Dietary Supplements, Selenium and
Chronic Disease Prevention
Saverio Stranges, MD, PhD
Clinical Sciences Research Institute
University of Warwick Medical School, UK
Outline
 Context on Dietary Supplements
 Physiological Role of Selenium
 Selenium and Human Health
 Perspectives
Dietary Supplement
“A dietary supplement is a preparation intended to
supply nutrients (such as vitamins, minerals, or
amino acids) that are missing or not consumed in
sufficient quantity in a person's diet”
Context:
Dietary Supplement Use in US
1990: “Nutrition Labeling and Education Act”
1994: “Dietary Supplement Health and Education Act”
1997-onwards: Dramatic increase in supplement sales
$18.8 billion in 2003
1999/2000: 52% of US adults take some
type of dietary supplements (NHANES)
Dietary Supplement Use in US Adults (≥ 20 ys)
Prevalence users (%)
60
50
56.7
Women
Men
46.9
38.0
40
31.7
30
13.5
20
11.7
10
1.0 1.1
0
Any dietary
supplement
Multivitamin/
multimineral
Vitamin E
Selenium
NHANES 1999-2000. Am J Epidemiol. 2004; 160:339-49
Trends in Daily Use of Vitamin/Mineral
Supplements - US Adults (≥ 18 ys)
38.7
Women
Prevalence users (%)
40
Men
35
30
26.8
25
28.7
26.8
20.2
19.2
20
15
10
5
0
1987
1992
2000
National Health Interview Survey. J Am Diet Assoc. 2004; 104:942-950
Context:
Dietary Supplement Use in Europe
 2002: Directive 2002/46/EC - Food Supplements Directive
 2004: Decreto Legislativo 169/2004 (Italy)
 150 millions euros/year in dietary supplements (Italy)
 20-30% dietary supplement users (among adults) in Europe
Dietary Supplements in the Market
Category
Single Vitamin
Example
Vitamin A, C, E
Multiple Vitamins
B complex, CentrumTM
Single Minerals
calcium, zinc, selenium
Multiple Minerals
Vitamins + Minerals (VM)
VM + other products
Amino Acids
Fish Oils
Glandulars
Fiber
iron and zinc, calcium and magnesium
centrumTM with minerals
One-a-DayTM with Gingko
lysine, methionine, tryptophan
omega-3 fatty acids
pancreas, liver, organ extracts
fiberwafersTM, florabiberTM
Botanicals, herbs
Echinacea, ginseng, St. John’s Wort
Antacids as calcium suppl.
Tums Antacid/Calcium SupplementTM
Why Do People Take Dietary
Supplements?
 Balance a poor diet/promote optimal health, fitness
 Prevent/manage minor ailments or chronic disease
 Distrust of conventional medicine
 Media pressure
 Co-responsibility of health professionals…
Social Perception of Dietary Supplement Use
Regular users
90
Nonusers
85
73
80
70
Yes (%)
60
49
50
40
34
30
33
24
19
20
10
0
Supplements are
good for health?
Access is very
important
Supplements are
adequately tested
Stop using
if ineffective
Blendon JB et al. Arch Intern Med. 2001; 161:805-810
Use of “Antioxidants” among Physicians…
44.0
45
39.0
Prevalence users (%)
40
32.0
35
30
25
19.0
20
15
10
5
0
Any
Vitamin E
Vitamin C
Am J Cardiol. 1997; 79:1558-60
β Carotene
It won’t hurt and
might help, so
why not take it?
Doctor, why
should I take
this pill?
BUT…
The Beta-Carotene and Retinol Efficacy Trial
Beta Carotene + Retinol (Vitamin A)
Lung Cancer Incidence
Mortality
CARETrial. N Engl J Med. 1996; 334:1150-5
Vitamin E Supplementation and Mortality
Miller ER et al. Ann Intern Med 2005;142:37-46
Mortality in Randomized Trials of
Antioxidant Supplements
1.3
*
RR (95% CI)
1.2
1.1
*
*
*
1
0.9
0.8
0.7
Overall
Beta
Carotene
Vitamin A
Vitamin C
Vitamin E
*P < .05
Bielakovic G. JAMA. 2007; 297:842-857
Selenium
…Selene, Moon Goddess…
Physiological Role of Selenium
 Selenium is an essential trace mineral
 Selenium is incorporated as seleno-cysteine (Sec)
 At least 25 seleno-proteins in humans
 Complex genetic mechanism encoded by the UGA codon
Selenium Metabolism
Papp LV. Antioxid. Redox Signal. 2007; 9:775-806
Physiological Functions of Selenium
 Redox Homeostasis
(e.g., glutathione peroxidases, thioredoxin reductases )
 Thyroid Hormone Metabolism
(iodothyronine 5’-deiodinase)
 Reproduction/Testosterone Biosynthesis
 Membrane Integrity
 Immune Function/Prostacyclin Production
Bioavailability of Selenium
 Geographical variations in soil selenium content
 Plant foods are the major dietary sources
 Meats, seafood, and bread are common sources
 55 µg/day: recommended intake (RDA) to optimize GPx activity
 70-90 µg/L: plasma Se levels to optimize GPx activity
 400 µg/day: tolerable upper intake level (UL)
 Increasing use of Se-enriched foods and fertilizers
Dietary Sources of Selenium
Food
µg
% Daily Value
Brazil nuts, 1 ounce
544
780
Daily Value (DV) for Selenium
70
100
Tuna, light, canned in oil, drained, 3 ounces
63
95
Beef, cooked, 3½ ounces
35
50
Cod, cooked, 3 ounces
32
45
Turkey, light meat, roasted, 3½ ounces
32
45
Chicken Breast, meat only, roasted, 3½ ounces
20
Noodles, enriched, boiled, 1/2 cup
17
25
Macaroni, elbow, enriched, boiled, 1/2 cup
15
20
Egg, whole, 1 medium
14
20
Cottage cheese, low fat 2%, 1/2 cup
12
15
Rice, white, enriched, long grain, cooked, 1/2 cup
12
15
Rice, brown, long-grained, cooked, 1/2 cup
10
Bread, enriched, whole wheat, 1 slice
10
High
Good
http://dietary-supplements.info.nih.gov/factsheets/selenium.asp
30
15
15
…Strategies to Increase Selenium Intake…
Dietary Selenium Intake Worldwide (90’s)
Optimal
GPx activity
Rayman MP. Lancet 2000; 356:233-241
Selenium Status in Italy
118.8 μg/L
Sesana G et al. Sci Total Environ. 1992 ;120:97-102.
Plasma Selenium and Selenoproteins
240
μg selenium/L plasma
200
Se-P
GPx
160
120
80
40
0
Modified from Burk RF. Nutr Clin Care. 2002; 5:75-79
Se-Met
Selenium and Human Health
Where Did it Begin…?
Keshan
Keshan Disease Research Group. Chin Med J. 1979; 92:471-476
Keshan Disease, Endemic Cardiomyopathy
Diseases Related to Selenium
Selenium Deficiency
• Keshan disease (endemic cardiomyopathy)
• Viral Infections (HIV) and immune disease
• Reproduction-related disorders (miscarriage, male infertility)
Selenium Status/Supplements and Chronic Disease
• Cancer, all-cause mortality
• Cardiovascular disease
• Metabolic disease: type 2 diabetes, serum lipids
Cancer IncidenceMortality
Geographic Studies: Selenium
Levels in Forage Crops*
10% higher cancer mortality for major cancer sites in low-Se areas
*L C Clark et al., 1991
Selenium Supplementation and
Chronic Disease Prevention
The Nutritional Prevention of
Cancer (NPC) Trial
Clark LC et al. JAMA 1996; 276: 1957-1963
Arizona Cancer Center
NPC Study Population
• Multi-center, double-blind, randomized, placebo-controlled
• 1,312 residents from Eastern United States
• Previous history of non-melanoma skin cancer
• Mean age, 63 years; range, 18-80 years; ¾ males
• 200 μg selenium per day (as selenium yeast) or placebo
• Blinded phase of the trial: 1983-1996
• Compliance: 79.3%
NPC Endpoints
Primary Endpoint
• Recurrent skin basal (BCC) and squamous cell (SCC) carcinomas
Secondary Endpoints
• All-cause mortality
• Total cancer mortality
• Total and site-specific cancer incidence (lung/prostate/colorectal)
• Cardiovascular disease (CVD) incidence and mortality
• Type 2 diabetes
200
250
Plasma Selenium Concentrations during NPC
150
Selenium
0
50
100
Placebo
0
12
24
36
48
60
72
84
96
Months from randomization
108
120
132
144
NPC Findings: Cancer Incidence
(1983-1996, 7.4 years follow-up)
Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639
NPC Findings: Cancer-Specific
(1983-1996, 7.4 years follow-up)
Cases
Adjusted hazard ratios*
Cancer
Se
Placebo
HR
95% CI
P
Total Cancer Incidence
105
137
0.75
0.58-0.97
0.03
Prostate
22
42
0.48
0.28-0.80
0.005
Colorectal
9
19
0.46
0.21-1.02
0.057
Total Cancer Mortality
40
66
0.59
0.39-0.87
0.008
1.17
1.02-1.34
0.03
Non-melanoma skin
*adjusted for age, gender, and smoking status at randomization
Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639
Duffield-Lillico AJ et al. J Natl Cancer Inst. 2003; 95:1477-81
NPC - Total Cancer Incidence
(1983-1996, 7.4 years follow-up)
Cases
Gender
Female
Male
Smoking status
Never
Former
Current
By baseline Se
≤ 105.2 (ng/ml)
105.3–121.6
>121.6 (ng/ml)
Adjusted hazard ratios
Se
Placebo
HR
95% CI
P
P, int
23
82
20
117
1.20
0.67
0.66–2.20
0.50–0.89
0.55
0.005
0.14
25
42
38
26
61
50
0.81
0.66
0.86
0.47–1.41
0.44–0.97
0.56–1.31
0.46
0.04
0.47
0.76
27
34
44
54
46
37
0.51
0.70
1.20
0.32–0.81
0.44–1.09
0.77–1.86
0.005
0.11
0.43
0.007
Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639
NPC - Total Cancer Incidence
(1983-1996, 7.4 years follow-up)
Adjusted* HR
Selenium Group
By baseline Se
≤ 105.2 (ng/ml)
105.3–121.6
>121.6 (ng/ml)
Placebo Group
By baseline Se
≤ 105.2 (ng/ml)
105.3–121.6
>121.6 (ng/ml)
95% CI
P
P trend
0.01
1.00
1.29
1.88
0.78–2.15
1.15–3.05
0.32
0.01
0.20
1.00
0.88
0.76
0.59–1.31
0.50–1.16
0.52
0.20
*adjusted for age, gender, and smoking status at randomization
Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639
SUMIVAX Trial, France
7.5 years follow-up, n=13,017
Cancer Incidence
Overall
Gender
Female
Male
Total Mortality
Overall
Gender
Female
Male
Int.
Placebo
RR
95% CI
P
267
295
0.90
0.76-1.06
0.19
P, int
0.02
179
88
171
124
1.04
0.69
0.85-1.29
0.53-0.91
0.53
0.008
76
98
0.77
0.57-1.00
0.09
0.11
36
40
35
63
1.03
0.63
0.64-1.63
0.42-0.93
0.92
0.02
100 μg Selenium +
120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc
Hercberg S et al. Arch Intern Med. 2004;164:2335-2342
Selenium Status and Cancer Mortality
NHANES III, 13,887 US adults
Bleys J et al. Arch Inter Med. 2008; 168:404-410
Selenium Status and All-Cause Mortality
NHANES III, US
Bleys J et al. Arch Inter Med. 2008; 168:404-410
CVD
Incidence/Mortality
Selenium Status and CVD
Eastern Finland
4
Low serum selenium (<45μg/l)
Serum selenium (≥45μg/l)
3
*
2.9
*
OR 2
2.2
*
2.1
1
0
CHD death
CVD death
*P < 0.001
Salonen JT et al. Lancet. 1982; 2:175-9
MI
Selenium Status and CVD Mortality
NHANES III, 13,887 US adults
Bleys J et al. Arch Inter Med. 2008; 168:404-410
Antioxidant Supplementation and CHD Incidence
SUMIVAX Trial, France, 7.5 years follow-up
CHD Incidence
Overall
Gender
Female
Male
Int.
Placebo
RR
95% CI
P
134
137
0.97
0.77-1.20
0.80
P, int
0.44
27
107
23
114
1.17
0.82
0.67-2.05
0.71-1.20
0.57
0.54
100 μg Selenium +
120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc
Hercberg S et al. Arch Intern Med. 2004;164:2335-2342
Selenium Supplementation and
CVD Incidence/Mortality
NPC Trial (1983-1996)
Participants without prevalent CVD at randomization (n = 1,004)
Mean follow-up: 7.6 years
Cases
CVD
Adjusted hazard ratios*
Se
Placebo
HR
95% CI
P
All CVD
103
96
1.03
0.78-1.37
0.81
All CHD
63
59
1.04
0.73-1.49
0.81
ALL CVA
40
37
1.02
0.65-1.59
0.94
CVD Mortality
40
31
1.22
0.76-1.95
0.41
All-cause Mortality
110
111
0.95
0.73-1.24
0.71
*adjusted for age, gender, and smoking status at randomization
Stranges S et al. Am J Epidemiol 2006; 163:694-699
Selenium Supplementation and Recurrent CVD
NPC Trial (1983-1996)
Participants with prevalent CVD at randomization (n = 246)
Mean follow-up: 5.5 years
Cases
CVD
Adjusted hazard ratios*
Se
Placebo
HR
95% CI
P
All CVD
56
65
0.79
0.55-1.14
0.21
All CHD
42
48
0.80
0.53-1.22
0.29
ALL CVA
14
17
0.76
0.37-1.55
0.45
CVD Mortality
30
28
1.06
0.63-1.78
0.81
All-cause Mortality
45
58
0.76
0.51-1.12
0.16
*adjusted for age, gender, and smoking status at randomization
Stranges S et al. Am J Epidemiol 2006; 163:694-699
Meta-analysis of Trials on Selenium and CHD
Mateo GF et al. Am J Clin Nutr 2006; 84:762-773
Type 2 Diabetes/Lipids
The Common Soil Hypothesis Revisited
Ceriello A, Motz E. ATVB 2004; 24: 816-823
Selenium Supplementation
and Incidence of Type 2 Diabetes
NPC Trial (1983-1996)
• To examine the efficacy of selenium supplementation in
the primary prevention of type 2 diabetes
• 1,202 participants free of type 2 DM at randomization
• Self-reported diagnosis/medical records for type 2 DM
ascertainment (for both incident and prevalent cases)
• 200 μg of selenium/day (n=600) or placebo (n=602)
Characteristics of Participants at Randomization
Characteristics
Participants randomized (no.)
Age, years
Education, years
Gender, males (%)
Body mass index, kg/m2
Smoking status (%)
Never
Former
Current
Pack-years of smoking
Plasma selenium, ng/ml
Mean
33rd
50th
66th
Selenium
600
63.4 (10.2)
12.9 (3.4)
74
25.6 (3.9)
Placebo
602
63.0 (9.9)
12.9 (3.3)
75
25.5 (4.1)
34.0
39.0
27.0
56.8 (40.3)
30.0
40.0
30.0
56.6 (39.0)
114.4 (22.6)
105.6
113.6
122.4
114.0 (21.5)
104.8
113.2
121.2
No difference between treatment groups was statistically significant (P ≤ 0.05)
0.15
Cumulative Incidence of Type 2 Diabetes
0.10
Selenium
0.05
Placebo
0.00
Log-rank test p value = 0.050
0
5
10
Years of follow-up
Stranges S et. al. Ann Intern Med 2007; 147:217-223
15
Incidence of Type 2 DM by Baseline Characteristics
Cases
Overall
Incidence
Adjusted hazard ratios*
Se
Placebo
Se
Placebo
HR
95% CI
P
58
39
12.6
8.4
1.55
1.03-2.33
0.03
P, int
0.88
Age (yrs.)
 65
25
18
9.8
6.7
1.53
0.83-2.82
0.17
> 65
33
21
15.9
10.8
1.60
0.92-2.76
0.09
0.54
Gender
Female
9
8
6.8
6.3
1.38
0.52-3.64
0.51
Male
49
31
14.8
9.2
1.62
1.04-2.55
0.03
*mutually adjusted for other baseline covariates
Incidence of Type 2 DM by Baseline Characteristics
Cases
Incidence
Adjusted hazard ratios*
Se
Placebo
Se
Placebo
HR
95% CI
P
Never
15
12
9.1
8.2
1.16
0.54-2.49
0.70
Former
30
18
17.2
10.0
1.67
0.93-3.00
0.09
Current
13
9
10.4
6.6
1.70
0.71-4.00
0.24
Smoking
P, int
0.53
0.23
BMI
< 25
18
9
7.8
3.6
2.11
0.95-4.72
0.08
≥ 25
40
30
17.5
14.7
1.25
0.78-2.00
0.36
*mutually adjusted for other baseline covariates
Incidence of Type 2 DM by Baseline Plasma Selenium
Cases
Se
Placebo
Incidence
Se
Placebo
Adjusted hazard ratios*
HR
95% CI
P
P, int
0.028
By median
 113.4
26
25
11.1
10.7
1.04
0.60-1.80
0.89
> 113.4
32
14
14.1
6.1
2.50
1.32-4.77
0.005
0.038
By tertiles
 105.2
18
18
11.6
11.3
1.13
0.58-2.18
0.72
105.3-121.6
14
10
8.8
6.5
1.36
0.60-3.09
0.63
> 121.6
26
11
17.5
7.3
2.70
1.30-5.61
0.008
*adjusted for age, BMI, gender, and smoking status at randomization
Summary of Results
• No benefit from selenium supplementation on type 2 DM
• Potential adverse effects of long-term se supplementation
• Higher risk of type 2 DM at higher selenium concentrations
client.dssimon.com/viewvideo/acp28.wmv
Limitations
• Diabetes incidence was not a primary end-point of the trial
• Small number of diabetes cases
• Self-reported diagnosis
• Lack of biomarkers of glucose metabolism
• Lack of additional potential confounders
• Selected nature of participants (elderly, eastern US)
Strengths
• Only trial with a long-term selenium supplementation
• High compliance with the intervention (80.3% s, 78.4% p)
Selenium Status and Prevalent Diabetes
NHANES III, 8,876 US adults
Cases/non-cases
Fully-adjusted OR
Se-Quintile 1
(<111.62 ng/ml)
285/1,708
1.00 (reference)
Se-Quintile 5
(137.66 ng/ml)
311/1,266
1.57 (1.16–2.13)
Bleys J et al. Diabetes Care. 2007; 30:829-834
Antioxidant Supplementation and Glucose Levels
SUMIVAX Trial, France, 7.5 years follow-up, n=3,146
β ± SE
P
ß-carotene, 0.5 µmol/L
–0.032 ± 0.008
<0.0001
Vitamin C, 4.9 µg/mL
–0.015 ± 0.007
0.0455
Vitamin E, 7.7 µmol/L
0.005 ± 0.007
0.5164
Selenium, 0.2 µmol/L
0.030 ± 0.008
<0.0001
Zinc, 1.8 µmol/L
–0.002 ± 0.008
0.8108
Baseline Plasma concentration
100 μg Selenium +
120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc
Czernichow S et al. Am J Clin Nutr. 2006; 84:395-399
Antioxidant Supplementation and Lipids
SUMIVAX Trial, France, 7.5 years follow-up, n=12,741
Lipids
Suppl vs. Placebo
Mean Cholesterol
Hypercholesterolemia
Mean triglycerides
Hypertriglyceridemia
P
No difference
Higher in Suppl (women)
<0.05
Higher in Suppl (both sexes)
<0.05
Higher in Suppl (men)
<0.05
100 μg Selenium +
120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc
Hercberg S et al. Lipids. 2005; 40:335-42
Selenium Status and Lipids
NHANES III, 5,452 US adults
Total Cholesterol
Apolipoprotein A1
LDL-cholesterol
Triglycerides
Apolipoprotein B
HDL-cholesterol
Bleys J, Navas-Acien A, Stranges S et al. Am J Clin Nutr. 2008; 88:416-23
Total Cholesterol by Se Quartiles:
UK NDNS 2000/01; US NHANES III
5.8
UK
mmol/L
5.6
US
5.4
5.2
5
4.8
Q1
<77.4
Q4
≥95.6
Q1
<113.7
Selenium Quartiles (µg/L)
Stranges S et al. (under review)
Q4
≥134.7
Selenium Status and CVD Risk Factors
Olivetti Heart Study
Jossa F et al. Atherosclerosis. 1991; 87:129-34
Biological Plausibility
Selenium Status in the NPC Trial vs. Europe
Rayman MP. Lancet 2000; 356:233-241
Plasma Selenium and Selenoproteins
200
µg selenium/L plasma
160
Se-P
GPx
120
80
40
0
Modified from Burk RF. Nutr Clin Care. 2002; 5:75-79
Se-Met
Humans
• Narrow therapeutic window of selenium
• Inter-individual variability in selenium metabolism
• Pro-oxidative/apoptotic effects (methylselenol, ROS), which
largely account for the Se-induced anti-cancer effects
• Hypothyroidism/body weight gain in high-selenium diets
• Adverse effects on growth hormone metabolism (low IGF-1)
• Upregulation of genes (FoXO) involved in insulin metabolism
Animal Models
• Over-expression of glutathione peroxidase activity
• Enzyme over-expression may cause insulin resistance
• Release of glucagon with hyperglycemia at high doses
• Insulin-mimetic activities at low doses
• Selenium may accumulate in the pancreatic tissue
Perspectives
• Balance of benefits and harms of selenium supplementation
• Consider dietary intake/selenium status of different populations
• Subtle toxicity for chronic high exposure
• Need to establish the optimal selenium intake to minimize risks
• Need for mechanistic studies/randomized trials
• High-quality prospective studies across different countries
• Concern on the widespread use of selenium supplements
Benefits and Harms of
Selenium Supplementation
Disease
Benefits
Overall Mortality
Unproved
Cancer Incidence
Total
Prostate
Colorectal
Possible
Possible
Possible
Non-melanoma Skin
Cardio-metabolic
CVD
Type 2 Diabetes
Hyperlipidemia
Harms
Possible
Unproved
Possible
Possible
Type 2 Diabetes
+
Selenium
?
Prostate Cancer
…Diabetes and Prostate Cancer Risk…
Non-diabetics
1.2
Diabetics
1
- 28%
0.8
OR 0.6
*
- 47%
*
*
0.4
0.2
0
*P < 0.001
Prostate
Cancer
Low grade
High grade
Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev. 2006; 15:1977-83
…Diabetes and Prostate Cancer Risk…
Hsing AW et al. Am J Clin Nutr 2007;86:843S-857S
Selenium and Vitamin E
Cancer Prevention Trial (SELECT)
Vitamin E
(400 μg/day)
Selenium
+
-
T
+
-
8,100
8,100
8,100
8,100
16,200
16,200
T
16,200
16,200
32,400
(200 μg/day)
 Cost: $175,000,000
http://www.cancer.gov/newscenter/pressreleases/SELECTresults2008
Review of Prostate Cancer Prevention Study Shows
No Benefit for Use of Selenium and Vitamin E Supplements
Initial, independent review of study data from the Selenium and Vitamin E
Cancer Prevention Trial (SELECT), funded by the National Cancer
Institute (NCI) and other institutes that comprise the National Institutes of
Health shows that selenium and vitamin E supplements, taken either
alone or together, did not prevent prostate cancer.
The data also showed two concerning trends: a small but not
statistically significant increase in the number of prostate cancer cases
among the over 35,000 men age 50 and older in the trial taking only
vitamin E and a small, but not statistically significant increase in the
number of cases of adult onset diabetes in men taking only
selenium.
Because this is an early analysis of the data from the study, neither of
these findings proves an increased risk from the supplements and both
may be due to chance.
Keshan
The Nutritional Prevention of
Cancer (NPC) Trial
Acknowledgments
James R Marshall
Richard P Donahue
Ana Navas-Acien
Mary E Reid
Joan M Dorn
Joachim Bleys
Raj Natarajan
Jo L Freudenheim
Eliseo Guallar
Gerald F Combs
Maurizio Trevisan
Larry C Clark†