Sharon K. Sagiv

A Time Series Analysis of Air Pollution and Preterm Birth in Pennsylvania, 1997--2001

Preterm delivery can lead to serious infant health outcomes, including death and lifelong disability. Small increases in preterm delivery risk in relation to spatial gradients of air pollution have been reported, but previous studies may have controlled inadequately for individual factors. Using a time-series analysis, which eliminates potential confounding by individual risk factors that do not change over short periods of time, we investigated the effect of ambient outdoor particulate matter with diameter ≤10 μm (PM10) and sulfur dioxide on risk for preterm delivery. Daily counts of preterm births were obtained from birth records in four Pennsylvania counties from 1997 through 2001. We observed increased risk for preterm delivery with exposure to average PM10 and SO2 in the 6 weeks before birth [respectively, relative risk (RR) = 1.07; 95% confidence interval (CI), 0.98–1.18 per 50 μg/m3 increase; RR = 1.15; 95% CI, 1.00–1. 32 per 15 ppb increase], adjusting for long-term preterm delivery trends, co-pollutants, and offsetting by the number of gestations at risk. We also examined lags up to 7 days before the birth and found an acute effect of exposure to PM10 2 days and 5 days before birth (respectively, RR = 1.10; 95% CI, 1.00–1.21; RR = 1.07; 95% CI, 0.98–1.18) and SO2 3 days before birth (RR = 1.07; 95% CI, 0.99–1.15), adjusting for covariates, including temperature, dew point temperature, and day of the week. The results from this time-series analysis, which provides evidence of an increase in preterm birth risk with exposure to PM10 and SO2, are consistent with prior investigations of spatial contrasts.

Prenatal Exposure to Mercury and Fish Consumption During Pregnancy and Attention-Deficit/Hyperactivity Disorder-Related Behavior in Children

OBJECTIVE To investigate the association of prenatal mercury exposure and fish intake with attention-deficit/hyperactivity disorder (ADHD)-related behavior. METHODS For a population-based prospective birth cohort recruited in New Bedford, Massachusetts (1993-1998), we analyzed data for children examined at age 8 years with peripartum maternal hair mercury measures (n = 421) or maternal report of fish consumption during pregnancy (n = 515). Inattentive and impulsive/hyperactive behaviors were assessed using a teacher rating scale and neuropsychological testing. RESULTS The median maternal hair mercury level was 0.45 μg/g (range, 0.03-5.14 μg/g), and 52% of mothers consumed more than 2 fish servings weekly. In multivariable regression models, mercury exposure was associated with inattention and impulsivity/hyperactivity; some outcomes had an apparent threshold with associations at 1 μg/g or greater of mercury. For example, at 1 μg/g or greater, the adjusted risk ratios for mild/markedly atypical inattentive and impulsive/hyperactive behaviors were 1.4 (95% CI, 1.0-1.8) and 1.7 (95% CI, 1.2-2.4), respectively, for an interquartile range (0.5 μg/g) mercury increase; there was no confounding by fish consumption. For neuropsychological assessments, mercury and behavior associations were detected primarily for boys. There was a protective association for fish consumption (>2 servings per week) with ADHD-related behaviors, particularly impulsive/hyperactive behaviors (relative risk = 0.4; 95% CI, 0.2-0.6). CONCLUSIONS Low-level prenatal mercury exposure is associated with a greater risk of ADHD-related behaviors, and fish consumption during pregnancy is protective of these behaviors. These findings underscore the difficulties of balancing the benefits of fish intake with the detriments of low-level mercury exposure in developing dietary recommendations in pregnancy.

Polymorphisms in XRCC1 Modify the Association between Polycyclic Aromatic Hydrocarbon-DNA Adducts, Cigarette Smoking, Dietary Antioxidants, and Breast Cancer Risk

The variability in DNA repair capacity of the general population may depend in part upon common variants in DNA repair genes. X-ray repair cross complementing group 1 (XRCC1) is an important DNA base excision repair gene and exhibits polymorphic variation. Using the Long Island Breast Cancer Study Project, a population-based case-control study, we evaluated the hypothesis that two common single nucleotide polymorphisms of XRCC1 (codon 194 Arg→Trp and 399 Arg→Gln) influence breast cancer susceptibility and interact with polycyclic aromatic hydrocarbon (PAH)-DNA adducts, cigarette smoking, and intake of fruits and vegetables and antioxidants. The available sample for genotyping included 1,067 cases and 1,110 controls. Genotyping was done by a high-throughput single-nucleotide extension assay with fluorescence polarization detection of the incorporated nucleotide. We observed no significant increases in risk among all subjects who were carriers of XRCC1 194Trp or 399Gln alleles. Among never smokers, we observed an increased risk of breast cancer in 399Gln carriers [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.0-1.7). Further analysis indicated a suggestive weak additive interaction between the 399Gln allele and detectable PAH-DNA adducts (OR for exposure with mutant genotype, 1.9; 95% CI, 1.2-3.1). The estimated age-adjusted interaction contrast ratio (ICR) and 95% CI (ICR, 0.38; 95% CI, −0.32 to 1.10) indicated that the departure from additivity was not statistically significant, but that there was some suggestion of a relative excess risk due to the interaction. In subjects with at least one copy of XRCC1 194Trp allele, there was a moderate interaction with high intake of fruits and vegetables (≥35 half-cup servings per week of any fruits, fruit juices, and vegetables, OR, 0.58; 95% CI, 0.38-0.89; ICR, −0.49; 95% CI, −0.03 to −0.95), and dietary plus supplement antioxidant intake with 33% to 42% decreases in breast cancer risk compared with those with the Arg194Arg genotype and low-intake individuals. These results do not show that the two genetic polymorphisms of XRCC1 independently influence breast cancer risk. However, there is evidence for interactions between the two XRCC1 single nucleotide polymorphisms and PAH-DNA adducts or fruit and vegetable and antioxidant intake on breast cancer risk. Further understanding of the biological function of XRCC1 variants and their interactions with PAH-DNA adducts, antioxidants, and other genes in the pathway are needed.

Organochlorine exposures during pregnancy and infant size at birth.

Background: Organochlorines, including polychlorinated biphenyls (PCBs) and pesticides, are environmentally persistent contaminants that concentrate in the food chain as well in human adipose tissue and readily cross the placenta. Methods: To follow up on studies suggesting an association of organochlorine exposure with reduced birth size, we investigated the association of PCBs and organochlorine pesticides (including p,p′-dichlorodiphenyl dichloroethene [p,p′-DDE], the major degradation product of p,p′-dichlorodiphenyl trichloroethane [p,p′-DDT], and hexachlorobenzene [HCB]), with birth weight, crown-heel length, and head circumference. We evaluated a cohort of 722 infants born between 1993 and 1998 to mothers residing near a PCB-contaminated harbor and Superfund site in New Bedford, Massachusetts. Results: Small negative associations were observed for PCBs and birth weight; associations were weaker for birth length and head circumference. There was evidence for effect modification by smoking during pregnancy on the association between PCBs and birth weight. No associations were found with p,p′-DDE or HCB for any measures of birth size. Conclusions: This study supports the growing literature that demonstrates at most a weak association between very low-level organochlorine exposure and birth size.

Cohort Profile: Project Viva

We established Project Viva to examine prenatal diet and other factors in relation to maternal and child health. We recruited pregnant women at their initial prenatal visit in eastern Massachusetts between 1999 and 2002. Exclusion criteria included multiple gestation, inability to answer questions in English, gestational age ≥22 weeks at recruitment and plans to move away before delivery. We completed in-person visits with mothers during pregnancy in the late first (median 9.9 weeks of gestation) and second (median 27.9 weeks) trimesters. We saw mothers and children in the hospital during the delivery admission and during infancy (median age 6.3 months), early childhood (median 3.2 years) and mid-childhood (median 7.7 years). We collected information from mothers via interviews and questionnaires, performed anthropometric and neurodevelopmental assessments and collected biosamples. We have collected additional information from medical records and from mailed questionnaires sent annually to mothers between in-person visits and to children beginning at age 9 years. From 2341 eligible women, there were 2128 live births; 1279 mother-child pairs provided data at the mid-childhood visit. Primary study outcomes include pregnancy outcomes, maternal mental and cardiometabolic health and child neurodevelopment, asthma/atopy and obesity/cardiometabolic health. Investigators interested in learning more about how to obtain Project Viva data can contact Project_Viva@hphc.org.

Prenatal Organochlorine Exposure and Measures of Behavior in Infancy Using the Neonatal Behavioral Assessment Scale (NBAS)

Background Previous literature suggests an association between organochlorines and behavioral measures in childhood, including inattention. Objective This study was designed to assess whether prenatal organochlorine exposure is associated with measures of attention in early infancy. Methods We investigated an association between cord serum polychlorinated biphenyls (PCBs) and p,p′-dichlorodiphenyl dichloroethene (DDE) levels and measures of attention from the Neonatal Behavioral Assessment Scale (NBAS) in a cohort of 788 infants born 1993–1998 to mothers residing near a PCB-contaminated harbor and Superfund site in New Bedford, Massachusetts. Results Medians (ranges) for the sum of four prevalent PCB congeners and DDE levels were 0.19 (0.01–4.41) and 0.30 (0–10.29) ng/g serum, respectively. For the 542 subjects with an NBAS exam at 2 weeks, we observed consistent inverse associations between cord serum PCB and DDE levels and NBAS measures of alertness, quality of alert responsiveness, cost of attention, and other potential attention-associated measures including self-quieting and motor maturity. For example, the decrement in quality of alert responsiveness score was −0.51 (95% confidence interval, −0.99 to −0.03) for the highest quartile of exposure to the sum of four prevalent PCB congeners compared with the lowest quartile. We found little evidence for an association with infant orientation, habituation, and regulation of state, assessed as summary cluster measures. Conclusions Our findings provide evidence for an association between low-level prenatal PCB and DDE exposures and poor attention in early infancy. Further analyses will focus on whether organochlorine-associated decrements in attention and attention-related skills in infancy persist in later childhood.

Polychlorinated biphenyls, organochlorine pesticides and neurodevelopment.

Purpose of review Although environmental levels of polychlorinated biphenyls and certain organochlorine pesticides – hexachlorobenzene, dichlorodiphenyl trichloroethane and its primary metabolite, dichlorodiphenyl dichloroethene – are generally on the decline, early-life exposures to these prevalent contaminants continue. The review will describe current understanding of the potential neurodevelopmental consequences of low-level exposures to these contaminants. Recent findings Animal models suggest that early-life exposures to polychlorinated biphenyls, dichlorodiphenyl trichloroethane/dichlorodiphenyl dichloroethene or hexachlorobenzene are associated with decreased cognitive or behavioral function in later development. Despite almost 30 years of research, however, results of human studies are inconsistent regarding the nature of the observed effects and their persistence over time. Overall, epidemiologic studies support modest associations of primarily prenatal polychlorinated biphenyl exposures with differences in neuromotor development, decrements in cognition and behavioral deficits, particularly regarding attention and impulse control. There are limited published human data regarding potential neurodevelopmental toxicities of early-life exposures to dichlorodiphenyl trichloroethane/dichlorodiphenyl dichloroethene and hexachlorobenzene. Summary Exposures to polychlorinated biphenyls, dichlorodiphenyl trichloroethane/dichlorodiphenyl dichloroethene and hexachlorobenzene are likely detrimental to neurodevelopment. Effective control of exposure is complicated by variable exposure sources and variable contaminant levels in food, particularly fish, for which it is important to balance the risk of contaminants with nutritional benefits.

Polymorphisms in Nucleotide Excision Repair Genes, Polycyclic Aromatic Hydrocarbon-DNA Adducts, and Breast Cancer Risk

Genes involved in the nucleotide excision repair (NER) pathway, which removes bulky DNA adducts, are potential low-penetrance cancer susceptibility genes. We recently reported an association between detectable polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer risk. Using a population-based breast cancer case-control study on Long Island, New York, we examined whether polymorphisms in NER genes modified the association between PAH-DNA adducts and breast cancer risk. We examined polymorphisms in ERCC1 (3′-untranslated region 8092C/A), XPA (5′-untranslated region −4G/A), XPD (Asp312Asn in exon 10), XPF (Arg415Gln in exon 8), and XPG (Asp1104His in exon 15) in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele in XPD was associated with a 25% increase in the odds ratio [OR, 1.25; 95% confidence interval (95% CI), 1.04-1.50] for breast cancer. The increase associated with homozygosity of the variant alleles for XPD and ERCC1 was stronger among those with detectable PAH-DNA adduct levels (OR, 1.83; 95% CI, 1.22-2.76 and OR, 1.92; 95% CI, 1.14-3.25 for detectable versus nondetectable adducts and homozygous wild-type genotype for XPD and ERCC1, respectively). We found no association between XPA, XPF, and XPG genotypes, PAH-DNA adducts, and breast cancer risk. When we combined genotypes for these NER pathway genes, there was a significant trend for increasing breast cancer risk with increasing number of putative high-risk alleles. Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in NER pathway genes and detectable PAH-DNA adducts. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2033–41)

Neuropsychological measures of attention and impulse control among 8-year-old children exposed prenatally to organochlorines.

Background: We previously reported associations between organochlorines and behaviors related to attention deficit hyperactivity disorder among boys and girls at 8 years of age using a teacher’s rating scale for a birth cohort in New Bedford, Massachusetts (USA). Objectives: Our goal was to corroborate these findings using neuropsychological measures of inattentive and impulsive behaviors. Methods: We investigated the association between cord serum polychlorinated biphenyls (PCBs) and p,p´-dichlorodiphenyl dichloroethylene (p,p´-DDE) and attention and impulse control using a Continuous Performance Test (CPT) and components of the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III). Participants came from a prospective cohort of children born during 1993–1998 to mothers residing near a PCB-contaminated harbor in New Bedford. Median (range) cord serum levels for the sum of four prevalent PCBs [congeners 118, 138, 153, and 180 (ΣPCB4)] and p,p´-DDE were 0.19 (0.01–2.59) and 0.31 (0–14.93) ng/g serum, respectively. Results: We detected associations between PCBs and neuropsychological deficits for 578 and 584 children with CPT and WISC-III measures, respectively, but only among boys. For example, boys with higher exposure to ΣPCB4 had a higher rate of CPT errors of omission [rate ratio for the exposure interquartile range (IQR) = 1.12; 95% confidence interval (CI): 0.98, 1.27] and slower WISC-III Processing Speed (change in score for the IQR = –2.0; 95% CI: –3.5, –0.4). Weaker associations were found for p,p´-DDE. For girls, associations were in the opposite direction for the CPT and null for the WISC-III. Conclusions: These results support an association between organochlorines (mainly PCBs) and neuropsychological measures of attention among boys only. Sex-specific effects should be considered in studies of organochlorines and neurodevelopment.

PAH–DNA Adducts, Cigarette Smoking, GST Polymorphisms, and Breast Cancer Risk

Background Polycyclic aromatic hydrocarbons (PAHs) may increase breast cancer risk, and the association may be modified by inherited differences in deactivation of PAH intermediates by glutathione S-transferases (GSTs). Few breast cancer studies have investigated the joint effects of multiple GSTs and a PAH biomarker. Objective We estimated the breast cancer risk associated with multiple polymorphisms in the GST gene (GSTA1, GSTM1, GSTP1, and GSTT1) and the interaction with PAH–DNA adducts and cigarette smoking. Methods We conducted unconditional logistic regression using data from a population-based sample of women (cases/controls, respectively): GST polymorphisms were genotyped using polymerase chain reaction and matrix-assisted laser desorption/ionization time-of-flight assays (n = 926 of 916), PAH–DNA adduct blood levels were measured by competitive enzyme-linked immunosorbent assay (n = 873 of 941), and smoking status was assessed by in-person questionnaires (n = 943 of 973). Results Odds ratios for joint effects on breast cancer risk among women with at least three variant alleles were 1.56 [95% confidence interval (CI), 1.13–2.16] for detectable PAH–DNA adducts and 0.93 (95% CI, 0.56–1.56) for no detectable adducts; corresponding odds ratios for three or more variants were 1.18 (95% CI, 0.82–1.69) for ever smokers and 1.44 (95% CI, 0.97–2.14) for never smokers. Neither interaction was statistically significant (p = 0.43 and 0.62, respectively). Conclusion We found little statistical evidence that PAHs interacted with GSTT1, GSTM1, GSTP1, and GSTA1 polymorphisms to further increase breast cancer risk.