An improved Mantel-Bryan procedure for "safety" testing of carcinogens.
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A published method by Mantel and Bryan for calculating "safe" doses of carcinogens is updated by incorporating several improvements. These improvements include more effective procedures for taking into account any spontaneous tumor rate and for combining data at several dose levels. An added feature is that it permits the combining of data from several experiments by postulating that it is only the spontaneous rate that differs between experiments. The improved method is illustrated with data from five hypothetical experiments, using a risk level of 10-8, a conservative slope of one probit or normal deviate per tenfold dose increase, and a nominal assurance level of 99%. The hypothetical experiments were geared to bring out particular pointsas, for example, the applicability of the model in the absence of control data. A large variety of issues involved in the determination of "safe" doses are discussed, including questions of experiment design and extrapolitan between species. A statistical appendix is provided, laying the framework for the calculating procedure and detailing complications therein. The "safe" dose approach helps resolve certain dilemmas in questions relating to food additives. A "no-detectable-level" prescription for chemical residues may be dangerous to the public where detection techniques are insufficiently sensitive, but it can become far too restrictive as exquisitely sensitive detection techniquesare developed. Only levels in excess of the "safe" dose would require detection. Calculated values for the "safe" dose could be updated and increased as more clear evidence of safety becomes available. (+info)
Statistical analysis on toxicity of a nitrofuran derivative, 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide.
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A food additive, furylfuramide or AF-2, which had been used in Japan since 1965 and structurally is composed of 5-nitro-2-furyl radical and acrylamide, was re-examined mainly on chronic toxicity by statistically reviewing published data. The conclusions are as follows: 1) The maximum safety dosage which shows no demonstrable change in rats must be corrected at least to 1/170 of the value which has been accepted by the Ministry of Health and Welfare of Japan (MHW). 2) The minimum effective dose to bacterial growth in food can not be lowered below the standard usage level with MHW determined, because the inactivation factor in food, decreasing effectivity to 1/20, must be taken into consideration. 3) In view of these two facts, AF-2 is found to be unacceptable as a food additive. 4) Great importance must also be attached to the possibility of mutagenicity and carcinogenicity of AF-2, pointed out recently. Both neurotoxicity and dermatitis observed in tofu (soybean curd) makers are also memtioned. (+info)
Report of occupational asthma due to phytase and beta-glucanase.
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OBJECTIVES: Occupational asthma is the principal cause of respiratory disease in the workplace. The enzymes phytase and beta-glucanase are used in the agricultural industry to optimise the nutritional value of animal feeds. A relation between these enzymes and occupational asthma in a 43 year old man was suspected. METHODS: Inhalation challenge tests were performed with the enzymes phytase, beta-glucanase, and amylase. Skin prick tests were performed with the enzymes diluted to a concentration of 1 mg/ml and 5 mg/ml. Specific IgE to phytase and beta-glucanase were measured with a radioallergosorbent test. RESULTS: Baseline spirometry values were normal. A histamine challenge test showed bronchial hyperreactivity. Exposure to phytase and beta-glucanase led to significant reductions in forced vital capacity and forced expired volume in 1 second. No significant differences were noted after exposure to amylase. Skin tests showed a positive reaction to beta-glucanase (5 mm) at a concentration of 1 mg/ml and positive reactions to beta-glucanase (7 mm) and phytase (5 mm) at a concentration of 5 mg/ml. Similarly specific IgE was present against both phytase and beta-glucanase, at 2.5% and 9.3% binding respectively (2% binding is considered positive). CONCLUSIONS: This is the first description of occupational asthma due to the enzymes phytase and beta-glucanase. Their addition to the ever increasing list of substances associated with occupational asthma will have notable implications for those exposed to these enzymes. (+info)
Effect of fasting and refeeding on duodenal alkaline phosphatase activity in monosodium glutamate obese rats.
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In the present work the effects of fasting and refeeding on fat pad weight and alkaline phosphatase activity in the brush border of individual duodenal enterocytes have been evaluated in male Wistar rats with obesity induced by monosodium glutamate (MSG) treatment during the early postnatal period. Neonatal rats were treated subcutaneously with MSG (2 mg/g b.w.) or saline (controls) for 4 days after birth. At 4 months of age, two types of experiments were performed. In the first experiment rats, were submitted to 3 or 6 days lasting food deprivation. In the second experiment the rats were refed for 3 or 6 days ad libitum or restrictedly (60% of pre-fasting intake) after a 6 day-fasting period. Fasting and refeeding influenced the body fat and function of the duodenum in MSG-treated rats differently as compared to the controls. However, alkaline phosphatase activity and the weight of epididymal and retroperitoneal fat depots were significantly increased in MSG obese rats (P<0.001) during all the periods examined. While 3 days of food deprivation resulted in both groups in a similar loss of adipose tissue weight and alkaline phosphatase activity, the decrements of these parameters after 6 days of fasting were lower in obese rats suggesting that their capacity to spare body fat stores was enhanced. After 3 days of ad libitum refeeding, a more marked adaptational increase of food consumption and also a significantly increased alkaline phosphatase activity above the pre-fasting level (P<0.01) was observed in the MSG-treated rats. Consequently, a more rapid body fat restoration was demonstrated in these animals. Refeeding of rats at 60% of the pre-fasting intake level resulted in a significant increase of alkaline phosphatase activity in both the MSG and control group; moreover, as food restriction continued, MSG-treated rats tended to further increase the enzyme activity. Our results revealed that MSG treatment of neonatal rats may significantly change the intestinal functions. Permanently increased alkaline phosphatase activity observed in MSG obese rats during all investigated periods suggests that this functional alteration is probably not a consequence of actual nutritional variation but could be a component of regulatory mechanisms maintaining their obesity at critical values. (+info)
Role of sulfite additives in wine induced asthma: single dose and cumulative dose studies.
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BACKGROUND: Wine appears to be a significant trigger for asthma. Although sulfite additives have been implicated as a major cause of wine induced asthma, direct evidence is limited. Two studies were undertaken to assess sulfite reactivity in wine sensitive asthmatics. The first study assessed sensitivity to sulfites in wine using a single dose sulfited wine challenge protocol followed by a double blind, placebo controlled challenge. In the second study a cumulative dose sulfited wine challenge protocol was employed to establish if wine sensitive asthmatics as a group have an increased sensitivity to sulfites. METHODS: In study 1, 24 asthmatic patients with a strong history of wine induced asthma were screened. Subjects showing positive responses to single blind high sulfite (300 ppm) wine challenge were rechallenged on separate days in a double blind, placebo controlled fashion with wines of varying sulfite levels to characterise their responses to these drinks. In study 2, wine sensitive asthmatic patients (n=12) and control asthmatics (n=6) were challenged cumulatively with wine containing increasing concentrations of sulfite in order to characterise further their sensitivity to sulfites in wine. RESULTS: Four of the 24 self-reporting wine sensitive asthmatic patients were found to respond to sulfite additives in wine when challenged in a single dose fashion (study 1). In the double blind dose-response study all four had a significant fall in forced expiratory volume in one second (FEV(1)) (>15% from baseline) following exposure to wine containing 300 ppm sulfite, but did not respond to wines containing 20, 75 or 150 ppm sulfite. Responses were maximal at 5 minutes (mean (SD) maximal decline in FEV(1) 28.7 (13)%) and took 15-60 minutes to return to baseline levels. In the cumulative dose-response study (study 2) no significant difference was observed in any of the lung function parameters measured (FEV(1), peak expiratory flow (PEF), mid phase forced expiratory flow (FEF(25-75))) between wine sensitive and normal asthmatic subjects. CONCLUSIONS: Only a small number of wine sensitive asthmatic patients responded to a single dose challenge with sulfited wine under laboratory conditions. This may suggest that the role of sulfites and/or wine in triggering asthmatic responses has been overestimated. Alternatively, cofactors or other components in wine may play an important role in wine induced asthma. Cumulative sulfite dose challenges did not detect an increased sensitivity to sulfite in wine sensitive asthmatics and an alternative approach to identifying sulfite/wine sensitive asthma may be required. (+info)
Fatal rhabdomyolysis after acute sodium monensin (Rumensin) toxicity: case report.
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Myoglobinuria or rhabdomyolysis occurs when myoglobin escapes into the blood and then into the urine after acute muscle necrosis. It can be a serious medical condition leading to renal failure and death. There are many causes including exertion, crush syndromes, ischaemia, metabolic disorders, exogenous toxins and drugs, heat stroke and hereditary disorders such as malignant hyperthermia. We report the case of a 17 year-old boy who developed myoglobinuria, renal failure and death 11 days after ingesting sodium monensin, possibly with the intention of developing muscles. Sodium monensin, the active principle of Rumensin(R), is a dietary additive used as a growth promoter for confined cattle. There are no previous reports of human intoxication. Accidental or experimental sodium monensin intoxication in animals produces similar findings to those seen in this case. (+info)
Effects of level of supplemental phytase on ileal digestibility of amino acids, calcium, and phosphorus in dehulled soybean meal for growing pigs.
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Ileally cannulated pigs were used to assess the effects of four dietary levels of microbial phytase (Natuphos) on the apparent and true digestibility of Ca, P, CP, and AA in dehulled soybean meal. Fourteen pigs (25 kg initial BW) were surgically fitted with T-cannulas at the terminal ileum and assigned to diets in a replicated 7 x 7 Latin square design. Following a 14-d recovery, four diets consisting of 30.5% soybean meal with 0, 500, 1,000, or 1,500 units of phytase/kg of diet were fed. Diets 5 (1.05% lysine, 0.90% Ca, and 0.75% P) and 6 (1.05% lysine, 0.90% Ca, and 0.75% P) contained 35.25% soybean meal and 27.0% soy protein concentrate, respectively. Diet 7 (0.37% lysine, 0.03% Ca, and 0.05% P) was a low-CP, casein-based diet used to estimate the nonspecific endogenous losses of Ca, P, CP, and AA in order to estimate the true digestibility of these nutrients. All diets contained cornstarch and dextrose and were fortified with vitamins and minerals. Chromic oxide was used as an indigestible indicator. The diets were fed daily at 9% of metabolic BW (BW0.75). Apparent and true ileal digestibility of P increased quadratically (P < 0.01) and true digestibility of Ca increased linearly (P < 0.07) with increasing levels of phytase. Apparent digestibility of Ca was unaffected (P = 0.15) by phytase level. Apparent and true ileal digestibility of CP and most AA increased slightly with the addition of 500 units of phytase/kg of diet, but not at higher levels of phytase supplementation (in most cases, cubic effect, P < 0.05). Apparent and true ileal nutrient digestibility coefficients were unaffected by soybean meal source (Diet 1 vs Diet 5), except for arginine and Ca. The apparent and true digestibility coefficients for most of the AA tended (P < 0.10) to be lower in diets containing soy protein concentrate vs the common source of soybean meal used in Diet 5, but ileal digestibilities of Ca and P were unaffected (P = 0.15). In this study, supplemental microbial phytase did not improve the utilization of AA provided by soybean meal but was an effective means of improving Ca and P utilization by growing swine fed soybean meal-based diets. (+info)
Technical note: methods for detecting liquid enzyme additives added to animal feeds.
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Methods for detecting and measuring the quantity of fibrolytic enzyme preparations added to feeds were investigated by enzymatic and tracer methods. Enzyme preparations added to corn silage, ryegrass silage, and a total mixed ration containing both silages and a concentrate could not be detected using their enzymatic activities. Glycosidase activities of solubles washed from the feed were more than an order of magnitude greater than glycosidases in the added enzymes. Carboxymethylcellulase and xylanase activity determinations, using reducing sugar release as the measurement, were subject to interference from reducing sugars present in the feed. A fluorescent tracer method, using fluorescein added at a rate of 1 g/L of feed enzymes, or 2 g/t of feed, was developed that enabled sensitive detection of liquid enzyme additions to feeds. (+info)