1 Centers for Occupational and Environmental Health and Family and Community Health, University of California, Berkeley, School of Public Health, Berkeley, CA.
2 National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC.
3 Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
4 Office of Groundwater and Drinking Water, US Environmental Protection Agency, Washington, DC.
5 US Environmental Protection Agency National Homeland Security Research Center, Cincinnati, OH.
6 University of California, Berkeley Survey Research Center, Berkeley, CA.
7 Division of Biostatistics, University of California, Berkeley, School of Public Health, Berkeley, CA.
Received for publication May 10, 2004; accepted for publication October 6, 2004
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ABSTRACT |
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drinking; epidemiologic studies; gastrointestinal diseases; intervention studies; randomized controlled trials; water; water supply
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INTRODUCTION |
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We report here the results of the Water Evaluation Trial, a full-scale trial designed after a pilot trial was completed (6). This full-scale trial was a randomized, controlled, triple-blinded, crossover intervention study performed in Davenport, Iowa, and its surrounding communities along the Mississippi River. The principal objective was to measure the change in the incidence of gastrointestinal illness from use of supplemental in-home drinking water treatment by a healthy population consuming tap water. This tap water was supplied by a municipal system using conventional treatment methods to purify microbiologically contaminated river water while maintaining the system to meet all current US regulatory standards.
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MATERIALS AND METHODS |
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Active and sham water treatment devices and installation
Point-of-use devices for the trial were solicited in a national bid with more than 20 respondents and were selected to maximize microbial disinfection while minimizing effects on taste and chemical properties. On the basis of our experience in the pilot study (6), countertop units were chosen to minimize difficulties with installation and use.
We selected 1-µm filtration and ultraviolet treatment to reduce potential microbial contamination with minimal effect on taste and other qualities of the water. Unlike reverse osmosis devices and devices that use carbon filtration, the device that was used does not change the chemical composition of the water. This characteristic was desirable to maintain participant blinding.
The device selected was designed and manufactured by a firm selling similar devices in domestic and international markets. The active device consisted of a 1-µm ceramic prefilter and ultraviolet treatment with an output of 35,00038,000 µW-second/cm2. Except for replacement of the pressed activated carbon block filter with a ceramic 1-µm filter (to avoid noticeable changes in the waters taste and odor usually associated with the use of carbon filters), the device is identical to a commercially available model (class A) certified by the National Sanitary Foundation (model E-8301J; Amway Access Business Group, Ada, Michigan), used extensively in Asia. The installed devices were rectangular, with approximate dimensions of 5 1/2 (13.34 cm) inches wide by 8 inches (20.32 cm) long by 11 1/2 inches (29.21 cm) high. A diverter was attached to the faucet and was connected to the device. The diverter could be set to receive water through the treatment device (treated water) or directly through the kitchen faucet (untreated water).
Sham devices were identical to active devices in every respect but had an empty filter chamber, and the ultraviolet bulb was surrounded by an ultraviolet absorbing glass sleeve instead of the quartz sleeve present in the active devices. This sleeve effectively blocks transmission of radiation while providing the same light and heat associated with ultraviolet lamps surrounded by the quartz sleeve.
Study area
Several criteria were used to select the site: the community had to receive drinking water from one microbiologically challenged (i.e., with known upstream-contaminated discharges containing human waste) surface water (river) source; the source water had to be treated at one water treatment plant; the water had to be treated by conventional drinking water treatment methods to meet all US microbial regulatory standards (1012); and the community had to be large enough so that we could recruit 400 households for a study (estimated to be about 100,000 households based on participation rates in prior trials) (36). An additional consideration was the willingness of the utility to provide data on treatment performance. The source water for the study site was one of the most contaminated of among 300 systems on which pathogen data were available (13).
Finding a study site that could provide useful data as one piece of information in the development of a national estimate of disease occurrence was a key concern in developing and weighing the importance of the different selection criteria. The goal was to select a system "typical" of the type that serves a large percentage of the US population (e.g., a large system that complies with drinking water regulations), and, recognizing that an affordable-size study would be able to detect only a large fraction of illness, such as measured in prior Canadian studies (3, 4), it was important that the system be subject to a high level of microbial risk (i.e., a system with extremely challenged source water). Other studies conducted at other sites in the United States with different water treatment characteristics would be needed to fully estimate a national attributable risk.
Numerous municipalities were considered by the CDC, the EPA, and our team. Ultimately, the Davenport/Bettendorf area of Scott County, Iowa, best fulfilled these criteria. The trial was performed in the cities of Davenport and Bettendorf and the associated neighboring communities of Panorama Park and Riverdale, all located in Scott County, Iowa, and served by the Iowa American Water Company.
Municipal water supply and treatment
The residents in the study area received their municipal water from a single source, the Mississippi River, which is treated at a single plant. Extensive monitoring for pathogens and indicators of fecal contamination conducted by the local water utility from 1990 to 1998 indicated that the Mississippi River at Davenport was a challenged source with evidence of human fecal contamination (14). Sampling during the time of the trial showed similar levels (data available on request from the authors). Finished water consistently met all state and federal standards for the year prior to the trial and during the trial. The utility is also one of a select group of utilities that have received the Directors Award from the Partnership for SafeWater (an organization founded by EPA, state regulators, and the drinking water industry) for their efforts to produce water that exceeds current regulatory filtration performance standards (15, 16).
The water utility uses "conventional" treatment consisting of coagulation, flocculation, sedimentation, filtration through granular activated carbon/sand filters, and chlorination. Granular activated carbon is used as a combination filtration/adsorption medium to remove organics and to treat objectionable tastes and odors (refer to the following website: www.iawater.com). Treatment performance and management of the distribution system during the intervention trial period are discussed in detail in a separate report (17).
Recruitment and enrollment
Recruitment began on October 16, 2000. The eligible population consisted of households served by the Iowa American Water Company in the communities of Davenport, Bettendorf, Riverdale, and Panorama Park. Apartments were excluded because of concern that their water may not be representative of the water in the community because of the potentially increased risk of plumbing cross-connections within apartment buildings. The water utility provided a list of all 40,403 residential service addresses. Of these, 2,050 addresses with post office boxes (likely to be businesses or apartments), out-of-service addresses, addresses outside the study area, and apartment numbers were excluded. Solicitations for enrollment were sent to the remaining 38,353 addresses in randomly selected blocks, taking a proportionate number of addresses from each ZIP Code between October 16, 2000, and January 25, 2001.
The mailing provided information about the study, with a toll-free telephone number and a postcard. Households were excluded if they contained an employee of the Iowa American Water Company, had an address outside the local utility water service area, consumed less than 75 percent of their in-home drinking water from the tap, contained an immunocompromised person (including one with human immunodeficiency virus or active cancer under treatment), or included any member who had been advised by a physician to drink only bottled or specially treated water.
For each participant, the entire trial was 54 weeks long (26 weeks during cycle A, a 2-week washout period, and 26 weeks during cycle B). During the washout period, participants used no device but continued to complete health diaries. The length of the washout period was chosen to be longer than the symptomatic period of most likely infectious causes of gastrointestinal illness (18). Enrollment was completed on May 30, 2001, with a final enrollment of 456 households and 1,296 individual persons.
Randomization and (triple) blinding
Households were randomly assigned by block in blocks of 14 with equal probability to receive either an active or a sham device. A randomized list of device assignment codes was prepared by an unblinded staff member not involved with installation or analysis and was sent to the manufacturer. Device assignments were hidden from the investigators and installers, the study subjects, and the data analysts. All analyses were conducted by using a noninformative code for device type. Investigators remained blinded to household assignment until after all analyses were completed and finalized and the first draft of this manuscript had been written and circulated. Households contacted the research center or returned postcards to participate. After consent forms were returned, randomly assigned devices were allocated from an offsite list.
Health outcomes
Adult household members recorded daily occurrences of illness in their health diaries. An adult member recorded responses for children under age 12 years. The principal health outcome measured was episodes of "highly credible gastrointestinal illness" (HCGI), a previously published measure (36). A new episode was defined as any of the following four conditions, preceded by at least six HCGI-free days: 1) vomiting, 2) watery diarrhea, 3) soft diarrhea and abdominal cramps, or 4) nausea and abdominal cramps. The requirement for six disease-free days between episodes was used to increase the likelihood that separate episodes truly represented distinct infections (rather than a prolonged course of one infection) (36).
Statistical methods
Blinding Index
Blinding was measured by using the "Blinding Index" of James et al. (19). Full details on its use in a drinking water intervention trial were reported in the pilot study (6).
Analysis of HGCI
The primary statistical analysis presented in this paper evaluated the effect of in-home water treatment on two individual-level outcomes: counts of the numbers of episodes of HCGI (the primary outcome of the study) and counts of the days (a prespecified secondary outcome) during each treatment cycle. We denote the outcome as Yi,j, the number of person-years of observation time as Ti,j , and ai,j as the treatment assignment for the ith individual during the jth cycle. The treatment variable ai,j = 0 if the individual was in a household receiving the active device during the jth cycle; otherwise, ai,j = 1. For the initial 6-month observation period (cycle A), we let j = 0, while, after the crossover, j = 1.
To estimate a treatment effect that can take into account both a cycle effect (before vs. after crossover) and a treatment-by-cycle interaction, we fit a log-linear generalized estimating equation model (20). This statistical model is appropriate for correlated count outcomes that may exhibit extra-Poisson variability. Using this approach, we modeled the log of the mean incidence rate for each individual measurement as follows: log E(Yi,j) = ß0 + log Ti,j + ß1j + ß2ai,j + ß3jai,j.
Here, ß1 is the period effect, ß2 is the effect of drinking untreated tap water, and ß3 is a treatment-cycle interaction. The parameter estimates are interpreted as being the change in a marginal log rate. For example, the parameter exp(ß2) can be interpreted as the ratio of the average rate of illness for an individual from an untreated household to the average rate of illness for an individual from a treated household during the first cycle. The effect of drinking untreated water during the second cycle is given by exp(ß2 + ß3). For maximal statistical efficiency, we used a working correlation matrix with a structure that accounted for both within-subject and within-household correlation. The standard errors of the parameter estimates are computed robustly and are asymptotically valid when the empirical variance-covariance matrix is used (20). Diggle et al. (21) illustrated the use of the generalized estimating equation approach to analyze data from a crossover trial with a dichotomous outcome.
Data (prior to dropout) from households that dropped out of the trial at any point after randomization were retained (intention-to-treat analysis).
Water consumption (exposure measurement)
Water consumption (i.e., the degree of exposure to the intervention) was measured in two ways. First, self-reported data were collected from participants by using questions inserted into the health diary at 2-week intervals. Participants estimated (in numbers of 8-ounce (240-ml) glasses) their daily consumption of drinking water at home (separately through the study device and through all other sources at home) and outside the home. Additionally, an electronic flow meter (a totalizer) had been installed in each device to measure the amount consumed and the time at which water was used.
Participants were provided with water bottles and were encouraged to carry water from the home device when outside the home. Mean water consumption was compared by study group using the two-sample t test.
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RESULTS |
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We evaluated the risk of HCGI episodes for the active-device group versus the sham-device group (the a priori study goal) during the entire study by using the generalized estimating equation model described above. In addition to the full model, we examined models without the interaction term and with only the device term (table 5). The full model suggested no device effect nor any cycle-by-device interaction, indicating that the device yielded no reduction in the relative rate of HCGI for either cycle A or cycle B. The final model provided a relative rate estimate (sham-device vs. active-device group) of 0.98 (95 percent confidence interval (CI): 0.86, 1.10). Similar analyses were conducted with the outcome defined as days of HCGI and suggested no significant effect of the device (table 5).
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We also analyzed the correlation of outcomes within person and within household during the study. Within person, the correlation of HCGI was 0.68. Within household (within the same cycle), the correlation was 0.241. Within household (in a different cycle), the correlation was 0.239 for HCGI.
We investigated the possibility that the device effect might vary within different subgroups of age, gender, employment status, water consumption, and completeness of participation (table 6). In none of these analyses did we detect any significant differences.
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DISCUSSION |
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In 1991, Payment et al. (3) published the results of the first randomized, controlled drinking water intervention trial using reverse osmosis filtration in a system with a challenged source water. Filters were installed in 299 households (including 1,206 individual persons), and another 307 households (1,202 individuals) were followed as controls (no device installed). During a 15-month period, these investigators concluded that 35 percent of the self-reported gastrointestinal illness was attributable to tap water.
Subsequently, Payment et al. (4) conducted a second drinking water trial that included treatment groups receiving regular tap water, tap water from a continuously purged tap, bottled treatment plant water, or purified bottled plant water in a system that met all Canadian and equivalent US water microbial treatment standards. This study, conducted in the same community as the first trial, concluded that 1440 percent of gastrointestinal illness could be attributed to tap water, depending on the comparison group. Participants in the first study and in the two groups in the second study who did not receive bottled water were not blinded to their treatment assignments. Although bottled water recipients were not informed of their group assignment, 50 percent of those receiving bottled water from the treatment plant withdrew from the trial, citing taste and odor problems. No significant difference in gastrointestinal illness rates was observed between the two groups drinking bottled water. The only significant differences were observed between the bottled water and the tap water groups. The authors noted that it was possible that reporting of gastrointestinal illness could have been affected by this lack of blinding. In our study, there was strong evidence, measured by the Blinding Index, that participants were successfully blinded. In both Payment studies (3, 4), the source water was contaminated by sewage and other materials, similar to the setting in which our trial was conducted.
In a randomized, controlled, drinking water trial in Australia, Hellard et al. (5) reported no difference in the rates of illness between sham and active treatment groups. A sham device was used in the Australian trial to blind participants, as in our trial. In the Australian trial, the source water was reported to be of high quality, from protected catchments unaffected by human activity, which differs markedly from the challenged source (Mississippi River) water used in our study.
Recently, our group published results from a randomized, controlled trial in Walnut Creek, California, among households consuming water from a contaminated source that was conventionally treated to meet all US federal standards (6). This trial confirmed that blinding of participants could be maintained successfully during such a drinking water study. Although the point estimate of the effect in the pilot trial (relative rate = 1.32, 95 percent CI: 0.75, 2.33) was consistent with the point estimate reported in the prior Payment studies (3, 4), this study was not large enough to be likely to detect a statistically significant effect.
The primary health outcome was episodes of HCGI, chosen both because of its high sensitivity (any of several different symptoms constitute an episode) and because of its use in prior trials (3, 5, 6). In an effort to be specific about significant illness, we also measured days lost from work or school. We found no significant differences between the devices within either cycle or over the entire trial.
We measured as a secondary (but specified a priori) outcome total days of HCGI. This measure was intended to provide a sense of the burden of illness in the two groups. Again, no differences between the groups were found.
Using data on water usage from the device reported by participants, we found no difference between groups with respect to use of the device during either cycle of the trial. Analysis of the data from the electronic totalizer in each device supported this finding, which suggests that our findings are not attributable to differential exposure to the untreated municipal water.
We noted a decline in the frequency of HCGI episodes over time in both groups (figure 2) very similar to that reported by others (3, 5). Although HCGI does have a strong seasonal component (table 5), we hypothesize that the decline seen during cycle 2 (equal in both groups) is more likely due to a loss of enthusiasm for reporting illness. Half of the subjects were randomly assigned to the active device in cycle 1 and the other half to the inactive device, and the decline in reporting was equivalent in the two arms. We also noted a strong effect of cycle (table 5). Because of the two-period crossover study design, cycle effects were not likely to bias the principal relation between device and HCGI, and there is no evidence that they did bias this relation (table 5).
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We examined the possibility that the effect of the device might differ within important subgroups defined by age (prior studies had reported such differences (23)), length of participation, level of use of the device (i.e., a type of dose response), gender, or employment status. In none of these subgroup analyses was a significant effect detected (table 6).
We considered the possibility that the lack of an observed effect of the device may have been attributable to use of water outside the home. This possibility would have had the effect of attenuating any true effect the device may have had in reducing illness. We examined the device effect for only those subjects who reported that 90 percent or more of their water consumption was from the device (relative rate = 1.08, 95 percent CI: 0.85, 1.37), suggesting that the results were not likely explained by water consumption outside the home.
Our trial has limitations. It is possible that subjects in both groups, faced daily with the device, were reminded constantly about the study and altered their behavior or illness reporting in unknown ways so as to change their incidence of reporting of gastrointestinal illness (and thus drive the results toward a null effect). We have no data to evaluate this possibility. In future trials, a third, unblinded group of subjects with no device could be enrolled as an additional comparison group, but such data might be difficult to interpret because of a lack of blinding. It is possible that any true device effect was too small to be detected by the study. Since subjects drank water away from home and were exposed to pathogens in food, water, and other sources, it is possible that any reduction in the incidence of gastrointestinal illness attributable to the device could not be detected by the study because of its size. The confidence interval in the Australian trial indicated that less than 15 percent of gastrointestinal illness is likely caused by drinking water (5); this finding is very similar to our results suggesting that less than 11 percent of gastrointestinal illness is likely attributable to drinking water. Our study was not designed to address important questions about risk in immunocompromised persons. Studies suggest that human immunodeficiency virus-positive persons may be more susceptible to some waterborne infections during both outbreak situations and times without any known outbreak under way (2427). Finally, because our study was conducted in a community with documented high standards of water quality treatment (refer to the Materials and Methods section), the generalizability of our results to other communities with different treatment efficiencies cannot be determined with our data.
Conclusion
We found no evidence that in-home drinking water treatment with combined filtration and ultraviolet light is effective in reducing the incidence of gastrointestinal illness in immunocompetent persons using water that exceeds regulatory standards. The results suggest that less than 11 percent of the gastrointestinal illnesses observed in a community with such standards can be attributed to the consumption of tap water among those who use tap water as their primary source of drinking water.
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ACKNOWLEDGMENTS |
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The authors gratefully acknowledge the contributions of the following persons, without whom this trial could not have been completed: Jeannette Apple, Srikesh Arunajadai, Dr. Rebecca Calderon, James Case, Yuteh Cheng, Brock Earnhardt, Dr. Christopher Fairley, Dr. Fred Hauchman, Dr. Allen Hightower, Ron Hoffer, Dr. Louis Katz, Dr. Mark LeChevalier, Joel Mohr, Dr. Pierre Payment, Dr. Judy Rees, Jeffrey Robinson, Dr. Martha Sinclair, Donald Sorenson, and Judy Starcevich.
Portions of this manuscript were presented at the International Society for Environmental Epidemiology in Perth, Australia, on September 26, 2003.
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NOTES |
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REFERENCES |
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