Table 2.

Effects of DBPs on the Reproductive System.

Chemical	Exposure Window	Dose	Model/Study Population	Effects	Conclusions	Reference
Trihalomethanes (THM4), haloacetic acids(HAA5), bromate	Developmental exposure	20–100 μg/mL	Zebra fish embryos	Adverse developmental effects, reduced tail length, increased malformation rates	Weak capacity of the selected disinfection products to cause developmental effects at environmentally relevant concentrations.	[44]
Chloroacetamide, bromoacetamide, iodoacetamide, chloroacetic acid, bromoacetic acid, iodoacetic acid, chloroacetonitrile, dichloroacetonitrile, trichloroacetonitrile, bromoacetonitrile, dibromoacetonitrile, iodoacetonitrile, n-nitrosodimethylamine, n-nitrosodiphenylamine, n-nitrosomorpholine	Developmental exposure	1–500 µM	Zebra fish embryos	Yolk sac and pericardial edema Axis, eye, snout, jaw, somite, pectoral fin, and caudal fin malformations Delayed developmental progression, reduced sensitivity to touch	The selected DBPs altered zebra fish development.	[45]
2,6-dichloro-1,4-benzoquinone, 2,5-dichloro-1,4-benzoquinone, 2,5-dibromo-1,4-benzoquinone, tetrachloro-1,4-benzoquinone, tetrabromo-1,4-benzoquinone, dichloroacetic acid, dibromoacetic acid, iodoacetic acid	Developmental exposure	0–16 µM	Zebra fish embryos	Increased mortality, reactive oxygen species, DNA damage, apoptosis, uninflated swim bladder, tail injury, pericardial edema, shortened body length, shortened yolk sac extension, developmental delay	Halobenzoquinones are acutely toxic, causing oxidative damage and developmental toxicity to zebrafish larvae.	[46]
Trichloroacetic acid, dichloroacetic acid, chloroacetic acid, bromoacetic acid, tribromoacetic acid, tri- fluoroacetic acid, difluoroacetic acid, dibromoacetic acid	Developmental exposure	1 to 17,000 µM	CD-1 mouse embryos	Prosencephalic hypoplasia, non-closure, impaired optic development, malpositioned and/or hypoplastic pharyn- geal arches, and perturbation of heart development	The selected haloacetic acids analyzed are potential developmental toxicants.	[47]
Dibromoacetic acid	Gestational, lactational, and adult exposure	0, 1, 5, or 50 mg/kg	Female Dutch-belted rabbits	Reduction in number of primordial follicles and total healthy follicles In adult animals, fewer primordial follicles	Chronic exposure to dibromoacetic acid diminishes the ovarian primordial follicle population.	[48]
Chloroacetic acid, bromoacetic acid, iodoacetic acid	48 and 96 h in vitro exposure of ovarian follicles	0.25–1.00 mM of chloroacetic acid; 2–15 µM of bromoacetic acid or iodoacetic acid	Ovarian follicles from CD-1 mice	Inhibition of antral follicle growth Reduction of estradiol levels	The selected monoHAAs inhibit the growth of antral follicles and reduce estradiol levels compared to controls in a dose-response manner.	[49]
Iodoacetic acid	96 h in vitro exposure of ovarian follicles	2–15 µM of iodoacetic acid	Ovarian follicles from CD-1 mice	Inhibition of antral follicle growth, reduction of estradiol levels Altered expression of genes related to the cell cycle, ovarian steroidogenesis, apoptosis, and estrogen receptors Altered levels of steroid hormones	Iodoacetic acid exposure inhibits follicle growth, decreases cell proliferation, and alters steroidogenesis in mouse ovarian follicles in vitro.	[50]
Chloroform, bromodichloromethane, chlorodibromomethane, bromoform chloroacetic acid, dichloroacetic acid, trichloroacetic acid, bromoacetic acid, dibromoacetic acid	Gestational exposure	1–72 mg/kg body weight	F344 rats	Increased pregnancy loss, embryo resorption, eye malformations (anophthalmia, microphthalmia)	Haloacetic acids cause pregnancy loss and contribute to the potency of the THM-HAA mixture in causing pregnancy loss.	[51]
106 DBPs and other chemicals identified or measured in a chlorinated concentrate water	Gestational, lactation, prepubertal exposure	N/A	Sprague−Dawley rats	Delayed puberty for F1 females Reduced caput epidydimal sperm counts in F1 adult males Increased incidence of thyroid follicular cell hypertrophy in adult females	Exposure to DBPs affects puberty, sperm production, and thyroid cells.	[52]
Dibromoacetic acid	Adult exposure	0, 125, 250, 500, 1,000, and 2,000 mg/L in the 2-week and 3-month studies, and 0, 50, 500, and 1,000 mg/L in the 2-year studies	F344/N rats and B6C3F1 mice	Delayed spermiation and atypical residual bodies in male rats and mice Atrophy of the germinal epithelium in rats	Dibromoacetic acid adversely affects male reproductive tissues/processes.	[53]
Chloroform, bromodichloromethane	Gestational exposure	Levels in the water-distribution systems: Chloroform: <50 µg/L, 50–74 µg/L, 75–99 µg/L, and 100 µg/L, and bromodichloromethane: <5 µg/L, 5–9 µg/L, 10–19 µg/L, and >20 µg/L	49,842 women who had a singleton birth in Nova Scotia, Canada between 1988 and 1995	Increased risk of neural tube defects Increased risk of chromosomal abnormalities	Chloroform and bromodichloromethane gestational exposure is associated with increased risk of neural tube defects and chromosomal abnormalities.	[54]
Trihalomethanes and haloacetic acids	Gestational exposure	Concentrations of trihalomethanes and haloacetic acids in the water-distribution systems (0.1–49.3 µg/L)	Pregnant women aged 25 to 34 years. Term newborn cases with birth weights <10th percentile (n = 571) were compared with 1925 term controls with birth weights ≥10th percentile. Québec City, Canada area	Increased risk of small for gestational age	Trihalomethane and haloacetic acid gestational exposure is associated with increased risk of small for gestational age.	[55]
Trihalomethanes and haloacetic acids	Gestational exposure	Maternal DBPs exposures (0.2–45.6 µg/L)	Longitudinal multi-ethnic birth cohort study in Bradford, England with pregnant women	Birth weight reduction of approximately 50 g	Exposure to trihalomethane during pregnancy is associated with adverse fetal growth, including reduced birth weight.	[56]
Chloroform, bromodichloromethane, dibromochloromethane, bromoform, trichloroacetic acid, dichloroacetic acid, monobromoacetic acid and summary DBP measures (trihalomethanes, haloacetic acids, brominated trihalomethanes, and DBP9 (sum of trihalomethanes, haloacetic acids)	Gestational exposure	Second-trimester disinfectant byproduct (µg/L) exposure levels for cases and controls, 1998–2004 (0–31.9 µg/L)	2460 stillbirth cases 1997–2004 in Massachusetts, US	Positive associations between stillbirth and DBP exposure	Trihalomethanes exposure increases risk of stillbirth.	[57]
Trihalomethanes	Adult exposure	Baseline blood concentrations of trihalomethanes (mean of 0.58–57.68 ng/L)	401 men in Wuhan, China between April 2011 and May 2012	Moderate levels of bromodichloromethane were associated with decreased sperm count and declined sperm linearity	Elevated trihalomethane exposure may lead to decreased sperm concentration and serum total testosterone.	[58]
Trihalomethanes	Adult exposure	Baseline blood concentrations of trihalomethanes (mean of 0.58–57.68 ng/L)	401 men in Wuhan, China between April 2011 and May 2012 and	Genetic polymorphisms of CYP2E1 and GSTZ1 were associated with semen quality	A combination of genetic susceptibility and environmental exposure to trihalomethanes may be associated with semen quality parameters.	[59]