hexachlorophene/autopsy/studies: May 2008

Here are some excerpts from the largest autopsy study of the effects of Hexachlorophene.

But there is also a question about the fate of survivers.

Note the emphasis on the need for follow-up into adulthood. It's in the last paragraph. As is common, the the bold emphasis is by me - not the author.

Lancet
Junurary 9,1982
Public Health
OUTBREAK OF ACCIDENTAL HEXACHLOROPHENE POISONING IN FRANCE Gilbert Martin-Bouyer Roger Lebreton Maurice Toga Paul D. Stolley Jean Lockhart Unit 165, Transmissible Diseases and Accidental Poisonings, French National Institute of Health and Medical Research (INSERM), he Vesinet Toxicology Laboratory, Department of Police, Medicolegal Institute, Paris; School of Medicine of Marseille, Marseille, France; Clinical Epidemiology Unit, University of Pennsylvania School of Medicine, Philadelphia; and American Academy of Pediatrics, Evanston, Illinois, U.S.A.

Summary 204 children were affected in an epidemic of percutaneous hexachlorophene poisoning in France, and 36 of them died. The syndrome consisted of ulcerative skin lesions and an encephalopathy. The source of the toxic agent was a talc "baby powder" which, because of a manufacturing error, contained 6 • 3% hexachlorophene. The cause of the epidemic was confirmed by chemical analysis of the talc, high hexachlorophene levels in affected children, characteristic histological findings, and toxicity tests of the talc in animals.

INTRODUCTION On Sept. 22, 1972, the Food and Drug Administration (F.D.A.) of the United States of America issued a regulation requiring that all over-the-counter (OTC) products containing hexachlorophene be sold only as prescription items. The products restricted included a popular 3% hexachlorophene emulsion. An important justification for this measure was the occurrence of an epidemic of an unexplained neurological illness in France in which 204 children became ill and 36 died. Because French law prohibited publication of the account of this unusual epidemic until litigation surrounding it was concluded, it is only now, 9 years after the event, that a full scientific report can be published (although brief news stories about the epidemic and subsequent legal trials have been published in France). The investigation of this epidemic was conducted by the • French authors of this article. The two American authors were intimately concerned with the issue of hexachlorophene toxicity because of their work with the F.D.A. J. L. was sent to France by the F.D.A. to observe and to report on the investigation of the epidemic; she was also an expert witness in the litigation in France. P. D. S. and G. M-B. have met regularly over the past 4 years to prepare this report in English. However, the investigation described below was the work of the French authors and their organisations. Hexachlorophene (3,4,6-trichlorophenol), a polychlorina- ted bisphenol, was developed in 1939 at the Givaudan Laboratories in New Jersey by W. C. Gump and patented in 1941. Its bacteriostatic properties, particularly its ability to inhibit the growth of gram-positive microorganisms, were recognised and described in the 1940s.1-2 Because hexachlorophene is fairly water insoluble, and is characterised by "substantivity" (i.e., the tendency to remain on the skin after rinsing), it is capable of penetrating to deep skin layers. Indeed, its use as an antiseptic for preoperative scrubbing derives from its property of being retained in the skin where it acts as a kind of sustained-release bacteriostatic agent, since it is not particularly effective as an "instantaneous germicide". However, this property has been contested by various authors.35 In the 1950s hexachlorophene was added to a wide variety of OTC products, including soaps, shampoos, acne medications, deodorants, toothpastes, "vaginal hygiene" preparations, and shaving creams. Many products containing hexachlorophene were sold in France, the rest of Western Europe, and the U.S.A. In the U.S.A., a 3% hexachlorophene emulsion gained popularity for a variety of uses in medical practice, such as preoperative surgical scrubbing, bathing of new-born infants to prevent infection, postoperative wound care, and burn care, and as a "general disinfectant," often available for handwashing at hospital sinks. The worldwide annual production of hexachlorophene in 1971 was estimated to be 2500 tons, and hexachlorophene was present in approximately 1500 products. The toxicity of orally ingested hexachlorophene in animals was first described in 1939 (report by Applied Research Laboratories, Inc., to Givaudan Corporation, unpublished). Percutaneous hexachlorophene toxicity in rabbits was also described in 1939 (report by Applied Research Laboratories, Inc., to Givaudan Corporation unpublished), and in 1952 (report by Rakistan N., to Givaudan Corporation, unpublished). Human percutaneous hexachlorophene poisoning involving so-called "healthy skin" was first reported in 1959,7 and further reports8"10 of accidental cutaneous poisoning due to application of the antiseptic to "damaged skin" followed. .Poisoning resulting from accidental ingestion of hexachlorophene has also been described—when 3% hexachlorophene emulsion transferred to unlabelled bottles was mistaken for milk-of-magnesia or antacid preparations;11'12 and when hexachlorophene was tried as a therapeutic agent for Chinese liver fluke infestation (Clonorchis sinensis).n Although the clinical pictures reported in these and other cases due to oral ingestion of large amounts of hexachlorophene show variability, there are some common features. These are lethargy, fever, and convulsions, often followed by paralysis, coma, and finally death,14 a sequence similar to that noted in the animal toxicity experiments.
A request to the U.S. Government by a manufacturing firm for a licence for a hexachlorophene-containing agricultural spray led to further tests of hexachlorophene by U.S. toxicology laboratories in 1969. Rats given 12-48 mg/kg hexachlorophene daily as topical application showed signs of neurotoxicity such as weakness and paralysis of the legs.15 When the animals were killed, microscopic examination of the brain revealed a peculiar lesion of the white matter which was characterised by vacuolisation and oedema and described as "status spongiosus". These data were under review by the Antimicrobial Review Panel of the United States Food and Drug Administration at the time of the epidemic described here.

THE EPIDEMIC Clinical Features On Aug. 17, 1972, the French Ministry of Health held an urgent meeting, to which national and local health officials, epidemiologists, virologists, toxicologists, and pediatricians were invited. The purpose of the meeting was to consider a mysterious outbreak of an apparently new disease characterised by severe "diaper rash", low-grade fever, and various neurological manifestations and sometimes leading to death. Those affected were infants and children aged 3 months to 3 years. The first such illnesses had occurred in March, 1972, but it was not until July that the Ministry of Health was notified that an epidemic existed. Several investigations undertaken in July were inconclusive. At the Aug. 17 meeting, the Unit of Transmissible Diseases and Accidental Poisonings of the French National Institute of Health and Medical Research (INSERM) was directed to conduct and coordinate the investigation of the epidemic, which at the time was regarded as probably due to viral encephalitis. A case was a child who had: (1) an erythematous, ulcerative rash in the diaper area and/or the neck; and (2) an encephalopathy not shown to be due to any specific viral or bacterial aetiological agent. Affected infants typically • presented with a red, oedematous, ulcerative skin lesion in the diaper area, moderate fever (at times exceeding 39 °C), irritability, and vomiting, followed by drowsiness alternating with excessive hypertonicity and startle responses. In the severe cases, convulsions developed within a day or so, followed by varying degrees of weakness and lethargy. Papilloedema and retinal haemorrhages indicated intracranial hypertension. 25% of the children went into coma (table I), and 18% died. Cerebrospinal fluid was acellular with normal protein levels. Electroencephalograms performed on some of the children showed diffuse slowing without focal features. Attempts to isolate infectious agents from cerebrospinal fluid, blood, stool, pharynx, and urine were uniformly unsuccessful, even though a variety of media and culture techniques, some very sophisticated, was used.

Epidemiological Features The first known case occurred during the week March 18-24, 1972 (week 12). A marked increase in the number of cases during the first week of April was followed by a 26-week plateau. The last case was reported to have started during the week beginning August 26 (week 36) (fig. 1). The total count was 224 poisonings among 204 subjects), of whom 36 died. 126 were infants and 78 were aged 1-3 years. 16 of the children who improved in the hospital and were discharged
had to be readmitted for recurrence of symptoms. 4 children had 3 episodes of poisoning because they were re-exposed when they went home. Child abuse was even suspected in one family in which 2 children had similar symptoms, 1 of whom died. The disease had an unusual geographical distribution. Almost all of the cases occurred in four areas—the Ardennes (northeast), Champagne (central), and Cote d'Azur and the Mediterranean (southeast, on the Mediterranean Sea). Only 8 cases occurred outside these areas including 1 in northern Italy, but for each one the "baby powder" used had been bought in one of these areas (see below). Furthermore, within these areas cases clustered around certain towns.
It was important to determine how many cans were contaminated, where they were distributed, and whether others were still available for sale. The powder was manufactured at a factory which also produced several types of cosmetic products. The factory manufactured five talc products supposed to contain hexachlorophene at concentrations ranging from 0 • 25 to 1 % and one talc product (Bebe Talc Morhange) which was not supposed to contain any hexachlorophene. The factory purchased barrels of hexachlorophene direct from the chemical's manufacturer. Apparently it was the practice in this factory to recover spilt talc from the factory floor for re-use. We believe that this recovered talc may have been stored in a barrel with some left¬ over hexachlorophene but which was merely labelled "G-ll", a trade code for hexachlorophene. Since hexachlorophene is a white powder similar in appearance to talc, we think that hexachlorophene plus recovered talc was added to a batch of Bebe Talc Morhange in the mistaken belief that it was only recovered talc which was being added. It is estimated that a barrel containing approximately 38 kg hexachlorophene and 12 kg recovered talc was added to other talc barrels in the production of a batch of 600 kg of powder. The result, a talc containing 38 kg or a 6 • 3% hexachloro¬ phene powder, was used to fill 2898 cans. These contaminated cans -were distributed on March 15, 1972, to the branch stores of four large chains operating in the four areas of France where the epidemic occurred. The epidemic began 10 days after the cans were delivered except for 1 early case which was traced to a can removed from the factory by a worker before delivery. For all but 11 cases the purchase of the contaminated talc could be traced to stores which received a delivery of the contaminated batch on March 15. The cases were clustered geographically around the point of purchase (fig. 2). Even for the few cases which occurred distant from the stores the talc had usually been bought from stores known to have sold the contaminated talc while the purchaser was on a visit. Once the source of the epidemic was determined, a search was made for unsold contaminated cans; 199 of the 2989 (7%)
The parents of the victims were interviewed and their homes were inspected by investigators from INSERM. Two facts soon became apparent: the victims had virtually no contact with one another, but most had used the same baby powder, 'Bebe Talc Morhange'. In July, initial toxicological and chemical analyses of cans of this powder obtained directly from the factory and from store shelves revealed only talc and fragrance (perfume scent). On Aug. 24, analysis of a sample of B£be Talc Morhange, obtained from the parent of a victim was found to contain 6-3% hexachlorophene by weight. Later on, 164 of the affected children were found to have used the same contaminated baby powder, and in all but 11 cases the store from which the talc was purchased was identified.

Toxicological and Other Postmortem Studies It was possible to obtain a blood sample from only 1 dying child for hexachlorophene levels. Gas chromatography16 showed that this child had a serum hexachlorophene level of 1 • 15 parts per million (ppm). Postmortem examinations were performed on the 36 children, mostly after exhumation (table II). 3 g of various organs were subjected to crushing, atomisation, extraction, purification, then gas chromatography. The levels found are shown in table II. They were up to 149 ppm in the brain, and TABLE II—HEXACHLOROPHENE CONTENT IN THE VISCERA OF 36 CHILDREN EXAMINED POST MORTEM
Tissue Brain Liver Lung Kidney Skin Femur Number 23 25 17 4 30 27 Hexachlorophene level (ppm) 20-6(1-149) 132-6(12-5-1080) 30-3(10-67) 25-9(17-43) 51-8(1-392) 3-3(0-05-7-5)
Results shown are means, ranges in parentheses up to 7 • 5 ppm in the femur, where hexachlorophene should not be found at all. Hexachlorophene was also found in organs where large amounts given to experimental animals produce only low concentrations.17 The range seen was wide and could be explained by differences in quantities of hexachlorophene applied to each child; differences in intervals between last exposure and death; and differences in intervals between the date of death and the date of sampling. Light microscopy of samples of brain and spinal cord tissue obtained from 12 children immediately after death showed vacuolisation of the white matter, similar to the "status spongiosus" lesions (fig. 3) described by Kimbrough and Gaines.15

TESTS IN ANIMALS Results of animal tests conducted under the direction of INSERM scientists were submitted as evidence in the legal
trial.18 Mice given the 6-3% hexachlorophene and talc powder by mouth showed hyperactivity, then drowsiness which was interrupted by periods of excitement and convulsive leaps. 3 h after ingestion of hexachlorophene paralysis was noted in the hind legs, they then developed in all four limbs, before coma and death supervened. Microscopic examination of the white matter of the brain and spinal cord revealed the characteristic vacuolisation.18 Electron microscopy showed damage to the internal third of the myelin sheaths, and wide intralamellar spaces and membrane fragments inside the vacuoles. Similar findings have been reported in rats and mice exposed to hexachlorophene. l9>2° Finally, four newborn baboons were shaved in the diaper area, and the contaminated Bebe Talc Morhange was applied in the same manner in which most of the mothers of the affected children had done when changing diapers. An illness similar to that which occurred in the 204 affected children occurred within a few days. At necropsy, the central nervous system changes as shown by light microscopy resembled those observed in the affected infants. Electron microscopy showed a diffuse status spongiosus involving the myelin sheath in the brain, cerebellum, pons, medulla oblongata, and medulla. In summary animal experiments showed that the talc contaminated with hexachlorophene was toxic after oral ingestion and often after cutaneous application, and a syndrome with characteristic neuropathology similar to that of the human victims could be reproduced in the animals.

DISCUSSION Often the recognition of an epidemic is delayed because of the lack of centralised reporting and unawareness of the simultaneous occurrence of similar cases. When cases labelled "encephalopathy of unknown aetiology" were first diagnosed in the four areas of France affected, no definitive diagnosis could be made. Many of the infants so affected were sent to hospitals in Paris with special intensive care and neurological diagnostic facilities. The realisation that an epidemic of a new neurological disorder existed was gradual, but once the situation was recognised, a search for all cases was undertaken by INSERM epidemiologists. Altogether there were 224 poisoning episodes among 204 individuals, of whom 36 died. Some children were poisoned more than once because, before the cause of the poisoning was known, they were re-exposed to the powder when they were discharged from hospital. For several children, the repeat exposures were fatal. Infants exposed to a powder with such a high concentration of hexachlorophene may be particularly vulnerable to its toxic effects because of the tendency of the skin of the diaper area to ulcerate. When new and unexplained diseases occur in populations and are distributed discretely in time and space, accidental intoxication should be considered. It is interesting to note that, although the first case of hexachlorophene intoxication occurred in March, 1972, it was not until August that INSERM was informed of the epidemic. During this 5 month period, all but 199 cans of the 600 kg batch of contaminated talcum powder had been sold. Had reporting of the cases to INSERM been delayed another month, there would probably have been more victims, and the accident which caused the epidemic might not have been identified, since the contaminated batch would by then not only have been sold but also probably used up. Tests of talc from a different batch would not have revealed the contamination.

A longitudinal study is in progress to investigate long-term or delayed health effects which may develop in survivors of the epidemic. The survivors have been matched for age and place of residence with unexposed controls. Since rats which have been pre-treated with hexachlorophene lose their ability to perform certain tasks,21 it is possible that survivors who at present show no muscular or neuromuscular sequel of the intoxication may show social or learning deficits in the future. Other studies suggest that hexachlorophene may be teratogenic in man.22-23 It remains to be determined whether the lesions of the central nervous system induced by hexachlorophene are completely reversible, whether the effects of exposure in childhood may persist into adulthood, and whether there are genetic effects which may affect offspring. Meanwhile, inspection of factories and quality control may prevent future accidents.

The members of the investigating team included Dr H. Beetens (Centre for Technological Studies and Research of Food Industries, Lille, France); Dr J. Garat (Mediolegal Institute, Toxicology Laboratory, Department of Police, Paris); Dr D. Graveleau (Department of Paediatrics, International Hospital of the University of Paris, Paris); Prof. H. Lestravet (Department of Paediatrics, Harold Hospital, Pans); Prof. P Satge (Institute of Pediatrics of Pans); and Dr M. Sebald (Pasteur Institute, Pans). We thank Mrs C. Barin, Mrs H. Guerbois, Mrs L. Vissouze, and Dr R. Ancelle (INSERM U. 165), Dr M. Berard (Faculty of Medicine, Marseille), Dr M. F. Tripier (INSERM U. 119), and Mr J. Tourneau and Mrs B. Plesse (Mediolegal Institute, Toxicology Laboratory, Department of Police, Pans) ' for their help; Dr A. Asbury (University of Pennsylvania School of Medicine) for reviewing the manuscript, photomicrographs, and EEG tracings; and Mrs Rita Schmnar (University of Pennsylvania) for technical help. Correspondence should be addressed to P. D. S., Clinical Epidemiology Unit, Section of General Medicine, University of Pennsylvania, Floor 2L Nursing Education Building 152, Philadelphia, Pennsylvania 19104, U.S.A. REFERENCES I Traub EF, Newhall CA. Fuher JR. The value of a new compound used in soap to reduce the bacterial flora of the human skm Surg GyrncolObstet 1944; 79:205-16. 2. SeastoneCV ObservationsontheuseofG-11 m the surgical scrub Surg Gynccol Obstei 1947: 84: 335-60 3. Price PB Fallacy of a current surgical fad: The three minute preoperauve scrub with hexachlorophene soap Ann Surg 1951, 134: 476-85. 4. Allen C Handwastung practices for the prevention of nosocomial infections Ann Intern Med 1975; 83: 683-90 5. Forfar JO. Gould JC, Maccabe AF. Effects of hexachlorophene on incidence of staphylococcal and gram-negative infection in the newborn Lancer 1968; u 177-79 6 White JJ, Wallace CK, Burnett IS. Skm disinfection. Johns Hopkins Med J 1970,126: 169-76 7. Herter WB Hexachlorophene poisoning. Kaiser Fnd Med Bull 1959; 7: 228- 30. 8 Carrol FE, Salak WW, Howard JM, Pairent FW Absorption of antimicrobial agents across experimental wounds Surg Gynecol Obslet 1967; 12S: 974-78 9. Mullick FG. Hexachlorophene toxicity. Human experience at the Armed Forces Institute of Pathology Pediatrics 1973; 51: 395-99 10 Larson DL Studies show hexachlorophene causes burn syndrome Hospitals \96&; 42: 63-64 II WearJB, Shanhan R, RatliffRK Toxicity of ingested hexachlorophene. JAMA 1952; 181: 587-89 12 LusngFW A fatal caseofhexachlorophene(pHiscHex)potsomng McdJAusi 1963, 50: 737-40 13. Liu J, Wang C, Yu J, et al Hexachlorophene in the treatment of chlonorchiasis sinensis Chinese Med J 1963; 82: 702-11 14. Lockhart JD How toxic is hexachlorophene? Pediatrics 1972, SO: 229-35 15 Games TB, Kimbrough RD. Linder RE The oral and dermal toxicity of hexachlorophene in rats Chamblee Toxicology Laboratory, Environmental Protection Agency, Chamblee, Georgia, 30314 16. Browning RS, Grego J, Warnngton HP Gas chromatographic determination of hexachlorophene in blood and urine. J Pharmacetu Sci 1968, 57: 2165-66 17. Talc Morhange Court proceedings. Tribunal de Grande Instance de Portoise, France. Feb. 11, 1980, Vol 7. 18. Garat J, Lebreton R, Martin-Bouyer G, Toga M Animal experiments of hexachlorophene. Volume VIII- Research report on the incident of BeBe Talc Morhange. Submitted as evidence in the trial proceedings, 1980 19. Towfighi J, Gonatas NK, McCree L Hexachlorophene neuropathy in rats lnt Acid Pathol 1973, 29: 428-36 20. LampertP, O'Brien J, GarrettR Hexachlorophene enccphalopathy ActaNeitropathol (Berl) 1973; 23: 326-33. 21. Weiss LR, Williams JT, Krops S Effects of hexachlorophene intoxication on learning in rats Toxicology 1978, 9: 331-40 22. Check W. New study shows hexachlorophene is leratogenic in humans JAMA 1978, 240: 513-14. 23 Janench DT. Environmental causes of birth defects: The hexachlorophene issue JAMA 1979; 241: 830-31.

hexachlorophene/autopsy/studies

Sunday, May 11, 2008

French Hexaachlorophene autopsy study

Hexachlorophene Autopsy Studies

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