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DuPont’s Spin About PFOA

PFCs: Global Contaminants: DuPont’s Spin About PFOA

April 3, 2003

April 2003

DuPont is in big regulatory trouble at EPA. And that could mean big economic trouble for the company. In response to increasing, unfavorable press reports DuPont has repeatedly made claims that exposures to PFOA, or C8, do not present a human health risk. This public relations spin is clearly out of step with recent conclusions drawn by the US EPA, with data published in peer-reviewed journals, and with data embedded in 50,000 pages of industry-sponsored studies submitted to EPA, which EWG has reviewed and posted in searchable form online (click for searchable database).

In summary, here is DuPont's spin on PFOA's health risks and EWG's analysis of current scientific knowledge:

  1. DuPont asserts that levels of PFOA found in human blood are too low to be a health risk. This conclusion is contradicted by recent findings from an industry-sponsored rat reproduction study. After seeing this study, the EPA initiated a “priority review” of PFOA to determine whether expedited regulatory action against the compound is warranted under Section 4(f) of the Toxic Substances Control Act (TSCA) due to concerns that the compound causes adverse developmental and reproductive effects in animals. The most recent step in EPA’s priority review is a draft risk assessment that shows blood levels of PFOA in women and girls are dangerously close to blood levels of PFOA that cause serious harm to laboratory animals.
  2. DuPont claims there is no evidence or data that demonstrates PFOA causes adverse human health effects. DuPont has reported only one health study in the public record on workers exposed to PFOA, and this study was limited to measuring liver enzyme levels, which were significantly increased in workers. More troublesome are findings from studies sponsored by 3M showing that workers with high PFOA exposures are significantly more likely to die of prostate cancer and cerebrovascular disease. Another PFOA study sponsored by 3M found that exposed workers are significantly more likely to seek care for prostate cancer, gastrointestinal tract lesions, biliary tract and pancreatic disorders, and urinary bladder inflammation. Interpreting these studies is complicated because they all have significant design flaws and are based on small numbers of people. Still, cancer and other disease relationships are found, and the consistency of health effects among workers and in laboratory studies is striking.
  3. DuPont denies that PFOA causes reproductive or developmental toxicity. EPA’s priority review of PFOA was initiated precisely due to concerns raised by EPA scientists regarding the developmental and reproductive toxicity of PFOA in animal studies.
  4. DuPont emphasizes that the liver is the most important target organ for PFOA toxicity. PFOA causes toxicity to virtually every organ or system tested, including the brain, pituitary, adrenal gland, thyroid, ovary, male reproductive tract, immune system and kidney. PFOA also causes mammary, testicular, pancreatic and liver tumors. Effects on the ovary, pituitary, kidney, spleen and seminal vesicles were affected by PFOA at or below doses where liver effects were observed.
  5. DuPont claims that PFOA causes toxic effects in laboratory animals by a single “mechanism of action” that is not relevant to people. PFOA causes adverse effects by at least five mechanisms of action, four of which are clearly relevant to humans. For only one of these mechanisms, “peroxisome proliferation,” are scientists debating the relevance to humans. Peroxisome proliferation is clearly linked to liver toxicity in rats. Scientists do not know if peroxisome proliferation is responsible for the liver toxicity observed in monkeys or high liver enzyme levels observed in workers, or whether a different mechanisms causes these effects. PFDA (C10), a sister chemical to PFOA, has been shown to cause peroxisome proliferation in human brain cells.

DuPont Spin vs. EWG Analysis

 

Relationship between human blood levels of PFOA and adverse effects in laboratory animals

 

Dupont spin. On March 18, 2003, DuPont staff presented the following information to the media, implying that humans would have to drink more than 2000 gallons of contaminated drinking water to reach exposures that harm laboratory animals [1] [slide 15]:

Assessing the Science: Is the dose (in animal studies) relevant?

Effect (Animal Model)

No Observed Effect Level

Equivalent Human Consumption Gal. of Water with 3 ppb PFOA

Chronic-liver
(rat and primate)

0.5 mg/kg

>2,000 gal. per day

Cancer
rat

2.0 mg/kg

>2,000 gal. per day

Reproduction/Developmental
(rat)

10 mg/kg

>40,000 gal. per day

Reproduction of DuPont graphic

 

EWG Analysis. DuPont has both misrepresented the “no effect” levels of these studies and implied that people could never be exposed to PFOA at levels high enough to approach the dose levels given to laboratory animals. In none of the studies DuPont refers to did scientists find a dose that did not cause significant harm to laboratory animals [EWG critical study summary table | EPA Hazard Assessment - PDF pages 60, 77, 78-79].

More disturbing is EPA’s conclusion that levels of PFOA in the general population are approaching the serum levels found in female rats fed 10 mg/kg/day, or the equivalent of drinking “>40,000 gal. per day” according to DuPont. Because people clearly do not drink anything approaching 40,000 gallons of water a day, the only interpretation of EPA’s analysis is that DuPont can’t explain how people all over the United States could have accumulated such substantial amounts of PFOA.

Residents living near DuPont Washington Works facility near Parkersburg, West Virginia who are exposed to PFOA through local contamination in air and drinking water, likely have higher PFOA blood levels than the levels in the general population about which EPA has expressed concern. DuPont has estimated that people living near Washington Works may have blood levels that exceed 1 part per million (ppm) by drinking water contaminated with 3 parts per billion (ppb) of PFOA for six years [Extract and EWG analysis].

This level of contamination in drinking water (3 ppb) is 50 times lower than a controversial drinking water screening level recently set by the West Virginia Department of Environmental Protection [2,3] [View news release]. Female rats with blood levels this high gave birth to pups that died early in life and had delayed sexual maturation, decreased growth, altered reproductive cycling, and showed damage to the liver, pituitary, brain, seminal vesicles, testes, epididymis, spleen and thymus in adulthood[4].

Table 1. Effects noted in critical PFOA studies (see more about effects noted in critical studies)

Effect (Animal Model)

No Observed Effect Level

Effects observed at the lowest dose tested

Chronic-liver
(primate)

DuPont claim: 0.5 mg/kg


Fact: DuPont did not even test 0.5 mg/kg in the chronic primate study [Extract]


Fact: PFOA caused effects at every dose [Full document PDF page 60]

3 mg/kg/day: one of four monkeys died, (the monkey had had hind-limb paralysis, muscle incoordination and did not respond to touch); increased liver weight; and increased total bilirubin, a pigment in bile that comes from hemoglobin in old red blood cells

Cancer
(rat)

DuPont claim: 2 mg/kg (~ 1.6 mg/kg/d or 30 ppm)


Fact: PFOA caused effects at every dose, including 1.6 mg/kg/d (30 ppm) [Full document PDF page 79]

1.6 mg/kg/day: cellular changes in the ovary, lung (female); salivary gland (male); muscle incoordination (female) and possible thyroid tumor (male)

Reproduction/ Developmental
(rat)

DuPont claim: 10 mg/kg


Fact: PFOA caused effects at every dose in male rats (1, 3, 10 and 30 mg/kg/d) [Full document PDF page 77]

1 mg/kg/d (male effects): decreased growth; damage to liver, kidney, seminal vesicle and spleen

Source: Compiled by Environmental Working Group.

PFOA and worker effects

 

 

DuPont spin. In the same March 18, 2003 media presentation, on slide 18, DuPont staff incorrectly state that no health effects have been observed in workers[1]:

Assessing the Science
Human Data

 

Endpoints Evaluated

Dupont statement

Mortality

No Effects

Cancer

No Effects

Liver Enzymes

No Effects

Cholesterol

No Effects

Reproductive Hormones

No Effects

Growth Hormones

No Effects

 

Reproduction of DuPont graphic

 

EWG Response:

PFOA linked to changes in liver enzymes. Belying the certainty of these claims, DuPont has reported only one health study in the public record on workers exposed to PFOA, and this study was limited to measuring liver enzyme levels, which were significantly increased in workers [Extract | Full document]. This study was conducted in 1981[5] in response to concerns raised in a memo from DuPont medical staff that chemical plant workers at the Washington Works plant were more likely to have high liver enzyme levels, indicating abnormal liver function. Marked “personal and confidential” DuPont medical staff noted that “My preliminary results suggest that C-8 [PFOA] exposed workers may possibly have positive liver function tests more often than the plant population as a whole, and that the number of active wage roll employees having myocardial infarction from 1974 through 1977 was somewhat higher than expected based on Company-wide experience”[6] [Extract]. DuPont failed to track cardiovascular disease in the follow-up study. Abnormal liver function tests are routinely found in laboratory animals exposed to PFOA.

PFOA linked to changes in mortality patterns among workers. Mortality studies have been conducted at 3M plants in Cottage Grove, MN[7,8][EWG Worker Study Document]. In these studies, serum levels of fluorochemicals were not measured. Instead, exposure was estimated based on job function. Cause of death was determined via death certificates. Long-term workers in the Chemical Division at 3M’s Cottage Grove, MN plant were found to be 3.3 times more likely to die from prostate cancer when compared to the workers who did not work in the Chemical Division[8] [Extract].

A follow-up mortality study found that workers with definite PFOA exposure were up to 15 times more likely die from cerebrovascular disease[7][Extract]. Other causes of death that were increased in Chemical Division workers, although not statistically significant, were cancers of the testis and pancreas [EWG Worker Study Document]. These studies have involved so few people, however, that a single incidence of cancer can change study results from a finding of “no increase” to “statistically significant increase.” However, it is notable that PFOA damages the prostate[4] and causes both testicular and pancreatic tumors in rats[9,10]. In addition, 3M workers at the Cottage Grove, MN plant were more likely to die from bladder cancer, regardless of job function, than the general population[11].

3M also conducted an “episode of care” study. It was conducted at the Decatur, AL plant to assess why DuPont workers sought medical care. Workers with the highest and longest exposure to perfluorochemicals were significantly more likely to seek care for prostate cancer, gastrointestinal tract neoplasms (especially benign colonic polyps), and disorders of the biliary tract and pancreas, cystitis and lower urinary tract infections[12][EWG Worker Study Document]

PFOA linked to cancer in animal and worker studies. Four of five tumor types caused by PFOA or PFOS in animals (liver, testicular, breast, and thyroid) have been significantly increasing in Americans during the last 10 to 25 years[13-15][Extract]. PFOA causes three of these tumor types - liver, testes and breast - in rats[16 pp. 78-79]. PFOA has been associated with statistically significant increases in prostate cancer death and with 3M workers seeking medical care for prostate cancer (in PFOA plant workers in two separate studies[7,12]). Other short-term studies show that chemicals that break down into PFOA cause cellular changes in the thyroid consistent with a “mechanism of action” known to lead to thyroid tumors in rodents [17-23].

PFOA linked to changes in cholesterol, reproductive hormones, and growth hormones in worker studies, animal studies, or both. Increased serum PFOA levels are significantly associated with increased triglyceride and cholesterol levels and decreased high-density lipoprotein (HDL) or “good” cholesterol. PFOA was also positively associated with triiodothyronine (T3), one type of thyroid hormone[24,25].

Analysis of hormone levels in blood collected from 3M's Cottage Grove workers in 1993 and 1995 found that workers in the highest exposure PFOA category (> 30 ppm in blood) had 10 percent higher estradiol levels than other PFOA employee groups. This effect was not statistically significant, which could be due to the small sample size in the high exposure group (only 4 in 1993 and 5 in 1995)[26]. An earlier study also found a relationship between PFOA and estrogen [29] [Extract | Full document]. PFOA has been shown to increase estradiol in animal studies[27]. Increased levels of estradiol cause significant reproductive damage in males[28]. Workers in the high exposure category also had increased levels of thyroid stimulating hormone, a signal that workers may be at risk for hypothyroidism[26,29] [Extract]. Hypothyroidism affects an estimated 4.6 percent of people in the US, mostly women, and is linked to fetal brain damage[30,31]. Because so few 3M chemical plant workers are women, they have limited ability to study deseases and reproductive function in women.

PFOA and cancer

 

 

DuPont spin. On slide 11 of the March 18 2003 media presentation, DuPont staff misleadingly state that PFOA is not a human carcinogen[1]:

Analysis of PFOA Health Effects

 

 

Yes

No

Animal Carcinogen

X

 

Human Carcinogen

 

X

 

Reproduction of DuPont graphic

 

EWG Response: DuPont unequivocally told the media on March 18, 2003 that PFOA is not a human carcinogen, yet DuPont has never reported cancer incidence in their workers exposed to PFOA. In fact, the last public record of DuPont studying the health of workers with high PFOA exposures was in 1981, and in this study DuPont looked only at liver enzyme levels, not cancer or any other health outcomes.

3M, the original producer of PFOA, has also never studied cancer incidence in workers exposed to the chemical, but they did study cancer mortality. They found that chemical division workers were more likely to die from prostate cancer than less exposed workers[8][Extract | Full Document]. Workers are also more likely to die of cerebrovascular disease [Extract]

3M also conducted what is referred to as “an episode of care study,” in which they found that PFOA-exposed workers were more likely to seek treatment for cancers of the male reproductive tract (including prostate cancer) compared to workers 3M believes are exposed to lower amounts of PFOA[12] [EWG Worker Study Document].

According to the latest EPA proposed cancer guidelines, released earlier this year, PFOA would probably be classified as a likely human carcinogen because it meets several proposed EPA criteria for this category[16 p. 62]:

• “An agent that has tested positive in more than one species, sex, strain, site, or exposure route, with or without evidence of carcinogenicity in humans;”

PFOA causes tumors in both male rats (testicular, liver, and pancreatic tumors) and female rats (mammary tumors), thus meeting this criterion by testing positive in more than one sex and in more than one site.

• “A positive study that is strengthened by other lines of evidence, for example, some evidence of an association between human exposure and cancer (but not enough to infer a causal association), or evidence that the agent or an important metabolite causes events generally known to be associated with tumor formation (such as DNA reactivity or cell growth control) likely to be related to the tumor response in this case; “

The cancer findings for PFOA to date are not sufficient to draw conclusions of causality in humans, but there is a striking concordance between evidence of cancer in PFOA workers and known PFOA target organs in animals [EWG Worker Study Document]. PFOA meets this criterion because it inhibits the ability of liver cells to communicate with each other, called gap junction intercellular communication (GJIC)[32].

Normally, cells do not multiply unchecked because neighboring cells secrete chemical signals, by processes like GJIC, to prevent excessive cell multiplication. Therefore, when GJIC is decreased, cells – including cancer cells- can grow unchecked. Decreased GJIC is a sign that PFCs could be acting as tumor promoters, which means that even if they do not directly damage DNA, they make it easier for a cancer cell to multiply and produce more cancer cells, eventually resulting in a tumor.

Finally, PFOA increases production of estradiol, a potent form of estrogen, by increasing liver activity of the enzyme that converts testosterone to estradiol (aromatase)[27,33]. Male workers at one of 3M's plants may also have increased blood levels of estrogen [26,29]. Although estrogen is required for normal body function, too much estrogen is a risk factor for certain types of cancer. For example, the type of estrogen used in hormone replacement therapy (HRT) is classified as a known human carcinogen, linked to uterine and breast cancer[34]. Increased estrogen levels have been implicated in testicular cancer[35] and abnormal prostate growth[28,36].

Four of five tumor types caused by PFOA or PFOS in animals (liver, testicular, breast, and thyroid) have been significantly increasing in Americans during the last 10 to 25 years[13-15][Extract]. PFOA causes three of these tumor types - liver, testes and breast - in rats[16 pp. 78-79]. Other short-term studies show that chemicals that break down into PFOA cause cellular changes in the thyroid consistent with a “mode of action” known to lead to thyroid tumors in rodents [17-23].

PFOA and developmental/reproductive toxicity

 

 

DuPont spin. Also, in Slide #11 from DuPont’s public presentation on March 18, 2003, DuPont staff state that PFOA is not a reproductive or developmental toxin, even after EPA initiated a priority review because of their concerns over results from a 2002 reproduction study:

Analysis of PFOA Health Effects

 

 

Yes

No

Developmental Toxin

 

X

Reproductive Toxin

 

X

 

 

Reproduction of DuPont graphic

 

EWG response: Far from considering PFOA “not developmentally toxic,” the U.S. EPA has so far concluded just the opposite. EPA developed a risk assessment as part of a “priority review” of PFOA to determine whether expedited regulatory action against the compound is warranted under Section 4(f) of the Toxic Substances Control Act (TSCA). EPA is considering this action because (according to the agency) “concerns for developmental toxicity were raised from the results of a rat two-generation reproductive toxicity study of APFO [PFOA]”[35 p. 56].

Based on powerful results from rat reproduction studies, and a comparison of blood levels in the affected animals with blood levels in people, EPA scientists have so far concluded that children with the highest measured blood levels of PFOA have less than one tenth the protection, or less than one tenth the margin of safety, than the level the agency considers to be safe. In EPA parlance, the “margin of exposure” for the most exposed children is just 7, when it should normally be at least 100[35 p. 51].

According to EPA scientists, PFOA causes “significant increases in treatment related deaths”[37 - PDF p. 37] [Full document] in offspring at doses that did not affect the mothers, and a range of serious changes in the weight of various organs, including the brain (decrease), prostate (decrease), liver (increase), thymus (decrease), pituitary (decrease) and kidneys (increase in lower dose groups, decrease in high dose group)[80 PDF pg 179-191] [Full document]. Both male and female offspring had delayed sexual maturation[4,37 PDF page 38-39] [Full document]. The deaths of a significant number of rat pups within 2 to 4 days after weaning in experiments in which the mother was exposed to PFOA is highly unusual, and raises grave concerns about the toxicity of PFOA to people.

In addition, PFOA causes a significant increase in low birth weight pups in animal studies. Low birth weight is recognized as a risk factor for insulin resistance or Type II diabetes, high blood pressure, and cardiovascular disease later in life[38,39]. Studies have also shown that health risks remain even for those low–birth weight children who achieve normal weight later in childhood, including risks for high blood pressure, stroke, insulin resistance and glucose intolerance[40-46].

Other studies have shown that PFOA causes numerous effects on male and female reproductive organs, such as testicular tumors[9,10,27], decreased sperm production[9], mammary gland tumors[9] and cellular effects in the ovary[9]. PFOA also affects the prostate gland, seminal vesicle, epididymis and testis[4], and increases estrogen levels[27,47,48].

PFOA and liver toxicity

 

 

Dupont spin. From the March 18, 2003 media presentation on slide #13, DuPont staff state that rats are the most sensitive animals model and that liver toxicity is the most sensitive effect:

Is the effect relevant?

  • Most sensitive animal model – rat
  • Most sensitive effect – liver enlargement
  • Do we understand why PFOA causes liver enlargement in rats?
          – Yes – induces peroxisome proliferation

Reproduction of DuPont graphic

 

EWG Response: The rat is the most studied animal model for PFOA, but may not be the most sensitive. Only two studies have looked at the effect of PFOA in monkeys[49,50], the laboratory species that is closest to humans biologically. It is difficult to say whether the rat or monkey is more sensitive because industry scientists have not been able to identify a dose of PFOA that does not cause harm to both species. One of four monkeys died in the lowest dose group in a 6-month PFOA exposure study [49] [Extract]. In addition, neither 3M nor DuPont has conducted a chronic exposure or reproduction study in monkeys; the longest study conducted to date equates to a mere 3.3% of a monkey’s lifespan and is equal to a little over two years exposure in people[51]. Moreover, the longest exposure monkey study for PFOA did not include females; only male monkeys were tested[49]. In their latest assessment of risk, EPA concludes that females are more sensitive than males to the effects of PFOA.

The liver is the most studied organ for PFOA, but is not the most sensitive. PFOA causes toxicity to virtually every organ or system tested, including the brain, pituitary, adrenal gland, thyroid, ovary, male reproductive tract, immune system and kidney. PFOA also causes mammary, testicular, pancreatic and liver tumors[35].

Both the rat cancer and reproduction study suggest that liver enlargement is just one of several sensitive effects. Effects on the ovary, pituitary, kidney, spleen and seminal vesicles were affected by PFOA at or below doses where liver effects were observed. In female rats, adverse effects on the ovary[9] occur at a dose 10 times lower than the dose that caused liver toxicity[Extract | Full document]. Likewise, in the rat reproduction study, significant increases in the number of dead pups and decreased pituitary size occurred in females exposed to PFOA at doses that did not cause liver enlargement. The male offspring in the reproduction study showed changes in four different organ weights at the lowest dose – the kidney, spleen, liver and seminal vesicle[4].

In monkeys, PFOA caused liver enlargement at the same dose that resulted in death for one of four monkeys tested[49][Extract]. DuPont has no idea what killed the monkey, so they cannot rule out that non-liver toxicity resulted in the monkey death[35 p. 54; p. 58].

Industry research does not establish what is causing the liver enlargement found in monkeys, which are more closely related to humans. Industry scientists found that PFOA increased the size of the liver in monkeys at every dose they studied, and cellular studies point to mitochondrial damage, not peroxisome proliferation[35 p. 5, p. 9] as the mechanism of action. Moreover, 3M and DuPont workers exposed to PFOA often have altered liver enzyme levels that signal liver damage[5,6,25,52]. Simply put, the worker findings and monkey studies show that PFOA liver toxicity is relevant to humans.

Relevance of laboratory animals findings to humans

 

 

DuPont spin. Also on slide #13, DuPont staff imply that the effects observed in laboratory animals are not relevant to humans:

Is the effect relevant?

  • Is this mechanism relevant to humans?
          – Unlikely

Reproduction of DuPont graphic

 

EWG Response: PFOA causes adverse effects by at least five mechanisms of action, four of which are clearly relevant to humans. The five mechanisms of action that have been identified for PFCs so far are: mitochondrial toxicity; cell membrane disruption that results in decreased cell communication; peroxisome proliferation; increased production of estrogen; and decreased thyroid hormone levels or hypothyroidism.

The relevance of only one of these mechanisms of action to people, called “peroxisome proliferation,” is currently under debate. Peroxisome proliferation is clearly linked to liver toxicity in rats, but it is unknown whether peroxisome proliferation or another mechanism of action is responsible for the liver toxicity observed in monkeys or high liver enzyme levels observed in workers. Peroxisome proliferation cannot account for all of the toxic effects of PFOA. PFOA causes toxicity to virtually every organ or system tested, including the brain, pituitary, adrenal gland, thyroid, ovary, male reproductive tract, immune system and kidney. PFOA also causes mammary, testicular, pancreatic and liver tumors. Effects on the ovary, pituitary, kidney, spleen and seminal vesicles were affected by PFOA at or below doses where liver effects were observed.

The relevance of peroxisome proliferation to humans is a subject of current debate. A decision in 1995 by the International Agency for Research on Cancer (IARC) held that peroxisome proliferation is not relevant to people as a mode of action for causing cancer but this conclusion has come under scrutiny[53-55]. In recent critiques, a leading government scientist notes that several human medications are peroxisome proliferators, so clearly humans respond to these chemicals. In addition, the IARC panel inexplicably ignored a critical paper that found increased peroxisome enzyme activity in human liver cells following exposure to another chemical peroxisome proliferator[54,56]. Recently, IARC panels have come under heavy criticism from numerous scientists as being too heavily weighted with industry scientists [53,54,57-62].

Arguments over the relevance of peroxisome proliferation to humans may be moot for PFOA because a sister chemical, C10 or PFDA, has been shown to cause peroxisome proliferation in human brain cells (liver cells were not studied)[63] [Extract].

Industry-sponsored studies disproportionately test effects of peroxisome proliferation over effects driven by other mechanisms of action. For PFOA, other major toxic effects are altered lipid metabolism, pancreatic tumors and damage to the immune system, thyroid, and reproductive tract (including testicular and mammary gland tumors)[4,10,27,33,49,64-70].

This “disproportionate testing of toxic effects” is extremely clear for C10, a sister chemical to PFOA that differs only by the addition of 2 carbon and 4 fluorine atoms. Between, 1985 and 1992, nine studies were published describing the effects of C10 (PFDA) on lipid metabolism and the thyroid gland, immune system and reproductive tract[71-79]. No studies published since 1992 has followed up one the dramatic effects in the thyroid, immune system and reproductive tract described between 1985 and 1992. C10 is also found in human blood [Extract | Full document], but has not yet come under regulatory scrutiny from EPA although its toxicity profile is virtually identical to PFOA, differing only in potency.


References

 

[1] DuPont (2003). March 18, 2003 DuPont media briefing presentation by Paul Bossert, plant manager of DuPont Washington Works.

[2] West Virginia Department of Environmental Protection (WVDEP) (2002). Press Release: Health Level for C8 announced by expert team.

[3] Hilderliter, PM and Jepson, GW. 2001. A simple, conservative compartmental model to relate ammonium perfluorooctanoate (APFO) exposure estimates of perfluorooctanoate (PFO) blood levels in humans. DuPont Haskell Laboratory for Health and Enviornmental Sciences.

[4] 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., US EPA Adminstrative Record AR226-1092, Reviewed in US EPA Adminstrative Record AR226-1137 (pages 282-295; PDF pages 179-191).

[5] Fayerweather, WE. 1981. Liver study of Washington Works employees exposed to C-8: results of blood chemistry testing (not published).

[6] DuPont. 1979. Personal and confidential memo from Dr. Fayerweather (epidemiologis) to Dr. Power (medical superintendent): Status report on Washington Works liver function survey and coronary heart disease mortality study - August 28. 1979.

[7] Alexander, B (2001). Mortality study of workers employed at the 3M Cottage Grove facility. Final Report. Division of Environmental and Occupational Health, School of Public Health, University of Minnesota, April 26, 2001, Reviewed in U.S. EPA Administrative Record AR226-1137 (pages 143-146; PDF pages 40-43).

[8] Gilliland, FD and Mandel, JS. 1993. Mortality among employees of a perfluorooctanoic acid production plant. J Occup Med 35(9): 950-4. Also reviewed in EPA Administrative Record document AR226-1137 (pages 140-42; PDF pages 37-39).

[9] Sibinski, LJ. 1987. Two-Year oral (diet) toxicity/carcinogenicity study of fluorochemical FC-143 (perfluorooctane ammonium carboxylate) in rats. Report prepared for 3M, St. Paul, Minnesota by Riker Laboratories Inc. Study No. 0281CR0012; 8EHQ-1087-0394, October 16, 1987 Reviewed in US EPA "Revised Draft PFOA Hazard Assessment-Robust Study Annex" AR226-1137, (pp. 260-267; PDF pp 157-164).

[10] Biegel, LB., Hurtt, ME., Frame, SR., O'Connor, JC and Cook, JC. 2001. Mechanisms of extrahepatic tumor induction by peroxisome proliferators in male CD rats. Toxicol Sci 60(1): 44-55.

[11] Alexander, B (2001b). Mortality study of workers employed at the 3M Decatur facility. Final Report. Division of Environmental and Occupational Health, School of Public Health, University of Minnesota, April 26, 2001, Reviewed in “Letter from Mr. Charles Auer and Draft Hazard Assessment of PFOA and its Salts with Page 8 was corrected on 4/15/02” U.S. EPA Administrative Record AR226-1093.

[12] Olsen, GW., Burlew, MM., Hocking, BB., Skratt, JC., Burris, JM and Mandel, JH. 2001. An epidemiologic analysis of episodes of care of 3M Decatur chemical and film plant employees, 1993-1998. Reviewed in US Environmental Protection Agency Administrative Record AR226-1137 (pages 156-159; PDF pages 53-56).

[13] Ries, LAG., Eisner, MP., Kosary, CL., Hankey, BF., Miller, BA., Clegg, L and Edwards, BK. 2002. SEER Cancer Statistics Review 1973-1999: Overview in a Single PDF. National Cancer Institute. Bethesda, MD. Available online at http://seer.cancer.gov/csr/1973_1999/sections.html.

[14] Ries, LAG., Eisner, MP., Kosary, CL., Hankey, BF., Miller, BA., Clegg, L and Edwards, BK. 2002. SEER Cancer Statistics Review 1973-1999: Childhood Cancer by the International Classification of Childhood Cancer (ICCC). National Cancer Institute. Bethesda, MD. Available online at http://seer.cancer.gov/csr/1973_1999/sections.html.

[15] Ries, LAG., Eisner, MP., Kosary, CL., Hankey, BF., Miller, BA., Clegg, L and Edwards, BK. 2002. SEER Cancer Statistics Review 1973-1999: Sections of the CSR, 1973-1999, Testis. National Cancer Institute. Bethesda, MD. Available online at http://seer.cancer.gov/csr/1973_1999/sections.html.

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[17] 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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