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PubMed2000

Effect of trihalomethanes on cell proliferation and DNA methylation in female B6C3F1 mouse liver.

Trihalomethanes (chloroform, bromodichloromethane, chlorodibromomethane, and bromoform) are regulated organic contaminants in chlorinated drinking water. In female B6C3F1 mouse liver, the 4 trihalomethanes have demonstrated carcinogenic activity when administered by oral gavage; however, chloroform was not carcinogenic when administered in drinking water. Female B6C3F1 mice were administered the trihalomethanes for 11 days by gavage at 2 dose levels or in the drinking water at approximately 75% saturation. When administered by gavage, the trihalomethanes were toxic to the liver, increased the liver:body weight (bw) ratio, and increased the proliferating cell nuclear antigen-labeling index (PCNA-LI). Chloroform and bromodichloromethane were the most toxic, and they increased the liver:bw ratio the most, while bromoform and chloroform increased the PCNA-LI the most. When administered in drinking water, the toxicity of the trihalomethanes was similar to their low gavage-dose. Furthermore, only chloroform significantly increased the liver:bw ratio and bromoform and chloroform increased the PCNA-LI. Chloroform and bromodichloromethane decreased the level of 5-methylcytosine in hepatic DNA. Methylation in the promoter region of the c-myc gene was reduced by the trihalomethanes. Chloroform administered by gavage was more efficacious than given in drinking water; the efficacy of the other trihalomethanes did not differ for the 2 routes. Thus, in mouse liver, the trihalomethanes administered by gavage enhanced cell proliferation and decreased the methylation of the c-myc gene, consistent with their carcinogenic activity. Furthermore, the more modest toxicity, enhancement of cell proliferation, and decreased methylation induced by chloroform administered in drinking water correlated with its lack of carcinogenic activity. Hence, the activity of the trihalomethanes was dependent on the rate of delivery, i.e. rapid by oral gavage and more slowly in drinking water.

Animals↗

PubMed1998

Trihalomethanes in drinking water and spontaneous abortion.

Trihalomethanes (chloroform, bromoform, bromodichloromethane, and chlorodibromomethane) are common contaminants of chlorinated drinking water. Although animal data indicate that these compounds may be reproductive toxicants, little information exists on their relation to spontaneous abortion in humans. We examined exposure to trihalomethanes and spontaneous abortion in a prospective study of 5,144 pregnant women in a prepaid health plan. Seventy-eight drinking water utilities provided concurrent trihalomethane sampling data. We calculated total trihalomethane levels by averaging all measurements taken by the subject's utility during her first trimester. We calculated exposures to individual trihalomethanes in an analogous manner. Women who drank > or = 5 glasses per day of cold tapwater containing > or = 75 micrograms per liter total trihalomethanes had an adjusted odds ratio (OR) of 1.8 for spontaneous abortion [95% confidence interval (CI) = 1.1-3.0]. Of the four individual trihalomethanes, only high bromodichloromethane exposure (consumption of > or = 5 glasses per day of cold tapwater containing > or = 18 micrograms per liter bromodichloromethane) was associated with spontaneous abortion both alone (adjusted OR = 2.0; 95% CI = 1.2-3.5) and after adjustment for the other trihalomethanes (adjusted OR = 3.0; 95% CI = 1.4-6.6).

Abortion, Spontaneous↗

PubMed2003

Factors influencing the formation and relative distribution of haloacetic acids and trihalomethanes in drinking water.

Various water quality and treatment characteristics were evaluated under controlled chlorination conditions to determine their influences on the formation and distribution of nine haloacetic acids and four trihalomethanes in drinking water. Raw waters were sampled from five water utilities and were coagulated with alum and fractionated with XAD-8 resin. The resulting four fractions--raw and coagulated water and the hydrophobic and hydrophilic extracts--were then chlorinated at pH 6 and 8 and held at 20 degrees C for various contact times. The results show that increasing pH from 6 to 8 increased trihalomethane formation but decreased trihaloacetic acid formation, with little effect on dihaloacetic acid formation. More trihalomethanes were formed than haloacetic acids at pH 8, while the reverse was true at pH 6. Hydrophobic fractions always gave higher haloacetic acid and trihalomethane formation potentials than their corresponding hydrophilic fractions, but hydrophilic carbon also played an important role in disinfection byproduct formation for waters with low humic content. The bromine-containing species comprised a higher molar proportion of the trihalomethanes than of the haloacetic acids. The hydrophilic fractions were more reactive with bromine than their corresponding hydrophobic fractions. Coagulation generally removed more haloacetic acid precursors than trihalomethane precursors. Waters with higher specific ultraviolet absorbance values were more amenable to removal of organic material by coagulation than waters with low specific ultraviolet absorbance values. Experimental evidence suggests that haloacetic acid precursors have a higher aromatic content than trihalomethane precursors.

Acetates↗

PubMed1982

Toxicity of trihalomethanes: I. The acute and subacute toxicity of chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats.

In an acute study, groups of 10 male and 10 female rats were given single oral doses of chloroform, bromodichloromethane (BDCM), chlorodibromomethane (CDBM), or bromoform and were observed for clinical symptoms for the following 14 days. Median lethal doses (LD 50) of the four trihalomethanes were found to be between 848 and 1388 mg/kg. Some groups which survived the treatment for 14 days showed reduced food intake, growth retardation and increased liver and kidney weight. Elevated serum cholesterol levels were observed in the surviving male rats treated with chloroform and CDBM, and in the females treated with chloroform. Decreased liver protein content occurred in male but not female rats fed chloroform and bromoform. In contrast, increase aniline hydroxylase activity was observed in female rats fed chloroform but not bromoform. Hematological values which were altered by the four trihalomethanes were hemoglobin, hematocrit, RBC, WBC, neutrophil and lymphocyte counts. Treatment-related histologic changes were observed in the liver and kidney of rats. These changes were qualitatively and quantitatively similar for the four trihalomethanes. These data indicate that trihalomethanes at large single oral doses can produce a wide range of toxic changes in the rat. In a subacute study, groups of 10 male rats were fed four trihalomethanes at 0, 5, 50 or 500 ppm in their drinking water for 28 days. The growth rate and food intake were not affected by treatment. A slight increase in relative kidney weight was observed in the groups fed 5 ppm chloroform; 500 ppm bromoform, 5 and 500 ppm BDCM. The animals fed the highest dose of chloroform showed decreased neutrophils. Serum biochemical parameters and hepatic microsomal enzyme activities were not altered by any of the four trihalomethanes. No histopathological changes were seen in the tissues examined.

Animals↗

PubMed2001

Trihalomethane removal by activated carbon fiber.

For the safety of drinking water, trihalomethanes are removed by adsorption onto activated carbon fiber from single-component solutions. The amounts adsorbed onto adsorbents with large surface area and/or pore volume were small. Stronger surface hydrophobicity of adsorbent was correlated with a larger amount of trihalomethanes adsorbed. A trihalomethane with bromine was adsorbed to a greater extent than that with chlorine. The differences in the amounts adsorbed among trihalomethanes can be explained by the polarity of trihalomethane molecules. The amount of trihalomethanes adsorbed was mainly dominated by the strength of hydrophobicity of activated carbon fibers.

Adsorption↗

PubMed1986

Comparison of the effect of trihalomethanes on lipid metabolism in rat liver slice.

The effect of a series of trihalomethanes, CHCl3, CHBrCl2, CHBr2Cl, and CHBr3, on in vitro lipid metabolism was compared using rat liver slices. The incorporation of 32Pi and [3H]glycerol into phospholipid of liver slices was inhibited in the presence of trihalomethanes. The inhibitory effect followed the number of bromine atoms in the trihalomethane molecule in the initial period of incubation. CHBr3 markedly inhibited the incorporation of [3H]glycerol into triacylglycerol (TG); CHBr2Cl was less effective and the other two trihalomethanes were without effect. The activities of glycerophosphate acyltransferase, phosphatidate phosphatase and diacylglycerol acyltransferase were changed by the exposure to trihalomethanes. The effects of CHBr2Cl and CHBr3 were much more severe as compared to those of CHBrCl2 and CHCl3. The change in the enzyme activities could explain the alteration in the incorporation of [3H]glycerol into TG.

Animals↗

PubMed2003

Evaluating trihalomethane content in drinking water on the basis of common monitoring parameters: regression models.

The presence of trihalomethanes (THMs) in potable-water sources is an issue of great interest because of the negative impact THMs have on human health. The objective of this study was to correlate the presence of trihalomethanes with more routinely monitored parameters of water quality, in order to facilitate THM control. Water samples taken at various stages of treatment from a water treatment plant were analyzed for the presence of trihalomethanes with the Fujiwara method. The data collected from these determinations were compared with the values obtained for free-residual-chlorine and combined-residual-chlorine levels as well as standard physico-chemical and microbiological indicators such as chemical oxygen demand (by the KMnO4 method), total chlorophyll, conductivity, pH, alkalinity, turbidity, chlorides, sulfates, nitrates, nitrites, phosphates, ammonia, calcium, magnesium, heterotrophic bacteria count, Pseudomonas spp., total and fecal coliforms, and fecal streptococci. The data from these determinations were compiled, and statistical analysis was performed to determine which variables correlate best with the presence and quantity of trihalomethanes in the samples. Levels of THMs in water seem to correlate directly with levels of combined residual chlorine and nitrates, and inversely with the level of free residual chlorine. Statistical analysis with multiple linear regression was conducted to determine the best-fitting models. The models chosen incorporate between two and four independent variables and include chemical oxygen demand, nitrites, and ammonia. These indicators, which are commonly determined during the water treatment process, demonstrate the strongest correlation with the levels of trihalomethanes in water and offer great utility as an accessible method for THM detection and control.

Environmental Monitoring↗

PubMed1993

Assessment of the carcinogenic potential of chlorinated water: experimental studies of chlorine, chloramine, and trihalomethanes.

BACKGROUND: Water chlorination has been one of the major disease prevention treatments of this century. While epidemiologic studies suggest an association between cancer in humans and consumption of chlorination byproducts in drinking water, these studies have not been adequate to draw definite conclusions about the carcinogenic potential of the individual byproducts. PURPOSE: The purpose of this study was to investigate the carcinogenic potential of chlorinated or chloraminated drinking water and of four organic trihalomethane byproducts of chlorination (chloroform, bromodichloromethane, chlorodibromomethane, and bromoform) in rats and mice. METHODS: Bromodichloromethane, chlorodibromomethane, bromoform, chlorine, or chloramine was administered to both sexes of F344/N rats and (C57BL/6 x C3H)F1 mice (hereafter called B6C3F1 mice). Chloroform was given to both sexes of Osborne-Mendel rats and B6C3F1 mice. Chlorine or chloramine was administered daily in the drinking water for 2 years at doses ranging from 0.05 to 0.3 mmol/kg per day. The trihalomethanes were administered by gavage in corn oil at doses ranging from 0.15 to 4.0 mmol/kg per day for 2 years, with the exception of chloroform, which was given for 78 weeks. RESULTS: The trihalomethanes were carcinogenic in the liver, kidney, and/or intestine of rodents. There was equivocal evidence for carcinogenicity in female rats that received chlorinated or chloraminated drinking water; this evidence was based on a marginal increase in the incidence of mononuclear cell leukemia. Rodents were generally exposed to lower doses of chlorine and chloramine than to the trihalomethanes, but the doses in these studies were the maximum that the animals would consume in the drinking water. The highest doses used in the chlorine and chloramine studies were equivalent to a daily gavage dose of bromodichloromethane that induced neoplasms of the large intestine in rats. In contrast to the results with the trihalomethanes, administration of chlorine or chloramine did not cause a clear carcinogenic response in rats or mice after long-term exposure. CONCLUSION: These results suggest that organic byproducts of chlorination are the chemicals of greatest concern in assessment of the carcinogenic potential of chlorinated drinking water.

Animals↗

PubMed1999

Trihalomethanes in public water supplies and adverse birth outcomes.

We conducted a retrospective cohort study to evaluate the relation between the level of total trihalomethanes in drinking water and adverse birth outcomes. The study population comprised women residing in an area with municipal surface water who had a singleton birth in Nova Scotia between January 1, 1988, and December 31, 1995, or a pregnancy termination for a major fetal anomaly. We found little association between trihalomethane level and the outcomes related to fetal weight or gestational age, but we found an elevated relative risk for stillbirths for average trihalomethane levels during pregnancy of 100 microg/liter or greater (adjusted relative risk = 1.66; 95% confidence interval = 1.09-2.52) relative to women exposed to trihalomethane levels of 0-49 microg/liter. We saw little evidence of an elevated prevalence or dose-response pattern for congenital anomalies, with the possible exception of chromosomal abnormalities (adjusted prevalence ratio = 1.38 and 95% confidence interval = 0.73-2.59 for women exposed to trihalomethane levels of 100 microg/liter or greater).

Abnormalities, Drug-Induced↗

PubMed1998

Female breast cancer and trihalomethane levels in drinking water in North Carolina.

Some studies indicate that chlorination by-products in drinking water may contribute slightly to breast cancer risk. This ecologic study describes the association between total trihalomethane levels in publicly supplied water and the incidence of female invasive breast cancer. We included 71 North Carolina water suppliers serving at least 10,000 customers in the summer of 1995 as the units of analysis. We estimated incidence rates using 6,462 cases who were either white or black and between 35 and 84 years old and were linked by zip codes to the water supplier. We treated ecologic measurements of age, income, education, urban status, and race as potential confounders. Total trihalomethane levels were not associated materially with breast cancer risk, adjusting for potential confounders. The rate ratio for 80.0 parts per billion (ppb) or more vs less than 40.0 ppb total trihalomethanes was 1.1 [95% confidence interval (CI) = 0.9-1.2]. When stratified by race, the observed association for the aforementioned total trihalomethane category was not very different in black women (rate ratio = 1.2; 95% CI = 0.8-1.8) than in white women (rate ratio = 1.1; 95% CI = 0.9-1.3). These ecologic data are compatible with trihalomethanes in drinking water being either unrelated or weakly related to breast cancer risk.

Adult↗

PubMed1998

Regenerative hyperplasia is not required for liver tumor induction in female B6C3F1 mice exposed to trihalomethanes.

Chloroform (TCM), a water disinfection by-product, induced liver tumors in female mice when administered by gavage in corn oil but not when given in drinking water at comparable daily doses. Because short-term studies showed that the gavage doses also induced liver toxicity, it has been suggested that the liver tumor response occurs secondary to cytotoxicity and consequent regenerative hyperplasia induced by oxidative metabolism of TCM to the toxic dihalocarbonyl intermediate. This study compares dose-response relationships of gavage-administered chlorinated/brominated trihalomethanes for hepatotoxicity, replicative DNA synthesis, and hepatocarcinogenicity in female B6C3F1 mice. The liver tumor data were obtained from previously published studies. Because bromine is a better leaving group than chlorine, metabolism of bromodichloromethane (BDCM) should produce the same intermediates as would be formed from TCM. Hence, the toxicity and carcinogenicity of BDCM was expected to be qualitatively similar to that of TCM. Dose responses for liver weight, serum sorbitol dehydrogenase and alanine aminotransferase (ALT) activities, hepatocyte degeneration, and hepatocyte labeling index (LI, a measure of replicative DNA synthesis) in female mice were similar following 3 weeks of gavage administration (once per day, 5 days per week) with TCM, BDCM, or chlorodibromomethane (CDBM). Fits of composite data for these trihalomethanes to a Hill equation model revealed sigmoidal dose responses for ALT activity and hepatocyte LI and a nearly linear low-dose response for liver tumor incidence. For this family of chemicals, the mouse liver tumor response was not associated with an elevated hepatocyte LI at doses of approximately 1 mmol/kg or less. High incidences of liver tumors were observed with BDCM and CDBM at doses that had a marginal effect or no effect on the hepatocyte LI. Thus, the carcinogenic effects of trihalomethanes are not simply a consequence of cytotoxicity and regenerative hyperplasia. The possible contributions from other activation pathways, including GSH conjugation and reductive metabolism, need to be considered in assessments of the carcinogenicity of the trihalomethanes.

Administration, Oral↗

PubMed1998

Exposure to trihalomethanes and adverse pregnancy outcomes.

Exposure during pregnancy to disinfection by-products in drinking water has been hypothesized to lead to several adverse reproductive outcomes. We performed a retrospective cohort study to examine the relation of trihalomethane exposure during the third trimester of pregnancy to low birthweight, term low birthweight, and preterm delivery. We matched Colorado birth certificates from January 1, 1990, through December 31, 1993, to historical water sample data with respect to time and location of maternal residence based on census block groups. After excluding births from all census block groups with no trihalomethane sample data and restricting to singleton white births with 28-42 weeks of completed gestation (>400 gm), we studied 1,893 livebirths within 28 census block groups. We found a weak association of trihalomethane exposure during the third trimester with low birthweight (odds ratio = 2.1 for the highest exposure level; 95% confidence interval = 1.0-4.8); a large increase in risk for term low birthweight at the highest level of exposure (odds ratio = 5.9; 95% confidence interval = 2.0-17.0); and no association between exposure and preterm delivery (odds ratio = 1.0 for the highest exposure level; 95% confidence interval = 0.3-2.8). The small number of adverse outcomes reduced the precision of risk estimates, but these data indicate a potentially important relation between third trimester exposure to trihalomethanes and retarded fetal growth.

Adult↗

PubMed1983

Acetone-induced potentiation of trihalomethane toxicity in male rats.

The acute hepato- and nephrotoxic potentials of two trihalomethane water contaminants, bromodichloromethane (BrCHCl2) and dibromochloromethane (Br2CHCl), were determined in male Sprague-Dawley rats. Br2CHCl possessed a greater hepatotoxic and lethal potential than BrCHCl2. However, both Br2CHCl and BrCHCl2 were weak hepatotoxicants as compared to a related trihalomethane, CHCl3. Br2CHCl and BrCHCl2 did not produce liver injury until near-lethal dosages were administered. Neither trihalomethane appeared to produce appreciable kidney injury during the 24-h challenge period. Pretreatment of rats with acetone (15 mmol/kg, p.o.) markedly potentiated the hepatotoxic response to BrCHCl2 and Br2CHCl. The potentiated response observed with acetone plus BrCHCl2 or Br2CHCl was equal to or greater than that observed with acetone plus an approximately equimolar dosage of CHCl3. That is, acetone appeared to convert these weak hepatotoxicants into strong hepatotoxicants.

Acetone↗

PubMed2004

A retrospective cohort study of trihalomethane exposure through drinking water and cancer mortality in northern Italy.

A few epidemiologic studies have suggested that consumption of drinking water with high trihalomethane content increases the risk of cancer. We investigated the mortality of a cohort of 5144 residents in Guastalla, northern Italy, who were supplied tap water with high chloroform and trihalomethane content between 1965 and 1987. Using death rates of a nearby community as reference rates, the standardized mortality ratio from all cancers between 1987 and 1999 was slightly increased for both males (1.2, 95% confidence interval 1.1-1.4) and females (1.1, 95% confidence interval 1.0-1.3). This was mainly due to a higher mortality from stomach, liver, lung, prostate and bladder cancer in males and from stomach, pancreas, breast and ovarian cancer and lymphocytic leukemia in females. We also noted excess mortality from melanoma in both males and females. Overall, our findings were consistent with an association between trihalomethane exposure and increased cancer risk at some sites. However, the point estimates were statistically imprecise, due to the limited number of deaths for some site-specific cancers. In addition, we were unable to rule out the possibility of confounding due to smoking and other life-style factors with regard to some of the excess rates.

Adolescent↗

PubMed1982

Trihalomethanes: II. Reversibility of toxicological changes produced by chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats.

Groups of 20 male and 20 female rats were fed 0, 5, 50, 500 or 2500 ppm trihalomethanes (chloroform, bromodichloromethane, chlorodibromomethane and bromoform) in their drinking water for 90 days. Ten rats from each group were killed at this time and the remaining animals were fed tap water for a further 90 days before they were sacrificed. Suppression of growth rate was observed in male and female rats fed 2500 ppm chloroform and bromodichloromethane (BDCM) for 90 days. After the subsequent 90-day recovery period, no effects on body weight gain in either sex were apparent. Food consumption was depressed in all groups of males and females receiving 2500 ppm chloroform, chlorodibromomethane (CDBM) and BDCM for 90 days and in these same groups during the recovery period. Bromoform at 2500 ppm suppressed food consumption of male rats but this effect was not evident 90 days after cessation of exposure. Decreased lymphocyte counts were only observed in the recovery groups fed chloroform (500 ppm, male), CDBM (2500 ppm, female) and bromoform (2500 ppm, females). Histological changes in the livers and thyroids of male and female rats were qualitatively and quantitatively similar for the four trihalomethanes. These changes were mild in nature, and were not evident 90 days after cessation of exposure. These data indicate that trihalomethanes can produce biochemical hematological and histological changes but most of these were reversible when exposure had terminated.

Animals↗

PubMed1995

Use of the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test to study the genotoxicity of four trihalomethanes.

Three short-term assays (the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test) were carried out to evaluate the genotoxicity of four trihalomethanes (chloroform, bromodichloromethane, chlorodibromomethane and bromoform). With the SOS chromotest, all the chemicals studied except chloroform were found to induce primary DNA damage in Escherichia coli PQ37. In the Ames-fluctuation test, only bromoform showed mutagenic activity on Salmonella typhimurium strain TA100. The newt micronucleus assay detected a clastogenic effect on the peripheral blood erythrocytes of Pleurodeles waltl larvae for bromodichloromethane and bromoform. It appeared that the presence of bromine substituent(s) generally led to significant genotoxic activity. Moreover, the use of the metabolic system significantly increased the genotoxicity of the brominated trihalomethanes in the SOS chromotest. Unlike previous investigations in which the SOS chromotest was always the least interesting assay, this study exhibited the good efficiency of this in vitro test on E.coli for the detection of trihalomethanes with bromine substituents.

Animals↗

PubMed1997

Assessment of the potential in vivo genotoxicity of three trihalomethanes: chlorodibromomethane, bromodichloromethane and bromoform.

Chlorination of drinking water results in the formation of chlorodibromomethane, bromodichloromethane and bromoform. These trihalomethanes have all shown evidence of genotoxicity in bacterial and mammalian cell systems in vitro and some evidence of carcinogenicity in rodents. Chlorodibromomethane and bromodichloromethane have previously been tested in the mouse micronucleus test and did not induce chromosome damage, but results from two previous micronucleus tests on bromoform are somewhat contradictory. In the present study, bromoform was tested in the mouse bone marrow micronucleus test in order to reassess the response in this system; all three compounds were evaluated using the rat liver unscheduled DNA synthesis test. Trihalomethanes are well absorbed by the oral route which was selected for this study as being that most relevant to humans. Bromoform did not induce micronuclei in mouse bone marrow, and chlorodibromomethane, bromodichloromethane and bromoform did not cause unscheduled DNA synthesis in rat liver. These trihalomethanes have not shown any evidence of genotoxicity in vivo and are most unlikely to have any significant genotoxic activity in mammals. Their mode of action as rodent carcinogens remains unexplained.

Animals↗

PubMed2001

Relation between trihalomethane compounds and birth defects.

OBJECTIVES: To evaluate the risk of birth defects relative to exposure to specific trihalomethanes in public water supplies. METHODS: A retrospective cohort study was conducted based on data from a population based perinatal database in Nova Scotia, Canada and from the results of routine water monitoring tests. The cohort consisted of women who had a singleton birth in Nova Scotia between 1988 and 1995 and who lived in an area with a municipal water supply. The birth defects analyzed included neural tube defects, cardiovascular defects, cleft defects, and chromosomal abnormalities. Two of the four trihalomethane compounds occur in large enough concentrations to be analyzed (chloroform and bromodichloromethane (BDCM)). RESULTS: Exposure to BDCM at concentrations of 20 microg/l or over was associated with an increased risk of neural tube defects (adjusted relative risk (RR) 2.5, 95% confidence interval (95% CI) 1.2 to 5.1) whereas exposure to chloroform was not. Exposure to BDCM of 20 microg/l and over was associated with decreased risks of cardiovascular anomalies (RR 0.3, 95% CI 0.2 to 0.7). There was a suggestion of an increased risk of chromosomal abnormalities associated with exposure to chloroform, and no evidence of any association between either trihalomethane compound and cleft defects. CONCLUSIONS: In this cohort, differences were found in the RR associated with exposure to chloroform and BDCM for each of the congenital anomalies under study. These findings point to the importance of examining specific byproduct compounds relative to risk for these birth outcomes and in particular implicate BDCM and other correlated disinfection byproducts in the aetiology of neural tube defects.

Abnormalities, Drug-Induced↗