Environmental exposure to polychlorinated biphenyls and breast cancer risk

Breast cancer is a major public health problem in the United States and in most industrialized countries. Although epidemiologic studies have identified a number of established risk factors for this disease, these factors explain only a small proportion of breast cancer incidence. Environmental exposure has been implicated in breast cancer etiology because of the vast geographic variation in breast cancer incidence rates across countries and regions within countries. Further, the steady increase in breast cancer rates over the past decades points to a potential role of environmental exposure in its development. One suspected environmental factor is the polychlorinated biphenyls (PCBs), which were manufactured commercially for a variety of industrial applications from the 1930s until the 1970s. PCBs have been associated with estrogenic, tumor promoting, and immunosuppressive activities, all of which are relevant in the development of breast cancer. The purpose of this review is to summarize the growing body of epidemiological evidence on the association between environmental PCB exposure and breast cancer risk. Three major types of study design have been used to investigate such a relation: clinic-based case-control studies, retrospective case-control studies, and nested case-control studies. Although findings from clinic-based case-control studies tend to point to an adverse effect of high PCB body burden on risk, the results from the more methodologically sound retrospective and nested studies do not provide strong support for a role of PCBs in breast cancer development. The association between PCB exposure and risk among racially and genetically susceptible subgroups may warrant further investigation. Methodological challenges in the design and analysis of epidemiologic studies on PCBs and breast cancer risk are discussed.     

Assessment of information to substantiate a health claim on the prevention of prostate cancer by lignans

Lignans and their in vivo metabolites, especially enterolactone (ENL), have attracted substantial interest as potential chemopreventive agents for prostate cancer. Preclinical and clinical interventions performed with lignan-rich flaxseed that use surrogate biomarkers as endpoints suggest that lignans may attenuate prostate carcinogenesis in individuals with increased risk or with diagnosed cancer. No unequivocal prostate cancer risk reduction has been found for lignans in epidemiological studies, suggesting that lignan concentrations found in populations consuming a regular non-supplemented diet are not chemopreventive in prostate cancer. Presumably, the main obstacles in assessing the efficacy of food lignans is limited knowledge of the serum and tissue lignan concentrations required for the putative prevention. Further clinical studies performed with the purified compounds are required to substantiate a health claim.     

Pharmacokinetics of enterolignans in healthy men and women consuming a single dose of secoisolariciresinol diglucoside

High concentrations of enterolignans in plasma are associated with a lower risk of acute coronary events. However, little is known about the absorption and excretion of enterolignans. The pharmacokinetic parameters and urinary excretion of enterodiol and enterolactone were evaluated after consumption of their purified plant precursor, secoisolariciresinol diglucoside (SDG). Twelve healthy volunteers ingested a single dose of purified SDG (1.31 micromol/kg body wt). Enterolignans appeared in plasma 8-10 h after ingestion of the purified SDG. Enterodiol reached its maximum plasma concentration 14.8 +/- 5.1 h (mean +/- SD) after ingestion of SDG, whereas enterolactone reached its maximum 19.7 +/- 6.2 h after ingestion. The mean elimination half-life of enterodiol (4.4 +/- 1.3 h) was shorter than that of enterolactone (12.6 +/- 5.6 h). The mean area under the curve of enterolactone (1762 +/- 1117 nmol/L . h) was twice as large as that of enterodiol (966 +/- 639 nmol/L . h). The mean residence time for enterodiol was 20.6 +/- 5.9 h and that for enterolactone was 35.8 +/- 10.6 h. Within 3 d, up to 40% of the ingested SDG was excreted as enterolignans via urine, with the majority (58%) as enterolactone. In conclusion, a substantial part of enterolignans becomes available in the blood circulation and is subsequently excreted. The measured mean residence times and elimination half-lives indicate that enterolignans accumulate in plasma when consumed 2-3 times a day and reach steady state. Therefore, plasma enterolignan concentrations are expected to be good biomarkers of dietary lignan exposure and can be used to evaluate the effects of lignans.     

CYP17 genotype modifies the association between lignan supply and premenopausal breast cancer risk in humans

Cytochrome P450c17alpha (CYP17) has been associated with alterations in steroid hormone levels and premenopausal breast cancer risk and could modify the association between phytoestrogen intake and breast cancer risk. We examined plasma concentrations of enterolactone and genistein, estimated dietary phytoestrogen intake, CYP17 5'-UTR MspA1 genetic polymorphism, and breast cancer risk in 267 premenopausal breast cancer patients and 573 age-matched population controls from Germany. Multivariate logistic regression was used to estimate breast cancer risk associated with quartiles of phytoestrogen intake by genotype and to investigate gene-nutrient interactions. Premenopausal breast cancer risk was not significantly associated with the CYP17 A2 genotype. We observed a significant modifying effect of CYP17 genotype on plasma enterolactone-associated breast cancer risk (P for interaction < 0.01). Plasma enterolactone was significantly inversely related to breast cancer risk only in A2A2 carriers, showing odds ratios and 95% CI of 0.02 (0.00-0.41) and 0.01 (0.00-0.21) for the third and fourth quartiles vs. the lowest quartile, respectively. This inverse association was also found for the calculated enterolignan production as well as matairesinol intake. Compared with A1A1 carriers with the lowest enterolactone supply, the risk reduction associated with a high enterolactone supply resulted in a comparably decreased breast cancer risk for all genotypes. For genistein, no clear indication for a differential effect by CYP17 genotype was obtained. Our results suggest that CYP17 genotype modifies the protective effect of lignans on premenopausal breast cancer risk. Women homozygous for A2 allele benefit most from high plasma enterolactone concentrations and a high consumption of dietary precursors.     

The risk of breast cancer associated with dietary lignans differs by CYP17 genotype in women

Lignans are plant compounds metabolized in the gut to produce the phytoestrogens enterolactone and enterodiol. Reduced breast cancer risks associated with higher urinary lignan excretion may be related to competitive inhibition of endogenous estrogens. Evidence exists that associations with reproductive risk factors for breast cancer differ according to cytochrome P450c17alpha (CYP17) genotype. Genetic variability in estrogen metabolism could affect lignan metabolism thereby modifying risk associations. We examined breast cancer risk, dietary lignans and CYP17 genotype among 207 women with primary, incident, histologically confirmed breast cancer and 188 controls frequency matched to cases by age and county of residence. Self-reported frequency of intake of 170 foods and beverages during the 2 y before the interview and other relevant data were collected by detailed in-person interviews. Dietary lignan intake was expressed as the sum of enterolactone and enterodiol production from foods. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression, adjusting for age, education and other breast cancer risk factors. Women in the highest tertile of dietary lignans tended to have reduced breast cancer risk (OR 0.45, 95% CI 0.20-1.01 and OR 0.59, 95% CI 0.28-1.27, pre- and postmenopausal women, respectively). Substantially reduced risks in the highest tertile of lignans were observed for premenopausal women with at least one A2 allele (OR 0.12, 95% CI 0.03-0.50). Our results suggest that CYP17 genotype may be important in modifying the effect on breast cancer risk of exogenous estrogens, particularly for premenopausal women.     

Breast cancer and environmental risks: where is the link?

Environmental factors may play an important role in the etiology of female breast cancer. This paper reviews existing evidence to compare and analyze environmental agents in relation to breast cancer. The authors have reviewed multiple studies focusing on xenoestrogens, organochlorines, polychlorinated biphenyls, and other environmental agents, and the results are cited. Current use of oral contraceptives and prolonged use of hormone replacement therapy moderately increase risk. Evidence regarding organochlorine exposure and breast cancer risk is mixed. Atrazine is not associated with breast cancer risk, but dieldrin and lindane are. The effects of polychlorinated biphenyls vary according to specific congeners. An observational study has linked benzene to breast cancer, but another case control study has refuted the association. Risk of breast cancer with smoking is strong in families with a history of breast cancer, ovarian cancer, or both. Studies have shown a positive association of breast cancer with heterocyclic amines in women who eat well-done meat. Thus, many environmental factors have been significantly associated with breast cancer. Differing distribution of socio-demographic factors, including race/ethnicity, parity, and, possibly, nutritional status, may explain some of the inconsistencies across studies. Further research is needed to verify associations.     

Phytoestrogens and prostate cancer risk

BACKGROUND: Phytoestrogens are natural plant substances. The four main classes are isoflavones, flavonoids, coumestans, and lignans. Phytoestrogens have anti-carcinogenic potential. For evaluation of the effect of phytoestrogens on prostate cancer risk, we reviewed analytical epidemiological data. METHODS: Up to now, there are few studies that have assessed the direct relation between the individual dietary intake of soy products and other nutrients with phytoestrogens and the risk of prostate cancer. We decided to review analytical epidemiological studies providing data on (a) dietary soy intake or flavonoids intake, (b) urinary excretion of isoflavones or lignans, or (c) blood measurements of isoflavones or lignans. Soy is used as a marker for isoflavone intake. RESULTS: Overall, the results of these studies do not show protective effects. Only four of these studies are prospective, and none of them found statistically significant prostate cancer reductions. Two prospective studies measured flavonoid intake and one reported a preventive effect on prostate cancer for the assumption of myricetin. One study assessed enterolactone concentrations in three different countries and showed no reduction in prostate cancer occurrence. CONCLUSION: Few studies showed protective effect between phytoestrogen intake and prostate cancer risk.     

Oral contraceptives and breast cancer

An attempt is made to summarize the results of recently conducted epidemiological studies relating to the possible adverse effects of oral contraceptives (OCs) on breast cancer. Evaluation of the safety of OCs is difficult. An important reason is that since preparations were introduced to the American market in 1959 the formulation of pills and the dosage of constituents have both changed markedly. A number of other considerations to be born in mind when evaluating the relevant literature were identified by a recent World Health Organization (WHO) Scientific Group. These include the following: there is usually a considerable latent period between 1st exposure to a carcinogen and the development of overt malignancy; and it is possible that exposure to contraceptive steroids may be particularly important at certain critical periods during reproductive life. After age, the most important risk factors during early life are a young age at menarche and a late age at 1st full term birth. There factors appear to operate independently and so the longer the period between menarche and 1st full term birth, the higher is the risk of breast cancer. A girl whose menarche occurs before age 12 is approximately twice as likely to develop breast cancer later in life as a girl whose menarche occurs after age 14. Similarly, a woman whose first full term birth occurs after age 35 is about 3 times more likely to develop breast cancer than a woman who gives birth before age 20. Nulliparous women have an intermediate risk. Other known risk factors include a family history of breast cancer, a past history of benign breast disease, and increased body weight. Possibly the most serious problem from an epidemiological perspective is the interrelationship between calendar time, age, and OC exposure. OC seems to be clearly associated with a decreased risk of benign breast disease of sufficient severity to require biopsy and the evidence is that the reduction in risk increases with duration of use. The epidemiological evidence available regarding OCs and breast cancer is reassuring. Data have been obtained from case control studies and cohort studies. A table summarizes the main features of 12 case control studies. Results of both groups of studies are reassuring in relation to breast cancer, yet there is usually a long period between exposure to a carcinogen and the development of overt malignancy and OCs have been in widespread use for only a relatively short time. Women who have never used OCs seem to present with more clinically advanced tumors than women who have used them. The differences in staging are reflected in patterns of survival. The difference may be due to a greater awareness of breast disease in OC users, but it could represent a beneficial biological effect of OCs.     

Consumption of dairy products and the risk of breast cancer: a review of the literature

Differences in eating patterns and breast cancer rates across countries suggest that several dietary components, including dairy products, could affect breast cancer risk. However, dairy products are a diverse food group in terms of the factors that could potentially influence risk. Some dairy products, such as whole milk and many types of cheese, have a relatively high saturated fat content, which may increase risk. Moreover, milk products may contain contaminants such as pesticides, which have carcinogenic potential, and growth factors such as insulin-like growth factor I, which have been shown to promote breast cancer cell growth. In contrast, the calcium and vitamin D contents of dairy products have been hypothesized to reduce breast cancer risk. We reviewed the current epidemiologic literature on the relation between dairy product intakes and breast cancer risk, focusing primarily on the results of cohort and case-control studies. Most of the studies reviewed showed no consistent pattern of increased or decreased breast cancer risk with a high consumption of dairy products as a whole or when broken down into high-fat and low-fat dairy products, milk, cheese, or butter. Measurement error may have attenuated any modest association with dairy products. The available epidemiologic evidence does not support a strong association between the consumption of milk or other dairy products and breast cancer risk.     

Factors to Consider in the Association Between Soy Isoflavone Intake and Breast Cancer Risk

It has been suggested that soy isoflavones have protective effects against breast cancer. However, data from epidemiological studies are not conclusive. A recent meta-analysis showed that soy intake was inversely associated with breast cancer risk in Asian but not Western populations, which indicates that protection against breast cancer may require that women consume levels of soy typical in Asian diets. In addition to the amount of soy isoflavones consumed, the form and food source of isoflavones, timing of isoflavone exposure, estrogen receptor status of tumors, and equol-producer status and hormonal profile of individuals may modify the association between soy isoflavone intake and the risk of breast cancer. These factors might explain the heterogeneity of results from studies. This present report contrasts background data from Japanese and Western women to identify the potential modifying of these factors.Key words: breast cancer, soy isoflavones, review     

Prospective Study of Dietary Phytoestrogen Intake and the Risk of Colorectal Cancer

Dietary phytoestrogen intake has been inversely associated with the risk of prostate and breast cancer and might also affect the risk of colorectal cancer. We evaluated the associations between dietary lignan intake, dietary isoflavonoid intake, dietary coumestrol intake, and dietary enterolignans and equol intake, and risk of colorectal cancer. Data from the Women's Lifestyle and Health (WLH) Cohort study was used. The WLH study is a prospective population-based cohort study including 48,268 Swedish women aged 30–49 years at the time of enrolment in 1991–92. Follow-up for colorectal cancer incidence, death, and emigration until the end of 2010 was performed through record linkage to the Swedish Cancer Registry and Total Population Register. During follow-up 206 incident colorectal cancer cases were identified. Cox proportional hazards models were fitted to estimate adjusted risk ratios with 95% confidence intervals. We found no statistically significant association between the intake of dietary lignans, dietary isoflavonoids, coumestrol, or enterolignans and equol, and risk of colorectal cancer. We found no association between dietary phytoestrogen intake and the risk of colorectal cancer. However, since the number of cancer cases was small, our results need to be confirmed. Future studies should investigate colon and rectal cancer separately.     

Early oral contraceptive use and breast cancer: theoretical effects of latency.

Many cancers and other chronic diseases are associated with a long delay between exposure to a putative risk factor and subsequent diagnosis. This presents well recognised problems in the elucidation of suspected risk factors by epidemiological methods. In this paper we discuss the interpretation in epidemiological studies of the effect of a possible risk factor when population exposure is recent and rapidly changing. An important contemporary example concerns the study of early oral contraceptive (OC) use in relation to the subsequent risk of breast cancer. Computer simulations reported here indicate that plausible delays in the manifestation of any effect on breast cancer incidence make it difficult to exclude early OC use as a risk factor for breast cancer, even when large well conducted epidemiological studies show no apparent increased risk. Methods for detecting a 'latent' effect are discussed.     

The relative bioavailability of enterolignans in humans is enhanced by milling and crushing of flaxseed

Flaxseed is one of the richest sources of lignans and is increasingly used in food products or as a supplement. Plant lignans can be converted by intestinal bacteria into the so-called enterolignans, enterodiol and enterolactone. For a proper evaluation of potential health effects of enterolignans, information on their bioavailability is essential. The aim of this study was to investigate whether crushing and milling of flaxseed enhances the bioavailability of enterolignans in plasma. In a randomized, crossover study, 12 healthy subjects supplemented their diet with 0.3 g whole, crushed, or ground flaxseed/(kg body weight . d). Each subject consumed flaxseed for 10 successive days separated by 11-d run-in/wash-out periods, in which the subjects consumed a diet poor in lignans. Blood samples were collected at the end of each run-in/wash-out period, and at the end of each supplement period. Plasma enterodiol and enterolactone were measured using LC-MS-MS. The mean relative bioavailability of enterolignans from whole compared with ground flaxseed was 28% (P < or = 0.01), whereas that of crushed compared with ground flaxseed was 43% (P < or = 0.01). Crushing and milling of flaxseed substantially improve the bioavailability of the enterolignans.     

Flavonoids and cancer prevention: a review of the evidence

The objective of this work is to review data from epidemiological and preclinical studies addressing the potential benefits of diets based on flavonoids for cancer prevention. Flavonoids are subdivided into subclasses including flavonols, flavones, flavanones, flavan-3-ols, anthocyanidins, and isoflavones. Epidemiological studies suggest dietary intake of flavonoids may reduce the risk of tumors of the breast, colon, lung, prostate, and pancreas. However, some studies have reported inconclusive or even harmful associations. A major challenge in the interpretation of epidemiological studies is that most of the data originate from case-control studies and retrospective acquisition of flavonoid intake. Differences in agricultural, sociodemographics, and lifestyle factors contribute to the heterogeneity in the intake of flavonoids among populations residing in the United States, Europe, and Asia. Dose and timing of exposure may influence the anticancer response to flavonoid-rich diets. A limited number of intervention trials of flavonoids have documented cancer preventative effects. Proposed anticancer mechanisms for flavonoids are inhibition of proliferation, inflammation, invasion, metastasis, and activation of apoptosis. Prospective studies with larger sample sizes are needed to develop biomarkers of flavonoid intake and effect. Mechanistic studies are needed to ascertain how flavonoid-rich diets influence gene regulation for cancer prevention.     

Epidemiological appraisal of studies of residential exposure to power frequency magnetic fields and adult cancers.

OBJECTIVES: To appraise epidemiological evidence of the purported association between residential exposure to power frequency magnetic fields and adult cancers. METHODS: Literature review and epidemiological evaluation. RESULTS: Seven epidemiological studies have been conducted on the risk of cancer among adults in relation to residential exposure to power frequency magnetic fields. Leukaemia was positively associated with magnetic fields in three case-control studies. The other two case-control studies and two cohort studies did not show such a link. Brain tumours and breast cancer have rarely been examined by these studies. Based on the epidemiological results, the analysis of the role of chance and bias, and the criteria for causal inferences, it seems that the evidence is not strong enough to support the putative causal relation between residential exposure to magnetic fields and adult leukaemia, brain tumours, or breast cancer. Inadequate statistical power is far more a concern than selection bias, information bias, and confounding in interpreting the results from these studies, and in explaining inconsistencies between studies. CONCLUSIONS: Our reviews suggested that the only way to answer whether residential exposure to magnetic fields is capable of increasing the risks of adult cancers is to conduct more studies carefully avoiding methodological flaws, in particular small sample size. We also suggested that the risk of female breast cancer should be the object of additional investigations, and that future studies should attempt to include information on exposure to magnetic fields from workplaces as well as residential exposure to estimate the effects of overall exposure to magnetic fields.     

Literature review of cancer mortality and incidence among dentists

This review assesses the epidemiological literature describing dentist mortality and cancer incidence risk. In the dental workplace a variety of hazards may have been historically present or currently exist which can impact dentists' long-term health, including their mortality and cancer incidence. The epidemiological literature of dentistry's health outcomes was reviewed with a focus on all cancers combined and cancers of the brain, lung, reproductive organs and skin. Relevant studies were identified using MEDLINE and NIOSHTIC through early 2006 and from references cited in the articles obtained from these databases. Dentist cancer mortality and incidence generally showed a favourable risk pattern for lung cancer and overall cancer occurrence. Nevertheless, several studies reported an increased risk for certain cancers, such as those of the skin and, to a lesser extent, the brain and female breast. These elevated risks may be related to social status or education level, or may alternatively represent the impact of hazards in the workplace. The evidence for an increased mortality or cancer incidence risk among dentists must be interpreted in light of methodological limitations of published studies. Future studies of dentists would benefit from the assessment of specific occupational exposures rather than relying on job title alone.     

An incident case-referent study on plasma enterolactone and breast cancer risk

Summary. Objective: Using a nested case-referent design, we evaluated the relationship between plasma levels of the lignan enterolactone and the risk of developing breast cancer. Methods: 248 cases and 492 referents were selected from three population-based cohorts in northern Sweden. Blood samples were donated at enrolment. All blood samples were stored at −80 °C. Cases and referents were matched for age, date of blood sample and sampling centre. Breast cancer cases were identified through the regional and national cancer registries. Results: Plasma enterolactone was lower among smokers in all cohorts and in subjects with BMI < 23 and BMI > 28 in one of the cohorts. Low plasma concentrations of enterolactone, below the 12.5^th percentile (mean plasma enterolactone 2.9 nmol/l), were associated with an increased risk of breast cancer. Also, high values of plasma enterolactone, above the 87.5^th percentile (mean plasma enterolactone 58.2 nmol/l) were significantly associated with an increased breast cancer risk among women from two cohorts with only incident cases and a higher number of pre-menopausal women. High plasma enterolactone concentrations among older women from a mammary screening project with mostly prevalent cases were associated with a non-significant slightly reduced breast cancer risk. Conclusion: Very low plasma concentrations of enterolactone were associated with an increased breast cancer risk in all three cohorts. In two of the cohorts, with only incident cases, very high plasma concentrations were also associated with an increased breast cancer risk. In the third cohort with mainly screen-detected cases from a mammary screening program, high plasma enterolactone concentrations were associated with a weak decreased breast cancer risk. Received: 4 January 2002, Accepted: 2 July 2002     

Determinants of infant feeding method in relation to risk factors for breast cancer

BACKGROUND: Breastfeeding is considered to be an important factor for maternal and children's health. However, the epidemiological findings related to the effect of breastfeeding on women's health, especially with respect to breast cancer development, are inconsistent. Determinants of infant feeding method may contribute to the inconsistency. METHODS: A total of 24,769 women aged 40-64 in Miyagi Prefecture, Japan, responded to a self-administered questionnaire survey in 1990. Using the data obtained from 22,085 parous women, we calculated odds ratios (ORs) for the choice of "breastfeeding only" during reproductive period. RESULTS: Late age at menarche (> or = 16 years, OR = 1.57) and high body mass index (BMI) at 20 years of age (> or = 24, OR = 1.31) were associated with the choice of breastfeeding only. Late age at birth of first child (> or = 28 years, OR = 0.29), history of breast cancer in mother (OR = 0.68), and high educational level (more than a high school education, OR = 0.53) reduced the possibility of choosing breastfeeding only. CONCLUSION: The results indicate that the choice of infant feeding method is associated with several breast cancer risk factors. Based on this finding, we should construct appropriate breast cancer risk models for parous women and investigate the changes in the effects of breastfeeding and other breast cancer risk factors among these risk models. Especially in a risk model controlling for breastfeeding, the effects of other breast cancer risk factors should be reevaluated. Through comparisons among different risk models, we may find the best-fitted risk model and identify the true effect of breastfeeding.     

Plasma enterolignan concentrations and colorectal cancer risk in a nested case-control study

Enterolignans are biphenolic compounds that possess several biologic activities whereby they may influence carcinogenesis. The authors investigated the association between plasma enterolactone and enterodiol and colorectal cancer risk in a Dutch prospective study. Among more than 35,000 participants aged 20-59 years, 160 colorectal cancer cases were diagnosed after 7.5 years of follow-up (1987-2003). Cohort members who were frequency-matched to the cases on age, sex, and study center were selected as controls (n = 387). Plasma enterodiol and enterolactone were not associated with risk of colorectal cancer after adjustment for known colorectal cancer risk factors (highest quartile vs. lowest: for enterodiol, odds ratio = 1.11, 95% confidence interval: 0.56, 2.20 (p-trend = 0.75); for enterolactone, odds ratio = 1.70, 95% confidence interval: 0.88, 3.27 (p-trend = 0.15)). However, sex (p-interaction = 0.06) and body mass index (p-interaction < 0.01) modified the relation between plasma enterolactone and colorectal cancer risk; increased risks were observed among women and subjects with a high body mass index. The association between plasma enterodiol and colorectal cancer risk was modified by smoking status; risk was increased among current smokers (p-interaction < 0.01). These findings do not support the hypothesis that high plasma enterodiol or enterolactone concentrations are associated with reduced risk of colorectal cancer.