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Cadmium exposure is associated with reduced grip strength in US adults
Environmental Research 180 (2020) 108819
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Cadmium exposure is associated with reduced grip strength in US adults a,b,∗
a
c
E. García-Esquinas , M. Carrasco-Rios , A. Navas-Acien , R. Ortolá F. Rodríguez-Artalejoa,b,c,d
T
a,b
,
a
Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid/ IdiPAZ, Madrid, Spain CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA d IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain b c
A R T I C LE I N FO
A B S T R A C T
Keywords: Grip strength Cadmium Ageing
Background: Muscle strength is a strong predictor of all-cause mortality in the general population. Recent studies have shown an association between environmental pollution and declined grip strength. No previous research has evaluated the specific association between cadmium exposure, a well-known risk factor of several chronic diseases, and muscle strength. Methods: Cross-sectional study among 4,197 individuals aged ≥40 years, who participated in the National Health and Nutrition Examination Survey (NHANES) 2011–2014, provided data on grip strength, and had either blood or urine cadmium determinations. Grip strength was measured using a Takei digital handgrip dynamometer, and combined grip strength was calculated as the sum of the largest reading from each hand. Results: Median (interquartile range) concentrations of blood (BCd) and creatinine-corrected urine cadmium (Cr–UCd) were 0.32 μg/L (0.20–4.56) and 0.27 μg/g (0.15–0.46), respectively. After adjusting for sociodemographic, anthropometric, health-related behavioral, and clinical risk factors, and serum creatine phosphokinase concentrations, the highest (vs lowest) quartile of BCd was associated with a reduction in combined grip strength of 1.93 kg (95% confidence interval [CI]: −3.51, −0.34), p-trend < 0.001. The corresponding values comparing Cr–UCd quartiles 4 vs 1 were −3.24 kg (95% CI: −5.68, −0.79), p-trend < 0.001. These results were consistent across socio-demographic and clinical subgroups. Conclusions: In the US adult population, higher cadmium exposure was associated with decreased grip strength. These results may have important public health implications given the widespread cadmium exposure.
1. Introduction Handgrip strength is a commonly used marker of muscle strength. Physiologically, its levels rise to a peak during early adult life, are maintained through midlife, and decline from midlife onwards (Dodds et al., 2014). Weaker grip strength has been associated with an increased risk of cardiovascular disease, cognitive decline, and mortality, both in middle-aged (Celis-Morales et al., 2018; Kim, 2019; Shimizu et al., 2018) and older adults (Cooper et al., 2011, 2010; Smith et al., 2019). Cadmium (Cd) is a toxic metal widely distributed in the environment (Nordberg, 1984). Its main sources of exposure in the general population are cigarette smoking, diet (mainly through shellfish, offal and vegetables) and ambient air pollution (especially in urban and industrial areas) (ATSDR, 2019). A number of meta-analyses of
prospective studies have shown that Cd exposure is a risk factor of major chronic conditions including cardiovascular disease (Tellez-Plaza et al., 2013), or hypertension (Gallagher and Meliker, 2010); and, according to the International Agency for Research on Cancer, there is sufficient evidence of its carcinogenicity in humans (IARC, 2012). Our group has provided some evidence suggesting that Cd is a risk factor of low gait speed and frailty (García-Esquinas et al., 2015; Kim et al., 2016), but there is a lack of data on the potential association between Cd exposure and muscle strength. We therefore examined the association of blood (BCd) and urine cadmium (UCd) concentrations with handgrip strength in a representative sample of U.S. middle-aged and older adults who participated in the National Health and Nutrition Examination Survey (NHANES) 2011–2014.
∗ Corresponding author. Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid, Calle del Arzobispo Morcillo 4, 28029, Madrid, Spain. E-mail address: [email protected] (E. García-Esquinas).
https://doi.org/10.1016/j.envres.2019.108819 Received 16 August 2019; Received in revised form 9 October 2019; Accepted 9 October 2019 Available online 16 October 2019 0013-9351/ © 2019 Elsevier Inc. All rights reserved.
Environmental Research 180 (2020) 108819
E. García-Esquinas, et al.
2. Methods
Mexican-American, and Other), physical activity (sex-specific tertiles of METs-Hour/week), smoking (never, ex-smoker, current smoker), alcohol consumption (never, ex-drinker, current drinker, unknown), diet quality based on the question “in general, how healthy is your overall diet?“, and history of physician-diagnosed chronic conditions. CVD was defined as a self-reported diagnosis of coronary heart disease, congestive heart failure, heart attack or angina. Definition of hypertension was based on a self-reported physician diagnosis, current use of antihypertensive medication, or a clinical blood pressure reading 140/ 90 mmHg. Definition of type 2 diabetes mellitus was based on a selfreported physician diagnosis, fasting glucose ≥126 mg/dL, or current use of anti-diabetic medication. Glomerular filtration rate (GFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) glomerular filtration rate equation that incorporates subjects measures of serum creatinine, age, race and sex. Weight and height were measured in standardized conditions, and the BMI calculated dividing weight in kg by squared height in m.
2.1. Study participants NHANES is an ongoing cross-sectional survey of a nationally representative U.S. population conducted by the CDC's National Center for Health Statistics. The survey includes an interview at home with a subsequent physical examination and additional interviews at mobile examination centers (NHANES, 2015). In total, 7,418 adults aged ≥40 years participated in NHANES 2011–2013, from which 6,032 had valid information on grip strength. From these, we excluded 1,699 participants with no information on BCd or creatinine-corrected UCd (Cr–UCd), as well as 136 with no information on body mass index (BMI), educational level, tobacco smoking or hypertension. In the final sample of 4,197 participants, 4,120 and 1,877 had BCd and Cr–UCd determinations, respectively. The study was approved by the National Center for Health Statistics Research Ethics Review Board, and written informed consent was obtained from all participants.
2.3. Statistical analyses We performed all statistical analyses with STATA version 14.0, by using the survey (svy) command to account for complex sampling design and weights in the NHANES. The distribution of BCd, Cr–UCd and grip strength was depicted for participants overall and by their main sociodemographic, lifestyle and clinical factors. To evaluate the association of Cd exposure with grip strength, we estimated the mean difference (95% confidence interval (CI)) in handgrip strength by blood and urine concentrations using linear regression models. We modeled blood and creatinine-corrected urine concentrations as quartiles; tests for trend were performed for ordinal Cd quartiles in regression models using integer values (0–3). We then ran restricted cubic spline models with knots at the 10th, 50th and 90th percentiles of Cd distribution in all participants. Finally, we also estimated the mean difference in grip strength by interquartile range (IQR) increase in log-transformed blood and creatinine-corrected urine Cd concentrations. We developed two sequential models to assess the influence of potential confounders: Model A was adjusted for the main sociodemographic factors (gender, age, race/ethnicity and education), and Model B further adjusted for lifestyle factors (physical activity, tobacco smoke, alcohol consumption, diet quality and BMI). Additionally, we fitted model C with further adjustment for hypertension, diabetes, cardiovascular disease, cancer and osteomuscular disease; this model served to evaluate the potential mediation of several comorbidities that may be induced by cadmium exposure and which have been associated with decreased strength (Kapella et al., 2011; Sternäng et al., 2015; Syddall et al., 2018). Finally, Model D was additionally adjusted for serum Creatine Phosphokinase (CKD), to assess the potential mediation of the study association by muscular damage (Clarkson et al., 2006). To evaluate the consistency of results across categories of potential confounders, we used interaction terms. Moreover, we performed a number of sensitivity analyses, further adjusting the models for other important nutrition (total protein intake and serum albumin) and smoking-related (pack-years and serum cotinine concentrations (ng/ mL)) variables, as well as for glomerular filtration rate (which may influence Cd levels), in the subset of participants with data on each of these variables. Also to rule out the potential influence of glomerular filtration rate in cadmium excretion, we repeated the analyses among individuals with GFR in the normal range (≥60 mL/min/1.73m2). Finally, to account for urine dilution, we also adjusted urine Cd models for creatinine instead of dividing Cd by creatinine.
2.2. Study variables 2.2.1. Cadmium exposure Whole blood and spot urine samples were collected during the physical examination, frozen at −20 °C, and shipped to the Division of Laboratory Sciences, National Center for Environmental Health, CDC (Atlanta, GA, USA) for analysis. All collection and storage materials used for metal analyses were prescreened for background contamination. Before analysis, 100 μL of whole blood were combined with 100 μL of ≥18 M-ohm cm water and 4,800 μL of diluent (Tetramethylammonium hydroxide (1% and 4% in NHANES, 2011–2012 and NHANES, 2013–2014, respectively), disodium ethylenediamine tetraacetate 0.05%, ethyl alcohol (5% and 1% in NHANES, 2011–2012 and 2013–2014, respectively), and Triton X-100 (0.05%)). Samples were analyzed for Cd using an inductively coupled plasmamass spectrometer dynamic reaction cell (Elan ICP-DRC-MS instrument). Standard Reference Material 3108 from the National Institute of Standards and Technology was used for external calibration. In addition, the laboratory prepared spiked pools for internal quality control. Quality-control samples incorporated bench samples. Further methodological details on the laboratory analyses are described elsewhere. For BCd, the limits of detection (LOD) and percentage of samples with values under the LOD were, respectively, 0.16 μg/L and 10.4% in 2011–2012, and 0.10 μg/L and 3.3% in 2013–2014. For UCd, these values were 0.056 and 1.64% in 2011–2012, and 0.036 and 3.2% in 2013–2014. NHANES reported a value equal to the LOD/√2 for blood and urine Cd levels below the LOD. To account for urine dilution, we divided urine Cd levels by urine creatinine (μg/g). 2.2.2. Hand grip strength Grip strength (kg) was evaluated using a Takei Digital Grip Strength Dynamometer, Model T.K.K.5401 (Takei Scientific Instruments Co., Niigata, Japan). Before measurement of handgrip strength, the dynamometer was adjusted to participants’ hands size, until the second joint of the index finger was at a 90° angle to the handle. Participants were asked to squeeze the dynamometer as hard as possible using one hand. Each hand was tested three times, alternating hands with a 60-s rest between measurements on the same hand. NHANES reported combined handgrip strength as the sum of the largest reading from each hand.
3. Results
2.2.3. Other variables We used information from a number of self-reported variables including age, sex, education (< high school, high school and > high school), race/ethnicity (Non-Hispanic White, Non-Hispanic Black,
Median (IQR) concentrations of blood (BCd) and creatinine-corrected urine cadmium (Cr–UCd) were 0.32 μg/L (0.20–4.56) and 2
Environmental Research 180 (2020) 108819
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Table 1 Median (IQR) concentrations of blood and creatinine-corrected urine cadmium and muscle strength in adults aged ≥40 from the US general population. Characteristics
Weighted
Blood cadmium (μg/L) (N = 4,120)
Creatinine-corrected urine cadmium (μg/L) (N = 1,877)
Muscle strength (kg)
Overall Age,yr 40-49 50-60 ≥60 Sex Men Women Race ethnicity Non-Hispanic White Non-Hispanic Black Mexican American Other Education < High School High School > High School Body mass index. Kg/m2 Underweight: < 18.5 Normal weight: 18.5 to 24.9 Overweight: 25 to 29.9 Obesity: ≥30 Physical activity, tertiles METs-hours/week Men/women: ≤8/≤3 Men/women: 8.1 to ≤48/3.1 to ≤27 Men/women: ≥48.1/27.1 Smoking Never Ex-smoker Current Alcohol consumption Never Ex-drinker Current Unknown Diet quality Excellent/Very good Good Fair/por Hypertension No Yes Diabetes mellitus No Yes Cardiovascular disease No Yes Cancer No Yes Osteoarthritis No Yes Chronic kidney disease egfr ≥60 mL/min per 1.73 m2 egfr < 60 mL/min per 1.73 m2
100
0.32 (0.2–0.56)
0.27 (0.15–0.46)
64.8 (53.0–85.5)
31.3 30.2 38.4
0.27 (0.16–0.52) 0.32 (0.18–0.62) 0.35 (0.24–0.55)
0.20 (0.11–0.38) 0.26 (0.18–0.44) 0.34 (0.20–0.54)
74.0 (60.0–93.8) 68.7 (54.9–89.8) 56.9 (46.3–73.2)
48.1 51.9
0.27 (0.17–0.51) 0.36 (0.24–0.60)
0.21 (0.13–0.38) 0.34 (0.20–0.54)
86.2 (73.8–97.3) 54.0 (46.5–61.1)
73.4 10.1 5.3 11.2
0.31 0.37 0.29 0.39
0.26 0.28 0.24 0.34
64.7 69.1 64.6 60.7
16.2 21.3 62.5
0.43 (0.26–0.83) 0.30 (0.18–0.62) 0.30 (0.20–0.51)
0.37 (0.21–0.58) 0.26 (0.15–0.45) 0.25 (0.15–0.44)
60.6 (47.8–81.8) 63.6 (50.9–88.3) 66.1 (54.6–85.6)
1.0 24.1 37.7 36.2
0.75 0.42 0.29 0.30
0.84 0.36 0.25 0.23
47.0 60.8 68.5 66.1
34.1 32.8 33.1
0.33 (0.21–0.59) 0.31 (0.20–0.52) 0.31 (0.19–0.59)
0.28 (0.17–0.46) 0.27 (0.15–0.45) 0.26 (0.15–0.47)
62.4 (50.4–83.8) 64.4 (52.7–85.4) 67.1 (55.1–88.3)
52.6 31.0 16.4
0.25 (0.17–0.38) 0.33 (0.22–0.52) 1.10 (0.69–1.65)
0.20 (0.13–0.35) 0.30 (0.19–0.46) 0.49 (0.35–0.74)
62.3 (51.7–83.8) 68.7 (53.5–86.5) 70.5 (55.5–88.3)
10.5 23.2 52.3 14.0
0.32 0.34 0.31 0.33
0.26 0.29 0.25 0.31
53.4 65.8 71.0 57.8
35.7 42.9 21.4
0.33 (0.21–0.52) 0.30 (0.19–0.56) 0.33 (0.21–0.67)
0.26 (0.15–0.46) 0.27 (0.16–0.45) 0.28 (0.17–0.47)
62.7 (53.1–82.2) 66.2 (52.6–88.0) 67.3 (53.5–86.7)
54.5 45.5
0.31 (0.20–0.54) 0.32 (0.20–0.58)
0.25 (0.15–0.44) 0.30 (0.17–0.52)
66.5 (54.8–87.6) 62.4 (50.0–83.8)
83.9 16.1
0.32 (0.21–0.58) 0.30 (0.18–0.48)
0.27 (0.15–0.46) 0.26 (0.17–0.44)
65.7 (53.4–86.7) 61.0 (50.1–82.4)
88.0 12.0
0.31 (0.20–0.54) 0.40 (0.25–0.66)
0.26 (0.15–0.45) 0.32 (0.22–0.54)
65.6 (53.5–86.4) 60.5 (47.0–82.2)
84.5 15.5
0.31 (0.20–0.56) 0.34 (0.22–0.56)
0.26 (0.15–0.46) 0.32 (0.21–0.48)
65.9 (53.5–86.6) 60.2 (48.8–79.5)
66.1 33.9
0.31 (0.20–0.54) 0.33 (0.21–0.60)
0.24 (0.14–0.43) 0.31 (0.18–0.53)
70.0 (56.0–89.2) 57.2 (47.5–77.0)
88.4 10.6
0.31 (0.19–0.54) 0.41 (0.26–0.64)
0.26 (0.15–0.45) 0.32 (0.19–0.47)
66.8 (54.1–87.8) 54.3 (43.5–69.4)
(0.19–0.53) (0.23–0.74) (0.18–0.47) (0.24–0.71)
(0.40–0.99) (0.26–0.78) (0.19–0.51) (0.19–0.48)
(0.21–0.50) (0.21–0.65) (0.19–0.54) (0.22–0.56)
0.27 μg/g (0.15–0.46), respectively (please see Table 1). Older individuals, women, those with lower education, BMI < 18.5 kg/m2, and current tobacco smoking, as well as those who with self-reported CVD, cancer, osteoarthritis or chronic kidney disease showed the highest concentrations of BCd and Cr–UCd, and the lowest grip strength (Table 1). In models adjusted for sociodemographic and lifestyle-related risk factors (Model B), and comparing participants in the highest vs lowest quartiles of BCd and Cr–UCd, combined muscle strength decreased by −2.36 kg (−3.85, −0.88) and −3.87 kg (−6.05; −1.70), respectively. The progressive inclusion of morbidity and CPK yielded a −13.6% and −18.2% change in BCd estimates, and a −22.5% and 16.3% change in Cr–UCd estimates (Tables 2 and 3). Figs. 1 and 2 show
(0.15–0.45) (0.16–0.46) (0.17–0.40) (0.19–0.60)
(0.62–0.96) (0.20–0.60) (0.14–0.45) (0.14–0.41)
(0.14–0.46) (0.16–0.47) (0.15–0.43) (0.19–0.57)
(53.0–86.7) (57.0–88.5) (51.6–83.8) (49.9–80.7)
(36.9–60.1) (51.2–77.6) (53.9–88.5) (53.5–87.5)
(42.7–65.5) (53.5–85.5) (55.7–90.0) (47.1–73.2)
the dose-response association of BCd and Cr–UCd with grip strength; there were no major departures from linearity in the observed associations. All sensitivity analyses yielded similar results (please see Supplementary Table 1). Fig. 3 shows results for the highest vs lowest quartiles of BCd and Cr–UCd across participants’ subgroups. Increasing BCd was associated with decreased grip strength across all subgroups. Regarding Cr–UCd, results were stronger among men (p interaction < 0.01) and showed no dose-response among non-Hispanic black participants (p interaction 0.05).
3
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Table 2 Mean differences (95% confidence interval) in grip strength (kg), by blood cadmium (Cd) concentrations (n = 4,120). Blood cadmium quartiles (μg/L)
No.
Model A
Model B
Model C
Model D
Q 1 (≤0.20) Q 2 (0.21–0.32) Q 3 (0.33–0.56) Q 4 (0.57–3.02) p-trend
855 970 1,089 1,206
Ref. 0.85 (−1.02; 2.71) −0.52 (−2.18; 1.13) −2.04 (−3.68; −0.39) < 0.001
Ref. 0.76 (−0.93; 2.45) −0.66 (−2.13; 0.82) −2.36 (−3.85; −0.88) < 0.001
Ref. 0.56 (−1.16; 2.28) −0.74 (−2.23, 0.76) −2.04 (−3.55, −0.53) < 0.001
Ref. 0.77 (−1.00; 2.55) −0.42 (−1.95; 1.11) −1.93 (−3.51; −0.34) 0.019
Model A: adjusted for age, sex, race/ethnicity and education. Model B: adjusted for Model A covariates plus BMI, physical activity, tobacco smoke, alcohol consumption and diet quality. Model C: adjusted for Model B covariates plus hypertension, diabetes, cardiovascular disease, cancer, arthritis. Model D: adjusted for Model C plus serum Creatine Phosphokinase. *Please note that sensitivity analyses adjusting for place of birth, poverty-to-income ratio, total protein intake, serum albumin, serum testosterone and glomerular filtration rate gave similar results.
4. Discussion In the US adult population, BCd and Cr–UCd showed an inverse dose–response relationship with grip strength. To our knowledge, there is only one very recent Korean investigation that has examined the association between BCd exposure and muscle strength (Kim et al., 2016). This study, based on 983 elderly participants recruited by convenience sampling from community welfare centers in Seoul and Asan, also found a positive linear relationship between BCd and handgrip strength (Kim et al., 2016). Our study expands this association to include younger adults and other races/ethnicities, while shows that the previously-described association can be found at much lower concentrations than those reported in the Korean study, with median BCd concentrations of 1.12μg/L. Furthermore, it presents an even stronger association with UCd, a biomarker of Cd cumulative body burden. We have found three previous epidemiological studies, all NHANESbased, linking Cd with other mobility-related outcomes, with inconclusive results (García-Esquinas et al., 2015; Kim et al., 2016; Lang et al., 2009). The first of these studies used data from NHANES 1999–2004 and found a crude association between UCd and self-reported “problems walking a quarter of a mile” (Lang et al., 2009). However, this association was lost after adjustment for urinary creatinine. The second study, based on NHANES 1999–2002, found an inverse dose-response association between blood, but not UCd, concentrations and gait speed (Kim et al., 2016). The third, showed some evidence of an inverse association between UCd and frailty prevalence in participants from NHANES III, but this association was lost after exclusion of participants with reduced glomerular filtration rate (García-Esquinas et al., 2015). This study proposes some potential mechanistic effects. Specifically, our results suggest that the association between cadmium exposure and decreased muscle strenght may be partly explained by an increased prevalence of chronic conditions in Cd-exposed individuals; and, only for BCd, by Cd-induced muscle damage, as determined by serum CPK
Fig. 1. Handgrip strength as a smooth function of blood cadmium concentrations among US adults. Mean differences (95% confidence intervals) in grip strength according to blood cadmium concentrations based on restricted cubic splines with knots at the 10th, 50th, and 90th percentile of blood cadmium distribution. The reference value is set at the 25th percentile of the cadmium distribution. Models are adjusted for age, sex, race/ethnicity, education, BMI, physical activity, tobacco smoke, alcohol consumption, diet quality, hypertension, diabetes, cardiovascular disease, cancer and arthritis. Lines represent mean differences (thick line) and 95% confidence interval (dashed lines), and vertical bars represent the histogram of blood cadmium distribution.
concentrations. In fact, there is evidence from in vitro studies that Cd can induce significant alterations in the differentiation mechanisms of skeletal muscle cells, increasing inflammation and oxidative stress, and compromising cell adhesion and cellular antioxidant defense mechanisms (Papa et al., 2014). Moreover, in vivo studies have shown that Cd causes muscle weakness (Sato et al., 1978), muscle atrophy (Sato et al., 1978), and reduced motor activity (Kotsonis and Klaassen, 1978). Strengths of this study are its large sample size, the national
Table 3 Mean differences (95% confidence interval) in grip strength (kg), by creatinine-corrected urine cadmium (Cd) (n = 1,887). Creatinine-corrected urine cadmium quartiles (μg/L)
No.
Model A
Model B
Model C
Model D
Q 1 (≤0.16) Q 2 (0.17–0.26) Q 3 (0.27–0.46) Q 4 (0.47–2.10) p-trend
382 445 480 570
Ref. −0.26 (−3.00; 2.51) −1.17 (−3.41; 1.07) −3.85 (−6.02, −1.68) < 0.001
Ref. −0.60 (−3.37; 2.17) −1.56 (−3.98; 0.85) −3.87 (−6.05, −1.70) < 0.001
Ref. −0.26 (−2.76; 2.24) −1.24 (−3.38, 0.90) −3.00 (−5.29, −0.71) 0.011
Ref. −0.26 (−2.84; 2.31) −1.22 (−3.32, 0.87) −3.24 (−5.68, −0.79) < 0.001
Model A: adjusted for age, sex, race/ethnicity and education. Model B: adjusted for Model A covariates plus BMI, physical activity, tobacco smoke, alcohol consumption and diet quality. Model C: adjusted for Model B covariates plus hypertension, diabetes, cardiovascular disease, cancer, arthritis. Model D: adjusted for Model C plus serum creatine phosphokinase. *Please note that sensitivity analyses adjusting for place of birth, poverty-to-income ratio, total protein intake, serum albumin, serum testosterone and glomerular filtration rate gave similar results. 4
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main limitations is its cross-sectional design, which precludes temporal assessment of the associations. However, we have no reason for believing that individuals with lower strength may be at increased risk of exposure to Cd and we, thus, think that reverse causation is unlikely. In any case, future prospective studies are warranted to confirm our findings. Second, we used a single spot urine sample to measure Cd; also, because serum creatinine is released from muscle mass and this is directly associated with muscle strength, creatinine correction may bias UCd results. Finally, CPK is an unspecific biomarker of muscular damage whose levels are influenced by a number of factors including physical activity or statin use. However, the fact that CPK only attenuated the magnitude of the association of BCd with grip strength is consistent with this biomarker being a better indicator of biologically active Cd than UCd. Finally our results have important practical implications. Of note is that in the US adult population, a 3-year increase in age was associated with a 2.14 kg decrease in combined grip strength, which is similar to the observed difference in strength between those in the highest vs the lowest quartile of Cd. Although the clinical relevance of a 2-kg decrease in combined grip strength at the individual level is uncertain, small changes in the distribution of muscle strength, resulting from the widespread exposure to Cd, may have an important impact in functional disability in the overall population. .
Fig. 2. Handgrip strength as a smooth function of creatinine-corrected urine cadmium concentrations among US adults. Mean differences (95% confidence intervals) in grip strength according to creatinine-corrected urine cadmium concentrations based on restricted cubic splines with knots at the 10th, 50th, and 90th percentile of cadmium distribution. The reference value is set at the 25th percentile of the cadmium distribution. Models are adjusted for age, sex, race/ethnicity, education, BMI, physical activity, tobacco smoke, alcohol consumption, diet quality, hypertension, diabetes, cardiovascular disease, cancer and arthritis. Lines represent mean differences (thick line) and 95% confidence interval (dashed lines), and vertical bars represent the histogram of blood cadmium distribution.
5. Conclusions In the US adult population, higher cadmium exposure was crosssectionally associated with decreased grip strength, a strong predictor of all-cause mortality. These results may have important public health implications given the widespread cadmium exposure. Still, future
representativeness of the US population, the high quality laboratory methods, the number of potential confounders evaluated, as well as the consistency of the various sensitivity analyses performed. Among its
Fig. 3. Mean differences (95% confidence interval) of muscle strength comparing participants in the highest to those in the lowest quartile of blood and creatinine-corrected urine cadmium concentrations by participant characteristics. Results are shown for the highest vs the lowest quartile of blood and urine Cd. P-values for interaction terms were computed in models for ordinal Cd quartiles. 5
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longitudinal cohort studies are needed to confirm these findings and to understand its biological mechanisms before we can draw any firm conclusions on the relationship between cadmium and grip strength.
Gallagher, C.M., Meliker, J.R., 2010. Blood and urine cadmium, blood pressure, and hypertension: a systematic review and meta-analysis. Environ. Health Perspect. 118, 1676–1684. https://doi.org/10.1289/ehp.1002077. García-Esquinas, E., Navas-Acien, A., Pérez-Gómez, B., Artalejo, F.R., 2015. Association of lead and cadmium exposure with frailty in US older adults. Environ. Res. 137, 424–431. https://doi.org/10.1016/j.envres.2015.01.013. IARC, 2012. Monographs Volume 100C Cadmium and Cadmium Compounds – IARC. [WWW Document]. (accessed 7.1.19). https://monographs.iarc.fr/iarcmonographs-volume-100c-cadmium-and-cadmium-compounds/. Kapella, M.C., Larson, J.L., Covey, M.K., Alex, C.G., 2011. Functional performance in chronic obstructive pulmonary disease declines with time. Med. Sci. Sport. Exerc. 43, 218–224. https://doi.org/10.1249/MSS.0b013e3181eb6024. Kim, J.-H., 2019. Effect of grip strength on mental health. J. Affect. Disord. 245, 371–376. https://doi.org/10.1016/j.jad.2018.11.017. Kim, K.-N., Lee, M.-R., Choi, Y.-H., Lee, B.-E., Hong, Y.-C., 2016. Associations of blood cadmium levels with depression and lower handgrip strength in a communitydwelling elderly population: a repeated-measures panel study. J. Gerontol. Ser. A 71, 1525–1530. https://doi.org/10.1093/gerona/glw119. Kotsonis, F.N., Klaassen, C.D., 1978. The relationship of metallothionein to the toxicity of cadmium after prolonged oral administration to rats. Toxicol. Appl. Pharmacol. 46, 39–54. Lang, I.A., Scarlett, A., Guralnik, J.M., Depledge, M.H., Melzer, D., Galloway, T.S., 2009. Age-related impairments of mobility associated with cobalt and other heavy metals: data from NHANES 1999-2004. J. Toxicol. Environ. Health 72, 402–409. https://doi. org/10.1080/15287390802647336. NHANES, 2015. National Health and Nutrition Examination Survey Homepage. [WWW Document]. (accessed 7.1.19). https://www.cdc.gov/nchs/nhanes/index.htm. Nordberg, M., 1984. General aspects of cadmium: transport, uptake and metabolism by the kidney. Environ. Health Perspect. 54, 13–20. https://doi.org/10.1289/ehp. 845413. Papa, V., Wannenes, F., Crescioli, C., Caporossi, D., Lenzi, A., Migliaccio, S., Di Luigi, L., 2014. The environmental pollutant cadmium induces homeostasis alteration in muscle cells in vitro. J. Endocrinol. Investig. 37, 1073–1080. https://doi.org/10. 1007/s40618-014-0145-y. Sato, K., Iwamasa, T., Tsuru, T., Takeuchi, T., 1978. An ultrastructural study of chronic cadmium chloride-induced neuropathy. Acta Neuropathol. 41, 185–190. https://doi. org/10.1007/BF00690433. Shimizu, M., Misumi, M., Yamada, M., Ohishi, W., Yamamoto, H., Kihara, Y., 2018. Choice reaction time and grip strength as predictors of cardiovascular mortality in middle-aged and elderly Japanese: from the Radiation Effects Research Foundation Adult Health study. Intern. Med. J. 48, 1331–1336. https://doi.org/10.1111/imj. 14002. Smith, L., Yang, L., Hamer, M., 2019. Handgrip strength, inflammatory markers, and mortality. Scand. J. Med. Sci. Sport. https://doi.org/10.1111/sms.13433. Sternäng, O., Reynolds, C.A., Finkel, D., Ernsth-Bravell, M., Pedersen, N.L., Dahl Aslan, A.K., 2015. Factors associated with grip strength decline in older adults. Age Ageing 44, 269–274. https://doi.org/10.1093/ageing/afu170. Syddall, H.E., Westbury, L.D., Shaw, S.C., Dennison, E.M., Cooper, C., Gale, C.R., 2018. Correlates of level and loss of grip strength in later life: findings from the English longitudinal study of ageing and the hertfordshire cohort study. Calcif. Tissue Int. 102, 53–63. https://doi.org/10.1007/s00223-017-0337-5. Tellez-Plaza, M., Jones, M.R., Dominguez-Lucas, A., Guallar, E., Navas-Acien, A., 2013. Cadmium exposure and clinical cardiovascular disease: a systematic review. Curr. Atheroscler. Rep. 15, 356. https://doi.org/10.1007/s11883-013-0356-2.
Author contributions EGE conceptualized the study. MCR acquired data. MCR and EGE conducted statistical analyses. MCR and EGE interpreted the results and drafted the initial manuscript. All authors reviewed the manuscript for important intellectual content and approved the final version as submitted. Sources of support This work has been supported by grants PI18/287 and 16/609 from the Instituto de Salud Carlos III, State Secretary of R+D+I, and FEDER/FSE. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.envres.2019.108819. References ATSDR, 2019. Toxicological profile: cadmium. [WWW Document]. https://www.atsdr. cdc.gov/toxprofiles/tp.asp?id=48&tid=15 (accessed 7.2.19). Celis-Morales, C.A., Welsh, P., Lyall, D.M., Steell, L., Petermann, F., Anderson, J., Iliodromiti, S., Sillars, A., Graham, N., Mackay, D.F., Pell, J.P., Gill, J.M.R., Sattar, N., Gray, S.R., 2018. Associations of grip strength with cardiovascular, respiratory, and cancer outcomes and all-cause mortality: prospective cohort study of half a million UK Biobank participants. BMJ 361, k1651. Clarkson, P.M., Kearns, A.K., Rouzier, P., Rubin, R., Thompson, P.D., 2006. Serum creatine kinase levels and renal function measures in exertional muscle damage. Med. Sci. Sport. Exerc. 38, 623–627. https://doi.org/10.1249/01.mss.0000210192. 49210.fc. Cooper, R., Kuh, D., Hardy, R., Mortality Review Group, 2010. Objectively measured physical capability levels and mortality: systematic review and meta-analysis. BMJ 341. https://doi.org/10.1136/bmj.c4467. Cooper, R., Kuh, D., Cooper, C., Gale, C.R., Lawlor, D.A., Matthews, F., Hardy, R., 2011. Objective measures of physical capability and subsequent health: a systematic review. Age Ageing 40, 14–23. https://doi.org/10.1093/ageing/afq117. Dodds, R.M., Syddall, H.E., Cooper, R., Benzeval, M., Deary, I.J., Dennison, E.M., Der, G., Gale, C.R., Inskip, H.M., Jagger, C., Kirkwood, T.B., Lawlor, D.A., Robinson, S.M., Starr, J.M., Steptoe, A., Tilling, K., Kuh, D., Cooper, C., Sayer, A.A., 2014. Grip strength across the life course: normative data from twelve British studies. PLoS One 9. https://doi.org/10.1371/journal.pone.0113637.
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Cadmium exposure is associated with reduced grip strength in US adults a,b,∗
a
c
E. García-Esquinas , M. Carrasco-Rios , A. Navas-Acien , R. Ortolá F. Rodríguez-Artalejoa,b,c,d
T
a,b
,
a
Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid/ IdiPAZ, Madrid, Spain CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA d IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain b c
A R T I C LE I N FO
A B S T R A C T
Keywords: Grip strength Cadmium Ageing
Background: Muscle strength is a strong predictor of all-cause mortality in the general population. Recent studies have shown an association between environmental pollution and declined grip strength. No previous research has evaluated the specific association between cadmium exposure, a well-known risk factor of several chronic diseases, and muscle strength. Methods: Cross-sectional study among 4,197 individuals aged ≥40 years, who participated in the National Health and Nutrition Examination Survey (NHANES) 2011–2014, provided data on grip strength, and had either blood or urine cadmium determinations. Grip strength was measured using a Takei digital handgrip dynamometer, and combined grip strength was calculated as the sum of the largest reading from each hand. Results: Median (interquartile range) concentrations of blood (BCd) and creatinine-corrected urine cadmium (Cr–UCd) were 0.32 μg/L (0.20–4.56) and 0.27 μg/g (0.15–0.46), respectively. After adjusting for sociodemographic, anthropometric, health-related behavioral, and clinical risk factors, and serum creatine phosphokinase concentrations, the highest (vs lowest) quartile of BCd was associated with a reduction in combined grip strength of 1.93 kg (95% confidence interval [CI]: −3.51, −0.34), p-trend < 0.001. The corresponding values comparing Cr–UCd quartiles 4 vs 1 were −3.24 kg (95% CI: −5.68, −0.79), p-trend < 0.001. These results were consistent across socio-demographic and clinical subgroups. Conclusions: In the US adult population, higher cadmium exposure was associated with decreased grip strength. These results may have important public health implications given the widespread cadmium exposure.
1. Introduction Handgrip strength is a commonly used marker of muscle strength. Physiologically, its levels rise to a peak during early adult life, are maintained through midlife, and decline from midlife onwards (Dodds et al., 2014). Weaker grip strength has been associated with an increased risk of cardiovascular disease, cognitive decline, and mortality, both in middle-aged (Celis-Morales et al., 2018; Kim, 2019; Shimizu et al., 2018) and older adults (Cooper et al., 2011, 2010; Smith et al., 2019). Cadmium (Cd) is a toxic metal widely distributed in the environment (Nordberg, 1984). Its main sources of exposure in the general population are cigarette smoking, diet (mainly through shellfish, offal and vegetables) and ambient air pollution (especially in urban and industrial areas) (ATSDR, 2019). A number of meta-analyses of
prospective studies have shown that Cd exposure is a risk factor of major chronic conditions including cardiovascular disease (Tellez-Plaza et al., 2013), or hypertension (Gallagher and Meliker, 2010); and, according to the International Agency for Research on Cancer, there is sufficient evidence of its carcinogenicity in humans (IARC, 2012). Our group has provided some evidence suggesting that Cd is a risk factor of low gait speed and frailty (García-Esquinas et al., 2015; Kim et al., 2016), but there is a lack of data on the potential association between Cd exposure and muscle strength. We therefore examined the association of blood (BCd) and urine cadmium (UCd) concentrations with handgrip strength in a representative sample of U.S. middle-aged and older adults who participated in the National Health and Nutrition Examination Survey (NHANES) 2011–2014.
∗ Corresponding author. Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid, Calle del Arzobispo Morcillo 4, 28029, Madrid, Spain. E-mail address: [email protected] (E. García-Esquinas).
https://doi.org/10.1016/j.envres.2019.108819 Received 16 August 2019; Received in revised form 9 October 2019; Accepted 9 October 2019 Available online 16 October 2019 0013-9351/ © 2019 Elsevier Inc. All rights reserved.
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2. Methods
Mexican-American, and Other), physical activity (sex-specific tertiles of METs-Hour/week), smoking (never, ex-smoker, current smoker), alcohol consumption (never, ex-drinker, current drinker, unknown), diet quality based on the question “in general, how healthy is your overall diet?“, and history of physician-diagnosed chronic conditions. CVD was defined as a self-reported diagnosis of coronary heart disease, congestive heart failure, heart attack or angina. Definition of hypertension was based on a self-reported physician diagnosis, current use of antihypertensive medication, or a clinical blood pressure reading 140/ 90 mmHg. Definition of type 2 diabetes mellitus was based on a selfreported physician diagnosis, fasting glucose ≥126 mg/dL, or current use of anti-diabetic medication. Glomerular filtration rate (GFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) glomerular filtration rate equation that incorporates subjects measures of serum creatinine, age, race and sex. Weight and height were measured in standardized conditions, and the BMI calculated dividing weight in kg by squared height in m.
2.1. Study participants NHANES is an ongoing cross-sectional survey of a nationally representative U.S. population conducted by the CDC's National Center for Health Statistics. The survey includes an interview at home with a subsequent physical examination and additional interviews at mobile examination centers (NHANES, 2015). In total, 7,418 adults aged ≥40 years participated in NHANES 2011–2013, from which 6,032 had valid information on grip strength. From these, we excluded 1,699 participants with no information on BCd or creatinine-corrected UCd (Cr–UCd), as well as 136 with no information on body mass index (BMI), educational level, tobacco smoking or hypertension. In the final sample of 4,197 participants, 4,120 and 1,877 had BCd and Cr–UCd determinations, respectively. The study was approved by the National Center for Health Statistics Research Ethics Review Board, and written informed consent was obtained from all participants.
2.3. Statistical analyses We performed all statistical analyses with STATA version 14.0, by using the survey (svy) command to account for complex sampling design and weights in the NHANES. The distribution of BCd, Cr–UCd and grip strength was depicted for participants overall and by their main sociodemographic, lifestyle and clinical factors. To evaluate the association of Cd exposure with grip strength, we estimated the mean difference (95% confidence interval (CI)) in handgrip strength by blood and urine concentrations using linear regression models. We modeled blood and creatinine-corrected urine concentrations as quartiles; tests for trend were performed for ordinal Cd quartiles in regression models using integer values (0–3). We then ran restricted cubic spline models with knots at the 10th, 50th and 90th percentiles of Cd distribution in all participants. Finally, we also estimated the mean difference in grip strength by interquartile range (IQR) increase in log-transformed blood and creatinine-corrected urine Cd concentrations. We developed two sequential models to assess the influence of potential confounders: Model A was adjusted for the main sociodemographic factors (gender, age, race/ethnicity and education), and Model B further adjusted for lifestyle factors (physical activity, tobacco smoke, alcohol consumption, diet quality and BMI). Additionally, we fitted model C with further adjustment for hypertension, diabetes, cardiovascular disease, cancer and osteomuscular disease; this model served to evaluate the potential mediation of several comorbidities that may be induced by cadmium exposure and which have been associated with decreased strength (Kapella et al., 2011; Sternäng et al., 2015; Syddall et al., 2018). Finally, Model D was additionally adjusted for serum Creatine Phosphokinase (CKD), to assess the potential mediation of the study association by muscular damage (Clarkson et al., 2006). To evaluate the consistency of results across categories of potential confounders, we used interaction terms. Moreover, we performed a number of sensitivity analyses, further adjusting the models for other important nutrition (total protein intake and serum albumin) and smoking-related (pack-years and serum cotinine concentrations (ng/ mL)) variables, as well as for glomerular filtration rate (which may influence Cd levels), in the subset of participants with data on each of these variables. Also to rule out the potential influence of glomerular filtration rate in cadmium excretion, we repeated the analyses among individuals with GFR in the normal range (≥60 mL/min/1.73m2). Finally, to account for urine dilution, we also adjusted urine Cd models for creatinine instead of dividing Cd by creatinine.
2.2. Study variables 2.2.1. Cadmium exposure Whole blood and spot urine samples were collected during the physical examination, frozen at −20 °C, and shipped to the Division of Laboratory Sciences, National Center for Environmental Health, CDC (Atlanta, GA, USA) for analysis. All collection and storage materials used for metal analyses were prescreened for background contamination. Before analysis, 100 μL of whole blood were combined with 100 μL of ≥18 M-ohm cm water and 4,800 μL of diluent (Tetramethylammonium hydroxide (1% and 4% in NHANES, 2011–2012 and NHANES, 2013–2014, respectively), disodium ethylenediamine tetraacetate 0.05%, ethyl alcohol (5% and 1% in NHANES, 2011–2012 and 2013–2014, respectively), and Triton X-100 (0.05%)). Samples were analyzed for Cd using an inductively coupled plasmamass spectrometer dynamic reaction cell (Elan ICP-DRC-MS instrument). Standard Reference Material 3108 from the National Institute of Standards and Technology was used for external calibration. In addition, the laboratory prepared spiked pools for internal quality control. Quality-control samples incorporated bench samples. Further methodological details on the laboratory analyses are described elsewhere. For BCd, the limits of detection (LOD) and percentage of samples with values under the LOD were, respectively, 0.16 μg/L and 10.4% in 2011–2012, and 0.10 μg/L and 3.3% in 2013–2014. For UCd, these values were 0.056 and 1.64% in 2011–2012, and 0.036 and 3.2% in 2013–2014. NHANES reported a value equal to the LOD/√2 for blood and urine Cd levels below the LOD. To account for urine dilution, we divided urine Cd levels by urine creatinine (μg/g). 2.2.2. Hand grip strength Grip strength (kg) was evaluated using a Takei Digital Grip Strength Dynamometer, Model T.K.K.5401 (Takei Scientific Instruments Co., Niigata, Japan). Before measurement of handgrip strength, the dynamometer was adjusted to participants’ hands size, until the second joint of the index finger was at a 90° angle to the handle. Participants were asked to squeeze the dynamometer as hard as possible using one hand. Each hand was tested three times, alternating hands with a 60-s rest between measurements on the same hand. NHANES reported combined handgrip strength as the sum of the largest reading from each hand.
3. Results
2.2.3. Other variables We used information from a number of self-reported variables including age, sex, education (< high school, high school and > high school), race/ethnicity (Non-Hispanic White, Non-Hispanic Black,
Median (IQR) concentrations of blood (BCd) and creatinine-corrected urine cadmium (Cr–UCd) were 0.32 μg/L (0.20–4.56) and 2
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Table 1 Median (IQR) concentrations of blood and creatinine-corrected urine cadmium and muscle strength in adults aged ≥40 from the US general population. Characteristics
Weighted
Blood cadmium (μg/L) (N = 4,120)
Creatinine-corrected urine cadmium (μg/L) (N = 1,877)
Muscle strength (kg)
Overall Age,yr 40-49 50-60 ≥60 Sex Men Women Race ethnicity Non-Hispanic White Non-Hispanic Black Mexican American Other Education < High School High School > High School Body mass index. Kg/m2 Underweight: < 18.5 Normal weight: 18.5 to 24.9 Overweight: 25 to 29.9 Obesity: ≥30 Physical activity, tertiles METs-hours/week Men/women: ≤8/≤3 Men/women: 8.1 to ≤48/3.1 to ≤27 Men/women: ≥48.1/27.1 Smoking Never Ex-smoker Current Alcohol consumption Never Ex-drinker Current Unknown Diet quality Excellent/Very good Good Fair/por Hypertension No Yes Diabetes mellitus No Yes Cardiovascular disease No Yes Cancer No Yes Osteoarthritis No Yes Chronic kidney disease egfr ≥60 mL/min per 1.73 m2 egfr < 60 mL/min per 1.73 m2
100
0.32 (0.2–0.56)
0.27 (0.15–0.46)
64.8 (53.0–85.5)
31.3 30.2 38.4
0.27 (0.16–0.52) 0.32 (0.18–0.62) 0.35 (0.24–0.55)
0.20 (0.11–0.38) 0.26 (0.18–0.44) 0.34 (0.20–0.54)
74.0 (60.0–93.8) 68.7 (54.9–89.8) 56.9 (46.3–73.2)
48.1 51.9
0.27 (0.17–0.51) 0.36 (0.24–0.60)
0.21 (0.13–0.38) 0.34 (0.20–0.54)
86.2 (73.8–97.3) 54.0 (46.5–61.1)
73.4 10.1 5.3 11.2
0.31 0.37 0.29 0.39
0.26 0.28 0.24 0.34
64.7 69.1 64.6 60.7
16.2 21.3 62.5
0.43 (0.26–0.83) 0.30 (0.18–0.62) 0.30 (0.20–0.51)
0.37 (0.21–0.58) 0.26 (0.15–0.45) 0.25 (0.15–0.44)
60.6 (47.8–81.8) 63.6 (50.9–88.3) 66.1 (54.6–85.6)
1.0 24.1 37.7 36.2
0.75 0.42 0.29 0.30
0.84 0.36 0.25 0.23
47.0 60.8 68.5 66.1
34.1 32.8 33.1
0.33 (0.21–0.59) 0.31 (0.20–0.52) 0.31 (0.19–0.59)
0.28 (0.17–0.46) 0.27 (0.15–0.45) 0.26 (0.15–0.47)
62.4 (50.4–83.8) 64.4 (52.7–85.4) 67.1 (55.1–88.3)
52.6 31.0 16.4
0.25 (0.17–0.38) 0.33 (0.22–0.52) 1.10 (0.69–1.65)
0.20 (0.13–0.35) 0.30 (0.19–0.46) 0.49 (0.35–0.74)
62.3 (51.7–83.8) 68.7 (53.5–86.5) 70.5 (55.5–88.3)
10.5 23.2 52.3 14.0
0.32 0.34 0.31 0.33
0.26 0.29 0.25 0.31
53.4 65.8 71.0 57.8
35.7 42.9 21.4
0.33 (0.21–0.52) 0.30 (0.19–0.56) 0.33 (0.21–0.67)
0.26 (0.15–0.46) 0.27 (0.16–0.45) 0.28 (0.17–0.47)
62.7 (53.1–82.2) 66.2 (52.6–88.0) 67.3 (53.5–86.7)
54.5 45.5
0.31 (0.20–0.54) 0.32 (0.20–0.58)
0.25 (0.15–0.44) 0.30 (0.17–0.52)
66.5 (54.8–87.6) 62.4 (50.0–83.8)
83.9 16.1
0.32 (0.21–0.58) 0.30 (0.18–0.48)
0.27 (0.15–0.46) 0.26 (0.17–0.44)
65.7 (53.4–86.7) 61.0 (50.1–82.4)
88.0 12.0
0.31 (0.20–0.54) 0.40 (0.25–0.66)
0.26 (0.15–0.45) 0.32 (0.22–0.54)
65.6 (53.5–86.4) 60.5 (47.0–82.2)
84.5 15.5
0.31 (0.20–0.56) 0.34 (0.22–0.56)
0.26 (0.15–0.46) 0.32 (0.21–0.48)
65.9 (53.5–86.6) 60.2 (48.8–79.5)
66.1 33.9
0.31 (0.20–0.54) 0.33 (0.21–0.60)
0.24 (0.14–0.43) 0.31 (0.18–0.53)
70.0 (56.0–89.2) 57.2 (47.5–77.0)
88.4 10.6
0.31 (0.19–0.54) 0.41 (0.26–0.64)
0.26 (0.15–0.45) 0.32 (0.19–0.47)
66.8 (54.1–87.8) 54.3 (43.5–69.4)
(0.19–0.53) (0.23–0.74) (0.18–0.47) (0.24–0.71)
(0.40–0.99) (0.26–0.78) (0.19–0.51) (0.19–0.48)
(0.21–0.50) (0.21–0.65) (0.19–0.54) (0.22–0.56)
0.27 μg/g (0.15–0.46), respectively (please see Table 1). Older individuals, women, those with lower education, BMI < 18.5 kg/m2, and current tobacco smoking, as well as those who with self-reported CVD, cancer, osteoarthritis or chronic kidney disease showed the highest concentrations of BCd and Cr–UCd, and the lowest grip strength (Table 1). In models adjusted for sociodemographic and lifestyle-related risk factors (Model B), and comparing participants in the highest vs lowest quartiles of BCd and Cr–UCd, combined muscle strength decreased by −2.36 kg (−3.85, −0.88) and −3.87 kg (−6.05; −1.70), respectively. The progressive inclusion of morbidity and CPK yielded a −13.6% and −18.2% change in BCd estimates, and a −22.5% and 16.3% change in Cr–UCd estimates (Tables 2 and 3). Figs. 1 and 2 show
(0.15–0.45) (0.16–0.46) (0.17–0.40) (0.19–0.60)
(0.62–0.96) (0.20–0.60) (0.14–0.45) (0.14–0.41)
(0.14–0.46) (0.16–0.47) (0.15–0.43) (0.19–0.57)
(53.0–86.7) (57.0–88.5) (51.6–83.8) (49.9–80.7)
(36.9–60.1) (51.2–77.6) (53.9–88.5) (53.5–87.5)
(42.7–65.5) (53.5–85.5) (55.7–90.0) (47.1–73.2)
the dose-response association of BCd and Cr–UCd with grip strength; there were no major departures from linearity in the observed associations. All sensitivity analyses yielded similar results (please see Supplementary Table 1). Fig. 3 shows results for the highest vs lowest quartiles of BCd and Cr–UCd across participants’ subgroups. Increasing BCd was associated with decreased grip strength across all subgroups. Regarding Cr–UCd, results were stronger among men (p interaction < 0.01) and showed no dose-response among non-Hispanic black participants (p interaction 0.05).
3
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Table 2 Mean differences (95% confidence interval) in grip strength (kg), by blood cadmium (Cd) concentrations (n = 4,120). Blood cadmium quartiles (μg/L)
No.
Model A
Model B
Model C
Model D
Q 1 (≤0.20) Q 2 (0.21–0.32) Q 3 (0.33–0.56) Q 4 (0.57–3.02) p-trend
855 970 1,089 1,206
Ref. 0.85 (−1.02; 2.71) −0.52 (−2.18; 1.13) −2.04 (−3.68; −0.39) < 0.001
Ref. 0.76 (−0.93; 2.45) −0.66 (−2.13; 0.82) −2.36 (−3.85; −0.88) < 0.001
Ref. 0.56 (−1.16; 2.28) −0.74 (−2.23, 0.76) −2.04 (−3.55, −0.53) < 0.001
Ref. 0.77 (−1.00; 2.55) −0.42 (−1.95; 1.11) −1.93 (−3.51; −0.34) 0.019
Model A: adjusted for age, sex, race/ethnicity and education. Model B: adjusted for Model A covariates plus BMI, physical activity, tobacco smoke, alcohol consumption and diet quality. Model C: adjusted for Model B covariates plus hypertension, diabetes, cardiovascular disease, cancer, arthritis. Model D: adjusted for Model C plus serum Creatine Phosphokinase. *Please note that sensitivity analyses adjusting for place of birth, poverty-to-income ratio, total protein intake, serum albumin, serum testosterone and glomerular filtration rate gave similar results.
4. Discussion In the US adult population, BCd and Cr–UCd showed an inverse dose–response relationship with grip strength. To our knowledge, there is only one very recent Korean investigation that has examined the association between BCd exposure and muscle strength (Kim et al., 2016). This study, based on 983 elderly participants recruited by convenience sampling from community welfare centers in Seoul and Asan, also found a positive linear relationship between BCd and handgrip strength (Kim et al., 2016). Our study expands this association to include younger adults and other races/ethnicities, while shows that the previously-described association can be found at much lower concentrations than those reported in the Korean study, with median BCd concentrations of 1.12μg/L. Furthermore, it presents an even stronger association with UCd, a biomarker of Cd cumulative body burden. We have found three previous epidemiological studies, all NHANESbased, linking Cd with other mobility-related outcomes, with inconclusive results (García-Esquinas et al., 2015; Kim et al., 2016; Lang et al., 2009). The first of these studies used data from NHANES 1999–2004 and found a crude association between UCd and self-reported “problems walking a quarter of a mile” (Lang et al., 2009). However, this association was lost after adjustment for urinary creatinine. The second study, based on NHANES 1999–2002, found an inverse dose-response association between blood, but not UCd, concentrations and gait speed (Kim et al., 2016). The third, showed some evidence of an inverse association between UCd and frailty prevalence in participants from NHANES III, but this association was lost after exclusion of participants with reduced glomerular filtration rate (García-Esquinas et al., 2015). This study proposes some potential mechanistic effects. Specifically, our results suggest that the association between cadmium exposure and decreased muscle strenght may be partly explained by an increased prevalence of chronic conditions in Cd-exposed individuals; and, only for BCd, by Cd-induced muscle damage, as determined by serum CPK
Fig. 1. Handgrip strength as a smooth function of blood cadmium concentrations among US adults. Mean differences (95% confidence intervals) in grip strength according to blood cadmium concentrations based on restricted cubic splines with knots at the 10th, 50th, and 90th percentile of blood cadmium distribution. The reference value is set at the 25th percentile of the cadmium distribution. Models are adjusted for age, sex, race/ethnicity, education, BMI, physical activity, tobacco smoke, alcohol consumption, diet quality, hypertension, diabetes, cardiovascular disease, cancer and arthritis. Lines represent mean differences (thick line) and 95% confidence interval (dashed lines), and vertical bars represent the histogram of blood cadmium distribution.
concentrations. In fact, there is evidence from in vitro studies that Cd can induce significant alterations in the differentiation mechanisms of skeletal muscle cells, increasing inflammation and oxidative stress, and compromising cell adhesion and cellular antioxidant defense mechanisms (Papa et al., 2014). Moreover, in vivo studies have shown that Cd causes muscle weakness (Sato et al., 1978), muscle atrophy (Sato et al., 1978), and reduced motor activity (Kotsonis and Klaassen, 1978). Strengths of this study are its large sample size, the national
Table 3 Mean differences (95% confidence interval) in grip strength (kg), by creatinine-corrected urine cadmium (Cd) (n = 1,887). Creatinine-corrected urine cadmium quartiles (μg/L)
No.
Model A
Model B
Model C
Model D
Q 1 (≤0.16) Q 2 (0.17–0.26) Q 3 (0.27–0.46) Q 4 (0.47–2.10) p-trend
382 445 480 570
Ref. −0.26 (−3.00; 2.51) −1.17 (−3.41; 1.07) −3.85 (−6.02, −1.68) < 0.001
Ref. −0.60 (−3.37; 2.17) −1.56 (−3.98; 0.85) −3.87 (−6.05, −1.70) < 0.001
Ref. −0.26 (−2.76; 2.24) −1.24 (−3.38, 0.90) −3.00 (−5.29, −0.71) 0.011
Ref. −0.26 (−2.84; 2.31) −1.22 (−3.32, 0.87) −3.24 (−5.68, −0.79) < 0.001
Model A: adjusted for age, sex, race/ethnicity and education. Model B: adjusted for Model A covariates plus BMI, physical activity, tobacco smoke, alcohol consumption and diet quality. Model C: adjusted for Model B covariates plus hypertension, diabetes, cardiovascular disease, cancer, arthritis. Model D: adjusted for Model C plus serum creatine phosphokinase. *Please note that sensitivity analyses adjusting for place of birth, poverty-to-income ratio, total protein intake, serum albumin, serum testosterone and glomerular filtration rate gave similar results. 4
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main limitations is its cross-sectional design, which precludes temporal assessment of the associations. However, we have no reason for believing that individuals with lower strength may be at increased risk of exposure to Cd and we, thus, think that reverse causation is unlikely. In any case, future prospective studies are warranted to confirm our findings. Second, we used a single spot urine sample to measure Cd; also, because serum creatinine is released from muscle mass and this is directly associated with muscle strength, creatinine correction may bias UCd results. Finally, CPK is an unspecific biomarker of muscular damage whose levels are influenced by a number of factors including physical activity or statin use. However, the fact that CPK only attenuated the magnitude of the association of BCd with grip strength is consistent with this biomarker being a better indicator of biologically active Cd than UCd. Finally our results have important practical implications. Of note is that in the US adult population, a 3-year increase in age was associated with a 2.14 kg decrease in combined grip strength, which is similar to the observed difference in strength between those in the highest vs the lowest quartile of Cd. Although the clinical relevance of a 2-kg decrease in combined grip strength at the individual level is uncertain, small changes in the distribution of muscle strength, resulting from the widespread exposure to Cd, may have an important impact in functional disability in the overall population. .
Fig. 2. Handgrip strength as a smooth function of creatinine-corrected urine cadmium concentrations among US adults. Mean differences (95% confidence intervals) in grip strength according to creatinine-corrected urine cadmium concentrations based on restricted cubic splines with knots at the 10th, 50th, and 90th percentile of cadmium distribution. The reference value is set at the 25th percentile of the cadmium distribution. Models are adjusted for age, sex, race/ethnicity, education, BMI, physical activity, tobacco smoke, alcohol consumption, diet quality, hypertension, diabetes, cardiovascular disease, cancer and arthritis. Lines represent mean differences (thick line) and 95% confidence interval (dashed lines), and vertical bars represent the histogram of blood cadmium distribution.
5. Conclusions In the US adult population, higher cadmium exposure was crosssectionally associated with decreased grip strength, a strong predictor of all-cause mortality. These results may have important public health implications given the widespread cadmium exposure. Still, future
representativeness of the US population, the high quality laboratory methods, the number of potential confounders evaluated, as well as the consistency of the various sensitivity analyses performed. Among its
Fig. 3. Mean differences (95% confidence interval) of muscle strength comparing participants in the highest to those in the lowest quartile of blood and creatinine-corrected urine cadmium concentrations by participant characteristics. Results are shown for the highest vs the lowest quartile of blood and urine Cd. P-values for interaction terms were computed in models for ordinal Cd quartiles. 5
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longitudinal cohort studies are needed to confirm these findings and to understand its biological mechanisms before we can draw any firm conclusions on the relationship between cadmium and grip strength.
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Author contributions EGE conceptualized the study. MCR acquired data. MCR and EGE conducted statistical analyses. MCR and EGE interpreted the results and drafted the initial manuscript. All authors reviewed the manuscript for important intellectual content and approved the final version as submitted. Sources of support This work has been supported by grants PI18/287 and 16/609 from the Instituto de Salud Carlos III, State Secretary of R+D+I, and FEDER/FSE. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.envres.2019.108819. References ATSDR, 2019. Toxicological profile: cadmium. [WWW Document]. https://www.atsdr. cdc.gov/toxprofiles/tp.asp?id=48&tid=15 (accessed 7.2.19). Celis-Morales, C.A., Welsh, P., Lyall, D.M., Steell, L., Petermann, F., Anderson, J., Iliodromiti, S., Sillars, A., Graham, N., Mackay, D.F., Pell, J.P., Gill, J.M.R., Sattar, N., Gray, S.R., 2018. Associations of grip strength with cardiovascular, respiratory, and cancer outcomes and all-cause mortality: prospective cohort study of half a million UK Biobank participants. BMJ 361, k1651. Clarkson, P.M., Kearns, A.K., Rouzier, P., Rubin, R., Thompson, P.D., 2006. Serum creatine kinase levels and renal function measures in exertional muscle damage. Med. Sci. Sport. Exerc. 38, 623–627. https://doi.org/10.1249/01.mss.0000210192. 49210.fc. Cooper, R., Kuh, D., Hardy, R., Mortality Review Group, 2010. Objectively measured physical capability levels and mortality: systematic review and meta-analysis. BMJ 341. https://doi.org/10.1136/bmj.c4467. Cooper, R., Kuh, D., Cooper, C., Gale, C.R., Lawlor, D.A., Matthews, F., Hardy, R., 2011. Objective measures of physical capability and subsequent health: a systematic review. Age Ageing 40, 14–23. https://doi.org/10.1093/ageing/afq117. Dodds, R.M., Syddall, H.E., Cooper, R., Benzeval, M., Deary, I.J., Dennison, E.M., Der, G., Gale, C.R., Inskip, H.M., Jagger, C., Kirkwood, T.B., Lawlor, D.A., Robinson, S.M., Starr, J.M., Steptoe, A., Tilling, K., Kuh, D., Cooper, C., Sayer, A.A., 2014. Grip strength across the life course: normative data from twelve British studies. PLoS One 9. https://doi.org/10.1371/journal.pone.0113637.
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