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EXECUT IVE SUGARY BACKGROUNI) Seven pesticides are registered with the Environmental Protection Agency (EPA) for control of subterranean termites: chlordane, hepeachlor, aldrin, dieldrin, lindane, pentachlorophenol, and chlorpyrifos. Chlordane is the most widely used of this group ~ and heptachlor the second most widely used. Before 1974, chlordane and aldrin accounted for 55 percent and 40 percent of market sales, respectively. The use of aldrin was drastically reduced after EPA cancellation hearings. However, because of recent increases in the price of chlordane, the use of aldrin to control termites is increasing, and it may soon account for 25 percent of the market. Dieldrin and lindane, although effective as termiticides, have rarely been used for this purpose. Pentachlorophenol is generally used for special applications, such as wood impregnation, and rarely for controlling subterranean termites. Chlorpyrifos is a newer product and only recently teas been marketed for the control of subterranean termites. Chlordane has been the pesticide of choice for termite control in military housing. There now are several reports of the presence of airborne chlordane in military housing long after application; such findings have caused concern over adverse health effects among residents. The problem has been related primarily to housing built on poured concrete slabs with heating and cooling ducts in or below the slabs. Contamination has occurred when the ducts cracked or when exterminators accidentally pierced the ducts during application of ch lordane. As a resul t, the Air Force in 19 78 asked the National Research Council's Committee on Toxicology, in the Board on Toxicology and Environmental Health Bssards, Commission on Life Sciences, to review the toxicity data on chiortane and to suggest an airborne concentration that could be used as a guideline in deciding whether the housing should be vacated. Two National Research Council committees had previously conducted detailed reviews on chlordane and some of the other tenmiticides (NBC, 1977a,b). However, neither of these studies involved an assesement of the possible health risks associated with airborne exposure of the ten~iticides. The Committee on Toxicology (NRC, 1979) concluded that it "could noe determine a level of exposure to chlordane below which there would be no biologic effect under conditions of prolonged exposure of families in military housing." However, it did suggest an interim airborne concentration of 5 ~g/m3, which was pragmatically determined on the basis of "own concentratione of chlordane in the military housing, a review of reported health complaints of residents of contaminated housing, and a comparison with the acceptable daily intake derived from long~term animal feeding studies. The Committee al so suggested that a prospective epidemiologic study of persons exposed to chlordane in military housing would help substantially in making a risk assesament. 1

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In 1960, the Comptroller General of ache United States (GAO, 1980) recommended that the EPA initiate a fon"1 risk-benefit review of chlordane to determine whether its registered uses for subsurface termite control should be 1 limited or canceled and whether the heal th of people living in housing treated with chlordane is being adversely affected. In response to these recommendations, the EPA has initiated a risk-benefie review of all seven pesticides registered for control of subterranean termites. Faced with recurring exposures of personnel to chlordane in military housing, the Department of Defense issued an order in May 198V prohibiting further applicat on of chlordane for buildings with subelab or intraelab ducts. It also recommended chat, where the risk and extent of possible termite damage in existing structures are considered unacceptable, studies be undertaken to determine the feasibility of sealing subelab or intraslab ducts and of renovating heating and cooling systems to use aboveground and above-alab ducts. As a second step in the review of chlortane, the Department of Defense, through the Anmet Forces Pest Management Board, requested in 1981 an independent review of the seven pesticides by the National Research Council's Committee on Toxicology. Specifically, the Committee was asked to evaluate the key information on the toxic effects of the pesticides; make a comparative assesament of the human~health risks associated with exposure to the pesticides; review the previously recommended exposure limit for airborne chlordane; and, if there are sufficient data, suggest airborne exposure 1 imits for the other pestic ides . HEALTH EFFECTS OF THE SPECIFIC PESTICIDES CYCLODIENES (CHLORDANE, HEPTAC~OR, ALDRIN, AND DIELDRIN ) The principal pesticides uset for control of subterranean termites are the chlorinated cyclodienes--chlordane, beptachlor, aldrin, and dieldrin. These all bad widespread use as pesticides until the mid-1970e, when cancellation hearings were held by the EPA. Their use since then has been severely limited, although their registration for control of termites was retained. Acute or chronic exposure of humane to cyclodienes can produce central nervous system symptoms characterized by headache, blurred vision, dizziness, involuntary muscle movements, tremors, and seizures. Date on chronic exposure at low airborne concentrations are Whited. ~ recent epidemiologic study of workers producing chlordane suggested that exposure has no long-term effects. However, because of abortcominge in the study and the suggestion of a trend in standard mortality ratio. for deaths due to cancer in workers with increasing length of employment, more complete Thea are needed before fin conclusions can be reached with regard to the long-term human~health risks of chlordane and the other cyclodienes. All four cyclodienes produced hepatocellular carcinomas in B6C3F1 mice; there was not a significant eumorigenic response in 2

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Osborne~Mendel rats. Central nervous System effect8--such as hyperexcitability, tremors, and convulsions--have also occurred in laboratory animals ted the cyclodiene termiticides. The cyclodienes are deposited in the body in fat, with biologic retention half lives on the order of days to several weeks. Because these compounds are al 1 persistent in the environment, they can oe effective as termiticides for up to 20 yr after appl ication. L INDANE Lindane is the gaunt isomer of hexachlorocyclohexane. It has had widespread appl ication as a pesticide, but its use has been Severely restricted in the last several years. As a termiticide, it is primarily sprayed on the ~oil, and it persists in the environment for approximately 10 yr. Lindane has al so been used widely in the treatment o f scabies and for 1 ous e infes tat ion. In humans, 1 indane exerts its toxic action on the central nervous system. Signs of poisoning include tremors, ataxia, convulsions, and prostration. In severe cases of acute poisoning, violent tonic and clonic convulsions have occurred. Acute exposure of animals to 1 indane has produced diarrhea, hypothermia, hyperirritability, incoordination, and convulsions. Long-term exposure has produced nervous symptoms and fatty degeneration of the 1 iver. Results of carcinogenicity tests in rodents have not been consistent, with both positive and negative resul to reported. However, z: appears that the 1 iver is one of the targe t organs at ter chronic exposure. PE NTACHLOROPHEN()L Pentachlorophenal is a wood preservative. As a termiticide, it is applied rarely to soil, but mainly directly to termite-infested wood. It is not as long-1 ived in the environment as the cyclodienes; its effectiveness as a termiticide after a single application lasts about 3 yr. Symptoms of pentachlorophenol intoxication in humans include lose of appetite, respiratory difficulties, anesthesia, hyperpyrexia, sweating, dyspnea, and coma. ADiDIal8 exposed to pentachlorophenol had pathologic changes in the liver and kidneys, in addition to symptoms associated with uncoupling of oxitative phosphorylation. There was no evidence of a carcinogenic effect in mice ant rats given pentachlorophenol orally for 1-2 yr. Embryotoxicity and fetotoxicity have been observed in offspring of rats given purified or commercial pentach 1 oropenol . CHLORPYRIFOS l Cblorpyrifos is an organophosphate pesticide with a wide variety of applications; only in recent years has it been used as a subsurface termiticide. Its effectiveness in controlling termites after a single application lasts about 4-10 yr. 3

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C1hlorpyrifos is in a different chemical class from the other termiticides discussed here, and its toxic effects also differ. The principal effect in has and animals exposed for shore periods is a reduction in plasma ant red-cell cholinesterase activity. These changes have occurred af ter oral, termal, ant inhalation exposure . There is no information on effects of long-eenm exposure of humans. Rats, mice, ant dogs have been given chlorpyrifos in the diet for up to 2 yr. At the dosages tested, the only effect observed was a decrease in cholinesterase activity. CONCLUSIONS AND RECO - ENDATIONS To evaluate the risks associated with exposure to the seven pesticides that are available for controlling subsurface termites and to assess which of them, if any, are most appropriate for use in military housing from the standpoint of health risks, the Committee has considered several factors. These include heal th effects themselves and environmental end points that influence potential airborne concentrations, such as vapor pressure, persistence in the environment, and amount of material that needs to be applied for optimal effectiveness. COHI?ARISON OF CARCINOGENIC RISK Information is insufficient to determine whether carcinogenesis is the critical biologic end point in h''~s exposed to these pesticides, but available animal data al low some useful comparisons of care inogenic risk. The four cyclodienes and lindane have been testes for c arc inogenic i ty under ~ imi 1 ar experimental pro tocol ~ . Each c ompound has produced hepatocellular carcinomas in male mice, and this end point can be used for comparing carcinogenicity. The EDlo (dosage producing an incidence of liver eumore 10 percent above background) was calculated to make comparisons. EDlo was chosen because it is the lowest effective dosage that can be estimated with satisfactory precision, owing to the size of the experimental groups. On the oasis of the Edits, heptachlor, aldrin, and d~eldrin had approximately the same carcinogenic activity and were more potent than calordane; lindane had about one~sixth the activity of chlordane. Ibe calculated EDlo. for dietary aldrin, dieldrin, heptachlor, chlordane, and lindens were 3.1, 3.6, 5.0' 16, and 103 ppm, respectively. me upper 95 percent conf idence bounds on 1 if etime cancer rick expressed as the probability of cancer after a lifetime consumption of 1 L of weeer per day containing the compound at a concentration of 1 ug/L have also been estimated. A 1 imitation in interpreting the results of the bioassays is that the route of exposure was the diet, whereas the primary route of exposure of humane to these pesticides applied for termite control is inhalation. However, given this limitation, and on the basis of the EDlo. and the upper conf idence bounds on 1 if etime cancer risk, the 4

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ranking from greatest to least risk would be: aldrin, dieldrin > heptachior ~ chlordane ~ lindane. The carcinogenic potential of chiorpyrifos was investigated in C0-1 mice; there did not appear to be any tumors related to administration of th is pesticide. Direc t c omparis on with the chlorinated hydrocarbons is not possible, because a different test protocol and a different strain of mice were used. However, using the highes t dosage in the chlorpyrifos study, 15.8 ppm, and the same experimental conditions, one could es timate the proportion of animals that woul d be expected to have tenors af ter exposure to the other pesticides. On the basis of this analysis, chlordane ant 1 indane would be expected to yield negative results if tested under the same conditions as chlorpyrifos. Obviously, one cannot predict from these data the carcinogenicity of chlorpyrifos at higher dosages. Data on the care inogenicity of pentachlorophenol are not adequate for comparisons with the other termiticides. OVERALL ASSESSMENT OF RISKS Because chlordane is the most widely used termiticide in military housing, the Committee used it as the reference material in making comparisons. The four cyclodiene eermiticides are 8 imilar in overal heal th risks; each exerts toxic effects on the central nervous system. Al though the data on aldrin, dieldrin, and heptachlor suggest a greater carcinogenic risk than that of chlordane, the Committee toes not believe that these differences alone are sufficient to make one cyclodiene more desirable than another. The effectiveness of the cyclodienes as termiticides is fairly comparable, and they all persist in the environment for about 20 yr after application. Aldrin and dieldrin are less volatile than chlordane. Therefore, although chiordane has a smaller carcinogenic risk, the possibility of greater airborne concentrations might result in a greater hazard than would be expected from health data alone. The carcinogenic risk of lindane is considerably less than that of chlortane on the basis of the mouse bioassay; other biologic end points, such as effects on the central nervous system, do not suggest that its toxicity differs fro. that of chlordane to arty great degree. However, lindane is several times more volatile than chlordane and would have to be applied more often to be as effective. Therefore, there is a potential for greater airborne concentrations. Neither pentachloropenol nor chlorpyrifo. has been shown to be carcinogenic, although they were not tested under the same conditions as the other te~iticides. There are no data on bumans, but peneachloropt~enol has been obown to be embryotoxic and f etotoxic in rats. Chlorpyrifo. differs from the other tenniticites in being an organophosphate. Its toxicity is related primarily to ef facts on . cholinesterase activity. Although the risk of chronic effects of pentachlorophenol and chlorpyrifo. may not be as great as that of chlordane, there is a potential for acute effects. Because these materials need to be applied more often than chlordane to be as effective, there is a potential for higher airborne concentrations, which could increase the likelihood of acute effects. 5

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RECOMMENDAT IONS Guidelines for At ro`, rho l;x~s~re The airborne exposure ~ imits suggested here are intended to provide guidance in estimating the health risks of the pesticides in military housing. These are not standards 1 ike those suggested by the Occupational Safety and Health Administration, and they do not guarantee absolute safety. Given the available data and the fact that under conditions of prolonged exposure of families in military housing there may be persons, such as young children, who in general are more susceptible to environmental insults, the Committee concluded thee it could not determine a level of exposure to any of the termiticides below which there would be no biologic effects. The exposure limits were derived on the basis of health considerations and ref lees the combined judgment of the Committee members; the feasibility of achieving the suggested airborne concentrations was not taken into account. However, every effort should be made to minimize exposure to the greatest extent feasible. In deciding which, if any, of the termiticites are most appropriate for use in military housing, one should take into account not only the toxicity and suggested airborne exposure limits, but also other factors that would influence the extent of exposure and hazard. Some of these factors are discussed briefly in this report; they include vapor pressure, persistence In the environment, and amount of material that needs to be applied. One suggested guidelines for airborne exposure should be retrieved again as soon as additional health-effects data become available. Chlordane. The Committee on Toxicology in 1979 suggested an interim guideline for airborne chlordane in military housing of 5 ~g/~3. mid was derived pragmatically on the basis of known concentrations of chlordane in military housing, a review of reported health complaints, and consideration of data from long-term animal-feeding studies. After an extensive review of the available literature on chlordane, ant in the absence of definitive information on the health risks in humane and anioale associated with various degrees of exposure to airborne chiordane, the Committee concludes that there are no new data that justify a change in tt~e guideline of 5 ug/m3 and suggests that it continue to be used. Because of the shortcomings of current data and in view of the Co~ittee's request that more definitive data be developed, the airborne concentration of 5 ~g/~3 should be regarded as an inter). guideline for exposures not exceeding 3 yr. This 3-yr period is sugges ted with the expectation that i t wil 1 provide adequate the for the nested health data to begin developing. Heptachlor, Al drin, Dieldrin. The best available data f or quantitatively comparing health risk are from the National Cancer Institute (NCI) mouse bioassaye. On the basis of the EDlo. estimated from these tests, heptachlor is approximately 3 times as carcinogenic and aldrin and dieldrin 5 times as carcinogenic as chlortane. Using these data, the Committee suggests interim 6

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guidelines for airborne heptachlos. and airborne aldrin/dieldrin of 2 and 1 ug/m3, respectively, for exposures not exceeding 3 yr. Lindane. Carcinogenic ity data on 1 indane are equivocal . Therefore, the Committee does not bet ieve that this information should be used as a basis for suggesting a guideline for airborne exposure to lindane relative to exposure to chlordane. In the absence of other data for quantitative estimation of the risks of exposure to airborne lintane and because lindane is not now used to control termites in military housing, the Committee does not suggest a guideline for airborne exposure. Pentachlorophenol. Because of the wide use of pentachlorophenol in ways other than as a termiticide, because it is not now used to control termites in military housing, because of its complex toxicity, and in the absence of definitive data on effects of long-term exposure to airborne pentachlorophenol, the Committee does not suggest a guide 1 ine f o r a irborne exposure . Ch lorpyrifos. The Commit tee on Toxicology previously suggested a guideline for airborne chlorpyrifos of 100 1lg/m3, applicable for 90-d continuous exposure of Navy personnel in submarines. That guideline was based on data from ingestion. In the absence of data on effects of long-term exposure to airborne chlorpyrifos, the Committee concludes that the ingestion studies of fer the best available information from which to derive a guideline. Because the population in military housing is more heterogeneous than that in submarines, the Co ~ ittee suggests an interim guideline of 10 ~g/m3 for exposures no t exceeding 3 yr. Research Recommendations The Committee s trongly recommends that more def initive human-heal th data be developed for a fuller assessment of the risks of exposure to these termiticides. With increasing reports of human exposure to some of these termiticites in military and civilian housing, a clearer understanding of the potential risks becomes even more important. To provide a stronger data base on which to compare these materials more fully, the following research is recommended: Lon~Term Animal-Inhalation Studies. The primary route of human exposure is inhalation, ant there is a minimum of information on such exposure. Differences between routes of administration could modify the relative or absolute rises of these materials. Therefore, long-term inhalation studies of the seven termiticides are recommended. Biologic end points to investigate in these studies include neurotoxicity, carcinogenicity, effects on blood-forming t issues, and teratogenic ant reproductive ef fects. Studies on the mechanisms of carcinogenicity (particularly for the cyclodienes) ant neurotoxicity of these termiticides should also be untereaken. In addition, the role of metabolism in influencing their toxic effects 7

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need e to be examined further. If resources are insufficient for the testing of all seven materials, it is suggested that testing begin with chlordane, aidrin, ant some of the noncyclodiene compounds, such as lindane and chlorpyrifos. Airborne Monitoring. An important consideration in assessing health hazards is knowledge of likely exposure concentrations. Published quantiteeive analytic data were available to the Committee only on chlordane; some preliminary data were available on altrin and dieldrin. It is suggested that a program be undertaken to determine the airborne concentrations of the termiticides under conditions ~ imilar to those now used. This program should be conducted over a sufficient period to delineate the effects of such variables as time and t emperature. 0 Epidemiology Data. In several episodes in recent years, people have been exposed to chlordane in military housing. This group can be followed more readily than the general population, because their health records and whereabouts are more easily traced. It is recommended teat, at a minimum, a biologic monitoring program be undertaken as a first step in a comprehensive analysis of the human health ef fects of culordane. Concentrations of chlortane and its metabolites in fat, blood, and urine of persons who lived in military housing where chlordane was applied should be measured. Comparisons of these concentrations before and after exposure would provide some information on extent of exposure and on whether chlordane has accumulated in the body. The health status of these persons should also be investigated. In particular, investigators should look for signs of neurotoxicity~-such as seizures, movement disorders, tremors, and chorea--and for ~ igns of anemia and diseases of blood-forming tissues. Neurologic symptoms appear to be the most sene~tz~e indicator of exposure in humans. It might be possible to develop a retrospective case~control study of those with suggestive necrologic symptoms and appropriate matched conerole (neighbors, unaffected siblings, etc.), including correlation with concentrations of the termiticides in tissues and in indoor air. Any of the other teraiticides for which there are sufficient data on exposure in military housing should be investigated in a si~lar fashion. 8