Exposure to melamine and its derivatives and aromatic amines among pregnant women in the United States: The ECHO Program.

BACKGROUND: Melamine, melamine derivatives, and aromatic amines are nitrogen-containing compounds with known toxicity and widespread commercial uses. Nevertheless, biomonitoring of these chemicals is lacking, particularly during pregnancy, a period of increased susceptibility to adverse health effects. OBJECTIVES: We aimed to measure melamine, melamine derivatives, and aromatic amine exposure in pregnant women across the United States (U.S.) and evaluate associations with participant and urine sample collection characteristics. METHODS: We measured 43 analytes, representing 45 chemicals (i.e., melamine, three melamine derivatives, and 41 aromatic amines), in urine from pregnant women in nine diverse ECHO cohorts during 2008-2020 (N = 171). To assess relations with participant and urine sample collection characteristics, we used generalized estimating equations to estimate prevalence ratios (PRs) for analytes dichotomized at the detection limit, % differences (%Δ) for continuous analytes, and 95% confidence intervals. Multivariable models included age, race/ethnicity, marital status, urinary cotinine, and year of sample collection. RESULTS: Twelve chemicals were detected in >60% of samples, with near ubiquitous detection of cyanuric acid, melamine, aniline, 4,4'-methylenedianiline, and a composite of o-toluidine and m-toluidine (99-100%). In multivariable adjusted models, most chemicals were associated with higher exposures among Hispanic and non-Hispanic Black participants. For example, concentrations of 3,4-dichloroaniline were higher among Hispanic (%Δ: +149, 95% CI: +17, +431) and non-Hispanic Black (%Δ: +136, 95% CI: +35, +311) women compared with non-Hispanic White women. We observed similar results for ammelide, o-/m-toluidine, 4,4'-methylenedianiline, and 4-chloroaniline. Most chemicals were positively associated with urinary cotinine, with strongest associations observed for o-/m-toluidine (%Δ: +23; 95% CI: +16, +31) and 3,4-dichloroaniline (%Δ: +25; 95% CI: +17, +33). Some chemicals exhibited annual trends (e.g., %Δ in melamine per year: -11; 95% CI: -19, -1) or time of day, seasonal, and geographic variability. DISCUSSION: Exposure to melamine, cyanuric acid, and some aromatic amines was ubiquitous in this first investigation of these analytes in pregnant women. Future research should expand biomonitoring, identify sources of exposure disparities by race/ethnicity, and evaluate potential adverse health effects.

Exposure to Contemporary and Emerging Chemicals in Commerce among Pregnant Women in the United States: The Environmental influences on Child Health Outcome (ECHO) Program.

Prenatal chemical exposures can influence maternal and child health; however, few industrial chemicals are routinely biomonitored. We assessed an extensive panel of contemporary and emerging chemicals in 171 pregnant women across the United States (U.S.) and Puerto Rico in the Environmental influences on Child Health Outcomes (ECHO) Program. We simultaneously measured urinary concentrations of 89 analytes (103 total chemicals representing 73 parent compounds) in nine chemical groups: bactericides, benzophenones, bisphenols, fungicides and herbicides, insecticides, organophosphate esters (OPEs), parabens, phthalates/alternative plasticizers, and polycyclic aromatic hydrocarbons (PAHs). We estimated associations of creatinine-adjusted concentrations with sociodemographic and specimen characteristics. Among our diverse prenatal population (60% non-Hispanic Black or Hispanic), we detected 73 of 89 analytes in ≥1 participant and 36 in >50% of participants. Five analytes not currently included in the U.S. biomonitoring were detected in ≥90% of samples: benzophenone-1, thiamethoxam, mono-2-(propyl-6-carboxy-hexyl) phthalate, monocarboxy isooctyl phthalate, and monohydroxy-iso-decyl phthalate. Many analyte concentrations were higher among women of Hispanic ethnicity compared to those of non-Hispanic White women. Concentrations of certain chemicals decreased with the calendar year, whereas concentrations of their replacements increased. Our largest study to date identified widespread exposures to prevalent and understudied chemicals in a diverse sample of pregnant women in the U.S.

A 3D Renal Proximal Tubule on Chip Model Phenocopies Lowe Syndrome and Dent II Disease Tubulopathy.

Lowe syndrome and Dent II disease are X-linked monogenetic diseases characterised by a renal reabsorption defect in the proximal tubules and caused by mutations in the OCRL gene, which codes for an inositol-5-phosphatase. The life expectancy of patients suffering from Lowe syndrome is largely reduced because of the development of chronic kidney disease and related complications. There is a need for physiological human in vitro models for Lowe syndrome/Dent II disease to study the underpinning disease mechanisms and to identify and characterise potential drugs and drug targets. Here, we describe a proximal tubule organ on chip model combining a 3D tubule architecture with fluid flow shear stress that phenocopies hallmarks of Lowe syndrome/Dent II disease. We demonstrate the high suitability of our in vitro model for drug target validation. Furthermore, using this model, we demonstrate that proximal tubule cells lacking OCRL expression upregulate markers typical for epithelial-mesenchymal transition (EMT), including the transcription factor SNAI2/Slug, and show increased collagen expression and deposition, which potentially contributes to interstitial fibrosis and disease progression as observed in Lowe syndrome and Dent II disease.

Opportunities for evaluating chemical exposures and child health in the United States: the Environmental influences on Child Health Outcomes (ECHO) Program.

The Environmental Influences on Child Health Outcomes (ECHO) Program will evaluate environmental factors affecting children's health (perinatal, neurodevelopmental, obesity, respiratory, and positive health outcomes) by pooling cohorts composed of >50,000 children in the largest US study of its kind. Our objective was to identify opportunities for studying chemicals and child health using existing or future ECHO chemical exposure data. We described chemical-related information collected by ECHO cohorts and reviewed ECHO-relevant literature on exposure routes, sources, and environmental and human monitoring. Fifty-six ECHO cohorts have existing or planned chemical biomonitoring data for mothers or children. Environmental phenols/parabens, phthalates, metals/metalloids, and tobacco biomarkers are each being measured by ≥15 cohorts, predominantly during pregnancy and childhood, indicating ample opportunities to study child health outcomes. Cohorts are collecting questionnaire data on multiple exposure sources and conducting environmental monitoring including air, dust, and water sample collection that could be used for exposure assessment studies. To supplement existing chemical data, we recommend biomonitoring of emerging chemicals, nontargeted analysis to identify novel chemicals, and expanded measurement of chemicals in alternative biological matrices and dust samples. ECHO's rich data and samples represent an unprecedented opportunity to accelerate environmental chemical research to improve the health of US children.

Identifying and Prioritizing Chemicals with Uncertain Burden of Exposure: Opportunities for Biomonitoring and Health-Related Research.

BACKGROUND: The National Institutes of Health's Environmental influences on Child Health Outcomes (ECHO) initiative aims to understand the impact of environmental factors on childhood disease. Over 40,000 chemicals are approved for commercial use. The challenge is to prioritize chemicals for biomonitoring that may present health risk concerns. OBJECTIVES: Our aim was to prioritize chemicals that may elicit child health effects of interest to ECHO but that have not been biomonitored nationwide and to identify gaps needing additional research. METHODS: We searched databases and the literature for chemicals in environmental media and in consumer products that were potentially toxic. We selected chemicals that were not measured in the National Health and Nutrition Examination Survey. From over 700 chemicals, we chose 155 chemicals and created eight chemical panels. For each chemical, we compiled biomonitoring and toxicity data, U.S. Environmental Protection Agency exposure predictions, and annual production usage. We also applied predictive modeling to estimate toxicity. Using these data, we recommended chemicals either for biomonitoring, to be deferred pending additional data, or as low priority for biomonitoring. RESULTS: For the 155 chemicals, 97 were measured in food or water, 67 in air or house dust, and 52 in biospecimens. We found in vivo endocrine, developmental, reproductive, and neurotoxic effects for 61, 74, 47, and 32 chemicals, respectively. Eighty-six had data from high-throughput in vitro assays. Positive results for endocrine, developmental, neurotoxicity, and obesity were observed for 32, 11, 35, and 60 chemicals, respectively. Predictive modeling results suggested 90% are toxicants. Biomarkers were reported for 76 chemicals. Thirty-six were recommended for biomonitoring, 108 deferred pending additional research, and 11 as low priority for biomonitoring. DISCUSSION: The 108 deferred chemicals included those lacking biomonitoring methods or toxicity data, representing an opportunity for future research. Our evaluation was, in general, limited by the large number of unmeasured or untested chemicals. https://doi.org/10.1289/EHP5133.

Development of a Gut-On-A-Chip Model for High Throughput Disease Modeling and Drug Discovery.

A common bottleneck in any drug development process is finding sufficiently accurate models that capture key aspects of disease development and progression. Conventional drug screening models often rely on simple 2D culture systems that fail to recapitulate the complexity of the organ situation. In this study, we show the application of a robust high throughput 3D gut-on-a-chip model for investigating hallmarks of inflammatory bowel disease (IBD). Using the OrganoPlate platform, we subjected enterocyte-like cells to an immune-relevant inflammatory trigger in order to recapitulate key events of IBD and to further investigate the suitability of this model for compound discovery and target validation activities. The induction of inflammatory conditions caused a loss of barrier function of the intestinal epithelium and its activation by increased cytokine production, two events observed in IBD physiopathology. More importantly, anti-inflammatory compound exposure prevented the loss of barrier function and the increased cytokine release. Furthermore, knockdown of key inflammatory regulators RELA and MYD88 through on-chip adenoviral shRNA transduction alleviated IBD phenotype by decreasing cytokine production. In summary, we demonstrate the routine use of a gut-on-a-chip platform for disease-specific aspects modeling. The approach can be used for larger scale disease modeling, target validation and drug discovery purposes.

[Neonatal herpes simplex infection]. / Neonatale infectie met herpes-simplexvirus.

Neonatal encephalitis caused by herpes simplex virus (HSV) is a familiar disease with a high mortality and morbidity rate. Isolated skin-eye-mouth infection is less familiar among professionals. In this article we present two neonates with an isolated skin lesion caused by an HSV infection. Of the neonates infected with HSV, 40-45% show isolated skin-eye-mouth disease. With correct treatment, the risk of spread to the central nervous system will decrease from 50-60% to 5-10%. Typical HSV skin lesions may present at a late stage of the disease or may be masked by a secondary bacterial infection. When a neonate presents with atypical skin lesions starting 7-12 days after the birth, immediate testing for HSV and immediate treatment are required, to decrease the risk of further progression of the disease.

Munc13-4*rab27 complex tethers secretory lysosomes at the plasma membrane.

Natural Killer (NK) cells and Cytotoxic T lymphocytes (CTL) are critical for the immune response against virus infections or transformed cells. They kill target cells via polarized exocytosis of lytic proteins from secretory lysosomes (SL). Rab27a and munc13-4 interact directly and are required for target cell killing. How they cooperate in the intricate degranulation process is not known. We identified critical residues in munc13-4 for rab27 interaction and tested binding mutants in several complementation assays. In a rat mast cell line we replaced endogenous munc13-4 with ectopically expressed munc13-4 constructs. Unlike wild type munc13-4, binding mutants fail to rescue ß-hexosaminidase secretion. In accord, expression of binding mutants in CTL of Familial Hemophagocytic Lymphohistiocytosis type 3 patients, does not rescue CD107 appearance on the plasma membrane. Total Internal Reflection Fluorescence (TIRF) imaging shows that munc13-4*rab27a restricts motility of SL in the subapical cytoplasm. We propose that rab27*munc13-4 tethers SL to the plasma membrane, a requirement for formation of a cognate SNARE complex for fusion.

A novel Dutch mutation in UNC13D reveals an essential role of the C2B domain in munc13-4 function.

BACKGROUND: UNC13D, encoding the protein munc13-4, is essential in intracellular trafficking and exocytosis of lytic granules. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a genetically heterogeneous, rare autosomal recessive immune disorder. How mutations affect function of munc13-4 is poorly understood. Since 2006 we genetically identified seven FHL patients with mutations in UNC13D. PROCEDURES: Here, we report for the first time a c.2695C>T (p.Arg899X) mutation in exon 28 of UNC13D in three young unrelated Dutch patients. The mutation causes a premature stop codon and encodes munc13-4(1-899), which lacks the C-terminal C2 domain. Genealogical research and haplotyping of the patient families demonstrated that a single ancestral founder introduced the mutation in the Netherlands. We then characterized the mutant protein phenotypically in cell biological and immunological assays. RESULTS: Munc13-4(1-899) was correctly targeted to CD63-positive secretory lysosomes, although its stability was reduced and dynamic turnover on the granule membrane became uncoupled from receptor signaling. In accord, and in contrast to wild-type munc13-4, ectopically expressed mutant failed to rescue degranulation in cells with silenced endogenous munc13-4. CONCLUSIONS: The functional and clinical data showed that this novel Dutch founder mutation leads to severe early onset of FHL3 due to misfolding and degradation of munc13-4(1-899).

The munc13-4-rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane.

Cytotoxic T lymphocytes (CTLs) kill target cells through the polarized release of lytic molecules from secretory lysosomes. Loss of munc13-4 function inhibits this process and causes familial hemophagocytic lymphohistiocytosis type 3 (FHL3). munc13-4 binds rab27a, but the necessity of the complex remains enigmatic, because studies in knockout models suggest separate functions. In the present study, we describe a noncanonical rab27a-binding motif in the N-terminus of munc13-4. Point mutants in this sequence have severely impaired rab27a binding, allowing dissection of rab27a requirements in munc13-4 function. The munc13-4-rab27a complex is not needed for secretory lysosome maturation, as shown by complementation in CTLs from FHL3 patients and in a mast cell line silenced for munc13-4. In contrast, fusion of secretory lysosomes with, and content release at the plasma membrane during degranulation, strictly required the munc13-4-rab27a complex. Total internal reflection fluorescence microscopy imaging revealed that the complex corrals motile secretory lysosomes beneath the plasma membrane during degranulation and controls their docking. The propensity to stall motility of secretory lysosomes is lost in cells expressing munc13-4 point mutants that do not bind rab27. In summary, these results uncovered a mechanism for tethering secretory lysosomes to the plasma membrane that is essential for degranulation in immune cells.

ISEA2007 panel: integration of better exposure characterizations into disaster preparedness for responders and the public.

An expert panel was convened in October 2007 at the International Society for Exposure Analysis Annual Meeting in Durham, NC, entitled "The Path Forward in Disaster Preparedness Since WTC-Exposure Characterization and Mitigation: Substantial Unfinished Business!" The panel prospectively discussed the critical exposure issues being overlooked during disaster responses and highlighted the needs for an optimal blending of exposure characterizations and hazard controls within disaster settings. The cases were made that effective and timely exposure characterizations must be applied during responses to any disaster, whether terrorist, manmade, or natural in origin. The consistent application of exposure sciences across acute and chronic disaster timelines will assure that the most effective strategies are applied to collect the needed information to guide risk characterization and management approaches. Exposure sciences must be effectively applied across all phases of a disaster (defined as rescue, reentry, recovery, and rehabitation-the four Rs) to appropriately characterize risks and guide risk-mitigation approaches. Failure to adequately characterize and control hazardous exposures increases the likelihood of excess morbidity and mortality. Advancing the infrastructure and the technologies to collect the right exposure information before, during, and immediately after disasters would advance our ability to define risks and protect responders and the public better. The panel provided conclusions, recommendations, and next steps toward effective and timely integration of better exposure science into disaster preparedness, including the need for a subsequent workshop to facilitate this integration. All panel presentations and a summary were uploaded to the ISES(1) website (http://www.iseaweb.org/Disaster_Preparedness/index.php).

Historia del tratamiento de la Sífilis / The history of Syphilis´ treatment

El nombre sífilis proviene del griego siph: cerdo y philus: amor. Recuerda al personaje de una obra, llamado Syphilo, que fue castigado por los dioses a sufrir una terrible enfermedad. Se analizan los datos sobre la sífilis en la antigüedad (que difieren según su fuente). Su mención en la Edad Media, su controversial origen, la ayuda de los paleopatólogos para encontrarlo. Luego de la Revolución Francesa y el inicio de la Edad Contemporánea, el porcentaje de enfermos fue creciendo y se acentuó la segregación de los mismos por la sociedad. Desde el año 1500 hasta principios del siglo XX el tratamiento de la sífilis dependía del mercurio. Tenía una gran variedad de formas de aplicación. La vía tópica: el ungüento gris, en calomelano o tabletas, en inyecciones, en fricciones y fumigaciones en donde el mercurio se introducía en el cuerpo por lo pulmones. Se adjudicó a la madera del guayaco pretendidas características curativas, que no poseía. Los ioduros se utilizaron para el terciarismo. Ehrlich en 1907, patentó el compuesto 606 o Salvarsan y en 1910, el Neo-Salvarsan o Arsfenamina (compuesto 914). Por estos descubrimientos recibió el Premio Nobel. En 1887, Julios Wagner Jauregg sugirió que la fiebre terapéuticamente inducida era útil en el tratamiento de enfermos psicóticos. En 1912 publicó sus satisfactorios resultados al tratar la paresias con una combinación de mercurio-iodo y tuberculina de Koch. En 1917 ingresó a su servicio un enfermo de malaria, con cuya sangre escarificaron la piel palúdica de tres paréticos, en lugar de darle inmediatamente quinina. Por ello fue galardona con el Premio Nobel. Se utilizó luego el bismuto, a partir de 1922, pero posteriormente fue sustituido por las sulfamidas, de aplicación dificultosa. El avance terapéutico más importante ocurrió en 1943, año en que se comenzó a utilizar la penicilina por Mahoney y colaboradores. Luego se confirmó la eficacia de la tetraciclina para los alérgicos a la penicilina. Últimamente se confirmó la eficacia de la azitromicina en dosis de 500mg cada día, durante los 10 días o el régimen de 500mg en días alternos.

The name Syphilis comes from greek language: Siph: Pig and Philus: Love, meaning, in honor of the Sheppard of a story where the Character, Named Syphilo, is punished by the gods to suffer a terrible disease. Data about Syphilis was analized in ancient times (which differ according to the source). Its mention in the middle age, its controversial origin, the help provided from paleopathologists to find it. When the French revolution and the beginning of the contemporary age began, the percentage of sick people grew. The segregation of these is proved by the society. From the year 1500 to the beginnings of the XX century, the treatment of Syphilis depended on mercury. There were a great variety of application methods: topical: the grey ointment, in «calomelanos or tabs¼, in injections, in frictions and fumigations where the mercury was introduced in the body by the lungs. Guayacos wood was named with curative features which it did not posses. The iodides were used for tertiary syphilis. In 1907, Ehrlich formulates the 606 compound or Salvarsan and in 1910 the Neo-Salvarsan or Arsfenamina or compound 914.Due to these discoveries he received the nobel prize. In 1887, Julius Wagner of Jauregg suggested that: the inducted therapeutic fiber was useful in the treatment of the psychosis. In 1912 he published his satisfactory results in treating the paresis with a combination of mercury and iodides and tuberculin of Koch. In 1917 he treated a patient who had malaria and instead of giving him immediately quinine, he made a scarification with his paludic blood the skin of 3 paretic patients. Because of this he was awarded with the nobel prize. Since 1922 bismuth was used, but then it was substituted by the sulphamidas of difficult application. The most important therapeutical advance happened in 1943, year in which penicillin was put in use by Mahoney and col. Later it was confirmed the efficiency of the tetracycline for the penicillin-allergic patients. Lately it has been confirmed the efficiency of the azithromizine in 500 mg dosis each day during 10 days or the regimen of 500 mg in alternate days.

A biological question and a balanced (orthogonal) design: the ingredients to efficiently analyze two-color microarrays with Confirmatory Factor Analysis.

BACKGROUND: Factor analysis (FA) has been widely applied in microarray studies as a data-reduction-tool without any a-priori assumption regarding associations between observed data and latent structure (Exploratory Factor Analysis).A disadvantage is that the representation of data in a reduced set of dimensions can be difficult to interpret, as biological contrasts do not necessarily coincide with single dimensions. However, FA can also be applied as an instrument to confirm what is expected on the basis of pre-established hypotheses (Confirmatory Factor Analysis, CFA). We show that with a hypothesis incorporated in a balanced (orthogonal) design, including 'SelfSelf' hybridizations, dye swaps and independent replications, FA can be used to identify the latent factors underlying the correlation structure among the observed two-color microarray data. An orthogonal design will reflect the principal components associated with each experimental factor. We applied CFA to a microarray study performed to investigate cisplatin resistance in four ovarian cancer cell lines, which only differ in their degree of cisplatin resistance. RESULTS: Two latent factors, coinciding with principal components, representing the differences in cisplatin resistance between the four ovarian cancer cell lines were easily identified. From these two factors 315 genes associated with cisplatin resistance were selected, 199 genes from the first factor (False Discovery Rate (FDR): 19%) and 152 (FDR: 24%) from the second factor, while both gene sets shared 36. The differential expression of 16 genes was validated with reverse transcription-polymerase chain reaction. CONCLUSION: Our results show that FA is an efficient method to analyze two-color microarray data provided that there is a pre-defined hypothesis reflected in an orthogonal design.

Assessing the measurement precision of various arsenic forms and arsenic exposure in the National Human Exposure Assessment Survey (NHEXAS).

Archived samples collected from 1995 to 1997 in the National Human Exposure Assessment Survey (NHEXAS) in U.S. Environmental Protection Agency Region 5 (R5) and the Children's Study (CS) in Minnesota were analyzed for total arsenic, arsenate [As(V)], arsenite, dimethyl arsenic acid (DMA), monomethyl arsenic acid (MMA), arsenobetaine (AsB), and arsenocholine. Samples for the CS included drinking water, urine, hair, and dust; both studies included food (duplicate plate, composited 4-day food samples from participants). Except for AsB and As(V), the levels for As species measured in the food and drinking water samples were very low or nonexistent. The analytical methods used for measuring As species were sensitive to < 1 ppb. During the analysis of food and drinking water samples, chromatographic peaks appeared that contained As, but they did not correspond to those being quantified. Thus, in some samples, the sum of the individual As species levels was less than the total As level measured because the unknown forms of As were not quantified. On the other hand, total As was detectable in almost all samples (> 90%) except for hair (47%), indicating that the analytical method was sufficiently sensitive. Population distributions of As concentrations measured in drinking water, food (duplicate plate), dust, urine, and hair were estimated. Exposures to total As in food for children in the CS were about twice as high as in the general R5 population (medians of 17.5 ppb and 7.72 ppb, respectively). In addition, AsB was the most frequently detected form of As in food eaten by the participants, while As(V) was only rarely detected. Thus, the predominant dietary exposure was from an organic form of As. The major form of As in drinking water was As(V). Spearman (rank) correlations and Pearson (log-concentration scale) correlations between the biomarkers (urine, hair) and the other measures (food, drinking water, dust) and urine versus hair were performed. In the NHEXAS CS, total As and AsB in the food eaten were significantly correlated with their levels in urine. Also, levels of As(V) in drinking water correlated with DMA and MMA in urine. Arsenic levels in dust did not show a relationship with urine or hair levels, and no relationship was observed for food, drinking water, and dust with hair. Urine samples were collected on days 3, 5, and 7 of participants' monitoring periods. Total As levels in urine were significantly associated across the three pairwise combinations--i.e., day 3 versus day 5, day 3 versus day 7, and day 5 versus day 7. Because the half-life of As in the body is approximately 3 days, this suggests that some exposure occurred continually from day to day. This trend was also observed for AsB, suggesting that food is primarily responsible for the continual exposure. DMA and MMA in urine were also significantly correlated but not in all combinations.

Cost/variance optimization for human exposure assessment studies.

The National Human Exposure Assessment Survey (NHEXAS) field study in EPA Region V (one of three NHEXAS field studies) provides extensive exposure data on a representative sample of 249 residents of the Great Lakes states. Concentration data were obtained for both metals and volatile organic compounds (VOCs) from multiple environmental media and from human biomarkers. A variance model for the logarithms of concentration measurements is used to define intraclass correlations between observations within primary sampling units (PSUs) (nominally counties) and within secondary sampling units (SSUs) (nominally Census blocks). A model for the total cost of the study is developed in terms of fixed costs and variable costs per PSU, SSU, and participant. Intraclass correlations are estimated for media and analytes with sufficient sample sizes. We demonstrate how the intraclass correlations and variable cost components can be used to determine the sample allocation that minimizes cost while achieving pre-specified precision constraints for future studies that monitor environmental concentrations and human exposures for metals and VOCs.

Use of pharmacokinetic modeling to design studies for pathway-specific exposure model evaluation.

Validating an exposure pathway model is difficult because the biomarker, which is often used to evaluate the model prediction, is an integrated measure for exposures from all the exposure routes and pathways. The purpose of this article is to demonstrate a method to use pharmacokinetic (PK) modeling and computer simulation to guide the design of field studies to validate pathway models. The children's dietary intake model is discussed in detail as an example. Three important aspects are identified for a successful design to evaluate the children's dietary intake model: a) longitudinally designed study with significant changes in the exposure for the route/pathway of interest, b) short biologic half-life of the selected chemical, and c) surface loading of the selected chemical at sufficient levels. Using PK modeling to guide a study design allowed a path-specific exposure model to be evaluated using urinary metabolite biomarkers.

Personal, indoor, and outdoor VOC exposures in a probability sample of children.

As part of the Minnesota Children's Pesticide Exposure Study we measured volatile organic compound (VOC) concentrations in a probability sample of households with children. The 6-day average concentrations for 10 common VOCs were obtained in urban and nonurban residences twice during this multiphase study: screening-phase indoor measurements were collected in 284 households, and in the intensive-phase matched outdoor (O), indoor (I), and personal (P) measurements were collected in a subset (N=72) of the screened households. Screening-phase households with smokers had significantly higher concentrations of benzene and styrene compared to nonsmoking households; households with an attached garage had significantly higher levels of benzene, chloroform, styrene, and m/p- and o-xylene compared to households without an attached garage; and nonurban residences, which had a greater prevalence of smokers and attached garages, had significantly higher 1,1,1-trichloroethane, styrene, and toluene and significantly lower tetrachloroethylene concentrations compared to urban households. The screening-phase weighted distributions estimate the mean and variability in indoor VOC concentrations for more than 45,000 households with children in the census tracts sampled. Overall, median indoor concentrations of most VOCs measured in this study were similar to or lower than indoor levels measured previously in the United States. Intensive-phase outdoor VOC concentrations were generally lower than other major metropolitan areas, but urban concentrations were significantly higher than nonurban concentrations for all compounds except 1,1,1-trichloroethylene. A consistent pattern of P>I>O was observed for nine of 10 VOCs, with 1,1,1-trichloroethylene (I>P>O) being the only exception to this pattern. For most children, the indoor at-home microevironment was strongly associated with personal exposure after controlling for important covariates, but the ratio of median to upper bound exposures was smaller than that observed in studies of adults. There are relatively little data on VOC exposures in children, so these results are useful for estimating the central tendency and distribution of VOC exposures in locations where children spend a majority of their time.

Assessment of data quality for the NHEXAS--Part II: Minnesota children's pesticide exposure study (MNCPES).

The Minnesota Children's Pesticide Exposure Study (MNCPES) of the National Human Exposure Assessment Survey (NHEXAS) was conducted in Minnesota to evaluate children's pesticide exposure. This study complements and extends the populations and chemicals included in the NHEXAS Region V study. One of the goals of the study was to test protocols for acquiring exposure measurements and developing databases for use in exposure models and assessments. Analysis of the data quality is one element in assessing the performance of the collection and analysis protocols used in this study. Data quality information must also be available to investigators to guide analysis of the study data. During the planning phase of MNCPES, quality assurance (QA) goals were established for precision, accuracy, and quantification limits. The data quality was assessed against these goals. The assessment is complex. First, data are not available for all analytes and media sampled. In addition, several laboratories were responsible for the analysis of the collected samples. Each laboratory provided data according to their standard operating procedures (SOPs) and protocols. Detection limits were authenticated for each analyte in each sample type. The approach used to calculate detection limits varied across the different analytical methods. The analytical methods for pesticides in air, food, hand rinses, dust wipe and urine were sufficiently sensitive and met the QA goals, with very few exceptions. This was also true for polynuclear aromatic hydrocarbons (PAHs) in air and food. The analytical methods for drinking water and beverages had very low detection limits; however, there were very little measurable data for these samples. The collection and analysis methods for pesticides in surface press samples and soil, and for PAHs in dust wipes were not sufficiently sensitive. Accuracy was assessed primarily as recovery from field controls. The results were good for pesticides and PAHs in air (75-125% recovery). Recovery was lower (<75%) for pesticides in drinking water and beverages. The recovery of pesticides from hand rinses met QA goals (75-100%), but surface press samples showed lower recovery (50-70%). Analysis by gas chromatography-mass spectrometry (GC-MS) did not confirm the presence of atrazine and other pesticides in hand rinse and surface press samples that had been detected by GC-ECD, but instead GC-MS confirmed background interferences. Assessment of the precision of sample collection and analysis is based on the percent relative standard deviation (%RSD) between the results for duplicate samples. Data are available only for pesticides and PAHs in air. Precision was good (<20% RSD) for analytes with measurable data. There were a few analytes with %RSD >20%, but the number of data pairs was very small in these cases. Precision for instrumental analysis of food sample extracts was excellent, with the median %RSD < 20 for all measurable pesticides. The median %RSD for the analysis of replicate aliquots of food from the same sample composite was considerably higher, indicating the potential for inhomogeneity of food homogenates.