Developmental toxicity of disinfection byproducts in F344 rats

Drinking water disinfection by-products (DBPs) form when oxidizing disinfectants (e.g., chlorine) react with organic material in source waters. Previously, we have shown that two of the regulated trihalomethanes (THMs), bromoform and bromodichloromethane, cause pregnancy loss (i.e., full-litter resorption; FLR) when administered to pregnant F344 rats. We have also shown that mixtures of THMs, haloacetic acids (HAAs), and THMs+HAAs all caused pregnancy loss in F344 rats. The HAA-containing mixtures also caused eye malformations in pups of dams exposed during gestation. The F344 rat is an inbred strain that is particularly susceptible to toxicant-induced pregnancy loss, apparently due to disruption of luteinizing hormone (LH) during the LH-dependent period of pregnancy. This strain is also susceptible to eye malformations (anophthalmia, microphthalmia). Here, we used the F344 rat model to compare the developmental toxicity of several THMs (chloroform, iodoform, chlorodibromomethane), HAAs (bromoacetic acid, dibromoacetic acid, diiodoacetic acid, trichloroacetic acid), and other DBPs (dibromonitromethane, iodoacetonitrile). DBPs were administered by gavage to timed-pregnant F344 rats on gestation days 6-10, encompassing the maternal LH-dependent period of pregnancy as well as the critical period of embryonic eye development. Dams were allowed to deliver and litters were examined on postnatal days (PD) 1 and 6. Uteri of nongravid rats were stained with 2% ammonium sulfide to confirm cases of FLR. All three THMs tested caused pregnancy loss; on a molar basis, iodoform was more potent than chloroform. None of the THMs caused eye malformations. For the HAAs, only trichloroacetic acid caused pregnancy loss. Except for bromoacetic acid, all of the HAAs tested caused eye malformations. Preliminary studies with dibromonitromethane and iodoacetonitrile showed no significant effects on the incidences of pregnancy loss or eye malformations. Thus, consistent with previous work, the THMs caused pregnancy loss but had no effect on eye development in surviving litters. Also consistent with previous work, most of the HAAs were teratogenic and caused eye malformations. Trichloroacetic acid, however, was unique among the HAAs in that it caused pregnancy loss as well as eye malformations in F344 rats.