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Yess, N. J., E. L. Gunderson, and R. R. Roy. 1993. U. S. Food and Drug Administration monitoring of pesticide residues in infant foods and adult foods eaten by infants/ children. J AOAC Int. 76( 3): 492 507. 5 22 Aldrin/ Dieldrin   February 2003 Zabik, M. E., M. J. Zabik, A. M. Booren, S. Daubenmire, M. A. Pascall, R. Welch, and H. Humphrey. 1995. Pesticides and total polychlorinated biphenyls residues in raw and cooked walleye and white bass harvested from the Great Lakes. Bull. Environ. Contam. Toxicol. 54 ( 3): 396 402. 6 1 Aldrin/ Dieldrin   February 2003 6.0 TOXICOKINETICS 6.1 Absorption Few studies pertaining to the direct measurement of the absorption of aldrin or dieldrin were found in the available literature, with quantitative human data being especially limited. Dose related increases in the blood and adipose tissue levels of dieldrin were reported for volunteers who had been fed approximately 0.0001, 0.0007, or 0.003 mg/ kg day of dieldrin for 18 to 24 months ( Hunter and Robinson, 1967; Hunter et al., 1969). After 18 months, the low, intermediate, and high exposures resulted in blood concentrations of dieldrin that had increased approximately 2, 4, and 10 fold ( to 3, 5, and 15 : g/ L), respectively. The authors determined that under steady state conditions, the concentration of dieldrin in the blood (: g/ L) was equal to approximately 8.6% of the amount ingested (: g/ day). In a case of acute poisoning, one of two children who ingested dieldrin died; 3 days later, the blood level of dieldrin in the surviving child was determined to be 0.27 ppm, decreasing to 0.11 ppm within 2 weeks ( Garrettson and Curley, 1969). Concentrations of dieldrin in the plasma of small groups of pregnant women were reported to range from 0.0001 to 0.0061 ppm, while those in whole cord blood of newborns ranged from 0.0002 to 0.0015 ppm ( Curley and Kimbrough, 1969; Curley et al., 1969).

Beyermann and Eckrich ( 1973) conducted inhalation studies with aldrin using human volunteers that suggested approximately 50% of inhaled aldrin vapor was absorbed and retained in the human body. However, based on a study of 10 male volunteers who were exposed to measured aldrin vapor concentrations of 1.31 : g/ m3, followed weeks later by a 60 minute exposure to 15.5 : g/ m3, actual retention may have been closer to 20%. In another study, apparently healthy workers who were occupationally exposed to aldrin and dieldrin were reported to have a mean plasma dieldrin concentration of 0.0185 ppm, with a mean of 5.67 ppm stored in adipose tissue ( Hayes and Curley, 1968). Although uncertain, exposure was likely to have been by both inhalation and dermal contact. Similarly, in a study discussed more fully below, Mick et al. ( 1971) demonstrated plasma levels of aldrin and dieldrin ( approximately 0.01 to 0.13 and 0.1 to 0.3 ppm, respectively) in six workers who had formulated 2 million lbs of aldrin over a 5 week period. Stacey and Tatum ( 1985) conducted a survey study of women in pesticide treated homes that demonstrated a correlation between home treatment and dieldrin levels in the women's breast milk.

Many distribution/ metabolism studies have also demonstrated that absorption of aldrin and dieldrin occurs in animals following oral exposure. After a single oral dose of 10 mg aldrin/ kg bw was given to neonatal rats, absorption was indicated by the presence of aldrin and/ or dieldrin in various tissues over the succeeding 6 days ( Farb et al., 1973). When 2 male rats were given 4.3 : g of radiolabeled aldrin/ day in corn oil for 90 days by gavage, 3.6% of the administered total dose remained in the carcass 24 hours after the final exposure ( Ludwig et al., 1964). These authors estimated that approximately 10% of the administered dose was absorbed by the gastrointestinal ( GI) tract.

Similarly, Hayes ( 1974) demonstrated that a single oral dose of 10 mg/ kg bw of dieldrin in corn oil given to male Sprague Dawley rats produced consistent concentrations of dieldrin in 6 2 Aldrin/ Dieldrin   February 2003 plasma and various other organs and tissues. When rats were fed 50 ppm of dieldrin in their diet, its concentration in blood and liver increased for the first 9 days before then remaining fairly constant over the next 6 months. Within 1 to 5 hours after orally dosing rats with radiolabeled aldrin or dieldrin, high levels of radioactivity were detected in the blood, liver, stomach, and/ or duodenum ( Heath and Vandekar, 1964; Iatropoulos et al., 1975). Heath and Vandekar ( 1964) were also able to demonstrate that absorption occurred primarily via the hepatic portal vein and not the thoracic lymph duct.

In vivo studies on the inhalation exposure of animals to either aldrin or dieldrin were not available, but Mehendale and El Bassiouni ( 1975) demonstrated that aldrin ( 0.2 to 3.0 : M) was taken up by simple diffusion in isolated, perfused rabbit lungs. Uptake of aldrin was biphasic, a slower phase following the initial rapid phase, and was followed by a slower metabolism to dieldrin, which was first detected 3 minutes after initiation of the experiment.

Several studies have demonstrated that aldrin and dieldrin can be absorbed through the intact skin of rabbits, dogs, monkeys, and humans ( Shah and Guthrie, 1976; Sundaram et al., 1978a; Fisher et al., 1985; ATSDR, 2000; IPCS, 1989). It appears to occur rapidly in humans, with aldrin and dieldrin being first detected in the urine of six volunteers just 4 hours after a single dermal application ( 0.004 mg/ cm2) of the radiolabeled compounds to the forearm ( Feldmann and Maibach, 1974). They reported that approximately 8% of the dermally applied compounds ( in acetone vehicle) were absorbed after 5 days. The accuracy of these observations has been questioned, however, as the dose and the 14C recovery in the urine were small, the major route of excretion was the feces and not the urine, and there was large inter individual variation.

In female rats, aldrin ( 0.006, 0.06, and 0.6 mg/ cm2) was rapidly and proportionally absorbed through the skin, with aldrin and dieldrin detectable in the skin after 1 hour at all three dose levels ( Graham et al., 1987). In vitro exposure of rat skin strips to aldrin showed that absorption was complete after 80 minutes ( Graham et al., 1987). In rabbits, dermal absorption was demonstrated from fabric that had been impregnated with up to 0.04% dieldrin ( Witherup et al., 1961).

6.2 Distribution As a result of its relatively rapid conversion to dieldrin ( see Section 6.3), aldrin is seldom observed in human tissues, and very little information is available concerning its distribution within the human body following absorption into the circulating blood ( ATSDR, 2000; IPCS, 1989; USEPA, 1992). Given their hydrophobic nature and high solubilities in fat, it is not surprising that the largest concentrations of aldrin, dieldrin, and their metabolites are generally found in adipose tissue, both in human and animal studies ( ATSDR, 2000; IPCS, 1989; USEPA, 1992, 1988, 1980).

Dale and Quinby ( 1963) determined the concentrations of chlorinated hydrocarbon pesticides in the body fat of 30 individuals 28 from the general population, 1 with previous aldrin exposure and 1 with previous DDT exposure. Mean body fat dieldrin concentration ( ± SE) for the general population was 0.15 ± 0.02 µ g/ g, while for the aldrin exposed individual it was 6 3 Aldrin/ Dieldrin   February 2003 0.36 µ g/ g. In several other studies of the same era, values for the adipose tissue concentration of dieldrin in the general population ranged from 0.04 : g/ g ( India) to 0.31 : g/ g ( U. S.) ( IARC, 1974b). As briefly noted in the section on absorption, Hayes and Curley ( 1968) examined the aldrin and dieldrin concentrations in 71 workers involved in manufacturing pesticides. In decreasing order, the mean concentrations ( ± SE) of dieldrin in adipose tissue, urine and plasma were 5.67 ± 1.11, 0.0242 ± 0.0063, and 0.0185 ± 0.0019 : g/ g, respectively; these were significantly higher than corresponding values reported for the general population.

In a study conducted on male volunteers, 3 men/ group ( 4 controls) received a daily oral dose of either 0, 10, 50, or 211 : g dieldrin ( approximately equivalent to 0, 0.0001, 0.0007, or 0.003 mg/ kg day) for 18 months ( Hunter and Robinson, 1967; Hunter et al., 1969). The 50 and 211 : g groups continued to receive these doses for another 6 months, whereas three of four controls and the 10 : g group were switched to the 211 : g dose. After 18 months, concentrations of dieldrin in the blood of the low, intermediate, and high dose groups had increased approximately 2, 4, or 10 fold ( to approximately 3, 5, or 15 : g/ L), respectively. It was noted that the increase in the low dose group had essentially been achieved by 5 months, with little change occurring thereafter. No significant increase in blood dieldrin concentration during the 18 to 24 month period was noted for the mid dose group, while the high dose group experienced a slight increase during months 18 to 21, but nothing significant thereafter. During the final 18 to 24 month period, the control and low dose subjects, who were then receiving 211 : g dieldrin/ day, experienced 3 fold or greater increases in blood concentrations of dieldrin. After 18 months, adipose tissue concentrations of dieldrin in the low, intermediate, and high dose groups had increased approximately 3, 4, or 11 fold ( to means of 0.4, 0.7, or 2 mg/ kg tissue), respectively. An apparent further increase in these values at 24 months may have been at least partly related to sampling techniques ( IPCS, 1989). Using empirically derived relationships between the amounts of dieldrin ingested and those found in the blood or adipose tissue, the authors calculated an adipose tissue to blood distribution ratio under steady state conditions ( among intake, storage, and elimination) of 136.

In examining tissue samples from a number of routine autopsies, De Vlieger et al. ( 1968) determined the mean dieldrin concentrations in adipose tissue, liver tissue, white matter of the brain, and gray matter of the brain to be 0.17, 0.03, 0.0061, and 0.0047, respectively. Figure 6 1, taken from IPCS ( 1989), represents the tentative tissue distribution scheme for dieldrin initially proposed by De Vlieger et al. ( 1968), as subsequently recalculated by Jager ( 1970) to incorporate the empirical formulas of Hunter et al. ( 1969).

Hunter and Robinson ( 1968) demonstrated that the leanest subjects had both the highest adipose tissue concentrations of dieldrin, as well as the smallest total body burdens; however, the subjects with the greatest total body fat retained the highest proportion of the total exposure dose in their adipose tissue. As no increase in blood levels of dieldrin were observed during surgical stress or periods of complete fasting, these authors concluded that the general population was not in danger of intoxication as a result of tissue catabolism during periods of illness or weight loss. It should also be noted that when Hunter et al. ( 1969) followed their subjects for a period of 8 months after the 2 year exposure, the concentration of dieldrin in the blood was observed to 6 4 Aldrin/ Dieldrin   February 2003 Figure 6 1. Distribution Scheme for Dieldrin Among Blood and Various Tissues in Humans [ De Vlieger et al. ( 1968) as Modified by Jager ( 1970); From IPCS ( 1989)]

decline exponentially with an approximate half life of 369 days. There were, however, significant differences among individuals in the rates of decline. This value compares with a mean half life of 266 days, which was estimated for dieldrin in the blood of 15 occupationally exposed workers during a 3 year period following termination of their exposure ( Jager, 1970). In the Garettson and Curley ( 1969) study of aldrin poisoning in children that was noted in Section 6.2, 47 ppm dieldrin was measured in a fat specimen taken 3 days after the exposure; 6 months later this value had declined to 15 ppm, where it remained after 8 months.

A study of women and their offspring during labor demonstrated that placental transfer of dieldrin can occur ( Polishuk at al., 1977). Higher concentrations of dieldrin were observed in fetal blood ( 1.22 mg/ kg) than in maternal blood ( 0.53 mg/ kg), and in the placenta ( 0.8 mg/ kg) than in the uterus ( 0.54 mg/ kg).

In the previously discussed ( Section 6.2) study of six workers occupationally exposed for 5 weeks via inhalation and dermal contact to aldrin, Mick et al. ( 1971) examined the distribution of aldrin and dieldrin among erythrocytes, plasma, and the alpha and beta lipoprotein fractions of blood. The epoxidation of aldrin to dieldrin led to higher plasma concentrations of dieldrin ( approximately 0.1 to 0.3 ppm) than aldrin ( approximately 0.01 to 0.13 ppm). Average dieldrin residues were approximately four times higher in plasma than in erythrocytes and this ratio tended to increase with increasing concentrations of dieldrin in the blood. Typically, higher dieldrin levels were associated with the beta lipoprotein fraction than with the alpha lipoprotein fraction. The in vitro study of human blood fractions by Skalsky and Guthrie ( 1978) also demonstrated that dieldrin could bind to albumin and beta lipoprotein. 6 5 Aldrin/ Dieldrin   February 2003 Distribution of aldrin and dieldrin has been studied in a number of animal species ( ATSDR, 2000; IARC, 1974a, b; IPCS, 1989; USEPA, 1992, 1988, 1980). Exposure of mammals to aldrin leads to deposition of dieldrin in their adipose tissue ( Jager, 1970). Deichmann et al. ( 1975) fed Swiss Webster mice diets containing 0, 5, or 10 ppm aldrin ( approximately equivalent to 0, 0.75, and 1.5 mg/ kg bw, based on Leyman [ 1959]) over the course of 7 generations ( from weaning to age 260 days for each generation, except F 4; see below). After 4 generations of aldrin feeding, metabolic conversion to dieldrin and subsequent retention led to significantly increased levels of dieldrin in abdominal fat and carcass total lipids. Significantly increased retention of dieldrin in the whole carcass was observed for the F 1 generation, with smaller and not statistically significant increases observed for the F 2 and F 3 generations. Dieldrin concentration in F 0 carcass total lipids was 60 mg/ kg, whereas the F 1 + F 2 + F 3 grouped means for males and females were 100 and 132 mg/ kg, respectively. Female mice thus retained higher residue levels in their body fat than male mice. From weaning through day 260, the F 4 generation was fed only the aldrin free control diet, and the pesticide residues that it absorbed in utero and through lactation were found to have been completely excreted by the time of sacrifice. Dieldrin concentrations in F 5 pups were < 1 mg/ kg; aldrin containing diets were resumed upon the weaning of these pups, with the findings from the F 4 through F 6 generations largely paralleling those from the F 0 through F 2 generations.

Two male Wistar rats were given daily doses of 4.3 : g 14C aldrin by gavage for 3 months, and then sacrificed 24 hours after the final dose ( Ludwig et al., 1964). Relative to the total administered amount of radiolabel, the amounts recovered in the carcass, abdominal fat, and other tissues were 3.60, 1.77, and 1.83%, respectively. A steady state among intake, storage, and excretion was reportedly achieved after 53 days. Ratios of dieldrin to aldrin found in the carcass and the abdominal fat were approximately 15: 1 and 18: 1, respectively. In neonatal Sprague Dawley rats given a single dose of 10 mg aldrin/ kg bw, aldrin was detectable up to 6 days later in the stomach and small intestine, but only for 3 days in the kidneys ( Farb et al., 1973). Aldrin concentrations in the liver increased during the first 6 hours to a maximum of 13% of the administered dose, then declined to < 0.1% by 72 hours. The only metabolite identified in the liver was dieldrin, which was detectable as early as 2 hours post treatment and which reached a maximum 31% of the administered radiolabeled dose after 24 hours.

Deichmann et al. ( 1969) administered 0.6 mg aldrin/ kg bw/ day in corn oil to 6 male beagle dogs for 10 months. Dieldrin concentrations in body fat and the liver were observed to progressively increase to 70 and 20 ppm, respectively, and then decline over the 12 months postexposure to 25 and 6 ppm, respectively. In a related study, aldrin was administered by capsule to 3 male beagles ( 0.3 mg/ kg bw) and 4 female beagles ( 0.15 or 0.3 mg/ kg bw), 5 days/ week for 14 months ( Deichmann et al., 1969, 1971). During the last 10 months of exposure, dieldrin concentrations in the blood and subcutaneous fat for the high dose animals were 0.042 to 0.183 and 37 to 208 mg/ L, respectively; those for the low dose females were 0.040 to 0.130 and 12 to 67 mg/ kg, respectively. The apparent subcutaneous fat to blood partition ratio was thus approximately 1000.

An extensive comparative study of the distribution and metabolism of dieldrin and its metabolites in male CFE rats and male CF 1 and LACG mice was conducted by Hutson ( 1976). 6 6 Aldrin/ Dieldrin   February 2003 14C dieldrin was administered as a single oral dose to animals, either with or without a 4 week pretreatment of dieldrin ( 20 mg/ kg diet for rats, 10 mg/ kg diet for mice), and the animals were sacrificed 8 days later. Concentrations of dieldrin were much higher in the fat than in the liver or kidneys of all animals, and were higher in the fat and liver of mice ( 11.6 and 0.94 mg/ kg) than of rats ( 5.6 and 0.11 mg/ kg). Tissue levels of a number of dieldrin metabolites ( see Section 6.3) were also assessed, including the 6,7 dihydroxy ( diol) derivative that was found to be below the level of detection (< 0.02 mg/ kg) in the fat, liver, and kidneys of all animals. Concentrations of the 9 hydroxy metabolite were very low (< 0.03 mg/ kg) in the fat and kidneys, but small amounts were found in the livers of both mouse strains. The pentachloroketone metabolite was found in rat liver in small amounts and in much larger amounts in the kidneys of rats, with or without pretreatment; small concentrations were also found in the fat of both groups. In both strains of mice, this metabolite was undetectable or present in only very small amounts in the fat, liver, and kidneys in the absence of pretreatment; with pretreatment, higher concentrations were observed ( e. g., ~ 1.3 mg/ kg in fat).

At 1 to 2 hours after dosing rats with radiolabeled dieldrin, Heath and Vandekar ( 1964) observed the highest concentration of dieldrin in adipose tissue; high levels were also seen in the liver and kidneys, with moderate concentrations found in the brain. It was also recoverable from the stomach, small and large intestines, and the feces after 1 hour. Following dietary exposure to radiolabeled dieldrin for 8 hours, high levels of radioactivity were detected in the kidneys of treated rats ( Matthews et al., 1971). While somewhat more radioactivity was found in the kidneys, lungs, stomachs, and intestines of males, in general, for the other organs and tissues, females had 3 to 4 times the radioactivity as did males. Similar results were observed in a 9 week ( 5 day/ week) feeding study with Osborne Mendel rats ( Dailey et al., 1970). Adipose tissue was again shown to be the principal storage depot for dieldrin, with significant levels also found in the kidneys, liver, lungs, and adrenals; lowest levels were seen in the spleen, brain, and heart. With the exception of the kidneys, more radioactivity was retained in the tissues of females than males. In a single oral dose rat study by Iatropoulos et al. ( 1975), radiolabeled dieldrin was rapidly taken up by the liver during the first 3 hours, then redistributed in a biphasic manner to adipose tissue ( the majority), kidneys, lymph nodes, etc. The lymphatic system appeared to be the principal redistribution pathway and parallel dieldrin increases in the lymph nodes and adipose tissue suggested an equilibrium between lymph and depot fat.

Female Osborne Mendel rats were fed a diet containing technical grade dieldrin ( 87% purity) at a concentration of 50 mg/ kg diet ( approximately 2.5 mg/ kg bw/ day) for 6 months ( Deichmann et al., 1968). Rats were sacrificed at various times up to 183 days and the retention of dieldrin in blood, liver, and fat was examined. Tissue levels increased rapidly over the first 9 days in the blood and liver, and over the first 16 days in fat; thereafter, concentrations fluctuated some but did not appear to significantly increase further. Over the final 4 months, distribution ratios and mean concentrations were: blood = 1 ( 0.240 mg/ L), liver = 28 ( 6.8 mg/ kg), and fat = 665 ( 159.5 mg/ kg).

Groups of Carworth Farm E rats ( 25/ sex; 45 controls/ sex) were fed 0, 0.1, 1.0, or 10 mg dieldrin/ kg diet for 2 years ( Walker et al., 1969). Animals were sacrificed after 26, 52, 78, and 104 weeks, and tissue levels of dieldrin in the blood, brain, liver, and fat were determined. 6 7 Aldrin/ Dieldrin   February 2003 Approximate plateau levels were reached by week 26; tissue uptake ratios ( tissue concentration/ diet concentration) of dieldrin for the 3 female exposure groups were 0.056 ( blood), 0.19 ( brain), 0.35 ( liver), and 8.8 ( fat), and were significantly higher than the corresponding values for males. Estimated partition ratios ( tissue concentration/ blood concentration) for male/ female animals were 1/ 1 ( blood), 3.3/ 2.6 ( brain), 7.8/ 5.9 ( liver), and 104/ 137 ( fat). After 104 weeks, tissue levels were found to be generally 2 to 10 times higher in females than in males ( Table 6 1). Robinson et al. ( 1969) fed Carworth rats 10 mg dieldrin/ kg diet for 8 weeks, then a control, dieldrin free diet for up to an additional 12 weeks. Again, the concentration of dieldrin was found to be substantially the greatest in adipose tissue, followed in descending order by that in the liver, brain, and blood. Following exposure, the decline of dieldrin concentrations in the tissues was approximately exponential, with half lives in adipose tissue and brain of 10.3 and 3 days, respectively. Elimination from the liver occurred in a rapid and then a slower phase, with respective half lives of 1.3 and 10.2 days; similar values were estimated for the blood.

Three groups of Sprague Dawley rats ( 2/ sex) were fed diets containing 0.04 mg 14Cdieldrin kg plus 0, 0.16 or 1.96 mg/ kg of unlabeled dieldrin ( totals of 0.04, 0.2, or 2.0 mg dieldrin/ kg diet) for 39 weeks ( Davison, 1973). For all three groups upon sacrifice, whole carcass radioactivity as a percentage of administered dose was significantly higher in females than males ( means of 6.9 versus 2.1%, respectively).

Table 6 1. Distribution of Dieldrin in Rats after 104 Weeks1 Sex Dieldrin Concentration ( mg/ kg)

Diet Blood2 Fat2 Liver2 Brain2 Male 0.0 0.0009 0.0598 0.0059 0.0020 0.1 0.0021 0.2594 0.0159 0.0069 1.0 0.0312 1.493 0.1552 0.1040 10.0 0.1472 19.72 1.476 0.4319 Female 0.0 0.0015 0.3112 0.0112 0.0077 0.1 0.0065 0.8974 0.0348 0.0224 1.0 0.0861 13.90 0.4295 0.2891 10.0 0.3954 57.81 2.965 1.130 1 Walker et al. ( 1969); as modified from USEPA ( 1980). 2 Geometric mean values. 6 8 Aldrin/ Dieldrin   February 2003 Baron and Walton ( 1971) fed male Osborne Mendel rats 25 mg dieldrin/ kg diet ( approximately 1.25 mg/ kg bw) for 8 weeks. They reported that an equilibrium level of 50 mg dieldrin/ kg had been achieved in adipose tissue by week 8, which upon return to a dieldrin free diet, rapidly declined with an estimated half life of 4 to 5 days. Within 15 days after the cessation of exposure to 75 ppm dieldrin in the diet, levels in the adipose tissue of rats had fallen to half that seen after 12 months of exposure ( Robinson and Roberts, 1968). In a study by Hayes ( 1974), male Sprague Dawley rats received a single dose of 10 mg/ kg bw of technical dieldrin ( 86% purity). At intervals up to 240 hours post dosing, animals were sacrificed and tissue levels of dieldrin were determined. In plasma, dieldrin concentrations reached a maximum of ~ 0.5 mg/ L after 2 hours, fluctuated from 0.2 to 0.5 mg/ L up to 48 hours, then declined to ~ 0.01 mg/ L at 240 hours. Maximum levels were reached in the brain after 4 hours (~ 1 mg/ kg), remaining more or less constant through 48 hours, then declining to a low level (< 0.2 mg/ kg) by 240 hours; similar time courses were reported for muscle, kidneys, and the liver. A slower rise of dieldrin concentration was observed in retroperitoneal fat, with 4 and 24 hours values being ~ 10 and 40 mg/ kg, respectively; after 48 hours, a decline similar to those for plasma and the brain was observed. For the 4 and 16 hour data, Hayes ( 1974) set the dieldrin concentrations in the brain equal to 1.00, then calculated the relative concentrations for the other tissues evaluated ( Table 6 2).

Table 6 2. Relative Tissue Levels of Dieldrin in the Rat Following a Single Oral Dose1 Hour Brain Muscle Liver Kidney Plasma Fat 4 1.00 ± 0 0.62 ± 0.05 2.30 ± 0.11 1.55 ± 0.22 0.20 ± 0.02 7.20 ± 1.18 16 1.00 ± 0 0.55 ± 0.06 3.17 ± 0.25 2.02 ± 0.56 1.35 ± 1.11 17.96 ± 3.23 1 Dieldrin dose of 10 mg/ kg, in corn oil ( Hayes, 1974; as modified from USEPA, 1980).

In vitro studies using rats and rabbits have reportedly examined the partitioning of 14Cdieldrin related radioactivity among the soluble protein and cellular components of the blood ( IPCS, 1989). Radioactivity was principally found in erythrocytes ( associated with hemoglobin and an unknown constituent) and the plasma, with much lower levels found in leukocytes, platelets, and erythrocyte membranes. In rat serum, it electrophoresed with pre and postalbumin whereas in rabbit serum, it was associated with albumin and " globulin. Ichinose and Kurihara ( 1985) demonstrated in vitro that transport of dieldrin between rat hepatocytes and the extracellular medium occurs much more rapidly than does intra hepatocyte metabolic transformation.

Several studies have been conducted on the distribution of dieldrin in dogs ( Richardson et al., 1967; Keane and Zavon, 1969; Walker et al., 1969). In three beagles fed 0.1 mg dieldrin/ kg bw for 128 days, blood levels of dieldrin increased curvilinearly to an approximate plateau of about 0.130 mg/ L by day 93 ( Richardson et al., 1967). One week post exposure, measured tissue 6 9 Aldrin/ Dieldrin   February 2003 levels of dieldrin were 0.150 mg/ L ( blood), 1.090 mg/ kg ( heart), 4.420 mg/ kg ( liver), 2.330 mg/ kg ( kidneys), 14.030 mg/ kg ( pancreas), 0.710 mg/ kg ( spleen), 1.227 mg/ kg ( lungs), 25.333 mg/ kg ( fat), and 0.566 mg/ kg ( muscle). There was reported a highly significant linear correlation between the logarithms of exposure duration and blood dieldrin level. Keane and Zavon ( 1969) orally dosed 4 male and 2 female mongrel dogs with 1 mg dieldrin/ kg bw ( in corn oil) for 5 days, then with 0.2 mg/ kg bw for the next 54 days. Small but significant increases in dieldrin concentration were observed in the blood of all animals for days 7 to 59 ( samples taken twice weekly from day 7 onward). Subcutaneous fat biopsies were taken on days 16 and 50 and the fat to blood partition ratios were 216 and 117, respectively.

In addition to the rat study discussed previously, Walker et al. ( 1969) orally dosed beagle dogs ( 5/ sex) by gel capsule with 0, 0.005, or 0.05 mg dieldrin/ kg bw ( equivalent to 0, 0.1, or 1.0 ppm in the diet) for 2 years. Blood dieldrin levels increased during the first 12 to 18 weeks, reaching a plateau during weeks 18 to 76. Thereafter, significant deviations from this apparent asymptotic value were observed; while the reasons for this were not clear, a tendency toward higher dieldrin concentrations was also noted in the control animals. Uptake and partition ratios ( previously defined) for males were 0.06 and 1.0 ( blood), 0.22 and 3.7 ( brain), 4.4 and 10 ( liver), and 10.0 and 169 ( adipose tissue). In contrast to the rat study, no significant sex differences in uptake were apparent.

Mueller et al. ( 1975a) administered 14C dieldrin ( 2.5 mg/ kg bw) to two female rhesus monkeys via intravenous injection, and to two males via a single oral dose of either 0.36 or 0.5 mg/ kg bw. Females and males were sacrificed at 75 and 10 days post exposure, respectively. In all animals, the highest radioactivity was observed in the adipose tissue, bone marrow and liver, with only a relatively small amount present in the brain (~ 2% that of adipose tissue). Metabolites, though present in the bile, were not detected in the organs or tissues examined. In another primate study, groups of male rhesus monkeys were fed diets containing 0, 0.01, 0.1, 0.5, or 1.0 ppm of technical grade dieldrin for 70 to 74 months ( Wright et al., 1978). Several monkeys were started at a 5.0 ppm dose, but when 1 died at 4 months, the others were reduced to a dose of 2.5 ppm for the next 5 months, then 1.75 ppm for a further 64 months. In one animal from this group, the 1.75 ppm dose was gradually increased back up to 5.0 ppm at month 23, where it remained for another 46 months. This study focused on interactions of dieldrin with the liver, and mean concentrations of dieldrin in the livers of the various groups ranged from 1.2 mg/ kg ( the 0.01 ppm group) to 23.3 mg/ kg ( the single 5, 2.5, 1.75ÿ5.0 ppm monkey). When the distribution of dieldrin in the liver's various subcellular fractions was examined, ~ 60% was localized in the microsomal fraction, ~ 12.5% in the soluble fraction, and ~ 9% each in the nuclear, mitochondrial, and lysosomal fractions. It was noted that at dietary intakes of about 0.1 ppm, tissue concentrations of dieldrin in rhesus monkeys and humans were similar. However, when compared to male rats, liver concentrations of dieldrin were 200 times higher in these monkeys at a dose only twice as high, suggesting a relatively slow metabolic clearance and a relatively high liver tolerance to dieldrin in this primate species.

With respect to dermal exposure, most of the dieldrin that is absorbed through the skin of guinea pigs, dogs, and monkeys has been found to accumulate in adipose tissue ( Sundaram at al., 1978a, b). In guinea pigs dermally exposed for 6 months to concentrations of 0.0001 to 0.1%, the 6 10 Aldrin/ Dieldrin   February 2003 highest tissue levels were observed in adipose tissue, with lesser concentrations appearing in the liver and brain ( Sundaram et al., 1978b). After 52 weeks of exposure to fabric strips containing up to 0.04% dieldrin, rabbits also evidenced a slight accumulation of the compound in omental and renal fat ( Witherup et al., 1961).

Distribution of dieldrin residues among the blood, brain, liver, and subcutaneous fat in rats following intraperitoneal injection was not found to be significantly different from that seen after oral exposure, i. e., the highest levels were again observed in adipose tissue ( Lay et al., 1982). Transplacental transport of dieldrin has been reported to occur to a significant extent in mice following intramuscular injection ( Baeckstroem et al., 1965) and after intravenous injections in rats ( Eliason and Posner, 1971) and rabbits ( Hathway et al., 1967). In pregnant mice exposed intramuscularly to 14C dieldrin, the highest radioactivities were observed in the adipose tissue, liver, intestines, and mammary glands, while moderate activities were reported for the ovaries and brain ( Baeckstroem et al., 1965). Transfer across the placenta was indicated by the moderate levels that were also found in fetal liver, fat, and intestines. Finally, numerous studies suggest that the toxicokinetics of aldrin and dieldrin in most domesticated animals are at least broadly similar to those seen in laboratory species ( IPCS, 1989).

Although apparently not a major transformation product in mammals, photodieldrin is likely a significant photodegradation product and microbial metabolite of dieldrin in the environment ( see Chapter 3), and therefore several studies have examined its distribution pattern in mammals. Collectively, subacute and subchronic studies in rats ( Dailey et al., 1970; Walker et al., 1971; Walton et al., 1971) and mice ( Brown et al., 1967) have demonstrated that females accumulate 2 to 15 fold higher concentrations of photodieldrin than do males in adipose and other tissues with the exception of the kidneys. The estimated half life of photodieldrin in adipose tissue is also longer in female rats ( 2.6 days) than in male rats ( 1.7 days) ( Brown et al., 1967). When a single oral dose of photodieldrin was administered to one male and one female dog, tissue levels were again reported to be significantly higher in the female than in the male, with the exception of in the liver ( Brown et al., 1967). In contrast, a 3 month feeding study in dogs demonstrated dose related concentrations in the liver, adipose tissue, and kidneys that were similar in both males and females ( Walker et al, 1971); additionally, the kidney levels of photodieldrin and pentachloroketone ( PCK; see Figures 6 2 and 6 3, Table 6 3, and associated text in Section 6.3) were approximately 0.1 to 0.2 mg/ kg, or about 1 to 3 orders of magnitude lower than those observed in rats.

6.3 Metabolism Radomski and Davidow ( 1953) first reported the epoxidation of aldrin to dieldrin. Since that time, many studies in a substantial number of organisms have shown this to be the initial and principal step in the biotransformation of aldrin; the reaction is mediated by mixed function oxidases, sometimes referred to as aldrin epoxidase, that are known to be found in substantial quantities in the endoplasmic reticulum of hepatocytes in vertebrates ( ATSDR, 2000; IPCS, 1989; USEPA, 1992, 1988). Perhaps understandably, no real metabolism studies of aldrin or dieldrin in humans were located or available, so data on the human metabolism of these compounds is sparse. Excretion data in humans have provided some insight, however, as the 6 11 Aldrin/ Dieldrin   February 2003 9 hydroxydieldrin metabolite was detected in the feces of workers having occupational exposure to aldrin and dieldrin ( Richardson and Robinson, 1971). Some additional excretion data from humans on these compounds and their metabolites are presented in Section 6.4.

A variety of metabolites have been isolated from microorganisms, invertebrates, and vertebrates, and the three dimensional chemical structures of many of these are presented in Figure 6 2. Their trivial, or common, names are listed in the companion Table 6 3. Those metabolic transformations thought to be most important in laboratory animals are illustrated in Figure 6 3, which again provides three dimensional chemical structures, as well as some of the enzymes implicated in these pathways. A discussion of some of the more important underlying animal and in vitro studies follows.

Winteringham and Barnes ( 1955) first demonstrated the epoxidation of aldrin to dieldrin ( Figure 6 2, compounds I and II; Figure 6 3) in mice, and were able to show that this conversion occurred more rapidly in males than in females; while other metabolites were not observed, methodological limitations may have hindered the detection of polar compounds. The formation of dieldrin from aldrin was also noted early on in cattle, pigs, sheep, rats, and poultry ( Bann et al., 1956), and Soto and Deichmann ( 1967) reported that subsequent to the intravascular administration of aldrin to dogs, approximately 30% was converted to dieldrin during the first 24 hours post exposure. Using rabbit lung perfusates, Mehendale and El Bassiouni ( 1975) were able to demonstrate dose dependent, in vitro metabolism of aldrin to dieldrin within the endoplasmic reticulum; at low doses, up to 70% conversion occurred during the first hour. Following dermal application of 0.1 to 10 mg/ kg to rats, the skin has also been shown capable of converting aldrin to dieldrin ( Graham et al., 1987). Dieldrin was detected in the skin as soon as 1 hour after application, and enzyme saturation was suggested because the highest percentage of conversion occurred at the lowest dose. The authors estimated that up to 10% conversion to dieldrin by skin enzymes could result in rats from the percutaneous absorption of aldrin. Graham et al. ( 1987) were also able to demonstrate the in vitro dermal conversion of aldrin to dieldrin in studies employing mouse skin microsomal preparations and whole skin strips from rats.

Using liver microsome preparations from male and female rats, Wong and Terriere ( 1965) were able to demonstrate the conversion of aldrin to dieldrin via nicotine adenine dinucleotide phosphate ( NADPH) dependent, heat labile mixed function oxidases, that the reaction proceeded more rapidly in the microsomes from male rat livers than in those from females, and that it could be inhibited by pesticide synergists, such as sesamex. These observations were largely confirmed by Nakatsugawa et al. ( 1965) using microsome preparations from male rats and rabbits; they also reported that dieldrin did not undergo further microsomal metabolism, that epoxidase activity in liver preparations was 10 fold higher than in lung preparations, and that no such activity was observed in preparations from the kidney, spleen, pancreas, heart, or brain. Wolff et al. ( 1979) demonstrated a three fold increase in dieldrin formation with microsomes taken from phenobarbital treated rats, whereas amounts were substantially decreased in microsomal preparations made from rats pretreated with 3 methylcholanthrene. These results suggested that aldrin epoxidation involved cytochrome P 450 rather than cytochrome P 448. 6 12 Aldrin/ Dieldrin   February 2003 Kurihara et al. ( 1984) have demonstrated that cultures of rat hepatocytes are effective in carrying out the epoxidation of aldrin to dieldrin. In other in vitro studies, Lang et al. ( 1986) investigated the epoxidation of aldrin to dieldrin in hepatic and various extra hepatic tissues in the rat. Unlike the liver, many organs and tissues contain little cytochrome P 450 activity, prompting these authors to look for the presence of an alternative oxidative pathway mediated by prostaglandin endoperoxide synthase ( PES) in liver, lung, seminal vesicle, and subcutaneous granulation tissues. In a two step process, PES utilizes cyclooxygenase activity to catalyze the bisdioxygenation of arachidonic acid to prostaglandin G 2 ( PGG 2), which is subsequently reduced to prostaglandin H 2 ( PGH 2) via hydroperoxidase activity; it is during this latter step that xenobiotics ( e. g., aldrin) may be co oxidized ( i. e., epoxidized). In hepatocytes and liver microsomes, aldrin epoxidation was reported to be completely NADPH dependent, whereas in lung microsomes, two pathways appeared involved ( Lang et al., 1986). The NADPH dependent and arachidonic acid dependent aldrin epoxidation activities were 1.5 and 0.3%, respectively, of the activities observed in liver preparations. Aldrin epoxidation was stimulated by arachidonic acid and inhibited by the cyclooxygenase specific inhibitor indomethacin, in microsomal preparations from seminal vesicle and subcutaneous granulation tissues. Therefore, the PES pathway would appear to be an alternative route for aldrin epoxidation in extra hepatic tissues.

In some early work with rabbits, Korte ( 1963) was able to identify one of the metabolites of aldrin as aldrin trans diol ( Figure 6 2, compound IV; Table 6 3, Figure 6 3). Heath and Vandekar ( 1964) reported that the principal route of excretion in rats was the feces, that little dieldrin was excreted unchanged, and that a somewhat polar metabolite could be found in the feces, along with other polar metabolites in both the feces and urine. After feeding 14C aldrin to rats for 3 months, Ludwig et al. ( 1964) found aldrin, dieldrin, and unidentified hydrophilic metabolites in the urine; these latter constituted 75 and 95% of the radioactivity excreted in the urine and feces, respectively. Two different metabolites were detected in the feces, with one of them and a third metabolite also detected in the urine. In rabbits dosed orally with 14C dieldrin for 21 weeks, Korte and Arent ( 1965) isolated 6 urinary metabolites, the major one ( 86%) being identified as 6,7 trans dihydroxydihydroaldrin, or the aforementioned aldrin trans diol. This enzymatic product of epoxide hydrase, however, appears to be of relatively minor importance in most other species ( IPCS, 1989).

Other than in mice and rabbits, aldrin trans diol has reportedly been found in rhesus monkeys and chimpanzees ( Mueller et al., 1975b), and its glucuronide conjugation product was detected in liver microsomal preparations from rats or rabbits incubated in the presence of 14Cdieldrin and uridine diphosphoglucuronic acid ( UDPGA) ( Matthews and Matsumura, 1969). This water soluble metabolite accounted for approximately 45% of the total radioactivity, while the unconjugated form was also found to be present in vitro. Matthews and Matsumura ( 1969) had additionally fed male rats a diet containing dieldrin for a month, and had noted a minor metabolite present in both the feces and the urine. Comparative thin layer chromatography in conjunction with the in vitro results indicated this compound to be the aldrin trans diol in the conjugated and/ or unconjugated forms. 6 13 Aldrin/ Dieldrin   February 2003 Figure 6 2. Metabolites of Aldrin and Dieldrin ( from IPCS, 1989). For the Identity ( Trivial Chemical Names) of These Compounds, See Table 6 3 6 14 Aldrin/ Dieldrin   February 2003 Table 6 3. Trivial Chemical Names of Aldrin, Dieldrin and Their Metabolites ( as Identified in Figure 6 2) 1 ID Code ( Fig. 6 2) Chemical Structure Trivial Names Alternative 1 Alternative 2 I Aldrin HHDN II Dieldrin HEOD III Photodieldrin IV Aldrin trans diol 6,7 trans dihydroxydihydroaldrin V Aldrin dicarboxylic acid VI 9 Hydroxy dieldrin 9 Hydroxydieldrin VII ( Bridged) Pentachloroketone PCK ( or Klein's metabolite)

VIII Dechloro aldrin dicarboxylic acid IX Dieldrin ketone X Photodieldrin ketone XI Photodieldrin trans diol Caged aldrin trans diol XII Photoaldrin dicarboxylic acid Caged aldrin acid XIII Photoaldrin 1 Taken principally from IPCS ( 1989) and ATSDR ( 2000). 6 15 Aldrin/ Dieldrin   February 2003 Figure 6 3. Proposed Principal Metabolic Pathways for Aldrin and Dieldrin ( from ATSDR, 1993, as Adapted from USEPA, 1987)

The conjugation of aldrin trans diol with glucuronic acid and/ or its further oxidation to aldrin dicarboxylic acid ( Figure 6 2, compound XII; Table 6 3, Figure 6 3) have also been reported by Baldwin et al. ( 1972), Hutson ( 1976), and Oda and Mueller ( 1972). Formation of the cis diol and its epimerization to the trans diol have been demonstrated to occur in rat microsomes ( McKinney et al., 1973).

In two studies involving the feeding of dieldrin to male rats for 7 months ( Richardson et al., 1968) or 1 month ( Matthews and Matsumura, 1969), two major metabolites were isolated from the urine and feces. The fecal metabolite proved to be 9 hydroxy dieldrin ( Figure 6 2, compound VI; Table 6 3, Figure 6 3); this reaction was found to be catalyzed by liver microsomal monooxygenases in rats, and to be inhibited by the monooxygenase inhibitor, sesamex ( Matthews and Matsumura, 1969). With the exception of the rabbit, in most of the 6 16 Aldrin/ Dieldrin   February 2003 species studied ( i. e., mice, rats, sheep, rhesus monkeys, chimpanzees), this has been the principal metabolite that has been found ( Feil et al., 1970; Mueller et al., 1975b). It has been detected in the feces, and either free or conjugated in the urine. After dosing sheep with 14C dieldrin, Hedde et al. ( 1970) isolated six hexane soluble and two water soluble urinary metabolites, postulating that one of the latter was the glucuronide conjugate of aldrin trans diol ( Figure 6 3). Two of the hexane soluble metabolites were subsequently identified as aldrin trans diol and 9 hydroxy dieldrin ( Feil et al., 1970). The glucuronide conjugate of 9 hydroxy dieldrin is formed both in vivo and in vitro and has been isolated in the bile of rats ( Chipman and Walker, 1979); passing through the bile duct into the lower intestines, it is largely converted there into the free 9 hydroxy metabolite before being excreted in the feces ( Hutson, 1976). When dieldrin is incubated in vitro with rat liver microsomes in the presence of UDPGA, 9 hydroxy dieldrin glucuronide is reported to form rapidly via the consecutive actions of microsomal monooxygenase and uridine diphosphoglucuronyl transferase ( Hutson, 1976; Matthews et al., 1971). As evidence of species differences in the rates of metabolism of dieldrin, a higher ratio of 9 hydroxy 14C dieldrin to 14C dieldrin has been observed in rats than in mice, indicative of a more rapid hydroxylation reaction in the former ( Hutson, 1976).

The second major metabolite ( i. e., the one found in the urine) that was reported in the rat studies of Richardson et al. ( 1968) and Matthews and Matsumura ( 1969) has been identified as pentachloroketone, or PCK ( Figure 6 2, compound VII; Table 6 3, Figure 6 3). Also known as Klein's metabolite, it has been found mainly in the urine and kidneys of male rats, but only in small amounts in female rats, mice, and other species ( Baldwin et al., 1972; Damico et al., 1968; Hutson, 1976; Klein et al., 1968; Matthews et al., 1971; Richardson et al., 1968). Male rats have been found to metabolize dieldrin 3 to 4 times more rapidly than females ( Matthews et al., 1971), a difference that has been ascribed to males' greater ability to convert dieldrin to its more polar metabolites, including 9 hydroxy dieldrin ( ATSDR, 2000) and especially PCK ( USEPA, 1980).

Comparative metabolism studies on male CFE rats and male CF 1 and/ or LACG mice revealed that much greater quantities of the PCK derivative were produced in the rat than in either mouse strain, smaller amounts of polar urinary metabolites were produced in the mice, and aldrin trans diol was found in the feces and a dicarboxylic acid derivative in the urine of all animals; both rats and mice produced 9 hydroxy dieldrin ( Baldwin et al., 1972; Hutson, 1976). In their study of rats dosed with radiolabeled dieldrin, Matthews et al. ( 1971) found that the greatest percentage of radioactivity in the feces of both males and females came from 9 hydroxy dieldrin, with aldrin trans diol and a second, unidentified polar metabolite also present. Significant amounts of PCK was found in the urine of male rats, with initially some aldrin transdiol and unchanged dieldrin. In female rats, most of the activity in urine was associated with aldrin trans diol and, initially, up to 20% with dieldrin.

It should also be noted that when photodieldrin ( Figure 6 2, compound III; Table 6 3), itself a degradation product of dieldrin, was fed to rats for 13 weeks, it and PCK were isolated from blood, brain, liver, and adipose tissue ( Baldwin and Robinson, 1969). When administered orally or intraperitoneally 5 days/ week for 12 weeks, PCK and small amounts of other more polar metabolites were found in the urine of rats ( Klein et al., 1970). In a female rhesus monkey given daily oral doses of 14C photodieldrin for 175 days, photodieldrin trans diol ( Figure 6 2, 6 17 Aldrin/ Dieldrin   February 2003 compound XI; Table 6 3) and its glucuronide conjugate were identified in the urine, and possibly only the diol in the feces ( Nohynek et al., 1979). A third metabolite, found both in the urine and feces, was speculated to be a mono hydroxy derivative of photodieldrin.

Finally, oral administration of dieldrin has been shown capable of inducing hepatic mixed function oxidases ( Kohli et al., 1977). Baldwin et al. ( 1972) have also been able to demonstrate some induction in the CFE male rat ( but not in the CF 1 male mouse) by prefeeding low doses of dieldrin for 3 weeks. It is relevant to keep this observation in mind when, for example, comparing the results of long term versus acute animal studies, or considering the potential effects of aldrin or dieldrin exposure in humans who are chronically exposed to at least low doses of mixed function oxidase inducers ( USEPA, 1980).

6.4 Excretion Much of the available information on the excretion of aldrin and dieldrin has already been introduced in the previous sections describing their absorption, distribution, and metabolism. Some of this information will again be briefly mentioned in this section, along with additional detail in some cases and supplemented with a number of additional studies. These compounds have been found in general to be excreted primarily in the feces, but also to some extent in the urine, in the form of metabolites that are more polar than the parent compounds. When exposure is kept constant, equilibrium levels of aldrin, dieldrin, and their metabolites are generally achieved in most organs and tissues. Body burdens will fluctuate in accordance with increases and decreases in exposure concentration.

Although the data is naturally much less extensive than in animals, excretion in humans following exposure to aldrin or dieldrin appears to occur largely through the bile and feces. In an early study of occupationally exposed workers, Cueto and Hayes ( 1962) were able to detect the presence of dieldrin and some of its metabolites in their urine. Somewhat later, Cueto and Biros ( 1967) reported that the mean concentrations of dieldrin found in the urine of five men and five women from the general population were 0.8 ± 0.2 and 1.3 ± 0.1mg/ L, respectively. These concentrations were compared with those of male workers ( a total of 14) who were deemed to have either low ( 5 males), medium ( 4 males), or high ( 5 males) occupational exposure to dieldrin and other chlorinated insecticides. The respective urinary concentrations of the three worker groups were 5.3, 13.8, and 51.4 mg/ L. In another study of workers occupationally exposed to various chlorinated pesticides, the concentrations of aldrin detected in 14 urine samples were all less than 0.2 mg/ L, while those for dieldrin ranged from 1.3 to 66.0 mg/ L ( Hayes and Curley, 1968). Two reports have described detecting 9 hydroxy dieldrin in the feces of seven workers having occupational exposure to aldrin and dieldrin ( Richardson, 1971; Richardson and Robinson, 1971). The mean and range of fecal 9 hydroxy dieldrin concentrations measured in the seven workers were 1.74 and 0.95 to 2.80 mg/ kg, respectively, while those determined from five males of the general population were 0.058 and 0.033 to 0.12 mg/ kg, respectively. Dieldrin at a mean concentration of 0.18 mg/ kg was also detected in the feces of the workmen, but it could not be detected in samples from the general population. Examination of the urine for dieldrin and four known metabolites led the authors to conclude that urinary excretion was a 6 18 Aldrin/ Dieldrin   February 2003 minor pathway in human males, although they failed to examine the urine for glucuronide or other conjugates of the potential hydroxy metabolites.

In a study by Hunter et al. ( 1969), 12 human volunteers ingested various amounts of dieldrin for up to 24 months; dieldrin concentrations in blood and adipose tissue were monitored during this exposure period, as were the blood concentrations for an additional 8 months. For 3 of the volunteers, blood dieldrin concentrations reportedly did not change significantly; for the remaining 9, the mean half life of dieldrin in the blood was estimated to be 369 days ( a range of 141 to 592 days). Though determined with a limited number of samples, this estimate was far longer than the value of less than 10 days that had been reported in animal studies. In an unpublished study by DeJonge, it was reported ( Jager, 1970) that in workers who had had previously high exposures to aldrin/ dieldrin, and thus high concentrations of the compounds in their blood before being transferred to other areas, the mean half life of dieldrin in the blood had been calculated to be 0.73 years ( or approximately 266 days). This estimate was reportedly based on measurements taken every 6 months for 3 years following cessation of exposure. It agrees reasonably well with that of Hunter et al. ( 1969), which was derived using limited data.

Feldman and Maibach ( 1974) demonstrated that 7.7% of a dose of 14C dieldrin ( 4 : g/ cm2 in acetone), applied once to the arm of volunteers, was excreted in the urine over a 5 day period; similarly, 3.3% of a single intravenous injection was excreted in the urine over the same period. Finally, dieldrin can be excreted via lactation in nursing mothers, and concentrations ranging from 1 to 29 ppb have been reported in human milk samples taken from women in various countries around the globe ( Curley and Kimbrough, 1969; Schecter et al., 1989; IARC, 1974b).

In one of the early animal studies examining the metabolism and excretion of these compounds, Ludwig et al. ( 1964) gave male Wistar rats daily oral doses of 14C aldrin ( 4.3 : g, or about 0.2 mg/ kg diet) for up to 3 months. They reported that approximately 9 times as much radioactivity was excreted in the feces as in the urine ( urinary excretion increasing from ~ 2% during week 1 to 9 to 10% during week 12). As a percent of administered daily dose, excretion increased from 31% on day 2, to about 80% during week 2, to 100% by weeks 8 to 12, indicating that a steady state, saturation level had been reached in the animals. Once exposure was discontinued, excretion of radiolabeled compounds diminished rapidly; 24 hours, 6 weeks, and 12 weeks after the final dose, 88, 98, and > 98% of the total administered dose had been excreted. Urine and fecal extracts were examined by paper chromatography, which indicated that aldrin content in both urine and feces decreased during the exposure period and afterward, while that of dieldrin somewhat increased. Hydrophilic metabolites increased during exposure, constituting after 12 weeks about 75 and 95% of the radioactivity excreted in feces and urine, respectively. Contrary to the predominance of fecal excretion seen in this rat study, it has been reported that male rabbits administered 14C aldrin excreted more radioactivity in their urine than in their feces ( IARC, 1974a). In rabbits orally administered 14C dieldrin for 21 weeks, Korte and Arent ( 1965) observed that right after the exposure period ( week 22), 42% of the total administered radioactivity had been excreted, with 2 to 3 times as much via the urine as the feces.

In female rats infused for 2.5 to 5 hours with total doses of 8 to 16 mg/ kg bw of 36Cldieldrin approximately 70 and 10% of the administered doses were recovered over the ensuing 6 19 Aldrin/ Dieldrin   February 2003 42 days in the feces and the urine, respectively, indicating that the predominant route of excretion was via the bile ( Heath and Vandekar, 1964). The authors also noted that dietary restriction markedly increased the blood dieldrin concentration as fat stores were mobilized. Comparable findings were observed in male rats with/ without biliary fistulas that received single intravenous doses of 14C dieldrin ( 0.25 mg/ kg bw) ( Cole et al., 1970). After 7 days, about 80% of the administered dieldrin dose had been excreted in the feces. At 1,4, and 7 days post exposure in the rats with biliary fistulas, approximately 30, 60, and > 90%, respectively, of the administered dose had been excreted via the bile. In experiments with isolated perfused rat livers, about 20% of the perfused dieldrin dose was collected in the bile during an 8 hour period ( Cole et al., 1970), and the rate of biliary excretion in those isolated from males was found to be approximately three times greater than in those from females ( Klevay, 1970). Chipman and Walker ( 1979) reported that in rats receiving dieldrin intraperitoneally, pretreatment with phenobarbital increased the rate of biliary excretion.

Dailey et al. ( 1970) reported that following exposure to radiolabeled dieldrin, excretion of radioactivity via urine and feces was higher in male rats than in female rats, a finding confirmed in a 39 week study by Davison ( 1973). The latter study also indicated that the maximal excretion of radioactivity occurred during the 6th week of exposure, regardless of the dieldrin dose, and that a steady state condition existed from weeks 6 through 39. Matthews et al. ( 1971) found a 10 fold higher level of radioactivity in kidneys isolated from males than from females in rats that had been fed 14C dieldrin. In male kidneys, most of the radioactivity was associated with PCK, whereas in female kidneys only dieldrin was detected. This greater ability of male rats to convert dieldrin to its more polar metabolites, especially PCK, was thought to underly the three to fourfold more rapid metabolism of dieldrin that is observed in male versus female rats.

Following the single oral administration of 0.5 mg 14C dieldrin/ kg bw to mice, rats, rabbits, rhesus monkeys, and one chimpanzee, urine and fecal samples were collected for 10 days and analyzed ( Mueller et al., 1975b). They reported the main route of excretion to be the feces for all species except the rabbit, accounting for 95, 95, ~ 18, 79, and 79% of the amounts excreted, respectively. The ratios of fecal to urinary excretion are thus approximately 19: 1 for rats and mice, 1: 5 for rabbits, and 4: 1 for rhesus monkeys and the chimpanzee. Ten days after dosing, the total amounts of radioactivity excreted were 37% ( mice), 11% ( rats), 2% ( rabbits), 20% ( rhesus monkeys), and 6% ( the chimpanzee) of the total administered dose. In all five species, the principal metabolites were 9 hydroxy dieldrin and aldrin trans diol; unchanged dieldrin, 9 hydroxy dieldrin, and its glucuronide were reported to predominate in rats, rhesus monkeys, and the chimpanzee, whereas mice and rabbits displayed higher amounts of aldrin trans diol. The glucuronide conjugate of aldrin trans diol was identified in the urine of the rabbits and rhesus monkeys, and aldrin dicarboxylic acid was noted as a minor metabolite in the feces of rats, rhesus monkeys, and the chimpanzee. As noted previously, Klein et al. ( 1968) had also detected PCK in the urine of rats fed 1.25 mg aldrin/ kg/ day.

Baldwin et al. ( 1972) compared the excretion of dieldrin in the CF 1 mouse and the CFE rat and found the amounts of labeled dieldrin excreted after 7 to 8 days were similar. The feces contained about 10 times the radioactivity found in the urine, and 50 to 70% of the administered dose was excreted during the 1 week collection period. As noted previously, the proportion of 6 20 Aldrin/ Dieldrin   February 2003 various metabolites varied between the two species, a principal difference being that PCK was found in significant amounts in rat urine, but was not detected in mouse urine. Hutson ( 1976) conducted a similar study on male CFE rats and male CF 1 and LACG mice after a single oral dose, with or without a period of dieldrin pretreatment ( see Section 6.3). Dieldrin pretreatment modestly increased the percentage fecal excretion ( of the total administered radiolabeled dose) from 62.4 to 69% in the rats, had no effect in the LACG mice ( 51.5%), and substantially increased it in CF 1 mice from 27.2 to 48.8%. Urinary excretion in the rats was 5.5 to 6.6%, whereas it was much lower in the mice ( 0.42 to 2.6%). In the male rats and CF 1 mice, the amount of urinary aldrin dicarboxylic acid was low compared with that of PCK + dieldrin, while in LACD mice it was twice as high. A much higher proportion of an unidentified metabolite was excreted in the urine of both mouse strains than in that of the rat. In rats, the major fecal metabolite was 9 hydroxy dieldrin with or without pretreatment; in both strains of mice, however, it became a major fecal metabolite only after pretreatment.

In a study of sheep dosed with 14C dieldrin, excretion of radioactivity was higher in the feces than in the urine ( Hedde et al., 1970). These authors noted that in two very fat sheep, the ratio of labeled dieldrin in feces to that in urine was > 10: 1, but in two thin sheep receiving the same dose, it was only slightly greater than 1: 1. Only 0.25% of the total dose was exhaled as 14CO 2, and after 5 to 6 days of collection, less than 50% of the administered dose was recovered.

For more information on the relatively rapid loss of dieldrin and/ or its metabolites from various organs and tissues, refer to the relevant studies previously discussed in Section 6.2 ( e. g., Robinson et al., 1969; Barron and Walton, 1971). Finally, the excretion of photodieldrin has been explored in rats ( Dailey et al., 1970) and monkeys ( Nohynek et al., 1979). After 12 weeks of daily dosing with 14C photodieldrin in the rat, urinary excretion was found to be significantly higher in males than in females, and to gradually increase during the 12 week exposure period. Fecal excretion was initially lower in females, but became greater during the latter part of the study ( Dailey et al., 1970). After orally dosing rhesus monkeys for 70 to 76 days with radiolabeled photodieldrin, a steady state between intake and excretion was reported ( Nohynek et al., 1979). At the end of exposure, the animals had excreted about 50% of the cumulative dose, and an additional 30% was excreted during the next 100 days. During dosing, photodieldrin was a major fecal metabolite, and 20 to 50% of the radioactivity was excreted in the urine; this amount increased to 60% when the dosing ceased. When one male and one female rhesus monkey were given a single intravenous injection of radiolabeled photodieldrin, excretion remained high during the first 7 days, but then rapidly decreased. By day 21, approximately 45 and 34% of the administered dose had been excreted in the male and female, respectively. 6 21 Aldrin/ Dieldrin   February 2003 References ATSDR. 2000. Agency for Toxic Substances and Disease Registry. Toxicological profile for aldrin/ dieldrin ( Update). Draft for public comment. Atlanta, GA: U. S. Dept. of Health and Human Services, Public Health Service, ATSDR.

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USEPA. 1980. U. S. Environmental Protection Agency. Ambient water quality criteria for aldrin/ dieldrin. Document no. EPA 440/ 5 80 019. Washington, DC: USEPA Office of Water, Office of Water Regulations and Standards, Criteria and Standards Division.

Walker, A. I. T., E. Thorpe, J. Robinson, and M. K. Baldwin. 1971. Toxicity studies on the photoisomerisation product of dieldrin. Meded. Fac. Landbouwwet. Rijksuniv. Gent. 36( 1): 398 409 ( as cited in IARC, 1974b; IPCS, 1989).

Walker, A. I. T., D. E. Stevenson, J. Robinson, E. Thorpe, and M. Roberts. 1969. The toxicology and pharmacodynamics of dieldrin ( HEOD): Two year oral exposures of rats and dogs. Toxicol. Appl. Pharmacol. 15: 345 373 ( as cited in ATSDR, 2000; IPCS, 1989; USEPA, 1980).

Walton, M. S., V. Beck Bastone, and R. L. Baron. 1971. Subchronic toxicity of photodieldrin, a photodecomposition product of dieldrin. Toxicol. Appl. Pharmacol. 20( 1): 82 88 ( as cited in IPCS, 1989). 6 29 Aldrin/ Dieldrin   February 2003 Winteringham, F. P. W. and J. B. Barnes. 1955. Comparative response of insects and mammals to certain halogenated hydrocarbons used as pesticides. Physiol. Rev. 35: 701 ( as cited in USEPA, 1980).

Witherup, S., K. L. Stemmer, J. L. Roberts, et al. 1961. Prolonged cutaneous contact of wool impregnated with dieldrin. The Kettering Laboratory in the Department of Preventive Medicine and Industrial Health, College of Medicine, University of Cincinnati. Cincinnati, OH ( as cited in ATSDR, 2000).

Wolff, T., E. Deml, and H. Wanders. 1979. Aldrin epoxidation, a highly sensitive indicator specific for cytochrome P 450 dependent monooxygenase activities. Drug Metab. Dispos. 7: 301 305 ( as cited in ATSDR, 2000).

Wong, D. T. and L. C. Terriere. 1965. Epoxidation of aldrin, isodrin, and heptachlor by rat liver microsomes. Biochem. Pharmacol. 14: 375 377 ( as cited in ATSDR, 2000; IARC, 1974a; USEPA, 1980).

Wright, A. S., C. Donninger, R. D. Greenland, K. L. Stemmer, and M. R. Zavon. 1978. The effects of prolonged ingestion of dieldrin on the livers of male rhesus monkeys. Ecotoxicol. Environ. Saf. 1( 4): 477 502 ( as cited in IPCS, 1989; TOXLINE, 2000c). 7 1 Aldrin/ Dieldrin   February 2003 7.0 HAZARD IDENTIFICATION The purpose of this section is to characterize the carcinogenic and non carcinogenic health effects of aldrin and dieldrin, based on an evaluation of information from both human epidemiological and case studies and from animal studies. In addition, mechanistic studies on these compounds from human, animal, and in vitro experiments are reviewed, and possible modes of action for some of their various non carcinogenic and carcinogenic effects are discussed.

7.1 Human Effects This section briefly highlights the rather limited number of human case and epidemiological studies that have reported acute to chronic effects resulting from exposure to aldrin and/ or dieldrin.

7.1.1 Short Term Studies The short term studies summarized below primarily reflect the oral exposure effects of aldrin and dieldrin reported in humans under accidental poisoning scenarios.

General Population Aldrin Jager ( 1970) reported the acute oral lethal dose of aldrin in an adult male to be 5.0 g ( approximately 70 mg/ kg, assuming a body weight of 70 kg). A somewhat lower ingested dose of aldrin ( 25.6 mg/ kg) has been reported to have caused convulsions in a 23 year old male after 20 minutes ( Spiotta, 1951). Although his convulsions ceased after treatment with pentobarbital, he continued to exhibit restlessness, hypothermia, tachycardia, and hypertension for up to 5 days, and electroencephalogram ( EEG) abnormalities for up to 6 months.

Severe acute intoxication following aldrin exposure in humans is characterized by a brief period of excitation or drowsiness, followed by convulsions, muscle twitching, and coma. Hypothermia generally accompanies death. The majority of individuals intoxicated with aldrin, however, usually regain consciousness and recover ( Hayes, 1982; Jager, 1970).

Dieldrin Dieldrin has been reported to cause hypersensitivity and muscular fasciculations that may be followed by convulsive seizures and associated changes in the EEG pattern. Acute symptoms of intoxication include hyperirritability, convulsions and/ or coma, sometimes accompanied by nausea, vomiting and headache; chronic intoxication may result in fainting, muscle spasms, tremors, and loss of weight. The lethal dose for humans is estimated to be about 5.0 g ( ACGIH, 1984). 7 2 Aldrin/ Dieldrin   February 2003 Black ( 1974) observed tachycardia, elevated blood pressure, and convulsions in a man who ingested 120 mg/ kg dieldrin. These cardiovascular effects were presumed to be due to altered activity in the central nervous system ( i. e., increased sympathetic output), as the symptoms were controlled by the administration of $ adrenergic blocking drugs. Persistent headaches, irritability, and short term memory loss were also reported following the patient's recovery from convulsions.

Sensitive Populations Children are generally considered at greater risk than adults to the toxic effects of chemicals for reasons that include underdeveloped/ developing organ systems or capacities ( e. g., nervous system, digestive and reproductive systems, immune systems, metabolic detoxication capacity), increased potential for exposure, increased chemical absorption, etc. One study reported that the ingestion of approximately 120 mg ( 8.2 mg/ kg) of aldrin by a 3 year old female resulted in collapse and convulsions within 5 minutes and death within 12 hours ( Hayes, 1982).

Garrettson and Curley ( 1969) reported convulsions in two children ( ages 2 and 4 years) who consumed an unknown amount of a 5% dieldrin solution ( also containing solvents and emulsifiers). The children began to salivate heavily, and then developed convulsions within 15 minutes; the younger child died, whereas the older brother had liver dysfunction prior to recovering completely.

7.1.2 Long Term and Epidemiological Studies The long term epidemiological studies were conducted mainly in populations working in pesticide manufacturing plants, although some utilized volunteers. In most cases, some combination of oral, inhalation, and dermal routes of exposure were probably involved.

General Populations Aldrin One male, employed 21 years at a chemical plant and reassigned to the handling of aldrin concentrate ( period and levels of exposure were not specified), experienced involuntary jerking ( rapid flexor movement) of his hands and forearms, vomiting, and chronic irritability, and insomnia ( Hodge et al., 1967). His EEG showed alpha wave irregularities, with discharges of slow and sharp waves. After exposure to aldrin was discontinued, his condition rapidly improved.

Dieldrin ( mean = 13 ng/ g whole milk) was found in the breast milk of women whose homes were treated annually ( or more frequently) with organochlorine pesticides ( Stacey and Tatum, 1985). A correlation between dieldrin levels in the milk and aldrin treatment of homes was observed. Dieldrin levels in breast milk rose until the seventh or eighth month after treatment of homes was discontinued. No data were provided on the health effects of children exposed to dieldrin contaminated breast milk. 7 3 Aldrin/ Dieldrin   February 2003 Edwards and Priestly ( 1994) reported elevated plasma dieldrin levels and hepatic enzyme activity ( as measured by urinary D glucaric acid excretion) in 33 workers ( 29 males and 4 females) from 2 south Australian suburban pesticide treatment businesses; they had worked in the industry ranging from 3 months to 20 years. The plasma dieldrin concentrations in workers applying aldrin ranged from 2.5 to 250 ng/ mL, while those for workers not involved with aldrin exposure ( office staff) had dieldrin levels ranging from 0.7 to 26 ng/ mL. However, there was no correlation between high D glucaric acid excretion and plasma dieldrin levels.

Dieldrin Hunter and Robinson ( 1967) observed no effect on central nervous system activity ( as measured by EEG), peripheral nerve activity, or muscle activity in volunteers administered dieldrin daily for 18 months at doses as high as 0.003 mg/ kg bw/ day.

Aldrin/ Dieldrin No increase in mortality from any cause was reported in workers ( n = 233) who had been employed in the manufacture of aldrin, dieldrin, and other pesticides at a facility in the Netherlands for more than 4 years ( Van Raalte, 1977; Versteeg and Jager, 1973).

Subsequent studies conducted from the Netherlands included several years of follow up, which may be summarized as follows. De Jong ( 1991) reported mortality data in a 20 year follow up study of cohorts exposed to insecticides for at least 1 year between 1954 and 1970 ( total cohorts = 570 workers). At the time of the vital status cut off date ( January 1, 1987), of these 570 workers, 445 ( 78%) were alive; 76 ( 13.3%) were deceased; 34 ( 6.0%) emigrated; and 15 ( 2.6%) were lost to the follow up. Workers on the study represented 14,740 person years of observation. Exposure estimates were made based on the available blood dieldrin data collected from 343 of the workers. The workers were divided into low, medium, and high exposure categories having estimated mean daily aldrin/ dieldrin intakes of 90, 419, and 1019 : g, respectively ( corresponding mean lifetime intake values were 88, 419, and 1704 mg). The standardized mortality ratios ( SMRs) for all causes of death for the workers exposed to aldrin/ dieldrin, as compared to Netherlands national mortality rates, were 80.6, 86.8, and 68.9 for low, moderate, and high exposures, respectively.

A more recent study from the Netherlands reported on the mortality of the same cohorts with a latter follow up date ( de Jong et al., 1997). Of the 570 workers, 70.5% ( 402) were alive; 20.7% were deceased ( 118); 6.2% ( 35) emigrated, and 2.6% ( 15) were lost to the follow up, at the cut off date of January 1, 1993. The total mortality observed from all causes of death in all the cohorts was lower than the expected number of deaths, calculated from national data according to age, period, and causes of specific mortalities ( 118 deaths observed versus 156 deaths expected; SMR = 75.6, with a 95% confidence interval of 63 to 91). Similar lower trends were observed for mortality rates from cardiovascular disease and non malignant respiratory disease. Of all the types of cancers, only two ( rectum and liver) had higher frequency than expected, but these results were not dose dependent. Six deaths from rectal cancer were observed in the cohorts, as compared to 1.5 expected ( SMR = 390.4, with a 95% confidence 7 4 Aldrin/ Dieldrin   February 2003 interval of 143 to 850). Two deaths due to liver cancer were observed in the cohorts, as compared to 0.9 expected ( SMR = 225, with a 95% confidence interval of 27 to 813). Stratification of the data according to the type of job ( operators, maintenance workers, supervisors) showed a significantly ( p < 0.01) increased mortality rate for rectal cancer only in the operator group ( de Jong et al., 1997).

Three follow up cohort studies were reported on the mortality rates of workers from a pesticide manufacturing plant in Denver, CO ( Ditraglia et al., 1981; Brown, 1992; Amaoteng Adjepong et al., 1995). In the first retrospective cohort study, Ditraglia et al. ( 1981) reported SMRs for 1,155 workers who had been employed at the plant for at least 6 months prior to 1964 and were exposed to aldrin/ dieldrin. Of the 1,155 workers, 75% ( 870) were alive, 15% ( 173) deceased, and 10% ( 112) were of undetermined vital status as of the study cut off date ( December 31, 1976). Workers in the study represented 24,939 person years of observation. They were mainly white males, and the mortality rates of the exposed population were compared to white male cause specific mortality rates in the U. S. The mortality rate for all causes of death ( combination of malignant, circulatory, nonmalignant respiratory, and nervous system diseases) was significantly lower in the exposed group than in the controls ( SMR = 84, with a 95% confidence interval of 72 to 98). The SMRs for neoplasms of the liver and the lymphatic/ hematopoietic system were not statistically different from 100, the values corresponding to 225 ( 95% confidence interval of 39 to 1267) and 147 ( 95% confidence interval of 54 to 319), respectively. However, the authors reported a significant increase in the SMR for nonmalignant respiratory disease at 212, with a 95% confidence interval of 133 to 320.

The study by Brown ( 1992) extended the observations reported by Ditraglia et al. ( 1981) having a study cut off date of December 31, 1987, and 1158 workers. Of these, 803 ( 70%) were alive, 337 ( 29%) were deceased, and 13 ( 10%) were of undetermined vital status. Workers in the study represented 34,479 person years of observation. The mortality rate for all causes of death ( combination of malignant, circulatory, nonmalignant respiratory, and cerebrovascular diseases) was lower for the exposed cohort than for controls ( SMR = 87, with a 95% confidence interval of 78 to 97). Comparing the cohort mortality rate to national, state, or county statistics did not affect the SMR for all causes of death. However, the SMR for liver/ biliary cancer was higher than expected, with values corresponding to 393 ( CI = 127 to 920), 510 ( CI = 165 to 1,191), or 486 ( CI = 157 to 1,136) when compared to U. S., state, or county mortality rates, respectively. Of the five observed cases of liver and biliary cancer, two were also in the dibromochloropropane ( DBCP) registry.

Finally, Amaoteng Adjepong et al. ( 1995) updated the SMRs of the workers in the Denver pesticide manufacturing plant; the study population is similar to those mentioned in the previous two studies ( Ditraglia et al. 1981; Brown, 1992), except that most of the employees worked at the plant between 1952 and 1982, and the race was reported for most ( n = 2,384). The unknown race of 262 workers was classified as white. The cohort had the vital status of 1,764 ( 74%), 496 ( 21%), and 124 ( 5.0%) for living, deceased, and unknown categories, at the time of the cut off date of January 1, 1991. Within the cohort, 87% of the workers consisted of white males ( n = 2,072); 10% were white females ( 234); 3% were black males ( n = 68); and < 1% were black females ( n = 10). The analysis of the data suggested no positive relationship between 7 5 Aldrin/ Dieldrin   February 2003 aldrin/ dieldrin exposure and mortality due to liver cancer or other causes of death ( respiratory, circulatory, or nervous system diseases).

Nair et al. ( 1992) reported finding aldrin and dieldrin levels in adipose tissue, breast milk, and serum samples collected from Delhi female residents ( 18 to 24 years old; n = 12) during 1989 through 1990. The subjects were from low socioeconomic status and were residing in parts of Delhi exposed to severe automobile pollution. The average aldrin concentrations were 0.048, 0.003, and 0.004 ppb in adipose tissue, breast milk, and serum, respectively, and the corresponding average dieldrin concentrations were 0.099, 0.06, and 0.002 ppb, suggesting greater concentration of aldrin/ dieldrin in adipose tissues. A significant correlation was reported between the levels of aldrin/ dieldrin found in adipose tissue and those found in serum ( p< 0.01; r = 0.503). The authors also observed that aldrin and dieldrin values were higher in the breast milk of primagravidae ( first time deliverers) when compared to women who had undergone their second delivery. They concluded that the aldrin/ dieldrin levels in Delhi residents were low when compared to the values found in populations from developed countries. Conflicting reports exist on the effect of aldrin/ dieldin on hematological parameters. A farmer with multiple exposures to insecticides that contained dieldrin died in a hemolytic crisis after developing immunohemolytic anemia ( Muirhead et al., 1959). Immunologic testing revealed a strong antigenic response to red blood cells coated with dieldrin. In another study, a worker from an orange grove developed aplastic anemia and died following repeated exposures to aldrin during spraying ( Pick et al., 1965). In the latter study, the relationship between aldrin exposure and the aplastic anemia was considerably more tenuous, being linked only in that the onset of symptoms corresponded with spraying and the condition deteriorated upon subsequent exposure. However, in another study of workers employed in a pesticide manufacturing plant for 4 years, no abnormal values for hemoglobin, white blood cells, or erythrocyte sedimentation rate were found ( Jager, 1970). Further, workers, who had been involved in either the manufacture or application of pesticides and who had elevated blood dieldrin levels, had no hematological effects of clinical significance ( Warnick and Carter, 1972).

Sensitive Populations No long term studies were located that examined the adverse health effects of aldrin or dieldrin exposure in children ( who in general are considered to be among the most sensitive populations for exposure to chemicals), or in any other potentially high risk population ( e. g., the aged or those with pre existing liver or neurological disease).

7.2 Animal Studies 7.2.1 Acute Toxicity ( Oral, Inhalation, Dermal)

Oral Exposure The oral median lethal dose ( LD 50) values for aldrin in laboratory animals are as follows: mice, 44 mg/ kg bw ( purity not reported; Borgmann et al., 1952); rats, 39 to 60 mg/ kg bw ( purity not reported; Gaines, 1969); guinea pigs, 33 mg/ kg bw ( purity not reported; Borgmann et al., 7 6 Aldrin/ Dieldrin   February 2003 1952); female rabbits, 50 to 80 mg/ kg bw ( purity, 95%; Treon and Cleveland, 1955); and dogs, 65 to 95 mg/ kg bw ( purity not reported; Borgmann et al., 1952).

The doses at which aldrin is acutely lethal in experimental animals are quite similar to those for dieldrin. Oral LD 50 values for single doses of aldrin in rats ranged from 39 to 64 mg/ kg bw ( Gaines, 1960; Treon et al., 1952), while those for single doses of dieldrin ranged from 37 to 46 mg/ kg bw ( Gaines, 1960; Lu et al., 1965; Treon et al., 1952). Aldrin was lethal in female rats at a slightly lower dose when it was administered in solution in oil ( LD 50 = 48 mg/ kg bw), than when it was administered in a kerosene vehicle ( LD 50 = 64 mg/ kg bw) ( Treon et al., 1952).

The age of the animals appeared to influence the acute toxicity of a single administration of dieldrin. Two week old rats had an LD 50 of 25 mg/ kg bw, which is lower, as expected, than the LD 50 value ( 37 mg/ kg bw) found in young adult rats ( Lu et al., 1965). However, newborn rats had a relatively high LD 50 of 168 mg/ kg bw ( Lu et al., 1965).

Acute toxicity in animals is characterized by increased irritability, salivation, hyperexcitability, tremors followed by clonic/ tonic convulsions, anorexia and loss of body weight, depression, prostration, and eventual death ( Borgmann et al., 1952; Hodge et al., 1967).

Inhalation Exposure Treon et al. ( 1957) exposed cats, guinea pigs, rats, rabbits, and mice to aldrin vapors and particles generated by sublimating aldrin at 200 ° C. Aldrin levels of 108 mg/ m3 for 1 hour resulted in the death of 9 out of 10 rats, 3 out of 4 rabbits, and 2 out of 10 mice. Cats and guinea pigs were less sensitive. One out of one cat and no guinea pigs died following exposure to 215 mg/ m3 for 4 hours. Interpretation of the results of this study is limited in that sublimation may have resulted in the generation of atmospheres containing a higher proportion of volatile contaminants than would be expected in atmospheres typical of most occupational exposures.

Dermal Exposure In rats, a single dermal application of aldrin in xylene produced an LD 50 value of 60 mg/ kg bw in female rats and 90 mg/ kg bw in male rats ( Gaines, 1960). A single 24 hour dermal exposure of rabbits to dry crystallized aldrin or dieldrin resulted in LD 50 values between 600 and 1,250 mg/ kg bw for both chemicals ( Treon et al., 1953).

7.2.2 Short Term Studies Oral Exposure In a short term study, Treon and Cleveland ( 1955) observed 100% mortality within 2 weeks in groups of male and female Carworth rats ( total number and number/ sex not reported) that were fed aldrin ( purity 95%) at a concentration of 300 ppm ( an approximate dose of 15 mg/ kg bw/ day, based on Lehman, 1959). No mortality was noted at lower doses. Administration of a diet containing 25 ppm aldrin ( purity 95%), an approximate dose of 0.625 mg/ kg bw/ day, to 7 7 Aldrin/ Dieldrin   February 2003 2 male and 3 female beagle dogs induced fatalities after periods of feeding ranging from 9 to 15 days ( Treon and Cleveland, 1955).

Kolaja et al. ( 1996a) investigated the short term effects in male Fisher 344 rats and B6C3F 1 mice ( 5 animals/ species/ group) after administration of dieldrin at 0 ( control), 0.1, 1.0, 3.0, or 10.0 mg/ kg bw diet for 7 or 14 days ( approximate doses in rats of 0.005, 0.05, 0.15, or 0.5 mg/ kg bw/ day, and in mice of 0.015, 0.15, 0.45, or 1.5 mg/ kg bw/ day; based on Lehman, 1959). Relative liver weights ( liver weight/ body weight) in mice were significantly increased at all doses tested compared to controls. However, in rats, apparent increases in relative liver weights were found only in the 10.0 mg/ kg bw diet dieldrin group after 7 days of treatment. Dieldrin was not severely hepatotoxic in either species, as evidenced by no changes in the activities of serum enzymes such as ALT and AST, and no histopathology.

In an another study, Kolaja et al. ( 1996b) reported selective promotion of hepatic focal lesions in male B6C3F 1 mice, but not in male Fisher 344 rats, following administration of dieldrin at 0.1, 1.0, or 10.0 mg/ kg bw diet ( 5 animals/ group) for 7 days ( approximate doses in rats of 0.005, 0.05, or 0.5, mg/ kg bw/ day, and in mice of 0.015, 0.15, or 1.5 mg/ kg bw/ day; based on Lehman, 1959). Study animals including controls were injected intraperitoneally with the hepatic carcinogen, diethyl nitrosamine ( 150 mg/ kg bw/ week, 2x for rats; 25 mg/ kg bw/ week, 8x for mice), prior to dieldrin treatment in order to enhance the formation of hepatic lesions. No significant effects on the number or volume of hepatic focal lesions ( total), DNA labeling index, or relative liver weight ( liver to body weight ratio) were observed in the rats. However, significant increases ( p < 0.05) in the number of hepatic focal lesions and in hepatic focal lesion volume, DNA labeling index, and relative liver weight were noted in the mice treated with the high dose of dieldrin. No changes in body weight or in the apoptotic index of the hepatic focal lesions were observed at any of the doses tested, either in rats or mice.

Inhalation Exposure No studies were obtained that investigated the short term toxic effects of aldrin or dieldrin in animals after inhalation exposure.

Dermal Exposure No studies were obtained that investigated the short term toxic effects of aldrin or dieldrin in animals after dermal exposure.

7.2.3 Subchronic Studies Oral Exposure Aldrin Decreased body weight gain and increased mortality were observed in the high dose group of Osborne Mendel rats ( 5/ sex/ group) fed aldrin ( technical grade, 95% pure) in the diet at 7 8 Aldrin/ Dieldrin   February 2003 concentrations of 0, 40, 80, 160, or 320 ppm aldrin ( doses of 0 and approximately 2, 4, 8, or 16 mg/ kg bw/ day, respectively, based on a food consumption factor of 0.05 from Lehman, 1959) for 42 days then and observed for an additional 14 days ( NCI, 1978). The No Observed Adverse Effect Level ( NOAEL) for this study was 160 ppm ( 8 mg/ kg bw/ day). This study was a range finding study for a long term carcinogenicity study; therefore, a complete toxicology profile was not obtained ( e. g., biochemical and hematology assessments were not performed).

In groups of B6C3F 1 mice ( 5/ sex/ group) fed aldrin ( technical grade, 95% pure) at concentrations of 0, 2.5, 5, 10, 20, 40, or 80 ppm ( doses of 0 and approximately 0.375, 0.75, 1.5, 3, 6, or 12 mg/ kg bw/ day, respectively, based on a food consumption factor of 0.15 from Lehman, 1959) in the diet for 42 days, 100% mortality was observed in the 40 and 80 ppm ( 6 and 12 mg/ kg bw/ day, respectively) groups. One male and one female died in the 20 ppm ( 3 mg/ kg bw/ day) group; 10 and 20 ppm ( 1.5 and 3 mg/ kg bw/ day, respectively) were therefore considered the NOAEL and Lowest Observed Adverse Effect Level ( LOAEL) values, respectively, for this study ( NCI, 1978). This study was a range finding study for a long term carcinogenicity study; therefore, a complete toxicology profile was not obtained.

Dieldrin Kolaja et al. ( 1996a) reported no statistically significant differences in either body weight gains, food consumption, or water consumption in male B6C3F 1 mice or Fisher 344 rats that were administered dieldrin at concentrations of 0.1, 1.0, 3.0, or 10.0 mg/ kg bw diet for 21, 28, or 90 days ( approximate doses in rats of 0.005, 0.05, 0.15, or 0.5 mg/ kg bw/ day, respectively, and in mice of 0.015, 0.15, 0.45, or 1.5 mg/ kg bw/ day, respectively; based on Lehman, 1959). Also, no severe hepatotoxicity was observed in dieldrin treated animals, as evidenced by no changes in activities of the serum enzymes ALT ( alanine aminotransferase) and AST ( aspartamine aminotransferase), and no apparent histopathology. However, relative liver weights ( liver/ body weight ratios) were significantly increased in mice ( but not in rats) at the highest dose tested.

In a subsequent report, Kolaja et al. ( 1996b) reported that dieldrin administered to groups of male B6C3F 1 mice or Fisher 344 rats ( 5/ group/ species/ dose) at concentrations of 0.1, 1.0, or 10.0 mg/ kg bw diet for 30 or 60 days ( approximate doses in rats of 0.005, 0.05, or 0.5 mg/ kg bw/ day, respectively, and in mice of 0.015, 0.15 or 1.5 mg/ kg bw/ day, respectively; based on Lehman, 1959) caused the selective promotion of hepatic focal lesions in the mice but not in the rats. Study animals, including controls, were injected intraperitoneally with the hepatic carcinogen, diethyl nitrosamine ( 150 mg/ kg bw/ week, 2x for rats; 25 mg/ kg bw/ week, 8x for mice), prior to dieldrin treatment in order to enhance the formation of hepatic lesions. No significant effects on the number or volume of hepatic focal lesions ( total) were observed for rats at any of the doses tested during the 30 or 60 days after dieldrin treatment. However, significant increases ( p < 0.05) in the number of hepatic focal lesions and in hepatic focal lesion volume and DNA labeling index were noted in mice treated with the high dose of dieldrin after 30 and 90 days. Dieldrin treatment also caused an inconsistent increase in relative liver weights in both rats and mice. Changes in body weight or in the apoptotic index of hepatic focal lesions were not observed at any dose or duration tested, in either rats or mice. 7 9 Aldrin/ Dieldrin   February 2003 Stevenson et al. ( 1995) also reported that dieldrin caused an increase in hepatotoxicity such as liver enlargement, increased DNA synthesis in hepatocytes, hypertrophy of centrilobular hepatocytes, and induction of hepatic ethoxyreosrufin 0 deethylase ( microsomal mixed function oxidase) activity at the highest dose in male B6C3F 1 mice fed with dieldrin at 1, 3, or 10 mg/ kg diet for 28 days ( approximate doses of 0.15, 0.45, or 1.5 mg/ kg bw/ day; based on Lehman, 1959).

Inhalation Exposure No studies were obtained that investigated the toxic effects of aldrin or dieldrin in animals after subchronic inhalation exposure.

Dermal Exposure Aldrin or dieldrin ( dry powder) applied to rabbit skin for 2 hours/ day, 5 days/ week for 10 weeks, was reported to have had no discernible effects ( IPCS, 1989).

7.2.4 Neurotoxicity Oral Exposure Aldrin Paul et al. ( 1992) reported behavioral impairments in Wistar rats ( 10/ group) that were administered 1 mg/ kg bw/ day aldrin ( technical grade, 90% pure) by gavage for up to 90 days. Aldrin inhibited muscle coordination ( measured using rota rod apparatus) beginning on the 15th day in both sexes, with greater motor deterioration occurring in males. Aldrin also inhibited learning ability and the conditioned avoidance response ( measured in a pole climbing apparatus), as the number of animals responding to simultaneous unconditioned and conditioned stimuli was significantly reduced ( p < 0.05) in aldrin treated groups when compared to controls.

Neurotoxic signs observed in cattle poisoned with unspecified dietary concentrations of aldrin included tremors, running, hyperirritability, and seizures ( Buck and Van Note, 1968). Casteel et al. ( 1993) reported neurological and muscular symptoms, such as ataxia, tremors, hypersalivation, diarrhea, and disorientation in 6 calves; lateral recumbency and intermittent tonoclonic convulsions in 2 calves; and severe signs such as death in 10 calves, in a group of feedlot cattle ( n = 90) exposed to aldrin contaminated feed in northwest Missouri. The selffeeders in the feedlot contained from 54 to 528 : g aldrin/ g of feed. Analysis of aldrin and dieldrin in the rumen content of two dead calves revealed the concentrations of aldrin as 20.6 and 22.4 : g/ g of ingesta. The mean dieldrin concentrations in fat samples that were collected 50 days after the withdrawal of contaminated feed from the calves ranged from 9.7 to 18.8 : g/ g, and the approximate half lives of dieldrin in the adipose tissue of calves ranged from 53 to 231 days. 7 10 Aldrin/ Dieldrin   February 2003 Dieldrin Convulsions were observed in rats given single doses of dieldrin ranging from 40 to 50 mg/ kg ( Wagner and Greene, 1978; Woolley et al., 1985). Transient hypothermia and anorexia were also reported following a single dose of 40 mg/ kg ( Woolley et al., 1985). Tremors were observed in rats receiving a dose of 0.5 mg/ kg bw/ day for 60 days ( Mehrotra et al., 1988), and hyperexcitability was observed with dieldrin at 2.5 mg/ kg bw/ day in an 8 week study ( Wagner and Greene 1978). Cerebral edema and small foci of degeneration were reported in rats exposed to dieldrin at 0.016 mg/ kg bw/ day for 2 years ( Harr et al., 1970), although the study had various limitations.

Operant behavior was reported to have been disrupted in rats following single doses of dieldrin ranging from 0.5 to 16.7 mg/ kg ( Burt, 1975; Carlson and Rosellini, 1987). A lower dose of dieldrin ( 0.025 mg/ kg bw/ day) for a longer duration ( 60 to 120 days) was also observed to impair operant behavior in rats ( Burt, 1975).

EEGs taken from dogs exposed to dieldrin at 0.05 mg/ kg bw/ day for 2 years were normal ( Walker et al. 1969). However, dogs were reported to develop convulsions when given 0.5 mg/ kg bw/ day for 25 months ( Fitzhugh et al. 1964).

Aldrin/ Dieldrin When aldrin or dieldrin was administered to rats for 3 days, convulsions were observed at a dose of 10 mg/ kg bw/ day ( Mehrotra et al., 1989). Histopathological changes were found in the brain cells of rats that were exposed for 6 months to 2.75 mg/ kg bw/ day of either aldrin or dieldrin ( Treon et al., 1951a).

Irritability, tremors, and convulsions were observed in rats fed aldrin/ dieldrin at dietary concentrations ranging from 0.1 to 65 ppm in several 1.5 to 2.5 year studies ( Deichmann et al., 1970; NCI, 1978; Walker et al., 1969). Hyperexcitability was observed in Osborne Mendel rats exposed for 74 to 80 weeks to aldrin in the diet at 30 and 60 ppm ( approximate doses of 1.5 and 3.0 mg/ kg bw/ day, respectively, according to Lehman, 1959) ( NCI, 1978), as were tremors and clonic convulsions after 31 months exposure to 20, 30, or 50 ppm ( approximate doses of 1.0., 1.5, or 2.5 mg/ kg bw/ day, respectively) ( Deichmann et al., 1970). Similarly, hyperexcitability was observed in Osborne Mendel rats fed 29 ppm dieldrin for 80 weeks or 65 ppm for 59 weeks ( approximate doses of 1.45 and 3.25 mg/ kg bw/ day, respectively) ( NCI, 1978). In a companion study ( NCI, 1978), Fischer 344 rats that were fed dieldrin for 2 years at 2, 10, or 50 ppm ( approximate doses of 0.1, 0.5, or 2.5 mg/ kg bw/ day, respectively) showed convulsions, tremors, and nervous behavior at the high dose. CF rats fed 0.1, 1, or 10 ppm dieldrin ( approximate doses of 0.005, 0.05, or 0.5 mg/ kg bw/ day, respectively) for 2 years displayed irritability, tremors, and convulsions ( Walker et al., 1969); the latter 2 effects were also noted in Osborne Mendel rats exposed to 20, 30, or 50 ppm dieldrin ( approximate doses of 1, 1.5, or 2.5 mg/ kg bw/ day, respectively) for 29 months ( Deichmann et al., 1970). 7 11 Aldrin/ Dieldrin   February 2003 B6C3F 1 mice showed slightly greater sensitivity than did the rats in the NCI ( 1978) 80 week bioassays, with hyperexcitability observed at dietary exposures of aldrin as low as 3 ppm ( females) and 4 ppm ( males) ( approximate doses of 0.45 and 0.60 mg/ kg bw/ day, respectively, according to Lehman, 1959); and with hyperexcitability, tremors, and hyperactivity observed at dietary exposures of dieldrin as low as 2.5 ppm for both sexes ( approximate dose of 0.38 mg/ kg bw/ day).

Dogs given aldrin at 0.89 to 1.78 mg/ kg bw/ day, or dieldrin at 0.73 to 1.85 mg/ kg bw/ day, for up to 9 months experienced neuronal degeneration in the cerebral cortex and convulsions ( Treon et al., 1951b). At these doses, aldrin treated dogs also displayed hypersensitivity to stimulation, twitching, and tremors, while at higher doses, the basal ganglia and cerebellum were reported to exhibit degenerative changes.

Inhalation Exposure No studies were obtained that investigated the neurotoxic effects in animals resulting from inhalation exposure to either aldrin or dieldrin.

Dermal Exposure In a study examining the effects of acute dermal exposure to aldrin or dieldrin, Treon et al. ( 1953) reported the induction of tremors and convulsions in rabbits. However, the doses associated with these effects were not reported.

Other Routes of Exposure Castro et al. ( 1992) reported the effects of prenatal exposure to aldrin on the behavioral development of 90 day old adult rats. Pregnant female rats ( 10 to 20/ group) were subcutaneously injected with either aldrin ( 1.0 mg/ kg bw) or its vehicle ( 0.9% sodium chloride plus Tween 80) from day 1 of pregnancy until delivery. Prenatal exposure to aldrin reportedly produced no changes at 90 days in aldrin or dieldrin levels in serum, or in cellular and structural organization of cerebral cortex neurons, or in the adult animals' behavior as determined by an avoidance learning test. However, prenatal administration of aldrin was found to produce a significant increase ( p < 0.05) in the locomotor frequency of experimental rats at 21 and 90 days. Also, the performance of adult rats in the hole board apparatus ( total number and duration of head dips) was significantly higher ( p < 0.05) in the aldrin treated groups when compared to that of the control rats. 7 12 Aldrin/ Dieldrin   February 2003 7.2.5 Developmental/ Reproductive Toxicity Oral Exposure Aldrin In a reproduction study reported by Deichmann et al. ( 1971), groups of beagles were administered 0.15 ( 4 females) or 0.3 ( 4 males, 3 females) mg/ kg bw/ day of aldrin ( purity 95%) by capsule, 5 days/ week for 14 months. Estrous cycles in the female dogs were delayed by 7 to 12 months, and 2 of the 4 females administered 0.15 mg/ kg bw/ day failed to achieve estrus during the 8 month period following cessation of aldrin exposure. However, such failure was not observed in dogs given 0.3 mg/ kg bw/ day. During lactation, the viability of pups from dams receiving either 0.15 or 0.3 mg/ kg bw/ day was decreased; 84, 75, and 44% of pups from dams ingesting 0, 0.15, and 0.3 mg/ kg bw/ day, respectively, survived until weaning. The reduced pup survival may have been due to a prenatal effect, or to toxicity associated with dieldrin in the mothers' milk. Mammary development and milk production also appeared to be severely depressed. Some males reportedly exhibited a depressed sexual drive.

Dieldrin Coulston et al. ( 1980) studied the reproductive effects of dieldrin on Long Evans rats. Pregnant rats ( 18 to 20/ dose) were administered 0 or 4 mg/ kg bw dieldrin ( purity not reported) by gavage, daily from day 15 of gestation through postpartum day 21. The treated group did not differ from the control group when examined for fecundity, number of stillbirths, perinatal mortality, or total litter weights. Pup malformations were not observed in either group.

Harr et al. ( 1970) fed dieldrin ( purity not specified) to 28 day old OSU Wistar rats ( 20/ sex/ group) until they were mated at 146 days of age; dietary concentrations were 0, 0.08, 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10, 20, or 40 mg/ kg ( 0 and approximately 0.004, 0.008, 0.016, 0.032, 0.063, 0.125, 0.25, 0.5, 1, or 2 mg/ kg bw/ day, respectively, based on Lehman, 1959). Mortality was observed in dams exposed to 1 or 2 mg/ kg bw/ day, and fertility and litter size were reduced in several groups without demonstrating a clear dose response relationship. At weaning, no pups survived in the 1 and 2 mg/ kg bw/ day groups, and the number of survivors was substantially reduced at doses down to 0.125 mg/ kg bw/ day. At these doses, pups died in convulsions ( 43%) or starved ( 57%), the latter occurring because both dams and pups were too hyperesthetic to permit adequate nursing. Neural lesions ( e. g., cerebral edema and hydrocephalus) were noted in pups of the 0.004 mg/ kg bw/ day group ( but evidently not in those of higher dose groups), and hepatic lesions were observed in rats exposed to $ 0.016 mg dieldrin/ kg bw/ day. This study has been considered somewhat limited by the lack of statistical analysis and by the uncertain affect on outcome that may have resulted from the use of a semisynthetic diet ( ATSDR, 2000).