Comprehensive Assessment of a Chlorinated Drinking Water Concentrate in a Rat Multigenerational Reproductive Toxicity Study

Abstract

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. Using a multigenerational rat bioassay, we evaluated an environmentally relevant "whole" mixture of DBPs representative of chlorinated drinking water, including unidentified DBPs as well as realistic proportions of known DBPs at low-toxicity concentrations. Source water from a water utility was concentrated 136-fold, chlorinated, and provided as drinking water to Sprague-Dawley rats. Timed-pregnant females (P0 generation) were exposed during gestation and lactation. Weanlings (F1 generation) continued exposures and were bred to produce an F2 generation. Large sample sizes enhanced statistical power, particularly for pup weight and prenatal loss. No adverse effects were observed for pup weight, prenatal loss, pregnancy rate, gestation length, puberty onset in males, growth, estrous cycles, hormone levels, immunological end points, and most neurobehavioral end points. Significant, albeit slight, effects included delayed puberty for F1 females, reduced caput epidydimal sperm counts in F1 adult males, and increased incidences of thyroid follicular cell hypertrophy in adult females. These results highlight areas for future research, while the largely negative findings, particularly for pup weight and prenatal loss, are notable.

Reproductive Toxicity of a Mixture of Regulated Drinking-Water Disinfection By-Products in a Multigenerational Rat Bioassay

“…Concentrations of each component DBP are listed in Table 1 . Chemical proportions were based on those reported at the water utility that provided water for our whole-mixture toxicity studies ( Narotsky et al 2012 , 2013 ); these proportions were held constant across dose levels (0, 500×, 1,000×, or 2,000× of the MCLs). Overall dose levels were selected based on results of a preliminary dose-range–finding study with pregnant and lactating rats.…”

“…On PND0, pups were examined for evidence of nursing (i.e., abdominal milk bands) and were sexed, counted, and weighed. In addition, 15 F 1 litters each from the control group and the high-dose group (2,000×) were selected randomly, and the anogenital distance (AGD) of each pup was measured as described previously ( Narotsky et al 2013 ). On PND6, pups were again sexed, counted, and weighed.…”

“…F 1 litter sizes were reduced on PND6 to a maximum of 10 pups (5 males and 5 females when possible). On PND13, each F 1 pup was examined for eye opening and nipple retention, as described previously ( Narotsky et al 2013 ). On PND21, F 1 pups were sexed and weighed.…”

Maternal Swimming Pool Exposure during Pregnancy in Relation to Birth Outcomes and Cord Blood DNA Methylation among Private Well Users

“…Endocrine disruptors are capable of altering neural transmission and the formation of neural networks (Kajta and Wójtowicz, 2013). Animal studies, using artificial mixtures of DBPs detected in drinking water, observed endocrine disrupting effects, but these effects were not found when using trihalomethanes or haloacetic acids alone (Narotsky et al, 2015(Narotsky et al, , 2013. Thus, the driving agents of the DBP mixture toxicity and implicated mechanisms remain an active area of investigation (Plewa et al, 2017).…”

Exposure to disinfectant by-products and the risk of stillbirth in Massachusetts

“…A study on F344 rats examining in utero exposure reported pregnancy loss following daily gavage administration (at 1  mL/ kg bodyweight) of three different DBP mixtures (ie, THM4, HAA5 (haloacetic acid, HAA5: the sum of monochloroacetic acid (MCAA), dichloroacetic acid (DCAA), trichloroacetic acid (TCAA), monobromoacetic acid (MBAA), dibromoacetic acid (DBAA)), DBP9 (ie, the sum of THM4 and HAA5)). 14 Another study in Sprague-Dawley rats reported no associations for a DBP mixture including 75 priority and regulated DBPs 15…”