Faculty Bibliography

Biomarkers of environmental metal exposure in children are important for elucidating exposure and health risk. While exposure biomarkers for As, Cd, and Pb are relatively well defined, there are not yet well-validated biomarkers of Mn exposure. Here, we measured hair Mn, Pb, Cd, and As levels in children from the Mid-Ohio Valley to determine within and between-subject predictors of hair metal levels. Occipital scalp hair was collected in 2009-2010 from 222 children aged 6-12 years (169 female, 53 male) participating in a study of chemical exposure and neurodevelopment in an industrial region of the Mid-Ohio Valley. Hair samples from females were divided into three two centimeter segments, while males provided a single segment. Hair was cleaned and processed in a trace metal clean laboratory, and analyzed for As, Cd, Mn, and Pb by magnetic sector inductively coupled plasma mass spectrometry. Hair Mn and Pb levels were comparable (median 0.11 and 0.15 µg/g, respectively) and were ~10-fold higher than hair Cd and As levels (0.007 and 0.018 µg/g, respectively). Hair metal levels were higher in males compared to females, and varied by ~100-1000-fold between all subjects, and substantially less (<40-70%) between segments within female subjects. Hair Mn, Pb, and Cd, but not As levels systematically increased by ~40-70% from the proximal to distal hair segments of females. There was a significant effect of season of hair sample collection on hair Mn, Pb, and Cd, but not As levels. Finally, hair metal levels reported here are ~2 to >10-fold lower than levels reported in other studies in children, most likely because of more rigorous hair cleaning methodology used in the present study, leading to lower levels of unresolved exogenous metal contamination of hair.

OBJECTIVE:To examine the association between 9/11-related exposures and self-reported hearing problems among 16,579 rescue/recovery workers in the World Trade Center (WTC) Health Registry. METHODS:Using Registry Waves 1 (2003 to 2004) and 2 (2006 to 2007), we modeled the association between two metrics of 9/11-related exposures and hearing difficulties. RESULTS:The prevalence of incident, persistent hearing problems was 4.4%. In a fully adjusted model, workers with higher environmental hazards scores were twice as likely (interquartile range OR 2.1; 95% confidence interval [CI] 1.8, 2.5) to report hearing problems. Based on the same fully adjusted model, workers unable to hear in the dust cloud were 2.3 (95% CI 1.8, 3.0) times more likely to report hearing problems as compared with workers not in the dust cloud. CONCLUSIONS:We observed a consistent association between WTC-related exposures and self-reported hearing problems among rescue/recovery workers.

Perfluoroalkyl substances (PFAS) were shown to be immunotoxic in laboratory animals. There is some epidemiological evidence that PFAS exposure is inversely associated with vaccine-induced antibody concentration. We examined immune response to vaccination with FluMist intranasal live attenuated influenza vaccine in relation to four PFAS (perfluorooctanoate, perfluorononanoate, perfluorooctane sulfonate, perfluorohexane sulfonate) serum concentrations among 78 healthy adults vaccinated during the 2010-2011 influenza season. We measured anti-A H1N1 antibody response and cytokine and chemokine concentrations in serum pre-vaccination, 3 days post-vaccination, and 30 days post-vaccination. We measured cytokine, chemokine, and mucosal IgA concentration in nasal secretions 3 days post-vaccination and 30 days post-vaccination. Adults with higher PFAS concentrations were more likely to seroconvert after FluMist vaccination as compared to adults with lower PFAS concentrations. The associations, however, were imprecise and few participants seroconverted as measured either by hemagglutination inhibition (9%) or immunohistochemical staining (25%). We observed no readily discernable or consistent pattern between PFAS concentration and baseline cytokine, chemokine, or mucosal IgA concentration, or between PFAS concentration and change in these immune markers between baseline and FluMist-response states. The results of this study do not support a reduced immune response to FluMist vaccination among healthy adults in relation to serum PFAS concentration. Given the study's many limitations, however, it does not rule out impaired vaccine response to other vaccines or vaccine components in either children or adults.

BACKGROUND:Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are immunotoxic in laboratory studies. Human studies of immune effects are inconsistent. Using the US National Health and Nutrition Examination Survey (NHANES), we examined PFAS serum concentration and indicators of prevalent immune function among 12-19-y-old children. METHODS:In this cross-sectional study, we examined PFAS serum concentration in relation to measles, mumps, and rubella antibody concentrations in NHANES 1999-2000 and 2003-2004 (n = 1,191) and to allergic conditions and allergic sensitization in NHANES 2005-2006 (n = 640). RESULTS:In adjusted, survey-weighted models, a doubling of perfluorooctane sulfonate (PFOS) concentration among seropositive children was associated with a 13.3% (95% confidence interval (CI): -19.9, -6.2) decrease in rubella antibody concentration and a 5.9% decrease in mumps antibody concentration (95% CI: -9.9, -1.6). We observed no adverse association between exposure and current allergic conditions, including asthma. Children with higher PFOS concentration were less likely to be sensitized to any allergen (odds ratio (OR): 0.74; 95% CI: 0.58, 0.95). CONCLUSION/CONCLUSIONS:Increased exposure to several PFAS was associated with lower levels to mumps and rubella antibody concentrations, especially among seropositive individuals. These lower antibody concentrations may indicate a less robust response to vaccination or greater waning of vaccine-derived immunity over time.

BACKGROUND:Rescue and recovery workers responding to the 2001 collapse of the World Trade Center (WTC) sustained exposures to toxic chemicals and have elevated rates of multiple morbidities. METHODS:Using data from the World Trade Center Health Program and the National Death Index for 2002-2011, we examined standardized mortality ratios (SMR) and proportional cancer mortality ratios (PCMR) with indirect standardization for age, sex, race, and calendar year to the U.S. general population, as well as associations between WTC-related environmental exposures and all-cause mortality. RESULTS:We identified 330 deaths among 28,918 responders (SMR 0.43, 95%CI 0.39-0.48). No cause-specific SMRs were meaningfully elevated. PCMRs were elevated for neoplasms of lymphatic and hematopoietic tissue (PCMR 1.76, 95%CI 1.06-2.75). Mortality hazard ratios showed no linear trend with exposure. CONCLUSIONS:Consistent with a healthy worker effect, all-cause mortality among responders was not elevated. There was no clear association between intensity and duration of exposure and mortality. Surveillance is needed to monitor the proportionally higher cancer mortality attributed to lymphatic/hematopoietic neoplasms.

Perfluorooctanoate (PFOA) is detectable in umbilical cord blood and amniotic fluid. Some toxicological findings suggest that perfluoroalkyl substances may be teratogenic. Using data from the C8 Health Project, a 2005-2006 survey in a Mid-Ohio Valley community exposed to PFOA through contaminated drinking water, we examined the association between estimated prenatal PFOA concentration and maternally reported birth defects (n=325) among 10,262 live singleton or multiple births from 1990 to 2006. Logistic regression models accounted for siblings using generalized estimating equations. There was generally no association between estimated PFOA concentration and birth defects, with the possible exception of brain defects, where the odds ratio adjusted for year of conception was 2.6 (95% confidence interval 1.3-5.1) for an increase in estimated PFOA exposure from the 25th to 75th percentile. This estimate, however, was based on 13 cases and may represent a chance finding. Further investigation of this potential association may be warranted.

BACKGROUND:In toxicology studies, perfluorinated compounds affect fetal growth, development, viability, and postnatal growth. There are limited epidemiologic studies on child development. METHODS:We recruited and evaluated 321 children who participated in the C8 Health Project, a 2005-06 survey in a mid-Ohio Valley community highly exposed to perfluorooctanoate (PFOA) through contaminated drinking water. We examined associations between measured childhood PFOA serum concentration and mother and teacher reports of executive function (Behaviour Rating Inventory of Executive Function), attention deficit hyperactivity disorder (ADHD)-like behaviour (Conner's ADHD Diagnostic and Statistical Manual of Mental Disorders IV Scales), and behavioural problems (Behaviour Assessment System for Children) assessed 3 to 4 years later at ages 6-12 years. RESULTS:Overall, neither reports from mothers nor teachers provided clear associations between exposure and child behaviour. Mother reports, however, did suggest favourable associations between exposure and behaviour among boys and adverse associations among girls. On the composite scale from the Behaviour Rating Inventory of Executive Function (n = 318), PFOA exposure had a favourable association among boys (highest vs. lowest quartile β = -6.39; 95% confidence interval [CI] -11.43, -1.35) and an adverse association among girls (highest vs. lowest quartile β = 4.42; 95% CI -0.03, 8.87; interaction P = 0.01). Teacher reports (n = 189) replicated some, but not all of the sex interactions observed in mothers' reports. CONCLUSIONS:Aggregate results did not suggest adverse effects of PFOA on behaviour, but sex-specific results raise the possibility of differing patterns by sex. Results are not consistent between mothers' and teachers' reports. Effect modification by sex may warrant further investigation.

BACKGROUND:Previous research suggests perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) may be associated with adverse pregnancy outcomes. OBJECTIVE:We conducted a population-based study of PFOA and PFOS and birth outcomes from 2005 through 2010 in a Mid-Ohio Valley community exposed to high levels of PFOA through drinking-water contamination. METHODS:Women provided serum for PFOA and PFOS measurement in 2005-2006 and reported reproductive histories in subsequent follow-up interviews. Reported singleton live births among 1,330 women after 1 January 2005 were linked to birth records (n = 1,630) to identify the outcomes of preterm birth (< 37 weeks gestation), pregnancy-induced hypertension, low birth weight (< 2,500 g), and birth weight (grams) among full-term infants. RESULTS:We observed little or no evidence of association between maternal serum PFOA or PFOS and preterm birth (n = 158) or low birth weight (n = 88). Serum PFOA and PFOS were both positively associated with pregnancy-induced hypertension (n = 106), with adjusted odds ratios (ORs) per log unit increase in PFOA and PFOS of 1.27 (95% CI: 1.05, 1.55) and 1.47 (95% CI: 1.06, 2.04), respectively, but associations did not increase monotonically when categorized by quintiles. Results of subanalyses restricted to pregnancies conceived after blood collection were consistent with the main analyses. There was suggestion of a modest negative association between PFOS and birth weight in full-term infants (-29 g per log unit increase; 95% CI: -66, 7), which became stronger when restricted to births conceived after the blood sample collection (-49 g per log unit increase; 95% CI: -90, -8). CONCLUSION/CONCLUSIONS:Results provide some evidence of positive associations between measured serum perfluorinated compounds and pregnancy-induced hypertension and a negative association between PFOS and birth weight among full-term infants.

BACKGROUND:In animal studies, perfluorinated compounds affect fetal growth, development, viability, and postnatal growth. The limited epidemiologic findings on child neurobehavioral development are mixed. METHODS:We recruited and evaluated 320 children who participated in the C8 Health Project, a 2005-2006 survey in a Mid-Ohio Valley community highly exposed to perfluorooctanoate (PFOA) through contaminated drinking water. We examined associations among estimated in utero PFOA exposure, measured childhood PFOA serum concentration, and subsequent performance on neuropsychological tests 3-4 years later at ages 6-12 years. We assessed Intelligence Quotient (IQ) reading and math skills, language, memory and learning, visual-spatial processing, and attention. All multivariable linear regression models were adjusted for age, sex, home environment, test examiner, and maternal IQ. Models with measured childhood PFOA were additionally adjusted for child body mass index. RESULTS:Children in the highest as compared with lowest quartile of estimated in utero PFOA had increases in Full Scale IQ (β 4.6, 95% confidence interval [CI] = 0.7-8.5) and decreases in characteristics of attention deficit/hyperactivity disorder as measured by the Clinical Confidence Index of Connors' Continuous Performance Test-II (β -8.5, 95% CI = -16.1 to -0.8). There were negligible associations between PFOA and reading or math skills or neuropsychological functioning. CONCLUSION/CONCLUSIONS:These results do not suggest an adverse association between the levels of PFOA exposure experienced by children in this cohort and their performance on neuropsychological tests.

BACKGROUND:Influenza virus infection is a major public health burden worldwide. Available vaccines include the inactivated intramuscular trivalent vaccine and, more recently, an intranasal live attenuated influenza vaccine (LAIV). The measure of successful vaccination with the inactivated vaccine is a systemic rise in immunoglobulin G (IgG) level, but for the LAIV no such correlate has been established. METHODS:Seventy-nine subjects were given the LAIV FluMist. Blood was collected prior to vaccination and 3 days and 30 days after vaccination. Nasal wash was collected 3 days and 30 days after vaccination. Responses were measured systemically and in mucosal secretions for cytokines, cell activation profiles, and antibody responses. RESULTS:Only 9% of subjects who received LAIV seroconverted, while 33% of patients developed at least a 2-fold increase in influenza virus-specific immunoglobulin A (IgA) antibodies in nasal wash. LAIV induced a localized inflammation, as suggested by increased expression of interferon-response genes in mucosal RNA and increased granulocyte colony-stimulating factor (G-CSF) and IP-10 in nasal wash. Interestingly, patients who seroconverted had significantly lower serum levels of G-CSF before vaccination. CONCLUSIONS:Protection by LAIV is likely provided through mucosal IgA and not by increases in systemic IgG. LAIV induces local inflammation. Seroconversion is achieved in a small fraction of subjects with a lower serum G-CSF level.