December 2008
volume 24 number 12
Investigation of Selenosis Associated with a Dietary Supplement
Background In March 2008, the Georgia Division of Public Health (DPH) began investigating a possible association between unusual symptoms (including hair loss, nail discoloration, and joint pain) reported by several persons and ingestion of a dietary supplement product named Total Body Formula or Total Body Formula Mega. According to the product label, both Total Body Formula (TBF) products are liquid dietary supplements containing 16 essential vitamins, 18 amino acids, 3 essential fatty acids, whole grape extract, coenzyme Q10, and over 70 minerals (which the manufacturer describes as trace minerals in a `colloidal' suspension formulation). At the same time, several states and the federal Food and Drug Administration (FDA) also began similar investigations. On March 27, the FDA issued a press release advising persons not to take any TBF product. The TBF manufacturer initiated a product recall, and all TBF product were removed from stores' shelves. Although the FDA investigation is still active and the results of the final laboratory analysis performed by the FDA have not been released, a preliminary analysis determined that TBF contained selenium far in excess of the amount listed on the product label.
the chemotherapeutic medication cisplatin. Selenium toxicity, or selenosis, is a rare condition in the United States. Case reports and epidemiologic studies from past poisonings, foreign and domestic, show a wide-range of symptoms associated with selenosis . 2-10 Progression of symptoms over time often mirrors the distribution of selenium from its entry into the gastrointestinal tract, to the well-perfused internal organs, and to other less-perfused tissues. Ingestion of excessive amounts of selenium commonly causes gastrointestinal effects such as diarrhea and vomiting. Internal organ toxicity caused by selenosis is often marked by jaundice and cardiac arrhythmias. Distribution of excessive amounts of selenium into musculoskeletal tissues has been shown to cause muscle pain and cramps, as well as joint pain. Selenosis can cause skin rash, hair loss and nail discoloration. Finally, selenosis has been shown to cause neuropathy. A diagnosis of selenosis is clinical and is based upon the occurrence of these symptoms 11. There is no proven antidote or curative treatment. Instead, treatment primarily involves stopping the exposure and providing supportive care for symptoms.
Selenium is a mineral required in trace amounts for good health, and is usually obtained from the diet. The Recommended Daily Allowance (RDA) is defined as the average daily intake that meets a nutrient requirement for nearly all (97-98%) healthy individuals. The RDA for selenium is 55 micrograms (mcg) per day for persons age 14 and over 1. The tolerable upper intake level or UL is defined as the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population. The UL of selenium is 400mcg 1. According to the TBF label, the daily dose of 30 milliliters (ml) would contain 200 mcg of selenium. Preliminary analysis by the FDA determined that TBF contained 40,800 mcg of selenium per 30ml, or approximately 200 times the labeled dose. The analysis also found several different chemical forms of selenium.
Selenium is a nonmetal element, similar to sulfur, that exists in many chemical forms. Selenium has at least an indirect role in immune system function, which has not been fully described. It is also used medically as adjunct treatment with
Biological samples such as serum or urine levels correlate poorly with the degree of toxicity in humans. One reason is that the rate of elimination of selenium depends on the serum concentration. Higher serum concentrations produce the fastest elimination rate, intermediate concentrations produce an intermediate rate of elimination, and lower concentrations produce the slowest elimination rate. Therefore, depending upon the actual dose ingested, very different and unpredictable serum levels of selenium may result. The chemical form of selenium also has an effect on the half-life of the substance, defined as the time required to decrease the concentration in the body by 50%. For example, comparing two common types of ingestible selenium, the amount of time required to decrease the concentration of selenium methionine by 50% can be approximately twice as long as the time to decrease the concentration of sodium selenite 11.
The objectives of the selenosis outbreak investigation in Georgia were to identify persons who ingested TBF, to identify cases and characterize their symptoms, and to prevent additional cases.
The Georgia Epidemiology Report Via E-Mail To better serve our readers, we would like to know if you would prefer to receive the GER by e-mail as a readable PDF file.
If yes, please send your name and e-mail address to Gaepinfo@dhr.state.ga.us. | Please visit, http://health.state.ga.us/epi/manuals/ger.asp for all current and past pdf issues of the GER.
Methods Persons who ingested TBF were identified by several means. A distribution list of Georgia stores selling the product was obtained from local FDA contacts. DPH then contacted the stores. Some store databases had contact information for patients known to have used TBF products either historically or through purchase records. A phone number to the DPH was left at the stores, so they could direct customers who inquired about TBF products to contact the DPH. Many persons who ingested TBF were identified by currently-identified users, including family and friends. The names of individuals who purchased TBF directly from the manufacturer's internet web site were part of the distribution list obtained from FDA. Names of Georgia residents who ingested TBF were also supplied by other states' health departments and poison centers.
To identify persons who became ill after ingesting TBF (cases), we constructed a case definition of selenium toxicosis based upon the recommendations of toxicologists at CDC's National Center for Environmental Health (NCEH), shown in Box 1. Based upon the case definition, a questionnaire was developed in collaboration with other affected state health departments and with toxicologists at NCEH. In April 2008, DPH began conducting telephone interviews of Georgia residents who were suspected of ingesting the recalled product. A follow up telephone survey was conducted in June 2008 to assess progression or resolution of symptoms.
Results In Georgia, 63 persons who ingested TBF were contacted in the first survey during April 2008, of whom 51 met the case definition for selenium toxicosis. The median age of the casepatients was 51 years. The youngest was 10, and the oldest was 87; 55% were male; 84% were non-Hispanic whites and 16% were non-Hispanic blacks. Symptoms and signs of this intoxication were diffuse, and they persisted and/or evolved over time. The most frequent symptoms reported during the first survey were fatigue, hair loss, joint pain, muscle pain or cramping, and nail discoloration (Table 1). Between the first survey in April and the follow up survey in June (in which 40 [78%] of the 51 case-patients were interviewed), there were notable declines in the frequencies of headache, fever, diarrhea, nausea, and vomiting and small increases in the frequencies of hair loss, nail discoloration, and difficulty controlling limbs (Figure 1). Hair loss and nail discoloration were the most frequent symptoms reported by casepatients during the second survey. Nail discoloration began as white bands that would then often necrose and turn black. This often resulted in loss of the affected nails. Some cases lost many, or even all, of their fingernails and toenails. In addition, 27% of respondents in the second survey reported mood change or memory loss.
Discussion Our investigation identified over 60 persons in Georgia who ingested a formulation of Total Body Formula dietary supplement containing high levels of selenium, 51 of whom met the investigation case definition of selenium toxicosis (Box 1). The majority of case-patients had symptoms of selenium intoxication, and for some, the symptoms were severe and illness lasted for months. During interviews, many cases said they did not suspect that a `health product' could make them ill, and they never mentioned to their healthcare providers that they were taking Total Body Formula, even after weeks of unexplained symptoms and multiple doctor visits. Some cases even reported increasing their dose to help them get over their illness. This underscores the importance of patients informing their healthcare providers about all dietary supplements in addition to herbal remedies, prescription, and over-the-counter medications.
In the manufacture of dietary supplements, depending upon the size of the operation, the manufacturer might contract with one or more pre-mixers. A pre-mixer is a separate company with whom the manufacturer contracts to weigh, measure, and provide specific ingredients, such as particular vitamins, minerals, or other ingredients. Pre-mixers vary in the number of employees they have. They can be very small operations with few or no professional chemists on staff. They can also be located outside the United States. The final mixer, i.e. the manufacturer, mixes all of the ingredients into the final formulation. The final mixer may then use a distributor, or sell directly to retailers or customers, depending upon the size of the company.
According to FDA regulations 12, the final mixer is responsible for the quality of the final product, which includes all ingredients received from each of their pre-mixers. However, routine testing is not currently required of pre-mixed ingredients, nor of the final product. Good Manufacturing Practices (GMPs), which govern the manufacturing process, but not necessarily the outcome, are also not required of all pre-mixers and final mixers 12. GMPs can be defined generally as a part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use. In September 2007, the FDA issued guidelines for the implementation of Good Manufacturing Practices based upon the number of employees. Supplement makers having greater than 500 employees had to meet GMPs by June 2008, those with 20 to 500 employees by June 2009, and finally, those with fewer than 20 employees by the year 2010. Neither the pre-mixers nor the final mixer were
Division of Public Health http://health.state.ga.us
S. Elizabeth Ford, M.D., M.B.A., F.A.A.P. Acting Director, State Health Officer
Martha N. Okafor, Ph.D., Deputy Director Health Information, Policy, Strategy, & Accountability
John M. Horan, M.D., M.P.H. State Epidemiologist
Director, Epidemiology Section http://health.state.ga.us/epi
Cherie Drenzek, D.V.M., M.S. Director, Acute Disease Epi Section
Georgia Epidemiology Report Editorial Board
Carol A. Hoban, M.P.H., Ph.D. Editor Kathryn E. Arnold, M.D.
Cherie Drenzek, D.V.M., M.S. John M. Horan, M.D., M.P.H. S. Elizabeth Ford, M.D., M.B.A., F.A.A.P. Angela Alexander - Mailing List Jimmy Clanton, Jr. - Graphic Designer
-2 -
Georgia Department of Human Resources
Division of Public Health
Two Peachtree St., N.W. Atlanta, GA 30303-3186 Phone: (404) 657-2588
Fax: (404) 657-7517
Please send comments to: gaepinfo@dhr.state.ga.us
subject to GMPs at the time of processing the implicated TBF Figure 1. Comparison (%) of reported symptoms among
products.
Georgia case-patients between April and June surveys.
Some aspects of this outbreak differed from a "typical" outbreak involving an infectious disease and presented different challenges for the investigation. The cause (selenosis) is rare, and cases presented with uncommon symptoms and/or uncommon combinations of symptoms, making the correct diagnosis difficult. Because the source of illness was ingestion of a toxic amount of a mineral, and not contact with an infected person or vector, there was less clustering of cases by time and place, and no secondary transmission occurred as a result of contact with cases. Also, as noted above, the common link among cases ingestion of the TBF products was difficult to identify if ill persons did not report this exposure to their healthcare providers.
The risk of events such as this can be reduced by ensuring products are produced in accord with recommended Good Manufacturing Practices. Additionally, routine testing of ingredients can help prevent incorrect formulations from being sold to the public. Also, patients and their healthcare providers should include products such as dietary supplements and herbal remedies, in addition to prescription and over-the-counter medications, when reviewing lists of patients' medications and supplements.
Box 1. Case Definition of Selenium Toxicosis A resident of Georgia who ingested Total Body Formula and experienced 2 or more of the following symptoms since January 1, 2008: - Headache, weakness - Gastrointestinal symptoms; foul breath - Jaundice or abnormal liver function tests - Muscle or joint pains - Oliguria/anuria or abnormal renal function tests - Anemia or hematological changes - Hair loss, fingernail discoloration or changes; rash
Table 1. Symptoms reported by Georgia case-patients in
April 2008 survey
n
% *
Fatigue
42
86
Hair Loss
37
79
Joint Pain
38
76
Muscle Pain/ Cramps
28
62
Nail Discoloration
26
53
Tingling Extremities Headache
24 22
51 47
* Percentages calculated as the number of cases
Nausea
22
46 who reported
Foul Breath Rash
15 17
42 40
the symptom divided by the total number
Vomiting
13
27 answering `yes'
Fever Diarrhea
9 35
21 21
or `no.' Missing or `unknown' answers were not
Difficulty Controlling Limbs
6
13 included.
100
90
80
70
60
50
40
30
20
(%)
10 0
April 2008 June 2008
Fatigue Hair MlousssJcolientppaainin/cNraamilpTdiiinnsggcloinlograintioenxtremitieHseadache NausFeoaul breath (Reported Symptoms)
RashVomiting
DFiffeicvuelrtyDicaornrhtreoalling
limbs
References 1. Supplements OoD. Facts sheet on selenium. Available at: http://
ods.od.nih.gov/factsheets/selenium.asp. 2. Bratter P, Negretti de Bratter VE, Jaffe WG, Mendez Castellano
H. Selenium status of children living in seleniferous areas of Venezuela. J Trace Elem Electrolytes Health Dis. Dec 1991;5(4):269-270. 3. Howe M. Selenium in the blood of South Dakotans. Arch Environ Health. Nov-Dec 1979;34(6):444-448. 4. Lo MT, Sandi E. Selenium: occurrence in foods and its toxicological significance--a review. J Environ Pathol Toxicol. Aug 1980;4(1):193-218. 5. Longnecker MP, Taylor PR, Levander OA, et al. Selenium in diet, blood, and toenails in relation to human health in a seleniferous area. Am J Clin Nutr. May 1991;53(5):1288-1294. 6. Swanson CA, Longnecker MP, Veillon C, et al. Selenium intake, age, gender, and smoking in relation to indices of selenium status of adults residing in a seleniferous area. Am J Clin Nutr. Nov 1990;52(5):858-862. 7. Wilber CG. Toxicology of selenium: a review. Clin Toxicol. Sep 1980;17(2):171-230. 8. Yang G, Yin S, Zhou R, et al. Studies of safe maximal daily dietary Se-intake in a seleniferous area in China. Part II: Relation between Se-intake and the manifestation of clinical signs and certain biochemical alterations in blood and urine. J Trace Elem Electrolytes Health Dis. Sep 1989;3(3):123-130. 9. Yang G, Zhou R, Yin S, et al. Studies of safe maximal daily dietary selenium intake in a seleniferous area in China. I. Selenium intake and tissue selenium levels of the inhabitants. J Trace Elem Electrolytes Health Dis. Jun 1989;3(2):77-87. 10. Yang GQ, Wang SZ, Zhou RH, Sun SZ. Endemic selenium intoxication of humans in China. Am J Clin Nutr. May 1983;37(5):872-881. 11. Prevention Af TSaDRCfDCa. ToxFAQsTM: Selenium. Vol Available on the web at: http://www.atsdr.cdc.gov/tfacts92. html. 12. Nutrition CfFSaA. Overview of Dietary Supplements. http:// www.cfsan.fda.gov/~dms/ds-oview.html.
This article was written by Paul Melstrom, Ph.D.
-3 -
The Georgia Epidemiology Report Epidemiology Branch Two Peachtree St., NW Atlanta, GA 30303-3186
Providers can contact Public Health IMMEDIATELY 24 hours a day, 7 days a week, by calling: 1-866-PUB-HLTH (1-866-782-4584) to report immediately notifiable diseases and public health emergencies
PRESORTED STANDARD U.S. POSTAGE
PAID ATLANTA, GA PERMIT NO. 4528
December 2008
Volume24Number12
Reported Cases of Selected Notifiable Diseases in Georgia, Profile* for September 2008
Selected Notifiable Diseases
Campylobacteriosis Chlamydia trachomatis Cryptosporidiosis E. coli O157:H7 Giardiasis Gonorrhea Haemophilus influenzae (invasive) Hepatitis A (acute) Hepatitis B (acute) Legionellosis Lyme Disease Meningococcal Disease (invasive) Mumps Pertussis Rubella Salmonellosis Shigellosis Syphilis - Primary Syphilis - Secondary Syphilis - Early Latent Syphilis - Other** Syphilis - Congenital Tuberculosis
Total Reported for September 2008
2008 53 319 27 4 52 220 6 8 17 7 2 2 0 2 0 326 76 9 55 31 67 0 44
Previous 3 Months Total Ending in September
2006
2007
2008
178
227
246
10080
11474
5279
103
113
79
18
26
18
240
208
223
5783
4904
2254
21
21
26
21
13
17
58
46
46
14
7
15
3
4
13
3
9
4
0
0
0
12
3
10
0
0
0
815
764
989
339
335
189
25
32
33
140
173
174
98
111
115
249
297
261
1
2
0
147
111
125
Previous 12 Months Total Ending in September
2006
2007
2008
561
675
717
38920
43185
36167
246
274
233
44
41
50
714
660
681
19765
18610
14100
114
128
145
64
68
53
196
162
159
38
41
48
8
9
26
18
25
21
5
0
2
31
19
22
0
0
0
1933
1880
2373
1043
1786
1342
129
111
121
489
568
676
402
429
467
1006
1144
1252
8
11
8
517
484
494
* The cumulative numbers in the above table reflect the date the disease was first diagnosed rather than the date the report was received at the state office, and therefore are subject to change over time due to late reporting. The 3 month delay in the disease profile for a given month is designed to minimize any changes that may occur. This method of summarizing data is expected to provide a better overall measure of disease trends and patterns in Georgia.
** Other syphilis includes latent (unknown duration), late latent, late with symptomatic manifestations, and neurosyphilis.
AIDS Profile Update
Report Period
Latest 12 Months
Disease
Total Cases Reported*
Classification <13yrs
>=13yrs Total
HIV, non-AIDS 19
3,149
3,168
Percent Female MSM
28
25
Risk Group Distribution %
IDU
MSM&IDU HS
Unknown Perinatal White
2
1
4
67
1
18
Race Distribution %
Black
Hispanic Other
77
4
1
11/07-10/08 AIDS
2
1,981
1,983
27
30
3
1
7
60
<1
19
75
5
1
Five Years Ago:**
HIV, non-AIDS -
-
-
-
-
-
-
-
-
-
-
-
-
-
11/03-10/04 AIDS
12
1,582
1,594
29
33
7
3
15
41
1
19
75
5
1
Cumulative: HIV, non-AIDS 222
12,853
13,075
31
28
6
2
10
53
2
21
75
4
1
07/81-10/08 AIDS
239
33,314
33,553
20
43
14
5
14
23
1
30
67
3
1
Yrs - Age at diagnosis in years
MSM - Men having sex with men
IDU - Injection drug users
HS - Heterosexual
* Case totals are accumulated by date of report to the Epidemiology Section ** Due to a change in the surveillance system, case counts may be artificially low during this time period
***HIV, non-AIDS was not collected until 12/31/2003
- 4 -