cadmium ( cd ) is often the result of environmental pollution caused by industrial and agricultural activities and it is widely dispersed into the environment ; hence , humans are exposed to it ubiquitously .
an earlier study showed that cd acts as a stressor and leads to metabolic alterations .
humans always come into contact with cd by occupational exposure , smoking , or diet .
however , diet is the primary way cd enters the bodies of those without occupational exposure and who do not live in cd - polluted regions .
it has been reported that dietary cd exposure is mainly from the relatively high cd content of agricultural crops and their products , such as rice , bread , potatoes , and vegetables . after entering the human body ,
the long - time biological effect of cd is that it may be a carcinogen . in 2008
, a population - based cohort study suggested that chronic dietary cd intake could increase risk of hormone - related cancers .
similarly , another population - based prospective cohort study reported that dietary cd intake played an important role in prostate cancer development .
thus , dietary cd intake may be associated with hormone - related cancers . for women
, bc is an estrogen - related cancer , and a laboratory study indicated that cd could malignantly transform breast cells , stimulate breast cell proliferation , and inhibit apoptosis .
the relationship between dietary cd exposure and bc risk has been supported by some observational studies , but the results of these studies were inconsistent [ 1013 ] , hence , a meta - analysis was conducted by cho et al . to clarify these inconsistent results , and
this study found that there was a significant positive relationship between dietary cd intake and bc risk .
recently , 2 recent prospective cohort studies have observed a relationship between dietary cd intake and bc risk ; however , neither of these studies found that dietary cd intake was a risk for bc .
thus , we performed a meta - analysis to update and quantitatively re - assess the association between dietary cd exposure and the risk of bc by summarizing the inconsistent results of all published studies .
thus , we intended to provide the best available evidence as to whether dietary cd exposure is a risk of bc .
we searched pubmed , medline , and embase to identify studies on the relationship between dietary cd exposure and risk of bc , published through september 2014 .
the following search terms were used in the searching strategy :  cadmium  combined with  breast cancer  and  breast carcinoma  .
in addition , references cited within relevant reviews were retrieved , and we contacted the authors for useful information .
we included studies that met the following criteria : 1 ) study designed as case - control or cohort study ; 2 ) the exposure of interest was dietary cd exposure ; 3 ) the outcome was bc incidence ; and 4 ) rr and corresponding 95% ci for the highest compared with the lowest of dietary cd exposure were reported .
initially , we reviewed the titles and abstracts to ascertain reports of interest ; if uncertain , a subsequent full - text assessment was conducted .
we extracted the following contents : the first author s surname , publication year , geographic area , age of the participants , number of cases and participants or controls , study design , range of cd exposure ; rr ( 95% ci ) for the highest vs. the lowest dietary cd exposure and variables used in a multivariate model .
the key components of designs ( e.g. , selection of study populations , ascertainment of exposure and outcome , duration of follow - up ) were used to estimate the quality of primary studies , rather than reporting the aggregate scores .
rr and the 95% ci were used to measure the association of dietary cd exposure and the risk of bc .
homogeneity test was performed with the use of q statistic and i statistic , and subgroups analysis was used to identify the source of heterogeneity .
sensitivity analysis was used to assess the influence of a single study on the overall risk estimate .
publication bias was detected by begg s and egger s test , if the p - value was less than 0.05 , it was considered as statistically significant .
we searched pubmed , medline , and embase to identify studies on the relationship between dietary cd exposure and risk of bc , published through september 2014 .
the following search terms were used in the searching strategy :  cadmium  combined with  breast cancer  and  breast carcinoma  .
in addition , references cited within relevant reviews were retrieved , and we contacted the authors for useful information .
we included studies that met the following criteria : 1 ) study designed as case - control or cohort study ; 2 ) the exposure of interest was dietary cd exposure ; 3 ) the outcome was bc incidence ; and 4 ) rr and corresponding 95% ci for the highest compared with the lowest of dietary cd exposure were reported .
initially , we reviewed the titles and abstracts to ascertain reports of interest ; if uncertain , a subsequent full - text assessment was conducted .
we extracted the following contents : the first author s surname , publication year , geographic area , age of the participants , number of cases and participants or controls , study design , range of cd exposure ; rr ( 95% ci ) for the highest vs. the lowest dietary cd exposure and variables used in a multivariate model .
the key components of designs ( e.g. , selection of study populations , ascertainment of exposure and outcome , duration of follow - up ) were used to estimate the quality of primary studies , rather than reporting the aggregate scores .
rr and the 95% ci were used to measure the association of dietary cd exposure and the risk of bc .
homogeneity test was performed with the use of q statistic and i statistic , and subgroups analysis was used to identify the source of heterogeneity .
sensitivity analysis was used to assess the influence of a single study on the overall risk estimate .
publication bias was detected by begg s and egger s test , if the p - value was less than 0.05 , it was considered as statistically significant .
we initially identified 224 potential articles from the databases . after screening the abstracts and titles ,
most of these were excluded because they were reviews , the exposure or outcome did not relate to our analysis , or they were laboratory studies .
overall , we identified 6 studies involving 321 315 participants and 11 978 cases [ 1013,15,16 ] .
2 were performed in europe , 2 in the usa , and 2 in japan .
in addition , 5 studies were cohort studies [ 1012,15,16 ] and one was designed as case - control study .
five results of these studies were reported by menopausal status in 4 studies , 4 results were conducted in postmenopausal women , and only 1 in premenopausal women .
data of these 6 studies were analyzed in a random - effects model to estimate the relationship between dietary ca exposure and bc risk . in our study , there was no statistically significant positive association between dietary cd exposure and bc , and the combined rr and corresponding 95% ci was 1.01 [ 0.88 , 1.14 ] .
figure 2 presents the results of our meta - analysis . according to menopause status , geographic area , and study design , we conducted subgroup - analysis to identify the source of heterogeneity .
evidence of heterogeneity was also found across the 2 european studies and the cohort design studies .
however , among these 3 subgroups , no significant positive correlation between dietary cd exposure and bc risk was found .
sensitivity analysis was conducted to estimate the influence of each individual study on combined rr by removing 1 study at a time .
the combined rrs were similar with one another , and no single study significantly changed the combined result , which indicated that the result was statistically stable and reliable .
publication bias was detected based in the shape of funnel plots and by begg s and egger s tests .
begg s funnel plot and egger s regression test showed a low probability of publication bias ( p=0.909 ) .
we initially identified 224 potential articles from the databases . after screening the abstracts and titles ,
most of these were excluded because they were reviews , the exposure or outcome did not relate to our analysis , or they were laboratory studies .
overall , we identified 6 studies involving 321 315 participants and 11 978 cases [ 1013,15,16 ] .
2 were performed in europe , 2 in the usa , and 2 in japan .
in addition , 5 studies were cohort studies [ 1012,15,16 ] and one was designed as case - control study .
five results of these studies were reported by menopausal status in 4 studies , 4 results were conducted in postmenopausal women , and only 1 in premenopausal women .
data of these 6 studies were analyzed in a random - effects model to estimate the relationship between dietary ca exposure and bc risk . in our study , there was no statistically significant positive association between dietary cd exposure and bc , and the combined rr and corresponding 95% ci was 1.01 [ 0.88 , 1.14 ] .
according to menopause status , geographic area , and study design , we conducted subgroup - analysis to identify the source of heterogeneity .
evidence of heterogeneity was also found across the 2 european studies and the cohort design studies .
however , among these 3 subgroups , no significant positive correlation between dietary cd exposure and bc risk was found .
sensitivity analysis was conducted to estimate the influence of each individual study on combined rr by removing 1 study at a time .
the combined rrs were similar with one another , and no single study significantly changed the combined result , which indicated that the result was statistically stable and reliable .
publication bias was detected based in the shape of funnel plots and by begg s and egger s tests .
begg s funnel plot and egger s regression test showed a low probability of publication bias ( p=0.909 ) .
our study did not show a statistically significant positive association between dietary cd exposure and bc risk for the highest compared with the lowest category of dietary cd exposure , and the combined rr(95% ci ) of bc was 1.01 [ 0.88 , 1.14 ] .
heterogeneity appears in a meta - analysis when the included studies have inconsistent conditions . in our study ,
evidence of heterogeneity was observed ; thus , we conducted subgroup - analysis to identify the source of heterogeneity .
table 2 shows that the 2 european studies   were the main source of heterogeneity .
julin et al . adjusted for a wide range of potential confounders for bc : age , height , bmi , education , use of oral contraceptives and postmenopausal hormones , age at menarche , age at first birth , alcohol consumption , glycemic load , total energy intake , and dietary intake of whole vegetables and grains
; however , the danish study of postmenopausal women adjusted for a relatively narrow range , not including age , total energy intake , or dietary intake of whole vegetables and grains .
the relationship between cd exposure and bc risk has been investigated to assess whether cd has any modifying effects on the etiology and process of bc .
these studies investigated women who were exposed to cd occupationally and who lived in cd - polluted areas ; a significant increase in frequencies of bc in cd - exposed women was found by a meta - analysis and systematic review .
however , diet is the primary way cd enters the human body among populations without occupational exposure and who do not live in cd - polluted areas .
the relationship between dietary cd exposure and bc risk also was considered in recent years . in our meta - analysis ,
6 studies on this topic were identified , but the results were inconsistent . in 2012 , adams et al . conducted a cohort study to examine whether dietary cd exposure increased risk of bc , and the result showed no significant association . however , a swedish population - based prospective cohort study including 55 987 participants and 2112 patients showed that dietary cd intake increased risk of postmenopausal bc .
the 2 japanese studies reported no significant positive relationships between dietary cd exposure and bc risk , but the case - control study found a statistically significant association for estrogen receptor - positive tumors among postmenopausal women . in 2013 , a meta - analysis of the relationship between dietary cd intake and cancer risk was conducted by cho et al . , who reported a significant association between dietary cd exposure and bc risk , and found that dietary cd intake increased risk of bc  the rr ( 95% ci ) was 1.15 [ 1.041.28 ] .
however , in 2014 , a prospective cohort study in danish postmenopausal women did not support the above result and reported that dietary cd intake was not linked to the risk of bc or other hormone - related cancers .
similarly , another cohort study indicated dietary cd intake had no statistical association with cancer risk .
thus , we performed a meta - analysis to update and quantitatively re - assess this relationship and we did not find a statistically significant positive association between dietary cd exposure and bc risk .
the subgroup - analysis of our study was conducted at the same time and no significant positive association between dietary cd exposure and bc risk was found in any subgroups .
cd acts as a metallo - estrogen and may play an important role in the estrogenic signaling pathway ; it can malignantly transform breast cells , stimulate breast cell proliferation , and inhibit apoptosis .
in addition , cd also can induce bc by a non - estrogen - related mechanism .
it can change normal breast epithelial cells into a basal - like breast carcinoma characterized by negativity of the er - a and the epidermal growth factor receptor 2 ( her2 ) , leading to reduced expression of bc susceptibility gene 1 , and increasing the expression of cytokeratin 5 and p63 .
although our study did not find a statistically significant positive association between dietary cd exposure and bc risk , many factors that may influence this association should be considered .
reported that iron deficiency led to increased absorption of cd in animal and human studies .
in addition , zinc can limit absorption of cd by decreasing in the intracellular cd accumulation and by the sequestration of cd by cd - induced metallothionein .
second , different types of diet may influence the bioavailability and/or kinetics of dietary cd .
for example , the swedish prospective cohort study showed that the low cd and high whole grain and vegetables intake groups had the lowest risk , but they had the highest risk of bc in relation to diets high in cd and low in whole grains and vegetables , which is why these food have a conflicting roles in the development of bc because whole grains and vegetables are relatively cd - rich foods .
for example , average urine cd concentration in never - smokers was lower than that in smokers . in our study , only 2 investigations reported a relationship between dietary cd exposure and bc risk in smokers and never - smokers , but no study showed a positive association .
our meta - analysis of 6 studies involving 321 315 participants and 11 978 cases improved the statistical power and found a more reliable result of the association between dietary cd exposure and bc risk .
first , other factors may influence this association and the effect of dietary cd exposure on the development of bc .
although most included studies adjusted for a wide range of factors , some studies did not exclude the potential factors .
second , in all included studies , cd exposure was assessed with a food frequency questionnaire ( ffq ) , so measurement error in individual studies might have led to incorrect classification of cd exposure .
third , none of the included studies reported whether the participants lived in a polluted area and , if so , for how long before the primary studies were started .
fourth , the inclusion criteria might induce selection bias and potential publication bias still existed .
fourth , all of our included studies were conducted in developed countries , and other studies in less - developed countries are warranted .
our study did not find a statistically significant positive association between dietary cd exposure and bc risk .
it is necessary to investigate this potential relationship among high - risk groups and more cohort studies based on diverse populations are needed .
 backgrounddiet is the primary way cadmium ( cd ) enters the body in those without occupational exposure and who do not inhabit cd - polluted regions . 
 findings on the relationship between dietary cd exposure and breast cancer ( bc ) risk have been inconsistent ; a meta - analysis has supported this association but 2 recent cohort studies showed inconsistent results . 
 hence , we performed an updated meta - analysis to re - evaluate the association between dietary cd exposure and bc risk.material/methodswe searched pubmed , medline , and embase to identify relevant studies published through september 2014 . 
 combined relative risks ( rrs ) and the corresponding 95% confidence intervals ( cis ) were used to assess the association between dietary cd exposure and bc risk.resultswe identified 6 studies involving 321 315 participants and 11 978 cases . 
 our study suggested there was no statistically significant positive association between dietary cd exposure and bc risk , the combined rr and corresponding 95% ci was 1.01 [ 0.88 , 1.14 ] . 
 the result was not modified by menopause status , geographic area , or study design.conclusionsour study did not find a statistically significant positive association between dietary cd exposure and bc risk . 
 it is necessary to investigate this relationship among the high - risk groups and more cohort studies based on diverse populations are needed . 
Background
Material and Methods
Literature search strategy
Study selection
Data extraction and quality assessment
Data analysis
Results
Literature search and study characteristics
Main analysis
Subgroup-analysis
Sensitivity analysis and publication bias
Discussion
Conclusions