 days and persisted in the highest dose group for 24 weeks on clean diet. Elevated serum sorbitol dehydrogenase activity was observed in the 50-ppm photomirex group and persisted for 12 weeks on clean diet. Histological changes in liver and thyroid were present up to 48 weeks on clean diet, whereas treatment-related testicular changes observed after 28 days were not evident after 12 weeks. Significant residues of photomirex were still evident in all tissues examined up to 48 weeks postexposure in the 50-ppm photomirex group. The data indicate that photomirex and mirex are extremely persistent compounds and can results in a variety of biochemical and histological changes long after exposure has ceased.

Phytotoxicity of fenitrothion to white pine seeds and seedlings

Seeds of white pine (Pinusstrobus L.) were stratified in water or a water–fenitrothion emulsion. Two concentrations of fenitrothion were used: 10ppm (equivalent to an approved field concentration) and 1000 ppm. Some toxicological changes were associated with the higher concentration of fenitrothion alone, others were associated with both concentrations of the insecticide. More water was imbibed by seeds treated with 1000 ppm and the amounts and distribution of basic proteins were mainly changed at the higher level of fenitrothion exposure. Cytological studies indicated that succinic dehydrogenases and the esterases were also affected by the lower field concentration of fenitrothion, especially in the hypocotyl region of the embryo. There was no apparent effect on the total insoluble polysaccharides or on DNA metabolism during the first 10 days of growth following either treatment. Although toxicological changes were associated with exposure to fenitrothion, no detrimental long-term effects were observed.