Teratogenic activity of trichloroacetic acid in the rat

Abstract

Trichloroacetic acid (TCA) is a by-product of the chlorine disinfection of water containing natural organic material. It is detectable in finished drinking water at levels comparable to the trihalomethanes (30-160 micrograms/L). TCA is also formed in vivo after ingestion of hypochlorite and has been identified as a major metabolite of chlorinated hydrocarbons such as trichloroethylene. The developmental effects of TCA were evaluated in the pregnant Long-Evans rat. Animals were dosed by oral intubation on gestation days 6-15 (plug = 0) with 0, 330, 800, 1,200, or 1,800 mg/kg/day. The vehicle control was distilled water. Maternal observations included clinical signs, weight change, and gross evaluation of organ weights and uterine contents at necropsy (day 20). Live fetuses were examined for external, skeletal, and soft tissue malformation. There were no maternal deaths associated with toxicity prior to sacrifice. Weight gain during treatment was reduced at 800, 1,200, and 1,800 mg/kg. Spleen and kidney weights were increased in a dose-related manner. The mean percent of resorbed implants per litter was 34, 62, and 90 at 800, 1,200, and 1,800 mg/kg, respectively. Live fetuses showed dose-dependent reductions in weight and length. The mean frequency of soft tissue malformations ranged from 9% at the low dose to 97% at the high dose. These were principally in the cardiovascular system (interventricular septal defect, levocardia). Skeletal malformations were found only at 1,200 and 1,800 mg/kg and were mainly in the orbit. Based on these observations TCA was considered to be developmentally toxic in the pregnant rat at doses of 330 mg/kg and above.

Threshold of trichloroethylene contamination in maternal drinking waters affecting fetal heart development in the rat.

“…Considerable information is available regarding the short-and long-term toxicity of these agents and, to a lesser extent, their general teratogenicity (13)(14)(15)(16)(17)(18). Recent research has implicated halogenated hydrocarbons as specific cardiac teratogens in animal models and has indicated their significance to health issues in the United States and abroad (14,(19)(20)(21).…”

The epidemiology and possible mechanisms of disinfection by-products in drinking water

“…Halogenated acetic acids have been found to cause testicular damage in rats through disruption of spermatogenesis and motility, with the brominated analogues being the strongest toxicants (Smith et al 1989;Toth et al 1992;Linder et al 1994a,b, et al (2001) chlorinated (average TTHM = 9.4 μg l −1 ) versus non-chlorinated 1.00 (0.91-1.10) * * Kramer et al (1992) 0 versus ≥10 μg l −1 CHCl 3 1.8 (1.1-2.9) * Bove et al (1995) ≤20 versus >100 μg l −1 TTHM 1.5 (1.2-1.9) * Dodds et al (1999) 0-49 versus >100 μg l −1 TTHM 1.08 (0.99-1.18) * * * Wright et al (2003) 0-60 versus >80 μg l −1 TTHM 1.14 (1.02-1.26) Wright et al (2004) >74-163 versus 0-33 μg l −1 TTHM 1.13 (1.07-1.20) Aggazzotti et al (2004) THMs ≥30 ≥53 versus <40 μg l −1 TTHM 1.09 (1.00-1.18) Yang et al (2007) THM4 >13.1 versus ≤4.9 μg l −1 0.96 (0.91-1.02) Hoffman et al (2008) 74.9-108.8 versus 2.2-4.6 1.3 (0.7-2.3) * ≤5th percentile; * * ≤10th percentile; * * * ≤2 s.d. Table 4.…”

The effect of disinfection by-products and mutagenic activity on birth weight and gestational duration.

“…The trihalomethanes (THMs) are not considered teratogenic, but growth retardation has been reported in mice exposed to chloroform (Murray et al 1979;Ruddick et al 1983;Schwetz et al 1974;Thompson et al 1974). Growth retardation has also been reported in mice exposed to dichloroacetic acid (Smith et al 1992) and trichloroacetic acid (Smith et al 1989a) and in rats exposed to dichloroacetonitrile (Smith et al 1989b) and trichloroacetonitrile (Smith et al 1987).…”