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PFC Health Concerns

PFCs: Global Contaminants: PFC Health Concerns

April 3, 2003

April 2003

In new laboratory work scientists find that low doses of PFOA harm lab animals — at estimated blood levels lower than those found in some children. The government initiated in-depth analyses of human risk on receiving 3M lab studies in May 2001. And now, with calculated risks to human health far too high, the government is poised to demand rare, expedited assessments.  

Industry’s most recent study shows organ weight changes — often a gross sign of toxicity and damage to organ function — among lab animals exposed to PFOA in the womb and into early adulthood. [Organ weight effects in: males | females] [Mortality and sexual development: Extract | Full document] Some human children and adults have more PFOA in their blood than the estimated levels for the animals in this study. Under duress from the Environmental Protection Agency, 3M and DuPont are handing over unprecedented amounts of health and safety data — some 50,000 pages worth to date.


Infographic showing levels of PFC chemicals in human blood



Three of the four tumors caused by PFOA are on the rise in people, including testicular, breast, liver and prostate. [Extract] PFOA also causes hypothyroidism in lab studies, a condition linked to fetal brain damage. Hypothyroidism strikes 4.6% percent of Americans, mostly women [1]. Levels of PFOA in some people’s bodies now appear to be in the range known to harm animals.

EPA’s new findings of high risk to humans. EPA instigated its in-depth analysis of human risk from PFOA exposures on receipt of a major new study, sponsored by 3M, in 2002. In this rat reproduction study scientists exposed rats to PFOA in utero through early adulthood, and found damage to organs in animals exposed to the lowest doses tested [2]. [Reproductive effects in: males | females]

At the lowest dose tested, with levels of PFOA in the maternal blood of approximately 40 parts per billion (ppb), the offspring were smaller at birth and the adult female rats exposed in utero (F1 generation females) decreased body weight gain at certain times in young adulthood [2] [Extracts: F1 newborn, F1 adult body weight | Full document Note: 22MB file]. At three of four doses tested, beginning with maternal blood at approximately 120 ppb, the adult F1 generation female rats had decreased growth of the pituitary gland [2] [Excerpt | Full document Note: 22MB file]. The pituitary gland is often called the “master gland” in the body because it secretes hormone that regulate many bodily processes, such as growth, maternal care, reproduction and metabolism. When the adult F1 female rats gave birth to their own babies (called the F2 generation), a greater number of the F2 pups were “found dead or presumed cannibalized” [2] [Extract | Full document Note: 22MB file]. This suggests that maternal care could have been altered, perhaps by damage to the pituitary gland. Alternatively, the F1 mothers may have ignored or cannibalized pups because the F2 offspring were not healthy.

At higher doses in the rat reproduction study, corresponding to 1 part per million (ppm) PFOA in maternal blood, seven of 60 male and six of 60 female offspring died [Reference to Extract | Full document Note: 22MB file]. No excess mortality was found in parental animals [Extract], which means that PFOA is more toxic to the young compared to adults. As a group, the male offspring were emaciated, cold to touch and less active than untreated rats. When scientists autopsied the male and female offspring, they found significant changes in eight organs, including the brain, liver, spleen, thymus, adrenal gland, kidney, prostate, testes and epididymides. Both male and female offspring reached sexual maturity later and the female offspring also had altered reproductive cycling.

3M workers involved with PFOA production typically have blood PFOA levels above 1 ppm, and as high as 114 ppm in one worker tested. DuPont does not readily disclose worker PFOA blood levels, although a document made public in recent litigation, marked “Personal and Confidential” shows that two of eight women tested at the Washington Works plant in 1981 had PFOA blood levels higher than 1 ppm. [Full Document] A recently publicized internal DuPont hazard assessment shows that people who drink water with 3 ppb PFOA for six years are expected to accumulate blood levels of 1 ppm.[Extract and EWG analysis] PFOA is found at this level in drinking water supplies near DuPont manufacturing facilities.

EPA classifies PFOA as carcinogenic in animals, causing testicular, pancreatic, mammary and liver tumors in rats [3]. Workers exposed to PFOA have elevated risks of dying from or seeking treatment for cancers of the pancreas and male reproductive tract, including those of the testis and prostate.[EWG Worker Study Document] Testicular, breast, and liver cancer have been increasing in the US during the past 10 to 25 years.[Extract] Liver cancer alone has increased an estimated average 4.7% a year between 1992 and 1999 [4].

Five studies have shown that PFOA alters reproductive hormones in the male, causing increased levels of estrogen and abnormal testosterone regulation [5-9] Increased levels of estrogen have been found in exposed workers [10, 11] [Extract | Full document]. In rats, PFOA alters growth of the prostate, testis, epididymides, and seminal vesicles.

Eleven studies show that PFOA or chemicals that break down into PFOA damage the thyroid gland. In 2002, monkeys exposed to PFOA for one month developed an underactive thyroid, a condition called hypothyroidism.[Extract] Hypothyroidism affects an estimated 4.6 percent of Americans [1], mostly women. Hypothyroidism can impair brain development, leading to hearing loss and impaired growth and intellectual development.

Four organs or tissues in the immune system and at least nine types of cells that regulate immune function are targets of PFOA [34-37]. Thus far, scientists have failed to find a dose of PFOA that does not damage the immune system.

So far, five different pathways have been identified that might explain how PFOA causes cancer and other types of toxicity. These include mitochondrial toxicity; cell membrane disruption that results in decreased cell communication; peroxisome proliferation; increased levels of estrogen and decreased levels of testosterone; and decreased thyroid hormone levels.


Cancer.

The federal government considers PFOA to be carcinogenic — causing liver, pancreatic, testicular, and mammary gland tumors in rats [3] [p. 6]. Three of these four cancers have been increasing in the US population in recent years. Breast cancer strikes one in eight women. The incidence of testicular cancer has risen in certain parts of the world during the last several decades and is now the most common type of cancer in men aged 15 to 35 [12].

In two-year cancer studies sponsored by 3M and DuPont, none of the 80 rats in the “control group” developed testicular or pancreatic tumors; in contrast, these tumors were found in eight of 76 (11%) exposed to PFOA [3, 9 pg. 75]. In a two-year cancer study conducted by 3M, PFOA doubled the incidence of mammary tumors in exposed laboratory animals [13].

3M has seen problems with these kinds of cancers among their workers as well. In various studies of their workers’ health, 3M reported increased rates of dying or seeking care for prostate cancer, testicular cancer, and pancreatic cancer or disease [14-16].[EWG Worker Study Document] These worker studies typically involve so few people that the increases are often considered to be statistically weak. Nevertheless, the consistency of cancers among workers and in laboratory studies is striking. While a cause and effect link between human cancers and PFOA exposures has not been established, the increases in these cancers, combined with ubiquitous PFOA contamination in human blood is cause for concern.


Breast cancer.

Among girls born today, one in eight is expected to get breast cancer and one in 32 is expected to die from it [4]. Breast cancer in women increased an average of 1.1 percent per year between 1992 and 1999 [4]. Among those 65 and younger, breast cancer incidence rose 1.4 percent per year [4]. If these trends continue, the granddaughters of today's young women could face a one-in-four chance of developing breast cancer [17, 18].


Testicular cancer.

At its current pace, the incidence of testicular cancer is doubling about every one and a half generations (39 years). In the U.S. the incidence of testicular cancer rose 41.5 percent between 1973 and 1996, an average of 1.8 percent per year [17, 18]. While rates of testicular cancer continue to drop among older men (65 and up), testicular cancer remains the most common cancer among young men, with the highest rate of diagnosis among men between the ages of 30 and 34.


Prostate cancer.

Prostate cancer rates rose 4.4 percent a year between 1973 and 1992, or more than a doubling of risk in a generation. Since 1992, the incidence has declined, but it is still 2.5 times the 1973 rate. Part of this increase can be explained by better detection, but increased incidence has also been accompanied by an increase in mortality — which better detection cannot explain. Prostate cancer is now the most common cancer among U.S. men, and the second most lethal [17, 18].

Worker studies show increased rates of developing and dying of certain cancers.

3M workers exposed to high levels of fluorochemicals like PFOA appear to be at higher risks for cancers of the male reproductive system [14, 15].[EWG Worker Study Document] Mortality studies of 3M workers at the Cottage Groove, MN plant found that Chemical Division workers with ten or more years of employment were 3.3 times more likely to die of prostate cancer compared to workers who did not work in PFOA production [14].[Extract] In two other studies, one conducted in Cottage Groove, MN and the other at a 3M plant in Decatur, Alabama, 3M found that exposed workers had elevated risk for dying of prostate cancer or visiting the doctor for reasons associated with having prostate cancer [15, 16]. While prostate cancer is fairly common among older men — one in 5 or 6 will develop the disease — only about one in 30 will die from prostate cancer and 50% of men with prostate cancer will die after the age of 79 [4]. 3M chose not to study cancer incidence among workers, but instead studied cause of death. The average age of death in men working in the chemical division of 3M was 54.2 years [14].

While these two studies did not report statistically elevated risk like Gilliland et al. did, the findings are consistent across the worker studies and also with animal studies showing that the prostate is a target organ of PFOA [2]. Workers in the two 3M plants are also more likely to die or seek treatment for pancreatic cancer or disease and any type of male reproductive tract cancer, which includes testicular and prostate cancer [15, 16]. Neither pancreatic or testicular cancers are as common in men as prostate cancer, and the likelihood of dying from these diseases is not high: the lifetime risk for dying of pancreatic cancer is about one in 87, and for testicular cancer about 1 in 5000 [4]. Again, 3M studied cause of death and not disease incidence. Because dying from these types of cancer is not common, it is all the more troubling that increased risks were noted for these diseases. If PFOA is causing these effects in workers, a much larger study than the studies conducted by 3M would be needed to find statistically significant effects. Nevertheless, the patterns of disease are remarkably consistent with animal studies.

All of the worker studies conducted by 3M and DuPont have significant flaws that prevent conclusive interpretation of study results. The flaws in the worker studies would tend to obscure the ability of scientists to discern exposure-driven health effects, making the many findings of health harms in various worker studies particularly compelling. For example, in some studies 3M classified workers into exposed or unexposed categories based on job occupation to see if there were differences in diseases between these workers [14-16, 19]. Yet, in 1996, authors of a study partially sponsored by 3M concluded that PFOA contamination among all workers was so ubiquitous that job history could not be used as a measure for exposure:

We expected the group of workers who were selected for the unexposed group based on job history to have total serum fluorine levels similar to the general population. However, we found that this group of workers was not unexposed, having levels 20-50 times higher than levels reported for the general population. We concluded that job history was not an accurate metric for exposure.

Hypothyroidism.

In eleven studies conducted between 1978 and 2002, scientists have documented damage to the thyroid gland following exposure to PFOA and chemicals that break down into PFOA, in monkeys and other animals [13, 20-26]. The damage includes cellular effects on the thyroid and hypothyroidism, a condition characterized by low levels of thyroid hormones that control growth and metabolism and that are critical for proper brain development.

Thyroid cancer and hypothyroidism are current human health concerns. An estimated 10 million people in the US have hypothyroidism [27]. The condition is of particular concern in pregnant women because thyroid hormones are critical for proper brain development in the fetus. Small reductions in maternal thyroid hormone levels during pregnancy have been associated with reduced IQs in children.

In a 1998 study at the Cottage Groove, MN plant, 3M found evidence of altered thyroid hormone regulation in workers. Medical staff measured significant increases in thyroid stimulating hormone (TSH) in workers with higher PFOA blood levels [10, 11].[TSH Findings: 1998 Study | DuPont Summary of TSH | Dupont Hazard Assessment] High TSH levels are one sign of an underactive thyroid and resulting low thyroid hormone levels; the pituitary gland in the brain will secretes extra TSH as a signal to stimulate thyroid hormone production.

Industry scientists found a trend towards decreased thyroid hormone levels in every group of PFOA-exposed animals in a 2002 monkey study, [20] [Extract] and increased cellular damage in the thyroids of rats exposed to chemicals that break down into PFOA [20-26]. The cellular changes are the same type caused by a prolonged state of hypothyroidism and are also associated with developing thyroid tumors in rodents [29, 30]. DuPont has never tested whether the chemicals that break down into PFOA cause tumors.

Three new studies show that compounds that break down into PFOA in the body also target the thyroid. Although detailed study information is claimed as CBI (Confidential Business Information) and redacted from the public record [23] [Extract], presentations made by DuPont to the EPA indicate that the thyroid was a target for all of the fluorinated telomers tested, including those known to break down into PFOA [25] [Extract | Full document]. DuPont interpreted these effects as “non-adverse physiological responses,” but under their claim of “CBI” privilege provided no information on the specific types of effects seen [23].

An underactive thyroid gland in adults can lead to fatigue, depression, anxiety, unexplained weight gain, hair loss, and low libido. More serious, however, are the effects of thyroid hormone disruption for the developing fetus and child. Fetuses, infants and children who experience more significant changes in hormone levels may suffer mental retardation, loss of hearing and speech, abnormal testicular development or deficits in motor skills. In older children, depressed thyroid levels have been associated with lower motivation to learn and attention deficit disorder [31, 32].

Industry attempts to obscure and minimize thyroid findings. 3M and DuPont continue to downplay the effects of PFCs on the thyroid. In a study co-authored mostly by industry scientists, the researchers state that “there were no APFO [PFOA]-related changes in clinical chemistry, hormones, or urinalysis, or hematological effects” in monkeys. Yet later in the article, the scientists include a table showing that PFOA exposures led to significantly decreased thyroid hormone levels, and the authors report that thyroid hormones became more normal after PFOA exposure stopped [20].[Extract]

Similarly, in 1998, 3M scientists published a study that included a table showing that workers with high blood levels of PFOA had statistically significant increases in TSH, a measure of hypothyroidism [11] [Extract]. Yet, they failed to discuss this finding in the study summary, results or discussion section.

DuPont recently presented data to the EPA showing that their fluorotelomer compounds affect the thyroid, but interpreted these effects as “non-adverse physiological responses,” and provided no specific details of the thyroid effects, citing this data as “Confidential Business Information” [23].

3M recently undertook a comprehensive assessment of the effects of PFOA to the fetus. Inexplicably, among the many health endpoints studied, they neglected to assess the thyroid at all [2], even though PFCs are so clearly linked to thyroid damage in other studies, and PFOA has been found to cause hypothyroidism in monkeys.

Immune system problems.

In laboratory studies PFOA causes toxicity to four organs or tissues in the immune system and at least nine types of cells that regulate immune function [2, 33, 37]. PFOA has long been known to damage the immune system, but in the most recent study scientists learned that exposures to PFOA early in life are more harmful than in adulthood. In this study scientists failed to find a dose that did not damage the immune system. The spleen and thymus, both critical to immune function, were atrophied among animals exposed in the womb and through early adulthood; spleen atrophy occurred at the lowest dose tested.

In industry’s latest animal study, every dose tested harmed the spleen, a gland where specialized cells called B cells mature and then produce antibodies critical to combating disease. The thymus gland seems particularly sensitive to chemicals in the PFC family. Lodged behind the breastbone and above the heart in humans, the gland plays a critical role in immunity, manufacturing T cells that recognize and destroy bacteria, viruses, and cancer cells. At least one PFC chemical (PFDA) causes the gland to rot away to the point where scientists can no longer find it in the animal: “Thymic tissue was not found in the majority of treated rats.” [38][Extract] While PFOA has not been shown to cause the thymus to completely disappear, it has been linked to atrophy of the gland in animals dosed in the womb and through early life, at doses that cause no thymus effects in animals exposed only during adulthood [2].

In a 1995 symposium on early-life immune impacts, a consensus statement from a diverse panel of scientists implies the significance of immune system damage in early life: “Life-long capacity for immune response is determined early in development, during prenatal and early postnatal development in mammals” [39]. Many immunotoxic chemicals produce more severe or long-lasting damage when exposure occurs early in life [40]. In the fetus and through early life, the thymus is instrumental in fostering the growth and development of the immune system. The type of thymic damage observed with PFOA could lead to permanent decrements in immune function, resulting in higher risk for infection and disease, including cancer.

Several studies by scientists in labs at Stockholm University and the Karolinska Institute in Sweden looked at the effects of PFOA on immune cells in detail. They found that PFOA decreased the number of every immune cell subpopulation they studied — eight in all — in the thymus and spleen [35, 37]. Yang et al. also found PFOA damaged immune cell function, a phenomenon as the cells were unable to mount a proper immune response to foreign cells, referred to as immunosupression [34].

A few of the effects of PFOA on immune system cells are due to activation of a receptor (peroxisome proliferating activating receptor-alpha or PPARa) that mediates several other toxic effects of PFOA and that is thought to be a more active mechanism in rodents than in humans. When scientists feed PFOA to mice in which the capacity for this mechanism has been genetically removed, many of the effects on the thymus cells remain, reinforcing the relevance of the laboratory studies for humans, and heightening the concern for in utero and early life human exposures to PFOA.

In workers, increased blood levels of PFOA are associated with increased white blood cells (leucocytes) [10], suggesting that workers are under stress from infection or disease [41], consistent with a picture of poor immune function.

Reproductive problems, birth defects.

PFOA is more toxic to fetuses and infants than to adult animals. For example, PFOA causes death in young rats at doses that do not affect survival in the parents.

Much of the EPA’s concern for PFOA stems from the results of a 2002 rat reproduction study paid for by 3M [2]. In this study, adult rats were dosed with PFOA prior to mating, during mating and pregnancy, and throughout lactation until their offspring are weaned at about 3 weeks of life. The offspring were further dosed with PFOA and allowed to breed. In this way, the EPA can see whether PFOA decreases fertility, as well as decide if PFOA exposure early in life causes developmental toxicity.

The rat reproduction study showed was that PFOA is more toxic to young animals [2]. Rats exposed to PFOA in the womb often died at weaning in the highest dose group even though mortality was not affected in adult rats at any dose level. Also, a greater number of organs were affected by PFOA in adult male rats exposed in utero at the lowest PFOA dose compared with adult male rats not exposed during fetal life.

In male rats exposed only during adulthood, two organ weights (liver and kidney) were increased at the lowest dose. Four organ weights were altered in adult males exposed to PFOA in the womb; animals in this group tended to have decreased body weight and had significantly increased liver, kidney, and seminal weights and decreased spleen weight. Organ weight changes are used as a gross measure of toxicity and often indicate impared organ function.

A 1982 study sponsored by 3M also showed that PFOA is more toxic to rabbits exposed in the womb than in adulthood [42]. In this study, rabbit fetuses had significantly increased number of skeletal abnormalities at a dose that did not cause effects on the mother.

DuPont tested for and found PFOA in the blood of female plant workers in Parkersburg. The company followed and documented pregnancy outcomes in exposed workers. Two of seven children born to female plant workers between 1979 and 1981 had birth defects, one an “unconfirmed” eye and tear duct defect, and one a nostril and eye defect.[Full Document] In 1981 fifty women were reassigned in the plant.

In addition to causing testicular tumors, PFOA causes many other effects on the male reproductive system, including increased size of the testes, epididymides and seminal vesicles[2], and decreased prostate in rats [2, 6]. In the female, PFOA causes mammary tumors and cellular effects on the ovary [13].

Beginning in 1992, DuPont scientists began to publish papers addressing how PFOA causes testicular tumors and other harmful effects on the male reproductive tract (they have not studied mammary gland and ovarian effects). First, they found that PFOA increases blood levels of estradiol (the major form of estrogen in humans and rodents) in male rats. They also found that PFOA affects testosterone regulation, tending to decrease blood levels of testosterone and alter the production of testosterone in testicular cells[5], effects that are likely due to a “lesion at the level of the testes” [10].

A follow-up study published by DuPont scientists in 1995 showed that PFOA increases levels of estrogen by increasing activity of liver aromatase, an enzyme that converts testosterone to estradiol [5]. Biegel et al. also found that PFOA increased testicular levels of a protein produced in high levels by cancer cells called transforming growth factor-alpha (TGFa) [5]. While DuPont scientists have not studied female rats as often as male rats, other studies have shown that estradiol stimulates excess release of TFG-a in mammary cells.

Because high levels of estrogen are a risk factor for the type of testicular tumor caused by PFOA, EPA suggested that the induction of Leydig cell tumors, a type of testicular tumor, by PFOA may be endocrine mediated, possibly by sustained elevation of estrogen [6].[Extract | Full Document]

Increased estradiol and decreased testosterone have been found in highly exposed 3M workers at a plant that produced PFOA in Cottage Groove, MN. [10, 11]. Three studies in two 3M plants have confirmed that exposed workers appear more likely to die or seek treatment for cancers of the male reproductive tract [14-16].


References:

 

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[2] York, RG (2002). Oral (gavage) two-generation (one litter per generation) reproduction study of ammonium perfluorooctanoate (APFO) in rats. Report prepared for 3M, St. Paul, MN by Argus Research (Horsham, PA). Sponsor's Study No. T-6889.6., Reviewed in US EPA AR226-1092.

[3] Environmental Protection Agency (EPA). 2002. Revised draft hazard assessment of perfluorooctanoic acid and its salts, November 4, 2002. U.S. EPA Administrative Record AR226-1136.

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[10] DuPont (1997). Hazard characterization for human health C8 exposure CAS registry no. 3825-26-1. Prepared by L.B. Biegel, Senior Research Toxicologist.

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[21] DuPont Haskell Laboratory. 2002. Developmental and one-generation reproduction study: Mixture of poly(difluoro-methylene), alpha-fluoro-omega [2-(phosphonooxy) ethyl]-, monoammonium salt (CAS# 65530-71-4); poly(difluoro-methylene), alpha-fluoro-omega[2-(phosphonooxy) ethyl]-, diammonium salt (CAS# 65530-72-5); poly(difluoromethylene), alpha, alpha’- [phosphinicobis(oxy-2,1-ethanediyl)bis [omega-fluoro-], ammonium salt (CAS# 65530-70-3); isopropyl alcohol (CAS# 67-63-0); and water (CAS# 7732-18-5). US Environmental Protection Agency: Toxic Substance Control Act (TSCA) Section 8(e) Submission Received from 01/02/03 to 1/15/03: 8EHQ-1202-15247A. December 20, 2002. Available online at http://www.epa.gov/opptintr/tsca8e/doc/new8e.htm.

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[23] DuPont. 2002. The updated copy of DuPont Product Stewardship on December 17, 2001. U.S. EPA Administrative Record AR226-1069.

[24] DuPont Haskell Laboratory. 2002. Results of an oral gavage combined 90-day repeated dose and one-generation reproductive toxicity study in rats for poly (oxy-1,2-ethanediyl) alpha-hydro-omega-hydroxy- ether, with alpha-fluoro- omega (2-hydroxyethyl) poly (difluoromethane) (1:1) (telomer B monoether)(CAS Number 65545-80-4; non-HPV). US Environmental Protection Agency: Toxic Substance Control Act (TSCA) Section 8(e) Submission Received from 10/15/01 thru 12/07/01: 8EHQ-1001-14915. November 5, 2001. Available online at http://www.epa.gov/opptintr/tsca8e/doc/8esub/8e101501.htm.

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[26] DuPont Haskell Laboratory. 2002. Results of a 2-week inhalation toxicity study in rats for n-diiodoperfluoro-alkanes mixture (no CAS); hexadecafluoro-1,8-diiodooctane (CAS 335-70-6); 1,1,2,2,3,3,4,4-octafluoro-1,4-diiodobutane (CAS 375-50-8); 1,6-diiodo-perfluorohexane (375-80-4); diiodofluoro chemical (?) (CAS Number 65975-18-0); non-HPV chemicals. US Environmental Protection Agency: Toxic Substance Control Act (TSCA) Section 8(e) Submission Received from 5/9/02 thru 5/22/02: 8EHQ-0502-13829D. May 7,2002. Available online at http://www.epa.gov/oppt/tsca8e/doc/8esub/2002/0509_052202.htm.

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[28] US EPA (2002). Draft hazard assessment of PFOA and its salts February 20, 2002.

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Footnotes for informational graphic

 

40 ppb (1 mg/kg/day)
Decreased growth;


120 ppb (3 mg/kg/day)
Decreased growth; decreased pituitary size (females); decreased breast-feeding; [c]


370 ppb (10 mg/kg/d)
Decreased growth; decreased pituitary size (females); [c]


1,000 ppb (30 mg/kg/d)
Death; decreased growth; delayed sexual maturation (males and female); increased number of fertility cycles (female); decreased breast feeding; decreased pituitary size (females); decreased kidney size (female);


[a] Changes in organ size are often used by scientist to is a crude measure of toxicity and often reflect damaged organ function

[b] Based on adult lactating female rats 3 weeks after giving birth

[c] Effects seen in adult male rats exposed in utero. Adult male rats have higher serum levels of PFOA than adult female rats and it is unclear if the greater number of effects seen in the adult male offspring compared to the male parent never exposed in utero is due to early in life

Note: Control rats had blood PFOA levels below the level of quantitation (5.3 ppb)