Adverse Events Associated With Ingestion of Gamma-Butyrolactone—Minnesota, New Mexico, and Texas, 1998-1999Farm Worker Illness Following Exposure to Carbofuran and Other Pesticides— Fresno County, California, 1998Recall of Tripedia™ VaccineAdverse Events Associated With Ingestion of Gamma-Butyrolactone—Minnesota, New Mexico, and Texas, 1998-1999Farm Worker Illness Following Exposure to Carbofuran and Other Pesticides— Fresno County, California, 1998Recall of Tripedia™ Vaccine FREE

MMWR. 1999;48:137-140

Products containing gamma-butyrolactone (GBL)* are marketed for many claimed purposes, including to induce sleep, release growth hormone, enhance sexual activity and athletic performance, relieve depression, and prolong life. GBL is converted by the body into gamma-hydroxybutyrate (GHB), a drug banned outside of clinical trials approved by the Food and Drug Administration (FDA). Recognized manifestations of GHB toxicity include bradycardia, hypothermia, central nervous system depression, and uncontrolled movements.¹ This report describes seven cases of GBL toxicity involving the product "Revivarant," which is labeled as containing 1.82 g of GBL per fluid ounce, reported from two hospital emergency departments (EDs) in Minnesota during October-December 1998 and summarizes an additional 34 cases of GBL toxicity reported to poison centers in New Mexico and Texas during October 1998-January 1999.

On November 26, 1998, a 24-year-old man vomited and had seizures shortly after drinking 3-4 oz of Revivarant. His behavior became unusual, and he alternated between extreme agitation and profound calm. Paramedics noted that his skin was warm, flushed, and profusely diaphoretic, and he had bradycardia (pulse as low as 45 beats per minute [bpm]). Systolic blood pressure was 110 mm Hg. Transcutaneous oxygen saturations (SpO2) were 96% on room air, and blood glucose by fingerstick was 90 mg/dL. During transport to an ED, he had periods of combativeness lasting 30 to 60 seconds followed by coma lasting 1-3 minutes. In the ED, he was unconscious with spontaneous eye opening, a positive withdrawal reflex, and no speech (Glasgow Coma Scale of 7); rectal temperature was 94.8 F (34.9 C). A urine toxicology screen and blood ethanol test were negative. He was intubated and admitted to the intensive-care unit (ICU) with a diagnosis of toxic encephalopathy. During the next 7 hours, his heart rate increased from 42 to 116 bpm and he became more alert. He had no recollection of events except for having ingested Revivarant. He was discharged with normal mental status.

On December 12, 1998, a 46-year-old woman had a seizure and lost consciousness after drinking approximately 2.7 oz of Revivarant in conjunction with ethanol. Paramedics found her unconscious and in severe respiratory depression with a pulse of 54 bpm. Oxygen was administered by mask; she had an SpO₂ of 87%. On arrival in the ED, physical examination identified sinus bradycardia (54 bpm); temperature of 96.1 F (35.6 C); and miotic pupils. A serum ethanol level was 0.11%. She was admitted to the ICU, mechanically ventilated through the night, and awoke in improved condition the next morning; she was discharged with no memory of the events.

On November 8, 1998, a 31-year-old man drank approximately 1 oz of Revivarant, four beers, and a large sip of wine. Shortly thereafter, he gradually lost consciousness and subsequently fell. He regained consciousness but had involuntary muscle movements and episodes of confusion. Paramedics noted that he was ambulatory but confused. On physical examination in the ED, he was agitated, anxious, and unable to recall the preceding events. His shoulders twitched, and he had a small abrasion below his left eye. He had a pulse of 64 bpm and hypothermia (oral temperature of 95.2 F [35.1 C]). Breath ethanol level was 0.08%. He denied previous GBL use or illicit drug use. He recovered completely and was discharged.

On October 31, 1998, a 24-year-old man (patient 4) and a 26-year-old man (patient 5) each drank 10-13 oz of Revivarant while drinking alcohol at a bar. On leaving the bar, witnesses observed them fall and become unresponsive. On arrival at the ED, they alternated between somnolence and confusion. When awake, neither patient could consistently follow commands. Patient 4 had fecal incontinence. Vital signs for both patients were within normal limits. Breath ethanol levels were 0.09% (patient 4) and 0.15% (patient 5). Neither patient had a history of using medications or illicit drugs. After 2 hours of observation, the patients recovered but were unable to recall most of the evening's events.

On December 12, 1998, a 19-year-old woman (patient 6) and a 22-year-old woman (patient 7) were brought to an ED by friends because of vomiting and decreased levels of consciousness. These symptoms followed ingestion of Revivarant (2 oz by patient 6 and an unknown amount by patient 7). Patient 6 had drunk one beer; patient 7 had had no ethanol. Vital signs were normal except for respiratory depression. On physical examination, patient 6 was lethargic and disoriented. Patient 7 exhibited intermittent periods of extreme agitation, necessitating chemical treatment and physical restraint, punctuated by moments of calm during which her attention focused on minor details. Mental changes for both patients resolved, and they were discharged approximately 4 hours after arrival.

From October 3, 1998, through January 29, 1999, the New Mexico Poison Center identified 14 cases of adverse events resulting in an ED visit among persons who had ingested GBL-containing products. Ten (71%) of the cases were reported in January. Patients' ages ranged from 14 to 36 years; nine were male. Products used included "Firewater" (11 cases), "Blue Nitro Vitality" (two), and "RenewTrient" (one). The approximate amount ingested ranged from 1 to 10 oz (mean: 3 oz). Five (36%) persons also had ingested ethanol and/or other drugs. Most of the patients were discharged from the ED within 13 hours of arrival; three were hospitalized. The most common symptoms and signs were nausea/vomiting (10 [71%]), obtundation (nine [64%]), bradycardia (seven [50%]), prolonged unconsciousness (six [43%]), syncope (six [43%]), seizures (four [29%]), confusion (four [29%]), combativeness (four [29%]), respiratory depression (three [21%]), amnesia (two [14%]), and euphoria (two [14%]). One person had cardiac arrest, one had respiratory arrest, and one had a motor-vehicle crash associated with the effects resulting from use of a GBL-containing product. No deaths were reported.

From October 2, 1998, through January 24, 1999, Texas poison-control centers identified 20 adverse events resulting in ED visits among persons who had ingested GBL-containing products. Twelve (60%) of the cases were reported in January. Patients' ages ranged from 11 to 41 years; 13 were male. Products known to have been used included "RenewTrient" (six cases), "Revivarant" (four), "Revivarant-G" (two), and "Blue Nitro Vitality" (two). Ten persons also ingested ethanol and/or other drugs. Ten patients were admitted to the hospital from the ED. The most common symptoms and signs were obtundation (13 [65%]), prolonged unconsciousness (nine [45%]), respiratory depression (nine [45%]), anxiety/nervousness (seven [35%]), nausea/vomiting (six [30%]), confusion (six [30%]), tremors/twitching (four [20%]), tachycardia (three [15%]), and combativeness (three [15%]). One person had respiratory arrest; no deaths were reported.

SW Smith, MD, AR Topliff, MD, M Danigelis, MD, DL Zvosec, PhD, LL Schrag, MD, SA Freiwald, MD, SR Gunn, MD, Dept of Emergency Medicine, Hennepin County Medical Center, Minneapolis; SC Setzer, Hennepin Regional Poison Center, Minneapolis; M Rock, MD, Methodist Hospital, St. Louis Park; MT Osterholm, PhD, State Epidemiologist, Minnesota Dept of Health. BE Benson, PharmD, New Mexico Poison Center, Albuquerque; J Padilla, MS, R Voorhees, MD, CM Sewell, DrPH, State Epidemiologist, New Mexico Dept of Health. L Williams, G Shepherd, North Texas Poison Center, Dallas; G Coody, PharmD, Div of Drugs and Medical Devices, Bur of Food and Drug Safety; DM Simpson, MD, State Epidemiologist, Texas Dept of Health. Center for Food Safety and Applied Nutrition, Food and Drug Administration. Environmental Hazards and Epidemiology Section, Health Studies Br, Div of Environmental Hazards and Health Effects, National Center for Environmental Health; Div of Applied Public Health Training, Epidemiology Program Office; and EIS officers, CDC.

GBL is metabolized to GHB in the body, but because of better absorption GBL has greater bioavailability than GHB on an equimolar basis.² Clinical effects of GHB appear to be dose-related and include reports of vomiting, hypotonia, tremors, seizures, aggression, impairment of judgment, coma, respiratory depression, hypothermia, and bradycardia.¹ GHB mixed with ethanol acts synergistically to produce central nervous system and respiratory depression.³ Symptoms usually resolve with supportive care within 2-96 hours.⁴ Death occurring when GHB was the sole intoxicant also has been reported.⁵ Toxic effects of GBL would be expected to be similar or identical to those of GHB, but previous clinical experience is limited.^6- 7 There is no antidote for GHB; treatment consists of supportive therapy until symptoms of toxicity subside. A withdrawal syndrome, which can include insomnia, tremor, and anxiety, has been reported following discontinuance of GHB in chronic, high-dose users.⁸

GBL is an industrial and household solvent of acrylate polymers, and unintentional poisonings have been reported.^6,9 It also is marketed as a dietary supplement at health food stores and on the World-Wide Web under several trade names. Although labeled as dietary supplements, GBL-containing products are illegally marketed, unapproved new drugs that have been involved in at least 55 reports of adverse events, including one death.¹⁰ On January 21, 1999, FDA asked manufacturers to recall their GBL-containing products and warned consumers through press releases to avoid taking these products.¹⁰ Public education efforts should inform consumers that FDA review procedures for drugs are different than those used for dietary supplements. Consumers should be alert to the potential dangers of these products and understand that terms such as "natural" do not necessarily imply safety. Physicians should counsel patients about these products and be prepared to recognize and treat the toxic reactions that some might produce. Chronic GBL users should be monitored for withdrawal symptoms when discontinuing use of the product. Depending on the severity of the withdrawal symptoms, medical intervention may be required. Physicians are encouraged to report serious adverse events associated with these products to FDA's MEDWATCH program, telephone (800) 332-1088.

*Also is known as dihydro-2(3H)-furanone; 4-butanolide; 2(3H)-furanone, dihydro; tetrahydro-2-furanone; and butyrolactone gamma.

MMWR. 1999;48:113-116

1 table omitted

In California, suspected pesticide-related illnesses and suspected work-related illnesses and injuries are reportable conditions. On July 31, 1998, the Occupational Health Branch of the California Department of Health Services (CDHS)* received a report from the California Department of Pesticide Regulation (CDPR) of a pesticide exposure incident in Fresno County involving 34 farm workers. CDHS investigated this incident by reviewing medical records of the 34 workers and interviewing 29. The findings indicated that the workers became ill after early reentry into a cotton field that had been sprayed with a cholinesterase-inhibiting carbamate pesticide.

On July 31 at 4 AM, a cotton field was sprayed aerially with a solution containing as active ingredients 0.26% carbofuran (n-methyl carbamate), 0.05% abamectin (macrolytic lactone), and 0.05% mepiquat chloride (growth regulator). Although carbofuran, when used on cotton, has a restricted entry interval (REI)† of 48 hours and requires both posting of treated fields and oral notification of workers, neither warning was provided. At 6 AM, the 34 workers (age range: 13-64 years; median: 31 years) entered the field to complete weeding begun the previous day. After weeding for approximately 4 hours, the workers were transported to a second field 212 miles away that had been sprayed 2 days earlier with a solution containing cyfluthrin (synthetic pyrethroid), diclofol (organochlorine), and mepiquat chloride. The REI for these pesticides is 12 hours. Within approximately 1/2 hour of entering the second field, the workers began feeling ill and stopped working.

Symptoms most commonly reported by the 34 farm workers were nausea (97%), headache (94%), eye irritation (85%), muscle weakness (82%), tearing (68%), vomiting (79%), and salivation (56%); the most commonly observed signs were bradycardia (21%), diaphoresis (15%), and miosis (pupillary constriction) (12%).

Thirty (88%) workers were transported immediately to a medical clinic; the other four went home, showered, and sought medical care 3-17 days later. All workers evaluated at the clinic were decontaminated by clothing removal and showering and were sent to six area hospitals. Twenty-nine were evaluated and released the same day. One worker was hospitalized overnight for new-onset atrial fibrillation. All workers received hospital treatment for symptoms, and most (28 [82%]) lost at least 1 day of work.

Plasma and red blood cell (RBC) cholinesterase samples obtained from 29 workers on the day of the incident were within laboratory normal values (no workers had baseline levels available). However, these specimens were not placed on ice when obtained and were tested by an outside laboratory after several hours' delay. In comparison, RBC (but not plasma) cholinesterase levels were lower than laboratory normal values in 10 workers who had second cholinesterase tests drawn at two local hospitals (3 hours after the original specimens were obtained); these samples were placed on ice and analyzed in hospital laboratories within 1 hour of collection. Urinary metabolites of carbofuran were detected by CDPR in 18 (58%) of 31 samples obtained up to 11 days following the exposure.

Foliage samples obtained in the first field by CDPR on July 31 showed carbofuran levels up to 0.77 µg/cm²; these levels were consistent with application of pesticide early that morning. Information about pesticide levels to be expected on leaf samples at 48 hours was not available. Other pesticide residues found on leaves in the first field were abamectin (up to 0.009 µg/cm²) and dicofol (up to 0.58 µg/cm²). Workers' clothing contained carbofuran residue (up to 91 mg per clothing item) and abamectin residue (up to 6000 µg per clothing item). CDHS is continuing follow-up on these workers to assess the subacute and chronic effects associated with carbofuran overexposure.

R Das, MD, R Harrison, MD, Occupational Health Br, California Dept of Health Svcs; P Sutton, MPH, A Souter, J Beckman, B Santamaria, MPH, Public Health Institute, Berkeley; C Steinmaus, MD, Univ of California, San Francisco; O Sablan, MD, Sablan Medical Clinic, Fresno; S Edmiston, L Mehler, MD, B Hernandez, F Schneider, Worker Health and Safety Br, California Dept of Pesticide Regulation. Div of Surveillance, Hazard Evaluations, and Field Studies, National Institute for Occupational Safety and Health, CDC.

Pesticide exposure can cause serious acute illness among farm workers. In the incident described in this report, workers entered a field well before the end of a label-specified REI and incurred pesticide exposure that resulted in moderately severe illness (as defined by the American Association of Poison Control Centers).¹ The incident demonstrates that (1) posted and oral warnings based on the REI are necessary to prevent illness among workers performing hand labor in fields recently treated with pesticides and (2) failure to adhere to an REI can result in substantial morbidity among exposed workers. Because this incident demonstrates that sole reliance on these control measures may be inadequate, the substitution of safer, less toxic alternative pesticides should be adopted when feasible.

Prompt, appropriate medical attention, including decontamination by clothing removal and showering, probably prevented more acute illness in this incident. However, some exposed workers went home before decontamination, increasing the potential for secondary contamination of children and other family members. Secondary contamination can be reduced by developing in advance appropriate procedures for decontaminating clothing, homes, and vehicles.² Illnesses among family members exposed to the workers were not reported.

Although the incident involved exposure to several pesticides, the agent with the greatest acute systemic toxicity is the broad-spectrum insecticide/nematocide carbofuran. Carbofuran exposure was the probable cause of illness based on biologic evidence (foliage and clothing samples and urine metabolites), signs and symptoms of cholinergic excess (voluntary and involuntary muscle movement, exocrine gland overactivity, and central nervous system effects), and laboratory evidence of cholinesterase depression. Although atrial fibrillation has been reported with other cholinesterase-inhibiting pesticides,³ this is the first report following carbofuran exposure. In 1995, 248,000 lbs of cholinesterase-inhibiting carbamate pesticide were used in California, primarily on alfalfa, rice, table and wine grapes, and cotton.⁴ During 1995, carbamate pesticides composed 1.8%, by weight, of all pesticides used and alone caused 30 (1.9%) of pesticide-related illnesses reported to CDPR.

Clinical diagnosis of carbamate toxicity is based primarily on known or suspected history of carbamate use and presence of cholinergic symptoms and signs.⁵ Isolated cases may be less recognizable, resulting in delays in diagnosis and treatment. Because cholinesterase inhibition by carbamates is rapidly reversible, cholinesterase testing may be unreliable in diagnosing carbamate poisoning. The incident described in this report also illustrates the importance of limiting the time between cholinesterase collection and analysis, placing specimens on ice, and using the most appropriate analytic techniques to conduct cholinesterase assays.⁶ Measurement of urinary metabolites may be useful to confirm suspected carbamate-related illness, but because this assay is highly chemical-specific and is performed only by certain reference laboratories, it is not a practical tool for most clinicians. Treatment of carbamate poisoning includes decontamination, supportive care, and the use of atropine in severe exposures.

Some of the symptoms reported by these workers are consistent with effects reported for other pesticides involved in this incident. However, the residues for these pesticides were either not assayed or found to be low, and unlike the cholinesterase-inhibiting pesticides, methods to assess the biologic effects of other pesticides are not readily available to clinicians. Several of these pesticides have been associated with adverse effects in animals, but reliable data for humans are lacking. The toxicity related to combined exposures to pesticides remains unresolved and requires further research.

References: 6 available

*CDHS participates in two CDC-funded pesticide illness prevention projects that use case reports generated by these mandatory reporting requirements: the Sentinel Event Notification System for Occupational Risks and Community Partners for Health Farming.

† REI are established by the U.S. Environmental Protection Agency for pesticides used on agricultural crops to which workers have substantial contact with treated surfaces during hand labor. No worker without prescribed protective clothing should enter a treated area to perform a hand labor task until the REI expires. The length of the REI depends on the specific pesticide but generally can be no less than 12 hours.

MMWR. 1999;48:147-148

1 table omitted

On January 27, 1999, the Food and Drug Administration initiated a voluntary recall of Tripedia™ diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP), lot number 0916490, manufactured by Pasteur Merieux Connaught USA.* Routine post-release stability testing completed in January 1999 indicated that the potency of the diphtheria toxoid component of this lot was below specification. The potency of the tetanus and pertussis components of this lot was acceptable.

The lot was distributed during February-June 1998. All lots of Tripedia™ met potency specifications before release. Previously tested lots of Tripedia™ met diphtheria potency specifications in routine stability testing after release; stability testing of additional lots is in progress.

A primary series (three doses) of fully potent diphtheria toxoid-containing vaccine is required to reliably induce protective antibody levels. Five doses of diphtheria toxoid-containing vaccine are recommended for preschool-aged children in the United States and provide optimal protection against diphtheria.

The risk for exposure to toxigenic strains of Corynebacterium diphtheriae in the United States is low; however, diphtheria remains endemic in many countries. Additional doses of diphtheria toxoid-containing vaccine beyond those recommended in the childhood immunization schedule are associated with an increase in local reactions and should be considered only for children vaccinated with Tripedia™ lot number 0916490 who may be at increased risk for exposure to toxigenic strains of C. diphtheriae. CDC, the American Academy of Pediatrics, and the American Academy of Family Physicians have developed recommendations for children who received one or more doses of Tripedia™ lot number 0916490. The complete text of the recommendations is available on CDC's National Immunization Program World-Wide Web site, http://www.cdc.gov/nip/news/recall.htm; in summary, the recommendations are as follows:

— Children remaining in the United States until the scheduled fourth dose of DTaP or traveling to countries where the risk for diphtheria is low do not require any supplemental doses of diphtheria toxoid-containing vaccine.

— Children traveling to a country where the risk for diphtheria is high† before their scheduled fourth dose of DTaP may require a supplemental dose of DT or a dose of DTaP on an accelerated schedule; the recommendations vary based on the number of doses of Tripedia™ lot number 0916490 received.

*Use of trade names and commercial sources is for identification only and does not imply endorsement by CDC or the U.S. Department of Health and Human Services.

†Travelers may be at substantial risk for exposure to toxigenic strains of C. diphtheriae, especially with prolonged travel, extensive contact with children, or exposure to poor hygiene. Countries comprise the following: Africa—Algeria, Egypt, and sub-Saharan Africa; Americas—Brazil, Dominican Republic, Ecuador, and Haiti; Asia/Oceania—Afghanistan, Bangladesh, Cambodia, China, India, Indonesia, Iran, Iraq, Laos, Mongolia, Myanmar, Nepal, Pakistan, Philippines, Syria, Thailand, Turkey, Vietnam, and Yemen; and Europe—Albania and all countries of the former Soviet Union.