Commentary: the role of the toxicologic pathologist in academia.

Veterinary pathologists working as toxicologic pathologists in academic settings fill many vital roles, such as diagnosticians, educators, and/or researchers. These individuals have spent years investigating pathology problems that mainly or exclusively focus on the reactions of cells, organs, or systems to toxic materials. Thus, academic toxicologic pathologists are uniquely suited both to help trainees understand toxicity as a cause of pathology responses and also to provide expert consultation on toxicologic pathology. Most toxicologic pathologists in academia are employed at colleges of medicine or veterinary medicine, even though specific toxicologic pathology faculty appointments are uncommon in Europe and North America. Academic toxicologic pathologists typically receive lower financial compensation than do toxicologic pathologists in industry, but academic positions generally provide alternative rewards, such as higher workplace autonomy and scheduling flexibility, professional enrichment through student interactions, and enhanced opportunities for collaborative research and advanced diagnostic investigations. Regular participation by academic toxicologic pathologists in professional training opportunities (eg, as pathology and toxicology instructors in medical and veterinary medical courses, graduate programs, and residencies) offers an important means of engendering interest and inspiring veterinarians to select toxicologic pathology and toxicology as their own areas of future expertise.

Inhibition of 7,12-dimethylbenz(a)anthracene-induced mammary tumors and DNA adducts by dietary selenite.

The present studies were designed to examine the influence of dietary selenite supplementation on the initiation phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis and to correlate selenite-induced changes in the binding of DMBA metabolites to rat mammary cell DNA with the ultimate tumor incidence. Diets formulated to contain selenium, as sodium selenite at 0.1, 0.5, 1, 2, or 4 micrograms/g were fed for 2 weeks prior to and 2 weeks following treatment with DMBA (5 mg/kg body weight). Food intake and weight gain did not differ among treatments. Tumor incidence correlated inversely to the quantity of selenium consumed (r = -0.99). Final tumor incidences were 52, 32, 24, 14, and 10% for rats fed 0.1, 0.5, 1, and 4 micrograms selenium/g, respectively. In a separate group of rats fed a diet containing 4 micrograms selenium/g during both the initiation and promotion stages the final tumor incidence was 4.8%. Selenite supplementation for 2 weeks markedly depressed the occurrence of individual and total DMBA-DNA adducts. The final mammary tumor incidence correlated positively with total DMBA-DNA adducts (r = 0.99). These studies clearly demonstrate that selenite can inhibit the initiation stage of mammary carcinogenesis. This reduction in tumor incidence is likely due to a reduction in carcinogen metabolism and ultimately adduct formation.

The accumulation of cystamine and its metabolism to taurine in rat lung slices.

The objective of these studies was to determine the accumulation and fate of the disulphide, cystamine by rat lung slices. Cystamine was accumulated by two active uptake systems that obeyed saturation kinetics, with apparent Km values of 12 and 503 microM, and maximal rates of 530 and 5900 nmol/g wet weight/hr respectively. The high affinity system was competitively inhibited by the diamine, putrescine and the herbicide paraquat, which are themselves accumulated. Thus, this pulmonary uptake process appears to be identical for all three compounds. In contrast, the low affinity process was not inhibited by putrescine, and this process results from the diffusion of cystamine into the cell and its subsequent metabolism. Upon accumulation, cystamine was metabolised, predominantly to the sulphonic acid, taurine, with 10-20% of the intracellular label covalently binding to protein. Conversion to taurine was unaffected by amine oxidase inhibitors, but was decreased after GSH depletion, suggesting that pulmonary cystamine metabolism is glutathione-dependent, and is not mediated by diamine oxidase. Both cystamine and taurine have been implicated as antioxidants, and we suggest that cystamine is actively accumulated by the lung as part of the process to protect pulmonary tissue against oxidative stress.

Fumonisin toxicosis in swine: an overview of porcine pulmonary edema and current perspectives.

Fumonisin toxicosis in swine was named porcine pulmonary edema (PPE) after outbreaks of a fatal disease in pigs fed Fusarium verticillioides (F. moniliforme)-contaminated corn screenings from the 1989 corn crop in Iowa, Illinois, and Georgia. Pigs that died had severe pulmonary edema, which has not been identified in other species after exposure to fumonisins. The disease has been reproduced experimentally by feeding of naturally contaminated corn, F. verticillioides culture material, and by intravenous administration of fumonisin B1 (FB1). Hepatic lesions consisting of apoptosis, necrosis, and hepatocyte proliferation also are observed. As in other species, alterations in clinical pathology reflect hepatic injury as well as elevated serum cholesterol concentration. In chronic studies, esophageal plaques, hyperplastic hepatic nodules, and right ventricular hypertrophy were found. In pigs, as in other species, fumonisin alters sphingolipid biosynthesis, with the greatest alterations in sphingosine and sphinganine concentrations in kidney, liver, lung, and heart. Our recent studies on fumonisin toxicosis in pigs have focused on immune effects and the pathogenesis of pulmonary edema. The specific immune system was not affected; however, FB1 inhibited phagocytosis and sphingolipid biosynthesis in pulmonary macrophages. Fumonisin induced an accumulation of membranous material in pulmonary capillary endothelial cells; this change appears specific to this cell type and to swine. In short-term cardiovascular studies, fumonisin decreased left ventricular dP/dt(max) (an index of cardiac contractility), mean systemic arterial pressure, heart rate, and cardiac output, and increased mean pulmonary artery pressure and pulmonary artery wedge pressure. These changes are compatible with the inhibition of L-type calcium channels by increased sphingosine and/or sphinganine concentration. Therefore, fumonisin-induced pulmonary edema in swine appears to result from acute left-sided heart failure mediated by altered sphingolipid biosynthesis.

Fumonisin B(1) increases serum sphinganine concentration but does not alter serum sphingosine concentration or induce cardiovascular changes in milk-fed calves.

Fumonisin B(1) is the most toxic and commonly occurring form of a group of mycotoxins that alter sphingolipid biosynthesis and induce leukoencephalomalacia in horses and pulmonary edema in pigs. Purified fumonisin B(1) (1 mg/kg, iv, daily) increased serum sphinganine and sphingosine concentrations and decreased cardiovascular function in pigs within 5 days. We therefore examined whether the same dosage schedule of fumonisin B(1) produced a similar effect in calves. Ten milk-fed male Holstein calves were instrumented to obtain blood and cardiovascular measurements. Treated calves (n = 5) were administered purified fumonisin B(1) at 1 mg/kg, iv, daily for 7 days and controls (n = 5) were administered 10 ml 0.9% NaCl, iv, daily. Each calf was euthanized on day 7. In treated calves, serum sphinganine concentration increased from day 3 onward (day 7, 0.237 +/- 0.388 micromol/l; baseline, 0.010 +/- 0.007 micromol/l; mean +/- SD), whereas, serum sphingosine concentration was unchanged (day 7, 0.044 +/- 0.065 micromol/l; baseline, 0.021 +/- 0.025 micromol/l). Heart rate, cardiac output, stroke volume, mean arterial pressure, mean pulmonary artery pressure, pulmonary artery wedge pressure, central venous pressure, plasma volume, base-apex electrocardiogram, arterial Po(2), and systemic oxygen delivery were unchanged in treated and control calves. Fumonisin-treated calves developed metabolic acidosis (arterial blood pH, 7.27 +/- 0.11; base excess, -9.1 +/- 7.6 mEq/l), but all survived for 7 days. We conclude that calves are more resistant to fumonisin B(1) cardiovascular toxicity than pigs.

Fumonisin B(1) is hepatotoxic and nephrotoxic in milk-fed calves.

Fumonisins are a group of mycotoxins that alter sphingolipid biosynthesis and induce leukoencephalomalacia in horses and pulmonary edema in pigs. Experimental administration of fumonisin induces hepatotoxicity in all species, including cattle, as well as nephrotoxicity in rats, rabbits, and sheep. We investigated the hepatotoxicity and nephrotoxicity of fumonisin B(1) to calves. Ten milk-fed male Holstein calves aged 7 to 14 days were instrumented to obtain blood and urine. Treated calves (n = 5) were administered fumonisin B(1) at 1 mg/kg, iv, daily and controls (n = 5) 10 ml 0.9% NaCl, iv, daily until euthanized on day 7. Fumonisin B(1)-treated calves were lethargic and had decreased appetite from day 4 onward, serum biochemical evidence of severe liver and bile duct injury, and impaired hepatic function. Treated calves also had biochemical evidence of renal injury that functionally involved the proximal convoluted tubules. Sphinganine and sphingosine concentrations in liver, kidney, lung, heart, and skeletal muscle were increased in treated calves. Sphinganine, but not sphingosine, concentration was increased in brains of treated calves. In fumonisin B(1)-treated calves, hepatic lesions were characterized by disorganized hepatic cords, varying severity of hepatocyte apoptosis, hepatocyte proliferation, and proliferation of bile ductular cells. Renal lesions in treated calves consisted of vacuolar change, apoptosis, karyomegaly, and proliferation of proximal renal tubular cells, as well as dilation of proximal renal tubules, which contained cellular debris and protein. This is the first report of fumonisin B(1)-induced renal injury and organ sphingolipid alterations in cattle.

Uptake and subcellular localization of tritiated dihydro-microcystin-LR in rat liver.

Microcystin-LR (MC-LR), a cyclic heptapeptide hepatotoxin (mol. wt = 994) produced by the blue-green alga (cyanobacterium), Microcystis aeruginosa, was reduced with tritium labeled sodium borohydride, converted to [3H]-dihydro-microcystin-LR ( [3H]-2HMC-LR), and purified to greater than 99% purity by C-18 reverse-phase high-performance liquid chromatography. The uptake and subcellular distribution of [3H]-2HMC-LR were determined in suspensions of hepatocytes at 0 degrees C and 37 degrees C, or following rifampicin pretreatment, and in perfused rat liver. The remaining cells were homogenized and subfractionated using sucrose gradient centrifugation. Suspensions of 7.5 x 10(6) hepatocytes also were incubated with 10 micrograms/ml of toxin, solubilized in Triton X-100, and ultracentrifuged to pellet the detergent insoluble fraction (containing actin). Isolated rat livers were perfused with media containing [3H]-2HMC-LR and the uptake of radiolabel was determined. Sequential biopsy samples were collected for histologic examination. The remaining liver was homogenized and subcellular fractions prepared. Uptake of radiolabel was rapid in both cell suspension at 37 degrees C and perfused liver; however, uptake in cell suspensions was reduced by about 50% at 0 degrees C and by rifampicin (50 micrograms/ml) pretreatment. Hepatocyte necrosis was observed in isolated perfused livers 45 min after initiation of perfusion with [3H]-2HMC-LR. In both hepatocyte suspensions and perfused livers 65 to 77% of the radiolabel was in the cytosolic fraction. In the hepatocyte suspensions, 13 to 18% of the radiolabel was present in the plasma membrane/nuclear fraction with lesser amounts in the other fractions. Trichloroacetic acid treatment of cytosolic fractions indicated that in hepatocyte suspensions, 50-60% of the radiolabel was bound to cytosolic protein. Studies using the perfused liver confirmed that the majority of the radiolabeled MCLR (78-88%) was bound to cytosolic protein. These data suggest that the uptake of [3H]-2HMC-LR occurs primarily by an energy-dependent transport process involving the rifampicin-sensitive hepatic bile acid carrier and that once inside the hepatocyte, the toxin binds to a cytosolic protein(s).

Structural modifications imparting reduced toxicity in microcystins from Microcystis spp.

A cyanobacterial (blue-green algal) bloom containing Microcystis aeruginosa (dominant), M. viridis, and M. wesenbergii, was collected from Homer Lake (Illinois, U.S.A.) in the summer of 1988 and microcystins were isolated. One microcystin of substantially reduced toxicity was isolated, together with ten hepatotoxic microcystins. The compound with reduced toxicity was nonlethal at 1 mg/kg (i.p. mouse) and was determined to have a (C3H7O2) mono-ester of the alpha-carboxyl on the Glu unit of microcystin-LR. The other nine microcystins apart from MCLR had approximate LD50S ranging from 97 micrograms/kg to 750 micrograms/kg.

Distribution of tritiated dihydromicrocystin in swine.

The distribution of tritiated dihydromicrocystin [3H]2H-MCLR was studied in anesthetized specific-pathogen-free pigs. Two doses were administered i.m. and one dose was given via an isolated ileal loop. At 4 hr after i.v. administration of the toxin at 25 micrograms/kg, 64.6% of the total dose (%TD) was located in the liver, with smaller amounts distributed to the kidneys (1.2% TD), lungs (1.75% TD), heart (0.22% TD), ileum (0.13% TD) and spleen (0.04% TD). A similar distribution was found at 4 hr postdosing in pigs given 75 micrograms/kg, although the liver contained a lower fraction of the total dose, at 46.99% TD, and the kidneys had somewhat more, at 2.19% TD, than the low dose. At the high dose, the fractions of the amount given accounted for by the lungs (0.55% TD), heart (0.23% TD), ileum (0.20% TD) and spleen (0.07% TD) were similar to those at the low dose. The livers of the pigs given 75 micrograms/kg via the ileal loop, at 5 hr postdosing, contained 49.5% TD and the ileum had 33.94% TD. Smaller amounts were distributed to kidneys (1.04% TD), lungs (0.65% TD), heart (0.81% TD) and spleen (0.16% TD). The livers of both groups dosed at 75 micrograms/kg contained higher concentrations of toxin, but lower percentages of the total dose, than the livers of pigs dosed at 25 micrograms/kg. Larger increases in serum arginase in the two 75 micrograms/kg groups were associated with histological evidence of more severe liver damage than at the 25 micrograms/kg dose. Analysis of radiolabeled compounds from hepatic tissue using fast atom bombardment mass spectrometry determined that the primary constituent was [3H]2H-MCLR, but two minor radioactive components were also isolated. These findings indicate that [3H]2H-MCLR is rapidly concentrated in the liver of swine, whether given i.v. or via an isolated ileal loop, that at extremely toxic doses uptake is slowed, and that it is as toxicologically active as the parent compound.

Toxicokinetics of tritiated dihydromicrocystin-LR in swine.

The toxicokinetics of tritiated dihydromicrocystin-LR ([3H]2H-MCLR) were studied in anesthetized, specific-pathogen-free pigs. Pigs were dosed with radiolabeled plus non-labeled 2H-MCLR at 25 or 75 micrograms/kg i.v., or via an isolated ileal loop at 75 micrograms/kg. The i.v. doses were rapidly removed from the blood. At either i.v. dose, more than half the radiolabel from [3H]2H-MCLR present in the blood at 1 min postdosing was cleared by 6 min. The blood clearance at the 75 micrograms/kg dose was slower than at the 25 micrograms/kg dose. Accordingly, at the high dose, the concentrations of the toxin in blood were disproportionately higher from 10 min after dosing until the study ended 4 hr later. The decreased clearance is presumably due to decreased elimination from the blood as a consequence of the hepatic injury that was observed histologically. Following administration of [3H]2H-MCLR at 75 micrograms/kg via the ileum, the maximal toxin concentration in blood was achieved at 90 min after dosing. At that time the [3H]2H-MCLR concentration in portal venous blood was 3.6 times higher than in peripheral venous blood. Although bile production varied, following i.v. dosing radioactivity was detected in bile as early as 12 min postdosing in one animal. This study demonstrated that [3H]2H-MCLR is rapidly removed from the blood of anesthetized swine and that excretion of the radiolabel into bile may begin within 30 min of dosing.

Effects of dimethyl sulfoxide (DMSO) on pulmonary fibrosis in rats and mice.

Dimethyl sulfoxide (DMSO), a putative anti-inflammatory agent and free radical scavenger, was shown to protect against acute bleomycin-induced pulmonary fibrosis in the rat (Pepin and Langner, Biochem. Pharmacol., 34 (1985) 2386). We examined the effect of DMSO on bleomycin-induced pulmonary toxicity in Swiss outbred mice and Sprague-Dawley rats, and on butylated hydroxytoluene (BHT)-induced pulmonary toxicity in Swiss outbred mice. Bleomycin (BL)-induced mortality in mice (20% at 0.1 units BL) and rats (50% at 1.5 units BL) was increased to 100% by daily DMSO (5 g/kg 50% in saline). Similar DMSO treatment after lower doses of bleomycin (1 unit BL in rats and 0.075 or 0.050 units in mice) increased lung hydroxyproline content in the rat but had no effect in the mouse. Lung hydroxyproline content in mice 14 days after 400 mg/kg BHT in corn oil was also slightly increased by daily DMSO at 5 g/kg, but not at 1 or 2 g/kg. Daily DMSO (5 g/kg) did not alter cellular proliferation [( 14C]thymidine incorporation into pulmonary DNA) in the lung at 2 or 5 days after BHT. Thus, we found that DMSO potentiated the lethality of bleomycin, and potentiated or had no effect on bleomycin or BHT-induced pulmonary fibrosis in the rat and mouse.

Nephrotoxicity of para-substituted thiobenzamide derivatives in the rat.

Histological examination, plasma urea nitrogen levels (BUN), and renal cortical slice uptake of paminohippurate (PAH) or tetraethylammonium (TEA) were used to assess the nephrotoxicity of thiobenzamide and its para-substituted derivatives in Sprague-Dawley rats. Intraperitoneal injection of p-methylthiobenzamide (PMTB) to rats resulted in dose-dependent nephrotoxicity as judged by increased BUN levels, decreased TEA uptake and histologic examination of the kidney. Para-methoxythiobenzamide and PMTB were more potent nephrotoxins than thiobenzamide, which was itself minimally nephrotoxic. Para-methylthiobenzamide-S-oxide (PMTBSO) was more nephrotoxic than PMTB. Rats were pretreated with 1-methyl-1-phenylbenzoylthiourea (MPBTU), a non-toxic arylthiourea which inhibits the metabolism and toxicity of thiocarbonyl compounds. The nephrotoxicity and hepatotoxicity of PMTB was reduced by treatment with MPBTU 30 min prior to PMTB. Pretreatment with MPBTU protected against the renal toxicity of PMTBSO. The results indicate that electron donating para-substituted thiobenzamides produce dose-dependent renal injury, dependent upon oxidative biotransformation.

Toxicity-distribution relationships among 3-alkylfurans in the mouse lung.

The present study was designed to investigate the extent to which a homologous series of 3-alkylfurans, 3-methylfuran, 3-ethylfuran, and 3-pentylfuran, may cause lung injury in mice in order to determine whether the chemical properties of these compounds are related to their toxic potential. The pulmonary concentration and pneumotoxicity of these and various other furan derivatives were also measured to determine if a correlation existed between the magnitude of pneumotoxicity produced by these toxins and their concentration in the lung. Along with the 3-alkylfurans, the other furan derivatives investigated were furan, 2-ethylfuran, 2-furamide, and 3-methylthiophene. The absence or presence of lung damage was evaluated by light microscopy. The quantitative index used to assess and rank the compounds as pneumotoxins was the incorporation of [14C]thymidine into DNA. The results obtained with the 3-alkylfurans showed that 3-methylfuran and 3-ethylfuran were toxic to the lung whereas 3-pentylfuran did not produce pneumotoxicity. 2-Ethylfuran, furan, and 2-furamide also caused lung damage but 3-methylthiophene did not. All the compounds, with the exception of furan, reach the lung in comparable concentrations; therefore, there does not seem to be a correlation between pneumotoxicity and concentration of the toxin in the lung. From these studies, it is also apparent that the pneumotoxicity of the 3-alkylfurans extends beyond the methyl group but that the toxicity decreases with increasing chain length.

Species and organ specificity of fumonisin-induced endothelial alterations: potential role in porcine pulmonary edema.

Fumonisins, mycotoxins that commonly contaminate corn, induce cardiovascular toxicity and pulmonary edema in pigs, leukoencephalomalacia in horses, and nephropathy in rats, rabbits, and lambs. The mechanisms of these species-specific target organ toxicoses are poorly understood. We have previously reported perinuclear accumulation of membranous material in pulmonary capillary endothelial cells of pigs fed fumonisin-containing culture material. We hypothesized that these endothelial accumulations may be important in the pathogenesis of fumonisin-induced pulmonary edema and target organ toxicity in other species. Both target and non-target tissues from fumonisin-exposed pigs, sheep, rabbits, and rats were examined ultrastructurally. Specifically, lung, liver, heart and kidney were examined. In agreement with our previous work (Gumprecht, L.A., Beasley, V.R., Weigel, R.M., Parker, H.M., Tumbleson, M.E., Bacon, C.W., Meredith, F.I., Haschek, W.M., 1998. Development of fumonisin-induced hepatotoxicity and pulmonary edema in orally dosed swine: morphological and biochemical parameters. Tox. Pathol. 26, 777-788), endothelial alterations were present in the pulmonary capillary endothelial cells of pigs fed fumonisin-containing culture material, but at doses that did not induce pulmonary edema, as well as in pigs injected intravenously with purified fumonisin B(1). These alterations were present only in the pulmonary capillary endothelium of pigs and not in other species. In addition, these endothelial alterations were not present in any other organ of pigs or other species examined. Thus, these endothelial alterations are induced by fumonisin B(1), but only in pulmonary capillary endothelium and only in pigs. Although evidence that these alterations play a role in fumonisin-induced pulmonary edema is limited, other endothelial functions may be affected by fumonisin treatment.

Nonciliated bronchiolar epithelial (Clara) cell necrosis induced by organometallic carbonyl compounds.

The administration of transition metal organometallic compounds such as manganese, chromium, and iron carbonyls by the i.p. route, and nickel by inhalation (mice) or intravenously (rats), resulted in selective necrosis of the nonciliated bronchiolar epithelial (Clara) cells and variable pulmonary parenchymal damage in BALB/c mice and Fischer-derived rats within 24 h of administration. The pulmonary toxicity of methylcyclopentadienyl manganese tricarbonyl (MMT), a representative of this group of compounds, was enhanced by pretreatment with piperonyl butoxide (PB), an inhibitor of the mixed-function oxidase system. This finding suggests that Clara cell necrosis can result from direct toxicity and that the specificity of toxic agents for Clara cells may not be related solely to the presence of the mixed-function oxidase system.

Toxicity of intraperitoneal doses of microcystin-LR in two strains of male mice.

Male Balb/C and Swiss Webster (SW) mice were administered various i.p. doses of microcystin-LR (MCLR) to establish dose-response curves and to determine if a sublethal dose of MCLR would protect against an approximate LD100 min given 2 or 3 days later. Micocystin-LR has an extremely steep dose-lethal response curve in BC mice--LD50 = 32.5 micrograms (micrograms)/kg, approximate LD0 max = 25 micrograms/kg and approximate LD100 min = 40 micrograms/kg. Liver weights increased 64% (BC) and 51% (SW) and kidney weights increased 32% (BC) and 20% (SW) within 200 minutes following administration of an approximate LD100 min of MCLR in naive mice. Grossly and histologically the marked increase in liver weight appeared to be caused primarily from intrahepatic hemorrhage and death is probably a result of hemorrhagic shock. Twenty-four hours following administration of a sublethal dose of MCLR to naive BC mice, liver weights were increased significantly (8.7%), but no clinical signs or histologic lesions were observed. In SW mice, administration of a LD23 of MCLR resulted in significantly increased survivability and survival times when an approximate LD100 min of MCLR was given 3 days later. Survivors of the LD23/LD100 min regimen had 96 hour postdosing liver weights not significantly different from those of mice which died acutely after the same hepatotoxin treatments. These survivors showed weakness, recumbency, anorexia, and icterus, and had marked gross liver lesions. Histologically these lesions were undergoing rapid reparative processes.

The role of intestinal microflora in the metabolism of trichothecene mycotoxins.

The role of faecal and intestinal microflora on the metabolism of trichothecene mycotoxins was examined in this study. Suspensions of microflora obtained from the faeces of horses, cattle, dogs, rats, swine and chickens were incubated anaerobically with the trichothecene mycotoxin, diacetoxyscirpenol (DAS). Micro-organisms from rats, cattle and swine completely biotransformed DAS, primarily to the deacylated deepoxidation products, deepoxy monoacetoxyscirpenol (DE MAS) and deepoxy scirpentriol (DE SCP). By contrast, faecal microflora from chickens, horses and dogs failed to reduce the epoxide group in DAS and yielded only the deacylation products, monoacetoxyscirpenol (MAS) and scirpentriol (SCP), in addition to unmetabolized parent compound. Intestinal microflora obtained from rats completely biotransformed DAS to DE MAS, DE SCP and SCP; and T-2 toxin to the deepoxy products, deepoxy HT-2 (DE HT-2) and deepoxy T-2 triol (DE TRIOL). Rat intestinal microflora also biotransformed the polar trichothecenes, T-2 tetraol and scirpentriol, to their corresponding deepoxy analogues. Deepoxy T-2 toxin (DE T-2) was synthesized from T-2 toxin and demonstrated to be 400 times less toxic than T-2 toxin in the rat skin irritation bioassay and non-toxic to mice given 60 mg/kg ip, demonstrating that epoxide reduction is a significant single step detoxification reaction for trichothecene mycotoxins.

Aldicarb toxicosis in a flock of sheep.

Aldicarb toxicosis was diagnosed in 200 sheep that died suddenly. Carbamate insecticide toxicosis was suspected based on observed clinical signs (hypersalivation, diarrhea, urination, paddling, seizures, miosis, and deaths occurring within 1 hour). Tissue samples were submitted from 4 Columbian ewes for pathologic and analytical evaluation. Severe diffuse pulmonary edema was observed on gross and histologic examination. Inhibition of cholinesterase activity in retina (21.2-68.1% of normal activity, n = 3), brain (40.6-45.6% of normal activity, n = 3), and whole blood (27% of normal activity, n = 1) supported a diagnosis of carbamate toxicosis. Reversal of brain and whole blood cholinesterase activities (reactivation factor greater than 1.4) following an in vitro 1 hour incubation at 37 C was also consistent with carbamate poisoning. Aldicarb toxicosis was confirmed following its detection in rumen contents at 1.5, 5.5, and 334 ppm using both high-pressure liquid chromatography with UV detection and gas chromatography with nitrogen/phosphorus detection.

Mechanism of inhibition of hepatic bioactivation of paracetamol by dimethyl sulfoxide.

Prior work has shown that DMSO inhibits paracetamol hepatotoxicity. In this paper we show that DMSO and its reduced metabolite dimethyl sulfide (DMS) can inhibit in vitro hepatic dimethylnitrosamine N-demethylase. We also show that DMSO can inhibit in vivo production of glutathione conjugates of paracetamol. Glutathione is known to conjugate the bioactivated form of paracetamol. Also, the isozyme of cytochrome P-450 responsible for dimethylnitrosomine N-demethylase, cytochrome P-450j, is thought responsible for paracetamol bioactivation. We therefore propose that DMSO inhibits paracetamol hepatotoxicity due to inhibition of cytochrome P-450j-dependent paracetamol bioactivation by DMSO and its metabolite DMS.

Comparative response of swine and rats to high-fiber or high-protein diets.

Twenty-four growing swine and 24 growing rats were fed high-protein (34%) diets on an ad libitum basis to determine their effects on body weight, carcass characteristics, intestinal microbiological profile and visceral organ weights. High dietary fiber reduced body weight gain and gain:feed ratio in both swine and rats and decreased body fatness in swine; it increased relative kidney weight (percentage of body weight) in both swine and rats and decreased relative liver weight in rats but increased it in swine. Absolute weights of stomach and large intestine were unaffected by high fiber in either species, but relative weight of small and large intestine was increased in swine and relative weight of stomach was increased in rats. High dietary protein increased absolute and relative weights of kidneys in both species and increased relative liver in swine but not in rats. Absolute weight of large intestine was increased by high dietary protein in rats and tended to be increased in swine; relative large intestine weight was increased in both species. The microbial profile of large intestinal contents of rats showed no effect of diet on Enterobacteriaceae, Campylobacter, Salmonella or total anaerobes and cellulolytic organisms, but coliforms were higher in rats fed high fiber or high protein than in controls. We conclude that dietary levels of fiber and protein influence growth of specific segments of the gastrointestinal tract of growing rats and swine, probably by different mechanisms of action.