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Toxicity of Ammonium Perfluorooctanoate in Male Cynomolgus Monkeys after Oral Dosing for 6 Months
Abstract
Ammonium perfluorooctanoate (APFO) is a processing aid in the production of fluoropolymers that has been shown to have a long half-life in human blood. To understand the potential toxicological response of primates, groups of male cynomolgus monkeys were given daily po (capsule) doses of either 0, 3, 10, or 30 (reduced to 20) mg/kg/day for 26 weeks. Two monkeys from each of the control and 10 mg/kg/day dose groups were observed for 90 days after the last dose. Clinical observations, clinical chemistry, determination of key hormones, gross and microscopic pathology, cell proliferation, peroxisomal proliferation, bile-acid determination, and serum and liver perfluorooctanoate (PFOA) concentrations were monitored. Toxicity, including weight loss and reduced food consumption, was noted early in the study at the 30 mg/kg/day dose; therefore, the dose was reduced to 20 mg/kg/day. The same signs of toxicity developed in 3 monkeys at 20 mg/kg/day, after which treatment of these monkeys was discontinued. One 30/20 mg/kg/day monkey developed the signs of toxicity noted above and a possible dosing injury, and this monkey was sacrificed in extremis on Day 29. A 3 mg/kg/day dose-group monkey was sacrificed in extremis on Day 137 for reasons not clearly related to APFO treatment. Dose-dependent increases in liver weight as a result of mitochondrial proliferation occurred in all APFO-treated groups. Histopathologic evidence of liver injury was not observed at either 3 or 10 mg/kg/day. Evidence of liver damage was seen in the monkey sacrificed in moribund condition at the highest dose. Body weights were decreased at 30/20 mg/kg. PFOA concentrations in serum and liver were highly variable, were not linearly proportional to dose, and cleared to background levels within 90 days after the last dose. A no observable effect level was not established in this study, and the low dose of 3 mg/kg/day was considered the lowest observable effect level based on increased liver weight and uncertainty as to the etiology leading to the moribund sacrifice of one low-dose monkey on Day 137. Other than those noted above, there were no APFO-related macroscopic or microscopic changes, changes in clinical chemistry, hormones, or urinalysis, or hematological effects. In particular, effects that have been associated with the development of pancreatic and testicular toxicity in rats were not observed in this study.
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Metadata
- Authors
- Butenhoff, J.
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-09-01
- Volume
- 69
- Issue
- 1
- Pages
- 244-257
- ISSN
- 1096-0929 (ISSN-L)
- OpenAlex
- W2105954461
- Cited by
- 259
- References
- 3
- FWCI
- 5.95
- Type
- journal article
- Language
- en
- Open access
- closed
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