Russell L. Dills

Macrocyclic and Other Non–group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue: Preliminary Results From 9 Patients With Normal Renal Function

ObjectiveThe purpose of this study was to determine whether gadolinium (Gd) is deposited in brain and bone tissues in patients receiving only non–Group 1 agents, either macrocyclic or linear protein interacting Gd-based contrast agents, with normal renal function. Group 1 agents are linear agents most associated with nephrogenic systemic fibrosis that the US Federal Drug Administration has defined as contraindicated in patients at risk for this disease. Materials and MethodsThis study was institutional review board approved and Health Insurance Portability and Accountability Act compliant for retrospective review of records and also had signed autopsy consent authorizing use of decedents tissue in research studies. Tissue samples were collected from 9 decedents undergoing autopsy who had contrast-enhanced magnetic resonance imaging (MRI) with only single agent exposure to a non–Group 1 Gd-based contrast agent. Decedents with only noncontrast MRI or no MRI served as controls. Multiple brain areas, including globus pallidus and dentate nucleus, as well as bone and skin, were sampled and analyzed for Gd using inductively coupled plasma mass spectrometry. Gadolinium levels were compared between groups of decedents using the Mann-Whitney test and between brain and bone tissues of the same cases using the Wilcoxon signed-rank test. ResultsOf the 9 decedents, 5 received gadoteridol (ProHance; Bracco Diagnostics, Princeton, NJ), 2 received gadobutrol (Gadovist; Bayer Healthcare, Whippany, NJ), and 1 each had gadobenate (MultiHance; Bracco Diagnostics) and gadoxetate (Eovist; Bayer Healthcare). Gadolinium was found with all agents in all brain areas sampled with highest levels in globus pallidus and dentate. Bone levels measured 23 times higher (median) than brain levels (P = 0.008 for bone vs globus pallidus) and showed a significant correlation (r = 0.81, P = 0.022). In controls, Gd levels in the brain were at or below limits of measurement and were significantly lower compared with study cases (P = 0.005 for globus pallidus). ConclusionGadolinium deposition in normal brain and bone tissue occurs with macrocyclic and linear protein interacting agents in patients with normal renal function. Deposition of Gd in cortical bone occurs at much higher levels compared with brain tissue and shows a notable correlation between the two. Thus, the bone may serve as a surrogate to estimate brain deposition if brain Gd were to become a useful clinical or research marker.

Determination of levoglucosan in atmospheric fine particulate matter.

Abstract A microanalytical method suitable for the quantitative determination of the sugar anhydride levoglucosan in low-volume samples of atmospheric fine particulate matter (PM) has been developed and validated. The method incorporates two sugar anhydrides as quality control standards. The recovery standard sedoheptulosan (2,7-anhydro-β-D-altro-heptulopyranose) in 20 μL solvent is added onto samples of the atmospheric fine PM and aged for 1 hr before ultrasonic extraction with ethylacetate/ triethylamine. The extract is reduced in volume, an internal standard is added (1,5-anhydro-D-mannitol), and a portion of the extract is derivatized with 10% by volume N-trimethylsilylimidazole. The derivatized extract is analyzed by gas chromatography/mass spectrometry (GC/MS). The recovery of levoglucosan using this procedure was 69 ± 6% from five filters amended with 2 μg levoglu-cosan, and the reproducibility of the assay is 9%. The limit of detection is ∼0.1 μg/mL, which is equivalent to ∼3.5 ng/m3 for a 10 L/min sampler or ∼8.7 ng/m3 for a 4 L/min personal sampler (assuming 24-hr integrated samples). We demonstrated that levoglucosan concentrations in collocated samples (expressed as ng/m3) were identical irrespective of whether samples were collected by PM with aerodynamic diameter ≤2.5 μm or PM with aerodynamic diameter ≤10 μm impactors. It was also demonstrated that X-ray fluorescence analysis of samples of atmospheric PM, before levoglucosan determinations, did not alter the levels of levoglucosan.

Phthalates and risk of endometriosis

BACKGROUND Phthalates are ubiquitous environmental chemicals with endocrine disruptive properties. The impact of these chemicals on endocrine-related disease in reproductive-age women is not well understood. OBJECTIVE To investigate the relationship between urinary phthalate metabolite concentrations and the risk of a hormonally-driven disease, endometriosis, in reproductive-age women. METHODS We used data from a population-based case-control study of endometriosis, conducted among female enrollees of a large healthcare system in the U.S. Pacific Northwest. We measured urinary phthalate metabolite concentrations on incident, surgically-confirmed cases (n=92) diagnosed between 1996 and 2001 and population-based controls (n=195). Odds ratios (OR), and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusting for urinary creatinine concentrations, age, and reference year. RESULTS The majority of women in our study had detectable concentrations of phthalate metabolites. We observed a strong inverse association between urinary mono-(2-ethyl-5-hexyl) phthalate (MEHP) concentration and endometriosis risk, particularly when comparing the fourth and first MEHP quartiles (aOR 0.3, 95% CI: 0.1-0.7). Our data suggested an inverse association between endometriosis and urinary concentrations of other di-2-ethylhexyl phthalate (DEHP) metabolites (mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP)) and ∑DEHP, however, the confidence intervals include the null. Our data also suggested increased endometriosis risk with greater urinary concentrations of mono-benzyl phthalate (MBzP) and mono-ethyl phthalate (MEP), although the associations were not statistically significant. CONCLUSIONS Exposure to select phthalates is ubiquitous among female enrollees of a large healthcare system in the U.S. Pacific Northwest. The findings from our study suggest that phthalates may alter the risk of a hormonally-mediated disease among reproductive-age women.

Unexpected results in a randomized dietary trial to reduce phthalate and bisphenol A exposures

Diet is a primary source of exposure for high-molecular-weight phthalates and bisphenol A (BPA), but little is known about the efficacy of various interventions to reduce exposures. We conducted a randomized trial with 10 families to test the efficacy of a 5-day complete dietary replacement (Arm 1; n=21) versus written recommendations to reduce phthalate and BPA exposures (Arm 2; n=19). We measured phthalate and BPA concentrations in urine samples at baseline, intervention, and post-intervention periods. We used Wilcoxon paired signed-rank tests to assess change in concentrations across time and multi-level mixed effects regression models to assess differences between Arms 1 and 2. Urinary di(2-ethylhexyl) phthalate (DEHP) metabolite concentrations increased unexpectedly from a median of 283.7 nmol/g at baseline to 7027.5 nmol/g during the intervention (P<0.0001) among Arm 1 participants, and no significant changes were observed for Arm 2 participants. We observed a statistically significant increase in total BPA concentration between baseline and intervention periods in Arm 1 but no significant changes in Arm 2. Arm 1 food ingredient testing for DEHP revealed concentrations of 21,400 ng/g in ground coriander and 673 ng/g in milk. Food contamination with DEHP led to unexpected increases in urinary phthalate concentrations in a trial intended to minimize exposure. In the absence of regulation to reduce phthalate and BPA concentrations in food production, it may be difficult to develop effective interventions that are feasible in the general population. An estimate of DEHP daily intake for children in the dietary replacement Arm was above the US Environmental Protection Agency oral reference dose and the European Food Safety Authority’s tolerable daily intake, suggesting that food contamination can be a major source of DEHP exposure.

Arsenic Exposure within the Korean Community (United States) Based on Dietary Behavior and Arsenic Levels in Hair, Urine, Air, and Water

Background Determining arsenic exposure in groups based on geographic location, dietary behaviors, or lifestyles is important, as even moderate exposures may lead to health concerns. Objectives/Methods The Korean community in Washington State, represents a group warranting investigation, as they consume foods (e.g., shellfish, rice, finfish, and seaweed) known to contain arsenic. As part of the Arsenic Mercury Intake Biometric Study, we examined the arsenic levels in hair and urine along with the diets of 108 women of childbearing age from within this community. Arsenic levels in indoor air and drinking water were also investigated, and shellfish commonly consumed were collected and analyzed for total and speciated arsenic. Results The six shellfish species analyzed (n = 667) contain total arsenic (range, 1–5 μg/g) but are a small source of inorganic arsenic (range, 0.01–0.12 μg/g). Six percent of the individuals may have elevated urinary inorganic arsenic levels (> 10 μg/L) due to diet. Seaweed, rice, shellfish, and finfish are principal sources for total arsenic intake/excretion based on mass balance estimates. Rice consumption (163 g/person/day) may be a significant source of inorganic arsenic. Air and water are not significant sources of exposure. Hair is a poor biometric for examining arsenic levels at low to moderate exposures. Conclusions We conclude that a portion of this community may have dietary inorganic arsenic exposure resulting in urine levels exceeding 10 μg/L. Although their exposure is below that associated with populations exposed to high levels of arsenic from drinking water (> 100 μg/L), their exposure may be among the highest in the United States.

Low and variable presence of valproic acid in human brain

We studied the distribution of valproic acid (VPA) between brain (gray matter) and serum in 13 patients receiving chronic VPA therapy who underwent cortical resections for intractable seizures. Valproate concentration in cerebral cortex was remarkably low compared with either total or unbound valproate concentration in serum. The respective brain-to-serum partition ratios based on total and free drug in serum were 0.111 ± 0.051 and 0.544 ± 0.175. In comparison with other commonly used antiepileptic drugs, valproate has the distinction of exhibiting the lowest brain-to-blood partitioning. Moreover, the brain-to-serum concentration ratio varied over a four-fold range between patients. Some of this variability was related to variation in serum protein binding, as indicated by a modest correlation between the partition ratio and serum free fraction (r = +0.687). However, the brain-to-unbound concentration ratio still showed a three-fold variation. The variability in distribution of VPA between brain and blood is probably one of the underlying factors for the lack of a clearly definable therapeutic range of serum VPA concentration in epileptic patient populations.

Toluene metabolites as biological indicators of exposure

The measurement of exhaled and excreted xenobiotics and their metabolites can provide accurate, non-invasive, and time-flexible measurements of internal dose. We analyzed rates of exhaled (2)H(8)-toluene and excreted urinary metabolites from 33 exposures of men to 50 ppm of (2)H(8)-toluene for 2 h at rest. The total dose was distributed as follows: exhaled (2)H(8)-toluene, 13 +/- 6.2%; (2)H(5)-hippuric acid, 75 +/- 6.4%; (2)H(7)-o-cresol, 0.31 +/- 0.22%; (2)H(7)-m-cresol, 0.53 +/- 0.44%; and (2)H(7)-p-cresol, 11 +/- 3.8%. Interindividual variability was assessed using the coefficients of variation for peak exhalation or excretion rates, and fractions of dose excreted: (2)H(8)-toluene, c.v.=60, 47%; (2)H(5)-hippuric acid, 29, 8.6%; (2)H(7)-o-cresol, 80, 73%; (2)H(7)-m-cresol, 37, 83%; and (2)H(7)-p-cresol, 38, 34%. Excretion rates of the cresols were stable over the first 5 h post-exposure, and o-cresol was determined to be the best urinary indicator of exposure, given the lower background levels of this isomer. The hippuric acid/cresol rate ratios for the first 5 h post-exposure could be described by single exponential terms, and thus provided a means for estimating time since exposure for any finite toluene duration/exposure combination.

QUANTIFICATION OF VOLATILE SOLVENTS IN BLOOD BY STATIC HEADSPACE ANALYSIS

A static headspace method for determination of volatile solvents in blood was developed. The solvents determined were 1,1,1-trichloroethane, toluene, xylene (o-, m- and p-), ethylbenzene, styrene, alpha-methylstyrene and 4-methylstyrene at concentrations ranging from 0.01 to 1 mug/ml. Internal standard calibration was used. Parameters affecting sensitivity and precision were determined and optimized.

Short term serum pharmacokinetics of diammine silver fluoride after oral application.

BackgroundThere is growing interest in the use of diammine silver fluoride (DSF) as a topical agent to treat dentin hypersensitivity and dental caries as gauged by increasing published research from many parts of the world. While DSF has been available in various formulations for many years, most of its pharmacokinetic aspects within the therapeutic concentration range have never been fully characterized.MethodsThis preliminary study determined the applied doses (3 teeth treated), maximum serum concentrations, and time to maximum serum concentration for fluoride and silver in 6 adults over 4 h. Fluoride was determined using the indirect diffusion method with a fluoride selective electrode, and silver was determined using inductively coupled plasma-mass spectrometry. The mean amount of DSF solution applied to the 3 teeth was 7.57 mg (6.04 μL).ResultsOver the 4 hour observation period, the mean maximum serum concentrations were 1.86 μmol/L for fluoride and 206 nmol/L for silver. These maximums were reached 3.0 h and 2.5 h for fluoride and silver, respectively.ConclusionsFluoride exposure was below the U.S. Environmental Protection Agency (EPA) oral reference dose. Silver exposure exceeded the EPA oral reference dose for cumulative daily exposure over a lifetime, but for occasional use was well below concentrations associated with toxicity. This preliminary study suggests that serum concentrations of fluoride and silver after topical application of DSF should pose little toxicity risk when used in adults.Clinical trials registrationNCT01664871.

Distribution of Unsaturated Metabolites of Valproate in Human and Rat Brain‐Pharmacologic Relevance?

Summary: The concentrations of valproate (VPA) and six of its pharmacologically active, unsaturated metabolites (E‐δ2‐VPA, Z‐δ3‐VPA, E‐δ3‐VPA, E, E‐δ2, 3.‐VPA, δ4‐VPA, and E‐δ2, 4‐VPA) were measured in serum and cortical brain samples from 24 patients undergoing epilepsy surgery. Collectively, the six metabolites were present at concentrations ≤13% of VPA brain concentrations. Because the six unsaturated metabolites were present at such low brain concentrations, we concluded that these metabolites probably did not contribute significantly to the anticonvulsant effect of VPA. Results from a parallel pharmacodynamic study in rats in which VPA was administered three times daily for 8 weeks supported this conclusion. Only three unsaturated metabolites (E‐δ2‐VPA, δ3‐VPA, E, E‐A2, 3‐VPA)were detected in rat brain. No correlation was observed between the time course of anticonvulsant effect [as measured by the timed intravenous pentylenetetrazol (PTZ) test] and the time course of VPA or metabolite concentrations in rat brain. Despite the structural similarity of VPA and its metabolites, striking differences were observed in their serum protein binding and blood‐brain distribution properties. In the human brain, VPA and δ4‐VPA exhibited brain‐to‐free serum concentration ratios that were less than unity. In contrast, compounds with the double bond at the 2‐or 3‐position had brain: free concentration ratios that were much higher than unity. The structure‐distribution relationship observed with VPA and its unsaturated metabolites suggested that these branched‐chain fatty acids differ in their asymmetric transport across the blood‐brain barrier (BBB).