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epidemiological data
Type of information:
read-across from supporting substance (structural analogue or surrogate)
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:
Associations between disinfection by-product exposures and craniofacial birth defects
Kaufman JA, Wright JM, Evans A, Rivera-Nunez Z, Meyer A, Narotsky MG
Bibliographic source:
JOEM 60 (2), 109-119

Materials and methods

Study type:
case control study (retrospective)
Test guideline
no guideline followed
Principles of method if other than guideline:
A case–control study of CFD cases in 113 Massachusetts towns with populations greater than 500 with complete THM4 (four trihalomethanes), HAA5 (five haloacetic acids, including MCA), water source, and disinfection type data from 1999 to 2004. Analysis was restricted to nonchromosomal craniofacial congenital anomalies (n=366 cases, five with multiple CFDs, for a total of 371 CFDs). the authors individually matched 10 controls to each case, randomly selected without replacement from all live births in Massachusetts based on week of conception, for a total study population of 4026
GLP compliance:
not specified


Type of population:
Ethical approval:
not specified
Details on study design:
CFD cases were diagnosed on the basis of the International Classification of Diseases 9th revision (ICD-9). This included CL +/- P (ICD-9 codes 749.1, 749.2), CP (749.0), CL/CP (749) (see below), anophthalmia (743.0), microphthalmia (743.1), anotia (744.01), and microtia (744.23) up to age one. Cases and controls were singleton live births who weighed at least 350 g and were between 22 and 44 gestational weeks. For matching and exposure assessment purposes, we calculated week of conception by subtracting gestational age derived from clinical estimates on the birth certificate from the date of birth.
Exposure assessment:
Details on exposure:
Public water system data on water source, disinfection treatment type, and DBP (Disinfection By-Products) concentrations based on quarterly sampling (1999 to 2004) to birth records by town of residence and month of birth. The Massachusetts Department of Environmental Protection and individual public water utilities supplied these exposure data.
Statistical methods:
SAS (version 9.4; SAS Institute, Inc., Cary, NC) for statistical analyses.
Spearman correlation coefficients to compare summary and individual DBP measures.
Conditional logistic regression to estimate aORs and 95% CIs for each of the DBP exposure categories.
Given the extensive amount of available birth data, a more than 10% change-in-estimate approach was used to identify potential confounding variables.
The covariates examined included: type of water source and treatment, infant’s sex, maternal weight gain during pregnancy, maternal race, maternal age, maternal education, marital status, maternal smoking, parity, number of previous pregnancy terminations, prenatal care payment source, area-level income, trimester prenatal care began, number of prenatal care visits, and various clinical factors. Birth weight was not included in the models due to the potential for collider bias, as there is evidence that DBPs can affect different fetal growth indices and low birth weight is more common among babies born with birth defects than those without birth defects.

Results and discussion

Elevated aORs for cleft palate were detected with DBP9 (highest quintile aOR=3.52; 95% CI: 1.07, 11.60), HAA5, trichloroacetic acid (TCAA), and dichloroacetic acid.
Elevated aORs for eye defects were detected with TCAA and chloroform.
Confounding factors:
Covariates identified as potential confounding variables using a more than 10% change in estimate standard for inclusion in adjusted regression models are listed in footnotes for the Tables. In addition, THM4 was included in the fully adjusted models for HAAs and HAA5 was included in fully adjusted models for THMs to try to isolate the potential effects of correlated DBPs between these groups.

Applicant's summary and conclusion

Elevated aORs for eye defects were detected with TCAA and chloroform, and thus not for MCA.
Although elevated aORs for cleft palate were found with DBP9 and HAA5, these were also found for trichloroacetic acid (TCAA) and dichloroacetic acid, implying these chemicals may have been responsible for the observed effects and not MCA.