Environment International 108 (2017) 170–175

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Environment International
journal homepage: www.elsevier.com/locate/envint

A role of low dose chemical mixtures in adipose tissue in carcinogenesis MARK

a,b,⁎ c d e,f
Duk-Hee Lee , David R. Jacobs Jr , Ho Yong Park , David O. Carpenter
a
Department of Preventative Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
b
BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Republic of Korea
c
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, United States
d
Department of Breast and Thyroid Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
e
Center for the Elimination of Minority Health Disparities, University at Albany, Albany, NY, United States
f
Institute for Health and the Environment, University at Albany, Rensselaer, NY, United States

A R T I C L E I N F O A B S T R A C T

Keywords: The Halifax project recently hypothesized a composite carcinogenic potential of the mixture of low dose che-
Adipose tissue micals which are commonly encountered environmentally, yet which are not classified as human carcinogens. A
Chemical mixtures long neglected but important fact is that adipose tissue is an important exposure source for chemical mixtures. In
Halifax project fact, findings from human studies based on several persistent organic pollutants in general populations with only
Obesity paradox
background exposure should be interpreted from the viewpoint of chemical mixtures because serum con-
Persistent organic pollutants
Weight loss
centrations of these chemicals can be seen as surrogates for chemical mixtures in adipose tissue. Furthermore, in
conditions such as obesity with dysfunctional adipocytes or weight loss in which lipolysis is increased, the
amount of the chemical mixture released from adipose tissue to circulation is increased. Thus, both obesity and
weight loss can enhance the chance of chemical mixtures reaching critical organs, however paradoxical this idea
may be when fat mass is the only factor considered. The complicated, interrelated dynamics of adipocytes and
chemical mixtures can explain puzzling findings related to body weight among cancer patients, including the
obesity paradox. The contamination of fat in human diet with chemical mixtures, occurring for reasons similar to
contamination of human adipose tissue, may be a missing factor which affects the association between dietary
fat intake and cancer. The presence of chemical mixtures in adipose tissue should be considered in future cancer
research, including clinical trials on weight management among cancer survivors.

1. Introduction in carcinogenic synergies (Goodson et al., 2015).

Traditionally, the carcinogenic potential of chemicals has been
evaluated based on a paradigm of risk assessment of single chemicals,
without regard to possible joint exposure to any other chemical. In the
modern world everyone is exposed to mixtures of many chemicals,
some of which are known to be carcinogenic and others not so identi-
fied. Little has been done to determine whether or not low dose chronic
exposure to chemical mixtures has the potential to increase risk of
cancer.
The Halifax project recently analyzed the carcinogenic potential of
low dose chemical mixtures (Goodson et al., 2015). In the literature-
based review on 85 chemicals which are not currently considered to be
known human carcinogens based on single chemical risk assessment,
they found that each of these chemicals met some of the “hallmarks of
cancer” criteria (Hanahan and Weinberg, 2000; Hanahan and
Weinberg, 2011), and concluded that the cumulative effects of in-
dividual chemicals acting on different pathways could plausibly result
Risk factors for cancer in humans are commonly classified into
personal lifestyle factors and occupational/environmental pollutants.
Compared to lifestyle factors such as cigarette smoking, overweight,
diet, and physical inactivity, the role of pollutants is generally con-
sidered to be minor (Doll and Peto, 1981; Peto, 2001). Notably, all
these lifestyle factors are directly or indirectly related to the exposure to
low dose chemical mixtures. Cigarette smoking clearly consists of ex-
posure to chemical mixtures. However, it is largely unrecognized how
other lifestyle factors are related to the exposure to low dose chemical
mixtures. In particular, human adipose tissue plays a role as an en-
dogenous reservoir of chemical mixtures (Lee et al., 2017). Obesity
research without consideration of chemical mixtures in adipose tissue
was recently criticized; reevaluation of obesity-related diseases from
the viewpoint of chemical mixtures is an important research gap (Lee
et al., 2017).
The purpose of this article is to discuss the role of adipose tissue as a
storage site for low dose chemical mixtures and the importance of

⁎
Corresponding author at: Department of Preventive Medicine, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea.
E-mail address: lee_dh@knu.ac.kr (D.-H. Lee).

http://dx.doi.org/10.1016/j.envint.2017.08.015
Received 19 June 2017; Received in revised form 7 August 2017; Accepted 23 August 2017
0160-4120/ © 2017 Published by Elsevier Ltd.
D.-H. Lee et al.
chronic release of chemical mixtures from adipocytes to the circulation
in carcinogenesis and prognosis of cancer patients. In fact, human
evidence on the carcinogenic potential of low dose chemical mixtures
may be illuminated through investigations of the interrelationship be-
tween obesity and low dose chemical mixtures. However, traditional
epidemiological studies based on the direct measurement of many
chemicals in bio-specimens and their associations with cancer outcomes
have several critical methodological issues which will be discussed
below. We also discuss how diet and physical inactivity are related to
low dose chemical mixtures.
2. Low dose chemical mixtures act as a potential carcinogen
2.1. The Halifax project
In the Halifax project, 174 scientists from 28 countries evaluated the
carcinogenic potential of 85 non-carcinogenic chemicals, using 11 well-
known cancer hallmarks which govern the transformation of normal
cells to cancer cells (Hanahan and Weinberg, 2000; Hanahan and
Weinberg, 2011). These hallmarks included genetic instability, tumor-
promoting inflammation, sustained proliferative signaling, insensitivity
to antigrowth signals, resistance to cell death, angiogenesis, tissue in-
vasion and metastasis, the tumor microenvironment and avoiding im-
mune destruction. The chemicals include some persistent chemicals,
other organic chemicals having varying lipophilicity that are not so
persistent, and some heavy metals.
In the final report, they concluded that each of the individual che-
micals affected one or more crucial cancer hallmarks and therefore the
mixture of 85 chemicals affected all cancer hallmarks (Goodson et al.,
2015). These environmental chemicals are thought to contribute to
carcinogenesis through epigenetic and non-genotoxic effects, which
would commonly be missed in a mutation-based risk assessment process
(Miller et al., 2017).
These 85 chemicals were selected as prototypical in the environ-
ment rather than for a specific carcinogenic suspicion of each chemical.
Thus, the findings from the Halifax project are not confined to these 85
chemicals, but apply to general chemical mixtures which are commonly
encountered from the environment. Also, as the doses of chemicals are
mostly within the range of typical human exposures, the Halifax Project
conclusion suggests that chronic exposure to low dose chemical mix-
tures might act as a carcinogen in humans (Goodson et al., 2015).
Under the current paradigm of chemical carcinogenesis, mutageni-
city of chemicals is considered the most important feature of carcino-
gens. However, replicative spontaneous mutations, unavoidable errors
which arise from DNA replication, are responsible for two-thirds of the
mutations in human cancers (Tomasetti and Vogelstein, 2015). If this is
the case, chronic exposure to chemical mixtures which affect processes
of proliferation or progression through epigenetic modulation may play
a more important role in the development of cancers in humans than
the exposure to individual carcinogens which can induce DNA muta-
tions.
2.2. Is there direct human evidence about the carcinogenic potential of low
dose chemical mixtures?
Inspired by the result of the Halifax Project, some epidemiologists
may consider human studies with direct measurement of the 85 che-
micals included in the Halifax project in bio-specimens such as blood or
urine and with comparison of cancer risk among different exposure
patterns of these 85 chemicals. Sophisticated statistical tools are often
suggested to approach complex chemical mixtures in human studies
(Taylor et al., 2016). However, there are critical methodological rea-
sons why such an approach may not provide conclusive results.
First, the exposure assessment of many chemicals in humans is often
unreliable due to the short half-lives and ubiquitous exposure sources of
many chemicals. Bisphenol A (BPA), which is related to many cancer
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Environment International 108 (2017) 170–175
hallmarks, was one of the 85 chemicals included in the Halifax Project.
However, human studies of BPA demonstrate a high day-to-day varia-
tion within-person, due to variable exposure and fast clearance (Ye
et al., 2011). Therefore BPA has low reproducibility among repeated
urine collections from the same person. Even 24-hour urine samples
would not accurately estimate the usual exposure status of BPA because
of huge day to day variability of BPA exposure (Ye et al., 2011). Human
studies without reliable exposure assessment have little meaning.
Second, a substantial number of chemicals in the Halifax Project
demonstrated non-linear dose-response patterns. Non-linearity often
leads to inconsistent results in human studies because the exposure
ranges of specific chemicals vary among populations. For example, let
us assume an inverted U-shaped risk association from dose 0 to 100
with the peak risk around dose 50. If population A has exposure range
from dose 10 to 40, samples from that population would show an in-
creasing dose-response relation. On the other hand, little association
would be observed when sampling from population B, which has ex-
posure range from dose 40 to 60. An inverse association would even be
possible in samples from a population C with exposure range from dose
50 to 100. This example is a hypothetical case with only one chemical.
When there are many chemicals with non-linear dose–response re-
lationships, it would be impossible to reliably predict net effects of
chemical mixture in humans.
Third, the possibility of effects of in-utero and early life exposures
and transgenerational effects means that we may not be able to solve
these puzzles in humans. As biological effects of chemicals during these
critical periods may differ depending on the timing of organ develop-
ment, the precise assessment of chemical mixtures considering the
critical stages of organ development may be more important than the
exposure during adulthood. Although birth cohort studies with several
snapshot measurements are now underway in many countries, we may
not reliably assess the carcinogenic effects of chemical mixtures either
during the critical period or over the whole lifetime. Thus the combi-
nation of low reliability of exposure assessment, non-linear dose re-
sponse relationships and critical windows of development pose sig-
nificant limitations.
Because of these limitations, a traditional epidemiological approach
based on direct measurement of concentrations of chemicals is not
likely to provide reliable evidence concerning the low dose chemical
mixtures hypothesis, regardless of study design and sample sizes. More
detailed discussion on methodological limitations on human studies on
chemical exposure can be found elsewhere (Lee and Jacobs, 2015).
Besides these methodological limitations, there is a more funda-
mental issue concerning the carcinogenic potential of chemical mix-
tures in humans because mixtures can lead to antagonistic effects in
addition to additive and synergic effects. For example, when one che-
mical with proliferative effects is mixed with another chemical with
apoptotic effects, the net effect may be null. Therefore, unlike the
conclusion of the Halifax project based on individual chemical-based
experiments, there is a substantial uncertainty about the carcinogenic
potential of chemical mixtures in humans.
Considering the complexity of these issues, we may need an indirect
alternative approach to test and understand the low dose chemical
mixtures hypothesis. Epidemiological study using the dynamics of
chemical mixtures in adipose tissue is a plausible study design to ad-
dress this hypothesis in humans.
2.3. Adipose tissue as a source of chemical mixtures
Adipose tissue plays an important but neglected role as a source of
exposure to chemical mixtures. Adipose tissue of all living organisms is
widely contaminated with various man-made chemicals (Geens et al.,
2012; Kim et al., 2014; Moon et al., 2012a; Moon et al., 2011; Moon
et al., 2012b). The most well-known class of chemicals in adipose tissue
is persistent organic pollutants (POPs). POPs include several hundred
halogenated compounds with common features such as strong
D.-H. Lee et al.
lipophilicity, resistance to biodegradation, and long half-lives (Lee
et al., 2014). Typical examples of POPs include chlorinated compounds
such as organochlorine pesticides, polychlorinated biphenyls (PCBs),
and dioxins (Lee et al., 2014). In addition, less lipophilic chemicals with
shorter half-lives, such as polycyclic aromatic hydrocarbons, BPA,
synthetic musk compounds, triclosan, nonylphenol, and other pesti-
cides are detected in human adipose tissue (Geens et al., 2012; Moon
et al., 2012b). Therefore, adipose tissue can be seen as an organ storing
various exogenous chemicals that are not easily metabolized and ex-
creted from the body.
Chemicals stored in adipose tissue are slowly released from adipo-
cytes to the circulation where they are in equilibrium with serum lipids
and can be eliminated through metabolism (Needham et al., 1990).
Upon release from adipose tissue, they reach crucial organs in the form
of chemical mixtures. Many chemicals in adipose tissue are currently
classified as carcinogenic, probably carcinogenic, and possibly carci-
nogenic to humans by the International Agency for Research on Cancer
(IARC). Some of these chemicals were specifically included in the Ha-
lifax project. Therefore, if the mixture of 85 non-carcinogenic chemicals
evaluated in the Halifax project can act as a potential carcinogen, we
can reasonably assume that chemical mixtures in adipose tissue, co-
contaminated with human carcinogens, has even more carcinogenic
potential.
2.4. Carcinogenic potential of POPs as a surrogate marker of chemical
mixtures in adipose tissue
Among chemicals mainly stored in adipose tissue, dioxins and PCBs
are currently classified as group 1 carcinogens by IARC. Chemicals
listed as group 1 carcinogens are considered to be “carcinogenic to
humans” based on sufficient evidence from epidemiological studies.
However, one criticism was that human studies on dioxins and PCBs
show more consistent results among general populations with back-
ground low dose exposure, compared to studies performed among oc-
cupationally exposed workers or among people exposed to high levels
of these chemicals due to accident (Golden and Kimbrough, 2009).
In epidemiological studies it is common to select occupationally or
accidentally high exposed persons as the most appropriate study sub-
jects and compare their cancer risks with those of persons not occu-
pationally or accidentally exposed as the reference group. When there
are inconsistent or weak associations in this approach, such research
tends to conclude that there is “insufficient human evidence”. From this
perspective of “the dose makes the poison”, human studies among
general populations with background low dose exposure which reveal
consistent results tend to be simply regarded as resulting from con-
founding or bias. Some have asserted that human studies on dioxins or
PCBs have reported this kind of pattern (Boffetta et al., 2011; Golden
and Kimbrough, 2009).
However, there are reasonable explanations for consistent results
among general populations with background low dose exposure. First of
all, as we discussed above, an inverted U-shaped association can lead to
a strong and consistent association within a population with low ex-
posure while it can show no association within a population with high
exposure.
In addition, the findings from human studies about dioxins and
PCBs from general populations with only background exposure should
be interpreted from the viewpoint of chemical mixtures, rather than
exclusively from the viewpoint of isolated exposure to those specific
chemicals. The reason is that serum concentrations of chemicals such as
dioxins, PCBs and other lipophilic chemicals are highly correlated with
each other in general populations (Porta, 2012; Porta et al., 2012). In
addition, the concentrations of dioxins and PCBs in serum reflect those
in adipose tissue because these chemicals follow common dispersal
patterns in the environment, then upon entering into body are primarily
stored in adipose tissue and slowly released as they are eliminated from
the blood to maintain equilibrium (Needham et al., 1990). As adipose
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Environment International 108 (2017) 170–175
tissue contains many other chemicals besides dioxins and PCBs, human
findings from general populations with background low dose exposure
to dioxins and PCBs can be interpreted as human evidence for the
carcinogenic potential of chronic exposure to low dose chemical mix-
tures.
3. Release of chemical mixtures from adipose tissue during
increased lipolysis
In situations with increased lipolysis of adipocytes, the mobilization
of chemical mixtures from adipose tissue to the circulation will be in-
creased. If mobilized chemical mixtures cannot be efficiently elimi-
nated, they can easily reach critical organs. If we considered only the
mass of fat tissue to be relevant to health, it would seem paradoxical
that examples of this situation are (1) obesity and (2) weight loss.
3.1. Obesity
Obesity is an established risk factor for many cancers (Calle and
Kaaks, 2004; Calle et al., 2003). Underlying molecular mechanisms
include insulin resistance, chronic hyperinsulinemia, increased bioa-
vailability of steroid hormones, and localized inflammation, even
though detailed mechanisms vary by cancer site (Calle and Kaaks,
2004).
However, another mechanism linking overweight/obesity to cancer
may be the release of various lipophilic chemicals from adipose tissue
to the circulation and reaching critical organs (Irigaray et al., 2007).
Uncontrolled lipolysis is a phenotype of the dysfunctional adipocyte
which is common among metabolically-unhealthy obese persons
(Saponaro et al., 2015). Therefore, the chronic release of chemical
mixtures from adipose tissue to the circulation during uncontrolled li-
polysis may be a mechanism for high cancer risk among obese persons.
It should be noted that chronic exposure to lipophilic chemical mixtures
such as POPs has recently been linked to the most well-known obesity-
related diseases such as type 2 diabetes and metabolic syndrome (Lee
et al., 2014; Ruzzin et al., 2012).
However, all obese persons do not have dysfunctional adipocytes.
Adipose tissue expansion occurs mainly through two mechanisms; in-
creasing adipocyte number (hyperplasia) and/or increasing adipocyte
size (hypertrophy). Hypertrophic, rather than hyperplastic, adipocytes
are more related to adipose tissue dysfunction with uncontrolled lipo-
lysis (Weyer et al., 2000). Therefore, hypertrophy-dominant obesity is
more relevant to the relation between obesity and cancer while hy-
perplasia-dominant obesity without uncontrolled lipolysis may reflect a
phenotype of metabolically healthy obesity. This feature may at least
partly explain why metabolically healthy overweight/obese adults have
a lower cancer risk than overweight/obese adults with metabolic dys-
function (Moore et al., 2014).
A key may be whether or not adipocytes can safely store POPs and
release POPs to circulation in a controlled way. From the viewpoint of
chemical mixtures, if the adipocytes function properly without un-
controlled lipolysis, more adipose tissue may be beneficial because it is
a larger storage site although the total amounts of chemical are higher
among obese persons than lean persons. The obesity-inducing effects of
chemicals have recently gained attention from researchers, media, and
public (Holtcamp, 2012), but these adipogenesis-promoting effects of
chemicals themselves may not be harmful if they expand a relatively
safe storage site through hyperplasia.
3.2. Weight loss
Shrinkage of adipocytes during weight loss will lead to the release of
POPs from adipose tissue into the circulation (Chevrier et al., 2000;
Tremblay et al., 2004). Blood concentrations following weight reduc-
tion are estimated to increase by 2–4% per kilogram weight loss for
most POPs (Jansen et al., 2017). An animal study also clearly
D.-H. Lee et al.
demonstrated that weight loss redistributed POPs from adipose tissue to
critical organs (Jandacek et al., 2005).
Unintentional weight loss pre-, peri-, and post-diagnosis is often
related to poor prognosis of cancer patients; it is generally interpreted
to be related to low tolerance or response to treatment, severity of
cancer, decreasing performance status, or comorbid conditions
(Andreyev et al., 1998; Dewys et al., 1980). However, the release of
POPs and other chemicals from adipose tissue to the circulation during
weight loss may contribute directly to poor prognosis.
Contrary to unintentional weight loss, intentional weight loss is
generally recommended to overweight and obese cancer survivors,
especially in the case of obesity-related cancers (Azrad and Demark-
Wahnefried, 2014; Protani et al., 2010). However, many observational
studies have reported poorer survival among cancer survivors with
weight loss, especially in those with large weight loss, compared to
those who maintain weight (Bao et al., 2015; Bradshaw et al., 2012;
Caan et al., 2008; Caan et al., 2012; Cespedes Feliciano et al., 2017;
Kroenke et al., 2005; Meyerhardt et al., 2017; Nichols et al., 2009).
Because whether weight loss was intended or not was not accurately
evaluated in most observational studies, this result was usually attrib-
uted to the disease-related unintentional weight loss (Jackson et al.,
2017). From the viewpoint of chemical mixtures, however, even in-
tentional weight loss can have an unexpected downside if POPs and
other chemicals are released from adipose tissue above the body's ca-
pacity to deal with and excrete them.
Even though no randomized controlled trial on the effects of in-
tentional weight loss among cancer survivors has been done yet, ad-
verse health effects after an intensive weight loss program was reported
in some studies, including a large randomized controlled trial among
patients with type 2 diabetes (Look et al., 2013; Wedick et al., 2002).
Therefore, the extent and rate of intentional weight loss should be
controlled to minimize potential harms due to the release of chemicals
from adipose tissue. Elderly survivors need to be especially careful
about weight loss even if it is intentional. The contamination of adipose
tissue with lipophilic chemicals like POPs accumulate with aging (Hue
et al., 2006), but the physiological ability to metabolize and excrete
xenobiotics decreases with age (McLachlan and Pont, 2012). Also,
weight cycling should be avoided even though it is a common result of
intentional weight loss, as chemical concentrations in some critical
organs further increase after weight cycling (Jandacek et al., 2005).
4. Obesity paradox in cancer
While obesity is an established risk factor for many cancers, excess
adiposity around diagnosis has been associated with better prognosis
among cancer patients in some studies (Lennon et al., 2016). This
phenomenon is known as the obesity paradox and is observed in pa-
tients with many diseases (Doehner et al., 2015). The obesity paradox
in cancer is more commonly observed among studies of elderly patients
compared to studies of younger patients (Brunner et al., 2013; Navarro
et al., 2010). Although many methodological issues such as the non-
specific measurement of obesity by using BMI, confounding, detection
bias, and selective survival are suggested as possible reasons for the
obesity paradox (Lennon et al., 2016), the role of adipose tissue as a
storage organ of chemicals has not been considered.
As we discussed above, from the viewpoint of lipophilic chemicals,
healthy adipose tissue may be a protective organ to defend other critical
organs against possible harms of chemicals (La Merrill et al., 2013).
Since lipophilic chemicals from the diet or other sources will be de-
posited primarily in adipose tissue, the larger the adipose tissue pool,
the lower the concentration in serum and critical organs. In this sense, if
this role of adipose tissue becomes more important among patients with
cancer or other diseases, better prognosis among obese patients than
lean patients may be expected.
One prospective study demonstrated that the protective role of fat
mass was observed only among elderly with high serum concentrations
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Environment International 108 (2017) 170–175
of POPs, not those with low serum concentrations of POPs (Hong et al.,
2012). A possible interpretation of these findings is that the importance
of adipose tissue as a storage site of POPs increases as the POPs burden
in the circulation increases. The fact that the obesity paradox was ob-
served among elderly cancer patients with high body burden of che-
micals (Brunner et al., 2013; Navarro et al., 2010), but not among
younger cancer patients, also supports the hypothesis that chemical
release can help explain the obesity paradox in cancer.
5. Health behaviors and chemical mixtures
5.1. Diet, chemical mixtures, and cancer
The major external exposure source of chemical mixtures is POPs-
contaminated fatty animal food such as meat, fish, and dairy products
(Lee et al., 2014). Therefore research on diet and cancer should con-
sider chemical mixtures. Although the association between dietary fat
intake and several common cancers such as colorectal, breast, ovary,
and prostate cancers received its strongest support from correlation or
migration studies based on populations, individual-based epidemiolo-
gical studies have reported inconsistent or weak results (Willett, 1998).
These inconsistent results are commonly attributed to differential
effects by type of fat (Saadatian-Elahi et al., 2004) or measurement
error in diet assessment (Bingham et al., 2003). Epidemiological studies
on fat intake have often focused on effects of specific fats (saturated,
trans, monounsaturated, and polyunsaturated). However, the con-
tamination with chemical mixtures may be an important missing factor
which significantly affects the association between dietary fat intake
and cancer. This could explain why there is little association in in-
dividual-based studies, but strong associations in population-based
studies. When there is a non-linear dose response relationship between
chemical exposure and cancer, weak or little associations among in-
dividual-based studies would be expected, despite the clear associations
among population-based studies.
Diets of laboratory animals are also widely contaminated with
chemical mixtures (Mesnage et al., 2015). When 13 rodent diets from 9
countries on 5 continents representative of diets used in academic re-
search and regulatory assessment were investigated, all were con-
taminated with pesticides, heavy metals, dioxins, and PCBs, with large
variability in the contents and amounts. The high incidence of tumors
and the fluctuation of tumors over years in control F344 rats from the
same breeders in carcinogenicity studies (Kuroiwa et al., 2013) may be
explained by the presence of diverse chemical mixtures in rodent diets.
5.2. Physical inactivity, chemical mixtures, and cancer
Lack of physical activity is a well-established risk factor for many
cancers even though detailed results differ depending on different site-
specific cancers (Lee, 2003). Physical activity also improves prognosis
among cancer survivors (Speck et al., 2010). Although many molecular
mechanisms can explain benefits of physical activity (Friedenreich,
2001), the role of chemical mixtures has been little considered.
Physical inactivity is closely related to the exposure to chemical
mixtures through indirect pathways. First, physical activity can in-
crease the metabolism and elimination of chemical mixtures through
increasing biotransformation enzyme activity in liver (Yiamouyiannis
et al., 1992). Chronic physical activity has been found to substantially
increase the hepatobiliary clearance of endogenous and exogenous
chemicals in animal experiments (Watkins et al., 1994; Yiamouyiannis
et al., 1993).
Second, many chemicals including POPs, heavy metals, bisphenol A,
and phthalate are excreted via sweat during exercise (Genuis, 2011;
Genuis et al., 2012a; Genuis et al., 2012b; Genuis et al., 2011; Genuis
et al., 2016). Supporting this idea, serum concentrations of POPs tended
to be lower in athletes in comparison with values measured among
sedentary obese or lean individuals (Pelletier et al., 2002). Therefore,
D.-H. Lee et al.
physical inactivity can at least partly contribute the development of
cancer by increasing the retention of chemical mixtures.
6. Conclusion
The carcinogenic potential of chemical mixtures may be more im-
portant than that of individual carcinogens in the real world. However,
human studies based on direct measurement of many chemicals in bio-
specimens may fail to detect evidence due to innate methodological
limitations. Instead, we can examine indirect evidence for the carci-
nogenic potential of low dose chemical mixtures using the fact that
adipose tissue serves as an internal exposure source of chemical mix-
tures,
The carcinogenic effects of POPs among general populations should
be interpreted in light of chemical mixtures stored in adipose tissue,
since serum concentrations of POPs in individuals with background
exposure levels reflect the chemical mixture in adipose tissue. Some
forms of obesity and weight loss pose a higher risk of releasing chemical
mixtures from adipose tissue to circulation due to increased lipolysis.
This paradoxical situation can explain some puzzling findings related to
body weight among cancer patients, including the obesity paradox.
Several clinical trials on intentional weight loss among overweight or
obese cancer survivals are ongoing (Villarini et al., 2012), focusing on
the amount and distribution of adipose tissue. However, these trials
should consider the possibility of harm due to the release of chemical
mixtures from adipocytes.
Funding
This work was supported by “The Korean Health Technology R & D
Project” (HI13C0715), funded by the Ministry of Health and Welfare,
and the “Environmental Health Action Program” (2016001370002),
funded by the Korea Ministry of Environment of the Republic of Korea.
Conflict of interest statement
None declared.
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