Developmental Toxicity of Disinfection Byproducts in F344 Rats: Effects on Pregnancy Maintenance and Eye Development.

Background: Epidemiological studies report associations of drinking water disinfection byproducts (DBPs) with adverse health outcomes, including birth defects. Here, we used a rat model susceptible to pregnancy loss (full-litter resorption; FLR) and eye malformations (anophthalmia, microphthalmia) to test 11 DBPs, including trihalomethanes, haloacetic acids (HAAs), and nitrogen-containing DBPs (N-DBPs).

Methods: Timed-pregnant F344 rats received gavage doses of chloroform, chlorodibromomethane, iodoform, chloroacetic acid, bromoacetic acid, dibromoacetic acid (DBA), diiodoacetic acid (DIA), trichloroacetic acid (TCA), dibromonitromethane, and iodoacetonitrile on gestation days (GD) 6-10.

Risks of obstructive genitourinary birth defects in relation to trihalomethane and haloacetic acid exposures: expanding disinfection byproduct mixtures analyses using relative potency factors.

Background: Some disinfection byproducts (DBPs) are teratogens based on toxicological evidence. Conventional use of predominant DBPs as proxies for complex mixtures may result in decreased ability to detect associations in epidemiological studies.

Objective: We assessed risks of obstructive genitourinary birth defects (OGDs) in relation to 12 DBP mixtures and 13 individual component DBPs.

Disinfection By-Product Exposures and the Risk of Musculoskeletal Birth Defects.

Background: Epidemiological studies suggest that exposure to water disinfection by-products (DBPs) may increase the risk of certain birth defects. However, evidence for musculoskeletal defects (MSDs) is limited. Previous MSD studies have not examined DBPs beyond trihalomethanes (THMs) and have not separately examined limb or diaphragm defects which may have distinct developmental etiologies.

Associations Between Disinfection By-Product Exposures and Craniofacial Birth Defects.

Objective: The aim of this study was to examine associations between craniofacial birth defects (CFDs) and disinfection by-product (DBP) exposures, including the sum of four trihalomethanes (THM4) and five haloacetic acids (HAA5) (ie, DBP9).

Methods: We calculated first trimester adjusted odds ratios (aORs) for different DBPs in a matched case-control study of 366 CFD cases in Massachusetts towns with complete 1999 to 2004 THM and HAA data.

Results: We detected elevated aORs for cleft palate with DBP9 (highest quintile aOR = 3.

A systematic evaluation of the potential effects of trichloroethylene exposure on cardiac development.

The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a controversial drinking water study in rats (Johnson et al. [51]), along with several other studies/endpoints to derive reference values. An updated literature search of TCE-related developmental cardiac defects was conducted.

Disinfection By-Product Exposures and the Risk of Specific Cardiac Birth Defects.

Background: Epidemiological studies suggest that women exposed to disinfection by-products (DBPs) have an increased risk of delivering babies with cardiovascular defects (CVDs).

Objective: We examined nine CVDs in relation to categorical DBP exposures including bromoform, chloroform, dibromochloromethane (DBCM), bromodichloromethane (BDCM), monobromoacetic acid (MBAA), dichloroacetic acid (DCAA), trichloroacetic acid (TCAA), and summary DBP measures (HAA5, THMBr, THM4, and DBP9).

Methods: We calculated adjusted odds ratios (aORs) in a case-control study of birth defects in Massachusetts with complete quarterly 1999-2004 trihalomethane (THM) and haloacetic acid (HAA) data.

Reproductive toxicity of a mixture of regulated drinking-water disinfection by-products in a multigenerational rat bioassay.

Background: Trihalomethanes (THMs) and haloacetic acids (HAAs) are regulated disinfection by-products (DBPs); their joint reproductive toxicity in drinking water is unknown.

Objective: We aimed to evaluate a drinking water mixture of the four regulated THMs and five regulated HAAs in a multigenerational reproductive toxicity bioassay.

Methods: Sprague-Dawley rats were exposed (parental, F1, and F2 generations) from gestation day 0 of the parental generation to postnatal day (PND) 6 of the F2 generation to a realistically proportioned mixture of THMs and HAAs at 0, 500×, 1,000×, or 2,000× of the U.

Comprehensive assessment of a chlorinated drinking water concentrate in a rat multigenerational reproductive toxicity study.

Some epidemiological studies report associations between drinking water disinfection byproducts (DBPs) and adverse reproductive/developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects.

Estimation of individual rodent water consumption from group consumption data for gestation, lactation, and postweaning life stages using linear regression models.

In rodent bioassays where chemicals are administered in the drinking water, water consumption data for individual animals are needed to estimate chemical exposures accurately. If multiple animals share a common water source, as occurs in some studies, only the total amount of drinking water consumed by all animals utilizing the common source is directly measurable, and water consumption rates for individual animals are not available. In the Four Lab Study of the US Environmental Protection Agency, which included a multigenerational rodent bioassay, a complex mixture of drinking water disinfection by-products was delivered to multiple Sprague-Dawley rats from a common drinking water container.

Developmental toxicity evaluations of whole mixtures of disinfection by-products using concentrated drinking water in rats: gestational and lactational effects of sulfate and sodium.

A developmental toxicity bioassay was used in three experiments to evaluate water concentrates for suitability in multigenerational studies. First, chlorinated water was concentrated 135-fold by reverse osmosis; select lost disinfection by-products were spiked back. Concentrate was provided as drinking water to Sprague-Dawley and F344 rats from gestation day 6 to postnatal day 6.

Prospective power calculations for the Four Lab study of a multigenerational reproductive/developmental toxicity rodent bioassay using a complex mixture of disinfection by-products in the low-response region.

In complex mixture toxicology, there is growing emphasis on testing environmentally representative doses that improve the relevance of results for health risk assessment, but are typically much lower than those used in traditional toxicology studies. Traditional experimental designs with typical sample sizes may have insufficient statistical power to detect effects caused by environmentally relevant doses. Proper study design, with adequate statistical power, is critical to ensuring that experimental results are useful for environmental health risk assessment.

Gestational atrazine exposure: effects on male reproductive development and metabolite distribution in the dam, fetus, and neonate.

Few studies have investigated the long-term effects of atrazine (ATR) following in utero exposure. We evaluated the effects of gestational exposure of Sprague Dawley dams to ATR (0, 1, 5, 20, or 100mg/kg-d) on the reproductive development of male offspring. We also quantified the distribution of ATR and its chlorinated metabolites in maternal, fetal, and neonatal fluid and tissue samples following gestational and/or lactational exposure.

The effects of prenatal exposure to atrazine on pubertal and postnatal reproductive indices in the female rat.

Atrazine (ATR) is an herbicide that exerts negative reproductive effects. We examined the effects of vehicle or ATR (1, 5, 20 and 100mg/kg-d), administered to Sprague-Dawley rats on gestational days 14-21, once daily or divided into two doses per day, on female offspring reproductive indices. Offspring body weights at birth were reduced and mortality increased in the 100mg/kg-d group shortly after birth; by PND 21 there were no significant effects.

Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action.

Reactions between chemicals used to disinfect drinking water and compounds present in source waters produce chemical mixtures containing hundreds of disinfection byproducts (DBPs). Although the results have been somewhat inconsistent, some epidemiological studies suggest associations may exist between DBP exposures and adverse developmental outcomes. The potencies of individual DBPs in rodent and rabbit developmental bioassays suggest that no individual DBP can account for the relative risk estimates reported in the positive epidemiologic studies, leading to the hypothesis that these outcomes could result from the toxicity of DBP mixtures.

Pregnancy loss and eye malformations in offspring of F344 rats following gestational exposure to mixtures of regulated trihalomethanes and haloacetic acids.

Chlorination of drinking water yields hundreds of disinfection by-products (DBPs). Among the DBPs, four trihalomethanes (THMs; chloroform, bromodichloromethane, chlorodibromomethane, bromoform) and five haloacetic acids (HAAs; chloroacetic, dichloroacetic, trichloroacetic, bromoacetic, and dibromoacetic acid) are U.S.

Concentration, chlorination, and chemical analysis of drinking water for disinfection byproduct mixtures health effects research: U.S. EPA's Four Lab Study.

The U.S. Environmental Protection Agency's "Four Lab Study" involved participation of researchers from four national Laboratories and Centers of the Office of Research and Development along with collaborators from the water industry and academia.

A novel water delivery system for administering volatile chemicals while minimizing chemical waste in rodent toxicity studies.

Rodent toxicity studies typically use water bottles to administer test chemicals via drinking water. However, water bottles provide inconsistent exposure of volatile chemicals due to varying headspace, and lead to excessive waste of test material. To refine drinking water toxicity studies in rodents by enhancing sample quality and consistency, and minimizing waste, we designed and implemented a novel water delivery system that keeps the water chilled, headspace free and protected from light.

The role of developmental toxicity studies in acute exposure assessments: analysis of single-day vs. multiple-day exposure regimens.

In accordance with most toxicity guidelines, developmental studies typically utilize repeated exposures, usually throughout gestation or during organogenesis in particular. However, it is known that developmental toxicity may occur in response to single exposures, especially during specific windows of susceptibility. An overview of the available literature gave sufficient evidence that for many agents, the same endpoints observed in repeated dose, multiple-day studies were also observed in single-day exposures, thus indicating the relevance of developmental toxicity to health assessments of acute exposures.

Integrated disinfection by-products research: assessing reproductive and developmental risks posed by complex disinfection by-product mixtures.

This article presents a toxicologically-based risk assessment strategy for identifying the individual components or fractions of a complex mixture that are associated with its toxicity. The strategy relies on conventional component-based mixtures risk approaches such as dose addition, response addition, and analyses of interactions. Developmental toxicity data from two drinking-water concentrates containing disinfection by-products (DBP) mixtures were used to illustrate the strategy.

Integrated disinfection by-products mixtures research: assessment of developmental toxicity in Sprague-Dawley rats exposed to concentrates of water disinfected by chlorination and ozonation/postchlorination.

Epidemiological and animal toxicity studies have raised concerns regarding possible adverse health effects of disinfection by-products (DBPs) found in drinking water. The classes and concentrations of DBPs are influenced by the choice of disinfection process (e.g.

Integrated disinfection by-products mixtures research: comprehensive characterization of water concentrates prepared from chlorinated and ozonated/postchlorinated drinking water.

This article describes the disinfection by-product (DBP) characterization portion of a series of experiments designed for comprehensive chemical and toxicological evaluation of two drinking-water concentrates containing highly complex mixtures of DBPs. This project, called the Four Lab Study, involved the participation of scientists from four laboratories and centers of the U.S.

Atrazine and reproductive function: mode and mechanism of action studies.

Atrazine, a chlorotriazine herbicide, is used to control annual grasses and broadleaf weeds. In this review, we summarize our laboratory's work evaluating the neuroendocrine toxicity of atrazine (and related chlorotriazines) from an historic perspective. We provide the rationale for our work as we have endeavored to determine: 1) the underlying reproductive changes leading to the development of mammary gland tumors in the atrazine-exposed female rat; 2) the cascade of physiological events that are responsible for these changes (i.

Effects of bromodichloromethane on ex vivo and in vitro luteal function and bromodichloromethane tissue dosimetry in the pregnant F344 rat.

Bromodichloromethane (BDCM), a drinking water disinfection by-product, causes pregnancy loss, i.e. full-litter resorption, in F344 rats when treated during the luteinizing hormone (LH)-dependent period.