The clinical toxicology of chlordecone as an example of toxicological risk assessment for man.

Safety assessment procedures still rely heavily if not exclusively on the results of tests carried out in laboratory animals, then extrapolated to man. There are few examples of environmental compounds examined extensively enough in both man and animals to permit a critical comparison of the accuracy of such risk assessment procedures. Chlordecone (Kepone) is a lipophilic, rodent liver carcinogen which now stands among the most extensively studied environmental agents in humans. More than five years of clinical investigations of workers heavily exposed to organochlorine pesticide have established the spectrum of human toxicity of Chlordecone, its dose-response relationships, tissue distribution, metabolic pathways, half-time for elimination, and the concentration at which its major toxic manifestations involving the central nervous system, the liver, and the testes are not observed (no observable effect level, NOEL). Taking advantage of this unique opportunity to proximately compare humans with experimental animals for a single compound administered at comparable doses, we find that none of the toxic effects produced in humans were unrepresented in animal testing. However, the animal testing produced numerous "false positive" results. Hence, accurately predicting the qualitative toxicity of chlordecone in man based on studies in rats would have been impossible. Indeed, proteinuria observed in rats fed small amounts of chlordecone for two years was chosen as a sensitive endpoint by the United States Environmental Protection Agency as the basis for establishing acceptable levels of human exposure. However, we never observed proteinuria even in humans whose dose of chlordecone was hundreds of times higher than that given to the rats. We conclude that greater emphasis should be placed on clinical investigation of humans exposed to environmental agents. A better understanding of the strength and also of the limitations of animal toxicity testing will improve the reliability of extrapolating results of animal testing to human exposure conditions.

Protection of chlordecone-potentiated carbon tetrachloride hepatotoxicity and lethality by partial hepatectomy.

Chlordecone (CD) pretreatment is known to markedly potentiate CCl4 hepatotoxicity. Previous studies have shown that prior exposure to CD obtunds the increased hepatocellular regeneration and repair observed in non-treated rats challenged with a single, low dose of CCl4. These observations allowed us to hypothesize that suppression of hepatic regeneration and tissue repair by CD + CCl4 combination treatment might be involved in this interaction. To test this hypothesis, CCl4 hepatotoxicity was evaluated in actively regenerating livers using CD-treated (10 ppm in the diet for 15 days), surgically partially hepatectomized (PH) male Sprague-Dawley rats. Rats undergoing no surgical manipulation (CTRL) and sham operation (SH) were included as appropriate controls. Surgical manipulations were conducted on day 15 of the dietary protocol. Based on liver-to-body weight ratios (LW/BW), mitotic indices, hepatic cytochrome P-450 content, and hepatic glutathione (GSH and GSSG) levels, PH-induced hepatocellular regeneration was not affected by pretreatment with CD. Thus, the PH model was considered valid for assessing the effects of CD + CCl4 combination treatment. CCl4 (100 microliter/kg; i.p.) was administered 1, 2, 4 or 7 days after the surgical manipulations. Hepatotoxicity was assessed 24 h later by measuring LW/BW and serum enzymes (SGPT, SGOT and ICD) in all four groups. Hepatic histopathological, histomorphometric and lethal effects were assessed in animals receiving CCl4 1 or 7 days after the surgical manipulations. CCl4-induced increases in LW/BW were observed in CD + PH rats receiving CCl4 4 or 7 days post-PH, but not in the 1 or 2 day post-PH groups in which the hepatocellular regeneration was maximal. CCl4-induced serum enzyme elevations were significantly less in the CD + PH rats as compared to CD + SH. This decrease in the serum enzyme elevations was most prominent in the 1 day post-PH group, where the hepatocellular mitotic activity was most pronounced. CCl4 lethality, assessed in the 1 day post-surgical manipulation group, was also decreased in the CD + PH rats in comparison to CD + SH rats. Such a protection was not observed in rats receiving CCl4 7 days post-PH. These data are consistent with and are supportive of the hypothesis that a suppression of otherwise normally stimulated hepatocellular regeneration following low-dose CCl4 administration is involved in the marked amplification of CCl4 toxicity by CD.

Transmission of occupational disease to family contacts.

As recognition of occupational illness increases, the scope of health problems related to work widens. An important area of concern is the worker's family, which has been shown to be at increased risk of disease attributable to the hazards previously thought to be relevant only to the worker. Such "para-occupational" disease occurs particularly in spouses and children through transport by the worker of hazardous materials from the worksite into the home. The most common vehicle has been contaminated work clothing brought home for cleaning. Outbreaks of severe illness caused by lead, beryllium, asbestos, and other compounds have been traced to home contamination by industrial dust. In this review, we describe reports of "para-occupational" illness that demonstrate the importance of early recognition by medical professionals of this cause of illness and of strict control of the dissemination of hazardous materials outside the workplace.

Detoxification of chlordecone poisoned rats with chlorella and chlorella derived sporopollenin.

Chlorella protothecoides accelerated the detoxification of chlordecone poisoned rats, decreasing the half-life of the toxin from 40 to 19 days. The ingested algae passed through the gastrointestinal tract unharmed , interrupted the enteric recirculation of the persistent insecticide, and subsequently eliminated the bound chlordecone with the feces. The detoxification was similar to that obtained with cholestyramine. Laboratory preparations were made to determine whether cell-free components retained the therapeutic properties of the whole cells. Acid and alkaline hydrolysis of the algae destroyed the cells except for the resistant cell wall components. One component was sporopollenin , a carotenoid polymer of limited natural occurrence among microorganisms and plants. Plant sporopollenin was not active, but algal cell walls and sporopollenin retained the therapeutic activity of the whole cells. The cells and cell walls have potential as detoxifying drugs for animals poisoned by chlordecone and other xenobiotic compounds with similar properties.

Kepone: a chemical disaster in Hopewell, Virginia.

One of the most costly chemical disasters in the United States involved a small, single-product manufacturer, ironically named Life Science Products Company, which made the pesticide Kepone for Allied Chemical Corporation. Life Science operated only 16 months in 1974 and 1975, in Hopewell, Virginia, yet managed to poison its workers and pollute the environment, causing millions of dollars of damage. The case dramatically demonstrates the links between hazards inside the factory and those outside the factory, and the confused responses of both administrative and judicial systems to a chemical disaster. In the Kepone case, as in other instances of toxic contamination, the victims confronted problems of care, compensation, and clean-up. The case illustrates two major causes of a chemical disaster: organizational pathologies of public bureaucracies, and irresponsible production by private corporations.

Neurological manifestations in humans exposed to chlordecone and follow-up results.

Chlordecone is an organochlorine insecticide which intoxicated a number of workers in 1975 because of excessive exposure in the industrial plant. The major manifestations were tremor, opsoclonus, arthralgias, pleural pain, and reduced sperm count. The half-life in blood was determined to be 165 days, but treatment with cholestyramine reduced this to 80 days. Despite initial high blood levels of chlordecone, follow up at six years indicated that in the workers reevaluated the chlordecone had been cleared completely from blood, with very low levels remaining in fat. As the chlordecone was cleared, the clinical manifestations abated, and many of the patients returned to work. Appropriate industrial hygienic and medical management would probably have quickly aborted the epidemic.

Therapeutic approaches for chlordecone poisoning in humans.

Due to lack of adequate industrial safety measures, workers in a small factory that manufactured the organochlorine pesticide chlordecone were exposed to large amounts of this toxic material for many months. High concentrations of chlordecone were present in samples of blood, liver, and fat from these workers. Toxic manifestations prominently involved the nervous system, liver and testes. Although a plasmaphoresis experiment indicated that chlordecone is rapidly transferred from tissues to blood, attempts to employ hemoperfusion as a means for removing chlordecone from the body were unsuccessful because chlordecone is avidly bound by plasma proteins and was not extracted by the hemoperfusion sorbents. An alternative approach to therapy was based on the observations that stool contains only a small fraction of the substantial amounts of chlordecone excreted in bile. Oral administration of cholestyramine, a nonabsorbable resin that binds chlordecone in vitro, increased fecal excretion of chlordecone and accelerated its disappearance from the body. This treatment was accompanied by amelioration of the clinical manifestations of toxicity, indicating that the subacute toxic effects of chlordecone are reversible. Studies of chlordecone excretion in one patient with a surgically created bile fistula disclosed the existence of the novel, nonbiliary mechanism for excretion of chlordecone in the stool. Further physiological studies are needed to explore the possible role of the gut in the excretion of many kinds of slowly eliminated lipophilic toxins.

Areawide chemical contamination. Lessons from case histories.

Nine case histories illustrate the mounting problems owing to chemical contamination that often extends beyond the workplace into the community. The effects include not only carcinogenesis and teratogenesis, so much in the public's mind, but also severe neurological and gonadal disabilities immediately after exposure. Recognition of causal relationships is often made by astute clinicians. The experience of the Atomic Bomb Casualty Commission in studying Japanese survivors in Hiroshima and Nagasaki serves as a model for future studies of communities exposed to unusual environmental contamination.

Demonstration of major metabolic pathways for chlordecone (kepone) in humans.

The hypothesis that liver is the site of the previously demonstrated chlordecone alcohol formation in man was tested. Human bile obtained from chlordecone-poisoned factory workers contained substantial amounts of free chlordecone, but little free chlordecone alcohol. However, when the same bile specimens were pretreated with beta-glucuronidase before analysis by gas-liquid chromatography, large amounts of chlordecone alcohol appeared, accounting for 75% of total organochlorine compounds. Confirmation of the identity of chlordecone and chlordecone alcohol was made by using gas liquid chromatography-mass spectrometry. Whereas biliary chlordecone alcohol was present predominantly as its glucuronide conjugate (93%), chlordecone was excreted primarily as the unaltered compound (72%) with only a small portion conjugated with glucuronic acid (9%). The remaining fraction of the total chlordecone measured in bile appeared to be a stable polar metabolite resistant to beta-glucuronidase. This unidentified metabolite could be converted to free chlordecone only by acid hydrolysis under harsh conditions. In contrast to human bile, rat bile contained only trace amounts of chlordecone alcohol (less than 0.5% of total chlordecone), thus indicating that hepatic metabolism of chlordecone is species-specific. We conclude that in man, the major metabolic route for chlordecone is its reduction in the liver followed by glucuronidation.

Psuedotumor cerebri and insecticide intoxication.

Three patients with headache and increased intracranial pressure had elevated blood, serum, and adipose levels of the organochlorine insecticide chlordecone (Kepone). These patients were among 23 employees who suffered from chronic chlordecone intoxication resulting from industrial exposure. In our three patients, investigations eliminated an intracranial mass or other known causes of psuedotumor cerebri. In all three patients, the capacity for cerebrospinal fluid (CSF) absorption was assessed by graded infusions into the subarachnoid space, and was found to be impaired even when papilledema was minimal.

Environmental pollutants and the epidemiology of cancer.

Cancer etiology involves the interplay of genetic and environmental factors. Striking geographic differences and changes in cancer incidence over time have led epidemiologists to infer that probably the major etiologic component is environmental. Recent experiences with vinyl chloride, kepone, and polybrominated biphenyl illustrate the problems involved in epidemiologic studies of proven or suspected environmental carcinogens. While epidemiologic studies will continue to be an essential means for monitoring potential human risks, the long latent periods involved in human carcinogenesis severely limit the usefulness of such approaches for disease prevention. While in vitro and animal test systems can never fully supplant human studies, they represent our only means for detecting potential carcinogenicity before human exposure has become widespread or long established.

Chlordecone intoxication in man. I. Clinical observations.

Industrial overexposure to chlordecone, an organochlorine insecticide, caused tremor in 76 of 148 exposed workers. Chlordecone was absorbed through oral, respiratory, and dermal routes, the last possibly the most significant. Epidemiology of this incident disclosed low-level, widespread environmental exposure of man to chlordecone. In 23 workers with chronic chlordecone intoxication, tremor was associated with opsoclonus, pleuritic pain and arthralgia. No seizures were reported. The site of action of chlordecone on the central nervous system is unknown. It concentrates in human adipose and hepatic tissue but is not biodegradable, either in humans or elsewhere in nature.