| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Community Health and Epidemiology, Queen’s University, Kingston, Ontario, K7L 3N6 Canada [W. D. K., C. G. W.], and Cancer Care Ontario and the Department of Public Health Sciences, University of Toronto, Toronto, M5S 1A8 Canada [L. D. M.]
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
50 µg/liter
and 75 µg/liter. Males exposed to chlorinated surface water for
35–40 years had an increased risk of colon cancer compared with those
exposed for <10 years (odds ratio, 1.53; 95% confidence interval,
1.13–2.09). Males exposed to an estimated THM level of 75 µg/liter
for 35 years had double the risk of those exposed for <10 years
(odds ratio, 2.10; 95% confidence interval, 1.21–3.66). In contrast,
these relationships were not observed among females. No relationship
was observed between rectal cancer risk and any of the measures of
exposure to chlorination by-products. The results of this study should
be interpreted with caution because they are only partially congruent
with the limited amount of literature addressing this issue. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The association between water chlorination and bladder cancer has been the focus of several individual-based epidemiological studies. There have been fewer investigations of cancers of the colon and rectum, and results from studies have been inconsistent (5) . Differences in study methods and the specific array of by-products present in different geographic areas may contribute to inconsistencies in results. Because information is generally lacking on historical levels of chlorination by-products, most studies have been based on characteristics of water source, such as chlorinated surface water that correlate, albeit imprecisely, with the level of chlorination by-products. This study used estimated THM levels in public water supplies to examine the relationship between risk of cancers of the colon and rectum and exposure to chlorination by-products.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Subjects.
Cases were 30–74-year-old residents of southern Ontario, Canada, with
a primary cancer of the colon or rectum (International Classification
of Diseases 9 site codes 153 and 154; Ref. 7
). Pathology
reports routinely submitted to the Ontario Cancer Registry identified
1722 colon and 1530 rectal cancer cases diagnosed between September 1,
1992, and May 1, 1994 who were eligible for the study. Of these,
consent was obtained from the physician to contact 2507 patients; the
physician could not be identified for 35 patients, 404 patients were
recently deceased or too ill to be contacted, and physicians would not
give consent for 306 patients.
To identify control subjects, households randomly selected from a database of residential telephone listings were contacted and a census of residents was taken. Where eligible residents were identified, one was selected to participate based on frequency matching to the age-gender distribution of the combined case series (bladder, colon, and rectal cancer cases). Of 10,219 households contacted, 91% provided a census identifying 2768 eligible subjects. Over 90% (n = 2494) agreed to have a questionnaire mailed to them.
Exposure Assessment.
A questionnaire was mailed to the participants, and responses
were recorded by a subsequent telephone interview. Participants were
queried regarding demographics (e.g., sex, date of birth,
and education), other potential risk factors (e.g., medical
history and usual diet before diagnosis), and information pertaining to
the primary exposures of interest (e.g., residence, water
source history, and usual water consumption). Volume of tap water
consumed was calculated from the reported daily consumption of water
and of beverages or foods made with water, 2 years before the
interview.
A database was created that characterized each water supply in the study area according to source (surface/ground), chlorination status (chlorinated/nonchlorinated), and level of THMs by geographic area and time. This was based on a survey of treatment plants that collected information on water source and characteristics, and treatment practices for the years of operation between 1950 and 1990. Water plant information was obtained for an average day in August in 5-year intervals, and that observation was used to represent water characteristics for the years surrounding that date. A model, based on data from the Ontario Drinking Water Surveillance Program for the years 1986–1992, was developed to predict the THM level in treated water based on water and treatment characteristics recorded in the database and available from the water plant survey. Application of this model using reported source and treatment characteristics provided by the survey resulted in an estimate of THM level for each plant by time period. Water from private wells was assigned a THM concentration of zero because it is not chlorinated.
Individual exposures were assigned by linking subject residence and
water source information to the relevant treatment plant data by time
and geographic area. Exposures occurring over the 40-year-period
preceding 2 years before the subject’s interview were considered, and
only subjects with 30 years of known water history were included.
Duration of exposure to chlorinated surface water and to water with an
estimated summer THM level 50 and 75 µg/liter were calculated by
summing the number of years in each exposure category. In addition,
THM-years, the sum of the products of continuous estimates of the
summer THM level and years at that level, was calculated as an estimate
of cumulative exposure.
Statistical Analyses.
ORs were used as estimates of the relative risk. For the exposures of
primary interest, unconditional logistic regression was used to obtain
ORs and 95% CIs adjusted for potential confounders (8)
.
Tests for trend were based on a likelihood-ratio test conducted by
assigning an ordinal value to each level of a categorical variable and
treating the variable as continuous in a logistic regression model. A
likelihood-ratio test was performed to evaluate the interaction between
cumulative THM exposure and volume of water consumed.
Age, sex, and dietary intake of energy (total kilocalories) were included in all analyses. Additional potential confounders were identified by using backward stepwise regression to build a parsimonious model predicting risk for each cancer site. The risk factors that were considered for inclusion on the basis of the cancer literature were: body mass index, education, consumption of alcoholic beverages (beer, wine, spirits), coffee consumption, previous medical conditions (history of Crohn’s disease or colitis), and dietary intake of protein, fat, fiber, cholesterol, calcium, and vitamin A. Exclusion of factors from the model was based on a score-test P > 0.10, a conservative criterion that ensured that all factors that might confound the relationship of interest were included in the model.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Covariates.
Controls were more often male (63%) compared with colon cases (56%)
and rectal cases (61%). This difference can be attributed to our
attempt to frequency match controls to a case series that also included
bladder cancer cases, 76% of whom were male. The average age of each
case group was slightly older than controls because of the difficulty
in identifying older control subjects (Table 1
).
|
A similar subset of factors was included in the parsimonious model predicting rectal cancer risk, but consumption of alcoholic drinks was not included and previous medical conditions were included. Cases with rectal cancer, on average, were less educated, were more likely to have a history of Crohn’s disease or colitis, had a higher body mass index, and had a higher intake of energy and cholesterol, but lower intake of coffee than controls.
Water Source.
Risk estimates for colon cancer according to exposure to various water
factors differed between the sexes (Table 2
). Increasing exposure to each water factor was associated with
increasing risks of colon cancer only among males. Among males, each
risk factor displayed a trend of increasing colon cancer risk across
categories of increasing exposure, which reached at least a 53%
elevation in risk for the highest exposure categories. Long-term (35
years) exposure to a THM level of 75 µg/liter was associated with a
doubled colon cancer risk among males (OR, 2.10; 95% CI, 1.21–3.66).
The highest quartile of cumulative THM-years exposure was associated
with an OR of 1.74 (95% CI, 1.25–2.43). The continuous representation
of cumulative THM exposure was associated with a 17% increase in risk
for each 1000 µg/liter-years (95% CI, 6–29%). In contrast, among
females, the risk of colon cancer was not positively associated with
exposure to chlorination by-products. Inverse associations were
observed in those exposed to a THM level of 50 g/liter for 20–34
years and in the highest quartile of THM-years.
|
Homogeneous Water Exposures.
Subjects used an average of 2.9 different water supplies during the
40-year exposure period. Therefore, in the preceding analyses, subjects
within each duration category may have had a heterogeneous mixture of
exposures as a result of living at residences with water sources that
varied among the exposure categories over time. The analyses presented
in Table 3
were restricted to those subjects who had homogeneous values for the
exposures considered in an attempt to examine the effect of
concentration of chlorination by-products while holding the duration of
exposure constant. That is, only subjects who had exposures for at
least 30 years within a single level of exposure (with respect to
either ground versus chlorinated surface water or THM level
in three categories) were included.
|
75 µg/liter for 30 years had an 87% increase
in risk compared with those exposed to levels <25 µg/liter (95% CI,
15–205%). Among females, water source (chlorinated surface
versus ground) was not associated with colon cancer risk. A
reduced risk of colon cancer was observed for females exposed to THM
concentrations between 25 and 75 µg/liter (OR, 0.46; 95% CI,
0.26–0.81), but not for those exposed to higher THM concentrations
(OR, 0.92; 95% CI, 0.49–1.71). No associations were observed between
these exposure factors and rectal cancer risk for either sex.
Risk by Volume of Water Consumed.
Inclusion of a variable representing the quantity of water ingested
provides an additional dimension of cumulative exposure to the analysis
of exposure to chlorination by-products. An analysis was done to assess
whether subjects who consumed greater volumes of water and had high
cumulative THM exposure were at greater risk of colon or rectal cancer.
Water consumption was categorized into three levels based on tertiles
of the distribution within controls. The referent category for all ORs
was comprised of those who consumed <1.5 liters/day and in the lowest
quartile of THM-years.
Relative risks for colon cancer among males are reported in Table 4
. Overall, the pattern of risk did not provide support for an
interaction between volume of water consumed and cumulative THM
exposure (P interaction > 0.05). However, the largest
colon cancer risk among males was observed for those consuming high
amounts of tap water with high cumulative THM exposure (OR, 2.42; 95%
CI, 1.28–4.56). Analyses for female colon and rectal cancer risk were
limited by the low number of subjects in some strata and are not
presented. No statistically significant relative risk estimates were
observed, and patterns of relative risk were inconsistent.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Colon cancer has been found to be associated with water characteristics in some other studies using exposure to chlorinated surface water as the measure of by-product exposure. In ecological studies, age- and sex-adjusted cancer mortality and incidence rates of colon and rectal cancers have frequently been associated with characteristics of water supply systems (9, 10) . Of five mortality case-control studies that examined both colon and rectal cancer and assessed exposure based on either residence at death (11–14) or more detailed residence information from supplementary data sources (15, 16) , two found an association with colon cancer (11, 12) and one reported an association with rectal cancer (15, 16) . A prospective cohort study of women that examined exposure to private well, ground, or surface water based on the residence at the time of entry into the cohort found an increased risk of colon cancer associated with use of surface water (17) . One incident case-control study reported a significant elevation in colon cancer risk associated with chlorinated water among subjects >60 years of age (18) .
Although levels of by-products are higher in chlorinated surface water supplies than ground water supplies, the levels of chlorination by-products in chlorinated surface water vary widely. We estimated summer THM level in an attempt to create a more specific measure of total chlorination by-product exposure. Therefore, more comparable to our study in methodology are two case-control studies that have obtained more comprehensive information by using THMs as a measurement of exposure and using incident cancer cases and subject interviews to ascertain residential histories, water exposures, and information about potential confounders (5, 19) . These studies, in contrast to our study, observed colon cancer risk estimates with exposure to chlorinated surface water or THM levels that were close to the null (5, 19) . Only one of these studies examined rectal cancer risk (5) and reported a more than doubling of risk for both sexes combined.
Associations between colon cancer risk and exposure to chlorination by-products in our study were observed for males, but not for females in contrast to other studies that did not find a sex difference (5) , or studies of women only that found an increased risk of colon cancer (12, 17) . However, other descriptive and analytical epidemiological findings suggest that colon cancer risk is influenced by gender. The observations that distal colon cancers occur more frequently in males than females (20, 21) and that different subsites may have different etiologies (22) suggest that the different sexes may have distinct risk factor profiles.
Because a high degree of correlation exists between each exposure
measure used in this study, the individual analyses should not be
considered wholly independent. However, several parameters of exposure
to chlorination by-products were used to help identify the most
meaningful exposures. Duration of exposure was examined at several
cutoffs of THM concentration to investigate whether the associations
were stronger at higher levels, and our use of cumulative THM exposure
was based on the assumption that it is the accumulation of a potential
carcinogen that influences cancer risk. The strongest risk estimates
for colon cancer among males were observed with 35 years of exposure
to a THM level 75 µg/liter, and for the highest quartile of
cumulative exposure. Restriction of the analysis dataset to those with
relatively homogeneous exposures facilitated the examination of the
effect of increasing THM level on risk while holding duration of
exposure constant. The observed trend in colon cancer risk among males
supports a dose-response relationship.
Perhaps the largest methodological limitation of this study is the representation of subject exposures. Possible sources of misclassification include the use of estimated historical THM levels and variation in individual behaviors not captured in this study that influence exposure. Because of the availability of historical treatment facility data, this study only considered exposures occurring over a 40-year time period, whereas other investigations have examined exposures of a longer duration (5) . Incorporating volume of water consumed accounted for a further dimension of individual variation in oral exposure. However, this dimension of frequency was not captured for other routes of exposure (e.g., inhalation and dermal) in this study. In addition, it is possible that total THMs correlate poorly with the important etiological agents in the chlorination by-product mixture.
A potential concern in this study is that a low proportion of potentially eligible cases were included in the analysis. Of 3252 colon and rectal cancer cases identified during the study, only 1399 (43%) are represented in the analysis. Case subjects were lost because of death and illness, their physician not providing consent or not responding to our requests, and refusal of the cases to participate. Study physicians and patients were not aware of the specific exposures of interest (e.g., THM levels) and therefore, it is unlikely that those included and those not included differed systematically with respect to our exposure measure.
It is also a concern that case or control participation may be related to a correlate of THM level, such as county of residence. The distribution by residence county at diagnosis for participating colorectal cancer cases was compared with the distribution of cases identified in the Ontario Cancer Registry. These distributions were within 1% for each of the 39 counties in the study area. In a similar manner, the representativeness of control subjects was examined by comparing the percentage of controls residing in each county with that expected based on Canada census data (23) . These distributions were similar with a difference of >1% occurring for only 2 of 39 counties. These observations suggest that a systematic selection of case or control subjects according to residence location did not occur.
The study was limited by incomplete water exposure history for some subjects. In particular, those residing outside the province of Ontario for a large number of years would have an incomplete water history. To minimize misclassification, the analysis was limited to those with at least 30 years of exposure information of the 40-year exposure time window. Of those subjects included in the analysis, the average number of years of water data was 38.1 for controls, 38.7 for colon cases, and 38.3 for rectal cases.
Chance and confounding must be considered when interpreting the results of this study. The observed association of exposure to chlorination by-products with colon cancer risk among males but not among females was unexpected. It is possible that the excess risk observed in males was a chance finding. The potential confounding effects of several known risk factors were taken into account in the analyses, but the possibility remains that unknown or unmeasured risk factors may have biased the results. Urbanicity was a confounder in one previous investigation (5) . In the present study, a proxy of urbanicity, the average population density of lifetime residences, was only weakly correlated with colon cancer risk and was not associated with rectal cancer risk. Adjustment for population density did not alter colon or rectal cancer risk estimates.
THMs were used in this study as a surrogate to represent exposure to chlorination by-products, and THMs themselves may not pose a health risk. Although chloroform accounts for a large proportion of the total THMs in most chlorinated water supplies, toxicological evidence suggests that other by-products, such as brominated by-products and haloacetic acids, may have greater carcinogenic potential (24, 25) . Brominated by-products and haloacetic acids have been observed in Ontario water supplies and may be responsible for the observed effects in this study (26) .
In summary, an excess risk of colon cancer among males was observed with long-term exposure to chlorination by-products. No association with exposure to chlorination by-products and risk of colon cancer was observed for females, nor of rectal cancer for males or females. These results are only partially congruent with the limited amount of literature addressing this issue.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
1 Supported by the Cancer Bureau of the Laboratory
Center for Disease Control, Health Canada and also by the National
Health Research and Development Program through a fellowship (to
W. D. K.). 
2 To whom requests for reprints should be
addressed, at Department of Community Health and Epidemiology, Abramsky
Hall, Queen’s University, Kingston, Ontario, K7L 3N6 Canada; Phone:
(613) 533-6000, extension 74735; Fax: (613) 533 6686; E-mail: kingw{at}post.queensu.ca
3 The abbreviations used are: THM, trihalomethane;
CI, confidence interval; OR, odds ratio.
Received 10/18/99; revised 5/17/00; accepted 5/19/00.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  T. L. Leavens, B. C. Blount, D. M. DeMarini, M. C. Madden, J. L. Valentine, M. W. Case, L. K. Silva, S. H. Warren, N. M. Hanley, and R. A. Pegram Disposition of Bromodichloromethane in Humans Following Oral and Dermal Exposure Toxicol. Sci., October 1, 2007; 99(2): 432 - 445. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kasim, P. Levallois, K. C. Johnson, B. Abdous, P. Auger, and and the Canadian Cancer Registries Epidemiology Re Chlorination Disinfection By-products in Drinking Water and the Risk of Adult Leukemia in Canada Am. J. Epidemiol., January 15, 2006; 163(2): 116 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Mcdorman, S. Chandra, M. J. Hooth, S. D. Hester, R. Schoonhoven, and D. C. Wolf Induction of Transitional Cell Hyperplasia in the Urinary Bladder and Aberrant Crypt Foci in the Colon of Rats Treated with Individual and a Mixture of Drinking Water Disinfection By-Products Toxicol Pathol, February 1, 2003; 31(2): 235 - 242. [Abstract] [PDF]
|
|
|
|
 |
|
 A. M. Easson, M. Cotterchio, J. A. Crosby, H. Sutherland, D. Dale, M. Aronson, E. Holowaty, and S. Gallinger A Population-Based Study of the Extent of Surgical Resection of Potentially Curable Colon Cancer Ann. Surg. Oncol., May 1, 2002; 9(4): 380 - 387. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
