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.