Acid Excretion Rate Research Articles

Effect of sorbic acid administration on urinary trans,trans-muconic acid excretion in rats exposed to low levels of benzene

Trans,trans-muconic acid ( t,t-MA) is a biomarker of benzene exposure reflecting metabolic activation to trans,trans-muconaldehyde. t,t-MA background urinary levels are highly variable, thus limiting its use to exposure monitoring of levels over 1 ppm of benzene. Actually, sorbic acid (SA) is known to influence background excretion of t,t-MA in man, but only a few examples suggest that SA ingestion can enhance t,t-MA levels occurring together with benzene exposure. In this study, the effect of SA was investigated in benzene-exposed male Sprague–Dawley rats exposed to 1 ppm benzene for 6 h. Exposed animals had a 24-h urinary t,t-MA excretion higher than that observed in non-exposed animals (87±13 μg/kg vs 19±3 μg/kg body weight). The oral dose of 8 mg/kg body weight SA had no effect on urinary t,t-MA both in control and in benzene-exposed rats. Increases of t,t-MA levels in urine occurred at SA doses of 50–200 mg/kg body weight, and co-exposure to benzene and SA (50 and 100 mg/kg body weight) produced additive enhancement of t,t-MA excretion. These data demonstrate the dose–response relationship between SA administration and t,t-MA excretion. Our study showed that SA ingestion at doses equal to or greater than 50 mg/kg body weight significantly affects the t,t-MA urinary levels in rats exposed to 1 ppm of benzene for 6 h. These data support the conclusion that in man t,t-MA is not suitable for biomonitoring of low levels of benzene exposure.

Potentiation of 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123)-induced liver toxicity by ethanol in guinea-pigs.

HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane), a substitute for the banned chlorofluorocarbons (CFCs), is a structural analogue of the well-known hepatotoxicant halothane. The objectives of these experiments were to investigate (1) whether, like halothane, multiple exposure increases the risk of HCFC-123-induced liver toxicity, and (2) whether ethanol, a potent CYP2E1 inducer, potentiates the liver toxicity of HCFC-123. In experiment 1, male Hartley guinea-pigs were exposed twice a week to 5000 ppm HCFC-123 (4 h) during 3 weeks followed by 2 weeks recovery, and then re-exposed or not during 4 h to 5000 ppm HCFC-123. A group with a single exposure to 5000 ppm HCFC-123 and a control group were also included. In experiment 2, guinea-pigs received 5 or 10% ethanol in drinking water during 12 days before a single 4-h exposure to 5000 ppm HCFC-123. A group receiving 10% only, a group exposed once to 5000 ppm HCFC-123 but not pre-treated with ethanol and a control group were also included. In both experiments, the liver toxicity was assessed, 24 h post-exposure, by the serum activities of alanine aminotransferase (ALT) and isocitrate dehydrogenase (ICDH) as well as by histopathology. In experiment 2 the urinary excretion rate of the main metabolites trifluoroacetic acid (TFA) and chlorodifluoroacetic acid (CDFA) was assessed and CYP2E1 activity was measured by the chlorzoxazone metabolic ratio. Multiple exposure to 5000 ppm HCFC-123 did not cause greater liver damage than a single exposure (ALT, ICDH 3-fold control values). At this level of exposure the liver lesions were totally reversible within two weeks. Ethanol consumption produced CYP2E1 induction, increased urinary excretion of both HCFC-123 metabolites (more than 2-fold the rate measured in the non-induced group) and markedly increased the liver toxicity of HCFC-123 as shown by the serum liver enzyme activities (ALT 8.5-fold increase, ICDH 13-fold increase), and the histopathology. The necrosis was predominantly localised in the intermediate zone of the hepatic lobules with vacuolisation of the centrilobular zones. The effects associated with 10% ethanol pre-treatment were less marked than those observed with ethanol 5% and could be explained by the remaining blood ethanol levels causing an inhibition of HCFC-123 biotransformation. Significant correlations were obtained between the serum enzyme activities, the histopathology, the excretion rate of the metabolites and CYP2E1 activity. It can be concluded that (1) multiple exposure to HCFC-123 did not increase the liver toxicity of HCFC-123 in this experimental model, and (2) chronic ethanol consumption, known to be CYP2E1 inducer, strongly enhanced the biotransformation of HCFC-123 and its liver toxicity.

A Poorly Fermented Gel from Psyllium Seed Husk Increases Excreta Moisture and Bile Acid Excretion in Rats

Psyllium seed husk (PSH) increases stool output and lowers blood cholesterol levels in humans. PSH and three fractions isolated from it were meal-fed to colectomized rats and fermented in vitro to test the hypothesis that viscous, gel-forming fraction B was responsible for these physiological actions. Control rats were fed 50 g/kg cellulose. The concentration of each PSH fraction in the test meals was equivalent to its concentration in PSH. Yields of the fractions were: A, 171; B, 575; and C, 129 g/kg of PSH. The wet weight and moisture content of ileal excreta (IE) from rats fed test meals containing PSH or fraction B were greater than those measured in excreta from rats fed meals containing cellulose or the other two PSH fractions. Total bile acids in IE did not differ between rats fed PSH or fraction B and were greater in these groups than in the other groups. Fraction A was not fermented during 3 d of incubation; fraction B was poorly fermented, with approximately 30% of the constituent sugars disappearing; and fraction C was rapidly and nearly completely fermented. These results indicate that the gel-forming fraction we isolated from PSH is the physiologically active component of the husks.

Human cholesterol 7α-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype

Bile acid synthesis plays a critical role in the maintenance of mammalian cholesterol homeostasis. The CYP7A1 gene encodes the enzyme cholesterol 7alpha-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. We report here a new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1. The mutation leads to a frameshift (L413fsX414) that results in loss of the active site and enzyme function. High levels of LDL cholesterol were seen in three homozygous subjects. Analysis of a liver biopsy and stool from one of these subjects revealed double the normal hepatic cholesterol content, a markedly deficient rate of bile acid excretion, and evidence for upregulation of the alternative bile acid pathway. Two male subjects studied had hypertriglyceridemia and premature gallstone disease, and their LDL cholesterol levels were noticeably resistant to 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. One subject also had premature coronary and peripheral vascular disease. Study of the kindred, which is of English and Celtic background, revealed that individuals heterozygous for the mutation are also hyperlipidemic, indicating that this is a codominant disorder.

Evaluation of circulating levels and renal clearance of natural amino acids in patients with Cushing's disease.

Although the hypercortisolism-induced impairment of protein homeostasis is object of several studies, a detailed evaluation of the complete amino acid profile of patients with Cushing's syndrome (CS) has never been performed. The aim of the current open transversal controlled study was to evaluate serum and urinary concentrations as well as renal clearance of the complete series of natural amino acids and their relationship with glucose tolerance in patients with Cushing's disease (CD). Twenty patients with CD (10 active and 10 cured) and 20 sex- and age-matched healthy controls entered the study. Measurement of serum and urinary levels of the complete series of natural amino acids was performed in all patients analyzed by cationic exchange high performance liquid cromatography (HPLC) after 2 weeks of a standardized protein intake regimen. The renal clearance (renal excretion rate) of each amino acid was calculated on the basis of the serum and urinary concentrations of creatinine and the specific amino acid. Fasting glucose and insulin levels, glucose and insulin response to standard glucose load, insulinogenic and homeostasis model insulin resistance (Homa-R) indexes were also evaluated and correlated to the circulating levels and renal clearances of each amino acid. Significantly higher serum (p<0.01) and urinary (p<0.05) levels of alanine and cystine, lower serum and higher urinary levels of leucine, isoleucine and valine (p<0.05) and higher renal excretion rates of leucine, isoleucine and valine (p<0.01) were found in patients with active CD than in patients cured from the disease and in controls. No difference was found between cured patients and controls. Creatinine clearance was similar in active and cured patients and in controls. In patients with active CD, urinary cortisol levels were significantly correlated to urinary cystine levels (r=0.85; p<0.01) and renal excretion rate of leucine (r=-0.76; p<0.05), isoleucine (r=-0.76; p<0.05) and valine (r=-0.66; p<0.05). Fasting blood glucose levels were significantly correlated to serum alanine levels (r=0.70; p<0.05). Although Homa-R was significantly correlated to BMI in active patients (r=0.74 p<0.05), it was not correlated to amino acid levels. In conclusion, the results of the current study demonstrate that patients with CD have significant changes in serum and urinary concentration of several amino acids and changes in renal clearance of some specific amino acids. Normalization of cortisol levels restored the amino acid profile.

Comparison of the Aluminum Tolerance ofMiscanthus sinensisAnderss. andMiscanthus sacchariflorusBentham in Hydroculture

Miscanthus sinensis Anderss. and Miscanthus sacchariflorus Bentham are typical perennial species that are widely distributed throughout Japan. Miscanthus sinensis dominates seminatural grasslands and grows on acid soil. By contrast, M. sacchariflorus grows on fertile lowlands and alluvial plains. The two species are sometimes distributed in the same area, but the more Al‐tolerant species might be expected to dominate with increasing acidity of the soil. To assess the tolerance to Al of the two closely related species of Miscanthus, an analysis was made of dry‐mass allocation and production of organic acids, which are involved in mechanisms of Al tolerance, using hydroponic culture. Plants were grown at seven (M. sinensis) and six (M. sacchariflorus) concentrations of Al. After 42 d, the dry mass of shoots and roots of M. sinensis was lower ($$P< 0.05$$) at 5 mg Al L−1 as compared to controls. Dry mass of M. sacchariflorus was lower ($$P< 0.01$$) at 2 mg Al L−1. The ratio of shoot to root dry mass (S/R) increased more in M. sacchariflorus at >5 mg Al L−1 than in M. sinensis. Miscanthus sinensis excreted twice as much citric acid from its roots (45 mg L−1 d−1), to form an Al‐chelate, as did M. sacchariflorus. Because of the higher excretion rate of citric acid from its roots, M. sinensis might tolerate Al better than M. sacchariflorus.

Endogenous endothelins mediate increased acidification in remnant kidneys.

Because endothelins (ET) mediate increased renal acidification induced by dietary acid and animals with reduced renal mass exhibit increased urinary ET-1 excretion, the hypothesis that ET mediate increased renal acidification in remnant kidneys was tested. Four weeks before the study, rats underwent a 5/6 nephrectomy (Nx) and a microdialysis apparatus was inserted into the remnant left kidney and the left kidney of sham-treated control animals, for measurements of renal ET-1 contents. Nx animals exhibited greater ET-1 addition to the renal dialysate than did control animals (681 +/- 91 versus 290 +/- 39 fmol/g kidney wt per min, P < 0.002) and greater urinary ET-1 excretion (346 +/- 79 versus 125 +/- 24 fmol/d, P < 0.02). Urinary net acid excretion rates were similar for Nx and control animals (732 +/- 106 versus 1005 +/- 293 microEq/d, P = 0.4), but Nx animals exhibited greater in situ HCO(3)(-) reabsorption in proximal (972.3 +/- 77 versus 482.6 +/- 42.4 pmol/min, P < 0.001) and distal (62.7 +/- 6.7 versus 24.3 +/- 2.5 pmol/min, P < 0.001) tubules. Orally administered bosentan, an ET(A/B) receptor antagonist, decreased urinary net acid excretion in Nx animals (to 394 +/- 99 microEq/d, P < 0.04 versus without bosentan); the decrease was mediated by decreased HCO(3)(-) reabsorption in both the proximal and distal tubules. Furthermore, bosentan decreased blood base excess in Nx animals (0.1 +/- 0.3 to -0.12 +/- 0.03 microM/ml blood, P < 0.002), consistent with acid retention. The data demonstrate that endogenous ET mediate increased urinary acid excretion in the remnant kidneys of Nx animals.

Rapid metabolic recovery following vigorous exercise in burrow-dwelling larval sea lampreys (Petromyzon marinus).

Although the majority of the sea lamprey's (Petromyzon marinus) life cycle is spent as a burrow-dwelling larva, or ammocoete, surprisingly little is known about intermediary metabolism in this stage of the lamprey's life history. In this study, larval sea lampreys (ammocoetes) were vigorously exercised for 5 min, and their patterns of metabolic fuel depletion and replenishment and oxygen consumption, along with measurements of net whole-body acid and ion movements, were followed during a 4-24-h postexercise recovery period. Exercise led to initial five- to sixfold increases in postexercise oxygen consumption, which remained significantly elevated by 1.5-2.0 times for the next 3 h. Exercise also led to initial 55% drops in whole-body phosphocreatine, which was restored by 0.5 h, but no significant changes in whole-body adenosine triphosphate were observed. Whole-body glycogen concentrations dropped by 70% immediately following exercise and were accompanied by a simultaneous ninefold increase in lactate. Glycogen and lactate were quickly restored to resting levels after 0.5 and 2.0 h, respectively. The presence of an associated metabolic acidosis was supported by very high rates of metabolic acid excretion, which approached 1,000 nmol g(-1) during the first 2 h of postexercise recovery. Exercise-induced ion imbalances were also rapidly alleviated, as initially high rates of net Na(+) and Cl(-) loss (-1,200 nmol g(-1) h(-1) and -1,800 nmol g(-1) h(-1), respectively) were corrected within 1-2 h. Although larval sea lampreys spend most of their time burrowed, they are adept at performing and recovering from vigorous anaerobic exercise. Such attributes could be important when these animals are vigorously swimming or burrowing as they evade predators or forage.

Role of perivenous hepatocytes in taurolithocholate-induced cholestasis in vivo

The magnitude of cholestasis induced by taurolithocholic acid (TLCA) and its relationship with phase I metabolism were analyzed in rats treated with bromobenzene (BZ), a chemical that causes selective necrosis of perivenous (zone 3) hepatocytes. Forty-eight hours after BZ administration (600 mg/Kg bw), a single dose of 20 μmol/Kg bw of TLCA was injected. Bile was collected during 180 min and bile flow and total bile acid excretion rate were determined. Biliary bile acid composition was analyzed by gas–liquid chromatography-mass spectrometry. BZ administration did not affect the development of TLCA-induced cholestasis, but exacerbated the bile acid-induced decrease in bile flow during the period of recovery from cholestasis. Biliary excretion of total bile acids after TLCA injection relative to basal value was not effected by BZ. The analysis of bile acid composition in bile revealed that TLCA was partially converted to hyodeoxycholic and muricholic acids. The cumulative excretion of all exogenous bile acids and their contribution to the composition of the biliary bile acid pool were not substantially affected by zone 3 necrosis, suggesting that synthesis and secretion of hydroxylated derivatives of TLCA were maintained by zone 1 and 2 hepatocytes. The relative content of endogenous bile acids was not affected by BZ during TLCA-induced cholestasis. Thus, it seems unlikely that the exacerbation of the cholestasis in BZ-treated rats is due to different choleretic properties and/or toxicity of the bile acid pool.

Identification of the dimethylbenzyl mercapturic acid in urine of rats administered with 1,2,4-trimethylbenzene

A study was undertaken of the mercapturic acid metabolism of 1,2,4-trimethylbenzene in the rat. Of three regioisomeric dimethylbenzyl mercapturic acids, i.e. 2,4-, 2,5- and 3,4-dimethylbenzyl isomers, the third isomer was not found in the urinary mercapturic acid isolated by preparative HPLC, from the comparison of NMR spectrum of the isolate with those of authentic specimens. The urinary mercapturate was then assigned to 2,4- and/or 2,5-dimethylbenzyl isomers. The excretion rate of the mercapturic acid was 14–20% of dose as 2,4-dimethylbenzyl isomer.

Safety of losartan in hypertensive patients with thiazide-induced hyperuricemia

Losartan, an angiotensin II receptor antagonist, has been shown to decrease serum uric acid and to increase urinary excretion of uric acid. To determine if this effect can increase the risk of acute urate nephropathy, 63 hypertensive patients with thiazide-induced asymptomatic hyperuricemia (serum uric acid 7.0 to 12.0 mg/dl) were randomized double-blind to losartan 50 mg every day (q.d.), losartan 50 mg plus hydrochlorothiazide (HCTZ) 50 mg q.d., HCTZ 50 mg q.d., or placebo for three weeks. To potentiate the risk of crystal formation, patients received a 2 g/kg protein diet one day prior to each clinic visit on days 0 (baseline), 1, 7, and 21. Adverse events typically associated with acute urate nephropathy, for example, flank pain, hematuria, or increased blood urea nitrogen/creatinine, were not reported. Uric acid excretion and urine pH increased four and six hours after losartan on day 1 compared with day 0. Dihydrogen urate, the primary risk factor for crystal formation, decreased at four and six hours on day 1 compared with day 0 associated with the concurrent rise in urine pH. Day 7 and 21 changes, compared with day 0, in uric acid excretion rate, urine pH, and dihydrogen urate with losartan were comparable to day 1 results but were not statistically significant. Serum uric acid was significantly reduced after 21 days of therapy with losartan. Losartan decreased serum uric acid and increased uric acid excretion without increasing urinary dihydrogen urate, the primary risk factor for acute urate nephropathy, during 21 days of dosing in hypertensive patients with thiazide-induced hyperuricemia.

MATERNAL BIOTIN DEFICIENCY CAUSES FETAL MALFORMATIONS BY INDUCING FETAL BIOTIN DEFICIENCY

62 Purpose: In the ICR mouse, maternal biotin deficiency during gestation results in specific fetal malformations (cleft palate, micrognathia, microglossia, and limb hypoplasia). However, the relationships of maternal and fetal biotin status to the incidence of fetal malformations have not been fully elucidated. Description: We sought to determine the effect of various egg-white diets (0, 1, 1.3, 2, 3, 5, 10, and 25%) on (a) the incidence of fetal malformations, (b) maternal biotin status assessed by the urinary excretion rate of 3-hydroxyisovaleric acid (3HIA, an organic acid that arises from the decreased activity of the biotin-dependent enzyme methylcrotonyl-CoA carboxylase), and (c) fetal biotin status as assessed by hepatic biotin and carboxylase activities at gestational day 17. Results: The incidence of fetal malformations increased as maternal and fetal biotin status decreased (Figure). The effect of diet was significant by ANOVA at p < 0.0001 for each malformation. Increasing egg white was associated with increased excretion rates of 3HIA, providing strong evidence that the egg-white diets caused maternal biotin status to decrease. Analysis of maternal and fetal livers from gestational day 17 confirmed an incremental reduction in maternal and fetal biotin status as the percentage of dietary egg-white increased. Conclusion: These data are consistent with the hypothesis that maternal biotin deficiency during gestation induces fetal biotin deficiency, which in turn results in an increased incidence of fetal malformations.FIG

Mechanism of the uricosuric action of E3040, a drug used to treat inflammatory bowel disease II: study using DBA/2N mice.

In the initial phase of clinical studies, it was shown that E3040, a new type of anti-inflammatory drug, reduced plasma uric acid levels. The present study describes a comparison of the excretion of uric acid in the proximal tubules of the kidney after administration of E3040 and its conjugates, sulphate and glucuronide, with that of other general uricosuric agents in DBA/2N mice. The aim of this investigation was to elucidate the mechanism for the uricosuric action of E3040. It was found that E3040 increased the excretion rate of uric acid in a dose-dependent manner, and the excretion rates following 10 and 50 mg/kg doses were significantly greater than that of the control group. The paradoxical effect observed with probenecid was not seen in the E3040 dose-response curve for the uric acid excretion rate. Neither E3040-sulphate nor E3040-glucuronide increased the excretion rate of uric acid significantly, even at a high dose, such as 200 mg/kg. In the pyrazinoic acid suppression test, the uric acid excretion rate after concomitant administration of E3040 and pyrazinoic acid was significantly higher than that after administration of pyrazinoic acid alone, and the rate after concomitant administration was 30% of the level after administration of E3040 alone. The change in the excretion rate of uric acid after concomitant administration of E3040 and pyrazinoic acid was similar to that of AA193, a selective inhibitor of the presecretory reabsorption of uric acid. From these results, it appears that E3040 may exert its uricosuric action by reducing the presecretory reabsorption of uric acid rather than increasing its secretion.

Effect of Simultaneous Exposure to Methanol and Toluene Vapor on Their Metabolites in Rats

Effect of Simultaneous Exposure to Methanol and Toluene Vapor on Their Metabolites in Rats: Hajime Horn, et al. Department of Environmental Management I, School of Health Sciences, University of Occupational and Environmental Health, Japan—Wistar male rats were exposed to methanol and toluene vapors by inhalation individually and simultaneously. Blood was sampled from the tail of the rats at 0, 1.5 and 3 h after a 6‐h exposure and the methanol and/or toluene concentrations were measured by the headspace‐gas chromatography‐mass spectrometry (GC/MS). Major metabolites of methanol and toluene, that is, formic acid and hippuric acid in urine were measured at 0,18 and 42 h after the end of the exposure. The toluene concentration in blood in the simultaneous exposure group was lower than that in the toluene exposure one. The biological half time of toluene in blood in the simultaneous exposure group was shorter than that in the single exposure one. The excretion rate of hippuric acid in urine in the simultaneous exposure group was significantly lower than that in the toluene exposure one when both the methanol and toluene concentrations were 300 ppm. These results suggest that the metabolic rate of toluene was enhanced by methanol. On the other hand, the biological half time of methanol in blood and the formic acid concentration in urine were not significantly different in the single and simultaneous exposure groups, although the methanol concentration in blood in the simultaneous exposure group was lower than that in the methanol exposure one.

Riboflavin and riboflavin-derived cofactors in adolescent girls with anorexia nervosa

Thyroid hormones, riboflavin, riboflavin cofactors, and organic acids were assessed in girls with anorexia nervosa. The objective was to examine the effect of malnutrition and low thyroid hormone concentrations on erythrocyte and plasma riboflavin metabolism and their relation with urinary organic acid excretion. Seventeen adolescent girls with anorexia nervosa [body mass index (BMI; in kg/m2): 14.8 +/- 2.2] and 17 age-matched, healthy girls (control subjects; BMI: 20.5 +/- 2.2) took part in the feeding study. Erythrocyte and plasma riboflavin as well as riboflavin cofactors (flavin mononucleotide and flavin adenine dinucleotide) were assessed by HPLC, whereas urinary organic acids were assessed by gas chromatography-mass spectrometry. Anorectic patients who began a feeding program had higher erythrocyte riboflavin (3.5 +/- 2.2 compared with <0.1 nmol/mol hemoglobin; P < 0.001), lower plasma flavin adenine dinucleotide (57.8 +/- 18.5 compared with 78.5 +/- 54.3 nmol/L; P < 0.05), and higher urinary ethylmalonic acid (7.12 +/- 4.39 compared with 1.3 +/- 2.8 micromol/mmol creatinine; P < 0.001) and isovalerylglycine (7.65 +/- 4.78 compared with 3.8 +/- 0.9 micromol/mmol creatinine; P < 0.05) concentrations than did control subjects. Triiodothyronine concentrations were low and negatively correlated with plasma riboflavin concentrations (r = -0.69, P < 0.01). Not all patients showed improvements in these biochemical indexes after 30 d of refeeding. The low triiodothyronine concentrations observed in anorexia nervosa could alter the extent of riboflavin conversion into cofactors, thus leading to high erythrocyte riboflavin concentrations, low plasma flavin adenine dinucleotide concentrations, and high rates of ethylmalonic acid and isovalerylglycine excretion.

Exposure Estimates to Disinfection By-Products of Chlorinated Drinking Water

Exposure to disinfection by-products (DBPs) of drinking water is multiroute and occurs in households serviced by municipal water treatment facilities that disinfect the water as a necessary step to halt the spread of waterborne infectious diseases. Biomarkers of the two most abundant groups of DBPs of chlorination, exhaled breath levels of trihalomethanes (THMs) and urinary levels of two haloacetic acids, were compared to exposure estimates calculated from in-home tap water concentrations and responses to a questionnaire related to water usage. Background THM breath concentrations were uniformly low. Strong relationships were identified between the THM breath concentrations collected after a shower and both the THM water concentration and the THM exposure from a shower, after adjusting for the postshower delay time in collecting the breath sample. Urinary haloacetic acid excretion rates were not correlated to water concentrations. Urinary trichloroacetic acid excretion rates were correlated with ingestion exposure, and that correlation was stronger in a subset of individuals who consumed beverages primarily within their home where the concentration measurements were made. No correlation was observed between an average 48-hr exposure estimate and the urinary dichloroacetic acid excretion rate, presumably because of its short biological half-life. Valid biomarkers were identified for DBP exposures, but the time between the exposure and sample collection should be considered to account for different metabolic rates among the DBPs. Further, using water concentration as an exposure estimate can introduce misclassification of exposure for DBPs whose primary route is ingestion due to the great variability in the amount of water ingested across a population.

Exposure estimates to disinfection by-products of chlorinated drinking water.

Exposure to disinfection by-products (DBPs) of drinking water is multiroute and occurs in households serviced by municipal water treatment facilities that disinfect the water as a necessary step to halt the spread of waterborne infectious diseases. Biomarkers of the two most abundant groups of DBPs of chlorination, exhaled breath levels of trihalomethanes (THMs) and urinary levels of two haloacetic acids, were compared to exposure estimates calculated from in-home tap water concentrations and responses to a questionnaire related to water usage. Background THM breath concentrations were uniformly low. Strong relationships were identified between the THM breath concentrations collected after a shower and both the THM water concentration and the THM exposure from a shower, after adjusting for the postshower delay time in collecting the breath sample. Urinary haloacetic acid excretion rates were not correlated to water concentrations. Urinary trichloroacetic acid excretion rates were correlated with ingestion exposure, and that correlation was stronger in a subset of individuals who consumed beverages primarily within their home where the concentration measurements were made. No correlation was observed between an average 48-hr exposure estimate and the urinary dichloroacetic acid excretion rate, presumably because of its short biological half-life. Valid biomarkers were identified for DBP exposures, but the time between the exposure and sample collection should be considered to account for different metabolic rates among the DBPs. Further, using water concentration as an exposure estimate can introduce misclassification of exposure for DBPs whose primary route is ingestion due to the great variability in the amount of water ingested across a population.

Curdlan and gellan gum, bacterial gel-forming polysaccharides, exhibit different effects on lipid metabolism, cecal fermentation and fecal bile acid excretion in rats.

The effects of curdlan (CD) and gellan gum (GG), bacteria-producing polysaccharides, on lipid concentrations of serum and liver, fecal bile acid composition and intestinal fermentation products were studied in rats fed diets containing cellulose powder (CP), CD or GG at 5% for 4 wk. The cecal weight of the CD group increased significantly as compared to that of the other two groups and the pH of its contents was significantly low. The gastrointestinal transit time in the GG group was significantly shorter than that in the CP and CD groups. No significant inter-group differences were observed in the serum concentrations of total cholesterol and HDL-cholesterol, but a significant decrease was observed in the hepatic total cholesterol concentration of the CD group as compared to that of the CP and GG groups. No significant difference in the total bile acid excretion in feces was observed among the groups, but significantly low values were observed in the proportion of secondary bile acids in the CD group as compared to those of the CP and GG groups. Amounts of short-chain fatty acids (acetic, propionic and butyric acid) and lactic acid in the cecal contents were significantly higher in the CD group than in the other two groups. These results reveal that dietary CD is easily degraded and fermented by intestinal bacteria in the cecum and lowers cholesterol concentration in the liver, while dietary GG shortens the gastrointestinal transit time, suggesting the promotion of evacuation.

Wheat bran fiber and development of adenomatous polyps: evidence from randomized, controlled clinical trials

Mutations in oncogenes and tumor suppressor genes are thought to initiate and promote the pathway to colorectal cancer, leading to hyperproliferation, the development of adenomas, and progression to gross malignancy. Intervention at any of these steps can potentially prevent the development of cancer. Several randomized, controlled trials have investigated the effect of dietary interventions, including the addition of wheat bran fiber, on the development of adenomatous polyps. In a familial adenomatous polyposis trial, patients were treated with 4 g of ascorbic acid plus 400 mg of α-tocopherol per day alone or with a grain fiber supplement (22.5 g/day) over a 4-year period. On an actual-intake basis, the combined intervention inhibited the development of rectal polyps. However, the Toronto Polyp Prevention Trial found no significant differences in polyp recurrence rates between patients who were counseled to follow a low-fat, high-fiber diet and patients consuming a typical Western diet with placebo fiber. A 9-month study of patients with resected colon adenomas found that dietary wheat bran fiber significantly reduced total, primary, and secondary fecal bile acid concentrations and excretion rates. Such bile acid levels are thought to be related to the risk of developing cancer. The Australian Polyp Prevention Project reported that the combination of fat reduction and a supplement of wheat bran reduced the incidence of large colorectal adenomas. These latter results suggest that intervention with a low-fat wheat bran supplemented diet inhibits the transition from smaller to larger adenomas, which may be a critical step in determining which adenomas progress to malignancy.

Relationship between Urinary Calcium and Net Acid Excretion as Determined by Dietary Protein and Potassium: A Review

Increasing urinary net acid (titratable acid + NH₄ – HCO^–₃) excretion is accompanied by an increased urinary Ca excretion because of reduced renal tubular reabsorption of filtered Ca. The relationships between urinary Ca excretion rates and urinary net acid excretion rates are reviewed for data: (1) among healthy adults eating constant diets when net acid excretion is increased by increasing dietary protein, administering NH₄Cl, or withdrawal of dietary KHCO₃ or reduced by administering KHCO₃; (2) among healthy adults eating constant diets providing varying amounts of protein and potassium, and (3) among healthy adults and Ca stone formers with and without idiopathic hypercalciuria eating ad libitum. The results show that urinary Ca excretion varies directly with net acid excretion by 0.035 mmol/mEq. The urinary net acid excretion increases by 0.10–0.15 mEq/mmol urinary urea, and urinary Ca increases by about 0.04 mmol/g dietary protein, while the urinary net acid excretion decreases as the ratio of urinary K/urea, a reflection of the dietary K relative to dietary protein, increases. The relationships between net acid excretion and both urinary urea and K/urea are similar among Ca stone formers without and with idiopathic hypercalciuria, but those with idiopathic hypercalciuria exhibit increased rates of urinary Ca excretion at all levels of net acid excretion.