Rachel B. Smith

Exposure to disinfection by-products, fetal growth, and prematurity: a systematic review and meta-analysis.

Background: Exposure to total trihalomethanes in drinking water has been associated with several adverse birth outcomes relating to fetal growth and prematurity. Methods: We carried out a systematic review and meta-analysis of epidemiologic studies featuring original peer-reviewed data on the association of total trihalomethane exposure and health outcomes related to fetal growth and prematurity. Results: A comprehensive literature search yielded 37 studies, 15 of which were selected for the extraction of relative risks relating adverse birth outcomes to trihalomethane exposure. Sufficient data were available for meta-analyses to be carried out for 4 adverse birth outcomes: low birth weight (LBW), term low birth weight (term LBW), preterm delivery, and small for gestational age (SGA) (including intra uterine growth retardation). We found little or no evidence for associations between third trimester trihalomethane exposure and LBW (odds ratio per 10 &mgr;g total trihalomethane/L = 1.00 [95% confidence interval = 0.97–1.03]), term LBW (1.03 [0.93–1.15]), or preterm delivery (0.99 [0.98–1.00]), but some evidence for SGA (1.01 [1.00–1.02]). Conclusions: There was little or no evidence for associations between total trihalomethane concentration and adverse birth outcomes relating to fetal growth and prematurity, with the possible exception of SGA. We discuss these findings and the uncertainties—relating particularly to exposure—that may have affected them.

The epidemiology and possible mechanisms of disinfection by-products in drinking water.

This paper summarizes the epidemiological evidence for adverse health effects associated with disinfection by-products (DBPs) in drinking water and describes the potential mechanism of action. There appears to be good epidemiological evidence for a relationship between exposure to DBPs, as measured by trihalomethanes (THMs), in drinking water and bladder cancer, but the evidence for other cancers including colorectal cancer is inconclusive and inconsistent. There appears to be some evidence for an association between exposure to DBPs, specifically THMs, and little for gestational age/intrauterine growth retardation and, to a lesser extent, pre-term delivery, but evidence for relationships with other outcomes such as low birth weight, stillbirth, congenital anomalies and semen quality is inconclusive and inconsistent. Major limitations in exposure assessment, small sample sizes and potential biases may account for the inconclusive and inconsistent results in epidemiological studies. Moreover, most studies have focused on total THMs as the exposure metric, whereas other DBPs appear to be more toxic than the THMs, albeit generally occurring at lower levels in the water. The mechanisms through which DBPs may cause adverse health effects including cancer and adverse reproductive effects have not been well investigated. Several mechanisms have been suggested, including genotoxicity, oxidative stress, disruption of folate metabolism, disruption of the synthesis and/or secretion of placental syncytiotrophoblast-derived chorionic gonadotropin and lowering of testosterone levels, but further work is required in this area.

Health impacts of long-term exposure to disinfection by-products in drinking water in Europe: HIWATE

There appears to be very good epidemiological evidence for a relationship between chlorination by-products, as measured by trihalomethanes (THMs), in drinking water and bladder cancer, but the evidence for other cancers, including colorectal cancer appears to be inconclusive and inconsistent. There appears to be some evidence for a relationship between chlorination by-products, as measured by THMs, and small for gestational age (SGA)/intrauterine growth retardation (IUGR) and preterm delivery, but evidence for other outcomes such as low birth weight (LBW), stillbirth, congenital anomalies and semen quality appears to be inconclusive and inconsistent.The overall aim of the HIWATE study is to investigate potential human health risks (e.g. bladder and colorectal cancer, premature births, SGA, semen quality, stillbirth, congenital anomalies) associated with long-term exposure to low levels of disinfectants (such as chlorine) and DBPs occurring in water for human consumption and use in the food industry. The study will comprise risk-benefit analyses including quantitative assessments of risk associated with microbial contamination of drinking water versus chemical risk and will compare alternative treatment options. The outcome will be improved risk assessment and better information for risk management. The work is divided into different topics (exposure assessment, epidemiology, risk assessment and management) and studies.

Tap water use amongst pregnant women in a multi-ethnic cohort.

BackgroundStudies of disinfection by-products in drinking water and measures of adverse fetal growth have often been limited by exposure assessment lacking data on individual water use, and therefore failing to reflect individual variation in DBP exposure.MethodsPregnant women recruited to the Born in Bradford cohort study completed a questionnaire which covers water exposure. Information was collected on water consumption, showering, bathing and swimming. Water exposure data from a subset of 39 women of the cohort are described here.ResultsMean total tap water intake was 1.8 l/day, and women on average spent 146 minutes per week showering and bathing. Most tap water intake occurred at home (100% for unemployed, 71.8% for employed). Differences between age groups were observed for total tap water intake overall (p = 0.02) and at home (p = 0.01), and for bottled water intake (p = 0.05). There were differences between ethnic groups for tap water intake at home (p = 0.02) and total tap water intake at work (p = 0.02). Total tap water intake at work differed by income category (p = 0.001). Duration per shower was inversely correlated with age (Spearmans correlation -0.39, p = 0.02), and differed according to employment status (p = 0.04), ethnicity (p = 0.02) and income (p = 0.02).ConclusionThis study provides estimates of water exposure in pregnant women in a multi-ethnic population in the north of England and suggests differences related to age, employment, income and ethnicity. The findings are valuable to inform exposure assessment in studies assessing the relationship between DBPs and adverse birth outcomes.

How to Establish and Follow up a Large Prospective Cohort Study in the 21st Century - Lessons from UK COSMOS.

Large-scale prospective cohort studies are invaluable in epidemiology, but they are increasingly difficult and costly to establish and follow-up. More efficient methods for recruitment, data collection and follow-up are essential if such studies are to remain feasible with limited public and research funds. Here, we discuss how these challenges were addressed in the UK COSMOS cohort study where fixed budget and limited time frame necessitated new approaches to consent and recruitment between 2009-2012. Web-based e-consent and data collection should be considered in large scale observational studies, as they offer a streamlined experience which benefits both participants and researchers and save costs. Commercial providers of register and marketing data, smartphones, apps, email, social media, and the internet offer innovative possibilities for identifying, recruiting and following up cohorts. Using examples from UK COSMOS, this article sets out the dos and don’ts for todays cohort studies and provides a guide on how best to take advantage of new technologies and innovative methods to simplify logistics and minimise costs. Thus a more streamlined experience to the benefit of both research participants and researchers becomes achievable.

Broad spectrum activity of a lectin-like bacterial serine protease family on human leukocytes.

The serine protease autotransporter from Enterobacteriaceae (SPATE) family, which number more than 25 proteases with apparent diverse functions, have been phylogenetically divided into two distinct classes, designated 1 and 2. We recently demonstrated that Pic and Tsh, two members of the class-2 SPATE family produced by intestinal and extraintestinal pathogenic E. coli, were able to cleave a number of O-glycosylated proteins on neutrophils and lymphocytes resulting in impaired leukocyte functions. Here we show that most members of the class-2 SPATE family have lectin-like properties and exhibit differential protease activity reliant on glycoprotein type and cell lineage. Protease activity was seen in virtually all tested O-glycosylated proteins including CD34, CD55, CD164, TIM1, TIM3, TIM4 and C1-INH. We also show that although SPATE proteins bound and cleaved glycoproteins more efficiently on granulocytes and monocytes, they also targeted glycoproteins on B, T and natural killer lymphocytes. Finally, we found that the characteristic domain-2 of class-2 SPATEs is not required for glycoprotease activity, but single amino acid mutations in Pic domain-1 to those residues naturally occurring in domain-1 of SepA, were sufficient to hamper Pic glycoprotease activity. This study shows that most class-2 SPATEs have redundant activities and suggest that they may function as immunomodulators at several levels of the immune system.

Impact of London's road traffic air and noise pollution on birth weight: retrospective population based cohort study

Abstract Objective To investigate the relation between exposure to both air and noise pollution from road traffic and birth weight outcomes. Design Retrospective population based cohort study. Setting Greater London and surrounding counties up to the M25 motorway (2317 km2), UK, from 2006 to 2010. Participants 540 365 singleton term live births. Main outcome measures Term low birth weight (LBW), small for gestational age (SGA) at term, and term birth weight. Results Average air pollutant exposures across pregnancy were 41 μg/m3 nitrogen dioxide (NO2), 73 μg/m3 nitrogen oxides (NOx), 14 μg/m3 particulate matter with aerodynamic diameter <2.5 μm (PM2.5), 23 μg/m3 particulate matter with aerodynamic diameter <10 μm (PM10), and 32 μg/m3 ozone (O3). Average daytime (LAeq,16hr) and night-time (Lnight) road traffic A-weighted noise levels were 58 dB and 53 dB respectively. Interquartile range increases in NO2, NOx, PM2.5, PM10, and source specific PM2.5 from traffic exhaust (PM2.5 traffic exhaust) and traffic non-exhaust (brake or tyre wear and resuspension) (PM2.5 traffic non-exhaust) were associated with 2% to 6% increased odds of term LBW, and 1% to 3% increased odds of term SGA. Air pollutant associations were robust to adjustment for road traffic noise. Trends of decreasing birth weight across increasing road traffic noise categories were observed, but were strongly attenuated when adjusted for primary traffic related air pollutants. Only PM2.5 traffic exhaust and PM2.5 were consistently associated with increased risk of term LBW after adjustment for each of the other air pollutants. It was estimated that 3% of term LBW cases in London are directly attributable to residential exposure to PM2.5>13.8 μg/m3during pregnancy. Conclusions The findings suggest that air pollution from road traffic in London is adversely affecting fetal growth. The results suggest little evidence for an independent exposure-response effect of traffic related noise on birth weight outcomes.

Birth Weight, Ethnicity, and Exposure to Trihalomethanes and Haloacetic Acids in Drinking Water during Pregnancy in the Born in Bradford Cohort.

Background: Evidence for a relationship between trihalomethane (THM) or haloacetic acid (HAA) exposure and adverse fetal growth is inconsistent. Disinfection by-products exist as complex mixtures in water supplies, but THMs and HAAs have typically been examined separately. Objectives: We investigated joint exposure at the individual level to THMs and HAAs in relation to birth weight in the multi-ethnic Born in Bradford birth cohort. Methods: Pregnant women reported their water consumption and activities via questionnaire. These data were combined with area-level THM and HAA concentrations to estimate integrated uptake of THMs into blood and HAA ingestion, accounting for boiling/filtering. We examined the relationship between THM and HAA exposures and birth weight of up to 7,438 singleton term babies using multiple linear regression, stratified by ethnicity. Results: Among Pakistani-origin infants, mean birth weight was significantly lower in association with the highest versus lowest tertiles of integrated THM uptake (e.g., –53.7 g; 95% CI: –89.9, –17.5 for ≥ 1.82 vs. < 1.05 μg/day of total THM) and there were significant trends (p < 0.01) across increasing tertiles, but there were no associations among white British infants. Neither ingestion of HAAs alone or jointly with THMs was associated with birth weight. Estimated THM uptake via showering, bathing, and swimming was significantly associated with lower birth weight in Pakistani-origin infants, when adjusting for THM and HAA ingestion via water consumption. Conclusions: To our knowledge, this is the largest DBP and fetal growth study to date with individual water use data, and the first to examine individual-level estimates of joint THM–HAA exposure. Our findings demonstrate associations between THM, but not HAA, exposure during pregnancy and reduced birth weight, but suggest this differs by ethnicity. This study suggests that THMs are not acting as a proxy for HAAs, or vice-versa. Citation: Smith RB, Edwards SC, Best N, Wright J, Nieuwenhuijsen MJ, Toledano MB. 2016. Birth weight, ethnicity, and exposure to trihalomethanes and haloacetic acids in drinking water during pregnancy in the Born in Bradford cohort. Environ Health Perspect 124:681–689; http://dx.doi.org/10.1289/ehp.1409480

Environmental, dietary, maternal, and fetal predictors of bulky DNA adducts in cord blood: A European mother–child study (NewGeneris)

Background: Bulky DNA adducts reflect genotoxic exposures, have been associated with lower birth weight, and may predict cancer risk. Objective: We selected factors known or hypothesized to affect in utero adduct formation and repair and examined their associations with adduct levels in neonates. Methods: Pregnant women from Greece, Spain, England, Denmark, and Norway were recruited in 2006–2010. Cord blood bulky DNA adduct levels were measured by the 32P-postlabeling technique (n = 511). Diet and maternal characteristics were assessed via questionnaires. Modeled exposures to air pollutants and drinking-water disinfection by-products, mainly trihalomethanes (THMs), were available for a large proportion of the study population. Results: Greek and Spanish neonates had higher adduct levels than the northern European neonates [median, 12.1 (n = 179) vs. 6.8 (n = 332) adducts per 108 nucleotides, p < 0.001]. Residence in southern European countries, higher maternal body mass index, delivery by cesarean section, male infant sex, low maternal intake of fruits rich in vitamin C, high intake of dairy products, and low adherence to healthy diet score were statistically significantly associated with higher adduct levels in adjusted models. Exposure to fine particulate matter and nitrogen dioxide was associated with significantly higher adducts in the Danish subsample only. Overall, the pooled results for THMs in water show no evidence of association with adduct levels; however, there are country-specific differences in results with a suggestion of an association in England. Conclusion: These findings suggest that a combination of factors, including unknown country-specific factors, influence the bulky DNA adduct levels in neonates. Citation: Pedersen M, Mendez MA, Schoket B, Godschalk RW, Espinosa A, Landström A, Villanueva CM, Merlo DF, Fthenou E, Gracia-Lavedan E, van Schooten FJ, Hoek G, Brunborg G, Meltzer HM, Alexander J, Nielsen JK, Sunyer J, Wright J, Kovács K, de Hoogh K, Gutzkow KB, Hardie LJ, Chatzi L, Knudsen LE, Anna L, Ketzel M, Haugen M, Botsivali M, Nieuwenhuijsen MJ, Cirach M, Toledano MB, Smith RB, Fleming S, Agramunt S, Kyrtopoulos SA, Lukács V, Kleinjans JC, Segerbäck D, Kogevinas M. 2015. Environmental, dietary, maternal, and fetal predictors of bulky DNA adducts in cord blood: a European mother–child study (NewGeneris). Environ Health Perspect 123:374–380; http://dx.doi.org/10.1289/ehp.1408613

Validation of trichloroacetic acid exposure via drinking water during pregnancy using a urinary TCAA biomarker

Disinfection by-product (DBP) exposure during pregnancy may be related to reduced fetal growth, but the evidence is inconclusive and improved DBP exposure assessment is required. The authors conducted a nested exposure study on a subset (n=39) of pregnant women in the Born in Bradford cohort to assess validity of TCAA exposure assessment based on tap water sampling and self-reported water-use; water-use questionnaire validity; and use of a one-time urinary TCAA biomarker. TCAA levels in urine and home tap water supply were quantified, and water use was measured via a questionnaire and 7-day diary, at 28 weeks gestation. Diary and urine measures were repeated later in pregnancy (n=14). TCAA level in home tap water supply was not correlated with urinary TCAA (0.18, P=0.29). Cold unfiltered tap water intake at home measured by questionnaire was correlated with urinary TCAA (0.44, P=0.007), but correlation was stronger still for cold unfiltered tap water intake reported over the 3 days prior to urine sampling (0.60, P<0.001). For unemployed women TCAA ingestion at home, derived from tap water sampling and self-reported water-use, correlated strongly with urinary TCAA (0.78, P<0.001), but for employed women the correlation was weak (0.31, P=0.20). Results suggest individual tap water intake is most influential in determining TCAA exposure variability in this cohort, and that TCAA ingestion at home is a valid proxy for TCAA exposure for unemployed women but less satisfactory for employed women.