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 -