OECD 414 supplementary prenatal developmental toxicity study of sodium molybdate dihydrate in the rat and benchmark dose evaluation.

In a continuing investigation of the potential for reproductive and developmental toxicity of molybdenum (Mo), consequent to the previous published OECD studies [1,2] and as directed by the European Chemicals Agency [3], a supplemental rat GLP-compliant Prenatal Developmental Toxicity (PNDT) study was conducted to investigate higher dose levels of sodium molybdate dihydrate (SMD) in an identical study design (OECD 414)[4] to Murray et al. 2014a [1], at dietary concentrations calculated to provide target Mo levels of 80 and 120 mg/kg bw/day (the maximum-tolerated dose). There was no effect on post-implantation loss, litter size, sex ratio or the incidence of external, visceral or skeletal fetal malformations or variations. Fetal weight was reduced proportionate to maternal dose. Minimal differences observed in the ossification status of some extremities of fetuses from females receiving 120 mg Mo/kg bw/day were confirmed as transient by skeletal examination of PND 21 pups from a further group of females receiving the same dose regime. There was no evidence of copper depletion in serum, placenta or liver. A benchmark dose evaluation using continuous and dichotomous approaches by combining the fetal body weight data from this study and the previous study determined that the BMD05 ranged from 47 to 57 mg Mo/kg bw/day, depending on the modelling approach and the BMDL05 estimates ranged from 37 to 47 mg Mo/kg bw/day. These levels are considered a more statistically robust point of departure for risk assessment for reproductive effects than the established NOAEL of 40 mg Mo/kg bw/day.

Progression of atherosclerosis with carnitine supplementation: a randomized controlled trial in the metabolic syndrome.

BACKGROUND: L-carnitine (L-C), a ubiquitous nutritional supplement, has been investigated as a potential therapy for cardiovascular disease, but its effects on human atherosclerosis are unknown. Clinical studies suggest improvement of some cardiovascular risk factors, whereas others show increased plasma levels of pro-atherogenic trimethylamine N-oxide. The primary aim was to determine whether L-C therapy led to progression or regression of carotid total plaque volume (TPV) in participants with metabolic syndrome (MetS). METHODS: This was a phase 2, prospective, double blinded, randomized, placebo-controlled, two-center trial. MetS was defined as ≥ 3/5 cardiac risk factors: elevated waist circumference; elevated triglycerides; reduced HDL-cholesterol; elevated blood pressure; elevated glucose or HbA1c; or on treatment. Participants with a baseline TPV ≥ 50 mm3 were randomized to placebo or 2 g L-C daily for 6 months. RESULTS: The primary outcome was the percent change in TPV over 6 months. In 157 participants (L-C N = 76, placebo N = 81), no difference in TPV change between arms was found. The L-C group had a greater increase in carotid atherosclerotic stenosis of 9.3% (p = 0.02) than the placebo group. There was a greater increase in total cholesterol and LDL-C levels in the L-C arm. CONCLUSIONS: Though total carotid plaque volume did not change in MetS participants taking L-C over 6-months, there was a concerning progression of carotid plaque stenosis. The potential harm of L-C in MetS and its association with pro-atherogenic metabolites raises concerns for its further use as a potential therapy and its widespread availability as a nutritional supplement. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02117661, Registered April 21, 2014, https://clinicaltrials.gov/ct2/show/NCT02117661 .

Acceptability of delivering an adapted Buurtzorg model in the Scottish care context.

OBJECTIVES: Given increasing epidemiological and financial pressures on services, there is a need to test new models of integrated health and social care. Crucial to this testing is determining acceptability, particularly to those delivering services. The Dutch 'Buurtzorg' model, characterised by self-managing nursing teams, has shown promise, but its principles are yet to be adapted and tested in Scotland. The study aim was to understand the experiences of working in a self-managing, integrated, health and social care team. STUDY DESIGN: This is a case study within a primary care setting. METHODS: The Integrated Neighbourhood Care Aberdeen (INCA) project comprised two self-managing teams of support workers and nurses working at different sites in Aberdeen. Acceptability was explored through semistructured interviews with staff. Data were recorded and analysed thematically. RESULTS: Staff reported high-quality patient care, which they attributed to autonomy over the frequency and duration of visits. Tensions between team members and between teams and management were apparent partly due to the predominantly social care caseload, confounding guidance on how to implement self-management and communication challenges. The team colocated within a General Practice reported positive relationships with other professionals. CONCLUSIONS: Self-management requires a clear framework in which to function. Allowing staff autonomy to vary care provision according to need may improve patient outcomes.

Outcomes of the Memorial Sloan Kettering Cancer Center International General Surgical Oncology Fellowship.

BACKGROUND: Training of foreign medical graduates in surgical oncology is an undervalued intervention for improving global cancer care. The aim of this work was to describe the design and results of a clinical training program for international surgeons from a single comprehensive cancer center. STUDY DESIGN: Of 39 international fellows trained during 20 years, 34 were surveyed about education, research, and current context of surgical practice. A citation and H-index calculation (ie h number of publications that each has at least h citations) was performed to assess scientific productivity of each graduated fellow. RESULTS: Twenty-one of 39 (54%) fellows came from countries in which English is not the primary language. Europe was the continent with the most graduates (17 of 39 [43%]), and only 5 of 39 (13%) were from Latin America. Three of 39 (8%) were women. Thirty-one of 39 graduated fellows (80%) returned to their countries of origin. The survey response rate was 73% (25 of 34). Seventeen of twenty-five (68%) work in an academic setting and 13 (52%) reported surgical oncology as their main clinical practice. Total number of citations and H-index are homogeneous among the different regions from which the fellows originated, with a median of 165 citations and median H-index of 5. CONCLUSIONS: The International General Surgical Oncology Fellowship has successfully trained foreign surgeons for academic practice in surgical oncology. Most of the graduates have returned to their country of origin and contributed to education and research there.

Evaluation of the mode of action of mouse lung tumors induced by 4-methylimidazole.

4-Methylimidazole (4-MEI) occurs in certain foods and beverages as a product of browning reactions. An increased incidence of lung tumors was reported in mice, but not rats, exposed to levels of 4-MEI in their diet that far exceed human dietary intake. This investigation evaluated the hypothesis that 4-MEI induces mouse lung tumors by the same mode of action (MOA) as styrene: CYP2F2 metabolic activation and increased BrdU labeling. Using styrene (200 mg/kg/day by gavage) as a positive control, histopathology and DNA synthesis (measured by BrdU incorporation) in the bronchiolar region were evaluated in: (1) a 5-day comparative toxicity study in C57BL/6 "wild type" and CYP2F2 "knock out" (KO) mice given 4-MEI at the same dietary concentrations used in the NTP cancer bioassay, and (2) a 13-week comparative toxicity study of C57BL/6 and B6C3F1 mice receiving 0, 1250 or 2500 ppm of 4-MEI in the diet for 6, 15, 34 and 91 days. In contrast to styrene, 4-MEI had no consistent effect on BrdU labeling or histopathology in the lungs of mice in the dose range that had been shown to produce lung tumors in another study. The results of these studies do not support the hypothesis that 4-MEI and styrene induce lung tumors by the same MOA.

Developmental toxicity study of sodium molybdate dihydrate administered in the diet to Sprague Dawley rats.

Molybdenum is an essential nutrient for humans and animals and is a constituent of several important oxidase enzymes. It is normally absorbed from the diet and to a lesser extent from drinking water and the typical human intake is around 2µg/kg bodyweight per day. No developmental toxicity studies to contemporary standards have been published and regulatory decisions have been based primarily on older studies where the nature of the test material, or the actual dose levels consumed is uncertain. In the current study the developmental toxicity of sodium molybdate dihydrate as a representative of a broad class of soluble molybdenum(VI) compounds, was given in the diet to Sprague Dawley rats in accordance with OECD Test Guideline 414. Dose levels of 0, 3, 10, 20 and 40mgMo/kgbw/day were administered from GD6 to GD20. No adverse effects were observed at any dose level on the dams, or on embryofetal survival, fetal bodyweight, or development, with no increase in malformations or variations. Significant increases in serum and tissue copper levels were observed but no toxicity related to these was observed. The NOAEL observed in this study was 40mgMo/kgbw/day, the highest dose tested.

90-Day subchronic toxicity study of sodium molybdate dihydrate in rats.

This study investigated the subchronic toxicity of molybdenum (Mo) in Sprague-Dawley rats given sodium molybdate dihydrate in the diet for 90days at dose levels of 0, 5, 17 or 60mgMo/kgbw/day. The study complied with OECD Test Guideline (TG) 408, with additional examination of estrus cycles and sperm count, motility, and morphology from OECD TG 416. The overall no-observed-adverse-effect level was 17mgMo/kgbw/day, based on effects on body weight, body weight gain, food conversion efficiency and renal histopathology (females only) at 60mgMo/kgbw/day. No treatment-related adverse effects on reproductive organ weights or histopathology, estrus cycles or sperm parameters were observed at any dose level. No adverse effects were observed in the high dose animals after the 60-day recovery period, with the exception that male rats did not fully recover from reduced body weight. Serum blood, liver and kidney samples were analyzed for molybdenum, copper, zinc, manganese, iron, cobalt and selenium; high levels of molybdenum and copper were found in the serum, blood, liver and kidneys of rats treated with 60mgMo/kgbw/day. In conclusion, the LOAEL and NOAEL for molybdenum were determined to be 60 and 17mgMo/kgbw/day, respectively.

The relationship between repeat-dose toxicity and aromatic-ring class profile of high-boiling petroleum substances.

A study was undertaken within the context of the U.S. EPA HPV Chemical Challenge Program to (1) characterize relationships between PAC content and repeat-dose toxicities of high-boiling petroleum substances (HBPS) and (2) develop statistical models that could be used to predict the repeat-dose toxicity of similar untested substances. The study evaluated 47 repeat-dose dermal toxicity and 157 chemical compositional studies. The four most sensitive endpoints of repeat-dose toxicity were platelet count, hemoglobin concentration, relative liver weight and thymus weight. Predictive models were developed for the dose-response relationships between the wt.% concentration of each of seven ring classes of aromatic compounds (the "ARC profile") and specific effects, with high correlations (r=0.91-0.94) between the observed and model-predicted data. The development of the mathematical models used to generate the results reported in this study is described by Nicolich et al. (2013). Model-generated dose-response curves permit the prediction of either the effect at a given dose or the dose that causes a given effect. The models generate values that are consistent with other standard measures. The models, using compositional data, can be used for predicting the repeat-dose toxicity of untested HBPS.

The relationship between developmental toxicity and aromatic-ring class profile of high-boiling petroleum substances.

In response to the US EPA HPV Challenge Program, this study was conducted to: (1) evaluate the relationship between PAC content and the developmental toxicity of high-boiling petroleum substances (HBPS) and (2) develop mathematical models to predict the developmental toxicity of similar untested substances based on their aromatic ring class (ARC) profiles. For this investigation, 68 developmental toxicity studies were reviewed. The ARC models relied on data from 21 rat dermal developmental toxicity studies conducted with similar experimental designs to ensure a consistent data set for comparison. The most sensitive general endpoints of developmental toxicity (i.e., decreased fetal survival and growth) were chosen for modeling. The ARC models demonstrated a strong correlation between the predicted vs. observed values for specific sensitive endpoints of these developmental toxicities (percent resorptions, r=0.99; live fetuses per litter, r=0.98; fetal body weight, r=0.94). Such associations provide a promising approach for predicting the developmental toxicity of untested HBPS. Efforts to corroborate the ARC models using test substances that were not used to build the ARC models produced mixed results, and further development and refinement of the ARC models is recommended before they can be reliably applied to all HBPS.

Evaluating the male and female reproductive toxicity of high-boiling petroleum substances.

To meet the EPA HPV Chemical Challenge Program requirement for reproductive toxicity data on sponsored high-boiling petroleum substances (HBPS), an analysis was conducted using the results of 39 repeat-dose and 59 developmental rat dermal toxicity studies on HBPS samples spanning the boiling range of the sponsored substances, and the results of three one-generation reproductive toxicity studies on two samples spanning the concentration range of polycyclic aromatic compounds of sponsored substances. The analysis found little evidence of male or female reproductive tract toxicity based on histopathology, reproductive organ weight, and sperm parameters, and no evidence of effects on fertility, while significant developmental toxicity and/or systemic repeat-dose toxicity were frequently observed. Among 14 samples of HBPS tested in both repeat-dose toxicity and developmental toxicity studies, there were no studies in which an adverse reproductive tract finding occurred at a dose lower than that producing developmental toxicity or other adverse effects in repeat-dose toxicity studies. The current analysis supports the hypothesis that effects in developmental and/or repeat-dose toxicity studies of HBPS occur at doses lower than those that might affect fertility in rat one-generation reproductive studies. When adequate developmental and repeat-dose toxicity studies are available, a reproductive toxicity study of HBPS appears unnecessary.

The development of statistical models to determine the relationship between aromatic-ring class profile and repeat-dose and developmental toxicities of high-boiling petroleum substances.

The repeat-dose and developmental toxicities of certain petroleum refinery streams are related to their polycyclic aromatic compound (PAC) content (Feuston et al., 1994). Building on this foundation, and working within the context of the US EPA High Production Volume (HPV) Chemical Challenge Program, we: (1) characterized relationships between PAC content and repeat-dose and developmental toxicities of high boiling petroleum substances (HBPS), and (2) developed statistical models that can be used to predict critical effects of similar untested substances. Data from 39 dermal toxicity studies of HBPS were used to develop statistical models to predict the dose-response relationships between the weight percent concentration of each of their 1-7 aromatic ring classes and 4 repeat-dose and 3 developmental endpoints (absolute thymus weight, hemoglobin count, platelet count, liver to body weight, live fetus count, fetal weight, and percent resorptions). The correlations between the observed and model-predicted values are >0.90. The predictive ability of the models was tested via a series of evaluation or corroboration methods. As is shown in the paper, using only compositional data of untested HBPS, the models can be used to predict the effect at a given dose or the dose that causes an effect of a stipulated magnitude.

Assessing the mammalian toxicity of high-boiling petroleum substances under the rubric of the HPV program.

In 1998, the US EPA announced the HPV Challenge Program, a voluntary chemical data collection effort. The Petroleum HPV Testing Group (PHPVTG(1)) volunteered to provide data on approximately 110 high boiling petroleum substances (HBPS), i.e. substances with final boiling points ≥ approximately 650°F (343°C). These HBPS are substances of unknown and variable composition (UVCBs) that are composed of numerous individual constituents. Toxicity studies have shown that some HBPS can produce systemic (repeat-dose) and developmental effects, and some are mutagenic under in vitro conditions. The papers in this supplement show that these effects are related to the profiles of aromatic constituents in these substances. Further, it is shown that the effects on selected repeat-dose and developmental toxicity endpoints and mutagenic activity in bacterial assays can be predicted from compositional information using models based on the aromatic-ring class profile, "ARC profile" as defined by gas chromatographic separation of the DMSO-soluble fraction of the starting materials. This chromatographic method and the predictive models provide an efficient means of characterizing for screening purposes the potential for repeat-dose, developmental effects and bacterial mutagenicity of HBPS and can reduce the number of animal tests that would be required if these tests were conducted on all 110 HBPS.

Delivering affordable cancer care in high-income countries.

The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and disability (not including direct medical costs) was estimated to be US$895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field-eg, the huge development costs for cancer medicines-there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.

Chronic feeding of a low boron diet adversely affects reproduction and development in Xenopus laevis.

The aims of this work were as follows: 1) to determine whether a purified diet currently used for studies with rats was acceptable for reproductive studies in frogs; and 2) to determine whether frogs are sensitive to a deficit of boron (B) in the diet. Adult Xenopus laevis were fed a nonpurified beef liver and lung (BLL) diet (310 microg B/kg), a purified diet supplemented with boron (+B; 1850 microg B/kg), or a purified diet low in boron (-B; 45 microg B/kg) for 120 d. Frogs fed the BLL and +B diets produced 11.3 and 12.2% necrotic eggs, respectively. Abnormal gastrulation occurred in <4% of the fertilized eggs in both groups, and 96-h larval survival exceeded 75% in both groups. In contrast, frogs fed the -B diet for 120 d produced a high proportion of necrotic eggs (54%). Fertilized embryos from the -B diet-fed frogs showed a high frequency of abnormal gastrulation (26.8%), and >80% of the embryos died before 96 h of development. Mean embryo cell counts at X. laevis developmental stage 7.5 (mid-blastula) were significantly lower in the -B embryos than in the BLL or +B embryos. BLL and -B embryos grown in low boron culture media had a high frequency of malformations compared with embryos grown in boron-supplemented media. These studies show that a purified diet that has been used in rodent studies was acceptable for reproduction studies in X. laevis. This work also demonstrates that a diet low in boron markedly impairs normal reproductive function in adult X. laevis, and that administration of the low boron diet results in an increase in both incidence and severity of adverse effects. In addition, these studies demonstrate the usefulness of the X. laevis model in nutrition studies.

Adverse reproductive and developmental effects in Xenopus from insufficient boron.

Frog embryo teratogenesis assay--Xenopus (FETAX) was utilized as a model system to evaluate the effects on embryo-larval development at various low boron (B) exposure levels in the culture media. Concentrations tested ranged from < 1 to 5000 microg B/L. A statistically significant (P < 0.05) increase in malformations was observed at < or = 3 microg B/L, but not at the greater concentrations. Abnormal development of the gut, craniofacial region and eye, visceral edema, and kinking of the tail musculature (abnormal myotome development) and notochord were observed. In subsequent studies, adult frogs were maintained for 28 d on two diets: (1) low B (LB, 62 microg B/kg) or (2) boric acid supplemented (BA, 1851 microg B/kg); the frogs were subsequently mated, and their offspring were cultured in media containing various levels of B. Results of the 28-d depletion studies indicated that frogs maintained under LB conditions produced a greater proportion of (1) necrotic eggs and (2) fertilized embryos, which abnormally gastrulated at a greater rate and were substantially less viable than embryos from frogs fed the BA diet. Malformations similar to those seen in the initial study were observed in embryos from the B-depleted adults maintained in an LB environment; 28 d on the LB diet enhanced the incidence of malformations associated with the LB culture media. These abnormalities were not observed in embryos cultured in > or = 4 microg B/L from adults cultured on the BA diet. These studies showed that insufficient B reproducibly interfered with normal Xenopus laevis development during organogenesis, substantially impaired normal reproductive function in adult frogs, and thus represent the first studies demonstrating the nutritional essentiality of B in an amphibian species.

Desulphurisation of benzothiophene and dibenzothiophene by actinomycete organisms belonging to the genus Rhodococcus, and related taxa.

Desulphurising enzymes remove the sulphur moiety from an organosulphur molecule leaving the carbon skeleton intact. Two kinds of desulphurisation reaction are recognised. The dibenzothiophene (DBT)-specific pathway desulphurises DBT to inorganic sulphite and 2-hydroxybiphenyl (HBP), and the benzothiophene (BTH)-specific pathway desulphurises BTH to 2-(2'-hydroxyphenyl)ethan 1-al (HPEal) and probably inorganic sulphite. The DBT-desulphurisation pathway was originally identified in Rhodococcus erythropolis strain IGTS8 (ATCC 53968), and the BTH-desulphurisation pathway in Gordonia sp. strain 213E (NCIMB 40816). These organisms do not further metabolise the organic product of desulphurisation. In this article current knowledge of the biochemistry and genetics of the desulphurisation enzymes is reviewed. The need for separate, DBT- and BTH-specific desulphurisation routes is rationalised in terms of the chemical differences between the two compounds. The desulphurisation pathway is compared with other microbial DBT-degrading enzyme systems. Finally some comments are made concerning the application of desulphurisation enzymes for fuel desulphurisation and on the relevance of these enzymes to the ecology of the mycolata (sensu Chun et al, 1996).

Blood boron concentrations in pregnant rats fed boric acid throughout gestation.

Timed-mated Sprague-Dawley rats (28 to 32/group) were exposed to boric acid (BA) in the diet from Gestational Day (GD) 0 to 20. Dietary concentrations of added BA (0%, 0.025%, 0.050%, 0.075%, 0.100%, or 0.200%) yielded average daily intakes equivalent to 0, 3, 6, 10, 13, or 25 mg boron/kg body weight/d. Dams and their fetuses were evaluated for evidence of maternal or developmental toxicity, as reported previously. At termination on GD 20, maternal whole blood was collected in heparinized Vacutainer tubes, stored frozen (-20 degrees C), and subsequently prepared by a high-temperature alkaline ashing procedure for analysis of boron by inductively coupled plasma optical emission spectrometry. Increasing dietary concentrations of BA were positively associated with whole blood boron concentrations in confirmed pregnant rats, specifically 0.229 +/- 0.143, 0.564 +/- 0.211, 0.975 +/- 0.261, 1.27 +/- 0.298, 1.53 +/- 0.546, or 2.82 +/- 0.987 micrograms boron/g whole blood (mean +/- SD) for the control through high-dose groups. Maternal blood boron concentrations were positively correlated with indices of maternal dietary intake of boron and with embryo/fetal toxicity observed at 0.100% and 0.200% BA in the diet reported previously. Thus, blood boron concentrations of 1.27 +/- 0.298 and 1.53 +/- 0.546 micrograms boron/g were associated with the no-observed-adverse-effect level (10 mg boron/kg/d) and lowest-observed-adverse-effect level (13 mg boron/kg/d) for developmental toxicity reported previously.

Therapeutic approaches to the problem of biliary sludge and gallstone formation during total parenteral nutrition.

Prolonged total parenteral nutrition is associated with the development of biliary sludge, which consists of super-saturated bile containing cholesterol crystals, bilirubin granules and a very high concentration of mucin glycoprotein. Reduced gallbladder contractility in TPN patients appears to be essential for the pathogenesis of sludge, which represents an important stage in the formation of gallstones, a common and well recognised complication of TPN. Possible approaches to the prevention of these biliary complications of TPN include: 1) inhibition of prostaglandin mediated mucin hypersecretion with aspirin, NSAIDs or possibly by n-3 essential fatty acids; 2) stimulation of gallbladder contractility by early oral feeding or the use of CCK; and 3) reduction of cholesterol saturation and mucin secretion by ursodeoxycholic acid.

Hypercalciuria in parathyroid disorders: effect of dietary sodium control.

Moderate dietary Na restriction (80 mmol/d for 7 days) during constant Ca intake can reduce high urinary Ca excretion to normal levels in idiopathic hypercalciuria (IH). A similar protocol was used to test its effect in primary hyperparathyroidism (PHPT) and also in hypoparathyroid subjects (HOPT) during treatment with dihydrotachysterol (DHT). Nine subjects with PHPT, 10 with HOPT, and one with pseudo-HOPT were evaluated after Na-restricted (80 mmol/d) and Na-supplemented (200 mmol/d) diets for 7 days each with dietary Ca constant. Na restriction resulted in a decrease in mean urinary 24-hour Ca excretion in PHPT subjects (10.6 v 7.6 mmol/d [424 v 304 mg], P less than 0.0001) and in one pseudo-HOPT subject, similar to the pattern seen previously in IH subjects. In contrast, Na restriction was not accompanied by significant change in Ca excretion in HOPT. There was no change in serum immunoreactive PTH (iPTH) or 1,25(OH)2 vitamin D levels in either group when Na intake was altered. Thus, the presence of parathyroid hormone (PTH) is necessary for sodium-related alterations in urinary Ca to occur. The effect of PTH appears to be "permissive" rather than "active." Dietary Na restriction may have a role in the management of hypercalciuria in mild PHPT cases when parathyroidectomy is contraindicated.

Pharmacokinetics of [125I]-2-iodo-3,7,8-trichlorodibenzo-p-dioxin in mice: analysis with a physiological modeling approach.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of hepatic microsomal enzymes. The influence of an inducing dose of TCDD on tissue distribution and other pharmacokinetic behavior of a TCDD analog in the mice was examined by employing a high specific activity radioligand. [125I]-2-iodo-3,7,8-trichlorodibenzo-p-dioxin (ITCDD). Female C57BL/6J mice were pretreated with 0.1 mumol/kg of TCDD or the vehicle only, followed by 0.1 nmol ITCDD/kg 3 days later. The control animals had the highest concentration of ITCDD-derived radioactivity in the fat, but the TCDD-pretreated animals had the highest concentration in their livers. Whole-body elimination of ITCDD approximated first-order behavior, and induction by pretreatment with the inducing dose of TCDD almost doubled the rate of excretion (control mice, t1/2 = 14.2 days; pretreated mice, t1/2 = 8.0 days). All disposition results in naive and pretreated mice were satisfactorily described by a consistent physiologically based pharmacokinetic model (Leung et al., 1988a) in which induction increased the amount of microsomal ITCDD-binding protein from 1.75 to 20 nmol/liver and increased the rate constant for metabolism of free ITCDD from 1 to 3/hr/kg liver. The binding affinity of the microsomal ITCDD-binding protein was the same (20 nM) in both induced and noninduced mice. Model simulations indicated a time delay in the elimination of nonparent ITCDD metabolites from the body and a more rapid absorption of the parent ligand in the pretreated mice. Consistent with previous physiological modeling with TCDD in different mouse strains, the primary factor influencing the liver/fat concentration ratio appears to be the affinity and capacity of the microsomal TCDD-binding proteins, which are altered by induction. These dose-dependent pharmacokinetic differences with ITCDD are important considerations for TCDD risk assessment in which data from high dose rodent experiments are extrapolated to predict behavior at much lower environmental concentrations in exposed humans.