Download Effects of Milk and Milk Products Consumption on Cancer: A Review

Effects of Milk and Milk Products Consumption on
Cancer: A Review
H. Davoodi, S. Esmaeili, and A.M. Mortazavian
Abstract: Milk is considered to be the only foodstuff that contains approximately all different substances known to be
essential for human nutrition. In terms of cancer risk, dairy foods have been reported as both protective and occasionally as
harmful. The evidence that dairy foods can protect against cancer, or increase the risk of cancer is not conclusive. Overall,
the proven health benefits of dairy foods greatly outweigh the unproven harm. Dairy foods should be encouraged as part
of a varied and nutritious diet as they are essential to maintain good bone and dental health, to prevent osteoporosis,
major cardiovascular disease risk factors, hypertension, type-2 diabetes, metabolic syndromes, as well as some cancers.
The Cancer Council and USDA recommend 3 servings of milk and milk products daily. This article reviews the potential
of milk and milk products (its indigenous or exogenous compounds) to inhibit different cancer risks. Also reviewed are
the reports over the years that have suggested milk and the dairy industry as responsible agents for causing cancer.
Introduction
the most important components of the human diet, particularly
in the Western world, and increasingly also in Asia (Tsuda and
others 2000). Milk is considered to be the only foodstuff that contains approximately all different substances known to be essential
for human nutrition (Goodman and others 2002; Laakkonen and
Pukkala 2008). Milk is an important source of protein, calcium,
and the B-group vitamins (thiamin, riboflavin, niacin, vitamin B6 ,
and folate), and provides vitamin A, vitamin C, magnesium, and
zinc as well (Jelen 2005; Miller and others 2007). Carbohydrates
are found in the form of lactose, which is generally considered
to be of low carcinogenicity. Also, approximately 1/3 of the fat
in whole milk is monounsaturated and small amounts of essential fatty acids are provided. Milk is one of the major sources of
conjugated linoleic acid (CLA) in the diet, although it is a minor
component of milk fat (Jelen 2005).
Several milk constituents such as vitamin D, proteins, calcium,
CLA, butyrate, saturated fatty acids, and contaminants such as
pesticides, estrogen, and insulin-like growth factor I (IGF-I) may
be responsible for either a prospective or a harmful association
between dairy products and cancers (McCann and others 2004;
Moorman and Terry 2004; Parodi 2005; Bingham and Day 2006;
Cui and Rohan 2006; Laakkonen and Pukkala 2008). The main
compounds in milk and dairy products that might affect cancer
MS 20121243 Submitted 8/9/2012, Accepted 3/12/2012. Author Davoodi is can be classified in several groups and are shown in Figure 1.
with Dept. of Clinical Nutrition and Dietology, National Nutrition and Food Tech- This article reviews the preventive and inductive effects of dairy
nology Research Inst., Faculty of Nutrition Sciences, Food Science and Technology, products on the risk of cancers.
Cancer is a leading global cause of death and disability, responsible for approximately 7.6 million deaths each year. The fact that
only 5% to 10% of all cancer cases are due to genetic defects and
that the remaining 90% to 95% are due to lifestyle factors (such as
smoking, diet and nutrition, alcohol, physical inactivity, obesity,
and sun exposure), infections, and environmental pollutants provides major opportunities for preventing cancer (La Vecchia and
others 1991). Within the lifestyle factors, it is globally accepted
that nutrition and related factors play an important role in cancer
occurrence (Gonzalez and Riboli 2010). Observational evidence
suggests that approximately 30% to 40% of cancer cases are potentially preventable via modification of nutritional factors and food
consumption patterns (Marmot and others 2007).
Milk and milk products are recognized as functional foods, suggesting that their use has a direct and significant effect on health
outcomes and their consumption correlates with a reduced risk
of numerous cancers (Keri Marshall 2004). Milk and other dairy
products were recognized as important foods as early as 4000 BC,
evidenced by stone drawings from the Sahara desert. It is one of
Shahid Beheshti Univ. of Medical Sciences, P.O. Box 19395-4741, Tehran, Iran.
Author Esmaeili is with Young Researchers Club, Varamin-Pishva Branch, Islamic
Azad Univ., Varamin, Iran. Author Mortazavian is with Dept. of Food Science Preventive Effects of Milk and Milk Products
and Technology, National Nutrition and Food Technology Research Inst., Faculty of Consumption on Cancer
Nutrition Sciences, Food Science and Technology, Shahid Beheshti Univ. of Medical
Sciences, P.O. Box 19395-4741 Tehran, Iran. Direct inquiries to author Mortazavian Effects of indigenous milk ingredients on cancer prevention
The positive effects of indigenous milk and milk products on
(E-mail: [email protected]/[email protected]) and Esmaeili (E-mail:
[email protected]).
cancers and related mechanisms are discussed below and shown in
Figure 2.
C 2013 Institute of Food Technologists®
doi: 10.1111/1541-4337.12011
Vol. 12, 2013 r Comprehensive Reviews in Food Science and Food Safety 249
Dairy products and cancer . . .
Milk
compounds
Vitamins
Minerals
Exogenous compounds
Indigenous compounds
of milk
of milk
Contaminants
Calcium
Chemical
CLA
Proteins
Omega 3
Functional enriched
compounds
Phytochemical
Probiotics
Synbiotic
Microbial
Vitamin D
Dairy additives
Fats
Heating
Maillard
Irradiation
Bioactive peptides
Lactose
Process-produced
compound
Fermentationproduced compound
IGF-1
Estrogens
Figure 1–Main compounds in milk and dairy products that might affect cancer.
Colorectal cancer
Colorectal cancer is the 3rd most common type of cancer worldwide with about 1.2 million new cases diagnosed in 2008 accounting for 9.7% of all cancers (Ferlay and others 2010). An increased
consumption of milk or dairy products is associated with a significant reduction in colon cancer (Elwood and others 2008). Cho
and others (2004a) conducted a large pooled analysis of data from
10 cohorts (n = 534, 536) from 5 countries and found 4992 individuals diagnosed with colorectal cancer at follow-up. Individuals
who consumed more than a glass of milk (≥250 g)/d had a 15% reduced risk of developing colorectal cancer (relative risk 0.85, 95%
CI 0.78 to 0.94), compared to those who consumed <70 g/d.
Several mechanisms may explain a protective effect of dairy foods
on colorectal cancer risk (Norat and Riboli 2003; Larsson and
others 2005).
The results of the large prospective cohort study showed as inverse association of cancers of the digestive system with dairy food
and calcium in both men and women, especially with colorectal
cancer (Park and others 2009). A variety of studies (epidemiological, animal, laboratory, and clinical trials) indicate that higher
ingestions of calcium and/or dairy foods reduce the risk of colon
cancer (Cho and others 2004a; Chan and Giovannucci 2010).
Calcium intakes of 1200 to 1500 mg/d, or 4 servings of dairy
products per day, seem to be the most protective against colon
cancer (Holick 2008). Dairy products are one of the main dietary
sources of calcium, which has been hypothesized to prevent colon
cancer by binding secondary bile acids and ionized fatty acids and
thus reducing their proliferative effects in the colonic epithelium
(Govers and van der Meet 1993). In addition, it has been shown
that calcium can influence multiple intracellular pathways that lead
to differentiation in normal cells and apoptosis in transformed cells
(Newmark and others 1984; Lamprecht and Lipkin 2001; Fedirko
and others 2009) and that calcium can reduce the number of mu-
tations in the K-ras gene in rat colorectal neoplasms (Llor and
others 1991; Aune and others 2012).
Several clinical trials have reported reduced cell proliferation in
the colon and rectum with intake of calcium and dairy products
(Holt and others 1998; Karagas and others 1998; Holt and others
2001; Ahearn and others 2011). Pooled data of dairy product intake from 10 cohort studies demonstrated a 12% reduction in colon
cancer risk with each 500 mL increase in milk intake. There was
17% reduction in colorectal cancer incidence with the ingestion
of Ricotta cheese greater than 25 mg/d (Cho and others 2004a,
b). Epidemiologic intake and intervention studies have shown that
calcium administration lowers colorectal adenomatous polyps as
well as cancer rates and this effect may be prolonged (Holt 2008).
Furthermore, the results of a case-control study in New Zealand
revealed that daily consumption of milk in childhood may reduce
colorectal cancer incidence, possibly by the action of calcium on
the development of adenoma. Participation in school milk programs was associated with a 2.1% reduction in the odds ratio for
colorectal cancer for every 100 half-pint bottles drunk (1 half-pint
bottle = 284 mL) (Cox and Sneyd 2011).
Most evidence suggests that the effect of calcium is dependent
or partially related to simultaneous vitamin D intake. Vitamin D
may also reduce colon cancer risk independent of the presence of
increased amounts of calcium or dairy products in the diet (Holt
2008). Vitamin D modulates the effects of calcium on colorectal
carcinogenesis (Mizoue and others 2008). The results of a largescale case-control study among a Japanese population found inverse
associations of dietary calcium and vitamin D with colorectal cancer risk that demonstrated dietary modification to increase calcium
intake while maintaining adequate vitamin D status through diet
and moderate sun exposure had large potential in the prevention
of colorectal cancer among Japanese adults (Mizoue and others
2008).
250 Comprehensive Reviews in Food Science and Food Safety r Vol. 12, 2013
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Dairy products and cancer . . .
Milk ingredients
compounds
Cancer
induction
Tumorigenesis
Reducing cellular proliferation
Cancer
prevention
Enhancing cellular differentiation
Inhibiting metastasis
IGF-1
Vitamin D
Inducing apoptosis
Preventing cell adhesion and migration
Increasing
mitotic activity
Increase DNA
replication error
Potential
carcinogenesis
Modulating effect of calcium
Estrogen
Conjugated linolenic acid
Promote markers of
Butyrate
Contaminants
Inducing expression of apoptosis
Cell differentiation
Cellular apoptosis
Cell growth
Increasing
cell division
Activating proto -oncogenes
Lactoferrin
Saturated
fatty acids
Anti-carcinogenic
properties
Calcium
Enhancement of apoptosis
Promotion of cellular differentiation
Except for
prostate cancer
Inactivating tumor
suppresser genes
Protect from toxic bile acid
Reduction in circulation
of vitamin D
Decrease of cell proliferation
Mitigate against the mitogenic and
antiapoptotic effects of PTH
Figure 2–The effects of indigenous milk ingredients on cancers with related mechanisms.
animals and in vitro have shown protective effects of CLA against
carcinogenesis in the mammary gland, potentially by inhibiting
the cyclooxygenase-2 or the lipo-oxygenase pathway or by inducing the expression of apoptotic genes (Kelley and others 2007). In
the Nurses’ Health Study II (Cho and others 2003), women with
a high consumption of low-fat dairy products during their premenopausal years had a nonsignificant negative association with
breast cancer risk. The findings of a meta-analysis of prospective
cohort studies indicated that low-fat, but not high-fat, dairy consumption is associated with a reduced risk of breast cancer and is
broadly in line with current evidence (Dong and others 2011).
Calcium intake has been inversely correlated with reducing the
risk of breast cancer in some prospective studies (Knekt and others
1996; McCullough and others 2005). The finding of a populationbased prospective cohort study showed a negative association between pre- and postmenopausal breast cancer risk and calcium
intake. The results also demonstrated a 50% decreased risk for
premenopausal breast cancer among women consuming 25 g of
white cheese per day compared to women consuming less than
6 g/d (Hjartåker and others 2010). Calcium may exert its anticarcinogenic properties through several mechanisms: a) decreasing
cell proliferation and inducing differentiation of mammary cells
(Cui and Rohan 2006), b) probably binding and neutralizing fatty
acids and mutagenic bile acids (Parodi 2005), and c) decreasing fatinduced epithelial hyperproliferation in rodent mammary glands.
Metabolically, calcium is closely related to vitamin D, which
also has been shown to influence breast carcinogenesis, and it has
been suggested that some of the anticarcinogenic effect of calcium
may be mediated through vitamin D (Cui and Rohan 2006). For
Breast cancer
Breast cancer is the most common cancer with an expected 1.4 instance, calcium may play an important role in 1, 25(OH)2 D (the
million females being diagnosed with breast cancer in 2010 (Dong active form of vitamin D) induced apoptosis (Sergeev 2005). A
and others 2011; Duarte and others 2011). Experimental studies in recent meta-analysis has provided evidence that vitamin D and
Some fat components of dairy products, including CLA and
butyric acid (Liew and others 1995), have been proved to be
protective in experimental studies (Hague and Paraskeva 1995;
Parodi 1997). The results of a Cohort study in Swedish women
showed the women who consumed ≥4 servings of high-fat dairy
foods per day (including whole milk, full-fat cultured milk, cheese,
cream, sour cream, and butter) had a multivariate rate ratio of
colorectal cancer of 0.59 (95% CI: 0.44, 0.79; P for trend = 0.002)
when compared to the women who consumed <1 serving/d.
Each increment of 2 servings of high-fat dairy foods per day
corresponded to a 13% reduction in the risk of colorectal cancer
(multivariate rate ratio: 0.87; 95% CI: 0.78, 0.96) (Larsson and
others 2005).
Casein, which makes up nearly 80% of the protein in cow
milk, has been demonstrated to have anticarcinogenic properties
(Goeptar and others 1997). Casein may protect against colon
cancer by inhibition of enzymes that are produced by intestinal
bacteria and are responsible for deconjugation of procarcinogenic
glucuronides to carcinogens. Moreover, casein protects also against
colon cancer by its effect on the immune system, especially by its
ability to simulate phagocytic activities and increase lymphocytes
(Parodi 1998). Other researchers suggest that the molecular
structure of casein contributes to its anticarcinogenic properties
(MacDonald and others 1994). Moreover, researchers in Australia
reported decreased levels of aberrant crypt foci, precancer markers,
in the proximal colon of rats fed whey protein concentrate and
treated with a chemical carcinogen (Belobrajdic and others 2003).
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Vol. 12, 2013 r Comprehensive Reviews in Food Science and Food Safety 251
Dairy products and cancer . . .
calcium intakes protect against breast cancer, particularly in premenopausal women (Chen and others 2010). The results of a large
cohort study showed women with the highest intake of dietary
calcium (>1250 mg/d) were at a lower risk of breast cancer than
those reporting ≤500 mg/d [RR, 0.80; 95% confidence interval
(95% CI), 0.67 to 0.95; P = 0.02] (McCullough and others 2005).
The results of latter study support the theory that dietary calcium
and/or some other components in dairy products may reduce the
risk of postmenopausal breast cancer.
Proteins and peptides existing in milk have been reported to be
cancer preventive agents (Knekt and others 1996; Tsuda and others
2000; Wakabayashi and others 2006; Rodrigues and others 2008).
For example, lactoferrin (LF) that is also known for its inhibitory
action on cell proliferation as well as for its anti-inflammatory
and antioxidant abilities (Tsuda and others 2002; Ward and others
2005; Rodrigues and others 2008; Iigo and others 2009. LF is
an iron-binding glycoprotein from the transferrin family. In vivo
studies showed that oral administration of bovine LF to rodents
significantly reduces chemically induced carcinogenesis in different
organs (breast, esophagus, tongue, lung, liver, colon, and bladder)
and inhibits angiogenesis (Tsuda and others 2002; Iigo and others
2009). Although the mechanisms of LF action are still not fully
understood, there is evidence representing its ability to interact
with some receptors, as well as to modulate genetic expression
of several molecules that are vital to the cell cycle and apoptosis
machinery.
Ovarian cancer
Ovarian cancer has the highest mortality rate of all the gynecological cancers and is the 4th leading cause of death from
cancer in women (Lefkowitz and Garland 1994). There is great
interest in the possibility that vitamin D might be a broadspectrum antineoplastic substance (Giovannucci 2005). Ovarian
cancer is one of the malignant diseases that has been linked to
vitamin D (Lefkowitz and Garland 1994; Grant 2003). There are
evidences that the ovarian epithelium contains receptors for the
active form of vitamin D (Saunders and others 1992) and in vitro
studies have shown that growth of ovarian carcinoma cells can
be inhibited by vitamin D and its analogues (Saunders and others
1995; Friedrich and others 2003). Dietary studies suggest a role for
vitamin D and calcium in the prevention of ovarian cancer (Toriola
and others 2010). There are biological reasons to suspect that the
active form of vitamin D, 1,25-(OH)2 D (Brommage and Deluca
1985) may be related to ovarian cancer incidence and mortality.
For example, the vitamin D nuclear receptor, which mediates the
effect of 1,25-(OH) 2 D (3 : 34), is found in human ovarian tumor
specimens and cell lines (Saunders and others 1992; Ahonen and
others 2000; Villena-Heinsen and others 2002). Moreover, 1,25(OH)2 D (Brommage and Deluca 1985) inhibits cell proliferation
in ovarian cancer cell lines (Saunders and others 1995; Ahonen
and others 2000) and induces apoptosis (Jiang and others 2004).
An inverse relationship between dietary calcium and ovarian
cancer has been reported in some studies but not all (Kushi
and others 1999; Bidoli and others 2001; Goodman and others 2002; Genkinger and others 2006; Koralek and others 2006;
Park and others 2009). Though the biological processes by which
calcium may influence ovarian cancer are largely unknown, possible mechanisms include: a) the effects of calcium on apoptosis,
cell growth, and proliferation (McConkey and Orrenius 1997;
Ramasamy 2006), b) effects of the calcium receptor (CaR) on
cell proliferation and differentiation (Rodland 2004; Ramasamy
2006) and c) effects of calcium on down-regulating parathyroid
hormone (PTH) production (Grant 2007). Hence, by downregulating PTH production, calcium potentially mitigates against the
mitogenic and antiapoptotic effects of PTH. The findings of a
case-control study indicated that low-fat milk consumption was
inversely associated with risk of ovarian cancer (Toriola and others
2010).
Bladder cancer
Bladder cancer is the 9th most common malignancy worldwide
(Parkin and others 2005). A role of diet and nutrition in bladder carcinogenesis is plausible since most substances or metabolites, including carcinogens, are excreted through the urinary tract
(Vecchia and Negri 1996; Larsson and others 2008). Consumption of milk and dairy products has been associated with decreased
bladder cancer incidence. Meta-analyses of cohort data available
to date support an inverse association between milk intake and
risk of colorectal and bladder cancers (Vecchia and Negri 1996;
Lampe 2011). It has been declared that consumption of skim milk
and fermented milk with a low-fat content is inversely and whole
milk with a high-fat content is positively associated with risk of
bladder cancer (Mao and others 2011). Casein is the major protein in skim milk powder and can display comparative anticancer
activity (McIntosh and others 1995). In laboratory animals, wheycontaining diets have been shown to reduce colon and mammary
cancers (Hakkak and others 2001; McIntosh and Le Leu 2001).
Prostate cancer
Prostate cancer (PCa) is the 2nd leading cause of cancer in
males (Greenlee and others 2000). While genetic factors have been
shown to play a role in the development of hereditary prostate cancer (HPC) (Nwosu and others 2001; Carpten and others 2002;
Rökman and others 2002), the protective effects and/or therapeutic benefits of various dietary substances have only recently
been unraveled (Chan and others 1998; Blumenfeld and others 2000; Schmitz-Drager and others 2001; Schulman and others
2001; Jankevicius and others 2002).
Interest in vitamin D as a preventive agent for prostate cancer
comes from several epidemiologic observations (Jemal and others
2004). Laboratory evidences indicate that high circulating levels of vitamin D and its active metabolite 1,25(OH)2 -vitamin D
(1,25(OH)2 D) (500- to 1000-fold more active than vitamin D)
inhibit prostate carcinogenesis in vitro by reducing prostate cellular proliferation and enhancing cellular differentiation (Reichel
and others 1989; Klein 2005). Also, induced apoptosis (Blutt and
others 2000) prevented cell adhesion and migration (Sung and
Feldman 2000) and inhibited metastasis (Lokeshwar and others
1999), although dietary intakes of dairy products rich in calcium,
which depresses serum level of vitamin D, are associated with a
higher risk of prostate cancer (Thompson and others 2003; Parodi
2009). There are a number of components in milk fat, such as
sphingolipids, CLA, butyric acid, branched-chain fatty acids, and
the fat-soluble vitamins, which in animal models have exhibited
anticancer action (Parodi 1999; Parodi 2008). Milk proteins have
also been shown to have anticancer properties (Parodi 2007).
Various studies indicate that milk protein, such as casein and
especially whey proteins, may protect against some cancers such
as colon, breast, and prostate gland (Parodi 2007). The anticancer
properties of bovine whey proteins may be attributed to their ability to increase cellular levels of glutathione, an antioxidant. Also,
whey proteins may reduce cancer risk by enhancing hormonal and
cell-mediated immune responses (Parodi 1998; Bounous 2000;
Micke and others 2001; Parodi 2001; Eliassen and others 2002;
252 Comprehensive Reviews in Food Science and Food Safety r Vol. 12, 2013
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Dairy products and cancer . . .
Table 1–Selected publications on cancer prevention of indigenous compounds of milk and milk product.
Reference
(Larsson and others 2008)
(Larsson and others 2005)
(Rayes and others 2008)
(Cox and Sneyd 2011)
(Larsson and others 2005)
(Aune and others 2012)
(Alvarez-León and others 2006)
(Cho and others 2004b)
(Cho and others 2004a)
(Thirabunyanon and others 2009)
(Larsson and others 2005)
(Cho and others 2004a)
(Holick 2008)
(Hjartåker and others 2010)
(McCullough and others 2005)
Note
Type of cancer
Women and men who consumed ≥2 servings of cultured milk per
day had a 38% lower risk of bladder cancer than did those who
never consumed cultured milk.
A significantly (53%) decreased risk of death due to bladder cancer
among Japanese men and women who consumed milk almost
every day in comparison with those who consumed 2 servings
milk/month.
Protective effect of natural fermented milk (NFM) containing
Lactobacillus spp. and Bifidobacterium spp. against cancer of the
liver.
Regular daily consumption of milk in childhood may reduce
colorectal cancer incidence. Participation in school milk programs
in New Zealand was associated with a 2.1% reduction (95% C I:
0 .7, 3. 5) in the odds ratio for colorectal cancer for every 100
half-pint bottles drunk (1 half-pint bottle = 284 mL).
Swedish women who consumed ≥4 servings of high-fat dairy foods
per day (including whole milk, full-fat cultured milk, cheese,
cream, sour cream, and butter) had a multivariate rate ratio of
colorectal cancer of 0.59 (95% CI: 0.44, 0.79; P for trend = 0.002)
when compared with the women who consumed <1 serving per
day. Each increment of 2 servings of high-fat dairy foods per day
corresponded to a 13% reduction in the risk of colorectal cancer.
The reduced risk was most pronounced at the higher levels of intake
(equivalent to 2–3 glasses of milk per day).
Consumption of less than a quarter of a glass of milk every day had
15% more risk of colorectal cancer than those who consumed ≥1
glass of milk a day.
12% reduction in colon cancer risk with each 500-mL increase in
milk intake.
17% reduction in colorectal cancer incidence with the ingestion of
ricotta cheese greater than 25 mg per day.
The probiotic strains of E. faecium RM11 and L. fermentum RM28
also triggered antiproliferation of colon cancer cells at the rates
of 21% to 29% and 22% to 29%, respectively.
Each increment of 2 servings of high-fat dairy foods per day
corresponded to a 13% reduction in the risk of colorectal cancer
(multivariate rate ratio: 0.87; 95% CI: 0.78, 0.96).
Consumption of more than a glass of milk (≥250 g) per day had a
15% reduced risk of developing colorectal cancer (relative risk
0.85, 95% CI 0.78 to 0.94), compared to those who consumed
<70 g/d.
Calcium intakes of 1200 to 1500 mg/d, or 4 servings of dairy per
day, seem to be the most protective against colon cancer.
A 50% decreased risk for premenopausal breast cancer among
women consuming 25 g of white cheese per day compared to
women consuming less than 6 g/d. In the analysis, corrected for
measurement errors, an increase of 5 g cheese decreased the risk
24%.
Women with the highest intake of dietary calcium (>1250 mg/d)
were at a lower risk of breast cancer than those reporting
≤500 mg/d.
Walzem and others 2002; Kent and others 2003; Tsuda and others
2010). It has been reported that whey proteins such as lactalbumin, lactoglobulin, lactoferrin, lactoperoxidase, and immunoglobulins exhibit biological effects such as anticarcinogenic activity
(McIntosh and others 1998).
Selected publications on cancer prevention of indigenous milk
and milk product compounds are listed in Table 1.
Effects of Exogenous Milk Compounds on Cancer
Prevention
Functional chemical-enriched compounds
A food can be regarded as “functional” if it is satisfactorily
demonstrated to beneficially affect 1 or more target functions in
the body, beyond adequate nutritional effects (saxelin and others
2003). Fortified-functional dairy products are added-value products in which milk or a milk product is enriched at least with 1
chemical or microbial component with a proven health benefit.
Mineral- and vitamin-enriched milk products are the most important fortified dairy products, as mineral and vitamin deficiencies
are a serious public health problem in many developing countries
C 2013 Institute of Food Technologists®
Type of product
Bladder
Cultured milk
Bladder
Milk
Liver
Fermented milk
Colorectal
Milk and dairy foods
Colorectal
Dairy foods
Colorectal
Milk
Colorectal
Milk
Colon
Milk
Colorectal
Ricotta cheese
Colon
Fermented dairy milks
Colon
High-fat dairy foods
Colorectal
Milk
Colon
Dairy products
Breast
Cheese
Breast
Dietary calcium
and often even occur in industrialized countries. Common mineral and trace element deficiencies involve iron, zinc, selenium,
iodine, and calcium. The most important vitamin deficiencies today are probably those of vitamin A, vitamin D, and folic acid
(Saxelin and others 2003).
Calcium enrichment of food and dairy products is gaining more
and more interest with the increased awareness about the importance of higher calcium intake. Apart from prevention of osteoporosis, adequate calcium intake has been associated with reduced
risk of hypertension, colon cancer, kidney stones, and lead absorption (McCarron and Heaney 2004). Therefore, dried milk
and flavored milk powders are often fortified with vitamins A and
D, calcium, and iron (Singh and others 2007). Although dairy
products are an excellent source of dietary calcium, they can be
further fortified with calcium salts to achieve higher calcium intake per serving (Vyas and Tong 2004). The recommended dietary
allowance for calcium in the United States is 800 and 1200 mg/d
for children and adults, respectively (RDAs and Allowances 1989).
Nowadays, calcium fortification of dairy products such as cheese,
ice cream, skim milk, and yogurt is a common practice.
Vol. 12, 2013 r Comprehensive Reviews in Food Science and Food Safety 253
Dairy products and cancer . . .
Iron deficiency is a common nutritional deficiency worldwide,
affecting mainly older infants, young children, and women of child
bearing age. Dairy products are an important source of nutrients
but are low in iron. Fortification of these products can increase
average dietary iron intake (Zhang and Mahoney 1989). Dairy
products that are often fortified with iron are cheddar cheese,
brown whey cheese, mozzarella cheese, white soft cheese, baker’s
and cottage cheese, Harvatti cheese, yogurt (nonfat and low fat),
and chocolate milk (Zhang and Mahoney 1991; Biebinger and
others 2008).
Zinc is necessary for the activity of over 100 specific enzymes
that are involved in major metabolic pathways, including physical
growth, immune competence, reproductive function, and neurobehavioral development. Zinc-fortified cheddar cheese could be
an excellent food source for replenishment of zinc levels in groups
at risk of zinc deficiency (Biebinger and others 2008; Kahraman
and Ustunol 2012).
Evidence demonstrates that current vitamin D intakes in adults
are inadequate (Vieth 2001). Several studies suggest that higher
serum vitamin D concentrations are associated with lower rates of
breast, ovarian, prostate, and colorectal cancers, as well as decreased
risk of developing multiple sclerosis (Vieth 2001). Therefore, fortification of fluid milk, cheese, yogurt, fermented dairy beverages,
and ice cream with vitamin D3 is an important public health program (Kazmi and others 2007).
Vitamin A is a fat-soluble vitamin and represents a group of
substances necessary for reproduction, cellular differentiation, the
immune system, gene regulation, and eye sight. The fortification
of whole milk with vitamin A is voluntary, whereas fortification
of low fat milk and skim milk is strongly recommended and even
mandatory in some countries because of the removal with cream
of fat-soluble vitamins during centrifugations.
The protective role of folic acid in the reduction of neural
tube defects, coronary heart diseases, and cancer has been recognized (Gangadharan and Nampoothiri 2011). Folic acid has also
been shown to reduce the risk of colorectal and breast cancers
(Prinz-Langenohl and others 2001). Milk and fermented dairy
products represent a good source of natural folate and folatebinding proteins that improve the bioavailability and stability of
folate (Gangadharan and Nampoothiri 2011). Folic acid can be
added successfully in plain yogurt up to the recommended daily
allowance of 400 μg (Boeneke and Aryana 2007).
CLA exerts a strong positive influence on human health, but its
intake is typically too low, and increased consumption of CLA is
recommended. A good way to increase the CLA content in the diet
without a change in eating habits is enrichment of commonly consumed food products with CLA supplements (Rodrı́guez-Alcalá
and Fontecha 2007). Many studies have demonstrated the feasibility of producing CLA-enriched dairy products with acceptable
sensory characteristics and shelf life (Jones and others 2005).
Prebiotic products contain a prebiotic (nondigestible) ingredient that beneficially affects the host by selectively stimulating the
growth and/or activity of colonic probiotic bacteria (Mohammadi
and others 2012). They are not digested in the upper gastrointestinal tract, because of the inability of the digestive enzymes. They are
digested in the colon (Schrezenmeir and de Vrese 2001). The end
products in the gut fermentation are mainly short chain fatty acids
(propionic and butyric acid), lactic acid, acetic acid, hydrogen,
methane, and carbon dioxide. Short chain fatty acids, especially
butyric acid, are known to act as an energy source for enterocytes
(Wollowski and others 2001). Heydari and others (2011) have
investigated the effects of adding different prebiotic compounds
to probiotic yogurt and its chemical, mirobiological, and sensory
characteristics (Heydari and others 2011). Mohammadi and Mortazavian (2010) reviewed the technological aspects of prebiotics in
probiotic fermented milk (Mohammadi and Mortazavian 2010).
Microalgae (cyanobacterial biomass) may be added into fermented milk in order to increase the functional characteristics of
the product (Varga and others 2002). Spirulina and chlorella are
blue–green microalgae that contain high antioxidant constituents,
multiple amino acids, high-quality proteins, Fe, Ca, unsaturated
fatty acids, and many vitamins including A, B2 , B6 , B9 , B12 , E,
and K. They have antiviral, anti-inflammatory, and antitumoral effects and reduce blood lipid profile, blood sugar, body weight, and
wound healing time (Gyenis and others 2005). Beheshtipour and
others (2012) considered adding microalgae to probiotic yogurt
based on its chemical, mirobiological, and sensory characteristics
(Beheshtipour and others 2012).
Functional Microbial-Enriched Compounds
Probiotics
Probiotic products contain at least one living probiotic
strain that beneficially affects the host by improving intestinal microbial balance (Giboson and Roberfroid 1995; Biström
and Nordström 2002. The most common species of bacteria used in probiotic dairy foods include L. acidophilus,
L. johnsonii, L. gasseri, L. crispatus, L. casei, L. paracasei, L. rhamnosus,
L. reuteri, L. plantarum, Bifidobacterium lactis, B. bifidum, B. infantis,
B. breve, B. animalis, and B. adolescentis (Kennedy and Bandaiphet
2004).
There are several epidemiological studies that support the
protective role of probiotics against cancers (Commane and others
2005). Consumption of fermented dairy products with LAB
may elicit antitumor effects. Studies on the effect of probiotic
consumption on cancer appear promising, since recent in vitro
and in vivo studies have indicated that probiotic bacteria may
reduce the risk, incidence, and number of tumors of the colon,
liver, breast, and bladder (de Moreno de LeBlanc and Perdigón
2010; Kumar and others 2010a). The protective impact against
cancer development may be ascribed to binding of mutagens
by intestinal bacteria (Kumar and others 2010a; Kumar and
others 2012). Probiotics may suppress the growth of bacteria
that convert procarcinogenic compounds into carcinogenic
compounds and thereby reducing the amount of carcinogens
in the intestine, reducing the enzymes beta-glucuronidase and
beta-glucosidase and deconjugation of bile acids, or by enhancing
the immune system of the host (de Moreno de LeBlanc and
Perdigón 2010). There are reports that administration of lactic
acid bacteria (LAB) results in increased activity of antioxidative
enzymes or modulating circulatory oxidative stress that protects
cells against carcinogen-induced damage (Burns and Rowland
2000; Hirayama and Rafter 2000; Karimi and others 2011; Kumar
and others 2011; Mohammadi and Mortazavian 2011).
A “symbiotic” product contains both probiotics and prebiotics
that beneficially affect the host by improving the survival and/or
activity of probiotic bacteria in the gastrointestinal tract (Kennedy
and Bandaiphet 2004; Cruz and others 2010). Possible mechanisms by which synbiotics manifest anticancer activity include a
change in gut pH, modulation of immune response, decreased
colonic inflammation, antimutagenic properties, antioxidant
properties, production of antitumorigenic compounds, and reduction of carcinogenic compounds (Cho 2010).
254 Comprehensive Reviews in Food Science and Food Safety r Vol. 12, 2013
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Dairy products and cancer . . .
Fermentation-Produced Compounds
Cancer-Induced Effects of Milk and Milk Products
Fermentation of milk can exert preventive effects on cancer
due to the bacterial cells of starter cultures or their metabolites.
The positive roles of starter cultures are significantly enhanced
when probiotics are used. Fermented dairy products contain live
LAB, and these bacteria and their metabolites have been shown to
modulate the immune response in animals (Kato and others 1994;
Matsuzaki 1998; Kato and others 1999), suppress carcinogenesis
in rodents (Kato and others 1994; Lim and others 2002), inhibit
the activity of enzymes related to carcinogenesis (Spanhaak and
others 1998), and bind mutagenic and carcinogenic heterocyclic
amines (Knasmüller and others 2001). Also, a major component
of milk and milk products that can possibly mediate association
with cancer risk is lactose. The fermentation process leads to a
reduction of the lactose content of milk and an increase in lactic
acid (Keszei and others 2010).
Bioactive peptides can be generated by the starter cultures
used in the manufacture of fermented dairy products. The proteolytic systems of LAB, especially of Lactococcus lactis, Lactobacillus helveticus, and L. delbrueckii ssp. bulgaricus, are well characterized. Some articles have reviewed the release of various bioactive
peptides from milk proteins through microbial proteolysis (Matar
and others 1996; Pihlanto-Leppälä and others 1998). The milkderived bioactive peptides include antithrombotic (Bal dit Sollier
and others 1996), antihypertensive (Seppo and others 2003), immunomodulating (Laffineur and others 1996), antioxidative (Sandrine and others 2001), antimicrobial (Saito and others 1994),
anticancer (Parodi 2007), mineral carrying (Meisel and FitzGerald
2003), and growth-promoting properties (Parodi 2007). In vitro
studies indicate that casein-derived peptides isolated from the microbial fermentation of milk inhibit colon cancer by altering cell
kinetics (MacDonald and others 1994).
The findings of a large prospective study of Swedish women
and men indicated that a high intake of cultured milk was correlated with a significantly lower risk of bladder cancer. Women
and men who consumed ≥2 servings of cultured milk per day
had a 38% lower risk of bladder cancer than did those who never
consumed cultured milk (Larsson and others 2008). The probiotic
strains of E. faecium RM11 and L. fermentum RM28 also triggered
antiproliferation of colon cancer cells at rates of 21% to 29% and
22% to 29%, respectively (Thirabunyanon and others 2009). The
results of a large Japanese case-control study on intake of LAB
suggested that the habitual intake of fermented milk with the
LcS strain reduces the risk of bladder cancer in the population
(Ohashi and others 2002). Numerous studies reported an inverse
correlation between cultured milk consumption and risk of various kinds of cancers such as colon, bladder, liver, and breast (Aso
and Akazan 1992; Tomita and others 1994; Aso and others 1995;
Lim and others 2002; Radosavljević and others 2003; Larsson and
others 2008; Rayes and others 2008; Thirabunyanon and others
2009; Keszei and others 2010; Kumar and others 2010a,b; Ahearn
and others 2011; Kumar and others 2012). LAB ferments lactose of milk into lactic acid (pH reduction) and flavor compounds
such as acetaldehyde and diacetyl. Carbon dioxide is among the
forms of other possible produced compounds. The aforementioned compounds inhibit the growth of most other bacteria
present in a safe and nutritious product. Fermented milk, especially yogurt, is considered to be both safe and nutritious (Fonden
and others 2003). The useful impact of fermented milk on cancer prevention is enhanced by the presence/addition of probiotic
bacteria.
Effects of indigenous milk ingredients on cancer induction
Prostate cancer. A collection of cancer rates and food supply
data from 42 countries revealed that milk was the food most closely
correlated with this cancer incidence (r = 0.711) and mortality (r =
0.766) (Ganmaa and others 2002). A quantitative analysis for the
published cohort studies suggested a statistically significant 10%
increase of prostate cancer risk for the consumption of milk and
dairy products (Qin and others 2007). In addition, a recent metaanalysis of prospective studies reported that men with the highest
intake of calcium had a 39% higher risk of prostate cancer than
those with the lowest intake (Gao and others 2005). These findings suggest that excessive consumption of milk and dairy products
increases the risk of prostate cancer. Gao and others (2005) quantified a dose-response model, indicating that, in adult males, intake
of 3 servings per day of dairy products was associated with about a
9% increase in risk of prostate cancer compared with current (U.S.)
average intake of 1.8 servings per day (a serving equates to 244 g
milk or yogurt, 43 g cheese, 5 g butter, or 132 g ice cream) (Givens
and others 2008). Parodi (2009) indicated that high consumption
of calcium in the diet could be a factor for the role of dairy products in prostate cancer (Parodi 2009).The findings of a case-control
cohort study showed that men who consumed more than 2000 mg
of calcium had a RR of 4.6 (95% CI = 1.9 to 11.0) for metastatic
and fatal prostate cancer compared with men consuming less than
500 mg (Giovannucci and others 1998). As a mechanism, some
researchers proposed that high calcium intake suppressed the conversion of 25(OH) vitamin D to 1,25(OH)2 vitamin D that has an
antitumor effect against prostate cancer (Veierød and others 1997;
Giovannucci 1998; Schuurman and others 1999; Chan and others
2000; Giovannucci and others 2006; Li and others 2007).
Dietary fat has been reported to increase the androgen level
associated with prostate cancer risk (Dorgan and others 1996;
Fleshner and others 2004). Also, high intake of animal fat has
been associated with increased testosterone levels (Dorgan and
others 1996) and this may lead to increased cell division, activation of proto-oncogenes, and inactivation of tumor suppressor
genes (Ross and Henderson 1994); and high testosterone levels
may influence prostate cancer risk (Gann and others 1996). The
results of a population-based prospective study in 43435 Japanese
men indicated that specific saturated fatty acids in dairy foods,
myristic acid and palmitic acid, increased the risk of prostate cancer in a dose-dependent manner (Kurahashi and others 2008).
However, a large prospective study in a prostate cancer screening trial about dairy products also showed that low fat types may
be modestly associated with increased risks for prostate cancer.
The authors argued that removal of fat from milk may remove
other components with potentially cancer-protective properties,
such as CLA. Also, low-fat milk generally contains higher levels of
calcium (Bodner-Montville and others 2006) that, as mentioned
above, may increase the risk of cancer (Ahn and others 2007). Current dietary guidelines for cancer prevention encourage meeting
recommended intake by choosing low-fat or nonfat dairy foods
(Kushi and others 2006). Subgroup analyses of dairy products
such as whole milk, low-fat milk, skim milk, cheese, and yogurt
found that the only significant positive correlation was between
high intake of skim milk and risk of advanced prostate cancer,
with an RR of 1.23 (0.99 to 1.54) (Parodi 2009). A number of
studies found that high intake of skim milk, but not whole milk,
was associated with an increased risk of prostate cancer (Parodi
2009).
C 2013 Institute of Food Technologists®
Vol. 12, 2013 r Comprehensive Reviews in Food Science and Food Safety 255
Dairy products and cancer . . .
Androgens and estrogen are affected by fat intake (Hill and others 1980; Hämäläinen and others 1984). Additionally, milk itself
contains considerable amounts of estrogens due to the fact that
commercial milk is mainly produced by pregnant cows in developed countries. Because 17β-estradiol, an estrogen, is a carcinogen
for prostate cancer, estrogen contained in milk and enhanced by
milk fat should not be ignored when considering milk as a risk factor for prostate cancer (Ganmaa and others 2004; Qin and others
2004a, b).
Cow milk contains high levels of IGF-I that plays an important
role in the regulation of cell proliferation, differentiation, apoptosis, and neoplasia (Jones and Clemmons 1995; Yu and Rohan 2000;
Jerome and others 2003; Pollak and others 2004), and may contribute to prostate cancer risk (Cadogan and others 1997; Holmes
and others 2002; Renehan and others 2004; Hoppe and others
2006; Parodi 2009). In a human study, plasma IGF-I concentration increased by 10% when healthy subjects consumed cow milk
(Heaney and others 1999). The high levels of estrogen and IGF-I
in milk were considered to be responsible for this effect (Qin and
others 2004b).
Ovarian cancer. The results of an experiment conducted with
a Swedish mammography cohort showed a correlation between
ovarian cancer risk and the quantity of milk consumed. Women
who consumed ≥4 servings of total dairy products per day doubled
their risk of ovarian cancer compared to women who consumed
<2 servings per day. Similarly, women who consumed ≥2 g glasses
of milk per day had double the risk of ovarian cancer compared to
women who never or seldom drank milk (Farlow and others 2009).
Also, the findings of cohort studies in a meta-analysis indicated a
10% to 15% increase in ovarian cancer risk per glass of milk drunk
per day. Although this result raises concern about the possible
causal link of dairy foods with ovarian cancer, more research is
needed.
Dairy foods and their constituents (lactose) have been hypothesized to possibly promote ovarian carcinogenesis. Although casecontrol studies have reported conflicting results for dairy foods
and lactose, several cohort studies have shown positive associations
between skim milk, lactose, and ovarian cancer (Genkinger and
others 2006). Also, results of case-control studies showed that lowfat milk consumption was inversely related and whole milk consumption positively associated with risk of ovarian cancer (Larsson
and others 2006a).
It has been proposed, on the basis of animal models and ecological studies, that consumption or metabolism of lactose may increase
the risk of ovarian cancer (Larsson and others 2006a). There are
studies suggesting a positive association between lactose intake and
ovarian cancer risk (Fairfield and others 2004, Larsson and others
2004). Lactose is a disaccharide found solely in milk and milk
products; it is cleaved by intestinal lactase to produce galactose and
glucose (Larsson and others 2006a). Galactose has been postulated
to increase the risk of ovarian cancer by its direct toxicity to the
ovarian germ cells and by causing gonadotropin levels to increase,
thereby stimulating the proliferation of the ovarian epithelium
eventually inducing ovarian neoplasia (Harlow and others 1991;
Cramer and others 1994). It is possible that high intake of dairy
foods and, consequently, of lactose increases the risk of ovarian
cancer only in certain subgroups of the population, such as those
with specific genetic or biochemical features of galactose (lactose
metabolite) metabolism (Larsson and others 2006a). Animal models have shown that high dietary galactose causes ovarian toxicity
(Swartz and Mattison 1988; Reichardt and Woo 1991). Furthermore, hypogonadism or ovarian failure occurs frequently among
women with galactosemia (Kaufman and others 1981) that arises
from an autosomal recessive defect in the galactose-1-phosphate
uridyl transferase (GALT) gene (Larsson and others 2006a). Impairment of the GALT gene might lead to an accumulation of
galactose and other metabolites in the body, including the ovaries
(Larsson and others 2006a).
The results of a pooled analysis of 12 cohort studies showed
that higher lactose intakes comparing ≥30 compared with 10 g/d
were associated with a statistically significant higher risk of ovarian
cancer, although the trend was not statistically significant (pooled
multivariate relative risk, 1.19; 95% confidence interval, 1.01 to
1.40; P trend = 0.19) (Genkinger and others 2006). This study
showed a modest elevation in the risk of ovarian cancer for lactose
intake equivalent to 3 or more servings of milk per day. The findings from prospective cohort studies, but not case-control studies,
revealed that high intakes of dairy foods and lactose may increase
the risk of ovarian cancer (Larsson and others 2006a).
Breast cancer. The major hypotheses that suggest an increased
risk of breast cancer risk associated with the consumption of dairy
products include the following:
(1) A high consumption of dairy products may reflect an overall
high dietary fat intake, particularly saturated fat, which, in
turn, has been associated with breast cancer risk. Total dairy
intake was nonsignificantly associated, and high-fat dairy
intake was positively associated with risk (Parodi 2005). Although not all dairy products have a high-fat content, a high
consumption of dairy products may be associated with overall high dietary fat intake (Terry and others 2001). Total fat
consumption has been thought to increase breast cancer risk
by increasing circulating estrogen concentrations, although
the evidence to prove this is weak (Holmes and others 1999;
Wu and others 1999). This claim was supported by experimental data in rodents and cell lines (Welsch 1992). Although several recent large prospective cohort studies have
documented a positive association between saturated fat
consumption and breast cancer (Thiébaut and others 2007;
Sieri and others 2008), epidemiologic studies, particularly
prospective cohort studies, have not shown that dietary fat
increases breast cancer risk (Lee and Lin 2000).
(2) Presence of organochlorines. It seems unlikely that the
occasionally high (but still legally allowed) presence of
organochlorines in dairy products could plausibly be linked
to breast cancer (Moorman and Terry 2004).
(3) Milk may contain growth factors, such as IGF-I, which
have been shown to promote breast cancer cell growth (Lu
and others 2001). In addition, experiments have shown that
IGF-I is likely to be involved in cell transformation because
removing or blocking IGF-I receptors from the cell membrane can abolish viral or cellular oncogene-induced malignant transformation (Lu and others 2001). Moreover, estrogens have been implicated in cancer at hormone-responsive
sites, such as the mammary glands, ovaries, endometrium,
and prostate gland in males (Parodi 2012). Modern genetically improved dairy cows continue to lactate throughout
almost the entire pregnancy. Hence, recent commercial cow
milk contains large amounts of estrogens and progesterone
(Ganmaa and Sato 2005). Estrogen metabolites (EMs) are
considered to be risk factors for multiple reasons: a) increased exposure to EM leads to increased mitotic activity
of endometrial cells, b) increased exposure leads to an increase of DNA replication errors, and c) somatic mutations
often result in a malignant phenotype (Ganmaa and Sato
256 Comprehensive Reviews in Food Science and Food Safety r Vol. 12, 2013
C 2013 Institute of Food Technologists®
Dairy products and cancer . . .
Table 2–Selected publications on cancer induction of indigenous milk and milk product compounds.
Reference
(Qin and others 2007)
(Gao and others 2005)
(Farlow and others 2009)
(Mommers and others 2005)
(Genkinger and others 2006)
(Dong and others 2011)
Note
Type of cancer
A statistically significant 10% increase of prostate cancer risk for the
consumption of milk and dairy products
Intakes of 3 servings per day of dairy products were associated with
about a 9% increase in risk of prostate cancer compared with current
(U.S.) average intakes of 1.8 servings per day (a serving equates to
244 g milk or yogurt, 43 g cheese, 5 g butter, or 132 g ice cream)
Women who consumed ≥4 servings of total dairy products per day
doubled their risk of serious ovarian cancer compared to women who
consumed <2 servings per day
A 10% to 15% increase in ovarian cancer risk per glass of milk drunk
per day.
High intakes of lactose, equivalent to 3 or more glasses (750 g) of milk
per day, may weakly raise the risk of ovarian cancer.
Increased consumption of total dairy products may be associated with a
risk of breast cancer.
2005; Yager and Davidson 2006; Farlow and others 2009).
Recent assays revealed that commercial milk would not
contain more than 5 pg/mL of free estradiol. Estradiol from
dairy products is extensively inactivated in the gastrointestinal tract and only about 5% survives the first pass to the liver
(Parodi 2012). Expected daily estradiol intake from dairy
products represents only about 0.25% of the FAO/WHO
upper acceptable daily intake of exogenous estradiol. Given
the multiple mechanisms cells possess to obtain estradiol for
their function, it is most unlikely that the small amount
of exogenous estradiol provided by dairy products would
influence carcinogenesis at estrogen-responsive sites (Parodi
2012).
Bladder cancer. The potential relationship between consumption of milk or milk products and risk of bladder cancer has been
investigated in several epidemiologic studies since 1980 (Li and
others 2011). However, the findings were contradictory and inconsistent (Li and others 2011). The findings of a large prospective
Dutch cohort study indicated positive association with butter consumption in women with the risk of bladder cancer (Keszei and
others 2010). Mao and others (2011) found that consumption of
whole milk with a high-fat content positively correlated with risk
of bladder cancer. This suggests a role of fat in milk for bladder
cancer risk. However, until now, a comprehensive assessment of
the association between milk or milk product intakes and risk of
bladder cancer has not been reported (Li and others 2011).
Selected publications on cancer induction of milk and milk
product consumption are listed in Table 2.
Effects of Exogenous Milk Compounds on Cancer
Induction
Dairy contaminants
Pesticides. Pesticide residues in milk may have a number of potential sources, including environmental (water, soil, and air drift),
contamination of the animal feed (fodder), or dairy animals in their
direct living environment to protect them against disease vectors
(mites, ticks, and insects). The very first or “pioneer” chemicals investigated since the 1960s were organochlorines (OC) such
as the insecticide 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane
(DDT) and certain organophosphate (OP) insecticides. Consumption of these compounds could lead to some cancers such as breast
cancer (Falck and others 1992; Hunter and Kelsey 1993). Although the applications of modern pesticides in agriculture to
food and forage plants practically do not harm the animals and
bear no risk of significant residues in milk, some residues (which
are now highly regulated) might be found in milk and dairy prod
C 2013 Institute of Food Technologists®
Type of product
Prostate
Milk and products
Prostate
Dairy products
Ovarian
Total dairy
products
Ovarian
Milk
Ovarian
Dairy foods
Breast
Total dairy
ucts. Levels of OC pesticides, potentially contaminating milk via
the environment, have been decreasing over the past decade(s)
and international efforts are underway to further reduce environmental contamination (Fischer and others 2011; Fuquay and Fox
2011). In this relation, most of the developed countries have established maximum residue levels (MRLs) of pesticides in milk and
milk products. Furthermore, heat treatment such as sterilization
and pasteurization showed some degradation of pesticide residues.
OC pesticides are fat soluble, so their residues were found predominantly in high-fat dairy products such as cream and butter.
Reduction of pesticides in yogurt may be due to the heat treatment of milk and the activity of the starter bacteria. Therefore,
generally, the consumption of milk products could be safer than
that of raw milk (Donia and others 2010).
Veterinary drugs. Antimicrobial drugs are administered to treat
bacterial infections or employed prophylactically to prevent spread
of disease, or to augment growth and yield in animals and
animal products. All antimicrobial drugs administered to dairy
animals enter the milk to a certain degree. The most frequently and commonly used antimicrobial drugs are antibiotics
used to combat mastitis-causing pathogens and include penicillins, cephalosporins, tetracyclines, macrolides, aminoglycosides,
quinolones, and polymyxins. A general concern linked to the
widespread use of antimicrobials is the potential development of
antibiotic-resistant pathogens, which may then complicate human
treatment. Also, sensitive individuals may exhibit allergic reactions
to residues of antibiotics and/or their metabolites, as mainly seen
with B-lactam antibiotics (Bhandari and others 2005; Fuquay and
Fox 2011).
Application of hormones to animals may serve a number of
purposes such as increased food production, medical treatment, or
improved reproductivity. It has been suggested that dairy products
that contain hormones (such as IGF-I) could increase breast cancer
risk (Moorman and Terry 2004) . Additionally, investigations have
shown that bovine growth hormone (BGH), which is sometimes
administered to dairy cattle to increase milk production, results in
increased concentrations of IGF-I in cow milk (Prosser and others
1989; Outwater and others 1997; Yu and Rohan 2000).
Melamine. Melamine, a molecule high in nitrogen content,
was illegally added to diluted milk to produce a false high reading of protein content in the standard measurement. Transfer of
melamine from melamine-containing feed to cow’s milk has been
reported. Furthermore, melamine is a minor metabolite of the
pesticide cyromazine and is also used in some fertilizers. Consequently, low levels of melamine can migrate into milk and dairy
products from food contact material. The primary target for the
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Dairy products and cancer . . .
toxic action of melamine is the kidneys and the urinary tract. Levels
of melamine reported in dairy products (including infant formula)
ranged from 0.09 to 6200 mg/kg (Fischer and others 2011).
Mycotoxins. Dairy contamination by mycotoxins can be via
fungus-infested (moldy) feedstuffs consumed by dairy animals.
Aflatoxin M1 (AFM1 ) is the hydroxylated metabolite of aflatoxin B1 (AFB1 ) and can be found in milk and subsequently
in other dairy products when lactating animals are fed with
mold-contaminated feedstuffs. Mammals that ingest aflatoxin
B1 (AFB1 )-contaminated diets excrete amounts of the principal
4-hydroxylated metabolite known as aflatoxin M1 into milk
(Prandini and others 2009).
Aflatoxins are toxic, carcinogenic, and/or teratogenic to humans and animals. AFM1 is relatively stable in raw and processed
milk products and is not destroyed by regular heat treatments including pasteurization. The International Agency for Research on
Cancer (1994) classified AFB1 as a class 1 human carcinogen and
AFM1 as a class 2B possible human carcinogen (Cathey and others
1994; Galvano and others 1996; Moss 2002). AFM1 is cytotoxic,
as demonstrated in human hepatocytes in vitro and its acute toxicity in several species is similar to that of AFB1 . AFM1 can also
cause DNA damage, gene mutation, chromosomal anomalies, and
cell transformation in mammalians cells in vitro, in insects, lower
eukaryotes, and bacteria (Prandini and others 2009). Overall, the
occurrence of AFM1 in milk makes it a particular risk for humans
because it has both chronic and acute effects on human health. The
acute symptoms of aflatoxins include vomiting, diarrhea, pyrexia,
and abdominal pain. The chronic symptoms are related to liver
cancer, hepatitis, jaundice, hepatomegaly, and cirrhosis (Turner
and others 2000). It has been reported that aflatoxins may also
play a role in Reye’s syndrome, kwashiorkor, and suppressing
of the immune system that, in turn, increases disease incidence
(Scudamore 1998).
Other environmental contaminants. Dioxins are formed as
inadvertent by-products in many chemical processes involving
chlorine and in any combustion process. Dioxins are very
potent toxicants. The known toxic effects of dioxin include
dermal toxicity, immunotoxicity, reproductive abnormalities,
teratogenicity, endocrine disruption, and carcinogenicity. Dairy
products contribute about 1/4 to 1/2 to the dietary intake of
total dioxins (Bhandari and others 2005).
Polychlorinated biphenyls (PCBs) are chlorinated hydrocarbons, the manufacture, processing, and distribution of PCBs have
been prohibited in almost all industrial countries since the late
1980s, their entry into the environment may still occur, especially
due to improper disposal practices or leaks from electrical equipment (such as transformers) and hydraulic systems still in use. PCBs
are of great health concern and can cause a variety of adverse effects. PCBs have been classified as probable human carcinogens. In
animal studies, PCBs have exhibited reproductive, developmental, and immunotoxic effects. Therefore, many countries have set
maximum residue limits for PCBs in dairy products (Fischer and
others 2011).
Heavy metals elements find their way into milk through several
routes. Elements such as chromium and nickel from stainless steel
dairy equipment or tin from soldered cans may enter milk through
direct contact. Heavy metals such as cadmium, lead, mercury, and
arsenic are not expected to have any direct contact with milk and
milk products except in accidental cases. For these elements, the
main pathway to milk is through the ingestion of contaminated
feed and water by milk-producing animals (Fischer and others
2011). The findings of previous studies have demonstrated that
long-term, even in low-level, exposure to inorganic arsenic is
related to increased risk of cancer in the lung, skin, bladder, and
possibly, other sites. Also, developmental arsenic exposure may
lead to increases in pancreatic and hematopoietic cancer (Yorifuji
and others 2010, 2011).
Nitrates/nitrites are from other environmental contaminations
that may be found in milk and milk products. Raw milk typically contains 1 to 5 mg/L of nitrate and ≤0.01 mg/L of nitrite.
Postsecretory contamination with nitrate is possible during milk
collection and processing. Nitric acid can be used to sanitize dairy
factory equipment so that inadvertent incorporation of NO3 is
possible. The other significant source of contamination is incoming wash-water or added water used for powder reconstitution
or in other addition in certain products. Hence, modern factories focus on water purification by deionization. Moreover, nitrate
contamination of dried milk products is significantly more likely
indirectly with heated spray dryers as compared to indirect steamheated systems, as a consequence of fuel gas combustion products
responsible for the formation of nitrogen oxides. Also, in the formulation of certain cheeses, nitrate is added in small quantities
(20 to 30 mg/kg bulk milk) to restrict late blowing and defects
associated with bacterial gas formation. However, nitrate in fresh
cheese is very unstable and is rapidly reduced to nitrite by milk
xanthine oxidase and various microbial nitrate reductases during
cheese maturation. Therefore, its content in cheese is typically
very low (Indyk and Woollard 2011). Most previous investigations
into the association between nitrate and nitrite and human cancer
have focused on gastrointestinal cancers, although the relationship
with thyroid cancer risk is biologically plausible (Forman 1989;
Boeing 1991; Van Loon and others 1997). A positive association
between nitrate intake and thyroid cancer was recently reported
in the Iowa Women’s Health Study (Ward and others 2010).
Process-Produced Compounds in Dairy Products
During the processing of milk and milk products, as well as during storage time, numerous compounds are produced or changed
that could associate with different types of cancer. Severe heating in the dairy industry and exposure to sunlight are the most
important factors that could produce changes in dairy ingredients
(such as proteins, fats, carbohydrates, and vitamins) and generate
compounds with carcinogenic and mutagenic potential. Improper
reactions such as pyrolysis, fat oxidation, and the Maillard reaction
can noticeably be intensified by elevated temperatures.
High-fat and creamy dairy products (such as some types of yogurt, cheeses, and desserts) are susceptible to fat auto-oxidation and
photo-oxidation and the oxidation reactions can lead to formation
of free radicals and polymerized compounds that are carcinogenic
(Belitz and others 2004). Severe heat treatments enhance fat oxidation.
The Maillard reaction has considerable consequences on the
quality of heated milk and milk products in terms of color, flavor, and nutritional value, and probable toxic compounds. Also,
some Maillard reaction products can enter oxidative reactions (van
Boekel 1998).
Heat treatments and homogenization of milk causes oxidation of
valuable anticancer CLA through exposure to high temperatures,
high pressures, and reduction of fat globule size (Norgauer 2005).
Cholesterol oxidation products (COPs) are found in dairy products. Published results have suggested that the content of COPs
in milk and dairy products is very small. Formation of COPs in
milk and milk products can only occur under harsh conditions
such as the application of high heating temperatures for a long
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Dairy products and cancer . . .
period or long storage at high temperatures, and in the case of
foods in the dehydrated state or at low water activities. In addition, powdered milk contains oxidized cholesterol, a product that
further contributes to the oxidative stress in those who consume
the milk (Bösinger and others 1993; Guardiola and others 1996;
Linseisen and Wolfram 1998; O’Brien and others 2000). COPs
have many biological effects such as atherogenic (Imai and others
1980), cytotoxic, mutagenic (Sevanian and Peterson 1986), and
carcinogenic (Sieber 2005).
Dairy Additives
Additives such as flavors, colors, sweeteners, antioxidants, and
antimicrobial preservatives could possess toxic side effects when
exceeding their respective permitted dose of consumption per day
(Fuquay and Fox 2011). For instance, brilliant blue FCF, used as
a coloring agent, can induce cancer, malignant tumors, asthma,
and hyperactivity. An acceptable daily intake (ADI) of Brilliant
Blue FCF is 12.5 mg/kg bw/d that has been previously evaluated
by the Joint FAO/WHO Expert Committee on Food Additives
(JECFA 1970) and the EU Scientific Committee for Food (SCF
1975). In 1984, according to the present data set on the absorption,
distribution, metabolism and excretion, genotoxicity, subchronic,
reproductive, developmental and long-term toxicity, and carcinogenicity, the SCF revised the ADI to 10 mg/kg bw/day (SCF
1984; EFSA 2010).
The studies in recent years about long-term administration of
carrageenan that is used as a thickening agent demonstrated that it
can cause intestine mucous membrane damage or ulcerous colonitis, and produce or promote tumor growth. It is necessary to perform more epidemiological and essential studies to evaluate the
safety of carrageenan (Watanabe and others 1978; Aihua 2009).
Frequent consumption of flavored dairy products that contain
sucrose may increase the risk of colorectal cancer by through production of insulin resistance that may be associated with colon
cancer (Slattery and others 1997) and pancreatic cancer by inducing frequent postprandial hyperglycemia, increasing insulin
demand, and decreasing insulin sensitivity (Larsson and others
2006b). Sweeteners such as saccharin and aspartame have been
reported to be carcinogenic agent (affecting the bladder). For instance, they are respected to the bladder cancer (Howe and others
1977), but their definite carcinogenic effect has been disputed and
these sweeteners are allowed to be used in many countries.
Conclusion
Milk and dairy products may have both beneficial and adverse
effects with regard to the risk of different cancers. The evidence
indicating healthful effects of milk and milk product consumption
on prevention of cancers is considerably greater than those representing harmful impacts. In fact, there is certainly no evidence
that milk consumption might increase death from any condition.
The occasional reports about the probable causative effect of milk
or milk product consumption on some types of cancer, such as
prostate cancer, that there is ample convincing evidence through
thousands of years of consumption that shows their definite impact
on health, health maintenance, survival, and longevity. Moreover,
a decisive and conscientious consideration of the relevant literature
reveals that the probable harmful effect of milk and dairy product consumption related to cancer is dose-dependent. Therefore,
harm for normal people could only occur with absolutely excessive and indiscriminate consumption rather than regular moderate
daily intake as advised by nutritionists and products that are grossly
C 2013 Institute of Food Technologists®
(and illegally) contaminated with environmental pollutants or certain toxicants could spell harm to human health.
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