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Expert Report of Samuel M. Cohen, M.D., Ph.D.

Regarding Angela Swartz and Teddy Swartz v. E. I. du Pont de Nemours and Company

May 30, 2019

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I. Personal Background

I am a professor at the University of Nebraska Medical Center. Details of my personal

background and expertise are provided in my report of September 16, 2016 and in the attached

curriculum vita. I will only mention a few updates here. I continue to be active as a surgical pathologist

and active in research and active on expert panels in addition to teaching. I have received additional

awards in recognition of my expertise and accomplishments, including the Distinguished Scientist

Award from the American College ofToxicology (2016) and the Merit Award from the Society of

Toxicology (201 7). In addition to other activities, I serve on the US Environmental Protection Agency

(EPA) Science Advisory Board (SAB).

II. Summary of Work and Principal Opinions

I have been requested to review the medical records and other information relating to Angela R.

Swartz, to evaluate the amount of increased risk of kidney cancer that she had from various risk factors,

and to respond to the relevant portions of the expert report concerning Mrs. Swartz submitted by Dr.

Vitaly Margulis. All of my opinions are stated to a reasonable degree of scientific and medical certainty.

I have been instructed to assume that C8 is capable of causing kidney cancer in humans,

including the plaintiff, and I have accepted this instruction. I have been asked to compare the amount of

increased risk of kidney cancer that Mrs. Swartz had from various other risk factors with the amount of

increased risk for kidney cancer that she had from her exposure to C8. In summary, Mrs. Swartz had

approximately a two-fold or more increased risk of developing kidney cancer due to her long-standing

obesity and also approximately a two-fold increased risk of developing kidney cancer due to her long

standing history of hypertension. Based on the relatively low levels to which she was exposed to C8 and

her measured blood level of C8 and comparing her substantial increased risk of kidney cancer posed by

her obesity and hypertension, it is my opinion that she would have developed kidney cancer even if she

was not exposed to C8.

The contribution of heredity to her risk of developing kidney cancer is unknown, since she does

not know her father or any of his family's history regarding kidney cancer, so that risk factor cannot be

excluded. She is a non-smoker, but there was likely a small increased risk for her developing kidney

cancer from her exposure to second hand smoke growing up and from her husband and sister, although

this amount of increased risk was likely to have been considerably less than her increased risk from

obesity and hypertension.

III. Mrs. Swartz' s History

Mrs. Swartz is a Caucasian female born July 2, 1961. She lived in Mason, West Virginia 1961

1979, Letart, West Virginia 1979-1996, and Gallipolis, Ohio 1996 to the present. She stated that she

drank public water from 1961 to 1996 while in West Virginia, but drank bottled water at home from 1996

to present. She claims exposure to drinking water containing at least 0.05 ppb of C8 while (1) working

part-time (about 23 hours a week) at Big Ben Food Land grocery store in Pomeroy, Ohio for about 16

months, starting in May 1992 and ending in October 1993; (2) visiting her mother, who lived in a house

served by the Pomeroy water district in 1990-1992; and (3) visiting her sister, who lived in a trailer served

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by the Tuppers Plains-Chester Water District from 1988 to the present. Her blood level of C8 in March

2006 was 16.5 ng/ml.

Mrs. Swartz presented to her doctor with a complaint of hematuria on December 27, 2016, which

led to a diagnosis of a small tumor in her right kidney that was excised by a robotic assisted laparoscopic

partial nephrectomy on March 14, 2017. The tumor was diagnosed as a clear cell renal cell carcinoma,

the most common type of kidney tumor, and was classified as grade 2, and was 2 cm. in greatest diameter

which makes it stage la. It was indicated in the pathology report that there was no extension outside of

the kidney and no invasion of the renal vein or kidney pelvis. However, it was indicated that the tumor

might microscopically be at the resection margin, although the urologist later restated his conclusion that

clear margins were achieved. Based on my review of the pathology, I agree with the pathologist that the

tumor microscopically appears to abut the resection margin. However, it is unlikely that there was any

residual tumor remaining as it appeared to be right at the margin and any residual tumor cells would have

been destroyed by the inflammatory reaction that occurred as a consequence of the healing of her kidney

following the resection. Moreover, as stated by the urologist, no residual tumor being present is further

supported by the fact that there has been no recurrence of cancer in over two years since the resection.

She had no prior history of renal disease, with her serum BUN and creatinine within the normal range,

and she shows no evidence of decreased renal function since the surgery.

She had a longstanding history of obesity with her BMI usually in the range of 35 to 40, and

occasionally greater than 40, which is defined as morbid obesity. She also had a long history of

hypertension, for which she received treatment. She also had histories of hypothyroidism and

hypercholesterolemia for which she received treatment.

IV. Materials Reviewed

To reach my opinions in this matter, I have reviewed an extensive amount of material. Various

specific references and materials are listed at the end of this report, and my general knowledge of the

fields of pathology, toxicology, carcinogenesis and evaluating the likelihood of harm have been utilized in

this evaluation, including all of the articles and chapters listed in my CV and the articles cited in those

publications.

I have also reviewed the medical files of Mrs. Swartz, the deposition transcripts and expert

reports identified at the end of this report, and other materials listed at the end of this report.

V. Kidney Cancer and Mrs. Swartz

Renal cell carcinomas commonly occur in the general United States population, and account for

approximately 2-3% of adult malignancies. They comprise the vast majority of kidney tumors in adults,

estimated at 80-85% of all kidney tumors (Murphy et al., 2004; Hakimi et al., 2013). In the United States,

it is estimated that there are about 35,000 new cases of renal cell carcinoma per year and approximately

12,500 deaths each year. Men are generally affected more commonly than women, in an approximate

ratio of 3 to 2. Renal cell carcinomas can occur at any age, but the incidence increases with age, and they

are usually detected after the age of 40. The reported incidence of renal cell carcinomas has been

increasing in the United States over the past two decades, and this has been primarily due to the increased

detection of small, low grade tumors (Hollingsworth et al., 2006; Murphy et al., 2004), and also likely

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secondary to the increasing incidence and severity of obesity (Hakimi et al., 2013; Renehan et al., 2008;

Chow et al., 2010; MacLeod et al., 2013; Kendall et al., 2015; Lauby-Secretan et al., 2016). Small tumors

are frequently detected incidentally during imaging studies in patients being evaluated for some other

disease or medical issue. The newer imaging technologies, especially CT and MRI scans, are able to

detect small kidney masses that could not be easily detected with standard x-rays (Jayson and Sanders,

1998; Hollingsworth et al., 2006).

There are several types of renal cell carcinoma, but the most common is classified as clear cell

renal cell carcinoma based on the clear appearance of the tumor cells in histopathologic sections (Murphy

et al., 2004). This sub-type is the most common form of kidney cancer, and accounts for approximately

70% of renal cell carcinomas. Another subtype of renal cell carcinoma, accounting for approximately 5%

of renal cell carcinomas, is the chromophobe carcinoma, classified based on its histopathologic

appearance, which is distinct from clear cell carcinomas. There are several other types of renal cell

carcinoma with distinctive histopathologic, cytogenetic and molecular characteristics (Murphy et al.,

2004; Jonasch et al., 2012). In addition, there are several uncommon tumors in the kidney that are not

included as renal cell carcinomas, such as urothelial cell carcinomas of the kidney pelvis and various nonepithelial tumors (Murphy et al., 2004).

For renal cell carcinoma there are known genetic and environmental factors that contribute to its

causation (Murphy et al., 2004, Jonasch et al., 2012; Hakimi et al., 2013). Several genetic disorders, such

as von Hippel-Lindau disease, are associated with the development of renal cell carcinomas. Birt-HoggDube is a syndrome with an increased risk of kidney tumors, most often chromophobe renal cell

carcinomas, oncocytomas, or tumors that are a mixture of these two types (Cohen and Zhou, 2005).

Several genes have been identified that appear to be associated with the development of renal cell

carcinoma, including the von Hippel-Lindau gene (VHL), fumarate hydrase (FH), and the folliculin gene

(FLCN) (in Birt-Hogg-Dube syndrome) (Jonasch et al., 2012).

Various environmental factors have also been identified as causal risk factors and associated with

an increased risk of renal cell carcinoma, including obesity, hypertension, and cigarette smoking (Murphy

et al., 2004; Hakimi et al., 2013; McCredie and Stewart, 1992; Adams et al., 2008; Macleod et al., 2013;

Chow et al., 2010; Colt et al., 2011; Dobbins et al., 2013; Calle and Kaaks, 2004; Flaherty et al., 2005;

Roberts et al., 2010; Lipworth et al., 2006; Kendall et al., 2015; Lauby-Secretan et al., 2016; World

Cancer Research Fund and American Institute for Cancer Research, 201 8). Some studies have suggested

a relationship with diabetes mellitus, but more specific investigations indicate that this is likely related to

the commonly co-associated factors of obesity and hypertension (Macleod et al., 2013; Murphy et al.,

2014).

Obesity is well-established as a major causal risk factor for the development of renal cell

carcinoma. Some studies indicate that overall, approximately 40% of renal cell carcinomas can be

attributed to obesity (Hakimi et al., 2013; McCredie and Stewart, 1992; Flaherty et al., 2005; Renehan et

al., 2008; Adams et al., 2008; Chow et al., 2010; MacLeod et al., 2013; Kendall et al., 2015; Pischon et

al., 2006; Lauby-Secretan et al., 2016). Studies have shown that the risk of kidney cancer increases with

the severity of the obesity, with an overall increased risk of about two-fold compared to non-obese

individuals. There is considerable evidence that the risk increases with increasing level of BMI. It is

estimated that those in the highest 5% by body mass index (BMI) have approximately a five-fold higher

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risk than an individual with a normal BMI (Murphy et ah, 2004). Some studies have reported that

individuals with morbid obesity (BMI > 40), have an attributable risk for developing renal cell carcinoma

of 60-90%, with risk increasing by about 30% per 5 BMI units above normal (Hakimi et ah, 2013;

Renehan et ah, 2008; Chow et ah, 2010). In a very large cohort study in Norway (Bjorge et ah, 2004)

involving two million individuals, the relative risk of renal cell carcinoma increased by 1 .05 (confidence

interval, 1.04 to 1 .06) per BMI unit above the normal range (a 4% increase per BMI unit). This included

individuals that were overweight and obese. A similar relative risk was calculated based on an extensive

meta-analysis (relative risk of 1.07, confidence interval of 1.05-1.09) (Bergstrom et ah, 2001). Mrs.

Swartz has had a BMI usually in the range of 35-40 for many years, occasionally over 40. Given that the

overall risk for obese individuals is about two-fold, and that individuals with higher BMI have a higher

risk, Mrs. Swartz had at least a two-fold increased risk of kidney cancer compared to individuals with a

BMI less than 25.

Hypertension is also a well-established causal risk factor for renal cell carcinoma (Lipworth et ah,

2006; Lindblad, 2004; Flaherty et ah, 2005; McCredie and Stewart, 1992; Yuan et ah, 1998; Shapiro et

ah, 1999; Colt et ah, 201 1). The overall risk of kidney cancer is increased approximately two-fold, but the

specific quantitative relationship to various blood pressure levels is difficult to ascertain because of the

variability in measurements during the day and the fact that many patients with hypertension receive

medical treatment for it. There has been some evidence that some of the increased risk associated with

hypertension could be related to use of anti-hypertensive drugs. Hypertension affects the kidney and is

known to produce damage to the kidney in ways that could lead to increased cell proliferation and an

increased risk of renal cell carcinoma. Overall, the evidence supports an increased risk of renal cell

carcinoma by hypertension, independent of the drugs used to treat it. In the Campbell-Walsh text on

Urology, the leading textbook on Urology, hypertension is listed as an etiologic factor for renal cell

carcinoma (Wein et al., 2011). In a leading textbook of urologic pathology (MacLennan and Cheng,

2008), they also state that "the bulk of epidemiologic evidence implicates it as a causal risk factor".

Based on her long-standing history of hypertension, even requiring treatment, it can be estimated that

Mrs. Swartz had approximately a two-fold increased risk of kidney cancer compared to non-hypertensive

people.

Cigarette smoking is also a causal risk factor for renal cell carcinoma (Murphy et ah, 2004;

Hakimi et ah, 2013; Adams et ah, 2008; MacLeod et ah, 2013; Chow et ah, 2010; Dobbins et ah, 2013;

Calle and Kaaks, 2004; Roberts et ah, 2010). Although not specifically addressed for renal cell

carcinoma, it is likely that second hand smoke is a risk factor for kidney cancer, as it is for the other

adverse effects related to cigarette smoking (Surgeon General, 2014). Mrs. Swartz indicated that she has

never been a cigarette smoker herself, but she has lived with individuals that smoked most of her life.

She claims that although they smoked in houses and vehicles that she frequented, they did not smoke

directly in her presence, and if true, that would reduce the amount of her increased risk. Although some

increased risk from second hand smoke cannot be excluded for Mrs. Swartz, it is likely that any increased

risk would have been insignificant compared to her increased risk from obesity and hypertension.

Scientific study continues as to whether other chemical exposures such as trichloroethylene are linked

with increased kidney cancer risk.

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Kidney cancer, like other cancers, also frequently arises spontaneously due to the spontaneous

errors that occur in the DNA during normal cell replication (Cohen and Ellwein, 1990; Moolgavkar and

Knudson, 1981; Tomasetti and Vogelstein, 2015).

For clinical management purposes and prognosis, renal cell carcinomas are evaluated on the basis

of grade and stage at the time the patient is diagnosed (Murphy et al., 2004; Chin et al., 2006). Grade

refers to the degree of differentiation of the tumor (how closely it resembles normal), with a 4 grade

system most commonly used (referred to as the Fuhrman grade). Grade 1 is the most well differentiated

and the least aggressive grade. It is associated with an excellent prognosis, relatively small tumors (<4

cm.), and is usually treated only with surgery, especially if the tumor is confined within the kidney.

Grade 4 is the most poorly differentiated and grades 2 and 3 are intermediate. Stage refers to the extent of

the disease. Stage I includes tumors that are 7 cm. in greatest dimension or less and are confined to the

kidney. Stage II includes tumors that are more than 7 cm. in greatest dimension but are still confined to

the kidney. Stage III refers to tumors that have spread outside the kidney locally or have spread to lymph

nodes. Stage IV includes tumors that have spread to distant tissues such as lung, bone, or elsewhere. Mrs.

Swartz had a small renal cell carcinoma (2 cm.) and it was low grade (Grade 2). Given the small size,

low grade and low stage (Stage la), Mrs. Swartz's prognosis is excellent.

VI. Overall Evaluation of Mrs. Swartz

Mrs. Swartz was 56 years old when she was diagnosed with a grade 2, 2 cm, Stage la clear cell

renal cell carcinoma treated in March 2017 with a laparoscopic partial nephrectomy. She had no evidence

of abnormal renal function, with her serum BUN and creatinine in the normal range, which continues to

the present. Her family history is unclear, since her father is unknown. Although there is no indication of

a hereditary basis for her renal cell carcinoma, that risk factor cannot be excluded. She had two very

significant risk factors for renal cell carcinoma, long standing obesity and hypertension. Her obesity has

occasionally been in the morbid range (BMI greater than 40). Although the overall increased risk for

obesity for renal cell carcinoma is approximately two-fold, individuals with morbid obesity generally

have higher risks, up to five-fold. Based on her history, Mrs. Swartz had at least a two-fold increased risk

of developing renal cell carcinoma compared to an individual with BMI <25. Her hypertension also gave

her a substantial increased risk of developing renal cell carcinoma of approximately two-fold. Although

she is not a cigarette smoker, she has lived with smokers most of her life. Second hand smoke cannot be

excluded as contributing to her risk, but the increase in risk is likely to have been insignificant compared

to the increased risk due to her obesity and hypertension.

I have assumed that Mrs. Swartz's exposure to C8 was sufficient for her to qualify as a member

of the Leach class, but her specific blood level (16.5 ng/ml) at the time it was measured (2006) was

relatively low compared to the C8 blood levels of exposed individuals in Ohio and West Virginia based

on the evaluation by Barry et al.(2013) and Vieira et al.(2013). Furthermore, as shown in the report by

Mr. Washburn, her measured blood level is within the range of measurements that have been made in the

general public in the United States, and elsewhere. The size of her tumor in March 2017 when it was

excised was 2 cm. The estimated growth of renal cell carcinomas is in the range of approximately 0.5 cm.

per year (Birnbaum et al., 1990; Bosniak et al., 1995; Oda et al., 2001; Zhang et al., 2009) indicating that

her tumor first developed in approximately 2013.

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The half-life of PFOA in human blood in community members is approximately 2.3 years (US

EPA, 2016). In the seven years between her measured C8 blood level in March 2006 and the beginning

of her tumor, there would have been approximately 3 half-lives of reduction in the C8 in her blood, so

that by the 2013-2015 time frame her blood level would have been approximately 2 ng/ml, well within the

background levels of the general public. Her amount of increased risk of developing kidney cancer from

her C8 exposure would have been very small, and insignificant compared to her substantial amount of

increased risk from her hypertension and her increased BMI.

I have also reviewed the expert opinion report of Dr. Vitaly Margulis.

statements in his report with which I disagree. He suggests that she might have had a history of hematuria

for a long time, but that is inconsistent with both her medical records and the biology of her tumor. He

intimates that her hip pain is related to her kidney cancer and her surgery, but that is highly unlikely given

her history of significant arthritis and hip pain complaints pre-dating her kidney cancer. He also states

that the amount of kidney removed was approximately one-third of the kidney. However, the pathology

report indicates that the total amount of tissue removed was 4.3 grams. A normal kidney in a female adult

is 115 to 155 grams, and since she had no evidence of renal disease other than the tumor and imaging

studies indicated a normal sized kidney, even assuming the lower end of the normal range of kidney

weight (115 grams), the amount of tissue removed at surgery amounts to less than 4% of a normal kidney.

He suggests that she could develop adhesions, but given the type of surgery that is unlikely. Given the

small size of the tumor and low grade, it is also unlikely that her tumor will recur. She is at increased risk

of developing a second kidney tumor as is any patient with a kidney carcinoma. It is also unlikely that

she had this carcinoma for the long period of time suggested by Dr. Margulis. My major disagreement

with Dr. Margulis is his dismissal of obesity and hypertension as major causes of kidney cancer. This is

not consistent with extensive literature on both issues as described above. Mrs. Swartz was clearly obese

in her adult life, with a BMI reaching over 40 at times, which is defined as morbid obesity. Also, she is

known to have had hypertension for several years and was being treated for it.

There are several

In summary, it is my opinion, based on a reasonable degree of medical and scientific certainty,

that Mrs. Swartz, with her long history of obesity and hypertension and relatively low exposures to C8,

would have developed her renal cell carcinoma even without her exposure to C8.

I reserve the right to revise or supplement these opinions if additional information becomes

available.

A listing of the cases in which I have given testimony in the past 4 years is attached as Exhibit B.

For my services on this case, I am being compensated at the rate of $600 per hour.

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