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CHLORDANE BACKGROUND INFO RMAT ION chlordane is a member of a group of chemical compounds generically termed "chlorinated cyclodienes." For its use as an insecticide, and especially as a termiticide, it is available in pure and technical grades. Pure chlordane in a viscous, colorless , odorless liquid. Its Volubility in water is approximately 9 ~g/L at 2S°C. It is highly soluble in most organic solvents, including petroleum hydrocarbons (Brooks, 1974a,b). Physical and chemical properties of chlordane are shown in Table 1. Technical chlordane is usually sold as an emulsifiable concentrate for use in dilute water suspension as a spray, but is also supplied in powder form diluted with talc or other inert mineral dust (Aldrich and Holmes, 1969) . Firs t produced connnercia1 ly in 194 7, chlordane has been used primarily for termite eradication around housing foundations and for control of soil insects in corn production. chlordane also has been an ac Live Ingredient in many household and garden pesticides (Infante et al., 1978~. The present review stems from exposure of several families living in housing on military bases; chlordane had been applied as a tenmiticide in and around the housing foundations several years earlier. Modifications in the heating systems and disruptions of the inground heat ducts are believed to nave resulted in the entry and dispersion of chlordane through the duct systems, which let to mitt to moderate systemic symptoms in residents. Such release of chlordane into the house environment can generally be controlled by repairing ducts or by c losing of f and c ircumventing the underground duct system. There are several reports of detection of airborne chlordane in residences. Livingston and Jones ( 1981 ) sampled the air of apartments at a Midwestern Air Force base for chlordane. These units had intraslab or subelab heating ducts arid had been treated with chlordane by high-pressure subelab injection or by soil drench before pouring of the slab. In a preliminary survey, 13 units treated in 1978 and 43 treated before 1978 were sampled. All but five of the apartments had detectable concentrations of airborne culordane, ranging from 0.4 to 263.5 ~ g/~3 . The ma jority had concentrations below 7.4 ug/~3, with only four units exceeding 22 ug/~3. In a wiser survey, 435 apartments treated with chlordane were investigated. Of these apartments, 335 had measurable airborne chlordane, ranging from trace amounts to 37.8 ng/~3. The mean chlordane concentration was approximately 2 ug/~3. The authors found no correlation between airborne chlorate concentrations and barometric pressure, temperature, relative humidity, or year of treatment. Lillie (1981) reported the results of an investigation of housing units at seven Air Force bases. Airborne chlordane was measured in 474 houses; 469 had the ventilation ducts in or below the slab, and five nad the ducts in crawl spaces. Houses were treated with chlordane by subelab injection or exterior ditching. The _ 9 _
concentration of airborne chlortane was below 0.b ~gtm3 in 130 of the rouses, 0.7-3.4 ~g/m3 in 278 of the houses, 3.5-6.5 1lg/m3 in 56 of the houses, and above 6~5 ug/m3 in 10 of the houses. There was no correlation between concentration of airborne chlordane and temperature, barometric pressure, or relative humility. Wright and Leidy ( 1982) reported the results of sampling of six single~family homes with a crawl space or combination crawl space-alab construction. Three houses were treated with chlordane and three with a chlordane/hepeachlor emulsion. Air samples were taken immediately after termiticide application and at 1 and 1 d and 1, 6, and 12 mot Concentrations of chlortane ranged from ().3 ng/m3 before treatment to 2.34-5.01 ug/m3 after treatment. me mean concentration of heptachlor was ().01 p'g/m3 before treatment and 1.0-1.8 pg/m3 after treatment . SUMMARY OF TOXICITY INFORMAT ION l Several reviews on the toxicity of chlordane are available (NRC, 1977a,b; EPA, 197Sla; IARC, 1979~. Acute poisoning associated with spraying, manufacture, or accidental ingestion of cyclodienes produces central nervous system symptoms, including headache, blurred vision, dizziness, alight involuntary muscular movements, tremor, sweating, insomnia, nausea, and general malaise. More severe illness is characterized by involuntary contractions of muscles or groups of muscles ant by epileptifonm convulaione, with lose of consciousnese, urinary ant fecal incontinence, disorientation, personal ity changes, psychic disturbances, and lose of memory. SUCh episodes, which may recur for 2-4 mo after cessation of exposure, are marked by abnormal encephalographic patterns (NRC, 1977b). The limited human studies with long-tenm exposure have not revealed any consistent or significant detrimental effect. Carcinogenicity data are essentially limited to lottery higb-dose exposure of mice (rats appeared res istant ~ . Chlordane absorption through the skin can produce toxic effects (Goseelin et al.' 1976~. Dental exposure is expected in manufacture or use of the pesticide. Absorption can range from negligible to that producing acute effects, depending on the degree of exposure. Ct~lordene could persist for tong periods on the skin of persons using it. In one study, bexane rinsings of the hand e of a former pest-control operator contained chlordane 2 ye af ted his last known exposure ~ haven at al ., 1974) . Niabet ( 1976resti~ted total tally intake of chlordane on the basis of the concentration of oxychlordane stored in tissue. A chiordane intake of 9 ug/day was calculated. Nisbet also identified highly exposed aegaents of the general population: children, as a result of mills consumption; fishermen and their families, because of high consumption of fish and shellfish, especially freshwater fish; persons living downwind from treated fields; and persons living In houses treated with chlordane to control pests. 10
EFFECTS IN INS Case Histories Several incident o involving accidental poisonings with chlordane have been reported. It is sometimes difficult to isolate the effects of chlordane from those of other fac tore. Aldrich and Holmes ( 1969) reported a case of chlordane ingestion in a 4-yr-old girl that resulted in intermittent clonic convulsions, loss of coordination, and increased excitability. Spontaneous vomiting was not reported. The use of gastric ravage and parenteral phenobarbital was followed by disappearance of these necrologic ~ igns and restoration of heal th. No residual manifestations were observed 24 h after the acute illness. Serum half-life was found to be 88 d. Curley and Garrettson ( 1969) reported an accidental ingestion of an unknown quantity of chlordane by a 20-mo-old boy. C1 inical features included vomiting and short interrupted seizures on admittance to the hospital. Results of liver-function tests and electroence p alographic and electrocardiographic tests were within normal limits 24 h after ingestion. Blood and fat samples were analyzed for culordane and contained 0.27 mg/100 ml and 3.1 mg/kg of body weight, respectively. Serum alkaline phosphatase content was increased af ter 3 ma of observation. Infant e _ al. (1978) reported a series of cases in children seen at a single pediatric hospital. Of 14 children diagnosed as having neuroblastoma between December 1974 and February 1976, five were known to b eve been exposed to chlordane during prenatal and postnatal development; the remaining nine had unknown chemical-exposure histories. Three cases of aplastic anemia ant three cases of acute leukemia associated with chlordane exposure were diagnosed in the same period. The f ive patients with neuroblastoma and chlordane exposure were 32 ma to 6 yr old at the time of diagnosis. In each case, either the child or the mother (while pregnant) lived in a house that had recently been treated with chlordane for termite infestation. No information on a control series ze available for comparison, and these case reports provided insufficient information to support conclusions concerning the 1 otters heal to risks of chlordane. Occupational Exposure Princi and Spurbeck (1951 ) evaluated 34 persons engaged in the manufacture of insecticides, including chlordane, and exposed through skin contact and inhalation for 11-36 mot Physical examinations, chest x rays, urinary dilution and concentration tests, complete blood coupes, routine urinalysis, hemoglobin measurement, sedimentation rate, and urinary porphyrin determinations failed to suggest any abnormalities in the men. Air was analyzed at several test locations f or total chl orinated hydrocarbons . The authors concluded that no adverse effects were detected in men working in a plant with air concentrations of chlorinated hydrocarbons as high as 10 mg/m3. 11
Alvarez and Lyman (1953) reported a cl inical and laboratory study of 24 men 21~49 yr old who were exposed to chlordane for 2 mo to 5 yr while Wordily in a plant where it was manufactured. Each man was given a complete examination, including blood chemistry ant urine studies. One person with diabetes and two with essential hyper~cension were found, but their diseases were felt to be incidental findings. Seven men were found to have slight fibrotic changes in the apices of the lunge. It was believed thee these lung findings were not related to the chlordane exposure. None of the 24 men had evidence of abnormalities in liver, kidneys, skin, nervous system, and blood-forming organs. Fifteen workers exposed to airborne chlordane at 0.0012-0.0017 mg/m3 over periods of 1-15 yr showed no evidence of toxic effects (Fishbein_ al., 1964~. Liver-function tests were normal in all instances, and there were no manifestations of nervous system disturbances or gas trointestinal or kidney disorders . Repeated topical exposures to chlortane for over a year produced seizures, elec troencephalographic dyerhythmia, convulsions, and twitching in a 47-yr-old nurseryman; these symptoms ceased when chlordane exposure was stopped (Barnes, 1967~. Wang and MacHshon (1979) studied a cohort of workers employed in the manufacture of chlordane and heptachlor at either of two locations between 1946 and 1976. Data obtained from death records, social security records, and employment History of 1,403 workers employed for longer than 3 ma in the production of the two compounds indicated no overall excess of teethe from cancer. While there were fewer deaths than expected overall for diseases of the circulatory system, there was a statistically significant excess of deaths from cerebrovascular disease (17 observed vet 9.3 expected). These deaths all occurred after ter~i~tion of employment and were not related to duration of exposure. Further study is neater to clarify the relationship between cerebrovascular disease and exposure to these cyclodienes. Shindell and Associates (1980) extended the previous study and reported on all fonner and current employees with 3 ma or more of employment at the Marshall, Illinois, plant of Velaicol Chemical Corporation between 1946 (when the manufacture of chlordane began) and the study cutoff date of June 3(1, 1976. The cohort from the Marshall plant totaled 783 persons: 689 white men, 10 nonwhite men, and 84 women. In only 20 cases could it not be confirmed whether the person was still alive (classified as "status unknowns. Most of the analyses in the report are based on a comparison of the workers' health with the health of comparable segments of the U.S. population. Table 2 summarizes the causes of death in Velaicol workers with Gracious periods of employment, compared with those in the U.S. population, and Table 3 presents the standard morality ratios in Velaicol workers by major cause of death and period of employment. The study concluded that the mortality of these workers was not significantly higher than expected. The "healthyqorker" bias could be a problem here, inasmuch as the observed numbers of deaths are markedly lower than the expected numbers based on the U. S . population. Because of this potential bias, it would have been 12
advantageous to compare production workers with nonproduction workers, whose exposure to chiordane was minim. There was a statistically significant positive trend in standard mortality ratio. for cancer deaths (Table 3) in workers with increasing duration of employment. On the basis of the nonparametric randomized trend test, the statistical significance for these data is ' 0.0083 (one-sided) and p ~ 0.0167 (two-sided). However, the increase in the standard mortality ratio. from one to 20 yr of exposure was not large. Also, these E: values must be interpreted in 1 ight of the fact that a large array of data are presented (which increases the opportunity to f ind unusual permutations); and the actual increase in standard mortal ity ratios may be due to changes in the healthy-worker bias with age, duration of employment, calendar year, etc. The findings on morbidity were entirely descriptive, and the authors described them as "unremarkable." The good health index of 75 percent among plant workers was compared with that of about 66 percent found in previous ~ tudies. Two additional features would have been desirable in thin study ~ Shindel 1 ant Associates , 1980) . First, measurements of extent of exposure presumably were not made; it may be assumed thee some workers--plant operators, engineers, and maintenance workers--were more heavily exposed than white-collar workers. Second, providing data on distributions of the number of years of employment and on the year of hiring would increase knowledge of the numbers of persons "exposed" for various durations ant the time since first exposure. The authors (Shindell and Associates, 1980) concluded that there was no evidence to indicate that current or past workers at Velaicol are at an increased risk for heal th relates problems. However, the suggestion of a trend in cancer deaths with duration of employment indicates thee more complete data are needed before firm conclusions can be reached with regard to the carcinogenicity of chlordane in humane. Publ ic Water Contamination Barrington et ale (1978) reported that a section of the public water system of Chattanooga, Tennessee, supplying 105 people in 42 houses, was contaminated with chlordane on March 24, 1976. Chlordane concentrations in the tap water of affected houses ranged from less than 0.1 to 92,SOO ppb. In 23 houses, the concentration exceeded 100 ppb; 11 of these hat concentrations greater than 1,000 ppb. In a door~to-door survey of 71 residents affected, 13 ( 18 percent) }lad symptoms compatible with milt acute chlordane toxicity, gastrointestinal sympeome ~ nausea, vomiting, or abdominal pain), and necrologic symptoms (dizziness, blurred vision, irritability, headache, paresthesia, or muscle dysfunctions. None was hospitalized, and all recovered within 48 h after exposure with no apparent chronic damage. 13
EFFECTS IN ANIMALS Acut e and Short-Term Exposure Tile oral LV50 of chordane for rats was 335 mg/kg of body weight for males and 430 mg/kg for females, and the derma1 LD50 for rats was 840 mg/kg for males ant 690 mg/kg for females (Gaines 1969~. Chlordane toxicity was characterized by central nervous system stimulation. Truhaut et al . ( 1974) reported that the oral LDso. of chlordane were 350 mg/kg for rats and 1,720 mg/kg for bametere; 200 mg/kg was not lethal to 10 rats, nor was 1,200 mg/kg lethal to 1() hamsters. Toxicity was characterized by liver enlargement and congestion of the 1 icier and kidneys. Were are only a few investigations of the acute inhalation toxicity of chlordane. Frings and O'Tousa (1Sl50) exposed 60 female mice to airborne chlordane; 16 for up to 16 wk at an airborne concentration estimated to be 25-50 percent of saturation and the remainder for up to 4 t to air saturated with chlordane. The chlordane was described as being 60~75 percent chlordane and 25-40 percent unspecified related compounds. In the first group, there was loss of activity and muscle coordination within a few weeks. Liver damage was observed after 6 wk. and all mice had died by 16 wk. In the other group, most mice died within 4 d and the remainder in the next 10 d. Ingle (1953) also investigated the effects of chlortane vapor. Twenty mice each were continuously exposed for 14 d to air saturated with chlordane. Pure and technical-grade chlordane were used, which were obtained from a source different from that reported by Frings and O'Tousa (1950~. Ingle (1953) observed no deaths and no effects on the liver or central nervous system. When hexachiorocyclopentadiene was added to the chlordane, there were toxic effects on the liver and CNS and fatalities. Ingle ( 1953) speculated that the toxicity reported by Frings and O'Tousa (1950) may have been causes by chlordane contaminated wi th hexachl orocyc lopentadiene . Ambrose et al. ( 1953) investigated cumulative effects of chlordane at tally doses of 6.25, 12.5, 25, 50, 100, or 200 mg/kg administered to albino rats by gastric intubation for 15 d. Six groups of five rats each were given the compound in cottonseed oil. "ts given chlordane at 25 mg/l~g or less in 15 daily doses showed no toxic reactions with respect to the characteristics evaluated--tremors, conwlsione, and death. However, `he investigators ~ tated that the adverse effect of chlordace was noted on histologic examination of liver at all dosages. The effect consisted of the presence of sbnon~ul intracytoplasaic bodies in the liver cells. These botzes ranged in size from small riDg-like structures to large rings or sheine of casino pilic hyaline material larger than the nuclei of cells. The investigators further stated that there was a positive correlation between the oral dosage and the number and size of the liver-cel1 inclusions. The effects of chlordane on the metabolism of estrogens in rats ant mice have been studied by Welch et al. (1911~. Daily 14
intraperitoneal administration of chiordane at 2 or 5 mg/kg for 7 d reduced the uterotropic action of tritiated estrone and the concentration of tritiated estrogen in the uterus. The total-body me tabol ism o f tri t iated es trogen was increased in ra to pre treated daily with intraperitoneal chlordane at 10 or 50 mg/kg for 7 d. Busuland et al. (1948) applies chlordane as a 1.5 percent spray to cattle and hogs and as a dip to sheep and goats. The material was also sponged onto horses. The treatments were applied eight times at 4-h intervals, and observations were continued for 30 d after treatment. The principal signs of toxicity of chlordane were necrologic ; the chief pathologic changer were enlarged ant fatty 1 ivers and subeerosal hemorrhages. Chronic Exposure and Care inogenic ity Lehman (1952) reported studies in which chlordane was administered to rats in the diet at 2.5, 25, or 75 ppm for 104 wk. At 75 ppm, gross e f fects were reported, including appetite 1 oss, growth retardation, and unspecified signs of poisoning. Microscopic changes in the liver were reported at 25 and 2.5 ppm. Ingle (1952) reported a study in which rats were given chlordane in the diet at 5, 10, 30, 150, or 300 ppm for 104 wk. Hyperexcitability, tremors, and convulsions were seen in rats exposed at 300 ppm by the twelfth week and at 150 ppm by the twenty-sixth week. Tremors were seen in some rats exposed at 30 ppm by about the eightieth week. Growth retardation and liver and kidney damage were reported at the two highest dosages. Only one male rat exposed at the highest dosage survived to the end of the experiment. There was a significant increase in mortality in tie group exposed at 150 ppm, compared with controls, by the forty-eighth week; no differences were seen in the rats exposed at 5, 10, or 30 ppm. The carcinogenicity data OF chlordane have been extensively reviewed (Epstein, 1976; NRC 1977a,b; IARC, 1979~. Chlordane was evaluated for carcinogenicity by the National Cancer Institute ( 197 7a) and found to be carcinogenic in B6C3F1 mice, with a high incidence of hepatocellular carcinoma. In this study, chlordane was given in the diet to groups of 50 B6C3F1 mice (at 3~) and 56 ppm for males and 30 and 64 ppm for females) and 50 Osborne-Mendel rats (at 204 and 407 ppm for males and 121 and 242 ppm for females) for 80 wk. There were dose-related increases in hepatocellular carcinomas in mice given chlordane~highly significant, compared with controls, at the nigh dosages and significant only for male mice, compared with pooled controls, at the lower dosage. In contrast with the findings in mice, hepatocellular carcinoma failed to appear at a significant incidence in rate given chlordane. It was concluded that, under the conditions of the bioassay, chlordane is carcinogenic for the liver of mice. Epstein (1976) reported a study of technical chlordane fed to CD-1 mice for 18 ma, in which 27~6 perccat of the test animals diet. "i~le received diets containing technical chlordane at 0, 5, 25, or 50 mg/kg of body weight; mortality at 18 ma was 27~49 percent at the lower dosages and 76 percent and 86 percent for females and males, 15
respectively, at the higher dosage. ~patocellular carcinoma incidence s were 3/33, 5t55, 41/52, and 32/39 for males and 0/45, 0/619 32/50, and 26/37 for females at the four dosages noted above, respectively . Teratogenicity ant ReDroductive Ef fects In the study of Ingle (1952) described earlier, 1 female rat from each of the test groups (chlordane in the diet at 0, 5, 10, 30, 150, or 300 ppm) was mated in the twenty-fourth or forty~eighth week. The author reported that there was no effect on litter number or size. Mutagenic ity Pure and technical chlordane has been tested for mutagenicity in the Salmonella/microsome assay, in other microbial assays, and in the dominant-lethal test (mouse). The pure compound was negative in all these test systems, but technical chlortane was mutagenic in Sa lmonel 1 a wi shout mama 1 fan ac ~ iva t ing e nzymes ~ ~ icon e t a 1 ., 1977~. The mutagenicity of technical chlordane in this test system may have been due to a chemical impurity. Ahmed et al. (1977) tested chlordane for mutagenicity in an assay based on the induction of ouabain resistance za mutant Chinese hamster V79 cells. A dose of chlortane that killed 55 percent of the cells induced mutations at a frequency of 27 per million surviving cells; in solvent controls, there was a 93 percent survival rate with 2 mutations per million survivors. Whether chlordane increased mutation frequency at concentrations that were not lethal to the test cells was not reported. When chiortane was administered in a single dose at 5¢) or 100 mg/kg of body weight to Charles River CD-1 male mice that were later mated to untreated f emales, no dominant 1 ethal ef facts were noted in the offspring (Arnold et al., 1971~. Toxicokinetice cis-Chlordane ant trane-chlordane are the primary components of the insecticide. Both are stable when heft under ambient conditions or mixed with the feed of experimental animals. A single oral dose of chlordane administered to rate resulted in approximately 6 percent absorption (Bernet" and Dorough, 1974~. Sell daily dosce result in greater absorptio - -10-15 percent. Feeding the pure cis ant bane isolate separately indicates that the cis isomer is more effectively e} if - ted from the rats than the tasks Isomer. Al though the difference is not large, the data indicate that, with locaters exposure, trane-chlordane would contribute more to the body burden of the exposed animals than would ci~chlordane. Polen et al. (1971) and Street and Blau (1972) found oxychlordane to be a primary mammalian metabolize of chlordane and to persist in adipose tissue. Street and Blau (1972) observed that the toxicity of oxychlordane was greater than that of the parent compound. Barnett 16
ant Dorougn (1974) tentatively identified several hydroxylated metabolites of chlordane, including oxychlordane, in rat excrete ant concluded that the metabolism of chlordane takes place via a series of oxidative enzyme reactions. Tashiro and Mate''=ura (1977) attempted to isolate and identify positively the metabolic products from chlordane to establish the route of its metabolism. The major route of metabolism for both cis-chlordane and trans-chlordane is via dichlorochlordene and oxychlordane. These metabol ic intermediates are further converted to two key metabolites, l~exo-hydroxy-2-chlorochlordene and 1-ex~hydroxy-2-endo~culoro-2, 3-exo~epoxychlordene, which are readily degraded further. trans-Chlordane is more readily metabol ized through this route. There za yet another ma jor metabol ic route for cis-chlordane, which involves a more direct hydroxylation reaction to fono 1-ex~hydroxy-dihydroculordenes and 1,2-trans-dihydroxy-dthydro- chlordene. cis-Chlordane is more readily degraded through this latter route. As judged by a toxicity test on mosquitoe larvae, none of the metabol ic end product ~ appears to be more toxic than the original ch 1 ordane or the intermediates. Most chlordane is excreted in the feces of rate. Only about 6 percent of the total intake is voided in the urine. Rabbits, however, provide a different pattern. Urinary el imitation of chlordane in rabbits is greater than excretion in the feces. This suggests that the conjugative metabol ic system is more ef f icient in rabbits than in rats. The patterns of excretion after inhalation of chlordane by rats follow the patterns reported for oral administration ~ Nye and Dorough, 1976) . Human half-life data were obtained when chlordane was accidentally ingested by a young boy (Curley and Garrettson, 1969~. A whole-body half-life of 21 d was calculated--long for a drug used in therapy, but quite short for a chlorinated insecticide. 8arnett and Dorough ( 1974) obtained a half-1 if e of about 23 d in studies with rats ted chlordane for 56 d. The serum half-life of chlordane in a young girl was found to be 88 d by Aldrich and Holmes (1969~. EX ISTING GUIDELINES AND STANDARDS The American Conference of Governmental Industrial ~ygieni8t8 ( 1981 ) has adopted a threshold limit value-time weighted average (TLV-TWA) of 0.5 mg/m3 for chlordane in workroom air. The short-term exposure 1 imit ( 15 min) was Bet at 2 mg/~3 . The Occupational Saf ety and Health Administration (1981) permissible workplace exposure limit is O.5 mg/m3. Both agencies noted that chlordane is absorbed through the skin ant that dermal exposure should therefore be avoided. The Committee on Toxicology (NRC, 1979) suggested an interim guideline for airborne chlordane in military housing of 5 ~g/m3. An acceptable daily tose for man has been estimated to be O.OO1 mung body weight (WHO/FAD, 1968~. Although a limit of 3 ug/L was original 1 y sugges ted f or chl ordane under the proposed Interim Primary Drinking Water Standards (EPA, 1975a), the f inal EPA regulations (EPA, 17
1975b) tid not include a twit, in view of the cancellation proceedings under the Federal Insecticide, Fungicide, and Rodenticite Act. In 1979, EPA ~19798) estimated that exposure of chiordane in drinking water at 0.12 ng/L would result in a lifetime cancer risk of 1~)~6. Canada nas established a tentative maximal permissible limit for chlordane of 3 ug/L, applicable to raw~water supplies (EPA, 1979a) 18 .