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.

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.

Brain organochlorines and Lewy pathology: the Honolulu-Asia Aging Study.

Although organochlorines have been reported more frequently in Parkinson's disease (PD) brains than in controls, the association with brain Lewy pathology is unknown. Honolulu-Asia Aging Study (HAAS) participants, exposed to organochlorines from a variety of sources during midlife, represent a population well suited to determining the relationship of brain organochlorines with Lewy pathology in decedents from the longitudinal HAAS. The study design included the measurement of 21 organochlorine levels in frozen occipital lobe samples from HAAS decedents. Alpha-synuclein immunostaining performed on 225 brains was used to identify Lewy bodies and Lewy neurites. With the potential for spurious associations to appear between Lewy pathology and 17 organochlorine compounds found in at least 1 brain, initial assessments identified heptachlor epoxide isomer b, methoxychlor, and benzene hexachloride b as being most important. The prevalence of Lewy pathology was 75% (6 of 8) among brains with any 2 of the 3 compounds, 48.8% (79 of 162) among those with 1, and 32.7% (18 of 55) for those with neither (P = .007 test for trend). Although findings persisted after removing cases with PD and dementia with Lewy bodies and after adjustment for age at death, body mass index, pack-years of cigarette smoking, and coffee intake (P = .013), the results were insignificant when correcting for multiple testing. Although consistent with earlier accounts of an association between organochlorines and clinical PD, associations with Lewy pathology warrant further study.

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).

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.

A correlation study of organochlorine levels in serum, breast adipose tissue, and gluteal adipose tissue among breast cancer cases in India.

We used data from a breast cancer pilot study carried out in Kerala, India in 1997, for which organochlorine levels were measured in three biological media, blood serum, breast adipose tissue, and gluteal adipose tissue, of 37 fasting breast cancer cases (pretreatment). Our objective was to investigate the relationships between organochlorine concentrations in different biological media. Gas-liquid chromatography determined serum, breast adipose, and gluteal adipose tissue levels of dichlorodiphenyltricholorethane, dichlorodiphenyldichloroethane, beta-benzene hexachloride, and polychlorinated biphenyl (PCB) congeners, PCB-153 and PCB-180. Correlation plots were made and Spearman correlation coefficients (r) calculated for breast adipose tissue versus serum, gluteal adipose tissue versus serum, and breast adipose versus gluteal adipose tissue. We also examined paired ratios of all summary statistics. There were strong correlations among serum, breast adipose tissue, and gluteal adipose tissue concentrations for most organochlorines analyzed, one exception being gluteal versus serum for PCB-153. The correlations for all other comparisons ranged from r = 0.65 to 0.94. Serum (ng/g) versus adipose ratios approached 1:1 for most of the organochlorine pesticide comparisons and did not vary by summary statistic. To our knowledge, this is the first study to use three different media from fasting subjects and to comprehensively investigate the relationship between organochlorines measured across the three media for both organochlorine pesticides and PCBs. These data indicate that blood serum reflects the present body burden of a range of organochlorines to the same extent as adipose tissue, and they support the view that serum may be collected in lieu of adipose tissue to obtain similar information. However, such measurements are a combination of both recent exposures and past exposures, which have metabolized slowly and may still persist. Therefore, investigators should use caution when assigning a level as lifetime body burden.

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.

Hair mercury levels in U.S. children and women of childbearing age: reference range data from NHANES 1999-2000.

Exposure to methyl mercury, a risk factor for neurodevelopmental toxicity, was assessed in U.S. children 1-5 years of age (n = 838) and women 16-49 years of age (n = 1,726) using hair mercury analysis during the 1999-2000 National Health and Nutrition Examination Survey (NHANES). The data are nationally representative and are based on analysis of cross-sectional data for the noninstitutionalized, U.S. household population. The survey consisted of interviews conducted in participants' homes and standardized health examinations conducted in mobile examination centers. Distributions of total hair mercury levels expressed as micrograms per gram hair Hg and the association of hair Hg levels with sociodemographic characteristics and fish consumption are reported. Geometric mean (standard error of the geometric mean) hair mercury was 0.12 microg/g (0.01 microg/g) in children, and 0.20 microg/g (0.02 microg/g) in women. Among frequent fish consumers, geometric mean hair mercury levels were 3-fold higher for women (0.38 vs. 0.11 micro g/g) and 2-fold higher for children (0.16 vs. 0.08 microg/g) compared with nonconsumers. The NHANES 1999-2000 data provide population-based data on hair mercury concentrations for women and children in the United States. Hair mercury levels were associated with age and fish consumption frequency.

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.

Respiratory symptoms and peak expiratory flow in children with asthma in relation to volatile organic compounds in exhaled breath and ambient air.

Indoor volatile organic compounds (VOCs) have been associated with asthma, but there is little epidemiologic work on ambient exposures, and no data on relationships between respiratory health and exhaled breath VOCs, which is a biomarker of VOC exposure. We recruited 26 Hispanic children with mild asthma in a Los Angeles community with high VOC levels near major freeways and trucking routes. Two dropped out, three had invalid peak expiratory flow (PEF) or breath VOC data, leaving 21. Children filled out symptom diaries and performed PEF maneuvers daily, November 1999-January 2000. We aimed to collect breath VOC samples on asthma episode and baseline symptom-free days, but six subjects only gave samples on symptom-free days. We analyzed 106 breath samples by GC-MS. Eight VOCs were quantifiable in >75% of breath samples (benzene, methylene chloride, styrene, tetrachloroethylene, toluene, m,p-xylene, o-xylene, and p-dichlorobenzene). Generalized estimating equation and mixed linear regression models for VOC exposure-response relationships controlled for temperature and respiratory infections. We found marginally positive associations between bothersome or more severe asthma symptoms and same day breath concentrations of benzene [odds ratio (OR) 2.03, 95% confidence interval (CI) 0.80, 5.11] but not other breath VOCs. Ambient petroleum-related VOCs measured on the same person-days as breath VOCs showed notably stronger associations with symptoms, including toluene, m,p-xylene, o-xylene, and benzene (OR 5.93, 95% CI 1.64, 21.4). On breath sample days, symptoms were also associated with 1-h ambient NO(2), OR 8.13 (1.52, 43.4), and SO(2), OR 2.36 (1.16, 4.81). Consistent inverse relationships were found between evening PEF and the same ambient VOCs, NO(2), and SO(2). There were no associations with O(3). Given the high traffic density of the region, stronger associations for ambient than for breath VOCs suggest that ambient VOC measurements were better markers for daily exposure to combustion-related compounds thought to be causally related to acute asthma. Alternatively, the low sample size of symptom responses (15-21 responses per 108 breath samples) may have led to the nonsignificant results for breath VOCs.

Sample preparation, extraction efficiency, and determination of six arsenic species present in food composites.

Several sample preparation techniques were investigated to maximize the efficiency of arsenic species extraction from food composites. The optimized method includes lyophilization of food followed by prewashing with acetone and extraction by sonication with 50/50 methanol/water. Six arsenic species were separated and quantitated using an ammonium carbonate buffer system by ion exchange chromatography coupled to inductively coupled plasma mass spectrometry. The performance of the method for speciated arsenic components was evaluated using a matrix containing high fat food composite fortified with arsenic species. A certified reference material, dogfish muscle, was used to evaluate extraction methods for total arsenic content in food composites. More than 200 food composite samples were analyzed during an 18 month period, demonstrating the reliability of the analytical method over a long time period.