Toxic oil syndrome: a current clinical and epidemiologic summary, including comparisons with the eosinophilia-myalgia syndrome.

In the spring and summer of 1981, an epidemic of a new illness now referred to as the toxic oil syndrome occurred in central and northwestern Spain, resulting in some 20,000 cases, 12,000 hospital admissions and greater than 300 deaths in the 1st year of the epidemic. The initial onset of illness was usually acute, and patients presented primarily with a respiratory syndrome involving cough, fever, dyspnea, hypoxemia, pulmonary infiltrates and pleural effusions. While approximately 50% of patients recovered from this acute phase of the illness without apparent sequelae, the remaining patients developed an intermediate or chronic phase, or both, of illness involving severe myalgia, eosinophilia, peripheral nerve damage, sclerodermiform skin lesions, sicca syndrome, alopecia and joint contractures, among other findings. Epidemiologic and analytic chemical studies have clearly linked the toxic oil syndrome to the ingestion of oil mixtures containing rapeseed oil denatured with aniline. However, the precise identity of the etiologic agent within this oil has never been determined. Aniline itself did not cause the illness, but the causal agent may be a reaction product of aniline with some oil component. Although many aspects of disease activity in the involved patients have lessened with time, the ultimate consequences of their disease are not clear and are the subject of ongoing study. The recently described eosinophilia-myalgia syndrome in the United States clinically resembles the toxic oil syndrome.

Chaparral-associated hepatotoxicity.

BACKGROUND: Personal health care practices that may include the use of dietary supplements are common in the United States. Products marketed as dietary supplements are diverse and may include botanicals, vitamins, and/or minerals. Chaparral (Larrea tridentata) is a botanical dietary supplement made from a desert shrub and used for its antioxidant properties. Several reports of chaparral-associated hepatitis have been published since 1990, but a complete picture of the clinical presentation is still unclear. MATERIALS AND METHODS: We reviewed the 18 case reports of adverse events associated with the ingestion of chaparral reported to the Food and Drug Administration between 1992 and 1994. These reports were from health care professionals, state health departments, and individual consumers. RESULTS: Of 18 reports of illnesses associated with the ingestion of chaparral, there was evidence of hepatotoxicity in 13 cases. Clinical presentation, characterized as jaundice with a marked increase in serum liver chemistry values, occurred 3 to 52 weeks after the ingestion of chaparral, and it resolved 1 to 17 weeks after most individuals stopped their intake of chaparral. The predominant pattern of liver injury was characterized as toxic or drug-induced cholestatic hepatitis; in 4 individuals, there was progression to cirrhosis; and in 2 individuals, there was acute fulminant liver failure that required liver transplants. CONCLUSIONS: These data indicate that the use of chaparral may be associated with acute to chronic irreversible liver damage with fulminant hepatic failure, and they underscore the potential for certain dietary supplement ingredients to cause toxic effects on the liver. Health professionals should be encouraged to inquire routinely about the use of dietary supplements and other products, to be alert to potential adverse effects that may be associated with these products, and, finally, to report any serious adverse events associated with these products through the MEDWatch Program of the Food and Drug Administration.

Eosinophilia-myalgia syndrome. A clinical case series of 21 patients. New Mexico Eosinophilia-Myalgia Syndrome Study Group.

We reviewed 21 cases of eosinophilia-myalgia syndrome to describe the range of clinical findings in these patients. Most patients were women (20 [95%]) and middle-aged (mean, 46 years) and had taken the food supplement L-tryptophan (95%). All cases involved eosinophilia (eosinophil count, greater than or equal to 2.0 x 10(9)/L) and incapacitating myalgias. Fourteen (88%) of the 16 patients tested had mild liver function abnormalities. Aldolase levels were abnormal in all patients tested. Muscle biopsies were done in five patients; four showed eosinophilic perimyositis, and one had interstitial inflammation. No physical finding was pathognomonic or universal, but muscle tenderness, tachycardia, and rash were the most common signs found during physical examinations. Seven patients were treated with prednisone, and six showed improvement in muscle pain and a decrease in eosinophilia. The cause of this disorder is still unknown.

The natural history of eosinophilia-myalgia syndrome in a tryptophan-exposed cohort in South Carolina.

BACKGROUND: In a previous study, we did follow-up on 418 patients who were exposed to tryptophan in 1989, of whom 47 (11%) had definite and 63 (9%) possible eosinophilia-myalgia syndrome (EMS). METHODS: We assessed mortality and clinical spectrum of illness since 1989 for 242 (58%) of the 418 tryptophan-exposed patients from the original study. To assess outcomes, we used hospital and death records, interviewer-administered questionnaires, physical examinations, and laboratory tests. RESULTS: During the follow-up interval, mortality from all causes was 19% in those with definite EMS, 7% in possible EMS, and 3% in those who were not ill. The age- and sex-adjusted mortality in those with definite EMS was more than 3 times that of the general population or of tryptophan users in the practice who were not ill. Six deaths (66%) among the definite EMS case patients occurred during the 18 months immediately after symptom onset. Compared with the tryptophan users who were not ill, survivors with definite EMS continued to report excess morbidity for 6 major EMS symptoms (myalgia, arthralgia, weakness, rash, alopecia, and sclerodermiform skin changes), but they also reported that the symptom number and severity diminished with time. None of the tryptophan users who were not ill in 1989 developed a symptom complex suggesting new EMS during the follow-up interval. CONCLUSIONS: This study assessing a tryptophan-exposed population found those persons who developed EMS during the 1989 epidemic were at increased risk for death, particularly early after disease onset. Survivors reported improvement or resolution of major symptoms, suggesting that the severity of EMS diminishes with time. We found no evidence of delayed onset of EMS in tryptophan users who were not ill in 1989, regardless of the brand used.

Synthsis and antitumor properties of bis(quinaldine) derivatives.

A series of 7-nitro- and amino-N,'-bis(4-quinaldinyl)-alpha, omega-diaminoalkanes related to the 6-amino derivative 1 was synthesized and tested in the mouse P-388 lymphocytic leukemia screen. There of the 7-nitro derivatives (12, 14, and 15) were found to have moderate activity (T/C 140-150%), while other nitro derivatives (11 and 13) were devoid of any antitumor properties. All five 7-amino compounds (2-6) were moderately to strongly active (T/C 134-196%). In addition, binding of amino derivatives 2-6 to DNA was examined by their ability to (1) stabilize DNA to thermal denaturation and (2) inhibit the DNA-dependent RNA polymerase reaction in vitro. Tm data suggest that these compounds bind to DNA and are strong inhibitors of the polymerase reaction (I50 = 6-9 X 10(-6) M).

Toxic oil syndrome and eosinophilia-myalgia syndrome: May 8-10, 1991, World Health Organization meeting report.

In May 1991, researchers and clinicians from throughout the world met at a workshop sponsored by the Regional Office for Europe of the World Health Organization in collaboration with the Fondo de Investigación Sanitaria, Spain, and the U.S. Food and Drug Administration, National Institutes of Health, National Institutes of Mental Health, and Centers for Disease Control and Prevention to share information about two very similar diseases--toxic oil syndrome and eosinophilia-myalgia syndrome. In this paper the interpretation of conference proceedings is presented, current knowledge of the two disorders is summarized, and some possible areas for future research are mentioned. Toxic oil syndrome and eosinophilia-myalgia syndrome have many similarities. Both are related to consumer products that were presumed to be safe but have been found to have numerous trace contaminants, many of which remain to be identified, including the etiologic agents of both disorders. Both illnesses affect patients clinically by causing intense, incapacitating myalgias and a marked peripheral eosinophilia. Other rheumatologic manifestations are common in both, including arthralgias, sicca syndrome, scleroderma-like skin changes, carpal tunnel syndrome, and joint contractures. No clinical or laboratory feature has been found to be pathognomonic of either disease, and accurate diagnosis rests on the clinical judgment of the attending physician. Deaths have occurred in both diseases, and the cumulative mortality for each is approximately 2.5% for the first 2 years. Long-term complications include pulmonary hypertension, peripheral neuropathies, and joint contractures. Although treatment with corticosteroids has resulted in significant symptomatic relief in persons with either disorder, it does not alter the clinical course or long-term outcome. Research into the etiologic agents, preferred treatments, and ways to avoid similar problems in the future is needed.

Toxic oil syndrome mortality: the first 13 years.

BACKGROUND: The toxic oil syndrome (TOS) epidemic that occurred in Spain in the spring of 1981 caused approximately 20000 cases of a new illness. Overall mortality and mortality by cause in this cohort through 1994 are described for the first time in this report. METHODS: We contacted, via mail or telephone, almost every living member of the cohort and family members of those who were known to have died in order to identify all deaths from 1 May 1981 through 31 December 1994. Cause of death data were collected from death certificates and underlying causes of death were coded using the International Classification of Diseases, 9th Revision. RESULTS: We identified 1663 deaths between 1 May 1981 and 31 December 1994 among 19 754 TOS cohort members, for a crude mortality rate of 8.4%. Mortality was highest during 1981, with a standardized mortality ratio (SMR) of 4.92 (95% confidence interval [CI]: 4.39-5.50) compared with the Spanish population as a whole. The highest SMR, (20.41, 95% CI: 15.97-25.71) was seen among women aged 20-39 years during the period from 1 May 1981 through 31 December 1982. Women <40 years old, who were affected by TOS , were at greater risk for death in most time periods than their unaffected peers, while older women and men were not. Over the follow-up period, mortality of the cohort was less than expected when compared with mortality of the general Spanish population, or with mortality of the population of the 14 provinces where the epidemic occurred. We also found that, except for deaths attributed to external causes including TOS and deaths due to pulmonary hypertension, all causes of death were decreased in TOS patients compared to the Spanish population. The most frequent underlying causes of death were TOS, 350 (21.1%); circulatory disorders, 536 (32.3%); and malignancies, 310 (18.7%). CONCLUSIONS: We conclude that while on average people affected by toxic oil syndrome are not at greater risk for death over the 13-year study period than any of the comparison groups, women <40 years old were at greater risk of death.

Toxic oil syndrome: traceback of the toxic oil and evidence for a point source epidemic.

Rapeseed oil denatured with aniline was the vehicle of the causal agent of the toxic oil syndrome (TOS) epidemic that occurred in Spain in 1981. Although the precise aetiologic agent remains unknown, researchers established that increasing concentrations of oleyl anilide and other fatty acid anilides were associated with an increased risk for disease. To examine the hypothesis that 5-litre plastic containers of rapeseed oil associated with TOS, and which contained oleyl anilide had a characteristic shape, we measured fatty acid, sterol and fatty acid anilide levels in oil from containers of different shapes. We identified 1673 bottles of oil that had been collected during the Spanish Government's oil exchange programme and linked these bottles to people with TOS as reported in the official government census of patients with TOS. Although rapeseed oil (identified by the presence of brassicasterol) was found in 798 (47.7%) of the 1673 bottles examined, contamination with fatty acid anilide occurred in only 329 (19.6%) of the 1673 bottles and 319 (97%) of the 329 were oil containers of the shape sold by RAELCA, an oil company in Madrid. The first aniline-denatured oil that RAELCA had purchased to be refined specifically for distribution was refined at the ITH refinery of Seville, and this oil has been most directly associated with the epidemic. Previous work has shown that the only toxic oil linked to a specific refinery was that associated with rapeseed oil from the ITH refinery in Seville, and the epidemic began shortly after this oil was delivered to RAELCA for retail sale. On the basis of these findings, we conclude that oil refined by ITH and distributed by RAELCA was the principal, and probably the only, oil responsible for the TOS epidemic. Information about the history and treatment of this oil may yield important clues towards identifying the aetiologic agent of TOS.

Manufacturing processes at two French rapeseed oil companies: possible relationships to toxic oil syndrome in Spain.

The toxic oil syndrome (TOS) epidemic that occurred in Spain in spring 1981 has been associated with the consumption of rapeseed oil that was denatured with aniline for industrial use but diverted for human consumption. The precise aetiologic agent in the oil responsible for the outbreak has not been identified. To learn more about possible contaminants and how the contamination might have occurred, we visited two French companies that process rapeseed oil and that were identified in Spanish administrative and judicial records as the ones exporting aniline-denatured rapeseed oil to Spain in 1981. With the apparently full and voluntary co-operation of personnel at both companies, we reviewed the processes involved in manufacturing, treating and transporting rapeseed oil, and we have summarized the information provided to us. Of particular importance is the finding that oil exported to Spain was taken from stock, the rest of which was sold for human consumption in the French domestic market, apparently without any adverse health effects. The differences between the oil exported to Spain and the oil sold as food in France were that aniline equivalent to 2% of the weight of the oil was added to most of the Spanish oil but not to that sold in France, and that contamination of the Spanish oil may have occurred in the tank trucks used for transportation to Spain, which had previously carried industrial chemicals. There is no assurance that the trucks were cleaned appropriately for transporting a food product before the oil was loaded for the journey to Spain. Since the clinical manifestations of TOS are not those of aniline toxicity, we conclude that the aetiological agent of TOS is likely to be one of the following: (1) a contaminant in the aniline, (2) a contaminant introduced during transportation, (3) a reaction product of normal oil components or materials used in refining with either aniline or the potential contaminants mentioned under (1) or (2) above.

Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome.

Evidence from an array of scientific studies strongly supports the conclusion that ingestion of products containing L-tryptophan (LT) produced by Showa Denko KK caused the 1989 epidemic of eosinophilia-myalgia syndrome (EMS) in the United State. In case-control studies of EMS, LT exposure was essentially universal among cases but rare among controls. Of 6 manufacturers of LT, only LT manufactured by Showa Denko KK was clearly associated with illness. The data meet other Hill criteria for inferring a causal relationship. Consistent findings were found in multiple independently conducted studies. There was a dose-response effect, with risk of illness increasing as a function of the amount of tryptophan consumed. The extremely small p values observed in the multiple independently conducted studies effectively rule out the possibility that the tryptophan-EMS association was the result of chance. Moreover, no potential confounding factor or bias explains the association. The incidence of EMS in the United States diminished abruptly once LT containing products were recalled.

Eosinophilia-myalgia syndrome among the non-L-tryptophan users and pre-epidemic cases.

OBJECTIVE: Eosinophilia-myalgia syndrome (EMS) has been associated with L-tryptophan (LT) use since 1989, but as yet no etiologic agent has been identified. We describe the non-L-tryptophan associated cases of EMS, and those patients with illness onset preceding the 1989 epidemic. METHODS: Review of all patients in the EMS national state based surveillance system administered by the Centers for Disease Control and Prevention (CDC) who satisfied the EMS surveillance case definition. RESULTS: Of 1345 persons with EMS that satisfied the CDC surveillance case definition for EMS, 26 (2%) persons reported not having used LT (non-LT). Persons who did not use LT were significantly younger (mean age 39 years; p = 0.02) and were more likely than LT users to have onset of their illness before the EMS epidemic (before July 1, 1989) (p < 0.001). Non-LT users reported fewer pulmonary symptoms but had rates of neuropathy and scleroderma-like skin changes similar to LT users. Non-LT users had lower mean eosinophil counts (5.6 x 10(9) cells/I LT users 6.2 x 10(9) cells/I), reported no EMS attributable deaths, but were hospitalized (48%) more often than LT users (34%). Of the 1345 EMS cases, 191 (14%) reported a pre-epidemic illness onset. Symptoms of peripheral edema, rash, scleroderma-like skin change, alopecia, and neuropathy were more prevalent in pre-epidemic patients. Mean eosinophil count was significantly higher for epidemic patients than for pre-epidemic patients (p = 0.004). CONCLUSION: Non-LT EMS cases were more likely to be younger and to have a pre-epidemic illness onset of EMS, but otherwise were similar to LT associated EMS cases. Pre-epidemic EMS cases were more likely to report the presence of neuropathy and scleroderma-like skin change, but not pulmonary symptoms, hospitalization, or death.

Survey of advertising for nutritional supplements in health and bodybuilding magazines.

The use of food supplements by the general public is poorly quantified, and little information on this subject is available in the medical literature. We surveyed 12 recent issues of popular health and bodybuilding magazines (1) to quantify the number of advertisements for food supplements, the number of products advertised, and the number and type of ingredients in these products; (2) to identify the purported health benefits of these products; and (3) as a preliminary effort to identify areas for future research. We counted 89 brands, 311 products, and 235 unique ingredients, the most frequent of which were unspecified amino acids; the most frequently promoted health benefit was muscle growth. We also found many unusual or unidentifiable ingredients, and 22.2% of the products had no ingredients listed in their advertisements. Health professionals may not be aware of how popular food supplements are or of a particular supplement's potential effects or side effects. In addition, patients may be reluctant to discuss their use of these products with traditional medical practitioners. We recommend that routine history taking include specific questions about patients' use of food supplements and that any possible adverse effects or side effects be reported to public health authorities.

Mass sociogenic illness by proxy: parentally reported epidemic in an elementary school.

In a cluster of illness reported among students at an elementary school parents mentioned many signs and symptoms including headache, pallor, dark circles under the eyes, nausea, and vomiting--which they attributed to exposure to recurrent leaks of natural gas at the school. It is likely that the parents spread among themselves the notion of toxic exposure at the school. A questionnaire revealed no spatial clustering, but increased reports of symptoms were related to intense media coverage. A thorough environmental and epidemiological investigation was negative, there being no evidence of a continuing gas leak or other potential causes. At a strictly biological level, the complaints in this reported "cluster" apparently represented the sporadic occurrence of common childhood illnesses. The possibility of an epidemic from toxic exposure at the school caused intense parental concern and led to a major public health problem. The established term "mass sociogenic illness" seems inapplicable here because complaints did not come principally from the students and the apparent epidemic illness was not transmitted among them. The term "mass sociogenic illness by proxy" is proposed to describe this incident, in which transmission in one group (the parents) resulted in reports of an epidemic in another group (students).

What's being used at home: a household pesticide survey.

OBJECTIVE: Since very little is known about the health effects that household pesticides have on children, we conducted this survey to identify what pesticides are being used in the home, where they are being used and stored, and what methods are used for their disposal. METHODS: In the spring of 1999 we conducted a survey in a community in the state of Arizona, in the United States of America, on the border with Mexico. To be eligible to participate in the survey, households had to have used a pesticide in the 6 mo prior to the survey and to have at least one child under the age of 10 years. We gathered general information on pesticide usage, storage, and disposal, in addition to specific information about each of the pesticides currently being used and/or stored in the home. RESULTS: In the 107 households surveyed, we found 148 pesticide products, for a mean of 1.4 per household. Half of the pesticides were stored less than 4 feet (1.22 m) from the ground, at a level a child could reach. Seventy percent of all the pesticides were stored inside the home, with the kitchen being the storage room most often mentioned. The kitchen was also the room where most of the pesticides were used, with 69% of the respondents saying they had used at least one pesticide there. CONCLUSIONS: From our research we conclude that it will be important to continue to investigate all avenues of pesticide exposure in order to fully evaluate childhood exposures. Understanding household pesticide use and developing a model of exposure will help in this process. Profiles of the use, storage, and disposal of products will also guide the development of effective education and poison prevention programs in the community.

L-tryptophan and eosinophilia-myalgia syndrome in New Mexico.

On Oct 30, 1989, the New Mexico Health and Environment Department learned of 3 patients with eosinophilia and severe myalgia who had been taking L-tryptophan. Further review of these and similar cases led to the initial recognition of the eosinophilia-myalgia syndrome (EMS) epidemic. To elucidate the apparent association between L-tryptophan-containing products (LTCPs) and EMS a case-control study was done. The case definition was unexplained peripheral eosinophilia (2000/microliters or more) and incapacitating myalgia. Cases were found through review of white blood cell counts from May 1 to Oct 31, 1989, in nine medical laboratories in New Mexico. 11 cases and 22 matched controls were interviewed for information on symptoms and other clinical findings, on the use of LTCPs, and on potential confounding factors. All 11 cases (100%) used LTCPs compared with only 2 controls. These findings led to a ban on the sale of LTCPs in New Mexico, followed by a nationwide recall of such preparations in the United States.