The Implications of Using a Physiologically Based Pharmacokinetic (PBPK) Model for Pesticide Risk Assessment

Background

A physiologically based pharmacokinetic (PBPK) model would make it possible to simulate the dynamics of chemical absorption, distribution, metabolism, and elimination (ADME) from different routes of exposures and, in theory, could be used to evaluate associations between exposures and biomarker measurements in blood or urine.

Objective

We used a PBPK model to predict urinary excretion of 3,5,6-trichloro-2-pyridinol (TCPY), the specific metabolite of chlorpyrifos (CPF), in young children.

Methods

We developed a child-specific PBPK model for CPF using PBPK models previously developed for rats and adult humans. Data used in the model simulation were collected from 13 children 3–6 years of age who participated in a cross-sectional pesticide exposure assessment study with repeated environmental and biological sampling.

Results

The model-predicted urinary TCPY excretion estimates were consistent with measured levels for 2 children with two 24-hr duplicate food samples that contained 350 and 12 ng/g of CPF, respectively. However, we found that the majority of model outputs underpredicted the measured urinary TCPY excretion.

Conclusions

We concluded that the potential measurement errors associated with the aggregate exposure measurements will probably limit the applicability of PBPK model estimates for interpreting urinary TCPY excretion and absorbed CPF dose from multiple sources of exposure. However, recent changes in organophosphorus (OP) use have shifted exposures from multipathways to dietary ingestion only. Thus, we concluded that the PBPK model is still a valuable tool for converting dietary pesticide exposures to absorbed dose estimates when the model input data are accurate estimates of dietary pesticide exposures.     

Variability and predictors of urinary bisphenol A concentrations during pregnancy

Background

Prenatal bisphenol A (BPA) exposure may be associated with developmental toxicity, but few studies have examined the variability and predictors of urinary BPA concentrations during pregnancy.

Objective

Our goal was to estimate the variability and predictors of serial urinary BPA concentrations taken during pregnancy.

Methods

We measured BPA concentrations during pregnancy and at birth in three spot urine samples from 389 women. We calculated the intraclass correlation coefficient (ICC) to assess BPA variability and estimated associations between log₁₀-transformed urinary BPA concentrations and demographic, occupational, dietary, and environmental factors, using mixed models.

Results

Geometric mean (GM) creatinine-standardized concentrations (micrograms per gram) were 1.7 (16 weeks), 2.0 (26 weeks), and 2.0 (birth). Creatinine-standardized BPA concentrations exhibited low reproducibility (ICC = 0.11). By occupation, cashiers had the highest BPA concentrations (GM: 2.8 μg/g). Consuming canned vegetables at least once a day was associated with higher BPA concentrations (GM = 2.3 μg/g) compared with those consuming no canned vegetables (GM = 1.6 μg/g). BPA concentrations did not vary by consumption of fresh fruits and vegetables, canned fruit, or store-bought fresh and frozen fish. Urinary high-molecular-weight phthalate and serum tobacco smoke metabolite concentrations were positively associated with BPA concentrations.

Conclusions

These results suggest numerous sources of BPA exposure during pregnancy. Etiological studies may need to measure urinary BPA concentrations more than once during pregnancy and adjust for phthalates and tobacco smoke exposures.     

Low-level lead exposure and elevations in blood pressure during pregnancy

Background

Lead exposure is associated with elevated blood pressure during pregnancy; however, the magnitude of this relationship at low exposure levels is unclear.

Objectives

Our goal was to determine the association between low-level lead exposure and blood pressure during late pregnancy.

Methods

We collected admission and maximum (based on systolic) blood pressures during labor and delivery among 285 women in Baltimore, Maryland. We measured umbilical cord blood lead using inductively coupled plasma mass spectrometry. Multivariable models were adjusted for age, race, median household income, parity, smoking during pregnancy, prepregnancy body mass index, and anemia. These models were used to calculate benchmark dose values.

Results

Geometric mean cord blood lead was 0.66 μg/dL (95% confidence interval, 0.61–0.70). Comparing blood pressure measurements between those in the highest and those in the lowest quartile of lead exposure, we observed a 6.87-mmHg (1.51–12.21 mmHg) increase in admission systolic blood pressure and a 4.40-mmHg (0.21–8.59 mmHg) increase in admission diastolic blood pressure after adjustment for confounders. Corresponding values for maximum blood pressure increase were 7.72 (1.83–13.60) and 8.33 (1.14–15.53) mmHg. Benchmark dose lower limit values for a 1-SD increase in blood pressure were < 2 μg/dL blood lead for all blood pressure end points.

Conclusions

A significant association between low-level lead exposures and elevations in maternal blood pressure during labor and delivery can be observed at umbilical blood lead levels < 2 μg/dL.     

Serum Cholinesterase Inhibition in Relation to Paraoxonase-1 (PON1) Status among Organophosphate-Exposed Agricultural Pesticide Handlers

Background

Animal studies have demonstrated that low paraoxonase-1 (PON1) status (i.e., low catalytic efficiency and/or low plasma PON1 activity) is associated with neurotoxic effects after exposure to several organophosphate (OP) insecticides. However, few human studies have investigated associations between PON1 status and intermediate end points, such as serum cholinesterase [butyrylcholinesterase (BuChE)] inhibition, among OP-exposed individuals.

Objectives

We evaluated the relation between plasma PON1 status and BuChE inhibition among OP-exposed agricultural pesticide handlers.

Methods

Agricultural pesticide handlers in Washington State were recruited during the 2006 and 2007 spray seasons when they were seen for follow-up ChE testing by collaborating medical providers as part of a statewide monitoring program. Blood samples were collected from 163 participants and tested for PON1 status based on plasma PON1 activity [arylesterase (AREase)] and PON1 Q192R genotype. We evaluated percent change in BuChE activity from baseline level in relation to PON1 status.

Results

We observed significantly greater BuChE inhibition among QQ homozygotes relative to RR homozygotes (p = 0.036). Lower levels of plasma PON1 activity were significantly associated with greater BuChE inhibition (p = 0.004). These associations remained after adjustment for year, days since baseline test, age, and OP exposure in the last 30 days.

Conclusions

We found that both low PON1 catalytic efficiency (i.e., the Q192 alloform) and low plasma PON1 activity were associated with BuChE inhibition among OP-exposed agricultural pesticide handlers. Corroborative findings from future studies with prospective collection of blood samples for PON1 testing, more sensitive markers of OP-related effects, and larger sample sizes are needed.     

Silver Impairs Neurodevelopment: Studies in PC12 Cells

Background

Exposure to silver is increasing because of silver nanoparticles in consumer products.

Objectives and methods

Many biological effects of silver entail actions of Ag⁺ (monovalent silver ions), so we used neuronotypic PC12 cells to evaluate the potential for silver to act as a developmental neurotoxicant, using chlorpyrifos (CPF), a pesticide known to evoke developmental neurotoxicity, as a positive control for comparison.

Results

In undifferentiated cells, a 1-hr exposure to 10 μM Ag⁺ inhibited DNA synthesis more potently than did 50 μM CPF; it also impaired protein synthesis but to a lesser extent than its effect on DNA synthesis, indicating a preferential effect on cell replication. Longer exposures led to oxidative stress, loss of viability, and reduced numbers of cells. With the onset of cell differentiation, exposure to 10 μM Ag⁺ evoked even greater inhibition of DNA synthesis and more oxidative stress, selectively impaired neurite formation without suppressing overall cell growth, and preferentially suppressed development into the acetylcholine phenotype in favor of the dopamine phenotype. Lowering the exposure to 1 μM Ag⁺ reduced the net effect on undifferentiated cells. However, in differentiating cells, the lower concentration produced an entirely different pattern, enhancing cell numbers by suppressing ongoing cell death and impairing differentiation in parallel for both neurotransmitter phenotypes.

Conclusions

Our results show that silver has the potential to evoke developmental neurotoxicity even more potently than known neurotoxicants, such as CPF, and that the spectrum of effects is likely to be substantially different at lower exposures that do not show signs of outright toxicity.     

Population-based inorganic mercury biomonitoring and the identification of skin care products as a source of exposure in New York City

Background

Mercury is a toxic metal that has been used for centuries as a constituent of medicines and other items.

Objective

We assessed exposure to inorganic mercury in the adult population of New York City (NYC).

Methods

We measured mercury concentrations in spot urine specimens from a representative sample of 1,840 adult New Yorkers in the 2004 NYC Health and Nutrition Examination Survey. Cases with urine concentrations ≥ 20 μg/L were followed up with a telephone or in-person interview that asked about potential sources of exposure, including ritualistic/cultural practices, skin care products, mercury spills, herbal medicine products, and fish.

Results

Geometric mean urine mercury concentration in NYC was higher for Caribbean-born blacks [1.39 μg/L; 95% confidence interval (CI), 1.14–1.70] and Dominicans (1.04 μg/L; 95% CI, 0.82–1.33) than for non-Hispanic whites (0.67 μg/L; 95% CI, 0.60–0.75) or other racial/ethnic groups. It was also higher among those who reported at least 20 fish meals in the past 30 days (1.02 μg/L; 95% CI, 0.83–1.25) than among those who reported no fish meals (0.50 μg/L; 95% CI, 0.41–0.61). We observed the highest 95th percentile of exposure (21.18 μg/L; 95% CI, 7.25–51.29) among Dominican women. Mercury-containing skin-lightening creams were a source of exposure among those most highly exposed, and we subsequently identified 12 imported products containing illegal levels of mercury in NYC stores.

Conclusion

Population-based biomonitoring identified a previously unrecognized source of exposure to inorganic mercury among NYC residents. In response, the NYC Health Department embargoed products and notified store owners and the public that skin-lightening creams and other skin care products that contain mercury are dangerous and illegal. Although exposure to inorganic mercury is not a widespread problem in NYC, users of these products may be at risk of health effects from exposure.     

Intellectual function in Mexican children living in a mining area and environmentally exposed to manganese

Background

Excessive exposure to manganese (Mn), an essential trace element, has been shown to be neurotoxic, especially when inhaled. Few studies have examined potential effects of Mn on cognitive functions of environmentally exposed children.

Objective

This study was intended to estimate environmental exposure to Mn resulting from mining and processing and to explore its association with intellectual function of school-age children.

Methods

Children between 7 and 11 years of age from the Molango mining district in central Mexico (n = 79) and communities with similar socioeconomic conditions that were outside the mining district (n = 93) participated in the cross-sectional evaluation. The revised version of the Wechsler Intelligence Scale for Children adapted for the Mexican population was applied. Concentrations of Mn in blood (MnB) and hair (MnH) were used as biomarkers of exposure.

Results

Exposed children had significantly higher median values for MnH (12.6 μg/g) and MnB (9.5 μg/L) than did nonexposed children (0.6 μg/g and 8.0 μg/L, respectively). MnH was inversely associated with Verbal IQ [β = −0.29; 95% confidence interval (CI), −0.51 to −0.08], Performance IQ (β = −0.08; 95% CI, −0.32 to 0.16), and Total Scale IQ (β = −0.20; 95% CI, −0.42 to 0.02). MnB was inversely but nonsignificantly associated with Total and Verbal IQ score. Age and sex significantly modified associations of MnH, with the strongest inverse associations in young girls and little evidence of associations in boys at any age. Associations with MnB did not appear to be modified by sex but appeared to be limited to younger study participants.

Conclusions

The findings from this study suggest that airborne Mn environmental exposure is inversely associated with intellectual function in young school-age children.     

Case-control study of blood lead levels and attention deficit hyperactivity disorder in Chinese children

Background

Attention deficit/hyperactivity disorder (ADHD) and lead exposure are high-prevalence conditions among children.

Objective

Our goal was to investigate the association between ADHD and blood lead levels (BLLs) in Chinese children, adjusting for known ADHD risk factors and potential confounding variables.

Methods

We conducted a pair-matching case–control study with 630 ADHD cases and 630 non-ADHD controls 4–12 years of age, matched on the same age, sex, and socioeconomic status. The case and control children were systematically evaluated via structured diagnostic interviews, including caregiver interviews, based on the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., revised criteria (DSM-IV-R). We evaluated the association between BLLs and ADHD using the Pearson chi-square test for categorical variables and the Student t-test for continuous data. We then performed conditional multiple variables logistic regression analyses with backward stepwise selection to predict risk factors for ADHD.

Results

There was a significant difference in BLLs between ADHD cases and controls. ADHD cases were more likely to have been exposed to lead during childhood than the non-ADHD control subjects, with adjustment for other known risk factors [children with BLLs ≥ 10 μg/dL vs. ≤ 5 μg/dL; OR = 6.0; 95% confidence interval (CI) = 4.10–8.77, p < 0.01; 5–10 μg/dL vs.≤ 5 μg/dL, OR = 4.9; 95% CI = 3.47–6.98, p < 0.01]. These results were not modified by age and sex variables.

Conclusions

This was the largest sample size case–control study to date to study the association between BLLs and ADHD in Chinese children. ADHD may be an additional deleterious outcome of lead exposure during childhood, even when BLLs are < 10 μg/dL.     

Urinary cadmium and osteoporosis in U.S. Women >or= 50 years of age: NHANES 1988-1994 and 1999-2004

Background

Urinary cadmium (U-Cd) has been associated with decreased peripheral bone mineral density (BMD) and osteoporosis. This association, however, has not been confirmed using femoral BMD, the international standard for diagnosing osteoporosis, at levels < 1.0 μg Cd/g creatinine.

Objectives

Our goal was to investigate the statistical association between U-Cd, at levels ≤ 1 μg/g creatinine, and osteoporosis, as indicated by hip BMD and self-report in a population-based sample of U.S. women ≥ 50 years of age.

Methods

We drew data from the National Health and Nutrition Examination Surveys for 1988–1994 (n = 3,207) and 1999–2004 (n = 1,051). Osteoporosis was indicated by hip BMD cutoffs based on the international standard and self-report of physician diagnosis. We analyzed U-Cd levels for association with osteoporosis using multiple logistic regression.

Results

Women ≥ 50 years of age with U-Cd levels between 0.50 and 1.00 μg/g creatinine were at 43% greater risk for hip-BMD–defined osteoporosis, relative to those with levels ≤ 0.50 μg/g (odds ratio = 1.43; 95% confidence interval, 1.02–2.00; p = 0.04). We observed similar effect estimates using self-report of physician-diagnosed osteoporosis. Smokers did not show a statistically increased risk.

Conclusions

Results suggest that U.S. women are at risk for osteoporosis at U-Cd levels below the U.S. Occupational Safety and Health Administration’s 3-μg/g safety standard. Given null findings among smokers, dietary Cd, rather than tobacco, is the likely source of Cd-related osteoporosis risk for the U.S. female population ≥ 50 years of age.     

Lithium in drinking water and thyroid function

Background

High concentrations of lithium in drinking water were previously discovered in the Argentinean Andes Mountains. Lithium is used worldwide for treatment of bipolar disorder and treatment-resistant depression. One known side effect is altered thyroid function.

Objectives

We assessed associations between exposure to lithium from drinking water and other environmental sources and thyroid function.

Methods

Women (n = 202) were recruited in four Andean villages in northern Argentina. Lithium exposure was assessed based on concentrations in spot urine samples, measured by inductively coupled plasma mass spectrometry. Thyroid function was evaluated by plasma free thyroxine (T₄) and pituitary gland thyroid-stimulating hormone (TSH), analyzed by routine immunometric methods.

Results

The median urinary lithium concentration was 3,910 μg/L (5th, 95th percentiles, 270 μg/L, 10,400 μg/L). Median plasma concentrations (5th, 95th percentiles) of T₄ and TSH were 17 pmol/L (13 pmol/L, 21 pmol/L) and 1.9 mIU/L, (0.68 mIU/L, 4.9 mIU/L), respectively. Urine lithium was inversely associated with T₄ [β for a 1,000-μg/L increase = −0.19; 95% confidence interval (CI), −0.31 to −0.068; p = 0.002] and positively associated with TSH (β = 0.096; 95% CI, 0.033 to 0.16; p = 0.003). Both associations persisted after adjustment (for T₄, β = −0.17; 95% CI, −0.32 to −0.015; p = 0.032; for TSH: β = 0.089; 95% CI, 0.024 to 0.15; p = 0.007). Urine selenium was positively associated with T₄ (adjusted T₄ for a 1 μg/L increase: β = 0.041; 95% CI, 0.012 to 0.071; p = 0.006).

Conclusions

Exposure to lithium via drinking water and other environmental sources may affect thyroid function, consistent with known side effects of medical treatment with lithium. This stresses the need to screen for lithium in all drinking water sources.     

Private drinking water wells as a source of exposure to perfluorooctanoic acid (PFOA) in communities surrounding a fluoropolymer production facility

Background

The C8 Health Project was established in 2005 to collect data on perfluorooctanoic acid (PFOA, or C8) and human health in Ohio and West Virginia communities contaminated by a fluoropolymer production facility.

Objective

We assessed PFOA exposure via contaminated drinking water in a subset of C8 Health Project participants who drank water from private wells.

Methods

Participants provided demographic information and residential, occupational, and medical histories. Laboratory analyses were conducted to determine serum-PFOA concentrations. PFOA data were collected from 2001 through 2005 from 62 private drinking water wells. We examined the relationship between drinking water and PFOA levels in serum using robust regression methods. As a comparison with regression models, we used a first-order, single-compartment pharmacokinetic model to estimate the serum:drinking-water concentration ratio at steady state.

Results

The median serum PFOA concentration in 108 study participants who used private wells was 75.7 μg/L, approximately 20 times greater than the levels in the U.S. general population but similar to those of local residents who drank public water. Each 1 μg/L increase in PFOA levels in drinking water was associated with an increase in serum concentrations of 141.5 μg/L (95% confidence interval, 134.9–148.1). The serum:drinking-water concentration ratio for the steady-state pharmacokinetic model was 114.

Conclusions

PFOA-contaminated drinking water is a significant contributor to PFOA levels in serum in the study population. Regression methods and pharmacokinetic modeling produced similar estimates of the relationship.     

Associations of plasma selenium with arsenic and genomic methylation of leukocyte DNA in Bangladesh

Background

Global hypomethylation of DNA is thought to constitute an early event in some cancers and occurs in response to arsenic (As) exposure and/or selenium (Se) deficiency in both in vitro and animal models. In addition, antagonism between As and Se, whereby each reduces toxicity of the other, has been well documented in animal models. Se status may therefore modify the health effects of As in As-exposed populations.

Objective

The primary objectives of our study were to test the hypothesis that Se deficiency is associated with genomic hypomethylation of lymphocyte DNA and to determine whether Se levels are associated with blood As (bAs) and urinary As (uAs) concentrations in adults exposed to As-contaminated groundwater in Bangladesh. A secondary objective was to explore the relationships between plasma Se and As metabolites.

Design

We assessed plasma Se concentrations, As metabolite profiles in blood and urine, and genomic methylation of leukocyte DNA in a cross-sectional study of 287 adults.

Results

After adjustment for potential confounders, we observed an inverse association between Se (micrograms per liter) and genomic DNA methylation (disintegrations per minute per 1-μg/L increase in Se): β = 345.6; 95% confidence interval (CI), 59–632. Se concentrations were inversely associated with total As concentrations (micrograms per liter) in blood (β = −0.04; 95% CI, −0.08 to −0.01) and urine (β = −20.1; 95% CI, −29.3 to −10.9). Se levels were negatively associated with the percentage of monomethylarsinic acid (β = −0.59; 95% CI, −1.04 to −0.13) and positively associated with the percentage of dimethylarsinic acid (β = 0.53; 95% CI, 0.04 to 1.01) in blood.

Conclusions

Our results suggest that Se is inversely associated with genomic DNA methylation. The underlying mechanisms and implications of this observation are unclear and warrant further investigation. In addition, Se may influence bAs and uAs concentrations, as well as relative proportions of As metabolites in blood.     

Electrocardiographic ST-segment depression and exposure to traffic-related aerosols in elderly subjects with coronary artery disease

Background

Air pollutants have not been associated with ambulatory electrocardiographic evidence of ST-segment depression ≥ 1 mm (probable cardiac ischemia). We previously found that markers of primary (combustion-related) organic aerosols and gases were positively associated with circulating biomarkers of inflammation and ambulatory blood pressure in the present cohort panel study of elderly subjects with coronary artery disease.

Objectives

We specifically aimed to evaluate whether exposure markers of primary organic aerosols and ultrafine particles were more strongly associated with ST-segment depression of ≥ 1 mm than were secondary organic aerosols or PM_2.5 (particulate matter with aerodynamic diameter ≤ 2.5 μm) mass.

Methods

We evaluated relations of air pollutants to ambulatory electrocardiographic evidence of cardiac ischemia over 10 days in 38 subjects without ST depression on baseline electrocardiographs. Exposures were measured outdoors in retirement communities in the Los Angeles basin, including daily size-fractionated particle mass and hourly markers of primary and secondary organic aerosols and gases. Generalized estimating equations were used to estimate odds of hourly ST-segment depression (≥ 1 mm) from hourly air pollution exposures and to estimate relative rates of daily counts of ST-segment depression from daily average exposures, controlling for potential confounders.

Results

We found significant positive associations of hourly ST-segment depression with markers of combustion-related aerosols and gases averaged 1-hr through 3–4 days, but not secondary (photochemically aged) organic aerosols or ozone. The odds ratio per interquartile increase in 2-day average primary organic carbon (5.2 μg/m³) was 15.4 (95% confidence interval, 3.5–68.2). Daily counts of ST-segment depression were consistently associated with primary combustion markers and 2-day average quasi-ultrafine particles < 0.25 μm.

Conclusions

Results suggest that exposure to quasi-ultrafine particles and combustion-related pollutants (predominantly from traffic) increase the risk of myocardial ischemia, coherent with our previous findings for systemic inflammation and blood pressure.     

Arsenic exposure in pregnancy increases the risk of lower respiratory tract infection and diarrhea during infancy in Bangladesh

Background

Previous studies have reported associations between prenatal arsenic exposure and increased risk of infant mortality. An increase in infectious diseases has been proposed as the underlying cause of these associations, but there is no epidemiologic research to support the hypothesis.

Objective

We evaluated the association between arsenic exposure in pregnancy and morbidity during infancy.

Methods

This prospective population-based cohort study included 1,552 live-born infants of women enrolled during 2002–2004 in Matlab, Bangladesh. Arsenic exposure was assessed by the concentrations of metabolites of inorganic arsenic in maternal urine samples collected at gestational weeks 8 and 30. Information on symptoms of lower respiratory tract infection (LRTI) and diarrhea in infants was collected by 7-day recalls at monthly home visits.

Results

In total, 115,850 person-days of observation were contributed by the infants during a 12-month follow-up period. The estimated risk of LRTI and severe LRTI increased by 69% [adjusted relative risk (RR) = 1.69; 95% confidence interval (CI), 1.36–2.09)] and 54% (RR = 1.54; 95% CI, 1.21–1.97), respectively, for infants of mothers with urinary arsenic concentrations in the highest quintile (average of arsenic concentrations measured in early and late gestation, 262–977 μg/L) relative to those with exposure in the lowest quintile (< 39 μg/L). The corresponding figure for diarrhea was 20% (RR = 1.20; 95% CI, 1.01–1.43).

Conclusions

Arsenic exposure during pregnancy was associated with increased morbidity in infectious diseases during infancy. Taken together with the previous evidence of adverse effects on health, the findings strongly emphasize the need to reduce arsenic exposure via drinking water.     

Fish consumption and mercury exposure among Louisiana recreational anglers

Background

Methylmercury (MeHg) exposure assessments among average fish consumers in the United States may underestimate exposures among U.S. subpopulations with high intakes of regionally specific fish.

Objectives

We examined relationships among fish consumption, estimated mercury (Hg) intake, and measured Hg exposure within one such potentially highly exposed group, recreational anglers in the state of Louisiana, USA.

Methods

We surveyed 534 anglers in 2006 using interviews at boat launches and fishing tournaments combined with an Internet-based survey method. Hair samples from 402 of these anglers were collected and analyzed for total Hg. Questionnaires provided information on species-specific fish consumption during the 3 months before the survey.

Results

Anglers’ median hair Hg concentration was 0.81 μg/g (n = 398; range, 0.02–10.7 μg/g); 40% of participants had levels >1 μg/g, which approximately corresponds to the U.S. Environmental Protection Agency’s reference dose. Fish consumption and Hg intake were significantly positively associated with hair Hg. Participants reported consuming nearly 80 different fish types, many of which are specific to the region. Unlike the general U.S. population, which acquires most of its Hg from commercial seafood sources, approximately 64% of participants’ fish meals and 74% of their estimated Hg intake came from recreationally caught seafood.

Conclusions

Study participants had relatively elevated hair Hg concentrations and reported consumption of a wide variety of fish, particularly locally caught fish. This group represents a highly exposed subpopulation with an exposure profile that differs from fish consumers in other regions of the United States, suggesting a need for more regionally specific exposure estimates and public health advisories.     

Selecting Adequate Exposure Biomarkers of Diisononyl and Diisodecyl Phthalates: Data from the 2005–2006 National Health and Nutrition Examination Survey

Background

High-molecular-weight phthalates, such as diisononyl phthalate (DINP) and diisodecyl phthalate (DIDP), are used primarily as polyvinyl chloride plasticizers.

Objectives

We assessed exposure to DINP and DIDP in a representative sample of persons ≥ 6 years of age in the U.S. general population from the 2005–2006 National Health and Nutrition Examination Survey (NHANES).

Methods

We analyzed 2,548 urine samples by using online solid-phase extraction coupled to isotope dilution high-performance liquid chromatography–tandem mass spectrometry.

Results

We detected monocarboxyisooctyl phthalate (MCOP), a metabolite of DINP, and monocarboxyisononyl phthalate (MCNP), a metabolite of DIDP, in 95.2% and 89.9% of the samples, respectively. We detected monoisononyl phthalate (MNP), a minor metabolite of DINP, much less frequently (12.9%) and at concentration ranges (> 0.8 μg/L–148.1 μg/L) much lower than MCOP (> 0.7 μg/L– 4,961 μg/L). Adjusted geometric mean concentrations of MCOP and MCNP were significantly higher (p < 0.01) among children than among adolescents and adults.

Conclusions

The general U.S. population, including children, was exposed to DINP and DIDP. In previous NHANES cycles, the occurrence of human exposure to DINP by using MNP as the sole urinary biomarker has been underestimated, thus illustrating the importance of selecting the most adequate biomarkers for exposure assessment.     

Effects of Ambient Coarse,Fine, and Ultrafine Particles and Their Biological Constituents on Systemic Biomarkers: A Controlled Human Exposure Study

Background

Ambient coarse, fine, and ultrafine particles have been associated with mortality and morbidity. Few studies have compared how various particle size fractions affect systemic biomarkers.

Objectives

We examined changes of blood and urinary biomarkers following exposures to three particle sizes.

Methods

Fifty healthy nonsmoking volunteers, mean age of 28 years, were exposed to coarse (2.5–10 μm; mean, 213 μg/m³) and fine (0.15–2.5 μm; mean, 238 μg/m³) concentrated ambient particles (CAPs), and filtered ambient and/or medical air. Twenty-five participants were exposed to ultrafine CAP (< 0.3 μm; mean, 136 μg/m³) and filtered medical air. Exposures lasted 130 min, separated by ≥ 2 weeks. Blood/urine samples were collected preexposure and 1 hr and 21 hr postexposure to determine blood interleukin-6 and C-reactive protein (inflammation), endothelin-1 and vascular endothelial growth factor (VEGF; vascular mediators), and malondialdehyde (lipid peroxidation); as well as urinary VEGF, 8-hydroxy-deoxy-guanosine (DNA oxidation), and malondialdehyde. Mixed-model regressions assessed pre- and postexposure differences.

Results

One hour postexposure, for every 100-μg/m³ increase, coarse CAP was associated with increased blood VEGF (2.41 pg/mL; 95% CI: 0.41, 4.40) in models adjusted for O_3, fine CAP with increased urinary malondialdehyde in single- (0.31 nmol/mg creatinine; 95% CI: 0.02, 0.60) and two-pollutant models, and ultrafine CAP with increased urinary 8-hydroxydeoxyguanosine in single- (0.69 ng/mg creatinine; 95% CI: 0.09, 1.29) and two-pollutant models, lasting < 21 hr. Endotoxin was significantly associated with biomarker changes similar to those found with CAPs.

Conclusions

Ambient particles with various sizes/constituents may influence systemic biomarkers differently. Endotoxin in ambient particles may contribute to vascular mediator changes and oxidative stress.

Citation

Liu L, Urch B, Poon R, Szyszkowicz M, Speck M, Gold DR, Wheeler AJ, Scott JA, Brook JR, Thorne PS, Silverman FS. 2015. Effects of ambient coarse, fine, and ultrafine particles and their biological constituents on systemic biomarkers: a controlled human exposure study. Environ Health Perspect 123:534–540; http://dx.doi.org/10.1289/ehp.1408387     

Windblown Lead Carbonate as the Main Source of Lead in Blood of Children from a Seaside Community: An Example of Local Birds as “Canaries in the Mine”

Background

In late 2006, the seaside community in Esperance, Western Australia, was alerted to thousands of native bird species dying. The source of the lead was thought to derive from the handling of Pb carbonate concentrate from the Magellan mine through the port of Esperance, begun in July 2005. Concern was expressed for the impact of this process on the community.

Objective

This study was designed to evaluate the source of Pb in blood of a random sample of the community using Pb isotope ratios.

Methods

The cohort comprised 49 children (48 < 5 years of age) along with 18 adults (> 20 years of age) with a bias toward higher blood lead (PbB) values to facilitate source identification.

Results

Mean PbB level of the children was 7.5 μg/dL (range, 1.5–25.7 μg/dL; n = 49; geometric mean, 6.6 μg/dL), with four children whose PbB was > 12 μg/dL. The isotopic data for blood samples lay around two distinct arrays. The blood of all children analyzed for Pb isotopes contained a contribution of Pb from the Magellan mine, which for young children ranged from 27% up to 93% (mean, 64%; median, 71%). Subtraction of the ore component gave a mean background PbB of 2.3 μg/dL. Several children whose PbB was > 9 μg/dL and most of the older subjects have complex sources of Pb.

Conclusions

The death of the birds acted as a sentinel event; otherwise, the exposure of the community, arising from such a toxic form of Pb, could have been tragic. Isotopic data and mineralogic and particle size analyses indicate that, apart from the recognized pathway of Pb exposure by hand-to-mouth activity in children, the inhalation pathway could have been a significant contributor to PbB for some of the very young children and in some parents.     

Polycarbonate Bottle Use and Urinary Bisphenol A Concentrations

Background

Bisphenol A (BPA) is a high-production-volume chemical commonly used in the manufacture of polycarbonate plastic. Low-level concentrations of BPA in animals and possibly in humans may cause endocrine disruption. Whether ingestion of food or beverages from polycarbonate containers increases BPA concentrations in humans has not been studied.

Objectives

We examined the association between use of polycarbonate beverage containers and urinary BPA concentrations in humans.

Methods

We conducted a nonrandomized intervention of 77 Harvard College students to compare urinary BPA concentrations collected after a washout phase of 1 week to those taken after an intervention week during which most cold beverages were consumed from polycarbonate drinking bottles. Paired t-tests were used to assess the difference in urinary BPA concentrations before and after polycarbonate bottle use.

Results

The geometric mean urinary BPA concentration at the end of the washout phase was 1.2 μg/g creatinine, increasing to 2.0 μg/g creatinine after 1 week of polycarbonate bottle use. Urinary BPA concentrations increased by 69% after use of polycarbonate bottles (p < 0.0001). The association was stronger among participants who reported ≥ 90% compliance (77% increase; p < 0.0001) than among those reporting < 90% compliance (55% increase; p = 0.03), but this difference was not statistically significant (p = 0.54).

Conclusions

One week of polycarbonate bottle use increased urinary BPA concentrations by two-thirds. Regular consumption of cold beverages from polycarbonate bottles is associated with a substantial increase in urinary BPA concentrations irrespective of exposure to BPA from other sources.     

Ambient air pollution and birth weight in full-term infants in Atlanta, 1994-2004

Background

An emerging body of evidence suggests that ambient levels of air pollution during pregnancy are associated with fetal growth.

Objectives

We examined relationships between birth weight and temporal variation in ambient levels of carbon monoxide, nitrogen dioxide (NO₂), sulfur dioxide (SO₂), ozone, particulate matter ≤ 10 μm in diameter (PM₁₀), ≤ 2.5 μm (PM_2.5), 2.5 to 10 μm (PM_2.5–10), and PM_2.5 chemical component measurements for 406,627 full-term births occurring between 1994 and 2004 in five central counties of metropolitan Atlanta.

Methods

We assessed relationships between birth weight and pollutant concentrations during each infant’s first month of gestation and third trimester, as well as in each month of pregnancy using distributed lag models. We also conducted capture-area analyses limited to mothers residing within 4 miles (6.4 km) of each air quality monitoring station.

Results

In the five-county analysis, ambient levels of NO₂, SO₂, PM_2.5 elemental carbon, and PM_2.5 water-soluble metals during the third trimester were significantly associated with small reductions in birth weight (−4 to −16 g per interquartile range increase in pollutant concentrations). Third-trimester estimates were generally higher in Hispanic and non-Hispanic black infants relative to non-Hispanic white infants. Distributed lag models were also suggestive of associations between air pollutant concentrations in late pregnancy and reduced birth weight. The capture-area analyses provided little support for the associations observed in the five-county analysis.

Conclusions

Results provide some support for an effect of ambient air pollution in late pregnancy on birth weight in full-term infants.