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ALDRIN/D IELDRIN BACKGROUND Aldrin and dieldrin, chlorinated cyclodienes, are broad-spectrum insecticides that are contact, stomach, and inhalation poisons. Aldrin is readily converted to dieldrin, which is considered one of the most persistent of all pesticides. These insecticides were used extensively in agricul Cure for over 20 yr until their use was suspended by EPA ( 1974~; their use for termite control was retained. Although the use of aldrin and dieldrin is banned in many countries, these insecticides were being manufactured in a number of European countries at least until 1978 ant are still used throughout the world. Physical and chemical properties of aldrin and dieldrin are shown in Table 1. SUMMARY OF TOXICITY INFORMAT ION Several comprehensive reviews are available on the toxicity of aldrin and dieldrin (NRC, 1977b; IARC, 1974; EPA, 1979c; NIOSH, 1978~. EFFECTS IN HUMANS Human poisoning from aldrin and dieldrin is characterized by major motor convulsions. Other effects include malaise, incoordination, headache, dizziness, ant gastrointestinal disturbances. The seizures have developed with and without other symptoms of poisoning. Several reports have described acute intoxication, including fatalities, from ingestion of aldrin and dieldrin (Hayes, 1957, 1959; Garrettson and Curley, 1969; Taylor et al., 1979~. Convulsions generally began within 30 min and lasted for up to 7 h. Patel and Rao (1958) investigated poisoning in workers spraying dieldrin. Exposure to the pesticide was not continuous, and there were periods of varied duration of aonspraying. Of 297 workers, 20 developed adverse effects, including headaches, gittinese, muscle twitching, convulsions, and lose of coneciousnese. Adverse ef fects developed 14-154 d after exposure began, and in 17 of the workers symptoms did not develop until the second spraying period. Abnor~1 EEGe have been fount in persons exposed to aldrin or dieldrin, as reviewed elsewhere (Taylor et al., 1979~. Aver and Czagledi-Janko (1970) examined 15 workers involved in aldrin production for 1-5 yr; of 40 workers, 15 were chose~-3 who tad shown symptoms and 12 others who were chosen randomly. Physical examinations, including EEGe, took place in the last month of exposure. Nine of the workers had BEG changes from increased frequency and ampl itude to changes indicative of c annul ~ ions. The three workers who had symp tome (epileptiform convulsions) were followed for 7 ma after exposure ended. By the end of this period, symptoms had subsided and EEGe were nodal. No environmental

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monitoring was done to give an indication of the extent of exposure to al drin. Jager (1970) reported an extensive study of 826 chemical workers involved in production of aidrin, dieldrin, endrin, and telodrin. Workers were exposed for various periods up to 15 yr. Physical examinations took place twice a year, ant blood concentrations of the pesticides were measured. 'me only effects reported were CNS symptoms associated with exposure to the pesticides. These symptoms generally subsided within a few weeks after removal from exposure. The author compared blood concentrations of dieldrin with symptoms of intoxication and found no cl inical effects at concentrations below 0.20 ~g/ml. Taking into account effects on enzyme induction in workers exposed to aldrin and dieldrin, the author reported that a blood concentration of dieldrin of 0.105 ug/ml could be considered a no~ef feet-l easel. An earlier analysis of some of these workers was re port et by Hoogendam_ al. (1962, 1965~. Of 225 workers exposed for less than 4 yr, 17 had convulsive episodes with slight to secrete EEG changes. Symptoms were reversed after removal from exposure. The authors also reported that 17 of 7() workers exposed for 4-9 yr nad some EEG changes; these changes were reversible. No impairment of 1 iver funct ion was found. Air samples of aldrin and d ieldrin were taken during two periods; the concentrations were 0. 5-8.5 mg/~3 and 0.02~0.2 mg/m3 for each period. Because airborne concentrations varied considerably from day to day and workers often moved from 1 ocation to 1 ocation in the pl ant, these ranges do not necessarily indicate the extent of exposure. The effects of long-term oral exposure of dieldrin have been investigated (Bunter and Robinson, 1967; Bunter et 81., 1969~. Thirteen men, aged 21-52 yr, were given various dosages of HEOD (pure dieldrin); three men were given HOOD at O ~g/d for 18 No and 211 ~g/d for 6 ma, three were given 10 ug/d for 18 ma and 211 ug/d for 6 ma, three were given 211 ug/d for 24 ma, three were given 50 ~g/d for 24 ma, and one was given no lIEOI). The men were also observed for 8 ma after exposure ended. No adheres effects were reported on body weight, EEGe, ECGe, aematologic tests, ant serum enzymes, and there were no symptoms of intoxication. Samples of blood sod adipose tissue were taken at various stages to measure the concentration of HEOD. At 18~24 ma, the blood concentration of HEOD was 5-8.6 ug/L, 1.5-12.7 ug/L, 2.9-12.8 tlg/L, and 12.4-32.2 ug/L for the subjects given dosages of 50, 0 ant 211, 10 and 211, and 211 tlg/d, respectively. There was onI'r a alight increase in the blood concentration, compared with controls, for the group given 10 ug/d, whereas the groups given 50 and 211 Aged bed about fourfold and tenfold increases, respectively. For the latter two groups, the HEOD blood concentration reached a plateau by about the tenth month for 54) God and oy the eighteenth month for 211 ug/d. The helf-life of HOOD in the blood of these person. was estimated to be 369 d, with a range of 141-592 d. The concentration of HEOD in adipose tissue followed a pattern misfiler to that in blood; when a constant dosage was administered, it plateauet by about 9-15 mot The ratio of the concentration of HEOD in adipose tissue to that in blood was estimated to be 136. - 24

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Aldrin and dieldrin are absorbed through the skin. Feldmann and Maibach (1974) applied 14C-labeled altrin and dieltrin to the forearms of six human at 4 tlg/cm2 and measured urinary excretion for 6 a. For altrin and dieldrin, respectively, 7.8 ant 7.7 percent of the total dose was recovered in the urine. EFFECTS IN ANIMALS Ac ute Exposure Aldrin and dieldrin are acutely toxic to laboratory animals by the oral, dermal, and inhalation routes. They are mildly irritating to the eye and to the skin. 80th aldrin and d~eldrin affect the central nervous sys tem, produc ing irritabil ity, tremors, and convul ~ ions (Heath and Vandekar, 1964~. The oral LD,o of aldrin for rats ranges from 46 mg/kg of body weight in peanut oil to 63 mg/kg as a wettable powder (Gaines, 1969~. The dermal LD,o for rats ranges from 98 to 274 mg/kg. The oral LD,o of dieldrin for rats ranges from 38 mg/kg in peanut oil to 52 mg/kg as a wettable powder; the dermal LDso ranges from 64 to 213 mg/kg. Ch Conic Exposure and Care inogenic ity Aldrin and tieltrin are carcinogenic in mice, having produced increased incidences of 1 iver tumors (NCI, 197da) . In the NCI bioassay, 50 86C3F1 mice of each sex were given aldrin in the diet for 80 wk (4 and 8 ppm for males and 3 and 6 ppm for females) or dieldrin in the diet at 2.5 and 5 ppm for 80 wk. All animals exhibited hyperexcitabil ity, compared with controls. There was a ~ igaif leant dose-relatet increase in hepatocellular carcinomas in male mice exposed to either aldrin or dieldrin. Other dietary studies have also demonstrated the ability of aldrin and dieldrin to produce hepatocellular carcinomas in mice (Davis and Fitzhugh, 1962; Walker et al., 1973), and dieldrin has produced lung tumors in mice (Walker et al., 197;3) . Studies of aldrin and tieldrin in rats have generally yielded negative results with regard to carcinogenicity. In NCI bioasesys, 50 Osborne-Mendel rats of each sex were given altrin in the diet at 3~) and 60 ppm or dieldrin in the diet at 29 ant 65 ppm for up to 80 wk (NCI, 197Ba), and 24 Fischer 344 rats of each sex were given dieldrin in the diet at 2, 10, and 50 ppm for up to 105 wk (NCI, 1978b). No ~ ignificant incidence of dose-related neoplasme was observed. In another study ~ Fitshugh et al ., 1964), Osborne-blendel rats were given aldrin or dieldrin in the duet at 0.5, 2, 10, 50, 100, and 150 ppm for 2 yr. A high incidence of multiple-site tumors was observed only at the lower concentrations, and there was no significant increase in liver tumors. 25

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Teratogenic and ~p~ Results of studies of the teratogenicity of aldrin and dieldrin have been equivocal. Ottolenghi et al. (~974) gave pregnant golden hamsters single oral doses of aldrin at 50 mg/kg and dieldrin at 30 mg/kg on day 7, 8, or 9 of gestation. There was an increase in fetal deaths, compared with controls, and an increase in anomalies, such as open eye, cleft palate, ant webbed foot. When mice were given aldrin at 25 mg/kg or dieldrin at 15 mg/kg on day 9 of gestation, there was no effect on fetal survival or weight; however, webbed foot and cleft palate were observed. Dix et al. (1977) administered dieldrin in corn oil (1.5 and 4 mg/kg per day) or in dimethyl sulfoxide (0.25, 0.5, and 1 mg/kg per day) to pregnant mice on days 6-14 of gestation. No teratogenic effects were observed. However, there were decreases in maternal and fetal body weights in the DMSO group ant in DMSO controls. In another experiment, mice and rats were given dieldrin in peanut oil orally at 1.5, 3, and 6 mg/kg per day on days 7-16 of gestation (Chernoff et al., 1975~. No teratogenic effects were observed, but at 6 mg/kg there was 41 percent mortality in rats and increased liver-to-body weight ratios and decreased weight gain in mice. Deichmann (1972) reported that, in a six-generation mouse reproduction study, aldrin and dieldrin at 25 mg/kg per day in the diet had marked effects on fertility, gestation, viability, and lactation. At lower dosages (3, 5, and 10 mg/kg per day), the effects were not as marked. Mutagenic ity Most of the available mutagenicity data are based on dieldrin Dieldrin was not mutagenic in several strains of Salmonella typhimurium with or without liver ac tivation systems ~ Bidwel 1 ee a 1 . , 1975; Marshall et al., 1976; Sbirasu et al., 1977~. With metabolic activation, Aldrich was also negative in several strains of Salmonella typhimurium (Shirasu et al., 1977~. Majumdar et al. (1977) reported that tieldrin was mutagenic in two of three strains of Salmonella typhimurium without activation. The mutagenic effect was more pronounced and appeared in all three strains when induced mouse~liver enzymes were acted. Toxicokinet ice l .. Aldrin is rapidly converted to 6,7-epoxide dieldrin through epaxidation of the double boot. This is a microso~1 oxidation reaction that occurs in soils, plants, and animals (Gannon and Bigger, 1958; Cannon and Decker, 1958b; Bann en al., 1956~. Further reaction of tieltrin yields photodieldrin (Mae~umura et al., 1970), which is more toxic than the parent compound. Hydroxy degradation products of aldrin are also found and are conjugated before being excreted. When t14C]dieldrin was administered as a single dose to rats and mice by garage, 50-70 percent was eliminated in 1 wk (Baldwin et al., 26

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197 2~. Most of the radioactivity was detected in the feces--10 times more than in the urine. Aldrin and dieldrin accumulate in adipose tissue. In workers exposes to aldrin and dieldrin, concentrations of dieldrin in adipose tissue and plasma were 5.67 ppm and 0.0185 ppm, respectively (Hayes and Curley, 1968~. Dieldrin has also been detected in the adipose tissue of the general population in a variety of countries (Curley et al., 1973; Abbott et al., 1972; Durham, 1969~. EXIST ING GUIDELINES AND STANDARDS On the basis of carcinogenicity data ant other information, EPA ( 1974) issued suspension notices for aldrin and dieldrin in October 1974. Evidence that was cited to support suspension included the following: Laboratory data indicated that two strains of mice fed a diet containing dieldrin at as low as 0.1 ppm had a significant increase in 1 iver tumors. A 1973 Food and Drug Administration marketbasket survey found 'measurable amounts" of dieldrin in composite samples of foods, such as dairy products. A 19 71 EPA sampl ing of human fat t issues revealed detectable residues of dieldrin in 99.5 percent of them. On the basis of NCI methods for estimating human cancer risk, the present average dietary intake of dieldrin subjects the human population to an unacceptably high cancer risk. Children (particularly from birth to 1 yr of age), because their diet is high in dairy products, consume considerably more dieldrin on a body~weight basis than any other segment of the population and may therefore be at an increased risk. the EPA (1979c) has estimated that exposure of aldrin and dieldrin in the drinking water at concentrations of 0. 0~)46 and 0.0044 ng/L, respectively, would result in a lifetime cancer rise of 10-6. NIOSH ~ 1978) recommended, on the basis of demonstrated potential for induction of t''more in laboratory animals, that aldrin and dieldrin be controlled and handled in the workplace as suspected carcinogens and that exposure be minimized to the greatest extent possible. NIOSI1 ( 1978) also recommended that the airborne c oncentrat ion 0 f e i ther a 1 drin or d Gel dri n i n the workpl ace ~ e no higher task 0.15 mg/m3, which was the lowest concentration detectable by validated analytic methods. The current permissible workplace exposure limit for aldrin and dieldrin enforced by the Occupational Safety and Health Administration is 0.25 mg/m3 (OSHA, 19811. The ACGIN (1981) has recommended for aldrin and dieldrin a ILV-TWA of 0.25 mg/~3 and a TL`J-STEL of 0.75 mg/m3. Both agencies noted that aldrin and dieldrin are absorbed through the skin and that dermal exposure should therefore be avoided. 27

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