Dietary determinants of cadmium exposure in the Strong Heart Family\nStudy
Urinary cadmium (Cd) concentrations in the Strong Heart Family Study (SHFS) participants are higher than in the general US population. This difference is unlikely to be related to tobacco smoking. We evaluated the association of consumption of processed meats and other dietary products with urinary Cd concentrations in the SHFS, a family-based study conducted in American Indian communities. We included 1725 participants with urine Cd concentrations (standardized to urine creatinine) and food frequency questionnaire data grouped in 24 categories, including processed meat. Median (IQR) urinary Cd concentrations were 0.44 (0.20\xe2\x80\x930.85) \xce\xbcg/g creatinine. The age, sex, smoking, education, center, body mass index, and total kcal adjusted geometric mean ratio (GMR) (95%CI) of urinary cadmium concentrations per IQR increase in each dietary category was 1.16 (1.04\xe2\x80\x931.29) for processed meat, 1.10 (1.00\xe2\x80\x931.21) for fries and chips, 0.87 (0.80\xe2\x80\x930.95) for dairy products, and 0.89 (0.82\xe2\x80\x930.97) for fruit juices. The results remained similar after further adjustment for the dietary categories associated with urinary Cd in the previous model except for fries and chips, which was no longer statistically significant. These findings revealed the potential importance of processed meat products as a dietary source of cadmium.
1. Introduction<!>2.1. Study population<!>2.2. Food frequency questionnaire<!>2.3. Urine cadmium<!>2.4. Other variables<!>2.5. Statistical analysis<!>3. Results<!>4. Discussion<!>5. Conclusions
<p>Cadmium is a toxic metal with multiple health effects including kidney
disease, bone fragility, cardiovascular disease and several cancers even at low
exposure levels (Tellez-Plaza et al., 2013a;
Tellez-Plaza et al., 2013b; García-Esquinas et al., 2014). Cadmium
half-life in the body is extremely long (20–35 years) due to its cumulative
capacity and binding to different proteins, especially in the kidneys and liver
(Jomova and Valko, 2011). Tobacco is a
major source of cadmium exposure in humans (Gil et
al., 2011), as tobacco leaves bio-concentrate cadmium, which is then
absorbed through the lungs during smoking. In non-smokers, the diet is the main
source of cadmium (ATSDR, 2012) including root
and leafy vegetables (e.g. potatoes, lettuce or spinach) (EFSA, 2009; Llobet et
al., 2003), shellfish (e.g. clams or mussels) (Olmedo et al., 2013) and organ meats (e.g. liver or
kidneys) (Jokanović et al.,
2013).</p><p>The characterization and prevention of cadmium exposures are warranted,
especially in disproportionately exposed populations. In the Strong Heart Study
(SHS), a population-based prospective cohort study conducted in American Indian
communities in Arizona, Oklahoma and North and South Dakota, baseline urinary
cadmium concentrations were markedly higher in the study participants compared to
the general US population, even among never smokers (Tellez-Plaza et al., 2013b, Pang et al.,
2016). These findings suggest there are unaccounted sources of cadmium
exposure in the SHS population. Fretts et al.
(2012) have reported a high consumption of processed meats in the SHS
communities (68% participants consumed at least 3 servings of processed
meats per week). Processed meat products, commonly consumed by low-income families
due to its low price, could constitute a relevant source of cadmium exposure as they
contain heavily processed animal tissues, some of them potentially including organ
meats. Several types of processed meats have historically been distributed free of
charge by U.S. Department of Agriculture food assistance program in some Indian
reservations and this distribution influences their diet (Smith et al., 1996; Taylor et al., 2006; Vaughan et al.
1997).</p><p>Baseline urinary cadmium concentrations, a biomarker of long-term exposure,
were positively associated with incident cardiovascular disease in the SHS, even
among non-smokers (Tellez-Plaza et al.,
2013b). The goal of this study was to assess the association of different
foods, with a specific interest on processed meat products, with urinary cadmium
concentrations in the Strong Heart Family Study (SHFS), a family-based extension of
the SHS that included a detailed food frequency questionnaire and urinary cadmium
measures during the 2001–2003 visit. Our main hypothesis was that higher
frequency and amount of processed meat consumption is associated with higher cadmium
concentrations in urine. Given relatively high urinary cadmium concentrations in the
SHS communities and its associated health effects, identifying relevant sources of
exposure is critical for the development of prevention interventions.</p><!><p>The SHFS is a multigenerational cohort recruited from the SHS (North et al., 2002). Families were eligible
if they had a core sibship consisting of 3 original SHS participants and at
least 5 additional living family members. During the 2001–2003 baseline
visit, 2474 SHFS participants (15 years of age and older) were recruited who
were free of diabetes at baseline and had urine metal concentrations measured as
part of an ancillary study to evaluate gene-environment interactions for
incident diabetes. We only included participants with dietary data available
(n=2188). We excluded 1 participant with missing urinary creatinine, 3
participants with abnormal concentrations of creatinine-corrected urine cadmium
(concentrations 24, 30 and 200 times higher than the 90th percentile), and
participants with missing values of educational level (n=8), body mass
index (n=7), and smoking status (n=1). We further excluded 443
participants from a community that has withdrawn their permission to conduct
research in 2016, leaving a total of 1725 participants in this analysis (see
participant flow chart in Supplemental Figure 1).</p><p>The study protocol was approved by the institutional review boards of the
Indian Health Service, the participating institutions and the participating
tribes. All participants provided written informed consent.</p><!><p>An interviewer-administered Block 119-item Food Frequency Questionnaire
(FFQ) was used to measure usual food intake as previously described (Fretts et al., 2012). Serving sizes,
described as standard units (e.g., 1 banana, 2 eggs, etc.) or standard
volume/weight portions, were assessed using photographs of various portions as
visual aids. Each participant was asked how often, on average, a particular food
was consumed during the past year. The quantity was assessed using frequency
measures of consumption (seasonally, never, a few times per year, once per
month, 2–3 times/mo, once per week, twice per week, 2–3
times/wk, 5–6 times/wk, daily) and adjusted for portion size (small,
medium, or large). In addition to standard Block FFQ food items, the FFQ
included foods commonly consumed among American Indians such as menudo, pozole,
guysava, red or green chili, Indian taco, fry bread, corn tortilla, flour
tortilla, and "spam" (a term that refers to canned meats,
usually a combination of heavily processed beef or pork meats, salt, sodium
nitrate, potato starch and water).</p><p>Average daily energy and macronutrient intakes were calculated for each
study participant by using the Block database (Block Dietary Systems). To obtain
measures of average daily energy and nutrient intake, the frequency response for
each food on the FFQ and American Indians supplementary foods questionnaire was
multiplied by the nutrient content of the documented portion size of the food,
then summed for all foods (Block et al.,
1998).</p><p>The food items in the FFQ were grouped in 24 different categories
according to their potential cadmium content based on data on cadmium
concentrations in US foods from the Total Diet Study Market Baskets 2006 through
2011 conducted by the US Food and Drug Administration (FDA, 2014). As an example, leafy vegetables, fries
and chips, nuts and seeds, organ meat and processed meat had their own
categories. For instance, the classification of fries and chips together and
separated from boiled or baked potatoes is due to different levels of cadmium
concentrations in these modalities of potato preparation. The specific food
stuffs included in each category is displayed in Supplemental Table 1. For
processed meats, for instance, our goal was to include meats made of mixed parts
of the animal and for that reason we did not include bacon or hamburgers. Total
intake for each food category was expressed as grams (g) consumed per day (Supplemental Figure
2).</p><!><p>Spot urine samples from baseline were collected in polypropylene tubes,
frozen within 1 to 2 hours of collection, shipped buried in dry ice and stored
in freezers at −70°C in the Penn Medical Laboratory, MedStar
Research Institute, Washington, DC. Strict controls on the sampling, transport
and storage of urine were conducted to ensure study quality (Strong Heart Study, 1991). The analyses of cadmium
and other metals were performed by Inductively Coupled Plasma Mass Spectrometry
ICP-MS (Agilent 7700x ICP-MS, Agilent Technologies, Waldbronn, Germany) and
urine samples have already been used to measure creatinine and albumin (Tellez-Plaza et al, 2013b; Scheer et al., 2012). The inter-assay and the
intra-assay coefficients of variation for urinary cadmium concentrations were
8.7% and 4.5%, respectively. Standard reference materials
(National Institute of Standards and Technology, NIST 1640a and 1643e) were used
to test the accuracy of the analyses. The limit of detection for urine cadmium
was 0.015 Î¼g/L (and the corresponding limit of quantification is 0.050
Î¼g/L), but our limit of detection is estimated conservatively so we kept
all values provided by the method above the limit of detection. A total of 87
(5.05%) samples were below the limit of detection and were replaced by
the limit of detection divided by the square root of two.</p><!><p>Study visits were performed by trained and certified staff following a
standard protocol (Lee et al., 1990).
Sociodemographic (age, sex, region and education) and lifestyle information
(smoking status) were obtained by questionnaire during the interview. Body mass
index was calculated from measured weight (kg) divided by measured height
(m2). Kcal per day were obtained from the FFQ based on total
grams of food estimated per day. To account for urine dilution, urine cadmium
was divided by urine creatinine (Î¼g per g of urine creatinine). Urine
creatinine was measured at the Laboratory of the National Institute of Diabetes
and Digestive and Kidney Disease, Epidemiology and Clinical Research Branch
(Phoenix, AZ) by an alkaline picrate rate method (Lee et al., 1990).</p><!><p>Urine cadmium corrected for urinary creatinine and intake of dietary
variables were right-skewed and log-transformed to improve normality. We
described the participant characteristics across urine cadmium quartiles and
assessed the differences between groups using Kruskal-Wallis tests for
continuous variables and χ2 tests for categorical
variables.</p><p>To assess the association between cadmium exposure and the different
food categories, including processed meats, we estimated geometric mean ratios
(GMRs) and corresponding 95% confidence intervals (95% CI) of
urinary cadmium concentrations for an interquartile range increase in daily
intake for each food type modeled. We used generalized estimating equations
(GEE) to account for the lack of independence among family members. We presented
the results in two models progressively adjusted. Model 1 was initially adjusted
for age (continuous), gender (male/female), educational level (more/less than 12
years or education), body mass index (continuous), smoking status
(never/former/current), center (Arizona/Oklahoma/North and South Dakota) and
total Kcal per day (continuous). Model 2 was further adjusted for other foods
showing a significant association with urinary cadmium concentrations in Model 1
as well as with other food categories established as potential sources of
cadmium exposure (see Supplemental Table 2), independently of statistical significance. To
allow for a flexible evaluation of the dose-response, we also graphically
described the association between cadmium and the food type based on restricted
quadratic splines with knots at 10th, 50th, and 90th percentiles of each intake
distribution, with the 10th percentile as the reference.</p><p>To evaluate the robustness of the results, we re-run the analyses with
the dietary variables in the original scale instead as of log-transformed, with
essentially identical results. We also run additional sensitivity analyses
further adjusting for cigarette pack-years, smokeless tobacco products and
exposure to secondhand tobacco smoke, with similar findings (Supplemental Table 3). We
also conducted analyses stratified by sex and smoking status. All analyses were
conducted with R software, version 3.1.2, the significance level was set at 0.05
and all tests were two-sided.</p><!><p>Median (IQR) urinary cadmium concentrations were 0.44 (0.20–0.85)
μg/g creatinine (0.31 (0.15–0.58) for men and 0.56
(0.27–1.02) for women). Participants with higher urinary cadmium
concentrations were more likely to be older, women, more educated, current smokers,
consume less Kcal per day and to be from North and South Dakota (Table 1). Before any adjustment, the food categories
positively associated with urinary cadmium concentrations (p<0.05) were
organ meat, leafy vegetables, root vegetables, non-alcoholic drinks, and oil and
fat; food categories negatively associated with urinary cadmium concentrations were
dairy products and fruit juices. Medians (IQR) intake in g/day were 23
(11–49) for processed meat, 27 (11–63) for fries and chips, 108
(38–268) for dairy products, and 140 (47–356) for fruit juices.
Processed meat intake was weakly positively correlated with the intake of fries and
chips (Spearman correlation coefficient of 0.20) (Supplemental Table 4). Dairy
products and fruit juice intake were weakly positively correlated (Spearman
correlation coefficient 0.24). Median (IQR) processed meat consumption was 20.9
(9.9, 41.0) for never smokers and 26.9 (11.9, 55.2) for ever smokers, respectively
(p-value <0.001).</p><p>As seen in Table 2, after adjustment
for sociodemographic and other participant characteristics (Model 1) the GMR
(95% CI) of urinary cadmium for an interquartile range in log-transformed
g/day for each food group was 1.16 (1.04, 1.29) for processed meat products, 1.10
(1.00, 1.21) for fries and chips, 0.87 (0.80, 0.95) for dairy products and 0.89
(0.82, 0.97) for fruit juices. After further adjustment for the food categories
associated with urinary cadmium in model 1 (processed meat products, fries and
chips, dairy products and fruit juices) and for food categories known to have higher
cadmium concentrations (organ meat, leafy vegetables, and baked and mashed potatoes)
processed meat products remained associated with higher urinary cadmium
concentrations (GMR 1.15, 95% CI 1.03–1.28), while dairy products
(GMR 0.88, 95% CI 0.80–0.97) and fruit juices (GMR 0.91, 95%
CI 0.83–0.99) remained associated with lower urinary cadmium concentrations
(Model 2). In analysis stratified by sex (Table
3), the association of urinary cadmium with processed meat consumption
was higher in males (GMR 1.31 95% CI 1.08–1.60) than in females (GMR
1.07 95% CI 0.95–1.20) (p-value for interaction 0.05). The negative
associations between urinary cadmium concentrations and dairy products and fruit
juices was also stronger in males compared to females. In analyses stratified by
smoking status (Table 3), the association
between cadmium and processed meat was stronger in ever smokers (GMR 1.23
95% CI 1.06–1.44) compared to never smokers (GMR 1.07 95% CI
0.92–1.25) although the interaction was not significant (p-value 0.46),
while dairy products and fruit juices displayed similar results in ever and never
smokers.</p><p>In flexible evaluations of the dose-response, processed meat intake was
associated with increased urinary cadmium concentrations only at levels of
consumption higher than 9.6 g/day (Figure 1).
Dairy products and fruit juice showed an inverse association throughout the range of
intake, although the decrease in urinary cadmium concentrations became more
accentuated after around 180 g/day for dairy products and 206 g/day of fruit juices.
The associations of cadmium with processed meats, dairy products and fruit juice
remained similar in analyses allowing for effect modification by sex and smoking
status (Supplemental Figure
3).</p><!><p>The findings of this study support that the consumption of processed meat
products are associated with higher cadmium concentrations in urine. The association
was non-linear, being observed at a daily intake of processed meats above 9.6 g/day
but not below that level. Other meat products evaluated (poultry, read meat, and
organ meat) were not associated with higher urinary cadmium concentrations,
supporting the specificity of the association with processed meat, not with other
types of meat. The association was stronger among men and ever smokers, compared to
women and never smokers, respectively, although the interaction by smoking status
was not statistically significant. In this respect, the markedly weaker and
non-statistically significant association among never smokers prevents this study to
reach firm conclusions regarding the association between processed meat and cadmium
exposure. Additional research is needed to assess whether our findings are due to
confounding, maybe by smoking status or other sources of cadmium that could
correlate with processed meat intake or whether high intake of this type of product
contributes to cadmium exposure in the population. Dairy products and fruit juices,
on the other hand, were associated with lower urinary cadmium concentrations.</p><p>Typically, organ meat (especially kidneys and liver) have been identified as
the major type of meat products associated with cadmium exposure due to their
capacity to accumulate cadmium (Hassan et al.,
2012; López-Alonso et al.,
2007). After adjustment for participant characteristics, we found no
association between the consumption of organ meat and urinary cadmium
concentrations. This can be explained by the relatively low consumption of organ
meats in the study population (Table 1).
Several studies have also found that despite the high concentration of cadmium in
organ meats, their contribution to dietary cadmium is small due to their infrequent
consumption. In Sweden, offal products provided only 4% of the total cadmium
dietary intake in a postmenopausal women cohort (Julin et al., 2012), and in another Swedish study for nonsmoking
participants living on farms, offal products contributed only 0.3% (range
0.5–3.6%) of dietary cadmium (Olsson
et al., 2002).</p><p>Very few studies have evaluated the association between processed meat
products or other types of meat and cadmium biomarkers. In Swedish adults, total
meat intake, measured through a food frequency questionnaire, was related to blood
cadmium concentrations, although the study did not distinguished between processed
and non-processed meats (Bjermo et al., 2013).
In children from the US, beef consumption (measured through a food frequency
questionnaire which included hot dogs as one of the beef food items), was associated
with blood cadmium concentrations (Davis et al.,
2014). In 3 year-old children from Ukraine, on the other hand, eating one
sausage or more per week was not associated with higher blood cadmium concentrations
(Friedman et al., 2006). Our study
constitutes one of the first studies specifically evaluating the potential
importance of these processed meat products in cadmium exposure. It is unclear,
however, why we observed a non-linear dose-response relationship or why the
association was stronger in men and ever smokers. On one hand, this could be related
to residual confounding by smoking, although our analyses were robust to additional
adjustment for cigarette pack-years, smokeless tobacco products, and secondhand
smoke exposure. On the other hand, these differences could also be related by
differences in the types of processed meats consumed, as it is possible that not all
types of processed meats contribute to increased cadmium exposure.</p><p>Food categories that were associated with higher urinary cadmium
concentrations in this study before adjustment for other foods included fries and
chips. Several studies have identified potatoes and root vegetables as an important
dietary contributor to cadmium exposure. In Sweden, a study in nonsmoking men and
women living on farms estimated that potatoes and other roots provided 24%
of the total dietary cadmium (Olsson et al.,
2002), while a study in Swedish postmenopausal women estimated that
potatoes provided 18% of total dietary cadmium intake (Julin et al., 2012). In the Total Diet Study by the FDA,
fries and chips show higher concentrations of cadmium as compared to potatoes cooked
with other cooking methods (FDA, 2014), which
could be related to the lower water content of fries and chips. In our study,
cereals such as wheat and rice, leafy vegetables, and nuts and seeds, foods that
have been commonly reported as dietary sources of cadmium (FDA, 2014; Olsson et al.,
2002, Tsukahara et al., 2003,
Baldantoni et al., 2016), were not
associated with increased urinary cadmium concentrations.</p><p>Dairy products and fruit juices showed an inverse association with urinary
Cd concentrations. Drinking milk has also been identified as inversely associated
with urinary cadmium concentrations in a study in premenopausal women aged
40–45 years from the US (Adams et al.,
2011). A similar inverse association of urinary cadmium with dairy
products and fruit juices has been reported in US adults in a Dietary-Wide
Association Study (DWAS) using NHANES and USDA data (Davis et al., 2014). Milk, cheese and yogurt were associated with lower
urinary or blood cadmium concentrations. Similarly, orange juice and apple juice
(this one just with blood cadmium) were associated with lower blood and urinary
cadmium concentrations (Davis et al., 2014).
The reasons behind these inverse associations are unknown. Potentially, these
products could decrease the gastro-intestinal absorption of cadmium. This is well
known, for instance, for dairy products and lead, which is also a toxic divalent
metal (de Almeida Lopes et al., 2015). An
adequate supply of calcium can protect against cadmium toxicity symptoms (Peraza et al., 1998). Regarding fruit juices,
one possible explanation could be related to increased vitamin C and the activation
of the iron transporter which could result in increasing iron while decreasing
cadmium uptake (Fox et al., 1980).
Interestingly, vitamin C supplementation has been observed to reduce elevated
cadmium concentrations in the kidneys and liver of pigs fed a copper-rich diet
(Peraza et al., 1998). Unfortunately in
our study we have no information on ferritin levels or iron stores.</p><p>This study has several strengths. The SHFS represents a unique resource to
evaluate the dose-response relationship between processed meat consumption and urine
cadmium concentrations due to the wide range of levels of processed meat consumption
in the study population. Strengths of the study include state-of-the art methods to
measure cadmium in urine with low limits of detection and the availability of
dietary information (Scheer et al., 2012).
The Block FFQ is one of the most widely used food questionnaires, showing
reliability and validity (Block et al., 1992;
Boucher et al., 2006; Caan et al., 1998; Subar
et al., 2001). The inclusion of an ethnic foods section on the FFQ
contributes considerably to increase group mean nutrient estimates and can
contribute to better food and energy intake estimates (Block et al., 2004).</p><p>A possible limitation is the lack of blood cadmium, a cadmium biomarker that
has a shorter half-life than urine cadmium and that could be useful to evaluate
together with urine cadmium concentrations. In the Strong Heart Family Study,
however, only urine cadmium is available. Other limitations include the use of a
single spot urine sample of cadmium determination as a biomarker of exposure and the
lack of tobacco biomarkers. Regression-dilution bias due to non-differential
measurement error in dietary assessment may have resulted in an underestimation of
the associations. We also lack information on other environmental or occupational
sources of cadmium in the population. Studies of other Native American populations
from the US, Canada and Mexico have suggested that sources of cadmium include nearby
contaminating factories and mining (Schmitt et al.,
2006; Moon et al., 1986), and
surface dust in jewelry-making homes (Gonzales et
al., 2004). Another activity that could be relevant for cadmium exposure
in our population is small-scale-motor vehicle repair (Yassin and Martonik, 2004).</p><!><p>Increased consumption of processed meat products was associated with
increased urinary cadmium concentrations in the SHFS participants, although the
association was weaker and non-statistically significant among never smokers.
Increased consumption of milk products and fruit juices, on the other hand, was
associated with lower urinary cadmium concentrations. This study revealed the
potential contribution of processed meat products to cadmium exposure and provides a
possible explanation for the high concentrations of urinary cadmium in the
population. Research is needed to confirm the association between processed meat
products and cadmium biomarkers in other populations, as well as to evaluate the
cadmium content of a diverse group of processed meat products, including those that
are more frequently consumed in American Indian communities. Meanwhile, our findings
support that promoting healthier dietary habits in American Indian communities,
including the reduction of consumption of processed meats and increasing the intake
of dairy and fruit juices, could contribute to reduce cadmium exposure.</p>