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Environmental Medicine: Integrating a Missing Element into Medical Education 25 Chlordane Toxicity Environmental ALERT… For over 35 years, chlordane was used as an agricultural insecticide and for termite control in and around homes. EPA estimates that 19.5 million structures have been treated with chlordane; as many as 52 million occupants may be exposed. Chlordane can persist in the environment for more than 30 years. Its residues are lipophilic and can remain in body fat stores for months. This monograph is one in a series of self-instructional publications designed to increase the primary care provider’s knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. See page 23 for more information about continuing medical education credits and continuing education units. Guest Contributor: Alan H.Hall, MD Guest Editor: Wayne R.Snodgrass, MD, PhD Peer Reviewers: John Ambre, MD, PhD; Charles Becker, MD; Jonathan Borak, MD; Joseph Cannella, MD; Richard J.Jackson, MD, MPH; Howard Kipen, MD, MPH; Jonathan Rodnick, MD; Brian Wummer, MD U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry
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Environmental Medicine: Integrating a Missing Element into Medical Education Case Study A young couple with neurologic symptoms and loss of appetite You are consulted by a couple in their mid-20s who moved to your southern rural community about 2 years ago and purchased an old farm. They have not felt well since their first winter in the home, when they began to experience general malaise and loss of appetite. They both have had transient nasal congestion and severe headaches that lasted 2 to 3 hours, sometimes accompanied by lightheadedness. These symptoms are especially noticeable after they work in their basement workshop. Once or twice, the wife was nauseated when she returned from the basement after several hours in the workshop. In a recent conversation with their neighbor, your patients learned that the previous occupants, a young couple, had left the farm convinced that the wife’s two miscarriages were due to termite fumigation of the house carried out 3 years before your patients moved in. They ask you if the association is possible, and whether this pesticide may also be the reason that they have not been able to conceive; they have not used birth control for about 1 1/2 years. On further questioning, you learn that the couple had been well before their move; they exercise regularly and are quite health-conscious. Neither has ever smoked tobacco, and they rarely drink alcohol. It was their desire to start a family and to seek a less stressful life that prompted them to leave their jobs in the city and to attempt organic farming. Further history reveals that the woman’s last menstrual period was 5 weeks ago, but her menses have always been irregular. She has had no previous pregnancies. Physical examinations are generally unrevealing. Complete blood counts, urinalyses, and chemistry profiles are all within normal limits, except for slight elevations of LDH and alkaline phosphatase in the man. (a) What problem lists would you consider for these patients? _________________________________________________________________ (b) What further investigations would you consider doing at this time? Where could you obtain assistance in investigating these complaints? _________________________________________________________________ _________________________________________________________________ (c) What is the likelihood that the miscarriages of the former occupant or the inability of these patients to conceive is related to the termite fumigation? Explain. _________________________________________________________________ _________________________________________________________________ Answers to the Pretest questions are on page 17.
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Environmental Medicine: Integrating a Missing Element into Medical Education Exposure Pathways ❑ Chlordane was used for more than 35 years as an termiticide and agricultural insecticide. Chlordane was the most commonly used member of the cyclodiene family of chlorinated insecticides that includes aldrin, dieldrin, and heptachlor. Depending on the degree of purity, chlordane may vary from a brown liquid to a white, crystalline solid. It has been described as odorless or having a chlorine-like or solvent-like odor. Technical or commercial-grade chlordane is a mixture of two chlordane isomers and more than 100 related reaction products. Chlordane manufactured before 1951 had a higher percentage of impurities than that produced later, which may have been responsible for some of the adverse health effects (especially irritant effects) associated with its earlier use. Trade names of chlordane-containing products include Chlor-Kil*, Dowchlor, Gold Crest C-100, Octa-Klor, Topiclor 20, and Velsicol 1068. ❑ Indoor air contaminated by misapplication of chlordane is the greatest source of exposure risk for the general population. From about 1950 until it was banned, chlordane was used widely as a spray to protect structures against termites and to control insects on lawns, turf, ornamental plants, agricultural crops, and in drainage ditches. Subterranean injection of chlordane was also done to control termites. The amount of chlordane applied in the United States in the past 40 years is conservatively estimated at 200 million pounds; each year approximately 1.2 million homes were treated for termites. ❑ Food grown on chlordane-contaminated land and fish from waters contaminated by agricultural runoff are potential sources of chlordane exposure. Concern about the risk of cancer and slow environmental degradation led the U.S. Environmental Protection Agency (EPA) to prohibit the use of chlordane on food crops in March 1978. Because no effective alternative chemicals were available at the time, chlordane’s use for termite control continued until April 1988. Since then, both the sale and use of chlordane in the United States have ceased, and several foreign countries have banned it as well. Nevertheless, an estimated 40 to 75 million pounds of chlordane may still exist unaltered in the environment. Chlordane may be found in food, air, water, and soil, and most people have some form of it in their adipose tissue. The major source of chlordane exposure today for the general U.S. population is indoor air, a result of the continuing volatilization from prior application in and around homes. Chlordane is usually undetectable in homes properly treated. However, homes treated improperly often have airborne levels of chlordane above the National Academy of Sciences (NAS) safety guideline of 5 micrograms per cubic meter (5 µg/m3) of air. Improper treatment includes pouring the chemical at the foundation line, carelessly injecting liquid chlordane directly into living spaces or air ducts, or spraying excessively in crawl spaces. If overspraying was done, emission of chlordane from joists and flooring can persist for 15 years after treatment. In addition to inhaling volatilized chlordane, persons can receive dermal exposure from contact with contaminated soil near treated houses or from previous ❑ Except in unusual circumstances, chlordane is unlikely to reach and contaminate underground water sources. * Use of trade names is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.
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Environmental Medicine: Integrating a Missing Element into Medical Education lawn, garden, or agricultural application. In soil, chlordane resists chemical and microbial decomposition, remaining biologically active for 30 years or more. Outdoor air contains only minute amounts of chlordane, primarily the result of volatilization from soil and water, as well as from wind erosion. Chlordane is readily degraded by photolysis and hydroxyl radical reactions, resulting in a half-life in outdoor air of about 1.3 days. In the environment, rain fallout and dry deposition are not significant transport mechanisms for chlordane. Most chlordane water contamination occurs in surface water, the result of industrial releases, urban or rural runoff, or spraying near or over exposed bodies of water. In lakes or streams, chlordane adsorbs almost completely to sediment in about 6 days. Because it is lipophilic and is only slowly metabolized and cleared from the body of many species, it bioaccumulates in aquatic life and has the potential to concentrate in the food chain. Groundwater contamination is not likely to occur because chlordane adsorbs strongly to soils high in clay or organic material. Around waste sites, however, organic solvents can facilitate leaching, thereby allowing chlordane to reach underground aquifers. Contaminated food is another source of chlordane exposure. Eating fish from chlordane-contaminated waters may add to a person’s total body burden. Contaminated fish and other foods are assumed to account for 90% of the body burdens in the populations of Nordic countries where chlordane use was minimal. Certain crops, especially corn, can absorb chlordane from previously treated soil. The daily U.S. intake of chlordane from all sources is estimated to be 0.1 micrograms per kilogram of body weight per day (0.1 µg/kg/day). The World Health Organization (WHO) recommends an upper limit acceptable daily intake (ADI) of 1 µg/kg/day. Additional information for the case study: The couple found a closed, half-empty bucket of a white powder in their basement. The label, which has been partially destroyed, has the words Topiclor 20, but the ingredients cannot be discerned. However, the directions that are legible include the words termiticide and insecticide. (1) If this bucket contains chlordane that was previously used on the farm, what are the most likely exposure sources for the patients in the case study? _________________________________________________________________ _________________________________________________________________
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Environmental Medicine: Integrating a Missing Element into Medical Education Who’s at Risk ❑ EPA estimates that 52 million persons are potentially exposed to chlordane in their homes. Persons with the greatest exposure to chlordane are most likely to be those employed in occupations in which handling the pesticide is common, including manufacture, distribution, and application. Because chlordane is now banned commercially in the United States, the only current occupational exposures would be from chlordane manufactured for export and from chlordane disposal. Chlordane has been found at 166 of 1300 hazardous waste sites on the EPA National Priorities List. When chlordane was available commercially, most cases of systemic chlordane toxicity occurred after acute dermal exposure or accidental or suicidal ingestion. Today, most people at increased risk of chlordane exposure (primarily via inhalation) are occupants of houses previously treated for termite control. Chlordane was used throughout much of the United States, but most treated structures are located in the South and far West, where termite infestations are a significant problem. In 1987, EPA estimated that as many as 52 million persons may be exposed to chlordane in their homes. Most homes have been treated properly, and the occupants are unlikely to experience adverse effects. However, it is not known what percentage of homes have been treated improperly; even a small percentage could affect a large number of persons. ❑ Infants may be at increased risk if the mother has had significant chlordane exposure. Children may have increased exposure risk. A chlordane metabolite, heptachlor epoxide, has been detected in maternal and fetal blood and in amniotic fluid, indicating potential exposure in utero. Chlordane accumulates in breast milk, which may increase the risk for nursing infants of significantly exposed mothers. In several surveys of nursing mothers who had no known exposures, chlordane or its metabolites were found in more than 50% of breast milk samples, but the levels found appeared to have no short-term effects on the infants. Children’s diet may contribute to their total body burden of this fat-soluble pesticide because they generally drink more milk and eat more foods that are high in fat content than do adults. Chlordane is metabolized in the liver, where it leads to enzyme induction of the cytochrome P-450 system. Enzyme induction can accelerate the metabolism of many drugs and hormones, requiring dosage adjustments in chlordane-exposed patients taking these medications.
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Environmental Medicine: Integrating a Missing Element into Medical Education Additional information for the case study: Two weeks after the couple’s initial visit, the woman’s pregnancy test is positive. (2) What advice can you give these prospective parents about potential prenatal and postnatal exposure of the infant? _________________________________________________________________ _________________________________________________________________ _________________________________________________________________ Biologic Fate ❑ Chlordane is absorbed systemically after ingestion, inhalation, and skin contact. Chlordane is absorbed well by all exposure routes. It has caused fatalities after ingestion or skin contact. An acute oral dose as low as 25 milligrams/kilogram (mg/kg) has caused death in humans. This is about tenfold lower than the oral LD50 dose reported for experimental animals. (The LD50 is the dose that is fatal to 50% of an experimental animal population; the lower the LD50, the more toxic the agent is.) The lethal dermal dose for humans is not known, but dermal LD50 values in animals are low. Once absorbed, chlordane is distributed rapidly throughout the body. Concentrations of chlordane and its metabolites are highest in adipose tissue, spleen, brain, kidney, liver, and breast milk. ❑ Chlordane and its metabolites are preferentially stored in adipose tissue. The hepatic metabolism of chlordane, which occurs slowly, has not been studied well in humans. Animal studies show that four metabolic pathways probably exist. The primary metabolites— oxychlordane, nonachlor, heptachlor, and heptachlor epoxide—are more toxic than the parent compound. ❑ Excretion of a chlordane dose may take weeks to months. Chlordane and its metabolites are preferentially stored in adipose tissues, and concentrations increase as exposure duration increases. Oxychlordane is the major metabolite in most species and can account for up to 90% of the chlordane residues in adipose tissue. In acute or subacute poisoning, the fat-to-serum ratio of chlordane residues can be as much as 100:1.
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Environmental Medicine: Integrating a Missing Element into Medical Education Chlordane metabolites are excreted mainly in the feces and, to a lesser degree, in the urine. Excretion is slow, taking weeks to months. Breast milk is a major route of excretion in lactating females. The metabolite oxychlordane has been reported in milk samples of women with no known chlordane exposure at concentrations ranging from 2 to 5 µg oxychlordane per liter of whole milk (2 to 5 parts per billion [ppb]). Concentrations of total chlordane residues in breast milk of mothers with chronic inhalation exposure were up to 188 ppb. Physiologic Effects ❑ Chlordane affects primarily the nervous system and the liver. Acute or chronic chlordane exposure may affect the neurologic and hepatic systems. Adverse respiratory and gastrointestinal effects from acute chlordane inhalation or skin contact are generally secondary to central nervous system (CNS) effects. Chlordane was often used as a spray, in which case it was dissolved in a petroleum distillate solvent. The solvent itself could produce adverse health effects. Because of experimental animal data, EPA considers chlordane a probable human carcinogen. Neurologic Effects ❑ Chlordane disrupts nerve transmissions and causes neuronal irritability. In experimental animal studies, chlordane significantly inhibited brain adenosine triphosphatase (ATPase), which may be involved in the mechanism of chlordane-induced neurotoxicity. Acute chlordane exposure in humans (usually an overdose or suicide attempt) has produced CNS excitation, generalized seizures that were difficult to control, and respiratory depression. Other CNS effects reported in acute and chronic poisonings have included confusion, irritability, hyperexcitability, hyperreflexia, loss of coordination, excessive salivation, muscle twitching and tremors, and coma. Hepatic Effects ❑ In experimental animals, chlordane is quite hepatotoxic. Liver damage (including hepatocellular carcinomas and adenomas) has been noted in chronic feeding studies in experimental animals, yet only mild hepatotoxic effects (e.g., jaundice; increased serum levels of triglycerides, creatine kinase, and lactic dehydrogenase; and hepatomegaly) have been reported in chronically exposed humans. A causal relationship between chlordane exposure and hepatotoxicity in humans remains uncertain, and more research is required to evaluate hepatic effects in chlordane-exposed persons.
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Environmental Medicine: Integrating a Missing Element into Medical Education Gastrointestinal Effects ❑ Gastrointestinal effects may result after chlordane exposure by any route. Anorexia, nausea, and vomiting can occur in acute or subacute chlordane poisonings by any exposure route, and anorexia and nausea may persist for months. In cases of inhalation and dermal exposure, these effects are most likely secondary to CNS effects. After deliberate ingestion in one case, chemical burns in the mouth, hemorrhagic gastritis, and hematochezia (passage of bloody stools) were reported; the material ingested may have been an older chlordane preparation that contained highly irritating hexachlorocyclopentadiene. Chlordane produced after 1951 does not contain this impurity and is nonirritating. Vomiting after ingestion of some chlordane preparations can result in pulmonary aspiration of the solvent vehicle, which may cause lipoid pneumonitis. Carcinogenicity ❑ Because of experimental animal data, EPA considers chlordane a probable human carcinogen. Results of various epidemiologic studies regarding chlordane’s carcinogenicity in humans are conflicting and inconclusive. Some studies have suggested a relationship between chlordane exposure and development of brain, blood, lung, or bladder cancers. However, studies of chlordane-manufacturing workers (theoreti cally the population that would receive the greatest exposure) do not confirm the relationship between chlordane exposure and cancer mortality. Because of the increased incidence of hepatocellular carcinomas in some experimental animals exposed to chlordane in their diet, EPA has placed chlordane in its Class B2 (probable human carcinogen) category. The International Agency for Research on Cancer (IARC) considers the evidence for carcinogenesis induced by chlordane limited in animals and inadequate in humans. Other Effects ❑ Various blood dyscrasias have been associated with environmental chlordane exposures, but the evidence is anecdotal and inconclusive. Various blood dyscrasias have been associated with chronic environmental exposure to chlordane, but not with occupational exposure. The blood dyscrasias noted have included aplastic anemia, refractory megaloblastic anemia, thrombocytopenic purpura, acute lymphoblastic leukemia, and acute myelocytic leukemia. The low incidence of most blood dyscrasias limits the feasibility of an epidemiologic study, and the association between these diseases and chlordane has been made on the basis of case reports. A clear causal relationship has not been shown. ❑ No data on reproductive and developmental effects of chlordane in humans are available. No studies regarding reproductive or developmental effects of chlordane in humans have been reported. When chlordane was administered by gavage to experimental animals, effects in offspring ranged from decreased fertility to hematopoietic and neurologic disorders.
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Environmental Medicine: Integrating a Missing Element into Medical Education (3) Are the complaints of the patients in the case study consistent with chlordane exposure? _________________________________________________________________ _________________________________________________________________ (4) What can you tell them about potential cancer risks? _________________________________________________________________ _________________________________________________________________ Clinical Evaluation History and Physical Examination ❑ Patients who are chronically exposed to chlordane may develop a variety of nonspecific complaints. ❑ Environmentally exposed patients often undergo considerable diagnostic testing before a connection is made with a possible toxic exposure. Because chlordane has been used extensively and persists in the environment, chronic chlordane poisoning is a concern. Acute poisoning is less likely because chlordane has not been available commercially since its ban in 1988, although private stocks may still be accessible. Diagnosis of chlordane toxicity is based on history of exposure, examination, and confirmatory laboratory or environmental testing. Persons chronically exposed to chlordane, with signs and symptoms of poisoning, have usually undergone a significant amount of diagnostic testing before being questioned about a possible toxic exposure. At a minimum, the medical history should include the following: occupational history residence: age, pest control use, location in relation to industrial facilities or hazardous waste sites hobbies, including gardening medications (For more information, see Case Studies in Environmental Medicine: Taking an Exposure History.)
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Environmental Medicine: Integrating a Missing Element into Medical Education ❑ Chlordane and metabolite levels can be measured in blood and adipose tissue, but the results do not correlate with degree of toxicity. If chlordane ingestion is suspected, the physical examination should include a careful neurologic examination looking for hyperreflexia, tremors, and myoclonus. The abdomen should be palpated for hepatomegaly. An incident of chlordane toxicity may be a sentinel event. Other persons, such as household occupants or coworkers, may be similarly exposed. Nervous system complaints, pulmonary complaints, fatigue, and appetite loss—symptoms compatible with exposure to chlordane or a similar pesticide—in more than one family member should increase the index of suspicion for toxic exposure. Signs and Symptoms Acute Exposure ❑ Generalized seizures are common in persons with acute chlordane poisoning. Acute chlordane poisoning is characterized by the rapid development of violent, generalized seizures between 1/2 to 3 hours after exposure. Nausea and vomiting can occur before the onset of seizures. Respiratory depression and cyanosis may develop secondary to convulsions. Mental confusion, apprehension, diplopia, blurred vision, muscle twitching and tremors, myoclonus, incoordination, ataxia, hyperexcitability, and coma are also signs of chlordane toxicity. Mania and convulsions culminating in death have been reported with acute ingestion exposure. Chronic Exposure ❑ Patients with chronic chlordane exposure usually have neurologic complaints. Persons chronically exposed to chlordane in termiticide-treated homes have complained of adverse effects such as headaches, nausea, lightheadedness, syncopal episodes, muscle twitching and tremors, fatigue, weakness, and visual disturbances. In one study of persons living in contaminated homes, a dose-response relationship was found for sinusitis, bronchitis, and migraine-type headaches. Hepatomegaly may also develop in chronically exposed persons. Although evidence linking blood dyscrasias with chlorinated compounds is inconclusive, persons with aplastic anemia or leukemia should have their environmental and occupational histories explored thoroughly for chronic exposure to chlordane (or other organochlorine compounds). Laboratory Tests Because mild hepatotoxicity has occurred in some patients with chlordane poisoning, liver-function tests would be appropriate. A complete blood count and urinalysis should also be obtained. If neurologic complaints are present, nerve conduction velocity testing and electromyograms may be useful. In patients who have seizures or severe headaches, intracranial mass lesions and idiopathic epilepsy should be ruled out.
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Environmental Medicine: Integrating a Missing Element into Medical Education When possible, chlordane levels in various areas in the home and surrounding soil should be measured before performing chlordane testing in biologic samples. If high levels are found in the person’s environment, blood or adipose tissue levels of chlordane and its metabolites may confirm exposure and assist in diagnosis. However, because there is no known relationship between chlordane levels in the body and adverse health effects, measuring chlordane levels in biologic samples is generally not helpful in managing symptomatic chlordane poisoning. Testing for chlordane in biologic samples is usually reserved for research. In the United States, a national study conducted from 1972 to 1983 on adipose tissue samples obtained during autopsies found average oxychlordane levels around 100 ppb (range, 30 to 500 ppb). Similarly, concentrations of chlordane in human adipose tissue specimens from around the world have generally been in the parts per billion range. Blood levels of total chlordane metabolites in pest control operators have ranged from 0.3 ppb after only 1 day of spraying to 5.6 ppb after 27 days of spraying. (5) Assuming chronic chlordane exposure for the couple in the case study, what further physical examination is suggested? _________________________________________________________________ _________________________________________________________________ _________________________________________________________________ (6) What additional diagnostic testing might be considered? _________________________________________________________________ _________________________________________________________________
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Environmental Medicine: Integrating a Missing Element into Medical Education Treatment and Management Acute Exposure ❑ Seizure control and maintenance of adequate respiration and oxygenation are primary concerns in the treatment of acute chlordane poisoning. ❑ There is no antidote for chlordane poisoning; treatment consists of supportive measures. There is no antidote for chlordane poisoning. If CNS, respiratory depression, or continuous seizures occur, airway patency and adequacy of oxygenation should be assured. Most seizures can be controlled by standard measures, using diazepam, phenobarbital, or phenytoin. Induced diuresis, hemodialysis, and hemoperfusion have not been shown to be effective for acute chlordane poisoning. Emesis should not be induced in patients who have ingested chlordane because of the danger of pulmonary aspiration of gastric contents if seizures or CNS depression occur. Gastric aspiration and lavage may be of benefit if done within the first hour after ingestion. Because chlordane has some enterohepatic recirculation, multiple doses of activated charcoal may be considered in serious poisoning. If skin exposure has occurred, contaminated clothing should be removed and the skin and hair washed several times with mild soap and shampoo, rinsing each time with copious water. Exposed eyes should be irrigated with tepid water or normal saline for at least 15 minutes. Chronic Exposure ❑ Preventing further exposure is an important step in managing chronic chlordane poisoning. However, abatement and remediation measures to decontaminate homes should not be undertaken without professional guidance. ❑ Administering cholestyramine may increase chlordane excretion, but clinical experience with this treatment is limited. Assessing the environment and preventing further exposure are the most important steps in managing cases of chronic exposure to chlordane. Local or state health and environmental officials, EPA, or the National Pesticide Telecommunications Network (24-hour hotline 858–7378) can help locate companies that measure chlordane levels in indoor air and soil surrounding a potentially contaminated dwelling. Decontamination or other mitigation methods should not be undertaken without first obtaining advice from public health or environmental professionals. (For further information on chlordane mitigation, see the attached Chlordane Environmental Fact Sheet.) No treatment specific for chlordane poisoning exists. Binding agents, such as cholestyramine, have been suggested to increase fecal elimination. However, clinical experience with this treatment modality is limited, and its effectiveness in chlordane poisoning is unproven.
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Environmental Medicine: Integrating a Missing Element into Medical Education Additional information for the case study: The results of air testing in the couple’s home reveal average chlordane levels of 72 µg/m3 in the basement and 16 µg/m3 in the living space. The testing was conducted under conditions that would maximize test results; that is, the house had been closed for 2 hours before testing began, and testing was done during a time when the heat was on and the humidity was low. Soil samples taken at 10 and 100 yards from the house and samples from the garden reveal significant chlordane contamination. (7) What measures could the couple take to reduce their exposure to chlordane? _________________________________________________________________ _________________________________________________________________ (8) Would administration of cholestyramine be useful in treating the couple? _________________________________________________________________ _________________________________________________________________ Standards and Regulations On March 6, 1978, registrations for all uses of chlordane on food crops were cancelled. Chlordane use on nonedible plants and its continued use for subterranean termite control were phased out over the following 5 years. In 1987, a negotiated agreement was reached with the primary U.S. chlordane manufacturer, banning the sale, distribution, and use of chlordane, effective April 14, 1988. The U.S. regulations and guidelines pertaining to chlordane in air, water, and food are summarized below. There are no guidelines for chlordane in soil. Workplace The workplace standard mandated by the Occupational Safety and Health Administration (OSHA) is a time-weighted average (TWA) of 0.5 milligrams per cubic meter of air (mg/m3), which is also the recommendation of the American Conference of Governmental Industrial Hygienists (ACGIH) and the National Institute for Occupational Safety and Health (NIOSH).
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Environmental Medicine: Integrating a Missing Element into Medical Education Environment Air There are no federal regulations for chlordane in ambient air. In 1979, NAS established an interim exposure guideline for indoor airborne concentrations of chlordane, which recommended that the level not exceed 5 µg/m3. Water To protect human health from the potential carcinogenic effects of chlordane through the ingestion of contaminated water and aquatic organisms, EPA regulates the level of chlordane in drinking water and has established guidelines to keep other water supplies safe. The enforceable maximum contaminant level (MCL) for public drinking water supplies is 2 µg/L (2 ppb). To protect freshwater aquatic life, EPA recommends that the water concentration in any body of water never exceed 2.4 µg/L (2.4 ppb). Chlordane is being considered for inclusion on the National Priority Drinking Water Regulation List. The nonenforceable maximum contaminant level goal (MCLG) for drinking water is zero. The WHO-recommended drinking water guideline is 0.3 µg/L (0.3 ppb). Food The Food and Drug Administration (FDA) has set action levels in food or feed to regulate residues of certain pesticides for which there are no tolerances. Action levels for chlordane include 0.1 ppm in many fruits, vegetables, and berries; and 0.3 ppm in fish or animal fat (rendered). The Food and Agricultural Organization/World Health Organization (FAO/WHO) has set an acceptable daily intake (ADI) for chlordane at 1 µg/kg.
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Environmental Medicine: Integrating a Missing Element into Medical Education Table 1. Standards and regulations for chlordane Agency* Focus Level Comments ACGIH Air-workplace 0.5 mg/m3 (skin designation) Advisory; TLV-TWA† NIOSH Air-workplace 0.5 mg/m3 (skin designation) Advisory; REL§ as TWA OSHA Air-workplace 0.5 mg/m3 (skin designation) Regulation; PEL¶ as TWA NAS Air-indoor 0.005 mg/m3 Advisory EPA Drinking Water 2 ppb Regulation MCL** 0 ppb Advisory; MCLG†† Fresh water (aquatic) 2.4 ppb Regulation WHO Drinking water 0.3 ppb Advisory FDA Food Residual chlordane: in food crops 0.1 ppm Regulation in fish 0.3 ppm Regulation in animal fat (rendered) 0.3 ppm Regulation *ACGIH=American Conference of Governmental Industrial Hygienists; EPA=Environmental Protection Agency; FDA= Food and Drug Administration; NAS=National Academy of Sciences; NIOSH=National Institute for Occupational Safety and Health; OSHA=Occupational Safety and Health Administration; WHO=World Health Organization †TLV-TWA (threshold limit value-time-weighted average)=time-weighted average concentration for a normal 8-hour workday and a 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. §REL (recommended exposure limit)=recommended level in air to which a worker may be exposed, averaged over an 8-hour workday. ¶PEL (permissible exposure limit)=legal concentration in air to which a worker may be exposed, averaged over an 8-hour workday. **MCL (maximum contaminant level)=enforceable level for drinking water. ††MCLG (maximum contaminant level goal)=nonenforceable level for drinking water.
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Environmental Medicine: Integrating a Missing Element into Medical Education Suggested Reading List General Brady UE, Attallah YH. Effectiveness of candidate barrier sprays for managing residues of chlordane on plywood. Bull Environ Contam Toxicol 1986;37:467–74. Dinsdale K. One family’s dream house poisoned. Woman’s Day 1986 Jan 21:88–130. Fenske RA, Sternbach T. Indoor air levels of chlordane in residences in New Jersey. Bull Environ Contam Toxicol 1987;39:903–10. Kutz KW, Wood PH, Bottimore DP. Organochlorine pesticides and polychlorinated biphenyls in human adipose tissue. Rev Environ Contam Toxicol 1991;120:1–82. Livingston JM, Jones CR. Living area contamination by chlordane used for termite treatment. Bull Environ Contam Toxicol 1981;27:406–11. Louis JB, Kisselbach KC Jr. Indoor air levels of chlordane and heptachlor following termiticide applications. Bull Environ Contam Toxicol 1987;39:911–8. Menconi S, Clark JM, Langenberg P, Hryhorczuk D. A preliminary study of potential human health effects in private residences following chlordane applications for termite control. Arch Environ Health 1988;43:349–52. Miyazaki T, Akiyama K, Kaneko S, Horii S, Yamagishi T. Chlordane residues in human milk. Bull Environ Contam Toxicol 1980;25:518–23. Move HA, Malagodi MH. Levels of airborne chlordane and chlorpyrifos in two plenum houses: Saranex S15 as a vapor barrier. Bull Environ Contam Toxicol 1987;39:533–40. Nomeir AA, Hajjar NP. Metabolism of chlordane in mammals. Rev Environ Contam Toxicol 1987;100:1–22. Taguchi S, Yakushiji T. Influence of termite treatment in the home on the chlordane concentration in human milk. Environ Contam Toxicol 1988;17:65–71. Wariishi M, Nishiyama K. Observations on the progress of chlordane contamination in humans by blood and sebum analysis. Arch Environ Contam Toxicol 1989;18:501–7. Epidemiologic Studies Infante PF, Freeman C. Cancer mortality among workers exposed to chlordane. J Occup Med 1987;29:908–11. MacMahon B, Monson RR, Wang HH, Zheng T. A second follow-up of mortality in a cohort of pesticide applicators. J Occup Med 1988;30:429–32. Shindell S, Ulrich S. Mortality of workers employed in the manufacture of chlordane: an update. J Occup Med 1986;28:497–501. Shindell S. Cancer mortality among workers exposed to chlordane (letter). J Occup Med 1987;29:909–11.
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Environmental Medicine: Integrating a Missing Element into Medical Education Clinical Berberian IG, Enan E. Neurotoxic studies in humans occupationally exposed to pesticides. J Soc Occup Med 1987;37:126–7. Curley A, Garrettson LK. Acute chlordane poisoning: clinical and chemical studies. Arch Environ Health 1969;18:211–5. Epstein SS, Ozonoff D. Leukemias and blood dyscrasias following exposure to chlordane and heptachlor. Teratogenesis Carcinog Mutagen 1987;7:527–40. Garrettson LK, Guzelian PS, Blanke RV. Subacute chlordane poisoning. J Toxicol Clin Toxicol 1985;22:565–71. Kutz FW, Strassman SC, Sperling JF, Cook BT, Sunshine I, Tessari J. A fatal chlordane poisoning. J Toxicol Clin Toxicol 1983;20:167–74. Ogata M, Izushi F. Effects of chlordane on parameters of liver and muscle toxicity in man and experimental animals. Toxicol Lett 1991;56:327–37. Olanoff LS, Bristow WJ, Colcolough J, et al. Acute chlordane intoxication. J Toxicol Clin Toxicol 1983;20:291–306. Related Government Documents Agency for Toxic Substances and Disease Registry. Toxicological profile for chlordane [update]. Atlanta: US Department of Health and Human Services, Public Health Service, 1993. Environmental Protection Agency. Analysis of the risks and benefits of seven chemicals used for subterranean termite control. Washington, DC: EPA, Office of Pesticides and Toxic Substances, 1983. Environmental Protection Agency. Pesticide fact handbook. Washington, DC: EPA, Office of Pesticide Programs, 1985. Environmental Protection Agency. Carcinogenicity assessment of chlordane and heptachlor/heptachlor epoxide. Washington, DC: EPA, Office of Health and Environmental Assessment, Carcinogen Assessment Group, 1986. Environmental Protection Agency, Office of Health Advisories. Chlordane. Rev Environ Contam Toxicol 1980;6:1245–51. Environmental Protection Agency. Recognition and management of pesticide poisonings. Washington, DC: EPA, Office of Pesticide Programs, 1989. EPA report no. EPA-540/9–88–001. National Academy of Sciences. An assessment of the health risks of seven pesticides used for termite control. Washington, DC: National Academy Press, 1982. Centers for Disease Control and Prevention. Chlordane contamination of a public water supply. MMWR 1981;30:571–8.
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Environmental Medicine: Integrating a Missing Element into Medical Education ANSWERS TO PRETEST AND CHALLENGE QUESTIONS Pretest questions are on page 1. Challenge questions begin on page 3. Pretest The problem lists for the man and woman include nasal congestion, fatigue, severe headaches, lightheadedness, and loss of appetite. In addition, the problem list for the woman includes nausea, amenorrhea, and possibly pregnancy. Further investigations might include additional laboratory testing and seeking more information about the couple’s present and past home and work environments. You might contact a public health official or the National Pesticide Telecommunication Network ( 858–7378) to discuss the patients’ symptoms and to determine if the termite fumigation could play a role. You could recommend that the couple increase ventilation in the house, especially the basement, and limit the time spent in the basement workshop. Encouraging the couple to keep a journal of their symptoms and activities could help to determine the effectiveness of these measures. If the symptoms persist, the journal could help to confirm a temporal relationship between symptom onset and activities. Advising the couple to have the indoor air tested is also a possibility. The association is unknown. The termiticides in use in 1987 (about the time of the termite fumigation) were organochlorine compounds, namely chlordane, dieldrin, aldrin, heptachlor, and endrin. Because the house is located in the South, it is probable the termiticide was chlordane. Although chronic exposure to chlordane has caused a variety of reproductive and developmental toxicities in experimental animals exposed by gavage, no data are available to assess these effects in humans. Challenge Because of the southern location, the house could have been treated with chlordane for termite control, resulting in potential exposure through inhalation of contaminated indoor air. If chlordane was used as an insecticide on the crops grown on the farm, it is most likely still in the soil because chlordane persists for 20 years or more in soil. Eating crops grown in contaminated soil would be a potential exposure source for the couple because some crops (especially corn and soybeans) can absorb chlordane from treated soil. The couple might also be exposed dermally by handling contaminated soil or by kneeling while gardening in contaminated soil. Another potential exposure source is water contaminated by aerial spraying or by runoff from contaminated fields. Unused pesticides should be disposed of. See Chlordane Environmental Fact Sheet, page 19, for organizations to contact for advice on proper disposal. Although chlordane has been found in umbilical cord blood and amniotic fluid, little is known about effects on the human fetus exposed to chlordane in utero. If the woman is chronically poisoned with chlordane, the pesticide will be excreted in the breast milk, thus exposing the nursing infant. Before the infant is breast-fed, a sample of the mother’s milk could be analyzed for chlordane and its metabolites. Consultation with a medical toxicologist may be advisable. Yes, neurologic complaints and nasal congestion are effects reported by in habitants of houses that were improperly treated with chlordane. However, such nonspecific symptoms as nausea, anorexia, lightheadedness, and headaches are obviously not unique to chlordane. The risk of developing cancer from chronic chlordane exposure is presently undefined, although EPA considers chlordane a potential human carcinogen on the basis of experimental animal data.
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Environmental Medicine: Integrating a Missing Element into Medical Education Further physical examination might include careful palpation of the abdomen for signs of hepatomegaly and a careful neurologic examination. Hyperreflexia, muscle tremors, and myoclonus may be present in chronically exposed residents of houses treated improperly with chlordane. Diagnostic evaluation would include liver-function tests and neurologic testing. If the history and clinical indications warrant, a CT (computerized tomography) scan or MRI (magnetic resonance imaging) may be appropriate to rule out intracranial pathology as a cause of the headaches. Further hematologic testing might be needed if CBC results are abnormal. Abatement and decontamination measures should be undertaken only with advice from a remediation specialist or other environmental professionals. Steps that can be taken to reduce the chlordane level of indoor air are increasing the ventilation; applying barrier coatings to contaminated walls, floors, and joists; removing or encapsulating chlordane-impregnated topsoil; and modifying the building’s structure (see page 20 in the attached Chlordane Environmental Fact Sheet). The couple should also discuss the soil contamination with an agricultural pesticide expert or consider having garden produce tested for chlordane and its residues before they continue to consume it. Cholestyramine has been shown to increase the fecal excretion of absorbed chlordane; however, clinical experience with this treatment modality is minimal, and its efficacy is unproven in treating chlordane-exposed patients. Therefore, it cannot be recommended in this case. Cholestyramine has been given safely to pregnant women for other indications, but there have been no controlled trials of its safety. When cholestyramine is administered to a pregnant patient, supplementation with prenatal vitamins 2 to 3 hours after dosing is recommended because cholestyramine decreases the absorption of fat-soluble vitamins such as A, K, and D. Consultation with a medical toxicologist or regional poison control center is advisable before beginning therapy. Sources of Information More information on treating patients exposed to chlordane can be obtained from ATSDR, the National Pesticide Telecommunications Network (24-hour hotline,  858–7378), your state and local health departments, and university medical centers. Case Studies in Environmental Medicine: Chlordane Toxicity is one of a series. To obtain other publications in this series, please use the order form on the inside back cover. For clinical inquiries, contact ATSDR, Division of Health Education, Office of the Director, at (404) 639–6204.
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Environmental Medicine: Integrating a Missing Element into Medical Education Chlordane Environmental Fact Sheet How does chlordane get inside houses? Vapors can enter houses after proper or Improper application of chlordane and other termiticides. Proper application: Factors that may contribute to vapors entering the home include cracks in concrete floors and walls, floor drains, sumps, joints, cracks in hollow block walls, and air ducts (heating, cooling, and ventilation ducts). Improper application: Indoor contamination can arise from careless injection of liquid chlordane directly into the living space of a house, onto interior walls, or into air ducts located in or below the slab. Surface spraying the soil or the wood in a crawl space is illegal in most states. In fact, any indoor surface spraying of chlordane is an improper application. Plenum construction: In this type of construction, air is circulated without ductwork through the open area below the house. This allows chlordane vapors to be drawn out of the soil and into the air of the house. Many chlordane labels prohibited application to plenum structures. Once chlordane vapors get inside a house, what happens? Chlordane vapors tend to persist inside a house. Indoor air monitoring studies conducted in homes treated properly with termiticides indicate that approximately 90% of the homes treated with chlordane have detectable levels of chlordane in the air 1 year after treatment. These studies also show that houses built on slabs (on the surface of the ground) had lower levels than houses with a basement or a crawl space. Basement rooms had the highest levels. Chlordane has also been found in the soil of treated areas 30 years or more after treatment. Does the existence of chlordane vapors inside a house necessarily affect the occupants’ health? Although human exposure to chlordane in the home may increase certain health risks, most people who are exposed are not likely to develop these health conditions. The individual risk of developing adverse symptoms is low. Health risks depend on the duration of exposure and the concentration of chemical involved. In humans, exposure to high levels commonly associated with misuse of chlordane has produced symptoms of headaches, dizziness, muscle twitching, weakness, tingling sensations, and nausea. However, these symptoms may also indicate a wide variety of illnesses unrelated to chlordane exposure. EPA also has concerns about long-term damage to the liver and the central nervous system. In addition, experimental animals exposed to chlordane over a lifetime have developed tumors. The long-term effects in humans exposed at levels lower than those likely to occur from misuse are not known. How does one know if a house was treated with chlordane? If a house was treated for subterranean termites before 1981, it is likely that chlordane was used. Also, before 1983, chlordane may have been used in the interior to control other household insects such as ants. Although new termiticides have been approved for use since 1981, chlordane was the one most commonly used before that date. If possible, contact the builder or pest control company that treated the home to determine what chemical was used for treatment.
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Environmental Medicine: Integrating a Missing Element into Medical Education If chlordane was used, how can the indoor air quality be improved? The following suggestions will minimize occupants’ exposure to chlordane and other indoor air pollutants (e.g., radon). Increase the circulation of clean air into the house. When weather permits, periodically open windows and doors, and use fans to mix the air. In crawl spaces, clear or add vents and install a fan to constantly vent crawl-space air to the outside. Seal areas that directly come in contact with treated soil, using grout, caulk, or sealant. Fill cracks in basement and ground floors and walls, joints between floors and walls, and openings around pipes, drains, and sumps. Periodically check these areas for signs of new cracks or broken seals because houses settle over time. Install a system that supplies outside air to appliances like clothes dryers and furnaces or fireplaces that normally draw air from inside the house. These may actually create a negative pressure within the house and help draw chlordane vapors from the soil into the house through walls, floors, and basements. Check the condition of ducts in the crawl space or basement. Use duct tape to seal openings and joints. If chlordane misapplication is suspected, what can be done? If improper application of chlordane is suspected, the suggestions above should be followed to improve the indoor air quality. In addition, the air in the home should be tested. Indications of misapplication may include the following: the presence of odors inside the house an increase in such odors when the heating or cooling system is operating evidence of a potential chlordane spill, such as stains, in the house similar symptoms in several household occupants How can a house be tested? It is important to ensure that the results of air testing are reliable by having qualified laboratory personnel collect and analyze air samples. A laboratory proficient in both indoor air sampling and pesticide analysis should be used. This type of service is generally available only from commercial laboratories. Costs vary according to the amount of testing, but could range from about $50 to $500. To locate a laboratory in the area, you can call the National Pesticide Telecommunications Network (NPTN) at (800) 858–7378 or contact your state or local health department. How does a person interpret the test results? In 1982, the National Academy of Sciences published interim guidelines for airborne levels of a number of termiticides. The recommended safe level for chlordane is 5 µg/m3. This guideline is not a critical cut-off point, however. The conditions under which the air sampling was performed will influence the test results. Levels will be higher if the house was closed prior to sampling and if the heat was on, but lower if the humidity is high. A qualified professional should be consulted before abatement or other remedial procedures are undertaken to reduce indoor levels.
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Environmental Medicine: Integrating a Missing Element into Medical Education What additional steps can be taken to reduce exposure? If the above suggestions for improving indoor air quality have been followed, the air in the house has been tested, and the air sample results are high, structural modifications may be useful to further reduce the level of chlordane. For homes that were treated properly, modifications are probably not worth the high expense. Modifications must be designed on a case-by-case basis, but may include replacing or relocating air ducts, replacing furnaces or ventilation systems with air exchangers, using barrier coatings of polyvinylidene chloride (e.g., Saranex) or polyamide (e.g., Capran-C), or sealing crawl-space soil with a layer of concrete. Decontamination measures or other mitigation methods should not be undertaken without professional advice. How can one dispose of unwanted chlordane? Chlordane can be a serious hazard to the environment as well as to human health. It is illegal to dump chlordane into sinks, toilets, storm drains, or any body of water. Any unused pesticide or its container must be disposed of according to both the instructions on the label and state laws. For clarification of label directions or additional guidance, call NPTN or contact your state pesticide or environmental control agency or a hazardous waste representative at the nearest EPA regional office. Are any alternatives to chlordane available? As of July 1987, two alternative termiticides, chlorpyrifos (e.g., Dursban) and permethrin (i.e., Torpedo and Dragnet) were registered with EPA and are available commercially. Chlorpyrifos is an organophosphate pesticide (see Case Studies in Environmental Medicine: Cholinesterase-Inhibiting Pesticide Toxicity), and permethrin is a synthetic pyrethroid pesticide. EPA has concluded that these termiticides, when used according to label directions, do not pose unreasonable risks. How can I get more information? Call the NPTN 24-hour hotline at (800) 858–7378.
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