On December 10, 2020 a
Exhibit,Appendix
was filed
involving a dispute between
Patsy Young,
and
Aventis Inc.,
Avon Products, Inc.,
Block Drug Company, Inc.,
Block Drug Corporation,
Brenntag North America, Inc.,
Brenntag Specialties, Inc. F K A Mineral Pigment Solutions, Inc.,
Charles B. Chrystal Company, Inc.,
Chattem, Inc.,
Colgate-Palmolive Company,
Cyprus Amax Minerals Company,
Cyprus Mines Corporation,
Glaxosmithkline Llc (Sued Individually And As Successor-In-Interest To Block Drug Corporation, Successor-In-Interest To The Gold Bond Sterilizing Powder Company A K A The Gold Bond Company And As A Successor-In-Interest To Novartis Corporation And
Novartis Consumer Health Inc.),
Gsk Consumer Health, Inc. F K A Novartis Consumer Health Inc. F K A Ciba Self-Medication, Inc.,
Insight Pharmaceuticals Corporation, A Subsidiary Of Prestige Brands Holdings, Inc.,
Insight Pharmaceuticals Llc,
Macy'S Inc. F K A Federated Department Stores, Inc.,
Novartis Pharmaceuticals Corporation,
Prestige Brands Holdings, Inc.,
Prestige Consumer Healthcare Inc. F K A Prestige Brands, Inc.,
Sanofi-Aventis U.S. Llc,
Sanofi Us Services, Inc.,
Whittaker Clark & Daniels, Inc.,
for Torts - Asbestos
in the District Court of Erie County.
Preview
FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020
NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023
EXHIBIT
U
21
FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020
NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023
DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
Memorandum
February 10, 1994
Date
Robert L. Bronaugh, Ph.D
From
Jeffrey J. Yourick, Ph.D.
subject Report on Talc Workshop
John E. Bailey, Ph.D.
T_j1r-u: D. Adele Dennis, Ph.D.
A workshop was held January 31 -
February 1, 1994 in Bethesda, MD entitled "Talc:
Consumer Uses and Health Prospectives". The workshop was jointly sponsored by FDA and the
International Society of Regulatory Toxicology and Pharmacology. It was attended by
approximately 100 persons from government, industry and academia.
Introductory comments were made by Dr. John E. Bailey (CFSAN, Acting Director,
Office of Cosmetics and Colors) and Dr. William E. Gilbertson (CDER, Director, Monograph
Review Staff). Talc is contained in numerous products regulated by both FDA centers. The
workshop focused on inhalation exposure to talc and the association of talc and ovarian cancer.
Presentations were made by renowned experts in these fields.
The use of talc in cosmetic products was discussed by CTFA's Dr. Stephen Gettings.
Cosmetic grade talc (mainly magnesium silicate) is considered to be 99% pure containing "200
mesh"
or approximately 75 µm particles. Industry specifications of cosmetic talc state that the
talc is free of asbestos and this is insured by industry quality control procedures (since the early
1970's). Dr. Gettings stated that the NTP inhalation study used talc particles of much smaller
dimension (10 µm) and as such would be more available for inhalation to the deep lung than
cosmetic grade talc.
It was estimated that application of body powder to an adult results in a respirable dust
concentration of 1.0 mg/m2. The ACGIH allowable value for industry talc dust concentration is
2.0 mg/m2. A 2,000 to 20,000 fold higher exposure to talc was used in the NTP inhalation
studies.
Inhalation Toxicity of Talc
Results from the NTP carcinogenesis bioassay of talc were presented by Dr. Gary
Boorman (NIEHS). Male and female rats and mice of both sexes were exposed to two dose levels
of talc over a period of approximately 2 years by the inhalation route (i.e., whole body).
Pheochromocytomas were present, however, it was thought that these were not directly related
to talc exposure. Tumors were discovered at the end of the study in lungs of female rats only.
Dr. Boorman stated that mechanistic studies were needed to establish the relevance of the animal
data when compared to potential human talc exposures at much lower levels. However, this
caveat has not been included in the widely disseminated NTP bioassay report. For comparison
to other compounds, it was noted that diesel exhaust, titanium dioxide and silica (all referred to
as nuisance dusts with inert particle not chemical effects) have also resulted in tumor formation
FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020
NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023
predominately in female rats. It was suggested by several participants that talc may simply fall
into the same category as an inert particle with nonspecific effects.
Presentations by Drs. Gunter Oberdõrster (University of Rochester) and Jay Goodman
(Michigan State University) contended that the dose of talc administered in the NTP bioassay was
excessive. They felt that the high dose of talc that resulted in the rat lung tumors likely caused
an overload on the body's defense mechanisms that would normally clear the lungs of inhaled
talc. Dr. Oberdörster stated that the rat seems to be a sensitive species to the effects of particle
overload and the formation of lung tumors. He stated that instead of the maximum tolerated dose
(MTD), NTP should have selected the maximum sensible dose. Ideally this dose should have
a minimal affect on the normal lung clearance of particles, i.e., talc. It was suggested that
humans may not be susceptible to lung tumors resulting from particle overload based on data
from the observation of coal miners. Dr. Goodman was the only dissenter on the NTP advisory
panel that reviewed the bioassay results. He provided evidence from several cytotoxicity
biomarkers that the high dose of talc exceeded that MTD since female mice developed chronic
lung toxicity (hence questioning the relevance of the dose). In addition, he stated that the NTP
talc control incidence for the pheochromocytomas was four-fold higher than the historical
controls.
Dr. James Crappo (Duke University) stated that anatomical differences between rat and
human lungs make it difficult to extrapolate linearly the effects of a toxicant. The structure of
the upper respiratory track and lungs would facilitate greater uptake and deeper penetration of
talc into the lungs of the rat.
Studies presented by Dr. Brooke Mossman (University of Vermont) showed that, in
contrast to asbestos, talc had no hemolytic/membranolytic activity, little-to-no activity in
genotoxicity tests and did not stimulate cellular proliferation.
Workshop Consensus
The general consensus of this workshop session was that the results from the NTP
bioassay in rodents were not indicative of a human health hazard from the inhalation of talc in
consumer products. It was suggested that the talc response observed was a nonspecific dust
response due to a lung clearance overloading dose of smaller than cosmetic grade talc particles.
Ovarian Toxicity of Talc
Ovarian cancer is responsible for 6% of the yearly cancer fatalities in women according
to Dr. Harland Austin (Emory University). Factors responsible for a decreased risk of ovarian
cancer are: (1) use of birth control pills, (2) previous term pregnancies, (3) breast feeding, and
(4) hysterectomy/tubal ligation. The risk of ovarian cancer increases as the length of a women's
ovulatory life increases. Dr. Arnold Brown (University of Wisconsin) stated a belief in the
association of ovarian cancer and talc exposure based on the 1971 report by Henderson which
claimed to find talc deeply imbedded in ovaries following talc exposure. Other studies did not
find a migration of talc particles outside of the lung or G.I. tract after inhalation or oral talc
exposure, respectively. It is at present unclear as to a mechanism of talc migration to the
ovaries.
Epidemiological studies of perineal talc exposure were discussed by Drs. Bernard Harlow
FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020
NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023
(Brigham & Woman's Hospital) and Patricia Hartge (National Cancer Institute). Dr. Harlow's
study showed that daily application of talc perineally resulted in an odds ratio of 1.8 (95%
confidence interval 1.1-3.0) for ovarian cancer. There was a modest increáse in risk with years
of exposure. The greatest cancer risk was seen in women with 10,000 or more lifetime talc
applications periods (odds ratio 95% confidence interval 1.4-5.4). Long-
during ovulatory 2.8,
term exposure to talc before 1960, when asbestos fiber contamination of talc was more likely,
posed an increased risk of ovarian cancer. However, these women were also at increased risk
because of long-term usage of talc. Dr. Hartge reported that the appropriate odds ratio from the
Harlow study should be 1.8 not the higher value of 2.8.She stated that the study demonstrated
a weak association between the use of talc and ovarian cancer.
Dr. Ernst Wynder (American Health Foundation) commented on methods used in
conducting epidemiological studies. He felt that more accurate information can be obtained from
control subjects if they are also hospital patients with a similar disease (instead of volunteers
selected from the community). He indicated that additional information on the current usage by
women of products containing talc would be helpful in assessing the potential health hazard.
Workshop Consensus
The general consensus of this workshop session was that there is a weak association
between the use of talc and ovarian cancer. Given a weak association, two points were
mentioned that could have better defined the association, use of hospital-gynecologic disease
controls and more information on general population talc use.
Pertaining to finding talc in cancerous tissue, only one histopathologic study has reported
the presence of talc in ovarian cancer tissue and the results of this study were questioned because
of methodological problems. To clarify this issue, it was recommended that future examination
of surgically removed cancerous ovarian tissue should include a search for evidence of talc in
the tissue by both histological and mineralogical techniques.
Even though there is a weak epidemiologic association for talc and ovarian cancer, the
sequence of events leading from perineal talc exposure to ovarian cancer is at present unclear.
It is not known how/if talc particles migrate to ovarian tissue. Conclusive evidence for the
presence of talc in ovarian tissue is lacking and if talc reaches ovarian tissue no mechanism for
talc carcinogenesis has been defmed. Hence, the biologic plausibility to support the statement
that talc exposure results in ovarian cancer requires additional evaluation.
FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020
NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023
February 4, 1994
Talc: Consumer Uses and Health Perspectives
Summary:
Talc Inhalation studies
Talc: hydrous magnesium silicate; 900,000 tons/year used in the
US; 48,000 tons/yr (6%) in cosmetics. Treatment of raw talc for
cosmetic use results in 90-95% pure talc. Uses: powders,
antiperspirants, pill coatings/fillers, foods (chewing
gum/anticaking), medical devices (surgical glove/condom coating;
Note: no longer used in surgical gloves). Cosmetic uses:
antiperspirants, semi-solid matrices (eye shadow), powders. Talc
used in powders is 200 mesh and is the only cosmetically used
talc which has the potential for being inhaled. This particle
size is too large to be respirable however. Most talc particles
in powders will be trapped in the nose. Talc and asbestos
materials are not formed under the same geologic conditions,
therefore careful selection of sites results is asbestos-
mining
free talc. Estimated human exposure via respiration when using
powder diapering: 0.2 - 2 mg/m3.
during baby
NTP study: Requested by NIOSH due to worker exposure. Talc
particles smaller than typically used in cosmetic products were
used in the NTP study to determine the effects on inhalation.
Larger particles would not have made it into the lungs. Two year
study; exposure levels tested in chronic study: 6, 18 mg/m3.
Rodent exposure 2,000 - 20,000 times greater than estimated human
exposure. Tumors formed only in female rats at the highest dose.
The species of female rats used are known to be particularly
sensitive to particulates. No tumors were observed in male or
female mice. Adrenal medulla neoplasms were also observed in
rats; origin is unknown. Talc exposure tested at the highest
level was an "overload"; clearance time from the lung at this
concentration is greatly increased. The smaller the particles
the longer the clearance time. In a related study, there was no
evidence for increased incidence of lung tumors in coal mine
workers exposed to coal dust whose estimated exposure was greater
than the exposure to particles in the talc rat study. Ti02,
chromium dioxide, volcanic ash and quartz dust have all produced
tumors in female rats (not male rats), by inhalation. A negative
dust control was not included in the NTP study which raises the
question: did the observed tumors result from talc or would they
have arisen from any particulate? There was one member of the
NTP review panel who did not agree with the conclusions prepared
by the study team. This person's comments included: (1) the
maximum tolerated dose was exceeded at 18 mg/m3, and was
therefore inappropriate; (2) there was an increase in tumors in
the controls over that observed historically for this animal
which was neglected in the study conclusions. Historically,
talc has been used as the negative control for inhalation studies
on silica and asbestos.
FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020
NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023
Caution was urged when extrapolating the rodent study results to
man. Lung branching between rodents and man is different and
this will effect which cells are exposed to particulates.
ovarian Cancer and Talc Use
US annual incidence of ovarian cancer: 15 per 100,000; 8 per
100,000 deaths per year. Trends in mortality and incidence of
ovarian cancer have been stable for 20 years. Factors which
decrease incidence: use of oral contraceptives, breast feeding,
child bearing, hysterectomy. (ie. Activities which reduce the
number of times the ovary has to repair itself following release
egg).'
of an
Talc can migrate to the ovaries, though the route is presently
unknown. There is some evidence that particulates can migrate to
other body tissues via the vascular system. Intestinal
absorption is negligible. Radiolabeled talc injected vaginally
into rabbits did not migrate to the ovaries.
Questions about talc migration to ovaries originated with a study
published by Henderson in 1971 in which talc was found in human
ovaries. The study was repeated in 1979 and talc was again
found, this time in the ovaries of nontumoragenic women. These
studies may have been flawed. Controls may not have been
adequately conducted. In another experiment, labeled talc was
deposited in the vagina but no translocation to the ovaries was
detected. Analytical techniques used by Henderson to determine
talc were questioned. Since many minerals are structurally
similar, misidentification was likely. Only in the last ten
years have methods become available for reliable talc
measurement. Mineralogical methods were used to measure talc
particulates and not histological techniques. Ovary tissues may
have been removed by physicians using gloves contaminated with
talc (though in the second study, ovarian tissue was removed with
forceps only). Talc granulomas following surgery due to talc on
gloves has been reported, but no granulomas were reported in
Henderson's studies, raising questions about what particulates
Henderson actually observed.
There have been 9 epidemiological studies of the relationship
between talc use and ovarian cancer. Two studies showed a
statistically significant increase in cancer incidence, the other
studies showed a negative correlation. The risk of ovarian
cancer prior to 1960 was greater than after 1960. This could be
due to the reduction of asbestos fibers in talc due to modern
processing techniques. Epidemiological studies suggest a small
risk of ovarian cancer for talc users: 1.3 relative risk where
1.0 is equivalent to no risk. There are a number of confounders
which will influence epidemiological studies including race,
marital status, age, education, history of tubal ligation, use of
oral contraceptives, and asbestos exposure. Inherent bias of
epidemiological studies were also mentioned including inaccurate
FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM
Preview
FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020 NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023 EXHIBIT U 21 FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020 NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Memorandum February 10, 1994 Date Robert L. Bronaugh, Ph.D From Jeffrey J. Yourick, Ph.D. subject Report on Talc Workshop John E. Bailey, Ph.D. T_j1r-u: D. Adele Dennis, Ph.D. A workshop was held January 31 - February 1, 1994 in Bethesda, MD entitled "Talc: Consumer Uses and Health Prospectives". The workshop was jointly sponsored by FDA and the International Society of Regulatory Toxicology and Pharmacology. It was attended by approximately 100 persons from government, industry and academia. Introductory comments were made by Dr. John E. Bailey (CFSAN, Acting Director, Office of Cosmetics and Colors) and Dr. William E. Gilbertson (CDER, Director, Monograph Review Staff). Talc is contained in numerous products regulated by both FDA centers. The workshop focused on inhalation exposure to talc and the association of talc and ovarian cancer. Presentations were made by renowned experts in these fields. The use of talc in cosmetic products was discussed by CTFA's Dr. Stephen Gettings. Cosmetic grade talc (mainly magnesium silicate) is considered to be 99% pure containing "200 mesh" or approximately 75 µm particles. Industry specifications of cosmetic talc state that the talc is free of asbestos and this is insured by industry quality control procedures (since the early 1970's). Dr. Gettings stated that the NTP inhalation study used talc particles of much smaller dimension (10 µm) and as such would be more available for inhalation to the deep lung than cosmetic grade talc. It was estimated that application of body powder to an adult results in a respirable dust concentration of 1.0 mg/m2. The ACGIH allowable value for industry talc dust concentration is 2.0 mg/m2. A 2,000 to 20,000 fold higher exposure to talc was used in the NTP inhalation studies. Inhalation Toxicity of Talc Results from the NTP carcinogenesis bioassay of talc were presented by Dr. Gary Boorman (NIEHS). Male and female rats and mice of both sexes were exposed to two dose levels of talc over a period of approximately 2 years by the inhalation route (i.e., whole body). Pheochromocytomas were present, however, it was thought that these were not directly related to talc exposure. Tumors were discovered at the end of the study in lungs of female rats only. Dr. Boorman stated that mechanistic studies were needed to establish the relevance of the animal data when compared to potential human talc exposures at much lower levels. However, this caveat has not been included in the widely disseminated NTP bioassay report. For comparison to other compounds, it was noted that diesel exhaust, titanium dioxide and silica (all referred to as nuisance dusts with inert particle not chemical effects) have also resulted in tumor formation FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020 NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023 predominately in female rats. It was suggested by several participants that talc may simply fall into the same category as an inert particle with nonspecific effects. Presentations by Drs. Gunter Oberdõrster (University of Rochester) and Jay Goodman (Michigan State University) contended that the dose of talc administered in the NTP bioassay was excessive. They felt that the high dose of talc that resulted in the rat lung tumors likely caused an overload on the body's defense mechanisms that would normally clear the lungs of inhaled talc. Dr. Oberdörster stated that the rat seems to be a sensitive species to the effects of particle overload and the formation of lung tumors. He stated that instead of the maximum tolerated dose (MTD), NTP should have selected the maximum sensible dose. Ideally this dose should have a minimal affect on the normal lung clearance of particles, i.e., talc. It was suggested that humans may not be susceptible to lung tumors resulting from particle overload based on data from the observation of coal miners. Dr. Goodman was the only dissenter on the NTP advisory panel that reviewed the bioassay results. He provided evidence from several cytotoxicity biomarkers that the high dose of talc exceeded that MTD since female mice developed chronic lung toxicity (hence questioning the relevance of the dose). In addition, he stated that the NTP talc control incidence for the pheochromocytomas was four-fold higher than the historical controls. Dr. James Crappo (Duke University) stated that anatomical differences between rat and human lungs make it difficult to extrapolate linearly the effects of a toxicant. The structure of the upper respiratory track and lungs would facilitate greater uptake and deeper penetration of talc into the lungs of the rat. Studies presented by Dr. Brooke Mossman (University of Vermont) showed that, in contrast to asbestos, talc had no hemolytic/membranolytic activity, little-to-no activity in genotoxicity tests and did not stimulate cellular proliferation. Workshop Consensus The general consensus of this workshop session was that the results from the NTP bioassay in rodents were not indicative of a human health hazard from the inhalation of talc in consumer products. It was suggested that the talc response observed was a nonspecific dust response due to a lung clearance overloading dose of smaller than cosmetic grade talc particles. Ovarian Toxicity of Talc Ovarian cancer is responsible for 6% of the yearly cancer fatalities in women according to Dr. Harland Austin (Emory University). Factors responsible for a decreased risk of ovarian cancer are: (1) use of birth control pills, (2) previous term pregnancies, (3) breast feeding, and (4) hysterectomy/tubal ligation. The risk of ovarian cancer increases as the length of a women's ovulatory life increases. Dr. Arnold Brown (University of Wisconsin) stated a belief in the association of ovarian cancer and talc exposure based on the 1971 report by Henderson which claimed to find talc deeply imbedded in ovaries following talc exposure. Other studies did not find a migration of talc particles outside of the lung or G.I. tract after inhalation or oral talc exposure, respectively. It is at present unclear as to a mechanism of talc migration to the ovaries. Epidemiological studies of perineal talc exposure were discussed by Drs. Bernard Harlow FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020 NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023 (Brigham & Woman's Hospital) and Patricia Hartge (National Cancer Institute). Dr. Harlow's study showed that daily application of talc perineally resulted in an odds ratio of 1.8 (95% confidence interval 1.1-3.0) for ovarian cancer. There was a modest increáse in risk with years of exposure. The greatest cancer risk was seen in women with 10,000 or more lifetime talc applications periods (odds ratio 95% confidence interval 1.4-5.4). Long- during ovulatory 2.8, term exposure to talc before 1960, when asbestos fiber contamination of talc was more likely, posed an increased risk of ovarian cancer. However, these women were also at increased risk because of long-term usage of talc. Dr. Hartge reported that the appropriate odds ratio from the Harlow study should be 1.8 not the higher value of 2.8.She stated that the study demonstrated a weak association between the use of talc and ovarian cancer. Dr. Ernst Wynder (American Health Foundation) commented on methods used in conducting epidemiological studies. He felt that more accurate information can be obtained from control subjects if they are also hospital patients with a similar disease (instead of volunteers selected from the community). He indicated that additional information on the current usage by women of products containing talc would be helpful in assessing the potential health hazard. Workshop Consensus The general consensus of this workshop session was that there is a weak association between the use of talc and ovarian cancer. Given a weak association, two points were mentioned that could have better defined the association, use of hospital-gynecologic disease controls and more information on general population talc use. Pertaining to finding talc in cancerous tissue, only one histopathologic study has reported the presence of talc in ovarian cancer tissue and the results of this study were questioned because of methodological problems. To clarify this issue, it was recommended that future examination of surgically removed cancerous ovarian tissue should include a search for evidence of talc in the tissue by both histological and mineralogical techniques. Even though there is a weak epidemiologic association for talc and ovarian cancer, the sequence of events leading from perineal talc exposure to ovarian cancer is at present unclear. It is not known how/if talc particles migrate to ovarian tissue. Conclusive evidence for the presence of talc in ovarian tissue is lacking and if talc reaches ovarian tissue no mechanism for talc carcinogenesis has been defmed. Hence, the biologic plausibility to support the statement that talc exposure results in ovarian cancer requires additional evaluation. FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020 NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023 February 4, 1994 Talc: Consumer Uses and Health Perspectives Summary: Talc Inhalation studies Talc: hydrous magnesium silicate; 900,000 tons/year used in the US; 48,000 tons/yr (6%) in cosmetics. Treatment of raw talc for cosmetic use results in 90-95% pure talc. Uses: powders, antiperspirants, pill coatings/fillers, foods (chewing gum/anticaking), medical devices (surgical glove/condom coating; Note: no longer used in surgical gloves). Cosmetic uses: antiperspirants, semi-solid matrices (eye shadow), powders. Talc used in powders is 200 mesh and is the only cosmetically used talc which has the potential for being inhaled. This particle size is too large to be respirable however. Most talc particles in powders will be trapped in the nose. Talc and asbestos materials are not formed under the same geologic conditions, therefore careful selection of sites results is asbestos- mining free talc. Estimated human exposure via respiration when using powder diapering: 0.2 - 2 mg/m3. during baby NTP study: Requested by NIOSH due to worker exposure. Talc particles smaller than typically used in cosmetic products were used in the NTP study to determine the effects on inhalation. Larger particles would not have made it into the lungs. Two year study; exposure levels tested in chronic study: 6, 18 mg/m3. Rodent exposure 2,000 - 20,000 times greater than estimated human exposure. Tumors formed only in female rats at the highest dose. The species of female rats used are known to be particularly sensitive to particulates. No tumors were observed in male or female mice. Adrenal medulla neoplasms were also observed in rats; origin is unknown. Talc exposure tested at the highest level was an "overload"; clearance time from the lung at this concentration is greatly increased. The smaller the particles the longer the clearance time. In a related study, there was no evidence for increased incidence of lung tumors in coal mine workers exposed to coal dust whose estimated exposure was greater than the exposure to particles in the talc rat study. Ti02, chromium dioxide, volcanic ash and quartz dust have all produced tumors in female rats (not male rats), by inhalation. A negative dust control was not included in the NTP study which raises the question: did the observed tumors result from talc or would they have arisen from any particulate? There was one member of the NTP review panel who did not agree with the conclusions prepared by the study team. This person's comments included: (1) the maximum tolerated dose was exceeded at 18 mg/m3, and was therefore inappropriate; (2) there was an increase in tumors in the controls over that observed historically for this animal which was neglected in the study conclusions. Historically, talc has been used as the negative control for inhalation studies on silica and asbestos. FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM INDEX NO. 815818/2020 NYSCEF DOC. NO. 179 RECEIVED NYSCEF: 03/03/2023 Caution was urged when extrapolating the rodent study results to man. Lung branching between rodents and man is different and this will effect which cells are exposed to particulates. ovarian Cancer and Talc Use US annual incidence of ovarian cancer: 15 per 100,000; 8 per 100,000 deaths per year. Trends in mortality and incidence of ovarian cancer have been stable for 20 years. Factors which decrease incidence: use of oral contraceptives, breast feeding, child bearing, hysterectomy. (ie. Activities which reduce the number of times the ovary has to repair itself following release egg).' of an Talc can migrate to the ovaries, though the route is presently unknown. There is some evidence that particulates can migrate to other body tissues via the vascular system. Intestinal absorption is negligible. Radiolabeled talc injected vaginally into rabbits did not migrate to the ovaries. Questions about talc migration to ovaries originated with a study published by Henderson in 1971 in which talc was found in human ovaries. The study was repeated in 1979 and talc was again found, this time in the ovaries of nontumoragenic women. These studies may have been flawed. Controls may not have been adequately conducted. In another experiment, labeled talc was deposited in the vagina but no translocation to the ovaries was detected. Analytical techniques used by Henderson to determine talc were questioned. Since many minerals are structurally similar, misidentification was likely. Only in the last ten years have methods become available for reliable talc measurement. Mineralogical methods were used to measure talc particulates and not histological techniques. Ovary tissues may have been removed by physicians using gloves contaminated with talc (though in the second study, ovarian tissue was removed with forceps only). Talc granulomas following surgery due to talc on gloves has been reported, but no granulomas were reported in Henderson's studies, raising questions about what particulates Henderson actually observed. There have been 9 epidemiological studies of the relationship between talc use and ovarian cancer. Two studies showed a statistically significant increase in cancer incidence, the other studies showed a negative correlation. The risk of ovarian cancer prior to 1960 was greater than after 1960. This could be due to the reduction of asbestos fibers in talc due to modern processing techniques. Epidemiological studies suggest a small risk of ovarian cancer for talc users: 1.3 relative risk where 1.0 is equivalent to no risk. There are a number of confounders which will influence epidemiological studies including race, marital status, age, education, history of tubal ligation, use of oral contraceptives, and asbestos exposure. Inherent bias of epidemiological studies were also mentioned including inaccurate FILED: ERIE COUNTY CLERK 03/03/2023 08:35 PM