Effects of HCFC-123 Exposure to Maternal and Infant Rhesus Monkeys on Hepatic Biochemistry, Lactational Parameters and Postnatal Growth

Abstract

Peroxisome proliferators are a class of nongenotoxic rodent hepatocarcinogens that cause peroxisome proliferation and liver tumors when administered to rats and mice; but other species, including guinea pigs, dogs, and primates are less sensitive or refractory to the induction of peroxisome proliferation. Therefore, rodent peroxisome proliferators are not believed to pose a hepatocarcinogenic hazard to humans. Some peroxisome proliferators produce developmental toxicity in rats that is expressed as suppressed postnatal growth. To evaluate the relevance of the rat developmental effect to primates, groups of 4 lactating female Rhesus monkeys and their infants were exposed for 6 h/day, 7 days/week for 3 weeks to air or 1000 ppm HCFC-123. Animals were evaluated for clinical signs, body weights, clinical pathology parameters, and biochemical and pathological evaluations of liver biopsy samples. The effect of HCFC-123 exposure on milk quality (protein and fat concentration) was evaluated. The concentrations of HCFC-123 and the major metabolite, trifluoroacetic acid (TFA), were measured in the blood of the mothers and infants and in the milk. Exposure of monkeys to 1000 ppm HCFC-123 did not result in exposure-related clinical observations, or changes in body weight, appetence and behavior. There were no exposure-related effects on serum triglycerides, cholesterol, or glucose levels. HCFC-123 and TFA were present in milk, although maternal HCFC-123 exposure did not affect milk protein and fat content. In general, HCFC-123 was not detected in maternal or infant blood. TFA was detected in the majority of the mothers and TFA levels in infants ranged from 2 to 6 times higher than levels in the corresponding maternal blood. A pharmacokinetic analysis in a maternal animal indicated a peak concentration of TFA at approximately 1 h post-exposure, with a half-life of approximately 20 h. Liver microsomal P450 and peroxisome oxidase activities showed exposure-related decreases in CYP4A1 and CYP2E1 and acyl-CoA oxidase for animals exposed to HCFC-123. Microscopic evaluation of maternal liver from HCFC-123 exposed animals revealed mild to moderate centrilobular hepatocyte vacuolation, trace to mild centrilobular necrosis, and trace to mild subacute inflammation. The histopathological damage and altered hepatic biochemical activities produced by HCFC-123 in monkeys are not consistent with the HCFC-123 peroxisome proliferation response observed in rat livers. These findings demonstrate that HCFC-123 is not a peroxisome proliferator in adult Rhesus monkeys and postnatal exposure to HCFC-123 does not affect body weight of nursing infant monkeys.

PFAS: forever chemicals—persistent, bioaccumulative and mobile. Reviewing the status and the need for their phase out and remediation of contaminated sites

“…In mice, TFA as a metabolite of 2-bromo-2-chloro-1,1,1-trifluoro-ethane (halothane) passes the placental barrier and accumulates in the fetus and amniotic fluid [264]. TFA was also found in breast milk of monkeys as metabolite of the refrigerant 1,1,1-Trifluoro-2,2-dichloroethane (HCFC-123) [265], Whereas in two recent studies on rats, TFA did not show any developmental effects with NOAEL of 150 and 382 mg/kg bw per day, respectively [261]. In rabbits, on the other hand, major abnormalities have been observed at 375 and 750 mg/kg bw per day as well as, to a lesser extent, at the lowest dose level of 180 mg/kg bw per day predominantly affecting the eyes [261].…”

The development of environmentally acceptable fluorocarbons

“…In addition to normal evaluations including liver biopsy, the effect of exposure on milk quality (fat and protein content) was evaluated and the levels of HCFC 123 and TFA were determined. While levels of HCFC 123 and TFA were found in the milk and TFA was found in the infants, there was no effect on body weight of the infants (Cappon et al 2002).…”

Trifluoroacetic Acid: Toxicity, Sources, Sinks and Future Prospects

“…However, another report suggested that the TFA concentrations measured by Duan et al [77] might result from its metabolic generation from longer-chain PFASs, or from elevated local exposure [78]. Both the detection of metabolically generated TFA in mammals and elevated TFA exposure from certain occupational sources have been reported [79][80][81]. If this is the case, concentrations reported by Duan et al [73] might not be representative of the general population.…”