Mireille B. Toledano

Chlorination disinfection byproducts in water and their association with adverse reproductive outcomes: a review

OBJECTIVES AND METHODS Chlorination has been the major disinfectant process for domestic drinking water for many years. Concern about the potential health effects of the byproducts of chlorination has prompted the investigation of the possible association between exposure to these byproducts and incidence of human cancer, and more recently, with adverse reproductive outcomes. This paper evaluates both the toxicological and epidemiological data involving chlorination disinfection byproducts (DBPs) and adverse reproductive outcomes, and makes recommendations for future research. RESULTS AND CONCLUSIONS Relatively few toxicological and epidemiological studies have been carried out examining the effects of DBPs on reproductive health outcomes. The main outcomes of interest so far have been low birth weight, preterm delivery, spontaneous abortions, stillbirth, and birth defects— in particular central nervous system, major cardiac defects, oral cleft, and respiratory, and neural tube defects. Various toxicological and epidemiological studies point towards an association between trihalomethanes (THMs), one of the main DBPs and marker for total DBP load, and (low) birth weight, although the evidence is not conclusive. Administered doses in toxicological studies have been high and even though epidemiological studies have mostly shown excess risks, these were often not significant and the assessment of exposure was often limited. Some studies have shown associations for DBPs and other outcomes such as spontaneous abortions, stillbirth and birth defects, and although the evidence for these associations is weaker it is gaining weight. There is no evidence for an association between THMs and preterm delivery. The main limitation of most studies so far has been the relatively crude methodology, in particular for assessment of exposure. RECOMMENDATIONS Large, well designed epidemiological studies focusing on well defined end points taking into account relevant confounders and with particular emphasis on exposure characterisation are ideally needed to confirm or refute these preliminary findings. In practice, these studies may be impracticable, partly due to the cost involved, but this is an issue that can be put right—for example, by use of subsets of the population in the design of exposure models. The studies should also reflect differences of culture and water treatment in different parts of the world. To identify the specific components that may be of aetiological concern and hence to fit the most appropriate exposure model with which to investigate human exposure to chlorinated DBPs, further detailed toxicological assessments of the mixture of byproducts commonly found in drinking water are also needed.

Changing international trends in mortality rates for liver, biliary and pancreatic tumours.

BACKGROUND/AIMS The age-standardized mortality rate for hepatocellular carcinoma is increasing in several countries. However, in England and Wales we previously reported an increase in mortality rates from intrahepatic cholangiocarcinoma. Trends in cholangiocarcinoma in most other industrialized countries are unknown. To further study trends in hepatobiliary and pancreatic tumours, we analysed mortality data from the United States, Japan, Australia and Europe. METHODS Age-standardized mortality rates for men and women for subcategories of liver tumours, tumours of the gall bladder and extrahepatic biliary tree and pancreas from 1979 to 1998 were obtained from the World Health Organization mortality database. RESULTS We confirmed previously reported increases in hepatocellular carcinoma, but also found increases in other countries, particularly Australia (3-year average rise from 1.20 to 2.27, men). Mortality for intrahepatic cholangiocarcinoma increased in men in all countries studied, with the largest increases in Australia (from 0.10 to 0.70) and England and Wales (from 0.20 to 0.83). CONCLUSIONS We present a hitherto unreported rise in age-standardized mortality rates from intrahepatic cholangiocarcinoma across four continents. The cause remains uncertain. An impact on the observed trends of improved diagnostic techniques and death certificate misclassification cannot be completely ruled out. Future research should include epidemiological studies to examine possible case-clustering and investigation of potential aetiological and host factors.

Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma

Cholangiocarcinoma (CCA) is a fatal cancer of the biliary epithelium, arising either within the liver (intrahepatic, ICC) or in the extrahepatic bile ducts (extrahepatic ECC). Globally, CCA is the second most common primary hepatic malignancy. Several recent epidemiological studies have shown that the incidence and mortality rates of ICC are increasing. This review of the literature on the international epidemiological rates of CCA, both intra- and extrahepatic, explores possible explanations for the trends found. The possible role of epidemiological artifact in the findings is discussed and the known risk factors for CCA are summarized. These include primary sclerosing cholangitis, liver fluke infestation, congenital fibropolycystic liver, bile duct adenomas, and biliary papillomatosis, hepatolithiasis, chemical carcinogens such as nitrosamines, Thorotrast, chronic viral hepatitis, cirrhosis, chronic non-alcoholic liver disease and obesity. Potential pathways involved in the molecular pathogenesis of CCA are also summarized.

Uptake of chlorination disinfection by-products; a review and a discussion of its implications for exposure assessment in epidemiological studies

We have reviewed the relevant issues in the exposure assessment of disinfection by-products (DBPs) of chlorination for epidemiological and health risk assessment. Various DBPs can be detected in drinking water and swimming pools, and the reported levels show a considerable range, but were generally below the current health standard for total trihalomethanes (TTHMs) (100 µg/l). Relatively little information is available on the correlation between the various DBPs in drinking water and in swimming pools. Chloroform was generally, but not always, the most predominant DBP. In epidemiological studies, TTHM levels have been used as an indicator for total DBP load, even though TTHM levels do not always correlate well with individual DPBs. Factors such as residence time, temperature, pH, organic content, including humic and fulvic acid and bromide levels affect the composition and levels of DBPs. Although there are biomarkers of DBPs, mainly for chloroform and more recently for the other volatile trihalomethanes (THMs) and the nonvolatile haloacetic acids (HAAs) such as trichloroacetic acid (TCAA) and dichloroacetic acid (DCAA), they have not been used in epidemiological studies. The THMs have been measured in exhaled breath and serum, while the HAAs have been measured in urine. These biomarkers have been useful to estimate the actual uptake of the DBPs and the relative contribution of various exposure routes. Physiologically based pharmacokinetic (PBPK) models exist for, e.g. chloroform, but their main target organs are the kidney and liver and they have not been used in epidemiological studies. Tap water ingestion, showering, bathing, swimming, boiling water and dishwashing are all activities that have been associated with the uptake of DBPs, and considerable variation in these activities has been observed between people. No studies have reported on the correlation between human uptake of DBPs and water-zone mean estimates, but various studies found a good correlation between THM concentrations in exhaled breath and THM concentrations in water during showering and swimming. In general exposure assessment in epidemiological studies has been limited which complicates the interpretation. These findings have implications for epidemiological studies, particularly with reference to Berkson and classical error type models, study power, attenuation and precision of health-risk estimates and study efficiency. Recommendations are made for further areas of study.

Endocrine disruptors in the workplace, hair spray, folate supplementation, and risk of hypospadias: case-control study.

Background Hypospadias is one of the most common urogenital congenital anomalies affecting baby boys. Prevalence estimates in Europe range from 4 to 24 per 10,000 births, depending on definition, with higher rates reported from the United States. Relatively little is known about potential risk factors, but a role for endocrine-disrupting chemicals (EDCs) has been proposed. Objective Our goal was to elucidate the risk of hypospadias associated with occupational exposure of the mother to endocrine-disruptor chemicals, use of folate supplementation during pregnancy, and vegetarianism. Design We designed a case–control study of 471 hypospadias cases referred to surgeons and 490 randomly selected birth controls, born 1 January 1997–30 September 1998 in southeast England. Telephone interviews of mothers elicited information on folate supplementation during pregnancy and vegetarianism. We used a job exposure matrix to classify occupational exposure. Results In multiple logistic regression analysis, there were increased risks for self-reported occupational exposure to hair spray [exposed vs. nonexposed, odds ratio (OR) = 2.39; 95% confidence interval (CI), 1.40–4.17] and phthalate exposure obtained by a job exposure matrix (OR = 3.12; 95% CI, 1.04–11.46). There was a significantly reduced risk of hypospadias associated with of folate use during the first 3 months of pregnancy (OR = 0.64; 95% CI, 0.44–0.93). Vegetarianism was not associated with hypospadias risk. Conclusions Excess risks of hypospadias associated with occupational exposures to phthalates and hair spray suggest that antiandrogenic EDCs may play a role in hypospadias. Folate supplementation in early pregnancy may be protective.

Relation of Trihalomethane Concentrations in Public Water Supplies to Stillbirth and Birth Weight in Three Water Regions in England

We investigated the association between total trihalomethanes (TTHMs) and risk of stillbirth and low and very low birth weight in three water regions in England, 1992–1998; associations with individual trihalomethanes (THMs) were also examined. Modeled estimates of quarterly TTHM concentrations in water zones, categorized as low (< 30 μg/L), medium (30–59 μg/L), or high (≥60 μg/L), were linked to approximately 1 million routine birth and stillbirth records using maternal residence at time of birth. In one region, where there was a positive socioeconomic deprivation gradient across exposure categories, there was also a positive, significant association of TTHM with risk of stillbirth and low and very low birth weight. Overall summary estimates across the three regions using a random-effects model to allow for between-region heterogeneity in exposure effects showed small excess risks in areas with high TTHM concentrations for stillbirths [odds ratio (OR) = 1.11; 95% confidence interval (CI), 1.00–1.23), low birth weight (OR = 1.09; 95% CI, 0.93–1.27), and very low birth weight (OR = 1.05; 95% CI, 0.82–1.34). Among the individual THMs, chloroform showed a similar pattern of risk as TTHM, but no association was found with concentrations of bromodichloromethane or total brominated THMs. Our findings overall suggest a significant association of stillbirths with maternal residence in areas with high TTHM exposure. Further work is needed looking at cause-specific stillbirths and effects of other disinfection by-products and to help differentiate between alternative (noncausal) explanations and those that may derive from the water supply.

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.

Chlorination disinfection by-products in drinking water and congenital anomalies: review and meta-analyses.

Objectives The aim of this study was to review epidemiologic evidence, provide summary risk estimates of the association between exposure to chlorination disinfection by-products (DBPs) and congenital anomalies, and provide recommendations for future studies. Data sources and extraction We included all published epidemiologic studies that evaluated a relationship between an index of DBP exposure (treatment, water source, DBP measurements, and both DBP measurements and personal characteristics) and risk of congenital anomalies. When three or more studies examined the same exposure index and congenital anomaly, we conducted a meta-analysis to obtain a summary risk estimate comparing the highest exposure group with the lowest exposure group. When five or more studies examined total trihalomethane (TTHM) exposure and a specific congenital anomaly, we conducted a meta-analysis to obtain exposure–response risk estimates per 10 μg/L TTHM. Data synthesis For all congenital anomalies combined, the meta-analysis gave a statistically significant excess risk for high versus low exposure to water chlorination or TTHM [17%; 95% confidence interval (CI), 3–34] based on a small number of studies. The meta-analysis also suggested a statistically significant excess risk for ventricular septal defects (58%; 95% CI, 21–107), but this was based on only three studies, and there was little evidence of an exposure–response relationship. We observed no statistically significant relationships in the other meta-analyses. We found little evidence for publication bias, except for urinary tract defects and cleft lip and palate. Conclusion Although some individual studies have suggested an association between chlorination disinfection by-products and congenital anomalies, meta-analyses of all currently available studies demonstrate little evidence of such an association.

Road traffic noise is associated with increased cardiovascular morbidity and mortality and all-cause mortality in London.

Aims Road traffic noise has been associated with hypertension but evidence for the long-term effects on hospital admissions and mortality is limited. We examined the effects of long-term exposure to road traffic noise on hospital admissions and mortality in the general population. Methods and results The study population consisted of 8.6 million inhabitants of London, one of Europes largest cities. We assessed small-area-level associations of day- (7:00–22:59) and nighttime (23:00–06:59) road traffic noise with cardiovascular hospital admissions and all-cause and cardiovascular mortality in all adults (≥25 years) and elderly (≥75 years) through Poisson regression models. We adjusted models for age, sex, area-level socioeconomic deprivation, ethnicity, smoking, air pollution, and neighbourhood spatial structure. Median daytime exposure to road traffic noise was 55.6 dB. Daytime road traffic noise increased the risk of hospital admission for stroke with relative risk (RR) 1.05 [95% confidence interval (CI): 1.02–1.09] in adults, and 1.09 (95% CI: 1.04–1.14) in the elderly in areas >60 vs. <55 dB. Nighttime noise was associated with stroke admissions only among the elderly. Daytime noise was significantly associated with all-cause mortality in adults [RR 1.04 (95% CI: 1.00–1.07) in areas >60 vs. <55 dB]. Positive but non-significant associations were seen with mortality for cardiovascular and ischaemic heart disease, and stroke. Results were similar for the elderly. Conclusions Long-term exposure to road traffic noise was associated with small increased risks of all-cause mortality and cardiovascular mortality and morbidity in the general population, particularly for stroke in the elderly.