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A critical review of talc and ovarian cancer

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The association between perineal talc use and ovarian cancer has been evaluated in several epidemiology studies. Some case-control studies reported weak positive associations, while other case-control and three large prospective cohort investigations found this association to be null. A weight-of-evidence evaluation was conducted of the epidemiology, toxicity, exposure, transport, in vitro, and mechanistic evidence to determine whether, collectively, these data support a causal association. Our review of the literature indicated that, while both case-control and cohort studies may be impacted by bias, the possibility of recall and other biases from the low participation rates and retrospective self-reporting of talc exposure cannot be ruled out for any of the case-control studies. The hypothesis that talc exposure induces ovarian cancer is only supported if one discounts the null results of the cohort studies and the fact that significant bias and/or confounding are likely reasons for the associations reported in some case-control investigations. In addition, one would need to ignore the evidence from animal experiments that show no marked association with cancer, in vitro and genotoxicity studies that did not indicate a carcinogenic mechanism of action for talc, and mechanistic and transport investigations that did not support the retrograde transport of talc to the ovaries. An alternative hypothesis that talc does not produce ovarian cancer, and that bias and confounding contribute the reported positive associations in case-control studies, is better supported by the evidence across all scientific disciplines. It is concluded that the evidence does not support a causal association between perineal talc use and ovarian cancer.
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Journal of Toxicology and Environmental Health, Part B
Critical Reviews
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A critical review of talc and ovarian cancer
Julie E. Goodman, Laura E. Kerper, Robyn L. Prueitt & Charlotte M. Marsh
To cite this article: Julie E. Goodman, Laura E. Kerper, Robyn L. Prueitt & Charlotte M. Marsh
(2020): A critical review of talc and ovarian cancer, Journal of Toxicology and Environmental
Health, Part B, DOI: 10.1080/10937404.2020.1755402
To link to this article: https://doi.org/10.1080/10937404.2020.1755402
© 2020 The Author(s). Published by Taylor &
Francis.
Published online: 13 May 2020.
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A critical review of talc and ovarian cancer
Julie E. Goodman
a
, Laura E. Kerper
a
, Robyn L. Prueitt
b
, and Charlotte M. Marsh
a
a
Gradient, Boston, MA, USA;
b
Gradient, Seattle, WA, USA
ABSTRACT
The association between perineal talc use and ovarian cancer has been evaluated in several
epidemiology studies. Some case-control studies reported weak positive associations, while other
case-control and three large prospective cohort investigations found this association to be null.
A weight-of-evidence evaluation was conducted of the epidemiology, toxicity, exposure, trans-
port, in vitro, and mechanistic evidence to determine whether, collectively, these data support
a causal association. Our review of the literature indicated that, while both case-control and
cohort studies may be impacted by bias, the possibility of recall and other biases from the low
participation rates and retrospective self-reporting of talc exposure cannot be ruled out for any of
the case-control studies. The hypothesis that talc exposure induces ovarian cancer is only
supported if one discounts the null results of the cohort studies and the fact that significant
bias and/or confounding are likely reasons for the associations reported in some case-control
investigations. In addition, one would need to ignore the evidence from animal experiments that
show no marked association with cancer, in vitro and genotoxicity studies that did not indicate
a carcinogenic mechanism of action for talc, and mechanistic and transport investigations that did
not support the retrograde transport of talc to the ovaries. An alternative hypothesis that talc
does not produce ovarian cancer, and that bias and confounding contribute the reported positive
associations in case-control studies, is better supported by the evidence across all scientific
disciplines. It is concluded that the evidence does not support a causal association between
perineal talc use and ovarian cancer.
KEYWORDS
Talc; ovarian cancer; weight
of evidence; mode of action
Introduction
Many epidemiology studies have been conducted to
investigate the potential association between perineal
exposure to cosmetic-grade talc and ovarian cancer.
Thereisnoknownwell-establishedcauseformost
cases of ovarian cancer (American Cancer Society
(ACS), 2019).Onehypothesisisthatthetissue
damage and subsequent repair to the ovary that
occurs during each ovulation may increase the risk
of cancer due to gene replication errors during the
tissue repair process (ACS 2019; Hankinson and
Danforth 2006;Purdieetal.2003). Another hypoth-
esis is that ovarian cancer may be mediated by fluc-
tuating levels of endogenous hormones or higher
endogenous levels of certain sex hormones in some
individuals (Hankinson and Danforth 2006;
Lukanova and Kaaks 2005).
Awomans risk of developing epithelial ovarian
cancer may be affected by a wide range of factors.
Approximately 10-20% of ovarian cancers are
believed to be initiated by inherited factors The
relative contributions of other risk factors are poorly
understood, and the remaining 80-90% of cases are
attributed to unknown causes (i.e., are idiopathic)
(Hankinson and Danforth 2006;Hunnand
Rodriguez 2012; Walsh et al. 2011). Factors associated
with an elevated risk of ovarian cancer include
increasing age; longer duration of menstruation (i.e.,
starting menstruation before age 12 or undergoing
menopause after age 52); obesity; hormone therapy
after menopause; family history or ovarian, colorectal,
or breast cancer; and personal history of breast cancer
(ACS 2019;CDC,2015;MayoClinic2019;Memorial
Sloan Kettering Cancer Center 2019;Booth,Beral,
and Smith 1989;LaVecchia2017). Factors associated
with a reduced risk of ovarian cancer include repro-
ductive history (risk decreases with each full-term
pregnancy in women under 35), oral contraceptive
use, and gynecologic surgery such as tubal ligation or
hysterectomy (ACS 2019; Memorial Sloan Kettering
Cancer Center 2019;Booth,Beral,andSmith1989;La
Vecchia 2017).
CONTACT Julie E. Goodman jgoodman@gradientcorp.com Gradient, One Beacon Street, Boston, MA 02108
JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH, PART B
https://doi.org/10.1080/10937404.2020.1755402
© 2020 Taylor & Francis
Cosmetic-grade talc is used in baby powders, fem-
inine hygiene products, antiperspirants, deodorants,
creams, hair care products, lipsticks, shampoos, shav-
ing products, wound ointments, foot powders, and
suncareproducts(Fiumeetal.2015). Talc is also used
in medical applications, including for pleurodesis,
which is a medical procedure performed to treat
malignant pleural effusions (Rosenman 2012). In
1976, cosmetic-grade talc specifications required that
there be no detectable fibrous, asbestos minerals
(Fiume et al. 2015).
Women have reported utilizing talc-containing
body powder in the genital/rectal area, on the feet
and or thighs, on sanitary napkins, and on under-
wear, as well as to store diaphragms (Cramer et al.
1999; Ness et al. 2000; Wong et al. 1999). Exposure
via the genital tract might also occur because
many brands of condoms use talc as a surface
lubricant (Cook, Kamb, and Weiss 1997).
The association between perineal talc use and
ovarian cancer was examined in a number of epide-
miology studies in the past 4 decades. Some case-
control studies and meta-analyses reported associa-
tions, while other case-control investigations, three
large prospective cohort studies, and a pooled ana-
lysis of cohort investigations found this association
to be null (Cramer et al. 1999; Gross and Berg 1995;
Huncharek, Geschwind, and Kupelnick 2003;
Huncharek and Muscat 2011; Huncharek et al.
2007; IARC, 2010;Langsethetal.2008; Musser
2014; NCI, 2016;OBrien et al. 2020;
Penninkilampi and Eslick 2018; Taher et al. 2019;
Wentzensen and Wacholder 2014).
In light of the questions surrounding talc and ovar-
ian cancer, a weight-of-evidence evaluation was con-
ducted of epidemiology, toxicity, exposure and
transport, in vitro, and mechanistic evidence to deter-
mine whether, collectively, relevant available evidence
supports a causal association. To our knowledge, this
is the first review of the body of evidence across
scientific disciplines that considers study quality and
risk of bias and their impact on the interpretation of
results.
Methods
Literature search strategy and study selection
The PubMed database was searched for studies
published through January, 2020, that examined
talc and ovarian cancer in humans or any cancer
in animals, genotoxic or in vitro effects of talc, or
exposure and transport of talc in the reproductive
tract using several search terms: (talc OR talcum)
AND (cancer OR tumor OR tumors OR neo-
plasm) AND animal; (talc OR talcum) AND
(ovarian OR ovary OR ovaries OR reproductive
OR fallopian OR uterus OR cervix OR cervical
OR vagina) AND (epidemiol* OR cohort OR
women OR female OR adult OR adults OR popu-
lation); (talc OR talcum) AND (genotoxic* OR
DNA); (talc OR talcum) AND in vitro; (talc
OR talcum) AND (perineal OR genital); (talc OR
talcum) AND (transport OR migration). In addi-
tion, references were checked in review articles of
talc and cancer to identify any studies that may
not have been identified by our literature search.
Weight-of-evidence evaluation
To assess whether talc use might result in an
increased risk of ovarian cancer, a weight-of-
evidence analysis was conducted across scientific
disciplines. This involved reviewing all relevant
studies, considering strengths and weaknesses of
each, and weighing their points of agreement and
contradiction. In a weight-of-evidence evaluation,
all relevant evidence must be considered as
a collective body to enable a robust and balanced
analysis. With this objective, all of the relevant
epidemiology, toxicity, exposure and transport,
and mechanistic evidence was assessed in the con-
text of the Bradford Hill considerations of strength
of association, consistency, specificity, temporality,
dose-response, biological plausibility, coherence,
experiment, and analogy. Both positive and null
studies were evaluated to determine overall plau-
sibility for causality in humans, bearing in mind
study quality and relevance, uncertainties and
inconsistencies in the evidence, and ad hoc
assumptions that may be required to accept
a causal association.
Study quality was determined by considering
study design, study size, participation rate, expo-
sure assessment, and adjustment for confounders.
Investigations were considered to be of higher
quality if exposures were assessed prospectively
and if these included a validation study to assess
the accuracy of self-reported exposures, a larger
2J. E. GOODMAN ET AL.
sample size, a higher participation rate, a longer
follow-up period, and adequate adjustment for
confounders. When evaluating results across epi-
demiology studies, more weight was placed on
higher quality studies such as those that consid-
ered their results to be more reliable and thus
informative to the evaluation of whether they sup-
port perineal talc use as a cause of ovarian cancer.
To determine consistency of results across epide-
miology studies, results were tabulated and
whether effects were evident across studies,
regardless of magnitude or statistical significance,
was assessed. If a pattern was observed, it might
indicate either a causal association or a consistent
bias or confounding factor across investigations.
To evaluate the evidence in animal studies, the
route, magnitude, and duration of exposure, and the
outcome such as presence of tumors were consid-
ered. For in vitro and genotoxicity studies, the mag-
nitude and duration of exposure to the cells, and the
cellular effects including cell proliferation, oxidative
stress, or DNA effects were taken into account. For
experiments of talc migration in the reproductive
tract and quantitation of talc in reproductive tissues,
the mode of talc delivery and comparative amounts
of talc (or particles identified as possible talc) in
tissues of women who had differing exposures
were considered, as well as the processes by which
the particle content of reproductive tissues were
evaluated. Experimental study quality was assessed
on the basis of exposure characterization, outcome
assessment, and control groups. Investigations were
given more weight if they included well-
characterized exposures that are relevant to humans
in terms of route and amount, sufficient time for
tumors to develop, appropriate statistical analyses,
and appropriate controls, including positive controls
for tumor development and negative controls for
inertdustexposure.
Results
Epidemiology
Three prospective cohort studies and 27 case-
control studies were identified that evaluated the
association between perineal talc or body powder
use and ovarian cancer. The cohort studies were all
conducted in the US and were described in 5
articles published since 2000 and a recent pooled
analysis. The characteristics and results of the
cohort studies are summarized in Table 1. The
case-control studies were conducted in a variety
of countries including the US, Canada, United
Kingdom, Norway, Greece, Australia, and China
and described in 33 papers published since the
early 1980s. Twenty-seven of these are population-
based, 5 are hospital-based studies, and one
includes both general and hospital-based popula-
tions. The characteristics and results of the case-
control studies are summarized in Table 2.
Study quality
In the cohort studies, perineal exposures to talc were
assessed prospectively (i.e., before the diagnosis of
ovarian cancer). This eliminates the possibility of
differential recall bias between those with and with-
out ovarian cancer. However, exposures were still
self-reported, with limited exposure information
that was not quantitative and often only assessed
frequency or duration of talc use, but not both. In
addition, exposure information was not updated
after the baseline interview, increasing the potential
for non-talc users to become talc users (and vice
versa). Each of these factors might lead to potential
exposure misclassification.
All three cohorts contained large sample sizes
and follow-up times that enabled detection of
small increases in ovarian cancer risk, although
the study by Gonzalez et al. (2016) included
a follow-up period (median 6.5 years) that was
relatively short with regard to latency for ovarian
cancer, given that information on talc use in this
study was only collected for the 12-month period
prior to participant enrollment (see below and
Table 1). Some of the cohort investigators col-
lected information on talc exposure duration,
such as whether talc use occurred for up to
30 years or more prior to participant enrollment
(Houghton et al. 2014;OBrien et al. 2020; Urban
et al. 2015). The cohorts also had ample informa-
tion on demographic, lifestyle, and reproductive
factors that enabled robust adjustment for poten-
tial confounders.
With regard to case-control studies, some were
more robust than others methodologically; for
example, some included fewer than 100 cases or
JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 3
Table 1. Talc and ovarian cancer cohort study characteristics and results.
Potential Confounders Adjusted
Risk Estimate
a
(95% Confidence Interval [CI])
for Mode of Perineal Talc Use
Extent of Perineal Talc
Exposure
p
trend
or Risk Estimate (95%
CI)
b
Histological Subtypes of Invasive Ovarian Cancer
c
Study Cohort
Sample
Size
Follow-
up
(years)
Loss to
Follow-
up (%) Age Obesity
Family
History Parity
OC
Use
Tubal
Ligation Hysterectomy
PMH
Use Any
Dusting
Powder
Sanitary
Napkin Diaphragm Frequency Duration Serous Mucinous Endometrioid
Clear
Cell
Gertig
et al.
(2000)
NHS 78,630 14 2 ✓✓ 1.09(0.86,
1.37)
0.89
(0.61, 1.28)
1.12
(0.82, 1.55)
d
1.4
(1.02, 1.91)
0.93
(0.53, 1.66)
0.91
(0.49, 1.87)
Gates
et al.
(2010)
NHS 108,870 24 4.86.4 ✓✓ 1.06
(0.84, 1.35)
e
1.50
(0.84, 2.66)
e
1.06
(0.66, 1.69)
e
Houghton
et al.
(2014)
WHI-OS 61,576 12.4
(average)
NR ✓✓ 1.06
(0.87, 1.28)
1.12
(0.92, 1.36)
0.95
(0.76, 1.20)
0.92
(0.68, 1.23)
0.77 1.13
(0.84, 1.51)
1.03
(0.47, 2.27)
1.29
(0.64, 2.61)
Urban
et al.
(2015)
WHI-OS 74,786 12.3
(average)
NR 0.97
(0.78, 1.22)
f
Gonzalez
et al.
(2016)
Sister Study 41,654 6.5
(median)
0.1 ✓✓0.73
(0.44, 1.2)
g
OBrien
et al.
(2020)
Pooled (NHS,
NHSII, WHI-OS,
Sister Study)
252,745 11.2
(median)
NR ✓✓1.08
(0.99, 1.17)
0.20 0.49 1.10
(0.97, 1.25)
h
1.03
(0.69, 1.54)
h
1.15
(0.83, 1.58)
h
1.17
(0.73,
1.89)
h
Notes:
NHS = NursesHealth Study; NHSII = NursesHealth Study II; OC = Oral Contraceptive; PMH = Postmenopausal Hormones; NR = Not Reported; WHI-OS = Womens Health Initiative Observational Study.
Bold denotes a statistically significant result.
(a) All studies used hazard ratios as the risk metric, with the exception of the two studies of the NHS cohort, which used relative risks.
(b) P
trend
is presented, unless otherwise noted.
(c) Risk estimates for invasive cancers are presented when available.
(d) Relative risk for daily talc use vs. never use.
(e) Relative risk for talc use at least once per week vs. less than once per week.
(f) Hazard ratio for talc use of a duration of more than 10 years vs. less than 10 years.
(g) For any talc use in the 12 months prior to study enrollment.
(h) Hazard ratio for ever use of talc vs. never use.
4J. E. GOODMAN ET AL.
Table 2. Talc and ovarian cancer case-control study characteristics and results.
Number Response Rates Potential Confounders Adjusted
Study Location Control Cases Controls Cases Controls Age Obesity Family History Parity OC Use Tubal Ligation Hysterectomy PMH Use
Cramer et al. (1982) US P 215 215 72.4% 48.2% ✓✓
Hartge et al. (1983) US H 135 171 NR NR
Whittemore et al. (1988) US H, P 188 539
d
NR NR ✓✓
Booth, Beral, and Smith (1989) UK H 235 451 NR NR
Harlow and Weiss (1989) US P 116 158 68.0% 74.0% ✓✓
Harlow et al. (1992) US P 235 239 69.0% 50.5% ✓✓
Chen et al. (1992) China P 112 224 48.7% 93.7% ✓✓
Rosenblatt, Szklo, and Rosenshein (1992) US H 77 46 77.1% NR ✓✓
Tzonou et al. (1993) Greece H 189 200 90.0% 94.0% ✓✓
Cramer and Xu (1995) US P 450 454 NR NR
Purdie et al. (1995) Australia P 824 860 90.0% 73.0%
Chang and Risch (1997) Canada P 450 564 71.3% 64.6% ✓✓
Cook, Kamb, and Weiss (1997) US P 313 422 64.3% 68.0%
Green et al. (1997) Australia P 824 855 90.0% 73.0% ✓✓
Godard et al. (1998) Canada P 170 170 87.0% 22.7%
Cramer et al. (1999) US P 563 523 64.2% 72.0% ✓✓
Wong et al. (1999) US H 499 755 NR NR ✓✓
Ness et al. (2000) US P 767 1,367 87.9% 74.0% ✓✓
Langseth and Kjaerheim (2004) Norway N 35 121 76.1% 57.1% ✓✓
Mills et al. (2004) US P 256 1,122 40.3% 57.1% ✓✓
Jordan et al. (2007) Australia P 363 752 84.0% 47.0% ✓✓
Merritt et al. (2008) Australia P 1,576 1,509 74.0% 47.1% ✓✓
Gates et al. (2008) US P 1,175 1,202 71.0% 68.0% ✓✓
Wu et al. (2009) US P 609 688 62.5% NR ✓✓
Moorman et al. (2009)
i
US P 550 533 66.5% 43.9%
Moorman et al. (2009)
j
US P 83 134
Rosenblatt et al. (2011) US P 812 1,313 76.7% 69.0% ✓✓
Kurta et al. (2012) US P 902 1,802 71.0% 46.1%
Terry et al. (2013) US, Canada, Australia P 8,525 9,859 NR NR ✓✓
Wu et al. (2015) US P 1,701 2,391 63.2% NR ✓✓
Cramer et al. (2016) US P 2,041 2,100 71.5% 56.4% ✓✓
Schildkraut et al. (2016) US P 584 745 50.0% 61.0% ✓✓
Gabriel et al. (2019) US P 2,040 2,100 71.0% 54.0% ✓✓
Relative Risk (95% Confidence Interval)
for Mode of Perineal Talc Use
Extent of Perineal Talc Exposure
p
trend
or Risk Estimate (95% CI)
a
Histological Subtypes of Invasive Ovarian Cancer
b
Study Any Dusting Powder Sanitary Napkin or Underwear
c
Diaphragm or Cervical Cap Frequency Duration Total Applications Serous Mucinous Endometrioid Clear Cell
Cramer et al. (1982) 1.61(1.04, 2.49)
Hartge et al. (1983) 2.5(0.7, 10.0) 0.8(0.4, 1.4)
Whittemore et al. (1988) 1.36(0.91, 2.04) 1.45(0.81, 2.60) 0.62(0.21, 1.80) 1.5(0.63, 3.58) 0.19 0.61
Booth, Beral, and Smith (1989) 1.3
e
(0.8, 1.9) Null 0.05
Harlow and Weiss (1989) 1.1(0.7, 2.1) 1.2(0.6, 2.6) 2.2(0.8, 19.8) 0.5(0.2, 1.4)
Harlow et al. (1992) 1.5(1.0, 2.1) 1.7(1.1, 2.7) 1.1(0.4, 2.8) 1.2(0.6, 2.4) 0.046 0.07 0.015
Chen et al. (1992) 3.9(0.9, 10.6)
Rosenblatt, Szklo, and Rosenshein (1992) 1.0(0.2, 4.0) 1.7(0.7, 3.9) 4.8(1.3, 17.8) 3.0(0.8, 10.8)
Tzonou et al. (1993) 1.05(0.28, 3.98)
Cramer and Xu (1995) 1.6(1.2, 2.1)
Purdie et al. (1995) 1.27(1.04, 1.54)
(Continued)
JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 5
Table 2. (Continued).
Relative Risk (95% Confidence Interval)
for Mode of Perineal Talc Use
Extent of Perineal Talc Exposure
p
trend
or Risk Estimate (95% CI)
a
Histological Subtypes of Invasive Ovarian Cancer
b
Study Any Dusting Powder Sanitary Napkin or Underwear
c
Diaphragm or Cervical Cap Frequency Duration Total Applications Serous Mucinous Endometrioid Clear Cell
Chang and Risch (1997) 1.42(1.08, 1.86) 1.31(1.00, 1.73) 1.26(0.81, 1.96) Null Null 1.34(0.96, 1.85) 1.59(0.97, 2.58) 1.67(1.00, 2.79)
Cook, Kamb, and Weiss (1997) 1.5(1.1, 2.0) 1.8(1.2, 2.9) 1.5(0.6, 3.6) 0.8(0.4, 1.4) Null 1.7(1.1, 2.5) 0.7(0.4, 1.4) 1.2(0.6, 2.3)
Green et al. (1997) 1.3(1.1, 1.6) Null
Godard et al. (1998) 2.49(0.94, 6.58)
Cramer et al. (1999) 1.60(1.18, 2.15) 1.45(0.97, 2.18) 1.45(0.68, 3.09) 0.48 0.68 1.70(1.22, 2.39) 0.79(0.44, 1.40) 1.04
f
(0.67, 1.61)
Wong et al. (1999) 0.92
(0.24, 3.62)
1.0(0.8, 1.3) 0.9(0.4, 2.0) Null
Ness et al. (2000) 1.5(1.1, 2.0) 1.7(1.2, 2.4) 0.6(0.3, 1.2) Null
Langseth and Kjaerheim (2004) 1.15
(0.41, 3.21)
Mills et al. (2004) 1.37(1.02, 1.85) 0.015 0.045 0.051 1.77(1.12, 2.81) 2.56(0.89, 7.39) 1.28(0.62, 2.62) 0.63(0.15, 2.64)
Jordan et al. (2007) 1.10(0.84, 1.45) 0.3
g
Merritt et al. (2008) 1.17(1.01, 1.36) 0.021 1.21(1.03, 1.44) 1.10(0.80, 1.52) 1.18(0.81, 1.70) 1.08(0.68, 1.72)
Gates et al. (2008) 1.40(1.15, 1.70) 0.002 1.62(1.26, 2.09)
Wu et al. (2009) 1.53(1.13, 2.09) 1.71(0.99, 2.97) 1.14(0.46, 2.87) 0.032
h
0.0004
Moorman et al. (2009)
i
1.04(0.82, 1.33)
Moorman et al. (2009)
j
1.19(0.68, 2.09)
Rosenblatt et al. (2011) 1.27
(0.97, 1.66)
0.82
(0.58,1.16)
0.72
(0.48, 1.10)
Null Null 1.01
(0.69, 1.47)
1.53
f
(0.91, 2.57)
Kurta et al. (2012) 1.40(1.16, 1.69)
Terry et al. (2013) 1.24(1.15, 1.33) 0.17 1.20(1.09, 1.32) 1.09(0.84, 1.42) 1.22(1.04, 1.43) 1.24(1.01, 1.52)
Wu et al. (2015) 1.46(1.27, 1.69) 1.14
k
(1.09, 1.20)
Cramer et al. (2016) 1.32(1.15, 1.53) 1.42(1.04, 1.96) 0.73(0.57, 0.93) <0.0001 0.002 0.02 1.42(1.19, 1.69) 0.87(0.53, 1.44) 1.38(1.06, 1.80) 1.01(0.65, 1.57)
Schildkraut et al. (2016) 1.44(1.11, 1.86) <0.01 0.02 0.01
Gabriel et al. (2019) 1.30
(1.131.50)
0.0001
h
1.39
(1.141.69)
0.97
(0.681.40)
1.26
(0.941.69)
1.08
(0.661.78)
Notes:
P= Population-based; H = Hospital-based; N = Nested within the same occupational cohort; NR = Not Reported; OC = Oral Contraceptive; PMH = Postmenopausal Hormones.
Bold denotes a statistically significant result. Results are classified as null if a study reported they were not statistically significant but did not report risk estimates or p-values.
(a) P
trend
is presented, unless otherwise noted.
(b) Risk estimates for invasive cancers are presented when available.
(c) If results for sanitary napkins and underwear were reported separately, I present the larger risk estimate of the two.
(d) 280 hospital-based controls, 259 population-based controls.
(e) Daily use.
(f) For endometrioid/clear cell combined.
(g) Frequency for use in the perineal region.
(h) Frequency and duration were evaluated together.
(i) Caucasian women.
(j) African American women.
(k) Relative risk for every five years of talc use.
6J. E. GOODMAN ET AL.
controls, whereas others included 1,000 or more
cases or controls (see Table 2). As with cohort
studies, some collected information on whether
talc exposure occurred for up to 30 years or more
(see Table 2 for investigations that examined
duration of exposure). However, many of the
case-control studies did not assess or adjust for
several established risk factors for ovarian cancer
such as obesity, oral contraceptive or postmeno-
pausal hormone use, and history of gynecological
surgeries. In addition, all of the case-control stu-
dies were subject to recall bias, given that study
participants needed to recall exposure that
occurred many years in the past, and none of
the investigations included a validation study to
assess the accuracy of these self-reports.
Even the higher-quality case-control studies
exhibited considerable methodological limitations.
For example, the study by Cramer et al. (2016) con-
tained extensive information on talc exposure and
other covariates, assessed the extent of talc use and
exposure-response relationships, and evaluated dif-
ferent histological subtypes of ovarian cancer; how-
ever, this study and several others reported
differential response rates between cases and con-
trols, and the response rate was very low (see Table
2), indicating a potential for selection bias.
Cohort studies
Below, results of the three prospective cohort stu-
dies that evaluated the association between peri-
neal exposures to talc and ovarian cancer are
described: The NursesHealth Study (NHS), the
Womens Health Initiatives Observational Study
(WHI-OS), and the Sister Study. A pooled analysis
is also presented that included results from each of
these cohort studies. The results of these studies
are summarized in Table 1.
The NursesHealth Study
Gertig et al. (2000) and Gates et al. (2010) evalu-
ated the association between perineal talc use and
ovarian cancer risk in the NHS, an ongoing large-
scale prospective cohort of 121,700 registered
female nurses in the US aged 3055 years in
1976. Questionnaires were mailed to participants
at baseline and every two years during follow-up,
to obtain information on medical history, lifestyle
factors, and health-related issues. Use of talc
powder was assessed on the 1982 questionnaire
by asking whether the participants had ever com-
monly applied talc, baby powder, or deodorizing
powder to the perineal area or on sanitary napkins.
The frequency of talc use was also assessed on that
questionnaire. Incident cases of ovarian cancer
were self-reported through biennial questionnaires
and searches of the National Death Index during
follow-up, and confirmed by medical record
review or death certificates. Potential confounders
including body mass index (BMI), physical activ-
ity, smoking, age at menarche, parity, oral contra-
ceptive use, tubal ligation, hysterectomy/
oophorectomy, menopausal status, age at meno-
pause, postmenopausal hormone use, and family
history of breast and ovarian cancer were assessed
in this cohort at baseline and/or on multiple ques-
tionnaires during follow-up.
Talc use was determined once at baseline in the
NHS prior to the onset of ovarian cancer in any
participant. Gertig et al. (2000) identified 307 incident
ovarian cancer cases during 14 years of follow-up
(19821996) and reported that having ever used talc
perineally was not associated with an elevated risk of
ovarian cancer (relative risk [RR] = 1.09, 95% confi-
dence interval [CI]: 0.861.37). Talc use on sanitary
napkins was also not associated with ovarian cancer
risk (RR = 0.89, 95% CI: 0.611.28). Ovarian cancer
risk did not change with increased frequency of peri-
neal talc use (< 1 use/week: RR = 1.14, 95% CI: 0.81-
1.59; 16 uses/week: RR = 0.99, 95% CI: 0.671.46;
daily use: RR = 1.12, 95% CI: 0.821.55). When stra-
tified by histological subtype of ovarian cancer, having
ever used talc was associated with a small rise in risk
for serous invasive cancers (RR = 1.40, 95% CI: 1.02-
1.91), but not for endometrioid cancers (RR = 0.91,
95% CI: 0.491.87) or mucinous cancers (RR = 0.93,
95% CI: 0.531.66). There was a borderline significant
linear trend between frequency of talc use and risk of
serous invasive cancers (< 1 use/week: RR = 1.29, 95%
CI: 0.812.04; 16 uses/week: RR = 1.49, 95% CI:
0.772.11; daily use: RR = 1.49, 95% CI: 0.982.26;
p
trend
=0.05).
The most recent analyses of talc use and ovarian
cancer in the NHS cohort were reported by Gates et al.
(2010). During 24 years of follow-up (19822006),
a total of 797 ovarian cases were identified with con-
firmed histological subtypes. A higher frequency of
use of talc on the perineum (at least once per week vs.
JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 7
less than once per week) was not associated with an
increased risk of ovarian cancer overall (RR = 1.06,
95% CI: 0.891.28), nor with any of the subtypes
(serous invasive: RR = 1.06, 95% CI: 0.841.35; endo-
metrioid: RR = 1.06, 95% CI: 0.661.69; mucinous:
RR = 1.50, 95% CI: 0.842.66). There was no evidence
that talc use might have different impacts on different
histological types (p
heterogeneity
= 0.55).
The Womens Health Initiatives Observational
Study
Houghton et al. (2014) and Urban et al. (2015)
examined talc use and ovarian cancer in the WHI-
OS. The WHI-OS cohort consisted of 93,676 post-
menopausal women aged 5079 years at enrollment
(19931998). Questionnaires were mailed to partici-
pants at baseline and annually during the follow-up
to obtain and update information on risk factors and
disease outcomes including ovarian cancer. Perineal
powder use was assessed at baseline. Information on
potential confounders, including alcohol consump-
tion, smoking status, physical activity, BMI, family
history of ovarian or breast cancer, age at menarche,
age at menopause, age at first birth, age at last birth,
parity, breastfeeding duration, history of tubal liga-
tion, history of hysterectomy, history of irregular
cycles, history of endometriosis, duration of oral
contraceptive use, and duration of postmenopausal
hormone use were also obtained at baseline. The
participants were followed for an average of
12.4 years, and 429 incident cases of ovarian cancer
were identified (Houghton et al. 2014). Having ever
been exposed to talc perineally was not associated
with an enhanced risk of ovarian cancer (hazard
ratio [HR] = 1.06, 95% CI: 0.871.28). The risk of
ovarian cancer also did not alter with increased
duration of perineal talc use (9 years: HR = 1.09,
95% CI: 0.881.36; 10 years: HR = 1.02, 95% CI:
0.801.30; p
trend
= 0.77). The results for each mode of
talc application were also null (perineal powder use:
HR = 1.12, 95% CI: 0.921.36; powder use on sani-
tary napkins: HR = 0.95, 95% CI: 0.761.20; powder
use on diaphragm: HR = 0.92, 95% CI: 0.681.23).
There were no exposure-response relationships
between ovarian cancer risk and duration of any
mode of talc application.
In an updated analysis of the WHI-OS cohort
(Urban et al. 2015), perineal talc use was dichot-
omized by duration (> 10 years vs. < 10 years).
Perineal talc use for > 10 years was not associated
with an increased risk of ovarian cancer compared
to use < 10 years (HR = 0.97, 95% CI: 0.781.22).
The Sister Study
Gonzalez et al. (2016) analyzed talc use and ovarian
cancer in the Sister Study, which consisted of
50,884 women in the US and Puerto Rico who
had sisters diagnosed with breast cancer. The parti-
cipants were aged 3574 years at enrollment (-
20032009) and completed a computer-assisted
telephone interview to provide information on
reproductive history, health conditions, and life-
style factors. The participants also completed a self-
administered questionnaire at baseline to report
personal care products used in the 12 months
prior to enrollment, including frequency and
mode of genital talc use. With a median follow-up
of 6.5 years, 154 incident ovarian cancers were
identified. Gonzalez et al. (2016) noted that talc
use in the 12 months prior to enrollment was not
associated with an increased risk of ovarian cancer
(HR = 0.73, 95% CI: 0.441.2).
In summary, the prospective cohort studies con-
sistently reported a null association between peri-
neal talc use and ovarian cancer, and a lack of
exposure-response between ovarian cancer risk
and frequency or duration of talc use. In addition,
talc exposure was not associated with increased
risks of any subtypes of ovarian cancer, and asso-
ciations did not appear to vary by subtype.
Pooled analysis of cohort studies
OBrien et al. (2020) conducted a pooled analysis of
data from the NHS, WHI-OS, and Sister Study
cohorts, as well as the NursesHealth Study II
(NHSII), a prospective cohort of 116,429 registered
female nurses in the US aged 2542 years in 1989, for
whom genital talc use was assessed via questionnaire
in 2013. With a pooled sample size of 252,745
women and a median follow-up of 11.2 years,
OBrien et al. (2020) found that having ever used
talc in the genital area was not associated with an
elevated risk of ovarian cancer (HR = 1.08, 95% CI:
0.991.17). Ovarian cancer risk also did not change
markedly for frequent (at least once per week) vs.
never use (HR = 1.09, 95% CI: 0.971.23; p
trend
= 0.20), long-term (at least 20 years) vs.neveruse
8J. E. GOODMAN ET AL.
(HR = 1.01, 95% CI: 0.821.25; p
trend
=0.49),orfor
ever vs. never use among cases with histologic sub-
types of serous (HR = 1.10, 95% CI: 0.971.25),
endometrioid (HR = 1.15, 95% CI: 0.831.58), muci-
nous (HR = 1.03, 95% CI: 0.691.54), or clear cell
(HR = 1.17, 95% CI: 0.731.89) ovarian cancer.
Case-control studies
In general, case-control studies reported a small
increase in ovarian cancer risk associated with
perineal exposure to talc, as most of the RR esti-
mates fell between 1 and 2 (see Table 2). These
investigators did not consistently observe positive
exposure-response relationships between extent of
talc exposure and ovarian cancer risk (see
Exposure-response section below and Table 2).
Different modes of perineal talc exposures were
not consistently associated with increased cancer
risks. Below, the two recent case-control studies
with the largest numbers of cases, the New
England Case-control (NECC) study (Cramer
et al. 1999,2016; Gabriel et al. 2019) and the
Ovarian Cancer Association Consortium (OCAC)
study (Terry et al. 2013), are discussed in more
detail.
The New England Case-control Study
Cramer et al. (2016) conducted the NECC study, in
which cases and controls were recruited from
Massachusetts and New Hampshire in three phases
spanning over two decades. Combining data from
the three phases, 2,041 pathologically confirmed
epithelial ovarian cancer cases and 2,100 population-
based controls were included in the analyses
(Cramer et al. 2016). Personal interviews were con-
ducted to obtain information on potential ovarian
cancer risk factors and talc use that occurred more
than one year prior to diagnosis for cases and
one year before the interview for controls. Specific
modes of talc application and extent of talc exposure
were assessed, and a number of established ovarian
cancer risk factors and potential confounders were
adjusted for in the analyses.
Cramer et al. (2016) noted that any genital
powder use was associated with an OR of 1.33
(95% CI: 1.161.52) for ovarian cancer. Similar
results were found in the most recent analysis of
the NECC study by Gabriel et al. (2019) (see Table
2), though this investigation focused on the joint
effects of genital talc use and douching. Cramer
et al. (2016) also reported significant exposure-
response relationships between ovarian cancer
risk and the frequency, the duration, months
per year, and total genital applications of talc use.
Women who were only exposed to talc via dia-
phragm use were at significantly reduced risks for
ovarian cancer (odds ratio [OR] = 0.73, 95% CI:
0.570.93).
The Ovarian Cancer Association Consortium
Study
The OCAC study, founded in 2005, is a consortium
of ovarian cancer case-control studies. Terry et al.
(2013) conducted a pooled analysis of 8 population-
based case-control studies in the OCAC study,
including the first two enrollment phases of the
NECC study. Information on genital powder use
varied across studies, and the OCAC pooled analysis
developed harmonized analytic exposure variables
by defining genital powder use as any type of powder
applied directly or indirectly (by application to sani-
tary pads, tampons, or underwear) to the genital,
perineal, or rectal area. The total number of applica-
tions was also estimated from duration and fre-
quency of genital powder use. Information on
known and suspected risk factors for ovarian cancer,
including oral contraceptive use, parity, tubal liga-
tion history, BMI, race, and ethnicity, was available
from each study. Histological subtypes of ovarian
cancer were also evaluated. A total of 8,525 ovarian
cancer cases and 9,859 controls were included in the
pooled analysis.
Terry et al. (2013) reported a pooled OR of 1.24
(95% CI: 1.151.33) associated with any genital
powder use. Study-specific ORs for genital powder
use ranged from 0.99 to 1.37, with most studies
demonstrating significant elevated risks. Terry
et al. (2013) also observed significant risks for
three histological subtypes of ovarian cancer: serous
(pooled OR = 1.20, 95% CI: 1.091.32), endome-
trioid (pooled OR = 1.22, 95% CI: 1.041.43), and
clear cell (pooled OR = 1.20, 95% CI: 1.091.32).
Different uses of talc
Several of the epidemiology studies assessed the
risks associated with different modes of talc
JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 9
powder use: powder on sanitary napkins, pads, or
underwear and talc on the diaphragm or cervical
cap. Among the prospective cohort studies,
Houghton et al. (2014) examined powder use on
the genitals, sanitary napkins, and diaphragms,
while Gertig et al. (2000) examined talc use on
perineum and on sanitary napkins. Both studies
reported null results for all of these specific pow-
der uses.
A number of the case-control studies also eval-
uated specific uses of talc. For dusting powder use
on the perineum, results from most case-control
studies suggest increases in ovarian cancer risk
(Booth, Beral, and Smith 1989; Chang and Risch
1997; Chen et al. 1992; Cook, Kamb, and Weiss
1997; Cramer et al. 1999,2016; Gates et al. 2008;
Godard et al. 1998; Green et al. 1997; Harlow et al.
1992; Kurta et al. 2012; Ness et al. 2000; Purdie
et al. 1995; Rosenblatt, Szklo, and Rosenshein
1992; Rosenblatt et al. 2011; Terry et al. 2013;
Whittemore et al. 1988; Wu et al. 2015,2009),
while other investigators noted null associations
(Harlow and Weiss 1989; Jordan et al. 2007;
Tzonou et al. 1993; Wong et al. 1999). For talc
use on sanitary napkins, pads, or underwear, 6
studies reported increased risks (Cook, Kamb,
and Weiss 1997; Cramer et al. 1999; Harlow and
Weiss 1989; Ness et al. 2000; Rosenblatt, Szklo,
and Rosenshein 1992; Wu et al. 2009), but 5
demonstrated null associations (Chang and Risch
1997; Harlow et al. 1992; Rosenblatt et al. 2011;
Whittemore et al. 1988; Wong et al. 1999). For talc
use on diaphragms or cervical caps, most investi-
gators reported null associations or reduced ovar-
ian cancer risks (Booth, Beral, and Smith 1989;
Cook, Kamb, and Weiss 1997; Cramer et al.
2016; Harlow et al. 1992; Harlow and Weiss
1989;Hartge et al. 1983; Ness et al. 2000;
Rosenblatt et al. 2011; Wu et al. 2009), and two
studies reported numerically higher risks that were
not statistically significant (Rosenblatt, Szklo, and
Rosenshein 1992; Whittemore et al. 1988).
A meta-analysis that included 8 of these studies
(those published through 2005) found no elevated
risk of ovarian cancer associated with use of talc
on diaphragms (summary RR of 1.03, 95% CI:
0.81.37) (Huncharek et al. 2007). Huncharek
et al. (2007) also conducted sensitivity analyses
that explored the effects of specific study
characteristics on this summary risk estimate and
reported that all resultant summary RRs indicated
no marked association between talc use on dia-
phragms and enhanced risk of ovarian cancer.
Exposure-response
Many epidemiology studies examined the expo-
sure-response relationship between ovarian cancer
risk and the extent of perineal talc exposure (as an
estimate of dose-response). The most frequently
assessed metrics of talc exposure include frequency
and duration of talc application and total applica-
tions (frequency × duration). Other metrics
include age at first use, age at last use, time since
first use, and time since last use. To compare
results across studies, this review focused on the
three most frequently evaluated metrics: fre-
quency, duration, and total number of talc appli-
cations. The p
trend
values for these metrics are
listed in Table 2.
Some case-control investigators found a significant
exposure-response association for frequency of talc
use (Cramer et al. 2016; Gates et al. 2008;Harlow
et al. 1992; Mills et al. 2004;Schildkrautetal.2016;
Wu et al. 2009). In contrast, several case-control stu-
dies(Booth,Beral,andSmith1989;ChangandRisch
1997;Jordanetal.2007; Whittemore et al. 1988)and
the NHS cohort (Gates et al. 2008;Gertigetal.2000)
(Table 2) demonstrated no marked relationship.
Six case-control studies reported a significant lin-
eartrendinovariancancerriskwithanincreased
duration of talc use (Cramer et al. 2016; Merritt et al.
2008; Mills et al. 2004; Schildkraut et al. 2016;Wu
et al. 2015,2009); while 8 case-control investigations
(Chang and Risch 1997;Crameretal.1999;Green
et al. 1997;Harlowetal.1992;Nessetal.2000;
Rosenblatt et al. 2011;Whittemoreetal.1988;
Wong et al. 1999) and the WHI-OS cohort
(Houghton et al. 2014) noted no marked correlation
(Table 2).
Several case-control studies evaluated ovarian
cancer risk and total applications (frequency ×
duration). As presented in Table 2, the results
from these studies were mixed (Cook, Kamb, and
Weiss 1997; Cramer et al. 1999,2016; Harlow et al.
1992; Mills et al. 2004; Rosenblatt et al. 2011;
Schildkraut et al. 2016; Terry et al. 2013;Wu
et al. 2009). Our focus was on the NECC
(Cramer et al. 2016) and OCAC study (Terry
10 J. E. GOODMAN ET AL.
et al. 2013), because these investigations had the
largest numbers of cases, and the OCAC study
combined data of several previous studies. As dis-
cussed above, the NECC study had three enroll-
ment phases. Combining data from three phases,
the results showed a significant positive exposure-
response relationship between total number of talc
applications and ovarian cancer risk. An earlier
publication of the NECC study (Cramer et al.
1999), which noted findings from the first enroll-
ment phases, did not demonstrate a significant
trend with elevated total talc applications. The
OCAC study included data from the first two
enrollment phases of the NECC study, as well as
data from 7 other population-based case-control
studies (Terry et al. 2013). Pooling data from all 8
case-control investigations and using uniform
exposure categories and confounder adjustment,
Terry et al. (2013) did not observe a significant
trend in ovarian cancer risk with increased total
talc applications.
Reviews and meta-analyses
A number of systematic reviews and meta-analyses
of epidemiology evidence regarding talc exposure
and ovarian cancer have been published (Cramer
et al. 1999; Gross and Berg 1995; Huncharek,
Geschwind, and Kupelnick 2003; Huncharek and
Muscat 2011; Huncharek et al. 2007; International
Agency for Research on Cancer (IARC) 2010;
Langseth et al. 2008; Musser 2014; National
Cancer Institute (NCI) 2016; Penninkilampi and
Eslick 2018; Taher et al. 2019; Wentzensen and
Wacholder 2014). These analyses reported similar
findings of modest, positive meta-RRs among rele-
vant case-control studies for ever vs. never talc use
and no marked associations among cohort studies.
It is noteworthy that several investigators indicated
that the influence of recall bias could not be ruled
out for case-control studies (Langseth et al. 2008;
Penninkilampi and Eslick 2018; Taher et al. 2019).
Animal studies
Three studies of talc effects in animals after direct
application to reproductive tissues or exposure in the
perineal area were identified. Because the data on
talc carcinogenicity in the reproductive tract were
limited, our scope was expanded to include studies of
the carcinogenicity of talc in other tissues. Several
animal studies were identified that examined tissues
for tumor development following talc exposure by
various routes (intraperitoneal (ip) injection, capsule
implantation, intratracheal (IT) instillation, inges-
tion, subcutaneous (sc) injection, or intrapleural
injection). These studies are described below.
Reproductive tract tissues
Two animal studies were identified that determined
the effects of talc application to reproductive tract
tissues specifically. Hamilton et al. (1984) injected
10 mg of asbestos-free talc per ovary directly into the
surrounding bursal space in rats and examined his-
topathology at various time points up to 18 months
after injection. Hamilton et al. (1984)foundfocal
areas of papillary change in the surface epithelium of
the ovaries in 4 of 10 treated animals but detected no
atypical cellular features that would indicate
a preneoplastic condition (e.g., no mitotic figures)
and no carcinogenicity. Hamilton et al. (1984)
hypothesized that the papillary changes may have
been produced not by talc directly, but by high con-
centrations of steroid hormones that likely accumu-
lated in the bursal space. Considering that a relatively
large amount of talc (10 mg) was applied directly
into the bursa sac that surrounds the rat ovary, this
study is not representative of potential exposure of
the ovaries to talc following perineal application. The
investigation also lacked a non-talc particle control
to determine whether the histological changes may
be attributed to properties specific to talc, or merely
to the presence of a large amount of foreign inert
particulate matter. The presence of granulomas in
the treated rat ovaries suggests that the ovarian tissue
was responding to the presence of an inert, nontoxic
agent (de Brito and Franco 1994).
Keskin et al. (2009) applied 100 mg of talc (type
unspecified) in a saline solution either intravaginally
or perineally to rats daily for three months. At the
end of the three months, genital and reproductive
tissues were evaluated for histopathological altera-
tions. There was no evidence of carcinogenicity in
any of the tissues. All of the rats that received talc
intravaginally or perineally (7 rats per treatment
group) developed reproductive tract infections. It is
unclear, however, whether the infections were talc
related, as 2 of 7 untreated (no injection or applica-
tion) animals also developed reproductive tract
JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 11
infections (including one ovary infection), and one
of 7 saline-injected rats developed endometritis. No
information was provided as to sterility of the test
materials or living conditions. This study is limited
by the small number of animals, a test period (three
months) that is not sufficient to study tumor devel-
opment, and a possible infection in the animal col-
ony unrelated to talc.
In an investigation of indirect talc application,
Boorman and Seely (1995)reportedfindingsfrom
the NTP (1993) study described below in which rats
and mice of both genders were exposed to high-purity
micronized talc at aerosol concentrations of 6 or
18 mg/m
3
via whole body inhalation (discussed in
more detail below). Although animals were exposed
by inhalation, the air concentrations were so high that
dermal (perineal) exposure was also present. As
described by Boorman and Seely (1995), animals
were exposed for 6 hours per day with talc covering
the fur and the cage bars, and there was ample oppor-
tunityforperinealaswellasoralandrespiratory
exposure. Boorman and Seely (1995) found no talc-
related lesions of the ovaries in either rats or mice. In
addition, no talc particles were identified in the ovar-
ian tissues of exposed rats. This investigation had
several strengths, including large numbers of animals
(4950 of each gender per treatment group), lifetime
exposure, and histological examination of both lung
(as a positive control) and ovarian tissue for the pre-
sence of talc particles from randomly selected animals
in each treatment group.
Non-reproductive tract tissues
Several experiments evaluated the influence on
rodents of non-reproductive tract talc exposure
via various exposure routes. Many of these studies
have methodologies that limit their interpretation
in terms of relevance to human exposures, includ-
ing small numbers of test animals, use of only one
dose level, a single administration, and/or a dose
that was much higher than any relevant human
exposures. In some investigations, the routes of
exposure (e.g., ip, intrapleural, or sc injection)
were not relevant to typical human exposures.
Some of the reseachers did not report the source
or grade of the talc used, and many did not
include a particulate matter control to assess
whether effects were specific to talc. In addition,
most of these experiments did not include an
assessment of talc effects on the reproductive
tract. Nevertheless, these are informative as to
talcs potential carcinogenicity in general.
Ozesmi et al. (1985) exposed mice to 20 mg of
UV-sterilized commercial talc in physiological
saline via ip injection and followed animals until
spontaneous death or obvious tumor formation.
Incidenceoftumorformationinexposed
mice was similar to controls. Pott, Huth, and
Friedrichs (1974) exposed rats to 4 ip injections
of 25 mg talc in saline and noted that the expo-
sure did not lead to the development of tumors
except for a few cases.Stanton et al. (1981)
tested 7 different samples of refined commercial
talc in the form of a gelatin capsule implanted
in the pleural surface of female rats for at least
one year. The samples were each from a different
source and meant to represent potential range in
dimension of talc. Stanton et al. (1981) found no
significant change in pleural sarcomas in any of
the talc-exposed rats compared to controls. No
local tumors were detected in mice observed for
life following a single sc injection of 80 g talc
(type unspecified) (Neukomm and de Trey,
1961, as cited in International Agency for
Research on Cancer (IARC) 2010).
Wagner et al. (1977)reportednoclearevi-
dence of carcinogenicity in rats following an
intrapleural inoculation with 20 mg Italian
00000 grade talc or dietary exposure to
100 mg/day Italian talc on 101 days over
a 5-month period. This Italian talc (mean parti-
cle size 25 µm) was selected for the experiments
duetoits50-yearhistoryofuseandbecauseit
served as the source of over 40% of cosmetic
grade talc in Great Britain at the time. In the
rats exposed via intrapleural inoculation, injec-
tion site granulomas were reportedly common
and one small pulmonary adenoma was identi-
fied as a possibly incidental finding. In the diet-
ary portion of the experiment, a single
leiomyosarcoma of the stomach was detected in
a talc-fed rat, but Wagner et al. (1977)were
unable to determine whether it was related to
exposure.Inaddition,twosarcomasofthe
uterus were found in treated rats but were not
considered treatment related due to the location
12 J. E. GOODMAN ET AL.
of the tumors and occurrence of this tumor type
in historical control animals.
Studies in hamsters (Stenback and Rowland
1978), rats (Friemann et al. 1999), and mice
(Sahu, Shanker, and Zaidi 1978) investigated pul-
monary effects following IT instillation of talc and
noted no marked alteration in tumors of the
respiratory system. Non-respiratory tumors were
either not investigated or not reported in the stu-
dies. Stenback and Rowland (1978) treated ham-
sters with 18 IT instillations of talc (United States
Pharmacopoeia grade; 93.3% of particle less than
25 µm). The hamsters showed signs of minor
respiratory disordersduring the treatment period
but did not develop any respiratory or non-
respiratory tumors attributed to the talc exposure.
Friemann et al. (1999) exposed rats to a single IT
instillation of 25 g of asbestos-free talc and exam-
ined histological effects of the respiratory system
to identify potential pre-neoplastic lesions. Talc-
exposed rats exhibited reversible proliferation of
bronchiolar epithelium but no respiratory neo-
plasms orsignificant changes in alveolar bronchio-
lization, an effect that was considered a pre-
neoplastic lesion. In a study of effects related to
pulmonary silicosis, Sahu, Shanker, and Zaidi
(1978) exposed mice to 5 mg talc dust sourced
from India (particle size < 5 µm) via IT instillation
and observed animals for a period of 210 days. No
gross pathological effects of the respiratory system
resembling neoplasms were detected.
Similarly, 3 of 4 inhalation studies reported no
excess tumors in rats (Wagner et al. 1977), hamsters
(Wehner, Zwicker, and Cannon 1977), or mice (NTP,
1993). Wagner et al. (1977) exposed rats to a mean
concentration of 10.8 mg/m
3
Italian talc (as previously
described) as respirable dust for 3, 6, or 12 months and
sacrificed rats following exposure or after a one-year
recovery period. A single lung adenoma was observed
in the 12-month exposure group, which was noted as
a possibly incidental finding, although no statistical
analysis was provided. Wehner, Zwicker, and
Cannon (1977) exposed hamsters to a respirable frac-
tion of approximately 8 to 10 mg/m
3
aerosolized cos-
metic grade talc for various exposure durations,
including a maximum of 300 days, and found no
treatment-related tumors in any of the exposed ani-
mals. National Toxicology Program (NTP) (1993)con-
ducted a standard cancer bioassay in which mice of
both genders were exposed to aerosols containing 0, 6,
or 18 mg/m
3
talc for up to 104 weeks. The high-purity
talc (MP 1052 grade) was sourced from a mine in
Montana, contained no tremolite or asbestiform
minerals, and had a maximum particle size of 10 µm
with 75% of particles between 1 and 3 µm. No signifi-
cant excess in tumor incidence was found, and NTP
concluded that there was no evidence of carcinogenic
activity of talc based on the findings in mice.
Also in the NTP (1993) study, female rats, but not
male rats, developed a significant excess of alveolar/
bronchiolar adenomas, carcinomas, and combined
adenomas and carcinomas at the highest dose only
(18 mg/m
3
for more than two years). NTP (1993)
also observed an excess of pheochromocytomas in
the high-dose male and female rats, but IARC (2010)
did not consider this increase to be talc-related
because pheochromocytomas may result from stress
and hypoxia, and background incidence of these
tumors is quite high in the F344/N rat strain that
NTP studied. NTP (1993) concluded that there was
clear evidence of carcinogenicityin female rats
based upon the findings of alveolar/bronchiolar ade-
nomas, carcinomas, and combined adenomas and
carcinomas or benign or malignant pheochromocy-
tomas of the adrenal gland.
Several investigators disagreed with NTPs con-
clusion, including a panel of experts at a 1994
International Society of Regulatory Toxicology &
Pharmacology (ISRTP)/US Food and Drug
Administration (FDA) workshop (Goodman 1995;
Musser 2014; Oberdorster 1995; Wehner 2002),
because of weaknesses in the study design and its
relevance to human risk. A talc concentration of
18 mg/m
3
, 6 hr/day, 5 days/week, is much higher
than any relevant occupational or consumer expo-
sures and would have resulted in lung overload to
the animals, which might result in tumor formation
due to an inflammatory reaction to even non-
carcinogenic particles (Oberdorster 1995; Wehner
2002). It is notable that the study did not include
positive or negative dust controls, which would have
permitted an assessment of talcs carcinogenicity
relative to other control dusts. The rats in the highest
exposure group also exhibited marked chronic lung
toxicity (chronic granulomatous inflammation, non-
neoplastic changes, and interstitial fibrosis), indicat-
ing that they were exposed at a level that produced
general toxicity (Goodman 1995). Experts at the
JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 13
1994 ISRTP/FDA workshop concluded that this
1993 NTP study had no relevance to human risk
(Musser 2014).
Summary
Several studies, described above, assessed whether talc
might induce ovarian cancer in experimental animals,
including two that evaluated talc directly applied to
reproductive tissues. Although the two studies of
direct application to reproductive tract tissues have
some methodological limitations, both reported no
marked association between talc exposure and ovarian
cancer, even at doses much higher than might reason-
ably be expected to result from consumer exposure to
talc. In addition, of all the studies examining other
routes of exposure, only one reported lung cancer in
female rats at the highest dose, but this finding has no
relevance to human risk (Musser 2014). No other
cancer in either gender or other species was found.
Genotoxicity
Endo-Capron et al. (1993) did not observe any marked
alterations in sister chromatid exchange, DNA repair,
or aneuploidy in rat pleural mesothelial cells that were
exposed to three different talc samples at concentra-
tions ranging from 2 to 50 μg/cm
2
, for 24 or 48 hr.
Litton Bionetics, Inc. (1974, as cited in Fiume et al.
2015) found no significant talc-initiated genotoxic
effects in host-mediated, cytogenetic, or dominant
lethal assays. In the host-mediated assay, male mice
were administered talc either by a single gavage, or
once daily for 5 days with 30, 300, 3,000, or 5,000 mg/
kg talc. The indicator organisms Salmonella typhimur-
ium TA1530 and G46 and Saccharomyces cerevisiae
D3 (injected into the host mouse abdominal cavity
and then withdrawn) did not exhibit any mutations.
In the cytogenetics assay, 2, 20, or 200 μg/ml talc were
added to human embryonic lung culture cells. Talc
produced no significant aberrations and was not gen-
otoxic. In the dominant lethal assay, no dominant
lethal mutations were detected following exposure of
rats to talc at 30, 300, 3,000, or 5,000 mg/kg.
In vitro studies
Three studies evaluated the influence of talc on ovar-
ian cells in vitro.BuzZard and Lau (2007)noted
neoplastic transformation and a time-dependent
increase in reactive oxygen species (ROS) in human
ovarian cell line cultures following addition of 0.5-
500 μg/ml talc for 2472 hr. This report is mislead-
ing, as the generation of ROS actually decreased with
increasing talc concentration in the ovarian cell lines.
Small increases were observed at 72 hr compared to
24 hr after talc addition at some, but not all, con-
centrations of talc. While the generation of ROS in
cells may be one step in a pathway leading to tumor
formation, it is not an indication of carcinogenesis
per se. Many different exposures and cell processes
lead to enhanced oxidation but do not result in
cancer development (Goodman and Lynch 2017).
BuzZard and Lau (2007) did not demonstrate that
the generation of ROS following talc exposure led to
cell damage or genetic alterations. In addition, there
was no recovery period, and thus it remains
unknown whether the concentration of ROS would
return to baseline levels after removal of talc.
The reported neoplastic transformation was
measured by an elevation in the ability of cells to
grow in soft agar, but findings were inconsistent.
In one ovarian epithelial cell line (OSE2a), the
increased growth occurred in a reverse exposure-
response relationship, with the greatest effect
occurring at 5 μg/ml talc, and a reduction in
growth at 100 μg/ml talc. In the stromal ovarian
cell line (GC1a), increasing talc concentrations
were associated with enhanced growth. In addition
to these inconsistencies, there was no discussion of
the relevance of the in vitro concentrations used in
the cell cultures in relation to any plausible dose
in vivo to the ovaries of women who use talc. This
study has not been replicated by other investiga-
tors, does not exhibit consistent talc effects in
a clear exposure-response-related manner, and is
not consistent with other genotoxicity findings.
Fletcher et al. (2019) exposed normal human
primary ovarian epithelial cells and several ovarian
cancer cell lines to 5, 20, or 100 μg/ml talc for
72 hr and demonstrated concentration-dependent
elevation in various markers of oxidative stress,
such as nitric oxide and inducible nitric oxide
synthase, and diminished expression of antioxi-
dant enzyme activities including catalase, super-
oxide dismutase, glutathione peroxidase, and
glutathione reductase. Fletcher et al. (2019) also
reported a rise in expression of CA-125 protein.
CA-125 is a biomarker of ovarian cancer but is not
14 J. E. GOODMAN ET AL.
specific to ovarian cancer, and may also be ele-
vated in patients with other, noncancerous condi-
tions of the reproductive tract and in patients with
some other types of cancer (Jelovac and
Armstrong 2011). Increased cell proliferation and
decreased apoptosis with talc treatment of both
normal and ovarian cancer cells were noted, as
well as an induction of specific mutations in key
oxidant and antioxidant enzymes that correlate
with alterations in their activities. As with the
study by BuzZard and Lau (2007), Fletcher et al.
(2019) did not discuss the relevance of the in vitro
concentrations employed in their study to any
plausible in vivo dose to the ovaries of women
who use talc. This is important because, as
Fletcher et al. (2019) also did not include any
inert particulate matter controls, they could not
rule out effects due to the presence of an overload
of inert particulate matter rather than talc specifi-
cally. Further, any parameters after a recovery per-
iod were not measured to determine whether the
changes were permanent, or if these might return
to baseline over time.
Mandarino et al. (2020) examined whether talc
exerted an effect on the ability of macrophages to
inhibit tumor growth in the presence of estrogen.
Mouse macrophage cell lines that were exposed to
talc, with or without estradiol, were co-cultured
with an ovarian cell line, and the cell line was
monitored for growth. There was more growth in
the ovarian cells cultured in the presence of
macrophages exposed to talc plus estradiol than
in the presence of macrophages exposed to either
substance alone. Mandarino et al. (2020) con-
cluded that the combination of talc plus estradiol
may inhibit the anti-tumor activity of macro-
phages in reproductive tissues. However, the
effects of talc and estradiol appear to be additive
in this study, which does not indicate a novel
mechanism of immune suppression that occurs
only when both agents are present. Mandarino
et al. (2020) did not specify the concentration of
talc used in most of the trials and did not indicate
the relevance of the amount of talc to human
exposures.
Taken together, these in vitro studies provide
inconclusive evidence regarding whether talc
induces pre-carcinogenic effects in the ovary at
human relevant doses. This is consistent with
longer-term studies of animals that do not indicate
carcinogenicity from talc exposure.
Exposure and transport evaluations
There are several types of exposure studies that may
be considered in evaluating whether perineal talc
application (either direct or by application to under-
wear or sanitary pads) and subsequent retrograde
transport into the reproductive tract comprise
a plausible exposure pathway that substantially con-
tributes to development of ovarian cancer. This type
of exposure information includes the following:
Biological monitoring data, including results
from studies that explored the presence of
talc in samples of ovarian cancer and healthy
ovarian tissues;
Mechanistic transport studies, which investi-
gated the movement of talc or other types of
particles in the female reproductive tract; and
Modeling evaluations that assessed the magni-
tude of exposures that might occur through this
pathway.
The exposure information collected in epidemiol-
ogy investigations also provides insights into this
transport pathway.
Biological monitoring and measurements in
ovarian tissues
The scientific literature includes a number of indi-
vidual case studies and small-scale studies that
explored the presence of talc particles in ovarian
tissues. These investigations examined tissue sam-
ples from surgical patients, including patients with
ovarian cancer, and others judged to have healthy
ovarian tissues.
Based on results from an extraction-replication
technique that their lab developed to examine the
presence of foreign particles in tissue samples,
Henderson et al. (1971) reported that talc was
present in tissue samples from 10 of 13 ovarian
tumors, 12 of 21 cervical tumors, and 5 of 12
samples judged to reflect normal ovarian tissues
from patients with breast cancer. There was some
question regarding whether the particles detected
in the samples may have been due to sample con-
tamination such as from particles on the gloves of
JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 15
individuals obtaining or analyzing the samples. In
a subsequent investigation, Henderson, Hamilton,
and Griffiths (1979) noted that talc was found in
all 9 additional samples: three samples from nor-
mal ovaries, three from cystic ovaries, and three
from adenocarcinomas. These investigators noted
they were particularly careful to avoid external talc
contamination sources. Using several microscopic
methods, Cramer et al. (2007) in a case study
indicated the presence of talc particles in samples
collected from the pelvic lymph nodes of a woman
with ovarian cancer. These investigators stated that
the use of polarized light microscopy identified
diffuse areas of birefringence compatible with
talc,and that examination of the samples using
scanning electron microscopy and X-ray spectro-
scopy confirmed the presence of talc.
In a study of ovarian samples from 100 women
with grossly normalovaries undergoing surgery
for pelvic disease, Mostafa et al. (1985)observed
crystalline foreign particlesin histological evalua-
tions of the samples from 9% of subjects.
Subsequently 4 samples containing foreign particles
were analyzed using a scanning electron microscope
and computer-assisted microscopic X-ray analysis to
evaluate elemental composition of the particles.
Based upon these analyses, Mostafa et al. (1985)
concluded that the particles were composed largely
of magnesium and silicon but did not definitively
confirm the observed particles as being talc; how-
ever, talc and asbestos were identified as the most
common compounds containing magnesium sili-
cates.In addition, these investigators did not report
any precautions taken to ensure that the particles
were not derived from contamination (from surgical
gloves, for example) during surgery and/or the pro-
cessing of the tissues for examination.
Heller et al. (1996) examined the presence of
talc particles in normal ovarian tissue samples
collected from 24 women undergoing incidental
oophorectomy (i.e., surgical removal of one or
both ovaries) to address benign ovarian neo-
plasms. Talc particles were identified in samples
from all 24 women by either polarized light micro-
scopy or analytic electron microscopy. Heller et al.
(1996) also collected information regarding the
study subjectsperineal talc use and approximated
talc exposure levels by estimating the subjects
lifetime talc applications.Data indicated that
talc particle counts from both types of microscopy
showed no quantitative relationship with esti-
mated level of talc use. For example, in unexposed
women, particle counts observed using light
microscopy ranged from 0 to 2,200/g, while counts
in exposed women ranged from 26-464/g. The
lowest particle count in the exposed group was
reported for the woman with the highest estimated
lifetime talc applications. In the electron micro-
scopy results, talc particle counts in exposed and
unexposed groups spanned a similar range, and
the counts for approximately one-half of the
women in each group were not-detectable (zero).
Two recent studies (McDonald et al. 2019b,
2019a) examined the ovaries, pelvic lymph nodes,
and other pelvic tissues of ovarian cancer patients
for the presence of talc particles. McDonald et al.
(2019a) measured talc particles in the pelvic lymph
nodes of 22 ovarian cancer patients. Results
demonstrated that the mean concentration of talc
particles in the pelvic lymph nodes of women who
used perineal talc was higher than that in women
who did not use perineal talc. However, of the 10
women who reported perineal talc use, 9 also
indicated regular use of talc on other parts of the
body. McDonald et al. (2019a) did not conduct an
analysis of talc in tissues of women who used talc
as a body powder vs. women who did not, thus it
is not possible to conclude that talc in the pelvic
area lymph nodes was specifically derived from
perineal application.
In another study, McDonald et al. (2019b) mea-
sured talc in lymph nodes, cervix, uterine corpus,
Fallopian tubes, and ovaries of 5 women with