Increased Liver Size Research Articles

The Clinical Course of Treated and Untreated Gaucher Disease. A Study of 45 Patients

ABSTRACT One hundred nineteen patients with Gaucher disease were examined in the past 13 years. Of these 45 were examined 3 or more times over a time-span exceeding one year and all such patients are included in this study. Adult patients showed little progression of disease. There were few alterations in the blood counts, no increase in size of liver and spleen, and changes in skeletal lesions were largely confined to pre-existing lesions. Some children appeared to have more progressive disease, but since many of the children in this study were treated with alglucerase, it is difficult to draw conclusions about the natural progression of the disease at earlier ages. Treatment with alglucerase resulted in gradual normalization of blood counts, decrease in the size of liver and spleen, and parallel decreases in the serum angiotensin converting enzyme and chitotriosidase levels. Skeletal symptoms were decreased in all patients, and skeletal lesions showed modest improvement in patients treated for two years or more. The response of patients to low dose/high frequency (2.3 U/Kg 3 × weekly; 30 U/Kg/Mo) therapy was indistinguishable from the response observed and previously reported by others with much larger doses. Changing the dosage from 30 U/Kg/Mo to 120 U/Kg/Mo was not attended by any significant changes in response. Criteria for the selection of patients for treatment with alglucerase are proposed. We suggest that a starting dose of 15 to 30 U/Kg/month, fractionated 3 times weekly be used for all patients, regardless of severity or site of involvement, and that upward dosage adjustments be made only in such rare patients who may not respond adequately to this dose in 6 to 12 months.

Comparison of daily versus continuous administration of somatotropin on growth rate, feed intake, and body composition in intact female rats1

The response to continuous delivery or daily bolus injection of porcine somatotropin (pST) was compared in mature, pituitary-intact female rats (225 g). Growth rate in control rats was approximately 1 g/d over the 14-d study. There was a dose-dependent (0, .4, 1.2, and 3.6 mg of pST/d; P < .001) increase in rate of gain with an interaction (P < .001) of dose and mode of delivery. The slope of the dose-response curve for growth rate was linear on a logarithmic scale for both modes of delivery but was greater for continuous delivery. At the low dose (.4 mg/d) pST stimulated gain (21.7 g/14 d above control, P < .05) when administered by daily injection but failed to stimulate gain (6.0 g/14 d above control, NS) when delivered continuously. At the high dose (3.6 mg/d), gain (above that in control rats) was 49.1 and 79.7 g/14 d for daily and continuous delivery; the two modes were different (P < .05) from each other. Feed intake and liver weights were also stimulated by pST in a dose-dependent manner. The increase in liver size was accompanied by a dose-dependent increase in liver DNA, indicative of an increase in cell number. Increased carcass gain was largely accounted for by increased carcass protein accretion. Rates of carcass lipid accretion were lower than those for protein accretion and were further decreased by pST, particularly by the high dose administered by continuous delivery, where a negative lipid accretion value was observed. Circulating IGF-I was increased by pST (P < .001) but was not affected by the mode of delivery. The results demonstrate that the increased gain observed in mature rats is largely due to lean tissue accretion and is accompanied by an increase in feed intake.

Pyruvate inhibits clofibrate-induced hepatic peroxisomal proliferation and free radical production in rats

In an effort to identify the effects of the 3-carbon compound pyruvate on free radical production, we measured hepatic total peroxisomal beta-oxidation and catalase activity and the production of lipofuscin-like products in male Sprague-Dawley rats consuming an adequate diet supplemented with pyruvate, vitamin E, or the peroxisome proliferator and free radical enhancer clofibrate for 22 days (n = 5 in each group). Clofibrate feeding induced hepatomegaly, a fivefold increase in total peroxisomal beta-oxidation activity, and a threefold increase in hepatic lipofuscin-like products (P < .05). Pyruvate but not vitamin E inhibited the increase in liver size by 70% (P < .05). Both pyruvate and vitamin E completely inhibited clofibrate-induced increases in lipofuscin-like products (P < .05). Pyruvate but not clofibrate or vitamin E increased plasma concentrations of the nitric oxide metabolites nitrite and nitrate (P < .05). We conclude that with clofibrate-induced peroxisomal proliferation and free radical production, pyruvate will inhibit peroxisomal proliferation and free radical production, inhibit free radical-induced lipid peroxidation, and enhance metabolism of nitric oxide.

Inhaled Nitric Oxide Improves Hepatic Tissue Oxygenation in Right Ventricular Failure

Inhaled Nitric Oxide Improves Hepatic Tissue Oxygenation in Right Ventricular Failure

Exposure of fish to biologically treated bleached‐kraft effluent. 1. Biochemical, physiological and pathological assessment of rocky mountain whitefish (prosopium williamsoni) and longnose sucker (catostomus catostomus)

AbstractA suite of biochemical, physiological, and pathological measures was used to assess possible effects of exposure to bleached‐kraft mill effluent (BKME) on wild longnose sucker (Catostomus catostomus) and mountain whitefish (Prosopium williamsoni) in the Wapiti/Smoky river system, as compared to similar populations in a reference river system without BKME inputs. Individual fish body burden data (i.e., metals, polychlorinated dioxins and furans, fatty and resin acids, chlorophenolics) were examined for correlations between chemical exposure and biological response. General incidence of gross pathology and histopathology showed no relationship with exposure to BKME, and no neoplastic or preneoplastic lesions were observed in either exposed or reference fish. The few significant differences observed in longnose sucker blood parameters were not correlated with exposure to BKME and appeared to reflect, at least in part, habitat gradients. Liver somatic indexes were higher for female BKME‐exposed longnose sucker, but were not significantly different in male sucker nor in mountain whitefish. Some differences in circulating sex steroid levels were observed in longnose sucker exposed to BKME (but not in mountain whitefish, the species with higher contaminant body burdens). Steroid profile differences may have been related to natural differences in duration of spawning periods in the two fish populations. Other measures of reproductive capacity (relative gonad size, fecundity, young‐of‐the‐year) showed no reductions in exposed fish. The detoxification enzyme cytochrome P4501A was induced in both species, with greater induction in whitefish than in longnose sucker. Whitefish P4501A induction correlated well with some BKME exposure measures, but not with liver or gonad weights, pathology, reproductive capacity, or population‐level parameters. Increased liver size and apparent differences in sex steroid profiles in longnose sucker did not translate to other health effects or population‐level effects. Thus, exposure to this biologically treated BKME produced one consistent biochemical marker of exposure (P4501A) in the two fish species that was not associated with any discernible adverse effects on individual fish health.

Survey of receiving‐water environmental impacts associated with discharges from pulp mills: 2. Gonad size, liver size, hepatic erod activity and plasma sex steroid levels in white sucker

AbstractFish collected from the receiving areas of 12 Canadian pulp mills were examined, including sites receiving effluent from kraft mills using chlorine as well as sulfite mills. Field collections included sampling of receiving water for chemistry and toxicity testing, and sampling of local fish for organ weights, hepatic MFO (ethoxyresorufin‐O‐deethylase, EROD) activity, plasma steroid levels, and levels of liver dioxins. The main objectives of this study were to determine whether the discharge of effluent from pulp mills to sites other than Jackfish Bay was associated with physiological or biochemical disruptions in wild fish, whether there was any correlation between waste treatment and the presence of biological responses in wild fish, and whether there was any association between the use of chlorine as a bleaching agent and these responses. Although white sucker collected near bleached‐kraft mills exhibited the highest EROD induction and dioxin levels, elevated enzyme activity was observed in fish from sites that did not use chlorine, and depressions in plasma sex steroid levels was not correlated with the level of EROD activity. The absence of chlorine bleaching or the presence of secondary treatment did not eliminate responses in fish, including decreased circulating levels of sex steroids, decreased gonadal size, and increased liver size. This survey has shown that (a) induction of hepatic EROD enzymes and depressions of plasma sex steroid levels during gonadal growth are found downstream of several pulp mills; (b) these changes are seen at some mills without chlorine bleaching and at mills that have secondary treatment; (c) substantial dilutions of nontoxic effluent do not appear to remove these responses; (d) the dominant factor determining the presence or absence of responses appeared to be dilution level; and (e) lab toxicity tests on invertebrates, rainbow trout, and fathead minnows could not predict the presence of these responses in wild fish.

Effect of the plant compound indole-3-carbinol on hepatic cholesterol homoeostasis

The aim of this study was to elucidate the effects of the compound indole-3-carbinol (I3C), which is found in cruciferous vegetables, on hepatic cholesterol homoeostasis and metabolism in male CD-1 mice. Oral administration of 500 and 750 mg I3C/kg/day to mice for 1 wk resulted in increased liver mass and microsomal protection content. Hepatic microsomal cholesterol levels were not significantly altered following treatment with 100 and 250 mg I3C/kg/day, but were significantly decreased following treatment with 500 and 750 mg/kg/day. Conversely, the lower doses of I3C administered decreased serum cholesterol levels whereas the higher doses of I3C had no effect on this parameter. Alterations in cholesterol homoeostasis by I3C were not related to liver hypertrophy, since administration of phenobarbital to mice increased liver size, but had no significant effect on hepatic microsomal or serum cholesterol levels. Activities of the hepatic enzymes cholesterol ester hydrolase and cholesterol 7α-hydroxylase were not altered by I3C. However, 500 and 750 mg I3C/kg/day elevated the activity of hepatic acyl-CoA:cholesterol acyltransferase (ACAT), the enzyme responsible for the formation of hepatic cholesteryl esters. These results demonstrate that (a) I3C lowers serum cholesterol levels at concentrations that have no discernible effect on hepatic cholesterol homoeostasis, and (b) at higher doses of I3C, hepatic microsomal cholesterol levels are significantly lowered and ACAT activity is significantly elevated. These latter effects are not accompanied by changes in serum cholesterol levels and may represent compensatory mechanisms to restore cholesterol homoeostasis in the body. Mechanisms responsible for the effects of I3C on cholesterol homoeostasis are proposed.

Fetal liver length in diabetic pregnancy

OBJECTIVES: Our purpose was to investigate whether liver size is increased in the fetuses of pregnant women with diabetes and whether there is any relationship between fetal liver size and maternal glycemic control. STUDY DESIGN: Eighty pregnant women with diabetes had ultrasonographic measurement of fetal liver length made at 18, 28, and 36 weeks' gestation. Twenty-four obese, nondiabetic women were studied at 36 weeks as controls. RESULTS: Fetal liver length measurements were significantly greater than normal by 18 weeks' gestation (12% above normal mean values, p < 0.001) and increased further (19%, p < 0.02) by 36 weeks. In the obese controls liver length was increased 9% and was significantly lower than in the diabetic subjects (p < 0.001). CONCLUSIONS: Fetal liver size is increased in pregnant women with diabetes and cannot be explained solely by maternal obesity. The major increase in liver size occurs early in pregnancy but appears to be modifiable by glycemic control later in gestation. OBJECTIVES: Our purpose was to investigate whether liver size is increased in the fetuses of pregnant women with diabetes and whether there is any relationship between fetal liver size and maternal glycemic control. STUDY DESIGN: Eighty pregnant women with diabetes had ultrasonographic measurement of fetal liver length made at 18, 28, and 36 weeks' gestation. Twenty-four obese, nondiabetic women were studied at 36 weeks as controls. RESULTS: Fetal liver length measurements were significantly greater than normal by 18 weeks' gestation (12% above normal mean values, p < 0.001) and increased further (19%, p < 0.02) by 36 weeks. In the obese controls liver length was increased 9% and was significantly lower than in the diabetic subjects (p < 0.001). CONCLUSIONS: Fetal liver size is increased in pregnant women with diabetes and cannot be explained solely by maternal obesity. The major increase in liver size occurs early in pregnancy but appears to be modifiable by glycemic control later in gestation.

Fetal liver length in diabetic pregnancy

OBJECTIVES: Our purpose was to investigate whether liver size is increased in the fetuses of pregnant women with diabetes and whether there is any relationship between fetal liver size and maternal glycemic control. STUDY DESIGN: Eighty pregnant women with diabetes had ultrasonographic measurement of fetal liver length made at 18, 28, and 36 weeks' gestation. Twenty-four obese, nondiabetic women were studied at 36 weeks as controls. RESULTS: Fetal liver length measurements were significantly greater than normal by 18 weeks' gestation (12% above normal mean values, p < 0.001) and increased further (19%, p < 0.02) by 36 weeks. In the obese controls liver length was increased 9% and was significantly lower than in the diabetic subjects (p < 0.001). CONCLUSIONS: Fetal liver size is increased in pregnant women with diabetes and cannot be explained solely by maternal obesity. The major increase in liver size occurs early in pregnancy but appears to be modifiable by glycemic control later in gestation. (AM J OBSTET GYNECOL 1994;170:1308-12.)

EXPOSURE OF FISH TO BIOLOGICALLY TREATED BLEACHED-KRAFT EFFLUENT. 1. BIOCHEMICAL, PHYSIOLOGICAL AND PATHOLOGICAL ASSESSMENT OF ROCKY MOUNTAIN WHITEFISH (PROSOPIUM WILLIAMSONI) AND LONGNOSE SUCKER (CATOSTOMUS CATOSTOMUS)

A suite of biochemical, physiological, and pathological measures was used to assess possible effects of exposure to bleached-kraft mill effluent (BKME) on wild longnose sucker (Catostomus catostomus) and mountain whitefish (Prosopium williamsoni) in the Wapiti/Smoky river system, as compared to similar populations in a reference river system without BKME inputs. Individual fish body burden data (i.e., metals, polychlorinated dioxins and furans, fatty and resin acids, chlorophenolics) were examined for correlations between chemical exposure and biological response. General incidence of gross pathology and histopathology showed no relationship with exposure to BKME, and no neoplastic or preneoplastic lesions were observed in either exposed or reference fish. The few significant differences observed in longnose sucker blood parameters were not correlated with exposure to BKME and appeared to reflect, at least in part, habitat gradients. Liver somatic indexes were higher for female BKME-exposed longnose sucker, but were not significantly different in male sucker nor in mountain whitefish. Some differences in circulating sex steroid levels were observed in longnose sucker exposed to BKME (but not in mountain whitefish, the species with higher contaminant body burdens). Steroid profile differences may have been related to natural differences in duration of spawning periods in the two fish populations. Other measures of reproductive capacity (relative gonad size, fecundity, young-of-the-year) showed no reductions in exposed fish. The detoxification enzyme cytochrome P4501A was induced in both species, with greater induction in whitefish than in longnose sucker. Whitefish P4501A induction correlated well with some BKME exposure measures, but not with liver or gonad weights, pathology, reproductive capacity, or population-level parameters. Increased liver size and apparent differences in sex steroid profiles in longnose sucker did not translate to other health effects or population-level effects. Thus, exposure to this biologically treated BKME produced one consistent biochemical marker of exposure (P4501A) in the two fish species that was not associated with any discernible adverse effects on individual fish health.

Changes in biliary lipid secretion during normal development and diurnal cycling in the rat

Biliary lipid secretion in conjunction with hepatic cholesterol synthesis was determined in normal male rats at 4, 5, 7, and 9 weeks of age, during a period of linear growth and a near fourfold increase in liver size. Studies were performed both at periods of low (mid-light cycle) and high (mid-dark cycle) hepatic cholesterol synthesis. Biliary bile salt, phospholipid, and cholesterol secretion (per g of liver) markedly decreased with an increase in liver size. Whereas the secretion of bile salts and phospholipid was not significantly different in mid-dark and mid-light periods for animals of the same age, cholesterol secretion was greater in the mid-dark than in the mid-light period at 5, 7, and 9 weeks of age. Relationships between biliary cholesterol secretion and bile salt and phospholipid secretion differed at mid-dark and mid-light periods, as follows: cholesterol secretion was not significantly related to bile salt secretion at mid-dark (r = 0.49, P > 0.05) but was related at mid-light (r = 0.73, P = 0.003); and although cholesterol secretion was significantly related to phospholipid secretion at mid-dark, this relationship was not nearly as strong as at mid-light (P < 0.005, comparing r = 0.95 at mid-light with r = 0.53 at mid-dark). In contrast, at mid-dark, biliary cholesterol secretion was strongly related to hepatic cholesterol synthesis (r = 0.84, P < 0.0001) whereas at mid-light the two were not significantly related (r = 0.13, P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Dehydroepiandrosterone regulation of the hepatic glucocorticoid receptor in the zucker rat. The obesity research program

Dehydroepiandrosterone (DHEA) decreases the activity of hepatic tyrosine aminotransferase (TAT), a glucocorticoid-inducible enzyme, in the obese, hypercorticosteronemic Zucker rat. To investigate the mechanism of this antiglucocorticoid action, the effect of exogenous DHEA on hepatic glucocorticoid receptor (GC) number and affinity was quantitated. Food supplementation with DHEA (0.6% w/w) for 1 or 7 days had no effect on either receptor number or affinity in obese Zucker rats. After 28 days, however, DHEA treatment resulted in a nearly 40% decrease in cytosolic hepatic receptor content (B max; fmol/mg cytosolic protein) without any change in affinity ( K d ) in both lean and obese rats. DHEA treatment for 28 days also resulted in an increased liver size and cytosolic protein content. When the hepatic GC receptor content was normalized based on the change in liver size and protein content, the apparent number of GC binding sites per liver was not affected by DHEA treatment. This observation suggests that DHEA's effect on GC receptor content may not be a specific action and that downregulation of the GC receptor is not the mechanism of DHEA action on GC induced TAT activity. This is supported by the effect of DHEA on obese rat TAT activity in the same experiment where the greatest inhibition occurred after only 1 day of treatment. From these experiments it is concluded that although long-term DHEA treatment may decrease the relative concentration of GC receptors in rat liver, this change is not the mechanism through which DHEA mediates its acute antiglucocorticoid action.

Clinical and Biochemical Phenotype in 11 Patients With Mevalonic Aciduria

Mevalonic aciduria is a consequence of the deficiency of mevalonate kinase, the first enzyme after 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the biosynthesis of cholesterol and nonsterol isoprenes. To establish the clinical and biochemical phenotype of mevalonic aciduria, the authors assembled their experience with 11 patients including attempts at therapeutic interventions. Mevalonic acid in body fluids was determined by stable isotope dilution gas chromatography/mass spectroscopy with selected ion monitoring, ubiquinone-10 concentrations by reversed-phase high-pressure liquid chromatography. Varying degrees of severity of clinical illness were observed despite uniform, virtual absence of residual activity of the enzyme. The most severely affected patients have had profound developmental delay, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, and anemia, as well as diarrhea and malabsorption, and have died in infancy. Less severely affected patients have had psychomotor retardation, hypotonia, myopathy, and ataxia. All patients have had recurrent crises in which there was fever, lymphadenopathy, increase in size of liver and spleen, arthralgia, edema, and a morbilliform rash. Neuroimaging studies revealed selective and progressive atrophy of the cerebellum. Mevalonic acid concentrations were found to be grossly elevated in body fluids of all patients. Concentrations of plasma cholesterol were normal or only slightly reduced. Concentrations of ubiquinone-10 in plasma were found to be decreased in most patients. Abnormalities such as hypoglycemia, metabolic acidosis, or lactic acidemia, the usual concomitants of disorders of organic acid metabolism, were conspicuously absent. These observations establish the broad range of clinical symptoms and biochemical findings in mevalonic aciduria. It is concluded that although patients with mevalonic aciduria have a recognizable phenotype of serious clinical manifestations, some patients are likely to remain undiagnosed and may be found in a variety of subspecialty clinics, including neurology, gastroenterology, cardiology, and genetics.

Mechanism of hypertriglyceridemia in Dahl rats.

Plasma triglyceride concentrations were shown to be higher in hypertensive (153 +/- 2 mm Hg) male Dahl salt-sensitive rats than in control Sprague-Dawley rats (122 +/- 2 mm Hg). These differences in triglyceride concentrations were seen when blood was drawn at 9 AM from unfasted animals (229 +/- 27 versus 111 +/- 8 mg/dL), at 1 PM after a 4-hour fast (186 +/- 13 versus 88 +/- 4 mg/dL), or at 9 AM after a 13-hour fast (151 +/- 6 versus 90 +/- 6 mg/dL), all p < 0.001. Total triglyceride secretion was also compared in groups of rats by determining the increment in plasma triglyceride concentration for 2 hours after blocking triglyceride removal from plasma by injecting Triton. Studies performed at 1 PM and 9 AM, after the 4- and 13-hour fast, demonstrated that total triglyceride secretion was greater (p < 0.05) in Dahl rats only when studied at 1 PM. Direct estimates of hepatic triglyceride secretion at 1 PM also demonstrated a significant (p < 0.02) increase in secretion rate by perfused livers from Dahl rats, due in part to their increased liver size. In addition, removal of prelabeled very low density lipoprotein-triglyceride in the intact rat was significantly (p < 0.05) decreased in Dahl rats. Lipoprotein lipase activity measured in skeletal muscle, heart, and adipose tissue was also significantly decreased at 9 AM and 1 PM (after 0 and 4 hours of fasting) in tissue from Dahl rats. These data confirm that Dahl rats have higher plasma triglyceride concentrations than Sprague-Dawley rats. Since both total and hepatic triglyceride secretion were somewhat greater in Dahl rats, in association with a decrease in both removal of very low density lipoprotein from plasma and decreased muscle and adipose tissue lipoprotein lipase activity, it seems likely that hypertriglyceridemia in Dahl rats results from a combination of increased triglyceride secretion and decreased triglyceride removal.

Hepatocellular proliferation in ibuprofen-treated mice.

Female B6C3F1 mice were treated with ibuprofen for 2 wk or 90 days to monitor effects on hepatocellular proliferation during acute and subchronic exposure. Proliferation was assessed by bromodeoxyuridine labeling. Mice treated with 100, 200, or 400 mg/kg ibuprofen for 2 wk had significantly increased liver weights. A dose-related increase in the number of labeled hepatocytes per 1,000 hepatocytes suggested that the weight increases were in part a result of hepatocellular proliferation. Hepatocellular hypertrophy also contributed to the increased liver size as indicated by decreases in the number of hepatocytes per high power field. Ultrastructural evaluation indicated that hepatocyte peroxisome size increased significantly in treated mice. Mice treated with 100 or 200 mg/kg ibuprofen for 90 days and given bromodeoxyuridine during the last 2 wk of ibuprofen exposure had statistically significant increases in relative liver weights. However, the number of labeled hepatocytes per 1,000 hepatocytes was not increased, and there was no evidence of hepatocellular hypertrophy. Mice given 200 mg/kg ibuprofen for 90 days had significantly decreased serum triglycerides. These findings indicate that ibuprofen treatment of mice results in hepatomegaly characterized by hepatocellular hypertrophy and hyperplasia. Peroxisomal changes may be contributory to the pathogenesis of this lesion.

Alcohol, hepatic sinusoidal microcirculation, and chronic liver disease

According to the “intact cell hypothesis,” ethanol (EtOH) primarily targets nonparenchymal hepatic sinusoidal and perisinusoidal cells, thereby promoting sinusoidal capillarization, which impairs microcirculatory exchange of nutrients and wastes, promotes tissue fibrosis, and only indirectly damages hepatic parenchyma. To test this hypothesis, sinusoidal ultrastructure and hepatic lymph flow and protein composition were examined in rats up to 16 weeks after intragastric EtOH (36% calories)-high fat infusion (Tsukamoto-French model) (TF). The findings were compared to dietary controls and interpreted in light of restricted transsinusoidal protein movement observed in patients with alcoholic cirrhosis. In vitro, alterations in rat hepatic sinusoidal endothelial cell (RSE) morphology, proliferative index, and trasendothelial macromolecular permeability (Evans bluealbumin uptake into microcarrier beads) were determined after acute and more chronic exposure to 0.1%–5 vol% EtOH. TF displayed 75% increased liver size, perisinusoidal collagenosis, and basal lamina deposition, ascitic fluid, and doubling of hepatic lymph liquid and protein flux. In vitro, 1% EtOH retracted RSE cell margins, enhanced transendothelial Evans blue-albumin flux and suppressed proliferative index. Thus, high EtOH concentration, clinically attainable in the portal blood during an alcoholic binge, both in vivo and in vitro, promotes early structural and functional alterations in sinusoidal endothelium, which over time may be responsible for progressive restriction of free intrahepatic exchange of liquid, macromolecules, and migrating immune cells.

Changes in Maturity, Plasma Sex Steroid Levels, Hepatic Mixed-Function Oxygenase Activity, and the Presence of External Lesions in Lake Whitefish (Coregonus clupeaformis) Exposed to Bleached Kraft Mill Effluent

Lake whitefish (Coregonus clupeaformis) exposed to primary treated bleached kraft mill effluent (BKME) had reduced gonadal development and increased liver size relative to two reference populations. These results parallel our previous work on the white sucker (Catostomus commersoni) exposed to BKME at the same Lake Superior site. More detailed studies conducted in 1990, after the installation of an aeration stabilization basin at the pulp mill, found that lake whitefish exhibited reduced gonad sizes, delayed age to maturation, decreased levels of the plasma sex steroids testosterone and 17β-estradiol, and elevated hepatic mixed-function oxygenase (MFO) activity. Liver size was smaller following operation of the secondary treatment system. More than 20% of the lake whitefish collected at the BKME site in 1990 exhibited lateral, slash-like lesions which penetrated the body cavity. Histological examination revealed no evidence of an infectious etiology, and the wounds could not be accounted for by known causes. Similar lesions were found in 1991 near a second BKME discharge.

Iron as a synergist for hepatocellular carcinoma induced by polychlorinated biphenyls in Ah-responsive C57BL/10ScSn mice

Male Ah-responsive C57BL/10ScSn mice received a single dose of iron-dextran (600 mg Fe/kg) and were fed a diet containing 0.01% of the PCBs mixture Aroclor 1254 for up to 12 months. Iron caused a marked synergistic increase in liver size from 2 months with greatly elevated mitotic rates, numbers of basophilic foci and incidences of bile duct and oval cell proliferation. Although at 4 months much of the liver enlargement was due to iron-depleted hyperplastic regions and lipid accumulation, by 8 months seven out of nine mice had nodules (hepatocellular adenomas) whereas none were observed in the Aroclor alone group. After 12 months, 16 out of 18 mice had multiple nodules and/or hepatocellular carcinomas whereas only one of 16 mice was positive in a group not given iron. Basophilic nodules were more common than clear cell nodules in those mice with carcinomas than in those animals without. Preloading with iron also greatly enhanced the development of cholangiofibrosis at 8 and 12 months. Preliminary experiments with the polybrominated biphenyl mixture Firemaster BP-6 indicated a similar synergistic interaction with iron. No effects of iron and Aroclor 1254 on the liver were observed in the Ah-nonresponsive strain DBA/2. Iron potentiated the development of uroporphyria after exposure to those chemicals in C57BL/10ScSn mice but not in the DBA/2 mice. Therefore in C57BL/10ScSn mice the carcinogenicity of PCBs and possibly PBBs, is modulated by iron status and probably not at a late stage where these chemicals may act in a promotional manner.

Acute inhalation toxicity of ammonium perfluorononanoate

Ammonium perfluorononanoate (CAS Registry No. 4149-60-4) is a white powder that can become airborne. Its acute inhalation toxicity in male rats was studied. Male rats were exposed for single 4-hr periods to dust concentrations ranging from 67 to 4600 mg/m 3. The LC 50 was determined to be 820 mg/m 3, with the lowest concentration causing death being 590 mg/m 3. Ammonium perfluorononanoate was classified as moderately toxic by the acute inhalation route. Exposure to ammonium perfluorononanoate caused a pronounced increase in liver size. The acute toxicity of ammonium perfluorononanoate appears to be similar to that of its 8-carbon homologue, ammonium perfluorooctanoate, but considerably less than that of the 10-carbon homologue, perfluoro- n-decanoic acid.

The acute and subchronic effects of ketoconazole on hepatic microsomal monooxygenases in the rat

Female adult Wistar rats were treated with single or repeated doses of ketoconazole ranging from 10 mg kg to 100 mg kg . Single dose treatment produced inhibition of hepatic microsomal ethoxy-resorufin O-deethylation (EROD) and aldrin epoxidation (AE) 2 hr after oral dosing. Twenty-four hours after a single dose, inhibition was still demonstrable after the low dose of 10 mg kg , but at higher doses increased microsomal activity was apparent. After 7 days repeated dosing liver weight and microsomal protein content were increased in a dose-dependent fashion. EROD and AE were induced at all doses after repeated treatment when the increase in liver size was considered. These effects were seen at doses within the antimycotic therapeutic range and add support to the suggestion that reported drug interactions with ketoconazole in man are due to the effects of this drug on hepatic microsomal activity.