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epidemiological data
Type of information:
other: epi study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
Maternal exposure to drinking-water chlorination by-products and small-for-gestational-age neonates
Levallois P, Gingras S, Marcoux S, Legay C, Catto C, Rodriguez M, Tardife R
Bibliographic source:
Epidemiol. 23, 267–276

Materials and methods

Study type:
case control study (retrospective)
Endpoint addressed:
developmental toxicity / teratogenicity
Test guideline
no guideline followed
Principles of method if other than guideline:
A population-based case-control study was conducted in the Quebec City (Canada) area. Term newborn cases with birth weights <10th percentile (n=571) were compared with 1925 term controls with birth weights >=10th percentile.
Because the last trimester is usually considered to be the critical period of exposure for intrauterine growth retardation,7,25–28 it was the main focus of our exposure assessment. However, exposure during the other trimesters of pregnancy was also evaluated.
GLP compliance:

Test material

Specific details on test material used for the study:
The chlorination by-products exposure of participants was based on assessment of the chlorination by-products concentration in the tap water at the participant’s residence, ingestion of trihalomethanes and haloacetic acids, and multiroute exposure to trihalomethanes expressed as total absorbed dose (ug/d).
Chemicals investigated were 4 trihalomethanes (chloroform, bromodichloromethane, chlorodibromomethane, and bromoform) and 9 haloacetic acids (monochloroacetic, dichloroacetic, trichloroacetic, monobromoacetic dibromoacetic, tribromoacetic,
bromochloroacetic, dibromochloroacetic, and bromodichloroacetic acid).


Type of population:
Ethical approval:
confirmed, but no further information available
Details on study design:
Cases and controls were selected using information recorded on these birth certificates. To be eligible for the study, the women had to be aged 16 years or older and have resided in no more than 2 residences in the study area during their entire pregnancy. Additionally, they should not have resided away from their residence for more than a month during their pregnancy.
Cases were term small-for-gestational-age (SGA) singletons born at 37 completed weeks or more of pregnancy to women living in the targeted study area during the 23-month recruitment period. A case of SGA corresponds to a neonate weighting less than the sex-specific 10th percentile of weight for gestational age, according to the Canadian sex-specific standards of birth weight for gestational age.
Three controls per case were randomly selected from the live birth database with frequency matching on period of birth. We defined a control as a singleton term infant born the same calendar week as the case with a birth weight at or above the 10th percentile sex-specific weight for gestational age. Because participation was slightly higher for controls, the ratio of controls to cases was 3.4.
An interviewer contacted potential participants by telephone to verify their eligibility and seek their participation. A computer-assisted telephone interview of participants lasting approximately 30 minutes gathered detailed information on all independent variables (water-use behavior and risk factors for SGA), as well as information on the birth outcome (infant weight, duration of pregnancy). In the event of any discrepancies in case status between a mother’s interview and a birth certificate, medical records were checked, and corrections were made based on medical records (this was necessary for 3 cases). The participation rates were 91% for eligible cases and 93% for eligible controls. The median time lag for completing an interview after birth was 9.1 weeks for cases and 9.3 for controls. Interview data were available for a total of 571 cases and 1925 controls.
Details on exposure:
A population-based case-control study was conducted in the greater Quebec City area (covering some 650,000 inhabitants). It includes the 16 water distribution systems serving the populations of Que´bec City and the city of Le´vis. Among these systems, 9 are supplied by surface water sources and 7 by groundwater sources. All use free chlorine for primary or secondary disinfection, but differ in water source, water treatment processes, population served, system size, and hydraulic conditions. The study population includes all singleton infants born between August 2006 and April 2008 to women residing in the areas served by the selected facilities.
Sampling campaigns tailor-made for the study were conducted from April 2006 to April 2008. Monthly sampling campaigns for trihalomethanes and haloacetic acids measurements at 46 sites distributed in the 9 surface water systems and 7 sites for the 7 systems supplied by groundwater (one site per system). Water samples were collected according to standard procedures after 5 minutes of flushing and were stored at 4°C. Analyses of the 4 trihalomethanes (chloroform, bromodichlorometh-
ane, chlorodibromomethane, and bromoform) and 9 haloacetic acids (monochloroacetic, dichloroacetic, trichloroacetic, monobromoacetic dibromoacetic, tribromoacetic, bromochloroacetic, dibromochloroacetic, and bromodichloroacetic acids) were carried out in accordance with EPA method 524.230 and EPA method 552.2,31 respectively. Internal and external quality controls were conducted during the study.
The doses (expressed in ug/day) of chlorination by-products absorbed by each participant via ingestion during a typical day of the last trimester of pregnancy were calculated for each trihalomethane and haloacetic acid by multiplying the daily ingested volume from various water sources (ie, cold and hot beverages) with the estimated chlorination by-products concentrations in the ingested water during this trimester. Information reported by the participants during the interview was used regarding sources of water consumed (ie, bottled water from private source, cold or hot water from public distribution system) and particular water handling (ie, filtering, boiling, storage in fridge) to adjust the chlorination by-products concentration in water
actually ingested. Intakes from inhalation and dermal absorption (expressed as ug/d) during one typical 24-hour day of the last trimester were calculated and added to the previous estimated ingested dose using a physiologically based toxicokinetic model.
Statistical methods:
Odds ratios (ORs) and their 95% confidence intervals (CIs) for association with the various indexes of exposure to chlorination by-products were determined using unconditional logistic regression models while controlling for possible covariates and for the calendar week of birth. All variables associated in univariate analysis with SGA (with P < 0.15) were included in the multivariate analyses. Tests for trend were based on a Wald X2 test conducted by assigning the median value to each level of a categorical variable and treating the variable on a continuous scale in a logistic regression model.

Results and discussion

When total trihalomethanes and the 5 regulated haloacetic acids concentrations were divided into quartiles, no clear dose-response relationship was found with SGA. However, increased risk was observed when haloacetic concentrations were above the fourth quartile and when either trihalomethanes or haloacetic acids concentrations were above current water standards (adjusted OR = 1.5 [95% confidence interval = 1.1–1.9] and 1.4 [1.1–1.9], respectively). Inhalation and dermal absorption of trihalomethanes did not contribute to this risk, but a monotonic dose-response was found with haloacetic acids ingestion.
Confounding factors:
The following variables documented during the interview were considered: maternal age, maternal ethnicity, maternal education, annual household income, working status, marital status, prepregnancy body mass index, parity, history of chronic disease, medical problem during pregnancy, active and passive maternal smoking throughout the pregnancy, coffee and alcohol consumption, and risky occupational exposure.

Applicant's summary and conclusion

Oral exposure to high levels of chlorination by-products in drinking water could be a risk factor for term SGA (Small for-Gestational-Age). In light of the consistent association with the oral route and a monotonic dose-response with haloacetic acids ingestion, this
study provides some support regarding the effects of nonvolatile haloacetic acids. However, this seems related to the presence of dichloro- and trichloroaectic acids rather than monochloroacetic acis (MCA).