Chlorine reduces oxygen in water.
Chlorine's potent oxidising power
causes it to react with naturally occurring organic material in raw water to
produce hundreds of chlorinated organic compounds, referred to generically as
chlorination disinfection by-products (CBPs).
One of the most commonly occurring
groups of CBPs, the trihalomethanes (THMs), was first identified at higher
concentrations in chlorinated drinking water than in natural raw water by Rook3
and by Bellar et al.4
Raw drinking water supplies were
found to have low background levels of mutagenic activity with relatively large
increases in mutagenicity after chlorination.5
The mutagenic activity of chlorinated
water is caused mainly by reactions of chlorine with natural humic substances
released by the breakdown of vegetation in the source waters.6
Recently, the chlorinated
hydroxyfuranones (e.g. MX) have been shown to be responsible for a major part of
the mutagenic activity. Other CBPs, including brominated THMs and haloacetic
acids, are also mutagenic.
The concentration of THMs correlates
strongly with the amount of organic precursors in raw water and, although
imperfect, it can be a useful indicator of the level of total CBPs in treated
water.
Although numerous CBPs have been
identified in chlorinated drinking water, very few have been subjected to
carcinogenicity bioassays. Chloroform induced significant increases in kidney
tumours in male rats when administered in high concentrations in drinking water.7
Chloroform also produced kidney
tumours in male rats and liver tumours in male and female mice when administered
by gavage in corn oil.8
Unlike the brominated THMs,
chloroform appears not to be carcinogenic through a direct DNA reactive
mechanism, acting instead through regenerative cell proliferation, possibly with
an exposure threshold.9
In studies of the three other THMs,
bromoform administered by corn oil gavage induced intestinal tumours in male and
female rats; chlorodibromomethane by corn oil gavage produced liver tumours in
both sexes of mice; and bromodichloromethane by corn oil gavage induced
intestinal and kidney tumours in male and female rats, kidney tumours in male
mice and liver tumours in female mice.10–12
After the THMs, the most commonly
occurring group of CBPs in drinking water is the haloacetic acids (HAAs).
Comparing published results from the
two most studied HAAs, dichloroacetate in drinking water induced hepatic tumours
in both rats and mice, but trichloroacetate induced hepatic tumours only in
mice.13–17
Both compounds appear to act as
tumour promoters, but likely via different mechanisms: trichloroacetate has been
shown to be a peroxisome proliferator, whereas dichloroacetate affects cell
cycle kinetics.18
While none of the brominated HAAs
have been tested in carcinogenicity bioassays, preliminary screening tests have
indicated a potential for the induction of liver tumours by bromochloroacetate,
dibromoacetate and bromodichloroacetate; lung tumours by bromodichloroacetate;
and colonic tumours by dibromoacetate.18,19
MX (3-chloro-4-(dichloromethyl)-5-
hydroxy-2(5H)-furanone) is a CBP and is one of the most potent known mutagens as
determined by the Ames assay.20
MX is reported to occur at much lower
concentrations than the THMs or HAAs, yet it appears to account for about one
third of the mutagenicity of chlorinated drinking water.21
DeMarini et al.22 found
that MX produced 50–70% hotspot 2-base deletions and 30–50% complex frameshifts;
no other compound or mixture is known to induce such high frequencies of complex
frameshifts.
MX caused several types of cancer or
benign tumours in rats, including thyroid, liver, adrenal gland, lung, pancreas,
breast, lymphomas and leukemias.23
As noted in the following report,
results of the epidemiologic studies of cancer have been most consistent in
showing an association between exposure to THMs and bladder cancer. Conflicting
results have been observed with respect to cancers of the colon and rectum.
In 1996, King and Marrett24
reported the results of a large population-based case-control study of bladder
cancer conducted in Ontario.
Persons exposed to chlorinated
surface water for 35 or more years had an increased risk of bladder cancer
compared with those exposed for less than 10 years (odds ratio = 1.41,
confidence interval [CI] = 1.10–1.81)).
Persons exposed to THM levels of at
least 50 µg/L for 35 or more years had 1.63 times the risk of those exposed for
less than 10 years (CI = 1.08–2.46).
The authors concluded that the risk
of bladder cancer increases with both duration and concentration of exposure to
chlorination by-products, with population-attributable risks of about 14–16% for
Ontario.
Approximately 1150 persons in Ontario
will be diagnosed with bladder cancer in 1998.25 If CBPs do cause
bladder cancer, then roughly 160–185 cases of bladder cancer per year in Ontario
are attributable to such exposure.
There have been about 20 case-control
and cohort epidemiologic studies of CBPs and cancer risk since 1978.
The US Environmental Protection
Agency (EPA) reviewed these studies26 and identified 5 case-control
studies (including the King and Marrett study) that met the criteria of being
population-based, well designed and having adequate exposure assessment.
The EPA concluded that, based on the
entire cancer epidemiology database, bladder cancer studies provide better
evidence than other types of cancer for an association between exposure to
chlorinated surface water and cancer.
The EPA recognised that a causal
relationship between chlorinated surface water and bladder cancer has not yet
been demonstrated conclusively by epidemiologic studies, but concluded that the
assumption of a potential causal relationship is supported by the weight of
evidence from toxicology and epidemiology.
Based on this assumption, the EPA
estimated that the attributable risk of bladder cancer due to exposure to
chlorinated water in the US is in the range of 2–17%; the annual number of
bladder cancer cases attributable to such exposure was estimated to be in the
1100–9300 range.
The EPA also stated that it believes
that the overall evidence from available epidemiologic and toxicologic studies
on chlorinated surface water continues to support a hazard concern and a prudent
public health protective approach for regulation.26
The expert working group convened by
the Laboratory Centre for Disease Control (see Workshop Report in this issue)
observed that the few available epidemiologic studies of CBP exposure and
pregnancy outcome indicated associations between exposure to THMs and
spontaneous abortion, growth retardation and birth defects.
However, these studies were weak in
exposure assessment and control of potential confounders.
When tested in rats, rabbits and
mice, chloroform was not teratogenic, but both bromodichloromethane and
chlorodibromomethane have shown evidence of fetotoxicity. Other CBPs have
produced adverse effects on the testes and on sperm production in male rats and
congenital heart defects in rats exposed in utero.
Recently, a prospective study27
that included concurrent trihalomethane sampling data showed that women who
drank at least five glasses per day of cold tap water containing at least 75
µg/L total THMs had an adjusted odds ratio of 1.8 for spontaneous abortion (CI =
1.1–3.0).
Of the four individual THMs, only
high bromodichloromethane exposure (consumption of at least five glasses per day
of cold tap water containing at least 18 µg/L of bromodichloromethane) was
associated with spontaneous abortion, both alone (adjusted OR = 2.0, CI =
1.2–3.5) and after adjustment for the other trihalomethanes (adjusted OR = 3.0,
CI = 1.4–6.6).
The expert group concluded that it
was possible (60% of the group) to probable (40% of the group) that CBPs pose a
significant cancer risk, particularly of bladder cancer.
The group concluded that the risk of
bladder and possibly other types of cancer is a moderately important public
health problem. They also determined that there was insufficient evidence to
establish a causal relationship between CBPs and adverse reproductive outcomes
in humans, but that confirmation of the available limited data could establish
CBPs as an important health problem.
Finally, the group concluded that
there were not enough data available to conduct a quantitative risk/benefit/cost
evaluation and recommended that developing health risk data be monitored to
determine when such an evaluation would be possible.
To the extent that epidemiologic
studies randomly misclassify individual exposures to CBPs, the resulting risk
estimates may be lower than the true risks.
It is likely that many of the
epidemiologic studies published to date have misclassified individual exposures
to chlorinated water or CBPs.
To lessen the impacts of this type of
misclassification, Lynch et al.28 recommended that future
epidemiologic studies of this type should quantify exposures more extensively.