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A role of low dose chemical mixtures in adipose tissue in carcinogenesis
Environment International 108 (2017) 170–175
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A role of low dose chemical mixtures in adipose tissue in carcinogenesis Duk-Hee Lee
a,b,⁎
c
d
, David R. Jacobs Jr , Ho Yong Park , David O. Carpenter
MARK
e,f
a
Department of Preventative Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Republic of Korea 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 b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Adipose tissue Chemical mixtures Halifax project Obesity paradox Persistent organic pollutants Weight loss
The Halifax project recently hypothesized a composite carcinogenic potential of the mixture of low dose chemicals which are commonly encountered environmentally, yet which are not classified as human carcinogens. A long neglected but important fact is that adipose tissue is an important exposure source for chemical mixtures. In fact, findings from human studies based on several persistent organic pollutants in general populations with only background exposure should be interpreted from the viewpoint of chemical mixtures because serum concentrations 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 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 identified. 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 literaturebased 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 individual chemicals acting on different pathways could plausibly result
⁎
in carcinogenic synergies (Goodson et al., 2015). 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 considered 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 exposure 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 endogenous 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: [email protected] (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.
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hallmarks, was one of the 85 chemicals included in the Halifax Project. However, human studies of BPA demonstrate a high day-to-day variation 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 increasing dose-response relation. On the other hand, little association would be observed when sampling from population B, which has exposure 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 relationships, 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 development, 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 combination of low reliability of exposure assessment, non-linear dose response relationships and critical windows of development pose significant 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 fundamental issue concerning the carcinogenic potential of chemical mixtures in humans because mixtures can lead to antagonistic effects in addition to additive and synergic effects. For example, when one chemical 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 address this hypothesis in humans.
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 between 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 wellknown 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, tumorpromoting inflammation, sustained proliferative signaling, insensitivity to antigrowth signals, resistance to cell death, angiogenesis, tissue invasion and metastasis, the tumor microenvironment and avoiding immune 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 chemicals 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 environment 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 mixtures might act as a carcinogen in humans (Goodson et al., 2015). Under the current paradigm of chemical carcinogenesis, mutagenicity of chemicals is considered the most important feature of carcinogens. 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 mutations. 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 chemicals 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 reasons 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
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 171
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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 mixtures.
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 pesticides 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 excreted from the body. Chemicals stored in adipose tissue are slowly released from adipocytes 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 carcinogenic to humans by the International Agency for Research on Cancer (IARC). Some of these chemicals were specifically included in the Halifax 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, cocontaminated with human carcinogens, has even more carcinogenic potential.
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 increased. If mobilized chemical mixtures cannot be efficiently eliminated, 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 bioavailability 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 lipolysis 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 obesityrelated 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; increasing adipocyte number (hyperplasia) and/or increasing adipocyte size (hypertrophy). Hypertrophic, rather than hyperplastic, adipocytes are more related to adipose tissue dysfunction with uncontrolled lipolysis (Weyer et al., 2000). Therefore, hypertrophy-dominant obesity is more relevant to the relation between obesity and cancer while hyperplasia-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 dysfunction (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 uncontrolled 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.
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 background low dose exposure, compared to studies performed among occupationally 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 subjects and compare their cancer risks with those of persons not occupationally 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 confounding 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 exposure 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
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 reduction are estimated to increase by 2–4% per kilogram weight loss for most POPs (Jansen et al., 2017). An animal study also clearly 172
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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 observed among elderly cancer patients with high body burden of chemicals (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.
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 DemarkWahnefried, 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 attributed to the disease-related unintentional weight loss (Jackson et al., 2017). From the viewpoint of chemical mixtures, however, even intentional weight loss can have an unexpected downside if POPs and other chemicals are released from adipose tissue above the body's capacity to deal with and excrete them. Even though no randomized controlled trial on the effects of intentional weight loss among cancer survivors has been done yet, adverse 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).
5. Health behaviors and chemical mixtures 5.1. Diet, chemical mixtures, and cancer The major external exposure source of chemical mixtures is POPscontaminated fatty animal food such as meat, fish, and dairy products (Lee et al., 2014). Therefore research on diet and cancer should consider 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 epidemiological 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 contamination 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 individual-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 individual-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 research and regulatory assessment were investigated, all were contaminated 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.
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 patients 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 nonspecific 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 deposited 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
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 sitespecific 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 increase 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, 173
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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 important than that of individual carcinogens in the real world. However, human studies based on direct measurement of many chemicals in biospecimens may fail to detect evidence due to innate methodological limitations. Instead, we can examine indirect evidence for the carcinogenic potential of low dose chemical mixtures using the fact that adipose tissue serves as an internal exposure source of chemical mixtures, 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. References Andreyev, H.J., Norman, A.R., Oates, J., Cunningham, D., 1998. Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? Eur. J. Cancer 34, 503–509. Azrad, M., Demark-Wahnefried, W., 2014. The association between adiposity and breast cancer recurrence and survival: a review of the recent literature. Curr. Nutr. Rep. 3, 9–15. Bao, J., Borja, N., Rao, M., Huth, J., Leitch, A.M., Rivers, A., Wooldridge, R., Rao, R., 2015. Impact of weight change during neoadjuvant chemotherapy on pathologic response in triple-negative breast cancer. Cancer Med. 4, 500–506. Bingham, S.A., Luben, R., Welch, A., Wareham, N., Khaw, K.T., Day, N., 2003. Are imprecise methods obscuring a relation between fat and breast cancer? Lancet 362, 212–214. Boffetta, P., Mundt, K.A., Adami, H.O., Cole, P., Mandel, J.S., 2011. TCDD and cancer: a critical review of epidemiologic studies. Crit. Rev. Toxicol. 41, 622–636. Bradshaw, P.T., Ibrahim, J.G., Stevens, J., Cleveland, R., Abrahamson, P.E., Satia, J.A., Teitelbaum, S.L., Neugut, A.I., Gammon, M.D., 2012. Postdiagnosis change in bodyweight and survival after breast cancer diagnosis. Epidemiology 23, 320–327. Brunner, A.M., Sadrzadeh, H., Feng, Y., Drapkin, B.J., Ballen, K.K., Attar, E.C., Amrein, P.C., McAfee, S.L., Chen, Y.B., Neuberg, D.S., Fathi, A.T., 2013. Association between baseline body mass index and overall survival among patients over age 60 with acute myeloid leukemia. Am. J. Hematol. 88, 642–646. Caan, B.J., Kwan, M.L., Hartzell, G., Castillo, A., Slattery, M.L., Sternfeld, B., Weltzien, E., 2008. Pre-diagnosis body mass index, post-diagnosis weight change, and prognosis among women with early stage breast cancer. Cancer Causes Control 19, 1319–1328. Caan, B.J., Kwan, M.L., Shu, X.O., Pierce, J.P., Patterson, R.E., Nechuta, S.J., Poole, E.M., Kroenke, C.H., Weltzien, E.K., Flatt, S.W., Quesenberry Jr., C.P., Holmes, M.D., Chen, W.Y., 2012. Weight change and survival after breast cancer in the after breast cancer pooling project. Cancer Epidemiol. Biomark. Prev. 21, 1260–1271. Calle, E.E., Kaaks, R., 2004. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer 4, 579–591. Calle, E.E., Rodriguez, C., Walker-Thurmond, K., Thun, M.J., 2003. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 348, 1625–1638.
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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 Duk-Hee Lee
a,b,⁎
c
d
, David R. Jacobs Jr , Ho Yong Park , David O. Carpenter
MARK
e,f
a
Department of Preventative Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Republic of Korea 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 b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Adipose tissue Chemical mixtures Halifax project Obesity paradox Persistent organic pollutants Weight loss
The Halifax project recently hypothesized a composite carcinogenic potential of the mixture of low dose chemicals which are commonly encountered environmentally, yet which are not classified as human carcinogens. A long neglected but important fact is that adipose tissue is an important exposure source for chemical mixtures. In fact, findings from human studies based on several persistent organic pollutants in general populations with only background exposure should be interpreted from the viewpoint of chemical mixtures because serum concentrations 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 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 identified. 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 literaturebased 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 individual chemicals acting on different pathways could plausibly result
⁎
in carcinogenic synergies (Goodson et al., 2015). 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 considered 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 exposure 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 endogenous 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: [email protected] (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.
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hallmarks, was one of the 85 chemicals included in the Halifax Project. However, human studies of BPA demonstrate a high day-to-day variation 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 increasing dose-response relation. On the other hand, little association would be observed when sampling from population B, which has exposure 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 relationships, 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 development, 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 combination of low reliability of exposure assessment, non-linear dose response relationships and critical windows of development pose significant 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 fundamental issue concerning the carcinogenic potential of chemical mixtures in humans because mixtures can lead to antagonistic effects in addition to additive and synergic effects. For example, when one chemical 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 address this hypothesis in humans.
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 between 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 wellknown 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, tumorpromoting inflammation, sustained proliferative signaling, insensitivity to antigrowth signals, resistance to cell death, angiogenesis, tissue invasion and metastasis, the tumor microenvironment and avoiding immune 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 chemicals 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 environment 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 mixtures might act as a carcinogen in humans (Goodson et al., 2015). Under the current paradigm of chemical carcinogenesis, mutagenicity of chemicals is considered the most important feature of carcinogens. 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 mutations. 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 chemicals 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 reasons 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
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 171
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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 mixtures.
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 pesticides 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 excreted from the body. Chemicals stored in adipose tissue are slowly released from adipocytes 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 carcinogenic to humans by the International Agency for Research on Cancer (IARC). Some of these chemicals were specifically included in the Halifax 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, cocontaminated with human carcinogens, has even more carcinogenic potential.
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 increased. If mobilized chemical mixtures cannot be efficiently eliminated, 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 bioavailability 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 lipolysis 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 obesityrelated 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; increasing adipocyte number (hyperplasia) and/or increasing adipocyte size (hypertrophy). Hypertrophic, rather than hyperplastic, adipocytes are more related to adipose tissue dysfunction with uncontrolled lipolysis (Weyer et al., 2000). Therefore, hypertrophy-dominant obesity is more relevant to the relation between obesity and cancer while hyperplasia-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 dysfunction (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 uncontrolled 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.
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 background low dose exposure, compared to studies performed among occupationally 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 subjects and compare their cancer risks with those of persons not occupationally 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 confounding 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 exposure 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
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 reduction are estimated to increase by 2–4% per kilogram weight loss for most POPs (Jansen et al., 2017). An animal study also clearly 172
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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 observed among elderly cancer patients with high body burden of chemicals (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.
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 DemarkWahnefried, 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 attributed to the disease-related unintentional weight loss (Jackson et al., 2017). From the viewpoint of chemical mixtures, however, even intentional weight loss can have an unexpected downside if POPs and other chemicals are released from adipose tissue above the body's capacity to deal with and excrete them. Even though no randomized controlled trial on the effects of intentional weight loss among cancer survivors has been done yet, adverse 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).
5. Health behaviors and chemical mixtures 5.1. Diet, chemical mixtures, and cancer The major external exposure source of chemical mixtures is POPscontaminated fatty animal food such as meat, fish, and dairy products (Lee et al., 2014). Therefore research on diet and cancer should consider 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 epidemiological 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 contamination 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 individual-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 individual-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 research and regulatory assessment were investigated, all were contaminated 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.
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 patients 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 nonspecific 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 deposited 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
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 sitespecific 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 increase 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, 173
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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 important than that of individual carcinogens in the real world. However, human studies based on direct measurement of many chemicals in biospecimens may fail to detect evidence due to innate methodological limitations. Instead, we can examine indirect evidence for the carcinogenic potential of low dose chemical mixtures using the fact that adipose tissue serves as an internal exposure source of chemical mixtures, 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. References Andreyev, H.J., Norman, A.R., Oates, J., Cunningham, D., 1998. Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? Eur. J. Cancer 34, 503–509. Azrad, M., Demark-Wahnefried, W., 2014. The association between adiposity and breast cancer recurrence and survival: a review of the recent literature. Curr. Nutr. Rep. 3, 9–15. Bao, J., Borja, N., Rao, M., Huth, J., Leitch, A.M., Rivers, A., Wooldridge, R., Rao, R., 2015. Impact of weight change during neoadjuvant chemotherapy on pathologic response in triple-negative breast cancer. Cancer Med. 4, 500–506. Bingham, S.A., Luben, R., Welch, A., Wareham, N., Khaw, K.T., Day, N., 2003. Are imprecise methods obscuring a relation between fat and breast cancer? Lancet 362, 212–214. Boffetta, P., Mundt, K.A., Adami, H.O., Cole, P., Mandel, J.S., 2011. TCDD and cancer: a critical review of epidemiologic studies. Crit. Rev. Toxicol. 41, 622–636. Bradshaw, P.T., Ibrahim, J.G., Stevens, J., Cleveland, R., Abrahamson, P.E., Satia, J.A., Teitelbaum, S.L., Neugut, A.I., Gammon, M.D., 2012. Postdiagnosis change in bodyweight and survival after breast cancer diagnosis. Epidemiology 23, 320–327. Brunner, A.M., Sadrzadeh, H., Feng, Y., Drapkin, B.J., Ballen, K.K., Attar, E.C., Amrein, P.C., McAfee, S.L., Chen, Y.B., Neuberg, D.S., Fathi, A.T., 2013. Association between baseline body mass index and overall survival among patients over age 60 with acute myeloid leukemia. Am. J. Hematol. 88, 642–646. Caan, B.J., Kwan, M.L., Hartzell, G., Castillo, A., Slattery, M.L., Sternfeld, B., Weltzien, E., 2008. Pre-diagnosis body mass index, post-diagnosis weight change, and prognosis among women with early stage breast cancer. Cancer Causes Control 19, 1319–1328. Caan, B.J., Kwan, M.L., Shu, X.O., Pierce, J.P., Patterson, R.E., Nechuta, S.J., Poole, E.M., Kroenke, C.H., Weltzien, E.K., Flatt, S.W., Quesenberry Jr., C.P., Holmes, M.D., Chen, W.Y., 2012. Weight change and survival after breast cancer in the after breast cancer pooling project. Cancer Epidemiol. Biomark. Prev. 21, 1260–1271. Calle, E.E., Kaaks, R., 2004. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer 4, 579–591. Calle, E.E., Rodriguez, C., Walker-Thurmond, K., Thun, M.J., 2003. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 348, 1625–1638.
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