Case control study of the geographic variability of exposure to disinfectant byproducts and risk for rectal cancer

At a global scale there are geographic differences in the prevalence of rectal cancer, and the highest rates generally occur in economically developed areas (e.g., Australia, Japan, New Zealand, and North America) compared with less developed areas (e.g., Africa and China). This is most often explained by environmental factors related to diet [1]. There are also geographic disparities within the United States; for example, Devesa et al. [2] summarized geographic patterns of urinary bladder and rectal cancers in the U.S. for the period 1950–94 and noted that throughout the period, high rates clustered in the northeastern United States. Other potential risk factors for rectal cancer include tobacco consumption [3, 4], alcohol consumption [5, 6], genetic disposition [7, 8], occupational exposures [9, 10], diet [5, 11–13], and disinfectant by-products (DBPs), the focus of the present study.

DBPs in water supplies are formed from the interaction of organic material in raw water and an introduced disinfectant. DBPs are particularly problematic in surface water supplies since they generally contain the largest amount of organic material [14]. Early work, published soon after their discovery, found that some of the byproducts of the disinfection process are carcinogenic [15–18]; however, the carcinogenic potential of many DBPs remains unknown [19, 20]. The geographic component of risk stems from the well-established association between DBP formation and pipe retention time [21–24]. If other post-disinfection variables are held constant (pipe condition, temperature etc.), DBP levels generally increase with increasing post-disinfection time (often related strongly to distance), measured from the fresh water treatment plant. Although the relationship between retention/reaction times and DBP formation is a complex one with many possible covariates, in an open pressure water distribution system (one in which greater distance from the treatment plant implies longer pipe retention times) we would expect the highest levels of DBPs to be at those areas at the far reaches of the network. This possible space-time relationship prompted us to examine if there were geographic disparities in the probability of developing rectal cancer within a single distribution system. Although much of the focus concerning the carcinogenic potential of DBPs has centered on the urinary bladder [25–27], some studies have demonstrated a relationship between DBPs and cancers of the colon and/or rectum [28–31], kidney [32], and possible adverse effects on birth outcomes [33–35].

Although mouse models generally support carcinogenicity of some THMs in the intestine, results of studies in human populations are mixed. Evidence in support of carcinogenicity of exposure to disinfected water in the course of everyday activities in human populations [27, 29, 36–40] is offset by equally compelling studies [30, 41, 42] suggesting no significant relationship. In an analysis of six rectal cancer studies conducted prior to 1992, Morris [43] reported a pooled risk of 1.38 for exposure to DBPs. In an earlier study conducted in the county adjacent to where the present study was conducted, Carlo [44] found no association between areas of increased THM levels and rectal cancer. Most similar to the present study, King and Marrett [30] accounted for individual THM intake and found that risk increased for colon cancer as years of exposure to THM increased, but found no such relationship for rectal cancer. Results of the present study suggest that lack of consistent statistical evidence of rectal cancer risk may be at least partially the result of not differentiating exposure to various components of the THM mixture. Rodent studies [45, 46] suggest the brominated compounds to be most carcinogenic in the intestine; however, the brominated compounds are only a component (generally a less volatile component than many other THM compounds, perhaps making it more likely to be consumed in drinking water vs. other routes of exposure) of the total trihalomethanes often used to test exposure-based risk in humans. A 1985 study [47] indicates assessment of relevant individual exposure to organics in drinking water a "thorny barrier to progress" in assessing the risk associated with development of cancer in the digestive tract, and this issue continues to be a challenge to assessing DBPs and cancer risk. We have attempted in the present study to provide some refinement of exposure measurement from previous studies of drinking water and cancer by differentiating and assessing some individual trihalomethane compounds; however, case sample size is limited, and assumptions have been made that also reduce the power of the present study as well.

Cases and controls were nearly identical in age, education, height, weight, and tap water consumption (Table 1). Controls had a slightly longer history using public water sources than cases. Both cases (88%) and controls (91%) spent the majority of their life consuming water at the source indicated during sampling.

per day on the risk of rectal cancer. Note that increasing consumption of alcohol and total calories increase risk, while increased consumption of beta carotene decreases risk. Tap water consumption by itself did not affect rectal cancer risk.

Figure 3 shows the spatial variation in point estimates of rectal cancer risk, resulting from the bromoform model shown in Table 4. Geographic patterns of tap water consumption (one component of consumption exposure, which is estimated as a composite of bromoform concentrations and total tap water consumption) were not as marked (Figure 4) as the geographic distributions of estimated bromoform concentrations (Figure 1). Spatial trends of bromoform estimates closely corresponded to the geographic trend associated with OR's (Figure 3). This suggests that, although both are important, bromoform levels within the system likely had a greater effect on OR's than the amount of tap water that study participants consumed.

This is one of the first studies to use GIS in the exposure assessment to evaluate cancer risk associated with DBPs. The study uses a combination of individual tap water consumption data from a case control study, and geographic-based exposure analysis of disinfectant byproducts and finds increased risk for males exposed to the highest levels of bromoform. The dose-response pattern found for bromoform (Table 5) strengthens the association. Chlorodibromomethane and bromodichloromethane had elevated point estimates and confidence intervals that were marginally significant (OR = 1.78; 95% CI 1.00–3.19, and OR = 1.15; 95% CI 1.00–1.32, respectively).

Chlorinated drinking water contains a large range of byproducts produced during the disinfection process, and although many remain unidentified (accounting for more than fifty percent of the mass of total organic halides) [20], some have been established as carcinogenic. Of the brominated byproducts produced, bromodichloromethane, and bromoform have been shown to be carcinogenic in laboratory animals [45, 46, 53], and chlorine and chloramines were not [46]. Although colorectal cancer risk has been linked with a variety of ecological based water studies [27–29], with the exception of rodent studies, we found no strong previous evidence in the literature suggesting and/or supporting a specific association of rectal cancer risk with exposure to bromoform in humans. Studies of risk associated with exposure to DBPs are often based on indirect exposure assessments that rely on relatively large scales of geographic classifications of DBPs [54], and classification of exposed and unexposed groups is often made based on town, parish, or areas served by specific water treatment systems [28, 29, 31, 42, 55].

We attempted to refine the exposure assessments to improve upon previous studies, and to define a specific amount of DBP consumption that may lead to increased risk. By determining exposure as a mixture of water use patterns for individuals and a more specific estimate for DBPs at the tap, our study builds upon previous work [30, 31, 39] and attempts to examine risk from specific THM components and thereby avoid grouping all THMs together. In our refinement of the THM component of risk, bromoform, bromodichloromethane, and chlorodibromethane stood out as potentially important in the development of rectal cancer. Weaknesses in the approach we use to determine byproduct exposure estimates include (a) a time lag between case control data collection and DBP data collection, (b) the related concern that DBP data were not collected during the most relevant period of exposure, (c) consequences of residential mobility influencing exposure, and (c) kriging has been used on a network, despite being an interpolation method designed for planar data. Despite these limitations, some refinement of exposure in this hybrid study has been attained.

To assess the first two of these limitations, we plotted a time series of THM maps within GIS. From these plots we were able to determine that, at least during the time for which THM data were available (1998–2003), levels decreased slightly, and spatial distributions remained relatively unchanged [52]. In addition, Moran's Index calculated for THM sample sites indicated spatial clustering of values, with the greatest number of samples over 75 ug/l (for Total 551) occurring in the first half (1998–2000) of the sample period [52]. Moran's I did not change much over the period, indicating little change in the spatial pattern. In addition, Figure 2 indicates that, for the period 1986 to 2007, there is not a pronounced tendency for levels to change substantially over time (aside from seasonal variation). In addition, the lines in the figure, representing individual sample sites, do not cross one another in a clear and consistent manner, supporting the contention that spatial variation has not changed substantially.

Cancer studies of DBPs represent a unique challenge that often requires estimating past exposures without the support of relevant measurements [56]. Faced with this problem, many studies of drinking water and cancer base exposure estimates on geographic residence, partitioning space into areas that receive disinfected water and those that do not. Case control studies such as the one presented here, that attempt to determine the effects of exposures that likely take a considerable amount of time to produce an outcome, are subject to subtle or even large changes in the lifestyle of study participants (such as tap water consumption) that may occur over long time periods, and may not be readily recalled or accounted for. The WNY Diet Study data for cases and controls were collected over the period from 1979–1985. Mean age of study participants during the time of data collection was approximately 64 years. On average, potential exposure to DBPs started in the 1950's and continued until the time of interview. Our assumptions are similar in some respect to those in the original study that examined drinking water and cancer [49]. These assumptions are that water intake indicated during the case control interview is representative of water intake levels during a significant part of the participant's life span, and that spatial-based estimates of THM levels are reasonable representations of spatial patterns of THM distributions in the past. Regardless of how DBP exposure is determined, either by direct testing at the tap (essentially a 'snapshot' of DBP levels), or some attempt to model exposure based on historic and or current DBP levels [26, 30] such assumptions regarding the spatial distributions of DBPs are required.

Residential mobility is unlikely to have had detrimental effects on our analyses. Cases and controls spent a large percentage of their lives at the water source indicated during interviews (Table 1). This reflects the relatively low mobility that characterizes the region.

Kriging DBP levels within a distribution system is a novel and potentially more accurate means of determining exposure in DBP cancer studies through spatial interpolation. Future work will be aimed at using network distance in place of planar distance in the spatial interpolation.

Although changes and reductions of some DBPs upon boiling are possible [57], we found no difference between hot water tap consumption and cold water tap consumption on rectal cancer risks in our study; this may be due in part to a sample size in the current study that may have been too small to measure such an effect. It may also be the case that bromoform is serving as a surrogate for exposure to some of the most mutagenic brominated forms of other DBPs such as MX that are not affected by volatization such as BMX-1, BMX-2, BMX-3 (58, 59).

Some studies [60, 61] indicate that the causal relationship between rectal cancer and THMs remains an open question; however, "evidence is somewhat stronger for rectal cancer than colon cancer" [60]. Although many of the myriad possibilities of exposure routes, some of which have shown to significantly affect THM blood levels [62, 63] (e.g. dishwashing, showering, swimming), have yet to be tested for their potential to influence risk, digestive tract cancers are more likely to be influenced by direct consumption than by inhalation or dermal routes. In addition, bromoform was not found to increase in the blood following certain daily activities [62].

Disinfectant byproducts in drinking water have garnered a considerable amount of attention since their discovery in 1975. Although many byproducts are thought to have carcinogenic potential, much of the focus has been on the trihalomethane group. Despite numerous clinical and field studies examining the effects on human health of DBP exposure, no conclusive paper has emerged that suggests what level of exposure might be acceptable. In the U.S.A, for many contaminants the Environmental Protection Agency establishes a health goal or maximum contaminant level (MCL). The goals are not necessarily legal limits with which water systems must comply. It should be noted that MCWA was well within compliance with federal standards for total trihalomethanes during the entire sampling period. At no time during the five-year testing period did the system exceed the previous (effective until 12/30/01) legal MCLs for total trihalomethanes of 0.10 mg/l²; the current standards for bromoform (0.08 ug/l²), were marginally exceeded only a handful of times for all samples.

It is certain that the present study has exposure misclassification, but we have no reason to believe that it is differential between cases and controls, and hence any misclassification should bias risk estimates towards the null. Nonetheless, we found elevated risk estimates for the highest estimated levels of exposure to THMs. Our study has the advantage of measures of individual intake of drinking water, and estimated exposure to THMs based on location of residence in the distribution system coupled with a study population with a stable residential history.

A logistic regression model based on data for 128 cases of rectal cancer and 253 controls in Monroe County, NY, revealed increased risk for rectal cancer with increased levels of particular DBPs. In particular we found that locations with a high level of bromoform in the water distribution system corresponded with an increase in the odds ratio (OR = 1.85; 95% CI = 1.25 – 9.56) for rectal cancer. In addition to bromoform level at a given location, consumption of bromoform was also significant. The highest quartiles of estimated consumption of bromoform (1.69–15.43 ug/day) led to increased risk for rectal cancer (OR = 2.32; 95% CI = 1.22–4.39). Two other THMs were marginally associated with a possible increase in risk (chlorodibromomethane (OR = 1.78, 95% CI = 1.00–3.19) and bromodichloromethane (OR = 1.15; 95% CI = 1.00–1.32)).