Literature Review of Meta-Analyses and Pooled Analyses of

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Chapter 24

Literature Review of Meta-Analyses and Pooled Analyses of Disinfection By-Products in Drinking Water and Cancer and Reproductive Health Outcomes Mark J. Nieuwenhuijsen,*,1,2 James Grellier,2 Nina Iszatt,2 David Martinez,1 Md Bayzidur Rahman,3 and Cristina M. Villanueva1 1CREAL,

Barcelona, Spain College London, United Kingdom 3The University of New South Wales, Australia * Address correspondence to: Mark J. Nieuwenhuijsen, Ph.D., Research Professor in Environmental Epidemiology, Center for Research in Environmental Epidemiology (CREAL), Parc de Recerca Biomèdica de Barcelona - PRBB (office 183.05) C. Doctor Aiguader, 88, 08003 Barcelona, Spain. Tel.: direct (+34) 93 2147337. Assistant: Anna Sillero: (++34) 93 2147390. Fax: (++34) 93 2147302. Email: [email protected]. Web pages: http://www.creal.cat/ http://www.prbb.org/. 2Imperial

Disinfection of drinking water has led to major improvements in public health in developed countries since its introduction in the first half of the 20th century. Chlorination disinfection by-products (DBPs) are formed when water is chlorinated and organic matter in the water reacts with chlorine. A number of meta-analyses and pooled analyses of exposure to DBPs and various health outcomes have been published and here we review these studies to provide an overall overview of the evidence of disinfection by-products and health effects. This review showed that various meta-analyses and pooled analyses have found statistically significant excess risk for some indicator of exposure to chlorinated water or trihalomethanes and bladder and colorectal cancer, small for gestational age, still birth, all congenital anomalies combined and ventricular septal defects, but no statistical significant excess risk for many other © 2010 American Chemical Society Halden; Contaminants of Emerging Concern in the Environment: Ecological and Human Health Considerations ACS Symposium Series; American Chemical Society: Washington, DC, 2010.

congenital anomalies. The excess risk was generally small, but robust, with little sensitivity to the results of individual studies or evidence of publication bias.

Acronyms OR:


RR:

CI:

LBW: TLBW: PTD: SGA: IUGR: THM: TTHM:

DBPs: Meta-analysis:

Pooled analysis:

Odds Ratio. It is a measure of the probability of having a disease provided a certain level of exposure compared to a referent category. OR is used in case-control and crosssectional studies and interpretation is similar to RR Relative Risk. It is a measure of the probability of having a disease provided a certain level of exposure compared to a referent category. RR is used in cohort studies and interpretation is similar to OR. Confidence Interval, usually given as 95% CI. Provides information on the statistical significance of a point risk estimate (odds ratio or relative risk). low birth weight , generally defined as birth weight < 2500 g term low birth weight, generally defined as birth weight < 2500 g at week 37 or older preterm delivery, generally defined as a birth with gestational age < 37 weeks small for gestational age, generally defined as birth weight below the 10%ile at a given gestational age intra uterine growth retardation, generally defined as birth weight below the 10%ile at a given gestational age Trihalomethane total trihalomethanes, the sum of chloroform, chlorodibromomethane, bromodichloromethane and bromoform disinfection by-products statistical method to combine the results of different studies, usually which have been peer reviewed, using the original risk estimates (e.g. RR, OR) of the individual studies to obtain an overall summary estimate(s) of exposure and disease statistical method to combine the results of different studies, usually which have been peer reviewed, using subject level data of the different studies to obtain an overall summary estimate(s) of exposure and disease

484 Halden; Contaminants of Emerging Concern in the Environment: Ecological and Human Health Considerations ACS Symposium Series; American Chemical Society: Washington, DC, 2010.


Introduction Disinfection of drinking water has led to major improvements in public health in developed countries since its introduction in the first half of the 20th century. It has now been more than 30 years since the discovery that by-products can be formed in small quantities as part of the chlorination process (1). Chlorination disinfection by-products (DBPs) are formed when water is chlorinated and organic matter in the water reacts with chlorine. Up to 600 DBPs have been identified (2, 3), and these chemicals differ considerably in their physicochemical properties, including volatility. Their formation and occurrence depend on many factors, including disinfectant dose, type of treatment, pH, temperature, residence time, water source, and bromine levels (4, 5). Different mixtures of by-products may exist in different locations depending on the various factors mentioned above, making it more difficult to ascertain the risk, if any, of health effects in relation to specific DBPs and mixtures of DBPs, as well as to compare findings from different epidemiological studies. The most frequently used disinfectants are chlorine and other chlorine-based chemicals (chlorine dioxide, chloramine, etc.). Other disinfectants used in drinking water are ozone, potassium permanganate, UV radiation, hydrogen peroxide, etc. All these are highly reactive chemical that produces a mixture of by-products after reacting with organic matter. The trihalomethanes (THMs) are the most commonly formed group of byproducts. Concentrations of four THMs are routinely monitored in many countries and have therefore been used most frequently as an indicator of exposure to DBPs. THMs are volatile and individuals may be exposed not only through ingestion but also through inhalation and dermal absorption, during activities such as showering, bathing, and swimming. Recent modelling of THM uptake suggest that dermal and inhalation exposure may lead to the highest levels in blood (6). For non-volatile DBPs, such as the haloacetic acids (HAAs), ingestion is thought to be the main route of exposure (4). Several reviews of associations between exposure to DBPs and several health outcomes have been conducted. Overall these reviews have concluded that relationships between DBP exposure and health outcomes remain unclear (5, 7–12). However, most of these reviews have been qualitative rather than quantitative, and have not attempted to provide overall summary estimates for DBP exposure and health effects. The reviews have not taken into account the size of individual studies, nor provided systematic analyses of methodological heterogeneities between the studies. Meta-analyses and pooled analyses systematically combine data from a number of studies to estimate overall summary measures of association, and permit the investigation of heterogeneities between studies. A number of meta-analyses and pooled analyses of exposure to DBPs and various health outcomes have been published and here we review these studies to provide an overall overview of the evidence of disinfection by-products and health effects, as well as discussing some of the limitations of the studies. Since meta-analyses and pooled analyses can only be conducted when a number of studies have been carried out, we focus on outcomes that have been more frequently studied and ignore the less investigated outcomes such as time to pregnancy, semen quality, and cancers of the kidney, lung and skin. 485 Halden; Contaminants of Emerging Concern in the Environment: Ecological and Human Health Considerations ACS Symposium Series; American Chemical Society: Washington, DC, 2010.

Meta-Analyses and Pooled Analyses of Health Effects Related to Exposure to Chlorination Disinfection By-Products


Cancers The first meta-analysis of the association between chlorinated drinking water and by-products and cancer was conducted by Morris et al. (13) and included ten studies on various types of cancer. It included 7 studies on bladder cancer, 7 studies on colon cancer, and 6 studies on rectal cancer. Consumption of chlorinated water, surface water, or water with high levels of chloroform was used as a surrogate for exposure to chlorination by-products. A meta-analysis of all cancer sites yielded a relative risk estimate for exposure to chlorination by-products of 1.15 (95% CI 1.09 to 1.20). Summary relative risk estimates for organ-specific cancers were 1.21 (95% CI 1.09 to 1.34) for bladder cancer, 1.38 (95% CI 1.01 to 1.87) for rectal cancer and 1.11 (95% CI 0.91 to 1.37) for colon cancer. Villanueva et al. (14) included six case-control studies (6084 incident bladder cancer cases and 10,816 controls) and two cohort studies (124 incident bladder cancer cases) in their meta-analysis of bladder cancer. “Ever consumed” (vs. “never consumed”) chlorinated drinking water was associated with an statistically significant increased risk of bladder cancer in men (combined odds ratio [OR]=1.4, 95% CI 1.1 to 1.9) and a statistically significant increased risk in women (combined OR=1.2, 95% CI 0.7 to 1.8). The combined OR for mid-term exposure for both sexes was 1.1 (95% CI 1.0 to 1.2) and for long-term exposure 1.4 (95% CI 1.2 to 1.7). The combined estimate of the slope for a linear increase in risk was 1.13 (95% CI 1.08 to 1.20) for 20 years and 1.27 (95% CI 1.15 to 1.43) for 40 years of exposure for both sexes.

Table I. Pooled analysis of bladder cancer and THM

*

THM Exposure level (µg/l)

Men OR* (95%CI)

Women OR* (95%CI)

0-1 ‡

1.00

1.00

>1-5

1.10 (0.92-1.31)

0.99 (0.72-1.36)

>25-50

1.25 (1.04-1.50)

1.04 (0.76-1.43)

>50

1.44 (1.20-1.73)

0.93 (0.67-1.28)

OR (95%CI) = Odds ratio (95% confidence interval).



In a pooled analysis, Villanueva et al. (15) included 2806 cases and 5254 controls, for which measures of exposure were known for at least 70% of the exposure window of 40 years, specifically, 45 to 5 years before the interview. Cumulative exposure to THMs was estimated by combining individual year-byyear average THM level and daily tap water consumption. The resulting adjusted OR for men exposed to an average of more than 1 µg/L THMs compared with those who had lower or no exposure was 1.24 (95% CI 1.09 to 1.41). Estimated relative risks increased with increasing exposure, with an OR of 1.44 (95% CI 1.20 to 1.73) for exposure higher than 50 µg/L. Similar results were found with other indices of THM exposure. Among women, THM exposure was not associated with bladder cancer risk (OR = 0.95; 95% CI 0.76 to 1.20) (Table I). After Villanueva et al. (15) Rahman et al. (16) conducted a meta-analysis of colorectal cancer with 13 studies (3 cohort and 10 case-control studies). In this meta-analysis the effect measures were pooled by using random effects methods comparing the highest exposure category with the lowest one. For colon cancer, the pooled relative risk (RR) from cohort studies was 1.11 (95% CI: 0.73 to 1.70), the odds ratio (OR) from case-control studies was 1.33 (95% CI: 1.12 to 1.57), and the pooled estimate combining both study types, assuming OR as a close estimate of RR, was 1.27 (95% CI: 1.08 to 1.50). For rectal cancer, pooled RR was 0.88 (95% CI: 0.57 to 1.35), pooled OR was 1.40 (95% CI: 1.15 to 1.70), and the pooled RR combining both study types was 1.30 (95% CI: 1.06 to 1.59).

Reproductive Outcomes Two meta-analyses by Hwang and Jaakkola (17) and Hwang et al. (18) reported evidence for an effect of exposure to chlorination by-products on the risk of neural tube, urinary system and ventricular septal defects, but risks for other anomalies were considered heterogeneous and inconclusive. However, the meta-analysis by Hwang and Jaakkola. (17) only included five studies and did not include more recent studies, while the study by Hwang et al. (18) generally focused on a few subcategories of anomalies, and also did not include the most up-to-date studies available. Nieuwenhuijsen et al. (19) conducted meta-analyses including all studies of DBPs and congenital anomalies. For all congenital anomalies combined, the meta-analysis presented evidence of an excess risk for high versus low exposure to water chlorination or TTHM (OR = 1.17, 95% CI 1.02 to 1.34), based on a small number of studies. The meta-analysis also suggested a statistically significant excess risk for ventricular septal defects (OR = 1.59 95% CI 1.21 to 2.07), but this was based on only three studies and there was little evidence of an exposure-response relationship. Other congenital anomalies did not show statistically significant excess risk. (Tables II and III).


Table II. Meta-analyses disinfection by-product exposure and congenital anomalies: highest versus lowest exposure Congenital anomalies

N*

OR** (95%CI)

All

5

1.17 (1.02-1.34)

Neural tube

8

1.06 (0.89-1.26)

Major Cardiac

8

1.16 (0.98-1.37)

3

1.59 (1.21-2.07)

Respiratory

4

1.12 (0.91-1.37)

Cleft lip/palate

7

0.98 (0.88-1.08)

Urinary tract

4

1.33 (0.92-1.92)

Hypospadias

4

1.03 (0.84-1.28)


Ventricular septal

*

N= number of studies.

**

= highest versus lowest exposure category.

Table III. Meta-analyses of disinfection by-product exposure and congenital anomalies: total trihalomethane exposure Congenital anomalies

N*

OR** (95%CI)

Neural tube

7

1.006 (0.950-1.065)

Major cardiac

5

0.993 (0.947-1.041)

5

1.003 (0.960-1.048)

Cleft lip/palate *

N= number of studies.

**

Per 10 µg/L increase in Total trihalomethanes.

After Nieuwenhuijsen et al. (19) Grellier et al. (20) conducted meta-analyses of total trihalomethane concentration and low birth weight (LBW), term low birth weight (TLBW), preterm delivery (PTD) and small for gestational age (SGA) (including intra uterine growth retardation (IUGR)). They found little or no evidence for associations between third trimester TTHM exposure and LBW (OR per 10 µg TTHM/L increase = 0.9999, 95% CI 0.9735 to 1.0270), TLBW (OR per 10 µg TTHM/L increase = 1.0337, 95% CI 0.9272 to 1.1525) or PTD (OR per 10 µg TTHM/L increase = 0.9896, 95% CI 0.9781 to 1.0013). They did find, however, evidence for an association with SGA (OR per 10 µg TTHM/L increase = 1.0100 95% CI 1.0006, 1.0194) (Table IV).


Table IV. Meta analyses of trihalomethane exposure and pre-term delivery, low birth weight and small for gestational age Exposure agent indicator

Exposure timing


Third trimester

Total THM

Any exposure timing

Entire pregnancy only

Health outcome

Number of studies included

OR Upslope Lower per CI per CI 10µg/L

LBW

4

0.9999 0.9735 1.0270 0.9876

PTD

6

0.9896 0.9781 1.0013 0.0814

SGA

6

1.0100 1.0006 1.0194 0.0361

LBW

5

1.0013 0.9747 1.0286 0.9267

PTD

8

0.9894 0.9777 1.0007 0.0653

SGA

8

1.0096 1.0009 1.0184 0.0309

SGA

4

1.0105 0.9712 1.0514 0.6059

p-value

Table V. Meta-analyses of disinfection by-product exposure and stillbirth



After Grellier et al. (20) A meta-analysis of exposure to chlorination byproducts and stillbirth conducted as part of this review chapter and presented in Table V showed a small excess risk of stillbirth (9%, 95%CI 2% to 17%) when comparing the highest with the lowest exposure groups in the studies. The study by Aschengrau et al. (21) was left out of this meta-analysis because it compared chlorination with chloramination, and including the study resulted in statistically significant heterogeneity. Including the study increased the summary estimate somewhat (15%, 95%CI 0-33%). Aschengrau et al. (21) was excluded from the analyses because the reference group was chloraminated. In Jaakkola et al. (23) the exposures are chlorination yes/no and colour (low, medium high)

Discussion This review showed that various meta-analyses and pooled analyses have found statistically significant excess risk for some indicator of exposure to chlorinated water or trihalomethanes and bladder and colorectal cancer, small for gestational age, still birth, all congenital anomalies combined and ventricular septal defects, but no statistical significant excess risk for many other congenital anomalies. The excess risk was generally small, but robust, with little sensitivity to the results of individual studies or evidence of publication bias. Epidemiological studies investigating exposure to disinfection by-products and health outcomes have been limited by a number of factors including the relative crude exposure assessment (perhaps with the exception of some of the more recent studies), small samples sizes, heterogeneity in some outcomes, and, to a lesser extent, potential for bias and confounding. The factors limiting the available meta-analyses and pooled analyses of this evidence base have been the lack studies on DBPs other than THMs and (explicit) inclusion of various exposure routes such as inhalation and dermal absorption. Furthermore, the number of epidemiological studies available has often been small which limits the possibility in meta-analysis of stratifying by study characteristics or carrying out meta-regression. These factors together may explain some of the mixed results, and possibly the lack of associations for some of the congenital anomalies. Furthermore, combined with the small number of studies included in the meta-analyses, these factors also reduce the strength of any conclusions that can be drawn from meta-analyses and pooled analyses. These analyses are therefore not meant to provide definitive conclusions on the subject, but instead serve as a useful tool to evaluate the current status of this growing body of research and to offer guidance for the way forward. Crude exposure assessment leading to exposure misclassification or measurement error may bias the measures of effect towards the null. The use of ecologic water supply zone estimates as an exposure index may result in exposure misclassification (27). Also, cancer studies involve retrospective exposure assessment and have to go back many years in time, which makes it more difficult to get good quality exposure data. Furthermore, whilst ingestion has 490 Halden; Contaminants of Emerging Concern in the Environment: Ecological and Human Health Considerations ACS Symposium Series; American Chemical Society: Washington, DC, 2010.


generally been the primary exposure route of interest, uptake through showering, bathing and swimming could be considerable, specifically for THMs due to their volatility, but these routes have only been considered in a few studies, and not in the meta-analyses and pooled analyses. In addition, exposure estimates in many reproductive studies have been based primarily on maternal residence at birth. This ignores any exposure which occurs outside the home, e.g. in the workplace (28), and also ignores the possibility e.g. that a mother may have moved her household during her pregnancy (29, 30). Exposure assessment based on maternal residence at birth may, therefore, result in exposure misclassification. On the whole, epidemiological studies have used THMs as a proxy for total DBP load, but THMs are not necessarily a good proxy measure. Some recent studies have therefore investigated other DBPs such as HAAs and mutagen X (MX) but for the meta-analyses and pooled analyses only THMs were available. The metabolism of different DBP species varies (5), so it is insufficient to analyse DBPs as a whole, or to use TTHM as a proxy. Investigation of the relation between non-THM by-products and the outcomes is required in order to help elucidate the specific DBP driving the associations observed. A detailed assessment of the DBP mixture is necessary to explain any observed epidemiological results. In addition, studies from some countries, including Scandinavia, have generally shown low levels of DBPs with a small range, making the assessment of risks more difficult due to both a higher probability of exposure misclassification and a smaller difference in exposure between dose groups. Where seasonal variability in DBPs has not been taken into account further errors in the exposure assessment are likely. Sample sizes have often been insufficient to produce robust results, specifically for congenital anomalies and, to a lesser extent, for stillbirth, and other outcomes. However, there are exceptions, for example, studies on SGA/IUGR, which provided sufficiently large numbers of cases to create various exposure categories with more robust risk estimates, which should improve the overall assessment of risk. Some outcomes such as congenital anomalies have not been well defined and/or are difficult to study. Congenital anomalies have often been analysed either as one group or in main categories e.g. neural tube, major heart and abdominal defects, due to the small number of cases in each study. These anomalies, however, are generally heterogeneous with respect to both phenotype and presumed aetiology. Nieuwenhuijsen et al. (31) showed that focusing on isolated subcategories may produce different findings. Furthermore, in some countries, registration of congenital anomalies may occur up to one year after the birth (e.g in Taiwan), which will improve the completeness of the registry, by including cases that are more difficult to identify at birth such as hypospadias. The retrospective and registry based nature of many of the reproductive studies has meant that information on potential confounders, and other risk factors for birth outcomes, such as maternal smoking and alcohol consumption have often been lacking. Investigation of gene-environment interaction and/or the effects on susceptible groups has been limited (e.g. (32–34)). Preliminary studies suggest that certain groups may be more susceptible to the influence of DBPs (35), and 491 Halden; Contaminants of Emerging Concern in the Environment: Ecological and Human Health Considerations ACS Symposium Series; American Chemical Society: Washington, DC, 2010.


thus these effects may be masked in studies which only look at the population in general. A limitation of the presented meta-analyses and pooled analyses is the relatively small number of studies, and therefore the need to conduct relatively simple analyses, comparing high versus low exposure categories and combining what could be regarded as different and/or inconsistent estimates of exposure (e.g. high vs. low TTHM concentration and chlorination vs. non-chlorination). However, what in one study is a high level of THMs may be low in another study. While it is assumed that the meta-analysis is statistically accurate, the biological basis for comparing studies with this degree of heterogeneity in the definition of exposure is more problematic and this should be taken into account when interpreting the results. Ideally, all the exposure categories have the same cutoffs but in practice this is often impossible because of the different local conditions. The analyses of TTHM exposure-response relationships combined more comparable exposure levels and are therefore probably more informative, but could only be conducted for a few endpoints because of the lack of a sufficient number of studies. The question is here though whether TTHM may be the putative agent or a (not so good) marker for something else. The Way Forward Given the many studies that have been conducted and the limited evidence for a strong association between chlorination by-products and cancer and reproductive outcomes, we might ask whether there is a need to conduct more studies, and if so, what should they look at? Disinfection of drinking water is an important part of public health and many people are potentially exposed to chlorination by-products; ongoing surveillance of any possible adverse health effects is therefore warranted, even though the relative risks may be small. As mentioned above, the mixture of the by-products may differ by geographical area and by time, for example because of changes in water treatment methods. However, generally only indicator substances such as TTHM have been used to examine the health risks. It is important that we understand the underlying mixture of the by-products, both of existing and new studies, and where possible examine any possible health risks of specific DBPs or mixtures. There is a need to study any possible effects in more specific places, for example where we can examine the potential effects of certain mixtures such as brominated species. Places such as Perth, Australia or Barcelona, Spain may be suitable locations because of the high levels of brominated compounds in their drinking water. Furthermore, it would be worthwhile examining the various exposure pathways and routes other than ingestion in more detail, specifically for volatile by-products such as THMs, since the level of exposure and metabolism may be different, and the measures for exposure prevention are likely to be different. The exposure assessment should also take into account the effect of post tap water processing methods (boiling, filtering, storing etc) on DBP concentration because filtering and boiling can substantially reduce some of the DBP concentration. For studies of cancer and congenital anomalies, this can probably only be done in case-control studies but these would have to be able to estimate exposure 492 Halden; Contaminants of Emerging Concern in the Environment: Ecological and Human Health Considerations ACS Symposium Series; American Chemical Society: Washington, DC, 2010.


during the most critical (early) periods of pregnancy, which may prove difficult. Prospective exposure assessment through a cohort design would be more ideal, but practical and financial constraints preclude such a study, as the size of the cohort would need to be extremely large to study rare diseases. Regarding the outcomes, the focus of future studies should be on subcategories of congenital anomalies, rather than on the whole group, and should focus on anomalies for which the ascertainment is reasonably complete and consistent if registry-based designs were used. Findings for ventricular septal defects should be followed up, preferably in well-designed case-control studies. Furthermore, the study by Nieuwenhuijsen et al. (31) showed an excess risk for bromoform and gastroschisis and this may worth examining in more detail, and in a different population. One of the problems in this study was the low levels of bromoform in England and Wales, and therefore it should be examined in places where bromoform levels are higher (such as Perth). Further work is needed on the relation between potential confounders such as smoking and alcohol intake and the relation with the by-products in the water and personal behavioural characteristics such as tap water ingestion (instead of bottled water), showering and bathing to examine to what extent confounding may explain findings for registry based studies where this information is missing. Mechanisms of action of DBPs are not clearly understood. There is some suggestion that some chlorination by-products may interfere with folate metabolism, and this and other potential mechanisms such as oxidative stress and genotoxicity, could be examined with biomarkers in pregnant women to assess to what extent this may be possible. Furthermore, genotyping may identify susceptible populations (for example according to variants of DBP metabolising enzymes such as CYP2E1, GSTT1, etc.).

Acknowledgements and Funding The work was conducted without specific allocated funding but contribution were made by researchers working on the INTARESE project (Integrated Assessment of Health Risks of Environmental Stressors in Europe), co-funded by the European Commission under the Sixth Framework Programme (2002-2006) and HIWATE (Health impacts of long-term exposure to disinfection by-products in drinking water in Europe) project, which is a three and a half year Specific Targeted Research Project, funded under the EU Sixth Framework Programme for Research and Technological Development by the Research Directorate-Biotechnology, Agriculture and Food Research Unit (Contract no Food-CT-2006-036224).

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