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https://ntp.niehs.nih.gov/go/tr598abs

Abstract for TR-598

Toxicology and Carcinogenesis Studies of Perfluorooctanoic Acid Administered in Feed to Sprague Dawley (Hsd:Sprague Dawley SD) Rats

CASRN: 335-67-1
Chemical Formula: C8HF15O2
Molecular Weight: 414.07
Synonyms/Common Names: PFOA
Report Date: May 2020

FULL REPORT PDF

Abstract

Perfluorooctanoic acid (PFOA) is a perfluorinated alkyl substance (PFAS) with widespread exposure in the environment and human population. Lifetime exposure to this chemical is likely, which includes in utero and postnatal development. Previously conducted chronic carcinogenicity studies of PFOA began exposure after these critical periods of development, so it is unknown whether the carcinogenic response is altered if exposure during gestation and lactation is included. The current PFOA chronic studies were designed to assess the contribution of combined gestational and lactational exposure (herein referred to as perinatal exposure) to the chronic toxicity and carcinogenicity of PFOA. The hypothesis tested was that including exposure during gestation and lactation (perinatal exposure) with postweaning exposure would change the PFOA carcinogenic response quantitatively (more neoplasms) or qualitatively (different neoplasm types) compared to postweaning exposure alone.

This hypothesis was tested using a design of exposing time-mated Sprague Dawley (Hsd:Sprague Dawley SD) rats to 0, 150, or 300 ppm PFOA during the perinatal period, after which the F1 male rats were provided 150 or 300 ppm PFOA (i.e., perinatal/postweaning exposures of 0/0, 0/150, 150/150, 0/300, and 300/300 ppm) and the F1 female rats were provided 300 or 1,000 ppm PFOA (i.e., 0/0, 0/300, 150/300, 0/1,000, and 300/1,000 ppm) during the postweaning period (n = 50/sex/dose). Female rats have a lower systemic exposure due to a faster PFOA elimination rate than males, so a higher feed exposure concentration was provided to female rats postweaning. An interim necropsy (n = 10/sex/group) at 16 weeks (19 weeks of age) was conducted.

Due to unanticipated toxicity in male rats observed at the 16-week interim time point, males were removed from the first study at week 21. A second study of males only was started that used lower postweaning feed concentrations. In this second study, the pregnant females were exposed to a single feed concentration of 300 ppm PFOA because this exposure was well tolerated.

Sixteen-week Interim Evaluation

In general, toxicity was observed in the liver, glandular stomach, kidney, and thyroid gland in males and in the liver, kidney, and thyroid gland in females at the 16-week interim evaluation. Body weights were lower in exposed groups of males and females compared to control groups as exposure concentrations increased. Plasma concentrations of PFOA were consistently higher in males compared to females and consistent between animals that were exposed to PFOA perinatally and postweaning versus postweaning exposure alone. Acyl-CoA oxidase activity in the liver was consistently elevated in males and females (males had higher activity than females) regardless of their exposure during the perinatal period.

Two-year Studies

Survival was unaffected by PFOA exposure, and there were exposure-related decreases in body weight compared to control groups in both male and female rats. Male rats had increased incidences of hepatocellular adenomas in the 0/40, 300/40, 0/80, and 300/80 ppm groups compared to the 0/0 ppm control group, and higher incidences of hepatocellular carcinomas were observed in the 300/80 ppm group compared to the 0/80 group. Increased pancreatic acinar cell adenomas and adenocarcinomas were observed in all postweaning exposed groups (20, 40, and 80 ppm) with or without perinatal exposure. Although not statistically significant, there were occurrences in female rats of pancreatic acinar cell adenomas and adenocarcinomas in the 0/1,000 and 300/1,000 ppm female groups compared to the 0/0 ppm control group. Marginally higher numbers of hepatocellular carcinomas and uterine adenocarcinomas were also observed in the PFOA-exposed groups regardless of perinatal exposure. Nonneoplastic lesions were only observed in the liver and pancreas of male rats, whereas lesions were increased in the liver, kidney, forestomach, and thyroid gland of female rats.

In general, very few significant differences were observed between the responses of groups of animals exposed to PFOA postweaning only versus groups with both perinatal and postweaning exposures, and most of these differences were considered sporadic. The response to PFOA in female rats was generally less than that of male rats, which was consistent with the lower internal plasma concentrations of PFOA in female rats relative to male rats.

Conclusions

Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of PFOA in male Hsd:Sprague Dawley SD rats based on the increased incidence of hepatocellular neoplasms (predominately hepatocellular adenomas) and increased incidence of acinar cell neoplasms (predominately acinar cell adenomas) of the pancreas. The additional effect of perinatal exposure in combination with postnatal exposure was uncertain and limited to the observation of hepatocellular carcinomas.

There was some evidence of carcinogenic activity of PFOA in female Hsd:Sprague Dawley SD rats based on the increased incidences of pancreatic acinar cell adenoma or adenocarcinoma (combined) neoplasms. The higher incidence of hepatocellular carcinomas and adenocarcinomas of the uterus may have been related to exposure. The combined perinatal and postweaning exposure was not observed to change the neoplastic or nonneoplastic response compared to the postweaning exposure alone in female rats.

Exposure to PFOA resulted in increased incidences of nonneoplastic lesions in the liver and pancreas of male rats and in the liver, kidney, forestomach, and thyroid gland of female rats.

National Toxicology Program (NTP). 2020. NTP technical report on the toxicology and carcinogenesis studies of perfluorooctanoic acid (CASRN 335-67-1) administered in feed to Sprague Dawley (Hsd:Sprague Dawley SD) rats. Research Triangle Park, NC: National Toxicology Program. Technical Report 598. https://doi.org/10.22427/NTP-TR-598

Studies

Summary of the Two-year Toxicology and Carcinogenesis Studies of Perfluorooctanoic Acid with and without Perinatal Exposure
  Male
Sprague Dawley Rats
Female
Sprague Dawley Rats
Concentrations in feed
Postweaning 0/0, 0/20, 0/40, 0/80 ppm 0/0, 0/300, 0/1,000 ppm
Perinatal + postweaning 300/0, 300/20, 300/40, 300/80 ppm 0/0, 150/300, 300/1,000 ppm
Survival rates
Postweaning 36/50, 42/50, 34/50, 36/50 23/50, 26/50, 23/50
Perinatal + postweaning 34/50, 38/50, 38/50, 39/50 23/50, 32/50, 22/50
Body weights
Postweaning 0/80 ppm group: 82–90% of the 0/0 ppm control group weight after week 6 0/1,000 ppm group: 78–88% of the 0/0 ppm control group weight after week 2
Perinatal + postweaning 300/80 ppm group: 83–90% of the 0/0 ppm control group weight after week 6 300/1,000 ppm group: 73–86% of the 0/0 ppm control group weight after week 2
Nonneoplastic effects
Postweaning Liver: hepatocyte, cytoplasmic alteration (0/50, 12/50, 34/50, 46/50); hepatocyte, hypertrophy (0/50, 13/50, 34/50, 43/50); hepatocyte, single cell death (1/50, 1/50, 11/50, 24/50); necrosis (2/50, 17/50, 23/50, 20/50); pigment (0/50, 7/50, 15/50, 30/50)

Pancreas: acinus, hyperplasia (18/50, 32/50, 37/50, 31/50)
Liver: hepatocyte, cytoplasmic alteration (0/50, 9/50, 49/49); hepatocyte, hypertrophy (0/50, 11/50, 48/49); hepatocyte, single cell death (0/50, 4/50, 29/49); necrosis (0/50, 1/50, 8/49); pigment (3/50, 5/50, 43/49); bile duct hyperplasia (16/50, 25/50, 22/49); hepatocyte, increased mitoses (2/50, 3/50, 4/49)

Kidney: papilla, urothelium, hyperplasia (4/50, 21/50, 40/49); papilla, necrosis (0/50, 0/50, 12/49); renal tubule, mineral (5/50, 6/50, 16/49)

Forestomach: ulcer (2/50, 2/50, 9/49); epithelium, hyperplasia (4/50, 5/50, 22/49); submucosa, inflammation, chronic active (3/50, 2/50, 16/49)

Thyroid gland: follicular cell, hypertrophy (4/50, 8/50, 28/49)
Perinatal + postweaning

Liver: hepatocyte, cytoplasmic alteration (0/50, 4/50, 29/50, 41/50); hepatocyte, hypertrophy (1/50, 4/50, 29/50, 42/50); hepatocyte, single cell death (1/50, 3/50, 5/50, 29/50); necrosis (1/50, 11/50, 14/50, 21/50); pigment (0/50, 4/50, 11/50, 26/50)

Pancreas: acinus, hyperplasia (23/50, 27/50, 38/50, 33/50)

Liver: hepatocyte, cytoplasmic alteration (0/50, 17/50, 49/50); hepatocyte, hypertrophy (0/50, 16/50, 49/50); hepatocyte, single cell death (0/50, 5/50, 32/50); necrosis (0/50, 4/50, 5/50); pigment (3/50, 10/50, 40/50); bile duct hyperplasia (16/50, 27/50, 27/50); hepatocyte, increased mitoses (2/50, 5/50, 10/50)

Kidney: papilla, urothelium, hyperplasia (4/50, 8/50, 45/50); papilla, necrosis (0/50, 0/50, 22/50); renal tubule, mineral (5/50, 8/50, 8/50)

Forestomach: ulcer (2/50, 1/50, 11/50); epithelium, hyperplasia (4/50, 3/50, 21/50); submucosa, inflammation, chronic active (3/50, 2/50, 18/50)

Thyroid gland: follicular cell, hypertrophy (4/50, 9/50, 19/50)
Neoplastic effects
Liver

Postweaning: hepatocellular adenoma (0/50, 0/50, 7/50, 11/50); hepatocellular carcinoma (0/50, 0/50, 0/50, 0/50); hepatocellular adenoma or carcinoma (0/50, 0/50, 7/50, 11/50)

Perinatal + postweaning: hepatocellular adenoma (0/50, 1/50, 5/50, 10/50); hepatocellular carcinoma (0/50, 0/50, 0/50, 4/50); hepatocellular adenoma or carcinoma (0/50, 1/50, 5/50, 12/50)
None
Pancreas

Postweaning: acinar cell adenoma (3/50, 28/50, 26/50, 32/50); acinar cell adenocarcinoma (0/50, 3/50, 1/50, 3/50), acinar cell adenoma or adenocarcinoma (3/50, 29/50, 26/50, 32/50)

Perinatal + postweaning: acinar cell adenoma (7/50, 18/50, 30/50, 30/50); acinar cell adenocarcinoma (0/50, 2/50, 1/50, 3/50), acinar cell adenoma or adenocarcinoma (7/50, 20/50, 30/50, 30/50)

Postweaning: acinar cell adenoma (0/50, 0/50, 1/49); acinar cell adenocarcinoma (0/50, 0/50, 1/49); acinar cell adenoma or adenocarcinoma (0/50, 0/50, 2/49) 

Perinatal + postweaning: acinar cell adenoma (0/50, 0/50, 3/50); acinar cell adenocarcinoma (0/50, 0/50, 2/50); acinar cell adenoma or adenocarcinoma (0/50, 0/50, 5/50) 
Equivocal findings
Liver None

Postweaning: hepatocellular carcinoma (1/50, 1/50, 3/49)

Perinatal + postweaning: hepatocellular carcinoma (1/50, 0/50, 4/50)
Uterus None

Postweaning: adenocarcinoma (1/50, 5/50, 8/50)

Perinatal + postweaning: adenocarcinoma (1/50, 3/50, 5/50)
Level of evidence of carcinogenic activity Clear evidence Some evidence