Walker et al. ( 1969) administered dieldrin ( recrystallized, 99% active ingredient) to Carworth Farm " E" rats ( 25/ sex/ dose; controls 45/ sex) for 2 years at dietary concentrations of 0, 0.1, 1.0, or 10.0 ppm. Based on intake assumptions presented by the authors, these dietary levels are approximately equivalent to 0, 0.005, 0.05, and 0.5 mg dieldrin/ kg bw/ day, respectively. Body weight, food intake, and general health remained unaffected throughout the 2 year period, although at 10.0 ppm ( 0.5 mg/ kg bw/ day) all animals became irritable and exhibited tremors and occasional convulsions. No effects were observed for various hematological and clinical chemistry parameters. At the end of 2 years, females fed 1.0 and 10.0 ppm ( 0.05 and 0.5 mg/ kg bw/ day, respectively) had increased liver weights and liver to body weight ratios ( p < 0.05). Histopathological examinations revealed liver parenchymal cell changes, including focal proliferation and focal hyperplasia. These hepatic lesions were considered by the authors to be characteristic of exposure to an organochlorine insecticide. Based on these toxic effects 8 3 Aldrin/ Dieldrin   February 2003 observed in the liver, the LOAEL was identified as 1.0 ppm ( 0.005 mg/ kg bw/ day) and the NOAEL as 0.1 ppm ( 0.005 mg/ kg bw/ day).

RfD Derivation The RfD for dieldrin was derived from the critical effect ( altered absolute and relative liver weights that were accompanied by histopathological changes) that it induced in rats during a 2 year chronic feeding study ( Walker et al., 1969). Liver toxicity was noticed only at the 1.0 and 10 ppm diet groups in female rats. The NOAEL dietary concentration of 0.1 ppm dieldrin served as the basis for the RfD derivation, after being converted to a dose of 0.005 mg dieldrin/ kg bw/ day utilizing the authors' assumptions on dietary intake ( which also comport with the 1 ppm = 0.05 mg/ kg bw/ day conversion factor of Lehman [ 1959] for food consumption in rats).

The RfD for dieldrin is calculated as follows:

RfD = = 5E 5 mg/ kg bw/ day 0 005 . mg / kg bw / day 100 where:

0.005 mg/ kg bw/ day = NOAEL, based on liver toxicity in rats exposed to dieldrin in the diet for 2 years 100 = uncertainty factor; this composite uncertainty factor was chosen in accordance with EPA or NAS/ OW guidelines in which uncertainty factors of 10 each were applied to extrapolate from rats to humans and to account for uncertainty in the range of human sensitivity ( i. e., to protect sensitive human subpopulations

8.1.2 Reference Concentration ( RfC) Determination No human or animal studies were identified that would currently support the derivation of RfC values for either aldrin or dieldrin.

8.2 Dose Response for Cancer Effects 8.2.1 Choice of Study/ Data With Rationale and Justification Aldrin Three marginally adequate to adequate long term carcinogenicity bioassays of aldrin have been conducted using B6C3F 1, C3HeB/ Fe, and C3H mice. Based on these studies, there is sufficient evidence that aldrin is carcinogenic for mice. Dietary administration of aldrin induced 8 4 Aldrin/ Dieldrin   February 2003 statistically significant increases in hepatocellular carcinomas in male B6C3F 1 mice ( p < 0.001) ( NCI, 1978), hepatomas in combined male plus female C3HeB/ Fe mice ( p < 0.001) ( Davis and Fitzhugh, 1962), and hepatomas in the combined sexes of C3H mice ( p < 0.05) ( Davis, 1965). Reevaluation of the hepatomas observed in the latter two studies indicated that most were actually hepatocellular carcinomas ( Epstein, 1975).

Dietary administration of aldrin was reported to increase the combined incidences of follicular cell adenomas and carcinomas of the thyroid in both male and female Osborne Mendel rats; however, the increase was not dose related and was significant ( p = 0.001) only at the low dose. This increase was not considered to be treatment related. Although the study authors concluded that aldrin was not carcinogenic to rats ( NCI, 1978), these data ( in conjunction with the adrenal cortex tumors observed in low dose female rats) have been subsequently considered equivocal or suggestive evidence of carcinogenicity in rats ( Griesemer and Cueto, 1980; Haseman et al., 1987; USEPA, 1987).

Based on the available data, IARC ( 1987) concluded that there was limited evidence for the carcinogenicity of aldrin in animals and inadequate evidence in humans. IARC's conclusion with respect to animal carcinogenicity was based on the occurrence of malignant liver neoplasms in mice, since one study using rats could not clearly associate the occurrence of thyroid tumors with aldrin treatment, three additional studies using rats gave negative results, and another rat study was judged to be inadequate. Consequently, IARC classified aldrin as a Group 3 chemical, a possible human carcinogen.

Applying the criteria described in EPA's guidelines for assessment of carcinogenic risk ( USEPA, 1986), aldrin may be classified in Group B2: probable human carcinogen. This category includes agents for which there is inadequate evidence of carcinogenicity in human studies and sufficient evidence of carcinogenicity in animal studies. Under the more recent Proposed Guidelines for Carcinogen Risk Assessment ( USEPA, 1996/ 1999), aldrin would probably be categorized as " likely" to produce cancer in humans by the oral route of exposure, while its carcinogenic potential via other routes of exposure would merit a classification of " cannot be determined due to inadequate data."

From the several carcinogenicity studies that have provided evidence that aldrin is carcinogenic in mice, three data sets have been deemed adequate for quantitative risk estimation ( USEPA, 1987): those for both male and female C3H mice in the Davis ( 1965) study, as reevaluated by Reuber and cited in Epstein ( 1975); and that for male B6C3F 1 mice in the NCI ( 1978) bioassay. Utilizing the linearized multistage model, the USEPA ( 1987) performed potency estimates for each of these data sets after interspecies dose conversion; they ranged from 12 to 23 ( mg/ kg bw/ day) 1. Their geometric mean, ( q1*) = 17 ( mg/ kg bw/ day) 1, was estimated as the cancer potency of aldrin for the general population.

Using this cancer potency estimate and assuming that a 70 kg human adult consumes 2 liters of water a day over a 70 year lifespan, the linearized multistage model yields a drinking water unit risk of 4.9 E 4 per : g/ L. This in turn can be used to estimate that concentrations of 8 5 Aldrin/ Dieldrin   February 2003 0.2, 0.02, and 0.002 : g/ liter of aldrin may result in excess cancer risks of 10 4, 10 5, and 10 6, respectively.

The linearized multistage model is only one of several that can be used for estimating carcinogenic risk. From the three aldrin data sets that were identified in the USEPA ( 1987) report as being suitable for quantitative cancer risk estimation, it was determined that one was also suitable for determining slope estimates using the probit, logit, Weibull, and gamma multihit models. Each model utilizes a different set of assumptions in order to extrapolate from observed experimental data to predicted cancer risks at the low doses more characteristic of human exposure scenarios. Based on current limitations in the understanding of biological mechanisms relevant to carcinogenesis, as well as in the availability of mechanistic data for most chemicals, the relative accuracy of these models cannot generally be predicted. The drinking water levels of aldrin estimated by each of these models ( at the upper 95% confidence limit) to be associated with an excess cancer risk of one per 1,000,000 persons exposed ( i. e., an excess risk of 10 6) were 0.00206 : g/ L ( multistage model), 0.00356 : g/ L ( probit model), 0.00376 : g/ L ( logit model), 0.00356 : g/ L ( Weibull model), and 0.00310 : g/ L ( multihit model) ( USEPA, 1992).

Dieldrin Applying the criteria described in EPA's final guidelines for assessment of carcinogenic risk ( USEPA, 1986), dieldrin also may be classified in Group B2, probable human carcinogen. Again, under the more recent Proposed Guidelines for Carcinogen Risk Assessment ( USEPA, 1996/ 1999), dieldrin would probably be categorized as " likely" to produce cancer in humans by the oral route of exposure, while its carcinogenic potential via other routes of exposure would merit a classification of " cannot be determined due to inadequate data." IARC ( 1982) has concluded that there is limited evidence for dieldrin's carcinogenicity in laboratory animals.

Evidence reported in a number of carcinogenicity studies indicates that dieldrin is carcinogenic to several strains of mice ( Davis and Fitzhugh, 1962; Davis, 1965; Walker et al., 1972; Thorpe and Walker, 1973; NCI, 1978; Tennekes et al., 1981; Meierhenry et al., 1983). Thirteen sex and strain specific data sets from these studies were judged adequate for quantitative risk estimation; for each of them, the USEPA generated potency estimates utilizing the linearized multistage model ( USEPA, 1987). These estimates ranged from 7 to 55 ( mg/ kg bw/ day) 1, with the geometric mean of q 1* = 16 ( mg/ kg bw/ day) 1 taken as the estimated potency of dieldrin for the general population.

Using this q 1* value and assuming that a 70 kg human adult consumes 2 liters of water a day over a 70 year lifespan, the linearized multistage model estimates a drinking water unit risk of 4.6 E 4 per : g/ L. Therefore, excess cancer risk levels of 10 4 , 10 5, and 10 6 would be estimated to result from drinking water concentrations of approximately 0.2, 0.02, and 0.002 : g dieldrin per liter, respectively.

As noted previously, the linearized multistage model is only one of several that can be used for estimating carcinogenic risk. From the 13 dieldrin data sets data that were identified in the USEPA ( 1987) report as being suitable for quantitative cancer risk estimation, it was 8 6 Aldrin/ Dieldrin   February 2003 determined that 5 were also suitable for determining slope estimates using the probit, logit, Weibull, and gamma multihit models. Again, each model utilizes a different set of assumptions in order to extrapolate from observed experimental data to predicted cancer risks at the low doses more characteristic of human exposure scenarios. Based on current limitations in the understanding of biological mechanisms relevant to carcinogenesis, as well as in the availability of mechanistic data for most chemicals, the relative accuracy of these models cannot generally be predicted. The drinking water unit risks ( those estimated for a 70 kg human drinking, over a the course of a lifetime, 2 L/ day of water containing 1 : g/ L of dieldrin) estimated by each of these models ( at the upper 95% confidence limit) have been reported as 4.78 × 10 4 ( multistage model), 7.7 × 10 12 ( probit model), 5.09 × 10 6 ( logit model), 1.13 × 10 4 ( Weibull model), and 5.68 × 10 4 ( multihit model) ( USEPA, 1988). 8 7 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.

Davis, K. J. 1965. Pathology report on mice fed aldrin, dieldrin, heptachlor or heptachlor epoxide for two years. Internal FDA memorandum to Dr. A. J. Lehman. FDA. July 19. ( as cited in USEPA, 1992).

Davis, K. J. and O. G. Fitzhugh. 1962. Tumorigenic potential of aldrin and dieldrin for mice. Toxicol. Appl. Pharmacol. 4: 187 189 ( as cited in USEPA, 1992).

Deichmann, W. B., W. E. MacDonald, E. Blum, M. Bevilacqua, J. Radomski, M. Keplinger, and M. Balkus. 1970. Tumorigenicity of aldrin, dieldrin and endrin in the albino rat. Ind. Med. Surg. 39( 10): 426 434 ( as cited in USEPA, 1992).

Epstein, S. S. 1975. The carcinogenicity of dieldrin. Part 1. Sci. Total Environ. 4: 1 52 ( as cited in USEPA 1993b).

Fitzhugh, O. G., A. A. Nelson, and M. L. Quaife. 1964. Chronic oral toxicity of aldrin and dieldrin in rats and dogs. Food Cosmet. Toxicol. 2: 551 562.

Griesemer, R. A. and C. Cueto, Jr. 1980. Toward a classification scheme for degrees of experimental evidence for the carcinogenicity of chemicals for animals. In: Montesano, R., H. Bartsch, and L. Tomatis, eds. Molecular and cellular aspects of carcinogen screening tests. IARC Scientific Publications No. 27. Lyon, France: International Agency for Research on Cancer, pp. 259 281.

Haseman, J. K., J. E. Huff, E. Zeiger, and E. E. McConnell. 1987. Comparative results of 327 chemical carcinogenicity studies. Environ. Health Perspect. 74: 229 235.

IARC. 1987. International Agency for Research on Cancer. Evaluation of the carcinogenic risk of chemicals to humans. Overall evaluations of carcinogenicity. Suppl. 7: 88 89.

IARC. 1982. International Agency for Research on Cancer. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Chemicals, industry process and industries associated with cancer in humans. IARC Monographs. Vols. 1 29, Supplement 4. Geneva, Switzerland: World Health Organization ( as cited in USEPA, 1988).

IPCS. 1989. International Programme on Chemical Safety. Aldrin and dieldrin. Environmental health criteria 91. Geneva, Switzerland: World Health Organization, IPCS. 8 8 Aldrin/ Dieldrin   February 2003 Lehman, A. 1959. Appraisal of the safety of chemicals in foods, drugs and cosmetics. Association of Food and Drug Officials of the United States ( as cited in USEPA, 1992 and USEPA, 1988).

Meierhenry, E. F., B. H. Reuber, M. E. Gershwin, L. S. Hsieh, and S. W. French. 1983. Deildrin induced mallory bodies in hepatic tumors of mice of different strains. Hepatology 3: 90 95 ( as cited in USEPA, 1993b).

NCI. 1978. National Cancer Institute. Bioassays of aldrin and dieldrin for possible carcinogenicity. DHEW Publication No. ( NIH) 78 821 and 78 822. National Cancer Institute Carcinogenesis Technical Report Series, No. 21 and 22. NCI CG TR 21, NCI CG TR 22 ( as cited in ATSDR, 2000; IPCS, 1989; USEPA, 1993a, 1993b, 1992, 1988, 1987).

Tennekes, H. A., A. S. Wright, K. M. Dix, and J. H. Koeman. 1981. Effects of dieldrin, diet, and bedding on enzyme function and tumor incidence in livers of male CF 1 mice. Cancer Res. 41: 3615 3620 ( as cited in USEPA, 1993b).

Thorpe, E. and A. I. T. Walker. 1973. The toxicology of dieldrin ( HEOD). Part II. Comparative long term oral toxicology studies in mice with dieldrin, DDT, phenobarbitone, beta BHC and gamma BHC. Food Cosmet. Toxicol. 11: 433 441 ( as cited in USEPA, 1993b).

Treon, J. F. and F. P. Cleveland. 1955. Toxicity of certain chlorinated hydrocarbon insecticides for laboratory animals, with special reference to aldrin and dieldrin. Agric. Food Chem. 3: 402 408 ( as cited in USEPA, 1987, 1992, 1993a and 1993b).

USEPA. 1996/ 1999. U. S. Environmental Protection Agency. Proposed Cancer Guidelines. Available on the Internet at http:// www. epa. gov/ ORD/ WebPubs/ carcinogen / carcin. pdf.

USEPA. 1993a. U. S. Environmental Protection Agency. IRIS document for aldrin. Available on the Internet at http:// www. epa. gov/ ngispgm3/ iris/ index. html.

USEPA. 1993b. U. S. Environmental Protection Agency. IRIS document for dieldrin. Available on the Internet at http:// www. epa. gov/ ngispgm3/ iris/ index. html.

USEPA. 1992. U. S. Environmental Protection Agency. Aldrin drinking water health advisory. Washington, DC: USEPA, Office of Water.

USEPA. 1988. U. S. Environmental Protection Agency. Dieldrin health advisory. Washington, DC: USEPA, Office of Water.

USEPA. 1987. U. S. Environmental Protection Agency. Carcinogenicity assessment of aldrin and dieldrin. EPA/ 600/ 6 87 006. Washington DC: USEPA, Office of Health and Environmental Assessment, Carcinogen Assessment Group. 8 9 Aldrin/ Dieldrin   February 2003 USEPA. 1986. U. S. Environmental Protection Agency. Guidelines for carcinogen risk assessment. Fed. Reg. 51( 185): 33992 34003. September 24 ( as cited in USEPA, 1992, and USEPA, 1988).

Walker, A. I. T., E. Thorpe, and D. E. Stevenson. 1972. The toxicology of dieldrin ( HEOD). I. Long term oral toxicity studies in mice. Food Cosmet. Toxicol. 11: 415 432 ( as cited in USEPA, 1988 and USEPA, 1993b).

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. 9 1 Aldrin/ Dieldrin   February 2003 9.0 REGULATORY DETERMINATION AND CHARACTERIZATION OF RISK FROM DRINKING WATER 9.1 Regulatory Determination for Chemicals on the CCL The Safe Drinking Water Act ( SDWA), as amended in 1996, required the Environmental Protection Agency ( EPA) to establish a list of contaminants to aid the Agency in regulatory priority setting for the drinking water program. EPA published a draft of the first Contaminant Candidate List ( CCL) on October 6, 1997 ( 62 FR 52193, USEPA, 1997). After review of and response to comments, the final CCL was published on March 2, 1998 ( 63FR 10273, USEPA, 1998). The CCL grouped contaminants into three major categories as follows:

Regulatory Determination Priorities  Chemicals or microbes with adequate data to support a regulatory determination,

Research Priorities  Chemicals or microbes requiring research for health effects, analytical methods, and/ or treatment technologies,

Occurrence Priorities  Chemicals or microbes requiring additional data on occurrence in drinking water.

The March 2, 1998, CCL included 1 microbe and 19 chemicals in the regulatory determination priority category. More detailed assessments of the completeness of the health, treatment, occurrence and analytical method data led to a subsequent reduction of the regulatory determination priority chemicals to a list of 12 ( 1 microbe and 11 chemicals), which was distributed to stakeholders in November 1999.

SDWA requires EPA to make regulatory determinations for no fewer than five contaminants in the regulatory determination priority category by August 2001. In cases where the Agency determines that a regulation is necessary, the regulation should be proposed by August 2003 and promulgated by February 2005. The Agency is given the freedom to also determine that there is no need for a regulation if a chemical on the CCL fails to meet one of three criteria established by SDWA and described in Section 9.1.1.

9.1.1 Criteria for Regulatory Determination These are the criteria used to determine whether or not to regulate a chemical on the CCL:

The contaminant may have an adverse effect on the health of persons,

The contaminant is known to occur or there is a substantial likelihood that the contaminant will occur in public water systems with a frequency and at levels of public health concern, 9 2 Aldrin/ Dieldrin   February 2003 In the sole judgment of the Administrator, regulation of such contaminant presents a meaningful opportunity for health risk reduction for persons served by public water systems.

The findings for all criteria are used in making a determination to regulate a contaminant. As required by SDWA, a decision to regulate commits the EPA to publication of a Maximum Contaminant Level Goal ( MCLG) and promulgation of a National Primary Drinking Water Regulation ( NPDWR) for that contaminant. The Agency may determine that there is no need for a regulation when a contaminant fails to meet one of the criteria. A decision not to regulate a contaminant is considered a final Agency action and is subject to judicial review. The Agency can choose to publish a Health Advisory ( a nonregulatory action) or other guidance for any contaminant on the CCL independent of its regulatory determination.

9.1.2 National Drinking Water Advisory Council Recommendations In March 2000, the EPA convened a Working Group under the National Drinking Water Advisory Council ( NDWAC) to help develop an approach for making regulatory determinations. The Working Group developed a protocol for analyzing and presenting the available scientific data and recommended methods to identify and document the rationale supporting a regulatory determination decision. The NDWAC Working Group report was presented to and accepted by the entire NDWAC in July 2000.

Because of the intrinsic differences between microbial and chemical contaminants, the Working Group developed separate but similar protocols for microorganisms and chemicals. The approach for chemicals was based on an assessment of the impact of acute, chronic, and lifetime exposures, as well as a risk assessment that includes evaluation of occurrence, fate, and dose response. The NDWAC Protocol for chemicals is a semi quantitative tool for addressing each of the three CCL criteria. The NDWAC requested that the Agency use good judgement in balancing the many factors that need to be considered in making a regulatory determination.

The EPA modified the semi quantitative NDWAC suggestions for evaluating chemicals against the regulatory determination criteria and applied them in decision making. The quantitative and qualitative factors for aldrin and dieldrin that were considered for each of the three criteria are presented in the sections that follow.

9.2 Health Effects The first criterion asks if the contaminant may have an adverse effect on the health of persons. Because all chemicals have adverse effects at some level of exposure, the challenge is to define the dose at which adverse health effects are likely to occur, and estimate a dose at which adverse health effects are either not likely to occur ( threshold toxicant), or have a low probability for occurrence ( non threshold toxicant). The key elements that must be considered in evaluating the first criterion are the mode( s) of action, the critical effect( s), the dose response for critical effect( s), the RfD for threshold effects, and the slope factor for non threshold effects. 9 3 Aldrin/ Dieldrin   February 2003 A description of the health effects associated with exposures to aldrin or dieldrin is presented in Chapter 7 of this document, and is summarized below in Section 9.2.2. Chapter 8 and Section 9.2.3 present dose response information.

9.2.1 Health Criterion Conclusions The data available on aldrin and dieldrin demonstrate the capacity of both chemicals to cause a variety of adverse systemic, neurological, reproductive/ developmental, immunological, genotoxic, and/ or tumorigenic effects in humans, animals, or both. While some of these noncancer effects are observed only at moderate to relatively high doses, others have been observed to occur at doses below 0.1 mg/ kg bw/ day. The current oral RfDs for aldrin and dieldrin are 3 × 10 5 and 5 × 10 5 mg/ kg bw/ day based on hepatic effects.

Both compounds have been convincingly demonstrated to be hepatocarcinogenic in several strains of mice in multiple bioassays, although they are apparently not carcinogenic to rats and have not been convincingly associated with human cancer in any of several large epidemiology studies. Based on the mouse studies and using the linear multistage model, the cancer potency for aldrin is 17 ( mg/ kg/ day) 1, and that for dieldrin, 16 ( mg/ kg/ day) 1. For both compounds, a drinking water concentration of 0.002 :/ L would lead to an estimated lifetime excess cancer risk of 10 6.

9.2.2 Hazard Characterization and Mode of Action Implications Following acute exposure to high doses, the primary adverse health effects of aldrin and dieldrin in humans are those resulting from neurotoxicity to the central nervous system, including hyperirritability, convulsions, and coma ( Jager, 1970; Spiotta, 1951; ACGIH, 1984). In some cases, these may be followed by cardiovascular effects, such as tachycardia and elevated blood pressure ( Black, 1974). Under conditions of longer term exposure to lower doses of these compounds, neurotoxic symptoms may also include headache, dizziness, general malaise, nausea, vomiting, and muscle twitching or myoclonic jerking ( Jager, 1970; ATSDR, 2000a). Dieldrin exposure has been linked to two cases of immunohemolytic anemia ( Hamilton et al., 1978; Muirhead et al., 1959), as has aldrin/ dieldrin exposure to several instances of aplastic anemia ( de Jong, 1991; Pick et al., 1965; ATSDR, 2000a). However, at least some of these associations are problematic, and in any case, hematological or immunological ( e. g., dermal sensitization) effects have not generally been found in humans following exposure to either compound.

Common acute or subchronic neurotoxic effects observed in animals are characterized by increased irritability, salivation, hyperexcitability, tremors followed by convulsions, loss of body weight, depression, prostration, and death ( Borgmann et al., 1952; Walker et al., 1969; Wagner and Greene, 1978; Woolley et al., 1985; NCI, 1978; Casteel, 1993). These symptoms are similar to those described above for humans exposed to aldrin or dieldrin. Various manifestations of hepatotoxicity ( elevated serum enzyme levels, reduced levels of serum proteins, hyperplasia, focal degeneration, necrosis, bile duct proliferation, etc.) have been observed in animals following subchronic to chronic exposure to moderate to high concentrations of aldrin/ dieldrin 9 4 Aldrin/ Dieldrin   February 2003 ( ATSDR, 2000a). Relatively low dose, chronic exposures to either compound have been associated with histopathological liver changes in rat studies ( e. g., Fitzhugh et al., 1964; Walker et al., 1969). There is some evidence from animals that aldrin/ dieldrin exposure may either induce renal lesions or exacerbate pre existing nephropathy ( ATSDR, 2000a; Fitzhugh et al., 1964; Harr et al., 1970).

Various in vivo and in vitro studies have provided evidence that aldrin and dieldrin may be weak endocrine disruptors. Effects on male and female hormone levels and/ or receptor binding, male germ cell degeneration and interstitial testicular ( Leydig) cell ultrastructure, estrus cycle, and proliferation of endometrial and breast cells have been noted ( see Sections 7.3.3 and 7.3.4; ATSDR, 2000a). Oral administration of aldrin/ dieldrin to maternal or paternal animals has produced somewhat equivocal evidence of decreased fertility ( Dean et al., 1975; Epstein et al., 1972; Good and Ware, 1969; Harr et al., 1970; Virgo and Bellward, 1975), and intraperitoneal injection of aldrin has produced various adverse effects on the male reproductive system ( ATSDR, 2000a). In general, animal studies have provided only mixed evidence that exposures to aldrin/ dieldrin at moderate to high levels can result in adverse reproductive or developmental effects, such as reduced fertility or litter size, reduced pup survival, fetotoxicity, or teratogenicity ( Section 7.2.5).

Immunosuppression by dieldrin has been reported in a number of mouse studies: a decrease in the antigenic response to the mouse hepatitis virus 3 after a single oral dose of $ 18 mg/ kg bw ( Krzystyniak et al., 1985); an increase in the lethality of Plasmodium berghei or Leishmania tropica infections at dietary concentrations as low as 1 ppm ( 0.15 mg/ kg bw/ day) for 10 weeks ( Loose, 1982); and decreased tumor cell killing ability after dietary concentrations as low as 1 ppm ( 0.15 mg/ kg bw/ day) for 3, 6, or 18 weeks ( Loose et al., 1981).

A number of long term bioassay studies have provided evidence that aldrin and dieldrin are hepatocarcinogens in the mouse ( Davis and Fitzhugh, 1962; Davis, 1965; Song and Harville, 1964; NCI, 1978; MacDonald et al., 1972; Walker et al., 1972; Thorpe and Walker, 1973; Tennekes et al., 1982, 1981, 1979; Meierhenry et al., 1983). In one mouse study, dieldrin was also found to have induced lung, lymphoid, and " other" tumors ( Walker et al., 1972). In contrast, neither compound has been found to induce liver tumors in various strains of rat ( Treon and Cleveland, 1955; Song and Harville, 1964; Deichmann et al., 1967, 1970; Deichmann, 1974; NCI, 1978; Fitzhugh et al., 1964; Walker et al., 1969), although a number of these studies suffered from one or more serious deficiencies. The NCI ( 1978) rat study also yielded some increased incidences of thyroid follicular cell and adrenal cortex adenomas/ carcinomas following aldrin exposure, which have been considered either unrelated to treatment ( NCI, 1978; USEPA, 1993a), or suggestive of equivocal evidence of aldrin's potential carcinogenicity in the rat ( Griesemer and Cueto, 1980; Haseman et al., 1987; USEPA, 1987).

Despite some sporadic statistically significant increases in rectal or liver/ biliary cancer, occupational and epidemiology studies have failed to provide any convincing evidence for the carcinogenicity of either aldrin or dieldrin in humans ( Van Raalte, 1977; Versteeg and Jager, 1973; de Jong, 1991; de Jong et al., 1997; Ditraglia et al., 1981; Brown, 1992; Amaoteng 9 5 Aldrin/ Dieldrin   February 2003 Adjepong et al., 1995). In fact, standardized mortality ratios of exposed vs. general populations for both specific causes and all causes of death have generally been less than 1.0.

Not a great deal is known about the modes of action that may underlie the various toxic effects produced by exposure to aldrin or dieldrin. The hyperexcitability associated with these compounds' neurotoxicity has generally been thought to arise from enhancement of synaptic activity throughout the central nervous system; but whether this results from facilitated neurotransmitter release at the nerve terminals, or from reducing the activity of inhibitory neurotransmitters within the central nervous system, has been unclear ( ATSDR, 2000a). Mehrota et al. ( 1988, 1989) have proposed that dieldrin may act by inhibiting calcium dependent brain ATPases, which would inhibit the cellular efflux of calcium and result in higher intracellular calcium levels that would promote neurotransmitter release. More recent work provides significant evidence that aldrin and dieldrin's principal mode of neurotoxic action likely involves their role as antagonists for the membrane receptor for the inhibitory neurotransmitter, gamma aminobutyric acid ( GABA), and blocking the influx of chloride ion through the GABA A receptor ionophore complex ( Klaassen, 1996; Nagata and Narahashi, 1994, 1995; Nagata et al., 1994; Brannen et al., 1998; Johns et al., 1998; Liu et al., 1997, 1998). Additionally, at least one in vitro study using fetal rat brain cells suggests that dieldrin may have an even greater functional effect on dopaminergic neurons ( Sanchez Ramos et al., 1998).

As noted previously, the cumulative evidence to date ( 2001) suggests that the carcinogenic potential of aldrin and dieldrin may largely be limited to the mouse. The preponderance of evidence from the studies reviewed in this document argues against a predominant role for genotoxicity in the mode of action for these compounds' carcinogenicity ( Sections 7.3.1 and 7.4.2). This appears especially true when considering the overwhelmingly negative results for aldrin and dieldrin's ability to induce gene point mutations ( 28 negative assays, 3 positive assays). However, when considering either direct DNA damage or chromosome related interactions ( aberrations, aneuploidy, SCEs), the assay results are significantly more balanced ( 15 negative, 2 most likely negative, 11 positive, 4 " questionably" positive).

Considering " epigenetic" modes of carcinogenic action, the capacity of aldrin and dieldrin to inhibit various forms of in vitro intercellular communication in both human and animal cells may be significant with respect to their in vivo effects on tumor production ( Kurata et al., 1982; Wade et al., 1986; Zhong Xiang et al., 1986; Mikalsen and Sanner, 1993). As discussed in Section 7.4.3, a number of recent studies have provided suggestive evidence that the apparent mouse specific hepatocarcinogenic effects of aldrin/ dieldrin may result from epigenetic modes of action that involve the induction of intracellular oxidative stress ( via the generation of reactive oxygen species that result in oxidative damage to DNA, protein, and lipid macromolecules), as well as increased hepatic DNA synthesis ( Kolaja et al., 1995, 1996a, b, 1998; Bachowski et al., 1997, 1998; Stevenson et al., 1995, 1999). These effects have been found to occur after aldrin/ dieldrin treatment in mice, but not in rats. After observing the frequency and patterns of c Ha ras protooncogene mutations appearing in the DNA of glucose 6 phosphatase deficient hepatic lesions found in control mice, or in those treated with dieldrin or phenobarbital, Bauer Haufmann et al. ( 1992) were able to conclude that the increase in hepatic 9 6 Aldrin/ Dieldrin   February 2003 lesions ( and thus tumors) resulting from dieldrin treatment likely resulted primarily from promotional, rather than initiation, events. It has been postulated that aldrin/ dieldrin induction of hepatic DNA synthesis may also result from the modulation of proto oncogene expression via various transcription factors ( Stevenson et al., 1999).

The available literature did not provide direct evidence for any human subpopulations that would be particularly sensitive to the toxic effects of chronic aldrin/ dieldrin exposure, or for which relevant toxicokinetics are known to be differ significantly from those for the general population. Speculatively, the fetus and very young children might be at increased risk from exposures to aldrin/ dieldrin as a result of immature hepatic detoxification and excretion functions, as well as developing target organ systems. Some support for this is found in a single case study involving acute exposure to aldrin ( Hayes, 1982) in which a 3 year old female child died after ingesting approximately 8.2 mg/ kg, or roughly an order of magnitude less than the estimated lethal dose for an adult male. Several mechanistic studies, which describe the prenatal effects of aldrin/ dieldrin on GABA receptor malfunctions and on subsequent behavioral impairment, may suggest an increased sensitivity of children ( Brannen et al., 1998; Liu et al., 1998; Johns et al., 1998; Castro et al., 1992). Declining organ and immune functions may also render the elderly more susceptible to aldrin/ dieldrin toxicity. Additionally, it is reasonable to expect that individuals with compromised liver, immune, or neurological functions ( as a result of disease, genetic predisposition, or other toxic insult) might also display increased sensitivity to these compounds.

9.2.3 Dose Response Characterization and Implications in Risk Assessment In adult humans, the acute oral lethal dose for aldrin/ dieldrin has been estimated at approximately 70 mg/ kg bw ( Jager, 1970; ATSDR, 2000a), which is about 3 times the dose reported to have induced convulsions within 20 minutes of ingestion ( Spiotta, 1951). Oral LD 50 values in various animal species for the two compounds have been reported to range from 33 to 95 mg/ kg bw, and appear to be affected by age at the time of exposure. In rats, LD 50 values were reported as 37 mg/ kg bw for young adults, 25 mg/ kg bw for 2 week old pups, and a somewhat surprisingly high 168 mg/ kg bw for newborns ( Lu et al., 1965).

Meaningful dose response relationships have not been adequately characterized in humans for any of the toxic effects of aldrin or dieldrin. In animals, oral exposure to aldrin/ dieldrin has produced a variety of dose dependent systemic, neurological, immunological, endocrine, reproductive, developmental, genotoxic, and tumorigenic effects over a collective dose range of at least three orders of magnitude (< 0.05 to 50 mg/ kg bw), depending on the specific endpoint and the duration of exposure ( Sections 7.2 and 7.3) ( ATSDR, 2000a). Doseresponse information for some key studies is summarized below in Table 9 1. For noncancer effects, the USEPA has determined oral RfDs for both aldrin and dieldrin ( see Sections <IP_ADDRESS> and <IP_ADDRESS>) based on the most sensitive relevant toxic effects ( critical effects) that have been reported. For aldrin, the critical effect was liver toxicity observed in rats after chronic exposure to approximately 0.025 mg/ kg bw/ day, the LOAEL and lowest dose tested ( Fitzhugh et al., 1964). This dose was divided by a composite uncertainty factor of 1,000 ( to account for rat tohuman extrapolation, potentially sensitive human subpopulations, and the use of a LOAEL rather 9 7 Aldrin/ Dieldrin   February 2003 than a NOAEL) to yield an oral RfD for aldrin of 3 × 10 5 mg/ kg bw/ day. Similarly for dieldrin, a chronic rat study NOAEL for liver toxicity of approximately 0.005 mg/ kg bw/ day ( Walker et al., 1969) was divided by a composite uncertainty factor of 100 ( to account for rat to human extrapolation and potentially sensitive human subpopulations) to yield an oral RfD of 5 × 10 5 mg/ kg bw/ day.

Based on the long term mouse bioassays discussed in Sections 7.2.7 and 7.4.2 to 7.4.4, the USEPA has classified both aldrin and dieldrin as group B2 carcinogens under the current cancer guidelines ( USEPA, 1986), that is, as probable human carcinogens with little or no evidence of carcinogenicity in humans, and sufficient evidence in animals. Under the USEPA's proposed cancer risk assessment guidelines ( USEPA, 1996/ 1999), the weight of evidence indicates that aldrin and dieldrin could be classified as rodent carcinogens that are " likely to be carcinogenic to humans by the oral route of exposure, but whose carcinogenic potential by the inhalation and dermal routes of exposure cannot be determined because there are inadequate data to perform an assessment." This characterization must be tempered by the lack of evidence for significant human carcinogenicity from epidemiological studies and by the general lack of corroborative evidence for carcinogenicity in rats. Mechanistic studies performed in vitro and in vivo suggest that one or more non genotoxic modes of action may underlie or contribute to the carcinogenic potential of aldrin and dieldrin, but these effects are not completely established, nor can a role for genotoxic mechanisms confidently be eliminated based on the available data. Based on these considerations, the quantitative cancer risk assessments of aldrin and dieldrin have been conducted conservatively using the linear default model. 9 8 Aldrin/ Dieldrin   February 2003 Table 9 1. Dose Response Information from Key Studies of Aldrin and Dieldrin Toxicity Study Species No./ Sex per Group Doses mg/ kg bw/ day Duration NOAEL mg/ kg bw/ day LOAEL mg/ kg bw/ day Effects Chronic Studies S Aldrin1 Fitzhugh et al.

( 1964) Rat Osborne

Mendel 12 M 12 F 0 0.025 0.1 0.5 2.5 5.0 7.5 2 yr S 0.5 0.025 2.5 Liver histopathology Increased mortality; enlarged livers; nephritis; distended and hemorrhagic urinary bladders Chronic Studies S Dieldrin1 Walker et al. ( 1969) Rat Carworth Farm " E" 25 M 25 F 0 0.005 0.05 0.5 2 yr 0.005 0.05 0.05 0.5 Increased absolute and relative liver weights Irritability, tremors, convulsions;

CHIRL2 Cancer Bioassay Studies S Aldrin3 Davis ( 1965) 4 Mouse C 3 H 100 M 100 F 0 1.5 2 yr S 1.5 Hepatomas and hepatocellular carcinomas ( not tabulated by sex) Table 9 1 ( continued)

Study Species No./ Sex per Group Doses mg/ kg bw/ day Duration NOAEL mg/ kg bw/ day LOAEL mg/ kg bw/ day Effects 9 9 Aldrin/ Dieldrin   February 2003 NCI ( 1978) Mouse B6C3F 1 50 M 50 F 0 0.45 ( F)

0.6 ( M)

0.9 ( F)

1.2 ( M) 80 wk S 0.6 ( M) Hepatocellular carcinoma ( M); no statistically significant tumor increases were observed in ( F)

NCI ( 1978) 5 Rat Osborne

Mendel 50 M 50 F 0 1.5 3 74 wk ( M)

80 wk ( F) S 1.5 ? Suggestive/ equivocal evidence of thyroid follicular cell adenoma and carcinoma ( M/ F) and adrenal cortex adenoma ( F) at low, but not high, dose Cancer Bioassay Studies S Dieldrin3 Davis ( 1965) 4 Mouse C 3 H 100 M 100 F 0 1.5 2 yr S 1.5 Hepatomas and hepatocellular carcinomas ( not tabulated by sex) Table 9 1 ( continued)

Study Species No./ Sex per Group Doses mg/ kg bw/ day Duration NOAEL mg/ kg bw/ day LOAEL mg/ kg bw/ day Effects 9 10 Aldrin/ Dieldrin   February 2003 Walker et al. ( 1972) Mouse CF 1 125 300 M 125 300 F 30 M 30F 0 0.015 0.15 1.5 0 0.188 0.375 0.75 1.5 3 132 wk 128 wk S S 0.15 0.375 Hepatocellular carcinoma ( F), no statistically significant tumor increase was observed at low dose; [ hepatocellular carcinoma and hepatoma at high dose ( M/ F);

lung and lymphoid tumors at low and medium doses ( F)]

Hepatocellular carcinomas and/ or hepatomas ( M/ F), no statistically significant tumor increases were observed at the low dose Thorpe and Walker ( 1973) Mouse CF 1 30 45 M 30 45 F 0 1.5 110 wk S 1.5 Hepatocellular carcinomas and hepatomas ( M/ F)

NCI ( 1978) Mouse B6C3F 1 50 M 50 F 0 0.375 0.75 80 wk S 0.75 ( M) Hepatocellular carcinomas ( M);

no statistically significant tumor increases were observed at the low dose ( M) or in ( F)

Tennekes et al.

( 1981) Mouse CF 1 139 M ( total; 252 controls) 0 1.5 110 wk S 1.5 ( M) Hepatocellular carcinomas and hepatomas ( M; 2 experiments with different diets) Table 9 1 ( continued)

Study Species No./ Sex per Group Doses mg/ kg bw/ day Duration NOAEL mg/ kg bw/ day LOAEL mg/ kg bw/ day Effects 9 11 Aldrin/ Dieldrin   February 2003 Meierhenry et al.

( 1983) Mouse C57BL/ 6J Mouse C3H Mouse B6C3F 1 69 71 M 50 M 62 76 M 0 1.5 0 1.5 0 1.5 85 wk 85 wk 85 wk S S S 1.5 ( M)

1.5 ( M)

1.5 ( M) Hepatocellular carcinomas ( and hepatomas in C57BL/ 6J and B6C3F 1 strains)

1 Studies serving as the principal basis for oral RfD determinations.

2 Chlorinated hydrocarbon insecticide rodent liver.

3 Studies utilized in the derivation of cancer potency estimates.

4 As reevaluated by Reuber and reported in Epstein ( 1975).

5 This study was not used for the derivation of cancer potency estimates, but is the source of the only data that provides any evidence of aldrin/ dieldrin's tumorigenic potential in the rat. 9 12 Aldrin/ Dieldrin   February 2003 This approach has yielded geometric mean cancer potency estimates for aldrin and dieldrin of 17 and 16 ( mg/ kg bw/ day) 1, respectively ( Sections <IP_ADDRESS> and <IP_ADDRESS>). These result in drinking water unit risks of 4.9 × 10 4 per mg/ L and 4.6 × 10 4 per mg/ L, respectively. For both compounds, a drinking water concentration of 0.002 : g/ L would lead to an estimated lifetime excess cancer risk of 10 6. This concentration, 0.002 : g/ L, was selected as the Health Reference Level ( HRL) for each chemical, and was used in Chapter 4 to put into context the levels of aldrin/ dieldrin detected in drinking water.

9.3 Occurrence in Public Water Systems The second criterion asks if the contaminant is known to occur, or if there is a substantial likelihood that the contaminant will occur, in public water systems with a frequency and at levels of concern for public health. In order to address this question, the following information was considered:

° Monitoring data from public water systems ° Ambient water concentrations and releases to the environment ° Environmental fate Data on the occurrence of aldrin and dieldrin in public drinking water systems were the most important determinants in evaluating the second criterion. EPA looked at the total number of systems that reported detections of aldrin/ dieldrin, as well those that reported concentrations of aldrin/ dieldrin above an estimated drinking water health reference level ( HRL). For noncarcinogens, the estimated HRL risk level was calculated from the RfD assuming that 20% of the total exposure would come from drinking water. For carcinogens, the HRL was the 10 6 risk level. The HRLs are benchmark values that are used in evaluating the occurrence data while the risk assessments for the contaminants are being developed.

The available monitoring data, including indications of whether or not the contamination is a national or a regional problem, are included in Chapter 4 of this document and are summarized below. Additional information on production, use, and environmental fate are found in Chapters 2 and 3.

9.3.1 Occurrence Criterion Conclusions Since aldrin and dieldrin have not been used in this country since 1987, there should be no new releases to the overall environment. The analyses presented previously for aldrin and dieldrin indicate that these chemicals are detected very infrequently and at very low concentrations in drinking water. Therefore, it is unlikely that aldrin and dieldrin will occur in public water systems with any significant frequency at levels of concern for public health. 9 13 Aldrin/ Dieldrin   February 2003 9.3.2 Monitoring Data Drinking Water As more fully discussed in Chapter 4, the analyzed drinking water occurrence data for aldrin and dieldrin were collected beginning in 1993 under " Round 2" of the Safe Drinking Water Act's Unregulated Contaminant Monitoring ( UCM) Program. Monitoring ended for small public water systems ( PWSs) on January 8, 1999, and for large PWSs on January 1, 2001. Round 2 UCM data were collected from 35 " primacy entities," which included 34 states and some Native American tribal systems. However, because the data from some states were incomplete and/ or otherwise biased, and because the data were not collected within a systematic or random statistical framework, the national representativeness of the combined data set is considered problematic. In an attempt to at least partially address these concerns, a cross section of state data sets was constructed that provides a reasonable representation ( although not a truly " statistically representative" sample) of national occurrence. This was accomplished by a process of first evaluating the data sets for completeness, quality, and bias; after eliminating unusable state data, the remaining states were reevaluated for their pollution potential ( from manufacturing and population density, and from agricultural activity) and their " geographic coverage" in relation to all states. The result of this process established a " national crosssection of Round 2 states ( AK, AR, CO, KY, ME, MD, MA, MI, MN, MS, NH, NM, NC, ND, OH, OK, OR, RI, TX, and WA).

It should be noted that while MA was included in the Round 2 cross section on the basis of usable and complete data for volatile organic compounds ( VOCs) and inorganic compounds ( IOCs), it was excluded from the analysis of synthetic organic compounds like aldrin and dieldrin because of incomplete and abnormal data ( atypically high percentage of detects in a relatively small number of PWSs). Therefore, the Round 2 cross section ( R2 X) data discussed here exclude that from MA and are based on the other 19 states; selected summary statistics are shown in Table 9 2. For perspective and to provide a conservative " upper bound" analysis of aldrin/ dieldrin occurrence in drinking water, certain summary statistics and national extrapolations based on all reporting Round 2 states ( i. e., " R2 ARS" data) are presented here and in Chapter 4.

The data indicate that both compounds are only infrequently detected in PWSs and only at very low concentrations. Because the HRL ( 0.002 : g/ L) is below all of the states Minimum Reporting Levels ( MRLs), any sample detect is also greater than the HRL and ½ HRL levels; thus, summary occurrence statistics are all the same, whether based on the MRL, HRL, or ½ HRL. Aldrin was detected in 0.016% of the R2 X PWSs at concentrations $ the HRL, which yields a national extrapolation of 11 PWSs serving 39,000 people. Although excluded from the Round 2 cross section, states with positively biased detect statistics ( e. g., AL) nonetheless represent real detections of aldrin in drinking water that are not adequately accounted for by R2 X data extrapolation. As a consequence, R2 X data extrapolation clearly underestimates the national occurrence of aldrin in PWSs. To provide a more conservative estimate, one which is likely an overestimate of national occurrence, R2 ARS data may be used for extrapolation. In 9 14 Aldrin/ Dieldrin   February 2003 this case, an R2 ARS PWS detection rate of 0.212% extrapolates nationally to 138 PWSs having aldrin concentrations $ the HRL, and serving 1,052,000 people.

Table 9 2. Selected Summary Statistics for Occurrence of Aldrin and Dieldrin in Drinking Water Parameter Round 2 Cross Section ( 19 States) 1 Round 2 Reporting States2 Aldrin Total samples 31,083 41,565 Percent of samples with detections 0.006% 0.132%

Median concentration ( all samples) <( Non detect) <( Non detect)

99th Percentile concentration ( all samples) <( Non detect) <( Non detect)

Median concentration ( detections only) 0.58 : g/ L 0.18 : g/ L 99th Percentile concentration ( detections only) 0.69 : g/ L 4.40 : g/ L Minimum Reporting Level ( MRL) variable variable Draft Health Reference Level ( HRL) 0.002 : g/ L 0.002 : g/ L Percent of PWSs with detections > MRL 0.016% 0.212%

Percent of PWSs with detections >( 1/ 2 HRL) 0.016% 0.212%

Percent of PWSs with detections > HRL 0.016% 0.212%

Dieldrin Total samples 29,603 40,055 Percent of samples with detections 0.064% 0.135%

Median concentration ( all samples) <( Non detect) <( Non detect)

99th Percentile concentration ( all samples) <( Non detect) <( Non detect)

Median concentration ( detections only) 0.16 : g/ L 0.42 : g/ L 99th Percentile concentration ( detections only) 1.36 : g/ L 4.40 : g/ L Minimum Reporting Level ( MRL) variable variable Draft Health Reference Level ( HRL) 0.002 : g/ L 0.002 : g/ L Percent of PWSs with detections > MRL 0.093% 0.211%

Percent of PWSs with detections >( 1/ 2 HRL) 0.093% 0.211%

Percent of PWSs with detections > HRL 0.093% 0.211%

1Based on data from the 20 State Cross Section, minus MA ( SDWIS/ FED, UCM Round 2, 1993). 2Based on data from all reporting states ( SDWIS/ FED, UCM Round 2, 1993). Source: Data taken from Tables 4 2 and 4 5 in Section 4.0 of this document. Abbreviations: HRL = Health Reference Level; MRL = Minimum Reporting Level; PWS = Public Water System. 9 15 Aldrin/ Dieldrin   February 2003 Although only five states ( AL, MA, NM, PA, TX) reported detecting aldrin in any of their PWSs, their distribution is sufficiently broad to categorize aldrin's drinking water occurrence as national in scope, rather than just regional or local. This conclusion is further supported by the observations that aldrin has been detected at NPL sites in at least 31 states, and at least in 40 states at sites listed in ATSDR's HazDat database. Independent analysis of data from the corn belt states of Iowa, Indiana, and Illinois revealed that aldrin was not detected in any surface or ground water PWS in Iowa or Indiana, or in any ground water PWS in Illinois. It was, however, detected in 1.8% of Illinois' surface water PWSs.

Similarly, dieldrin was detected in 0.093% of the R2 X PWSs at concentrations $ the HRL, which yields a national extrapolation of 61 PWSs serving 150,000 people. As with aldrin, a more conservative estimate ( a likely overestimate) of national dieldrin occurrence in drinking water may be derived using R2 ARS data for extrapolation. In this case, an R2 ARS PWS detection rate of 0.211% extrapolates nationally to 137 PWSs with dieldrin concentrations $ the HRL, serving 793,000 people.

Again, although only eight states ( AL, AR, CT, MA, MD, NC, PA, TX) reported detecting dieldrin in any of their PWSs, their distribution is sufficiently broad to categorize dieldrin's drinking water occurrence as national in scope, rather than just regional or local. This conclusion is further supported by the observation that dieldrin has been detected at NPL sites in at least 31 states and at least in 40 states at sites listed in ATSDR's HazDat ( ATSDR, 2000b) database. Independent analysis of data from the corn belt states of Iowa, Indiana, and Illinois revealed that dieldrin was not detected in any surface or ground water PWS in Iowa, or in any ground water PWS in Illinois or Indiana. It was, however, detected in 1.8% of Illinois' and 2.1% of Indiana's surface water PWSs.

Ambient Water In the context of drinking water, " ambient water" may be defined as source water that exists in surface waters and aquifers before treatment ( Chapter 4). The U. S. Geological Survey's ( USGS's) National Ambient Water Quality Assessment ( NAWQA) Program, which began in 1991, provides the most comprehensive and nationally representative data available that describe ambient water quality. Unfortunately, aldrin was not selected as an analyte for either the NAWQA's ground water or surface water studies. However, the NAWQA did analyze for aldrin in aquatic biota tissue and stream bed sediments at 591 sites from 20 of its 59 " study units" ( i. e., significant watersheds and aquifers) during the period from 1992 to 1995. While aldrin was not detected in any aquatic biota tissue samples, it was detected above the Method Detection Limit ( MDL) of 1 mg/ kg in 0.4% of all sites ( urban = 0.0%, mixed land use = 0.5%, agricultural = 0.6%, forest rangeland = 0.0%). Additionally, a mid 1980s survey of community water supply wells in Illinois detected aldrin in only 0.3% of the wells, using an MRL of 0.004 mg/ L.

In contrast to aldrin, dieldrin was selected as an NAWQA analyte for both surface and ground water studies during the first round of intensive monitoring ( 1991 to 1996), which targeted 20 study unit watersheds. Dieldrin detection frequencies at two MDLs ( 0.001 mg/ L; 0.01 mg/ L) were as follows for stream surface waters: urban ( 3.67%; 1.83%), integrator ( 3.27%; 9 16 Aldrin/ Dieldrin   February 2003 1.63%), agricultural ( 6.90%; 3.90%), and total sites ( 4.64%; 2.39%). For ground water sources, the comparable data were: shallow urban ( 5.65%; 3.32%), shallow agricultural ( 0.97%; 0.65%), major aquifers ( 0.43%; 0.21%), and total sites ( 1.42%; 0.93%). As with aldrin, the NAWQA program also analyzed for dieldrin in aquatic biota tissue and stream bed sediments at 591 sites from 20 of its 59 " study units" during the period from 1992 to 1995. It was detected at levels above the MDL of 1 mg/ kg in 13.7% of the sediments from all sites, and at levels above the MDL of 5 mg/ kg in 28.6% of whole fish samples and in 6.4% of bivalve samples. Additionally, a 1991 to 1992 survey of surface waters from the Mississippi River and six of its tributaries that drain the corn belt reported 8% of all samples and 71% of all sites registered detections above the MRL of 0.02 mg/ L.

9.3.3 Use and Fate Data Both aldrin and dieldrin are SOC pesticides that were at one time extensively used in a wide variety of agricultural and residential/ urban pest control applications ( Chapters 2 and 4). They were manufactured and distributed in the United States by the Shell Chemical Company until 1974. From 1974 through 1985 ( except 1979 to 1980), Shell International ( Holland) imported lesser amounts ( e. g., 1 to 1.5 million lb/ year from 1981 to 1985). Importation information for dieldrin was not available. In 1972, the USEPA cancelled all but three specific uses of these compounds ( subsurface ground insertion for termite control, dipping of non food plant roots and tops, and moth proofing in manufacturing processes using completely closed systems). This decision was finalized in 1974, and by 1987 these remaining uses were voluntarily cancelled by the manufacturer.

Use of aldrin in the U. S. peaked at 19,000,000 lbs in 1966, decreasing to 10,500,000 lbs by 1970; during the same period, dieldrin use declined from 1,000,000 to 670,000 lbs ( ATSDR, 2000a). By the time the Toxic Release Inventory ( TRI) was mandated in 1986 by the Emergency Planning and Community Right to Know Act ( EPCRA) and then subsequently implemented, the manufacture, import, and use of aldrin/ dieldrin had been cancelled. The EPCRA mandates that facilities with more than 10 full time employees that manufacture/ import more than 25,000 lbs, or use more than 10,000 lbs, of a TRI chemical are required to report the lb/ year of the chemical that were released to the environment, both on site and off site. It was not until 1995 that hazardous waste treatment and disposal facilities were added to the list of those required to report TRI data. In 1998, the first year for which this requirement became effective, hazardous waste facilities in three states ( AR, MI, TX) reported releases of aldrin totaling 25,622 lbs. No such releases of dieldrin were reported.

The environmental fate of aldrin and dieldrin is extensively summarized in Chapter 3. Briefly, under most environmental conditions, aldrin is largely converted biologically or abiotically to dieldrin, which is significantly more environmentally stable. Most of these compounds are released to the environment via the soil, where relatively high log K ow and K oc are indicative of their low water solubility and strong affinity for adsorption to soil. Over time, significant quantities may volatilize to the atmosphere or be carried aloft by wind born particles, where they are subject to certain photodegradation processes and/ or subsequent " washout" in rainfall. Because of their low water solubilities and strong soil adsorption tendencies, aldrin and 9 17 Aldrin/ Dieldrin   February 2003 dieldrin slowly migrate downward through the soil or enter surface or ground water. Most aldrin/ dieldrin found in surface water is thought to result from particulate surface run off ( the compounds being bound to soil particles). In summary, these characteristics will tend to maintain relatively low levels of water contamination over relatively prolonged periods of time.

Obviously, neither compound is used as a drinking water treatment chemical, nor is either likely to be a leachate from drinking water contact surfaces. However, it is not unreasonable to expect that they may co occur in drinking water with each other, as well as with certain other persistent pesticides; in such cases, additive or synergistic toxic effects may be possible.

9.4 Risk Reduction The third criterion asks if, in the sole judgment of the Administrator, regulation presents a meaningful opportunity for health risk reduction for persons served by public water systems. In evaluating this criterion, EPA looked at the total exposed population, as well as the population exposed above the estimated HRL. Estimates of the populations exposed and the levels to which they are exposed were derived from the monitoring results. These estimates are included in Chapter 4 of this document and are summarized in Section 9.4.2.

In order to evaluate risk from exposure through drinking water, EPA considered the net environmental exposure in comparison to the exposure through drinking water. For example, if exposure to a contaminant occurs primarily through ambient air, regulation of emissions to air provides a more meaningful opportunity for EPA to reduce risk than regulation of the contaminant in drinking water. In making the preliminary regulatory determination, the available information on exposure through drinking water ( Chapter 4) and information on exposure through other media ( Chapter 5) were used to estimate the fraction that drinking water contributes to the total exposure. The EPA findings are discussed in Section 9.4.3.

In making its preliminary regulatory determination, EPA also evaluated effects on potential sensitive populations, including the fetus, infants, and children. The sensitive population considerations are included in Section 9.4.4.

9.4.1 Risk Criterion Conclusions The data discussed in this section and Section 9.3.3 indicate that there is not a substantial likelihood that aldrin and dieldrin will occur in public water systems with frequencies and at levels of concern for public health.

9.4.2 Exposed Population Estimates As noted previously, because the HRL of 0.002 mg/ L for these compounds is below the MRL, any recorded detection will be above all three reference levels ( MRL, HRL, ½ HRL). Therefore, estimates of the national population exposed to concentrations greater than any of these levels will be equivalent. Summary data for exposed population estimates are provided below in Table 9 3. 9 18 Aldrin/ Dieldrin   February 2003 It must be remembered that the complete R2 ARS based estimates are very conservative in nature, in that they are derived from a collective database that includes incomplete and biased state data sets, and because only a single detection is sufficient to classify a PWS as " positive" S these factors will tend to significantly overestimate the true sizes of the exposed populations. On the other hand, using data only from the Round 2 cross section ( from 19 states, the R2 X based estimates), which have been screened to remove incomplete, biased, and otherwise unusable data and then selected to geographically represent the entire nation, is less likely to overestimate and may even underestimate to some extent the potentially exposed national populations.

For aldrin, the median and 99th percentile concentrations of detections based on all Round 2 UCM data were 0.18 and 4.40 : g/ L, respectively. Based only on the 19 state Round 2 crosssection data, the corresponding values are 0.58 and 0.69 : g/ L. The respective two sets of values for dieldrin are 0.42 and 4.40 : g/ L, and 0.16 and 1.36 : g/ L. While these values are above the HRL of 0.002 : g/ L, it must also be kept in mind that the corresponding values for all samples were below the detection limit, and that the HRL itself is likely a very conservative estimate of any human risk resulting from exposure to these chemicals.

Table 9 3. National Population Estimates for Aldrin and Dieldrin Exposure via Drinking Water Population of Concern Round 2 Cross Section ( 19 States) 1 Round 2 Reporting States2 Aldrin Served by PWS with detections 38,871 1,051,989 Served by PWSs with detections > ( 1/ 2 HRL) 38,871 1,051,989 Served by PWSs with detections > HRL 38,871 1,051,989 Dieldrin Served by PWS with detections 149,827 792,703 Served by PWSs with detections > ( 1/ 2 HRL) 149,827 792,703 Served by PWSs with detections > HRL 149,827 792,703 1Based on data from the 20 State Cross Section, minus MA ( SDWIS/ FED, UCM Round 2, 1993). 2Based on data from all reporting states ( SDWIS/ FED, UCM Round 2, 1993). Source: Data taken from Tables 4 2 and 4 5 in Section 4.0 of this document. Abbreviations: HRL = Health Reference Level; PWS = Public Water System. 9 19 Aldrin/ Dieldrin   February 2003 9.4.3 Relative Source Contribution Analysis of relative source contribution compares the magnitude of exposures ( i. e., intakes) expected via consumption of drinking water with those estimated for other relevant media such as food, air, and soil. The data summarized in Chapter 4.0 provide the basis for estimating the amounts of aldrin and dieldrin ingested via drinking water in exposed populations. For this exercise, the non conservative approach was taken by utilizing the median and 99th percentile detect concentrations derived from only UCM Round 2 cross section data ( realizing that this will certainly underestimate to some degree the true contribution of drinking water to the exposed population's total intake of aldrin/ dieldrin).

For a 70 kg adult consuming 2 L/ day of water containing aldrin at either 0.58 : g/ L ( median detect concentration) or 0.69 : g/ L ( 99th percentile detect concentration), the corresponding aldrin intake values from drinking water are 1.7 × 10 5 and 2.0 × 10 5 mg/ kg bw/ day, respectively. For a 10 kg child consuming 1 L/ day of water, the comparable values are 5.8 × 10 5 and 6.9 × 10 5 mg/ kg bw/ day.

Similarly, for median and 99th percentile detect concentrations of dieldrin ( 0.16 and 1.36 : g/ L, respectively), the corresponding adult drinking water intake values of dieldrin are 0.46 × 10 5 and 3.9 × 10 5 mg/ kg bw/ day, respectively. Dieldrin drinking water intake values for the 10 kg child are 1.6 × 10 5 and 14 × 10 5 mg/ kg bw/ day.

Chapter 5 presents data on the estimated daily dietary intake of aldrin and dieldrin ( see Tables 5 3 and 5 4). Combining estimates for non fish food with those for fish and shellfish, adult and child dietary intakes of aldrin are estimated at 3.3 to 6.5 × 10 5 and 13 to 18 × 10 5 mg/ kg bw/ day, respectively. For dieldrin, the comparable adult and child dietary intakes are 3.6 × 10 5 and 14 × 10 5 mg/ kg bw/ day.

Comparing these derived estimates for intakes via drinking water and diet, the ratios of dietary intake to drinking water intake for aldrin range from 1.7 to 3.8 across all combinations of age and drinking water concentration level. For dieldrin, the food/ water intake ratios for adults and children are 0.9 and 1.0 using the 99th percentile water concentration, and 7.8 and 8.8 using the median water concentration. Applying the more " conservative" aldrin/ dieldrin water concentrations based on the monitoring data of all reporting UCM Round 2 states would reduce all of these food/ water ratios by a factor of approximately 3 to 6. Thus, when conservatively analyzed relative to the diet, drinking water could potentially be responsible for a significant portion of total daily intake of aldrin/ dieldrin, but only for limited populations under exposure circumstances that are considered unlikely.

Referring again to Tables 5 3 and 5 4, it can be seen that the estimated daily intakes of aldrin and dieldrin from air for adults and children range from 0.013 × 10 5 to 0.24 × 10 5 mg/ kg bw/ day. Despite the fact that these values are likely significant overestimates since they are based on data that is 30 years old, they are still small relative to drinking water and dietary intakes. Although soil data were not available for aldrin, those for dieldrin indicate that ingestion of soil represents only a minor exposure pathway for these compounds. 9 20 Aldrin/ Dieldrin   February 2003 9.4.4 Sensitive Populations The issue of sensitive populations has already been addressed to the extent currently possible. While there is some reasonable basis to suspect that fetuses, young children, the elderly, and those having compromised liver, immune, or even neurological function may be at increased risk for one or more of the toxic effects of aldrin/ dieldrin, such susceptibility has not yet been convincingly demonstrated or adequately quantified in the scientific literature.

9.5 Regulatory Determination Summary While there is evidence that aldrin/ dieldrin may have adverse health effects, including the probability to cause cancer in humans,. neither contaminant has been used in the US since 1987. Furthermore, monitoring data indicate that the contaminants' concentrations have been declining since the cancellation of their registrations as pesticides. Their occurrences in public water systems have also been very limited and at very low concentrations. For these reasons, regulation of aldrin and dieldrin may not present a meaningful opportunity for health risk reduction for persons served by public water systems. Therefore, EPA may not propose to regulate aldrin/ dieldrin with NPDWRs. All final determinations and future analysis will be presented in the Federal Register Notice covering CCL proposals. 9 21 Aldrin/ Dieldrin   February 2003 References ACGIH. 1984. American Conference of Governmental Industrial Hygienists. Documentation of the threshold limit values for substances in workroom air. 3rd ed. Cincinnati, OH: ACGIH, p. 139 ( as cited in USEPA, 1988).

Amaoteng Adjepong, Y., N. Sathiakumar, E. Delzell and P. Cole. 1995. Mortality among workers at a pesticide manufacturing plant. J. Occup. Environ. Med. 37: 471 478 ( as cited in Stevenson et al., 1999).

ATSDR. 2000a. 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.

ATSDR. 2000b. Agency for Toxic Substances and Disease Registry. Hazardous Substance Release and Health Effects Database. Available on the Internet at: http:// www. atsdr. cdc. gov/ hazdat. htm. Last modified August 19, 2000.

Bachowski, S., K. L. Kolaja, Y. Xu, C. A. Ketcham, D. E. Stevenson, E. F. Walborg, Jr., and J. E. Klaunig. 1997. Role of oxidative stress in the mechanism of dieldrin's hepatotoxicity. Ann. Clin. Lab. Sci. 27: 196 209.

Bauer Hofmann, R., A. Buchmann, J. Mahr, S. Kress, and M. Schwarz. 1992. The tumour promoters dieldrin and phenobarbital increase the frequency of c Ha ras wild type, but not of c Ha ras mutated focal liver lesions in male C3H/ He mice. Carcinogenesis 13: 477 481.

Black A. M. S. 1974. Self poisoning with dieldrin: A case report and pharmacokinetic discussion. Anesth. Intensive Care 2: 369 374 ( as cited in ATSDR, 2000a).

Borgmann, A. R., C. H. Kitselman, P. A. Dahm, J. E. Pankaskie and F. R. Dutra. Kansas State College. 1952. Toxicological studies of dieldrin on small laboratory animals. Unpublished report. July. ( as cited in USEPA, 1992).

Brannen, K. C., L. L. Devaud, J. Liu, and J. M. and Lauder. 1998. Prenatal exposure to neurotoxicants dieldrin or lindane alters tert butylbicyclophosphorothionate binding to GABA( A) receptors in fetal rat brainstem. Dev. Neurosci. 20: 34 41.

Brown, D. P. 1992. Mortality of workers employed at organochlorine pesticide manufacturing plants an update. Scand. J. Environ. Health 18: 155 161 ( as cited in Stevenson et al., 1999).

Casteel, S. W., F. T. Satalowich, J. D. Kendall, G. E. Rottinghaus, H. S. Gosser, and N. R. Schneider. 1993. Aldrin intoxication and clearance of associated dieldrin residues in a group of feedlot cattle. J. Am. Vet. Med. Assoc. 202: 83 85. 9 22 Aldrin/ Dieldrin   February 2003 Castro, V. L., M. M. Bernardi, and J. Palermo Neto. 1992. Evaluation of prenatal aldrin intoxication in rats. Arch. Toxicol. 66: 149 152.

Davis, K. J. 1965. Pathology report on mice fed aldrin, dieldrin, heptachlor or heptachlor epoxide for two years. Internal FDA memorandum to Dr. A. J. Lehman. FDA. July 19. ( as cited in USEPA, 1987, 1992, 1993a, 1993b).

Davis, K. J. and O. G. Fitzhugh. 1962. Tumorigenic potential of aldrin and dieldrin for mice. Toxicol. Appl. Pharmacol. 4: 187 189 ( as cited in USEPA, 1987, 1992, 1993a, 1993b).

de Jong, G., G. M. Swaen and J. J. Slangen. 1997. Mortality of workers exposed to dieldrin and aldrin: a retrospective cohort study. Occup. Environ. Med. 54: 702 707.

de Jong, G. 1991. Long term health effects of aldrin and dieldrin. A study of exposure, health effects and mortality of workers engaged in the manufacture and formulation of the insecticides aldrin and dieldrin. Toxicol. Lett. Suppl. 1 206 ( as cited in Stevenson et al., 1999).

Dean, B. J., S. M. A. Doak and H. Somerville. 1975. The potential mutagenicity of dieldrin ( HOED) in mammals. Food Cosmet. Toxicol. 13: 317 323 ( as cited in ATSDR, 2000a; GAP2000, 2000b).

Deichmann, W. B. 1974. Statement of testimony for aldrin/ dieldrin hearings suspension phase, before the U. S. Environmental Protection Agency, August 23, 1974 ( as cited in USEPA, 1987).

Deichmann, W. B., W. E. MacDonald, E. Blum, M. Bevilacqua, J. Radomski, M. Keplinger and M. Balkus. 1970. Tumorigenicity of aldrin, dieldrin and endrin in the albino rat. Ind. Med. Surg. 39( 10): 426 434 ( as cited in USEPA, 1987, 1992, 1993a, 1993b).

Deichmann, W. B., M. Keplinger, F. Sala, and E. Glass. 1967. Synergism among oral carcinogens in the simultaneous feeding of four tumorigens to rats. Toxicol. Appl. Pharmacol. 11: 88 103 ( as cited in USEPA, 1987).

Ditraglia, D., D. P. Brown, T. Namekata, and N. Iverson. 1981. Mortality study of workers employed at organochlorine pesticide manufacturing plants. Scand. J. Work. Environ. Health. 4: 140 146 ( as cited in Stevenson et al., 1999).

Epstein, S. S., E. Arnold, J. Andrea, W. Bass, and Y. Bishop. 1972. Detection of chemical mutagens by the dominant lethal assay in the mouse. Toxicol Appl. Pharmacol 23: 288 325 ( as cited in ATSDR, 2000a; GAP2000, 2000a, b).

Epstein, S. S. 1975. The carcinogenicity of dieldrin. Part 1. Sci. Total Environ. 4: 1 52 ( as cited in USEPA 1993b).

Fitzhugh, O. G., A. A. Nelson, and M. L. Quaife. 1964. Chronic oral toxicity of aldrin and dieldrin in rats and dogs. Food Cosmet. Toxicol. 2: 551 562. 9 23 Aldrin/ Dieldrin   February 2003 GAP2000. 2000a. Genetic Activity Profiles ( program version 1.3.0, file version <IP_ADDRESS>), data record for aldrin. Database and software are a joint effort of the U. S. Environmental Protection Agency and the International Agency for Research on Cancer. Lohman, P. H. M. and W. J. A. Lohman, authors. Downloaded from http:// www. epa. gov/ gapdb on January 19, 2001.

GAP2000. 2000b. Genetic Activity Profiles ( program version 1.3.0, file version <IP_ADDRESS>), data record for dieldrin. Database and software are a joint effort of the U. S. Environmental Protection Agency and the International Agency for Research on Cancer. Lohman, P. H. M. and W. J. A. Lohman, authors. Downloaded from http:// www. epa. gov/ gapdb on January 19, 2001.

Good, E. E. and G. W. Ware. 1969. Effects of insecticides on reproduction in the laboratory mouse. IV. Endrin and dieldrin. Toxicol Appl Pharmacol. 14: 201 203 ( as cited in ATSDR, 2000a; IPCS, 1989).

Griesemer, R. A. and C. Cueto, Jr. 1980. Toward a classification scheme for degrees of experimental evidence for the carcinogenicity of chemicals for animals. In: Montesano, R., H. Bartsch and L. Tomatis, eds. Molecular and cellular aspects of carcinogen screening tests. IARC Scientific Publications No. 27. Lyon, France: International Agency for Research on Cancer, pp. 259 281.

Hamilton, H. E., D. P. Morgan, and A. Simmons. 1978. A pesticide ( dieldrin) induced immunohemolytic anemia. Environ. Res. 17: 155 164 ( as cited in USEPA, 1992).

Harr J. R., R. R. Claeys, J. F. Bone, and T. W. McCorde. 1970. Dieldrin toxicosis: Rat reproduction. Am. J. Vet. Res. 31: 181 189 ( as cited in ATSDR, 2000a; IPCS, 1989; USEPA, 1987).

Haseman, J. K., J. E. Huff, E. Zeiger, and E. E. McConnell. 1987. Comparative results of 327 chemical carcinogenicity studies. Environ. Health Perspect. 74: 229 235.

IARC. 1974. International Agency for Research on Cancer. Evaluation of the carcinogenic risk of chemicals to humans. Aldrin. Lyon, France: IARC Monograph 5: 25 38.

IPCS. 1989. International Programme on Chemical Safety. Aldrin and dieldrin. Environmental health criteria 91. Geneva, Switzerland: World Health Organization, IPCS.

Jager, K. W. 1970. Aldrin, dieldrin, endrin and telodrin: an epidemiological and toxicological study of long term occupational exposure. Amsterdam, London, New York: Elsevier Publishing Company, 234 p ( as cited in IARC, 1974; IPCS, 1989; USEPA, 1980).

Johns, J. M., J. Liu, N. Bhasin, D. R. Grayson, L. L. Devaud, S. Moy, D. Lubin, and J. M. Lauder. 1998. Prenatal exposure to organochlorine pesticide dieldrin: Effects of postnatal expression of GABA A receptors and behavior in the rat. Society of Neuroscience. 24( Pt 1): 101 ( Abstract). 9 24 Aldrin/ Dieldrin   February 2003 Klaassen, C. D. 1996. Casarett & Doull's Toxicology. The Basic Science of Poisons. Toxic effects of Pesticides. Fifth Edition. McGraw Hill. C. D. Klaassen, M. O. Amdur, J. Doull ( Editors). p. 652 653.

Kolaja, K. L., Y. Xu, E. F. Walborg, Jr., D. E. Stevenson, and J. E. Klaunig. 1998. Vitamin E modulation of dieldrin induced hepatic focal lesion growth in mice. J. Toxicol. Environ. Health 53: 479 492.

Kolaja, K. L., D. E. Stevenson, J. T. Johnson, E. F. Walborg, Jr., and J. E. Klaunig. 1996a. Subchronic effects of dieldrin and phenobarbital on hepatic DNA synthesis in mice and rats. Fundam. Appl. Toxicol. 29: 219 228.

Kolaja, K. L., D. E. Stevenson, E. F. Walborg, Jr., and J. E. Klaunig. 1996b. Selective dieldrin promotion of hepatic focal lesions in mice. Carcinogenesis 17: 1243 1250.

Kolaja, K. L., D. E. Stevenson, J. T. Johnson, E. F. Walborg, Jr., and J. E. Klaunig. 1995. Hepatic effects of dieldrin and phenobarbital in male B6C3F 1 mice and Fisher 344 rats: species selective induction of DNA synthesis. Prog. Clin. Biol. Res. 391: 397 408.

Krzystyniak, K., P. Hugo, D. Flipo, and M. Fournier. 1985. Increased susceptibility to mouse hepatitis virus 3 of peritoneal macrophages exposed to dieldrin. Toxicol. Appl. Pharmacol. 80: 397 408 ( as cited in ATSDR, 2000a).

Kurata, M., K. Hirose, and M. Umeda. 1982. Inhibition of metabolic cooperation in Chinese hamster cells by organochlorine pesticides. Jpn. J. Cancer Res. 73: 217 221 ( as cited in GAP2000, 2000a, b).

Liu, J., K. C. Brannen, D. R. Grayson, A. L. Morrow, L. L. Devaud, and J. M. Lauder. 1998. Prenatal exposure to the pesticide dieldrin or the GABA A receptor antagonist bicuculline differentially alters expression of GABA A receptor subunit mRNAs in fetal rat brainstem. Dev. Neurosci. 20: 83 92.

Liu, J. A. L. Morrow, L. L. Devaud, D. R. Grayson, and J. M. Lauder. 1997. Regulation of GABA A receptor subunit mRNA expression by the pesticide dieldrin in embryonic brainstem cultures: A quantitative competitive reverse transcription Polymerase chain reaction study. J. Neurosci. Res. 49: 645 653.

Loose, L. D. 1982. Macrophage induction of T suppressor cells in pesticide exposed and protozoan infected mice. Environ Health Perspect. 43: 89 97 ( as cited in ATSDR, 2000a; IPCS, 1989).

Loose L. D., J. B. Silkworth , T. Charbonneau, and F. Blumenstock. 1981. Environmental chemical induced macrophage dysfunction. Environ. Health Perspect. 39: 79 92 ( as cited in ATSDR, 2000a; IPCS, 1989). 9 25 Aldrin/ Dieldrin   February 2003 Lu, F. C., D. C. Jessup, and A. Lavallee. 1965. Toxicity of pesticide in young versus adult rats. Food Cosmet. Toxicol. 3: 591 596 ( as cited in ATSDR, 2000; IPCS, 1989b).

MacDonald, W. E., W. A. D. Anderson, M. Bevilacqua, E. Blum, and W. B. Deichmann, unpublished. 1972. The tumorigenicity of dieldrin in the Swiss Webster mouse ( as cited in USEPA, 1987, citing Epstein, 1975).

Mehrotra, B. D., K. S. Moorthy, S. R. Reddy, and D. Desaiah. 1989. Effects of cyclodiene compounds on calcium pump activity in rat brain and heart. Toxicology 54: 17 30 ( as cited in ATSDR, 2000a).

Mehrotra, B. D., S. R. Reddy and D. Desaiah. 1988. Effect of subchronic dieldrin treatment on calmodulin regulated Ca++ pump activity in rat brain. J. Toxicol. Environ. Health. 25: 461 469 ( as cited in ATSDR, 2000a).

Meierhenry, E. F., B. H. Reuber, M. E. Gershwin, L. S. Hsieh, and S. W. French. 1983. Deildrin induced mallory bodies in hepatic tumors of mice of different strains. Hepatology 3: 90 95 ( as cited in USEPA, 1987, 1993b).

Mikalsen, S. O. and T. Sanner. 1993. Intercellular communication in colonies of Syrian hamster embryo cells and the susceptibility for morphological transformation. Carcinogenesis 14: 251 257 ( as cited in GAP2000, 2000b).

Muirhead, E. E, M. Groves, R. Guy et al. 1959. Acquired hemolytic anemia, exposure to insecticides and positive Coombs test dependent on insecticide preparations. Vox Sang 4: 277 292 ( as cited in ATSDR, 2000a).

Nagata, K. and T. Narahashi. 1995. Multiple actions of dieldrin and lindane on the GABA A receptor chloride channel complex of rat dorsal root ganglion neurons. Pestic. Sci. 44: 1 7.

Nagata, K., B. J. Hamilton, D. B. Carter, and T. Narahashi. 1994. Selective effects of dieldrin on the GABA A receptor channel subunits expressed in human embryonic kidney cells. Brain Res. 645: 19 26.

Nagata, K. and T. Narahashi. 1994. Dual action of the cyclodiene insecticide dieldrin on the gamma aminobutyric acid receptor chloride channel complex of rat dorsal root ganglion neurons. J. Pharmacol. Exp. Ther. 269: 164 171.

NCI. 1978. National Cancer Institute. Bioassays of aldrin and dieldrin for possible carcinogenicity. DHEW Publication No. ( NIH) 78 821 and 78 822. National Cancer Institute Carcinogenesis Technical Report Series, No. 21 and 22. NCI CG TR 21, NCI CG TR 22 ( as cited in ATSDR, 2000a; IPCS, 1989; USEPA, 1993a, 1993b, 1992, 1988, 1987).

Pick A., H. Joshua, M. Leffkowitz, et al. 1965. [ Aplastic anemia following exposure to aldrin.] Medicine 68: 164 167. ( Hebrew) ( as cited in ATSDR, 2000a). 9 26 Aldrin/ Dieldrin   February 2003 Sanchez Ramos, J., A. Facca, A. Basit, and S. Song. 1998. Toxicity of dieldrin for dopaminergic neurons in mesencephalic cultures. Exp. Neurol. 150: 263 271.

Song, J. and W. E. Harville. 1964. Carcinogenicity of aldrin and dieldrin in mouse and rat liver. Fed. Proc. Fed. Am. Soc. Exp. Biol. 23: 336 ( as cited in USEPA, 1987, 1993b).

Spiotta, E. J. 1951. Aldrin poisoning in man. Arch. Ind. Hyg. Occup. Med. 4: 560 566 ( as cited in USEPA, 1992).

Stevenson, D. E., E. F. Walborg, Jr., D. W. North, R. L. Sielken, Jr., C. E. Ross, A. S. Wright, Y. Xu, L. M. Kamendulis, and J. E. Klaunig. 1999. Monograph: Reassessment of human cancer risk of aldrin/ dieldrin. Toxicol. Lett. 109: 123 186.

Stevenson, D. E., J. P Kehrer, K. L. Kolaja, E. F. Walborg, Jr., and J. E. Klaunig. 1995. Effect of dietary antioxidants on dieldrin induced hepatotoxicity in mice. Toxicol. Lett. 75: 177 183.

Tennekes, H. A., L., Edler, and H. W. Kunz. 1982. Dose response analysis of the enhancement of liver tumor formation in CF 1 mice by dieldrin. Carcinogenesis 3: 941 945 ( as cited in USEPA, 1987).

Tennekes, H. A., A. S. Wright, K. M. Dix, and J. H. Koeman. 1981. Effects of dieldrin, diet, and bedding on enzyme function and tumor incidence in livers of male CF 1 mice. Cancer Res. 41: 3615 3620 ( as cited in USEPA, 1993b).

Tennekes, H. A., A. S. Wright, and K. M. Dix. 1979. The effects of dieldrin, diet, and other environmental components on enzyme function and tumor incidence in livers of CF 1 mice. Arch. Toxicol. 2: 197 212 ( as cited in USEPA, 1987).

Thorpe, E. and A. I. T. Walker. 1973. The toxicology of dieldrin ( HEOD). Part II. Comparative long term oral toxicology studies in mice with dieldrin, DDT, phenobarbitone, beta BHC and gamma BHC. Food Cosmet. Toxicol. 11: 433 441 ( as cited in USEPA, 1987, 1993b).

Treon, J. F. and F. P. Cleveland. 1955. Toxicity of certain chlorinated hydrocarbon insecticides for laboratory animals, with special reference to aldrin and dieldrin. Agric. Food Chem. 3: 402 408 ( as cited in IPCS, 1989; USEPA, 1987, 1992,1993a, and 1993b).

USEPA. 1998. Announcement of the Drinking Water Contaminant Candidate List; Final Rule. Fed. Reg. 63( 274): 10274. March 2.

USEPA. 1997. Announcement of the Draft Drinking Water Contaminant Candidate List; Notice. Fed. Reg. 62( 193): 52193. October 7.

USEPA. 1996/ 1999. U. S. Environmental Protection Agency. Proposed Cancer Guidelines. Available on the Internet at http:// www. epa. gov/ ORD/ WebPubs/ carcinogen / carcin. pdf. 9 27 Aldrin/ Dieldrin   February 2003 USEPA. 1993a. U. S. Environmental Protection Agency. IRIS document for aldrin. Available on the Internet at http:// www. epa. gov/ ngispgm3/ iris/ index. html.

USEPA. 1993b. U. S. Environmental Protection Agency. IRIS document for dieldrin. Available on the Internet at http:// www. epa. gov/ ngispgm3/ iris/ index. html.

USEPA. 1992. U. S. Environmental Protection Agency. Aldrin drinking water health advisory. Washington, DC: USEPA Office of Water.

USEPA. 1988. U. S. Environmental Protection Agency. Dieldrin health advisory. Washington, DC: USEPA Office of Water.

USEPA. 1987. U. S. Environmental Protection Agency. Carcinogenicity assessment of aldrin and dieldrin. Document no. EPA 600/ 6 87/ 006, August 1987. Washington, DC: USEPA Office of Health and Environmental Assessment, Carcinogenesis Assessment Group.

USEPA. 1986. U. S. Environmental Protection Agency. Guidelines for carcinogen risk assessment. Fed. Reg. 51( 185): 33992 34003. September 24.

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.

Van Raalte, H. G. S. 1977. Human experience with dieldrin in perspective. Ecotox. Environ. Saf. 1: 203 210 ( as cited in ATSDR, 2000a).

Versteeg, J. P. J. and K. W. Jager. 1973. Long term occupational exposure to the insecticides aldrin, dieldrin, endrin, and telodrin. Br J Ind Med 30: 201 202 ( as cited in ATSDR, 2000a).

Virgo, B. B. and G. D. Bellward. 1975. Effects of dietary dieldrin on reproduction in the Swiss Vancouver ( SWV) mouse. Environ. Physiol. Biochem. 5: 440 450 ( as cited in ATSDR, 2000a; IPCS, 1989).

Wade, M. H., J. E. Trosko, and M. Schindler. 1986. A flourescence photobleaching assay of gap junction mediated communication between human cells. Science 232: 525 528 ( as cited in GAP2000, 2000b).

Wagner, S. R. and F. E. Greene. 1978. Dieldrin induced alterations in biogenic amine content of rat brain. Toxicol. Appl. Pharmacol. 43: 45 55 ( as cited in ATSDR, 2000a).

Walker, A. I. T., E. Thorpe, and D. E. Stevenson. 1972. The toxicology of dieldrin ( HEOD). I. Long term oral toxicity studies in mice. Food Cosmet. Toxicol. 11: 415 432 ( as cited in USEPA, 1987, 1988, and 1993b). 9 28 Aldrin/ Dieldrin   February 2003 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, 2000a; IPCS, 1989; USEPA, 1980).

Woolley, D., L. Zimmer, D. Dodge, and K. Swanson. 1985. Effects of lindane type insecticides in mammals: Unsolved problems. Neurotoxicity 6: 165 192 ( as cited in ATSDR, 2000a).

Zhong Xiang, L., T. Kavanagh, J. E. Trosko, and C. C. Chang. 1986. Inhibition of gap junctional intercellular communication in human teratocarcinoma cells by organochlorine pesticides. Toxicol. Appl. Pharmacol. 83: 10 19 ( as cited in GAP2000, 2000a, b). 10 1 Aldrin/ Dieldrin   February 2003 10.0 REFERENCES ACGIH. 1984. American Conference of Governmental Industrial Hygienists. Documentation of the threshold limit values for substances in workroom air. 3rd ed. Cincinnati, OH: ACGIH, p. 139 ( as cited in USEPA, 1988).

Agnihotri, N. P., G. Kulshrestha, V. T. Gajbhiye, S. P. Mohapatra, and S. B. Singh. 1996. Organochlorine insecticide residues in agricultural soils of the Indo Gangetic Plain. Environ. Monit. Assess. 40: 279 288.

Ahmed, F. E., D. Hattis, R. E. Wolke, and D. Steinman. 1993. Risk assessment and management of chemical contaminants in fishery products consumed in the USA. J. Appl. Toxicol. 13 ( 6): 395 410.

Ahmed, F. E., R. W. Hart, and N. J. Lewis. 1977a. Pesticide induced DNA damage and its repair in cultured human cells. Mutat. Res. 42: 161 174 ( as cited in USEPA, 1993b; GAP2000, 2000 a, b).

Ahmed, F. E., N. J. Lewis, and R. W. Hart. 1977b. Pesticide induced ouabain resistant mutants in Chinese hamster V79 cells. Chem. Biol. Interact. 19: 369 374 ( as cited in GAP2000, 2000b).

Aigner E. J., A. Leone, and R. L. Falconer. 1998. Concentrations and enantiomeric ratios of organochlorine pesticides in soils from the U. S. corn belt. Environ. Sci. Technol. 32: 1162 1168.

Amaoteng Adjepong, Y., N. Sathiakumar, E. Delzell, and P. Cole. 1995. Mortality among workers at a pesticide manufacturing plant. J. Occup. Environ. Med. 37: 471 478 ( as cited in Stevenson et al., 1999).

Anderson, D. J. and R. A. Hites. 1988. Chlorinated pesticides in indoor air. Environ. Sci. Technol. 22: 717 720 ( as cited in Wallace et al., 1996).

Anderson, D. and J. A. Styles. 1978. An evaluation of six short term tests for detecting organic chemical carcinogens. Appendix 2. The bacterial mutation test. Br. J. Cancer 37: 924 930 ( as cited in GAP2000, 2000b).

Arnold, S. F., D. M. Klotz, B. M. Collins, P. M. Vonier, J. R. L. J. Guillette, and J. A. McLachlan. 1996. Synergistic activation of estrogen receptor with combinations of environmental chemicals. Science 272: 1489 1492 ( as cited in Ramamoorthy et al., 1997 and Wade et al., 1997).

Ashwood Smith, M. J., J. Trevino, and R. Ring. 1972. Mutagenicity of dichlorvos. Nature 240: 418 420 ( as cited in GAP2000, 2000a, b).

Atlas, E. and C. S. Giam. 1988. Ambient concentration and precipitation scavenging of atmospheric organic pollutants. Wat Air Soil Pollut. 38: 19 36 ( as cited in ATSDR, 2000). 10 2 Aldrin/ Dieldrin   February 2003 ATSDR. 2000 ( Sections 1, 2, 3, 5, 6, 7, 8, 9). 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.

ATSDR. 2000 ( Section 4). Agency for Toxic Substances and Disease Registry. Hazardous Substance Release and Health Effects Database. Available on the Internet at: http:// www. atsdr. cdc. gov/ hazdat. htm Last modified August 19, 2000.

ATSDR. 2000b ( Section 9). Agency for Toxic Substances and Disease Registry. Hazardous Substance Release and Health Effects Database. Available on the Internet at: http:// www. atsdr. cdc. gov/ hazdat. htm Last modified August 19, 2000.

ATSDR. 1993. Agency for Toxic Substances and Disease Registry. Toxicological profile for aldrin/ dieldrin: Update. Atlanta, GA: U. S. Dept. of Health and Human Services, Public Health Service, ATSDR.

Bachowski, S., Y. Xu, D. E. Stevenson, E. F. Walborg, Jr., and J. E. Klaunig. 1998. Role of oxidative stress in the selective toxicity of dieldrin in the mouse liver. Toxicol. Appl. Pharmacol. 150: 301 309.

Bachowski, S., K. L. Kolaja, Y. Xu, C. A. Ketcham, D. E. Stevenson, E. F. Walborg, Jr., and J. E. Klaunig. 1997. Role of oxidative stress in the mechanism of dieldrin's hepatotoxicity. Ann. Clin. Lab. Sci. 27: 196 209.

Baeckstroem, J., E. Hannson, and S. Ullberg. 1965. Distribution of 14C DDT and 14C dieldrin in pregnant mice determined by whole body autoradiography. Toxicol. Appl. Pharmacol. 7: 90 96 ( as cited in IPCS, 1989b).

Baldwin, M. K., J. Robinson, and D. V. Parke. 1972. A comparison of the metabolism of HEOD ( dieldrin) in the CF 1 mouse compared with that of the CFE rat. Food Cosmet. Toxicol. 10: 333 351 ( as cited in ATSDR, 2000; IARC, 1974b; IPCS, 1989b; USEPA, 1988, 1980).

Baldwin, M. K. and J. Robinson. 1969. Metablism in the rat of the photoisomerization product of dieldrin. Nature ( London) 224( 5216): 283 284 ( as cited in IPCS, 1989b).

Bann, J. M., T. J. DeCino, N. W. Earle, and Y. P. Sun. 1956. The fate of aldrin and dieldrin in the animal body. J. Agric. Food Chem. 4: 937 941 ( as cited in IARC, 1974a).

Barber, L. B. and J. H. Writer. 1998. Impact of the 1993 Flood on the distribution of organic contaminants in bed sediments of the upper Mississippi River. Environ. Sci. Technol. 32 ( 14): 2077 2083.

Baron, R. L. and M. S. Walton. 1971. Dynamics of HEOD ( dieldrin) in adipose tissue of the rat. Toxicol. Appl. Pharmacol. 18: 958 963 ( as cited in ATSDR, 2000; IPCS, 1989b; USEPA, 1980). 10 3 Aldrin/ Dieldrin   February 2003 Bauer Hofmann, R., A. Buchmann, J. Mahr, S. Kress, and M. Schwarz. 1992. The tumour promoters dieldrin and phenobarbital increase the frequency of c Ha ras wild type, but not of c Ha ras mutated focal liver lesions in male C3H/ He mice. Carcinogenesis 13: 477 481.

Benes, V. and R. Sram. 1969. Mutagenic activity of some pesticides in Drosophila melanogaster. Ind. Med. 38: 442 444 ( as cited in GAP2000, 2000a, b).

Beyermann, K. and W. Eckrich. 1973. Gas chromatographische bestimmung von insecticidspuren in Luft [ Gas chromatographic determination of insecticide traces in air.] Anal. Chem. 265: 4 7 ( In German, translation; as cited in IPCS, 1989b; USEPA, 1992).

Bidwell, K., E. Weber, I. Neinhold, T. Connor, and M. S. Legator. 1975. Comprehensive evaluation for mutagenic activity of dieldrin. Mutat. Res. 31: 314. ( Abstract) ( as cited in USEPA, 1993b).

Black A. M. S. 1974. Self poisoning with dieldrin: A case report and pharmacokinetic discussion. Anesth. Intensive Care 2: 369 374 ( as cited in ATSDR, 2000).

Blynn et al. 1994. Citation not found.

Bond, A. E., G. G. Akland, R. G. Lewis, and C. J. Nelson. 1993. A pilot study for measuring environmental exposures from agricultural applications of pesticides: an overview. In: Proceedings of the 1993 USEPA/ AWMA symposium on measurements of toxic and related air pollutants ( Research Triangle Park, N. C. May 3 7, 1993). VIP 34. Air and Waste Management Association, Pittsburgh, PA. p. 691 697.

Borgmann, A. R., C. H. Kitselman, P. A. Dahm, J. E. Pankaskie, and F. R. Dutra. Kansas State College. 1952. Toxicological studies of dieldrin on small laboratory animals. Unpublished report. July. ( as cited in USEPA, 1992)

Brannen, K. C., L. L. Devaud, J. Liu, and J. M. Lauder. 1998. Prenatal exposure to neurotoxicants dieldrin or lindane alters tert butylbicyclophosphorothionate binding to GABA( A) receptors in fetal rat brainstem. Dev. Neurosci. 20: 34 41.

Brown, D. P. 1992. Mortality of workers employed at organochlorine pesticide manufacturing plants an update. Scand. J. Environ. Health 18: 155 161 ( as cited in Stevenson et al., 1999).

Brown, E., D. R. Abramovich, H. M. Wallace, P. W. Johnston, S. C. Riley, N. P. Groome, and P. A. Fowler. 1998. Testosterone and inhibin B secretion by human fetal testicular explants are suppressed by in vitro exposure to the environmental toxicant dieldrin. J. Reprod. Fertil. 21: 26 ( Abstract).

Brown, V. K. H., J. Robinson, E. Thorpe, and J. W. Barrett. 1967. Preliminary studies on the acute and subacute toxicities of a photoisomerization product of HEOD. Food Cosmet. Toxicol. 5: 771 779 ( as cited in IPCS, 1989b). 10 4 Aldrin/ Dieldrin   February 2003 Buck, W. B. and W. Van Note. 1968. Aldrin poisoning resulting in dieldrin residues in meat and milk. J. Am. Vet. Med. Assoc. 153: 1472 1475 ( as cited in ATSDR, 2000).

Budavari, S,, M. J. O'Neil, A. Smith, and P. E. Heckelman, ( eds.). The Merck index, 11th ed. Rahway, NJ: Merck & Co., Inc., pp. 223, 490.

Burt, J. S. and G. F. Ebell. 1995. Organic pollutants in mussels and sediments of the coastal waters off Perth, Western Australia. Mar. Pollut. Bull. 30 ( 11): 723 732.

Burt, G. S. 1975. Use of behavioral techniques in the assessment of environmental contaminants. In: Weiss, B, and V. G. Laties, eds. Behavioral toxicology. New York, NY: Plenum Press, pp. 241 263 ( as cited in ATSDR, 2000).

Cadmus. 2000. Methods for Estimating Contaminant Occurrence and Exposure in Public Drinking Water Systems in Support of CCL Determinations. Draft report submitted to EPA for review July 25, 2000.

Cadmus. 2001. Occurrence estimation methodology and occurrence findings report for six year regulatory review. Draft report submitted to EPA for review October 5, 2001.

Carlson J. N. and R. A. Rosellini. 1987. Exposure to low doses of the environmental chemical dieldrin causes behavioral deficits in animals prevented from coping with stress. Psychopharmacology 91: 122 126 ( as cited in ATSDR, 2000).

Casteel, S. W., F. T. Satalowich, J. D. Kendall, G. E. Rottinghaus, H. S. Gosser, and N. R. Schneider. 1993. Aldrin intoxication and clearance of associated dieldrin residues in a group of feedlot cattle. J. Am. Vet. Med. Assoc. 202: 83 85.

Castro, V. L., M. M. Bernardi, and J. Palermo Neto. 1992. Evaluation of prenatal aldrin intoxication in rats. Arch. Toxicol. 66: 149 152.

Chatterjee, S., A. Ray, P. Bagchi, and C. Deb. 1992. Estrogenic effects of aldrin and quinalphos in rats. Bull. Environ. Contam. Toxicol. 48: 125 130.

Chernoff, N., R. J. Kavlock, J. R. Kathrein, J. M. Dunn, and J. K. Haseman. 1975. Prenatal effects of dieldrin and photodieldrin in mice and rats. Toxicol. Appl. Pharmacol. 31: 302 308 ( as cited in IPCS, 1989b; USEPA 1988, 1987).

Chipman, J. K. and C. H. Walker. 1979. The metabolism of dieldrin and two of its analogues: the relationship between rates of microsomal metabolism and rates of excretion of metabolites in the male rat. Biochem. Pharmacol. 28: 1337 1345 ( as cited in ATSDR, 2000).

Cole, J. F., L. M. Klevay, and M. R. Zavon. 1970. Endrin and dieldrin: a comparison of hepatic excretion in the rat. Toxicol. Appl. Pharmacol. 16: 547 555 ( as cited in ATSDR, 2000; IPCS, 1989b; USEPA, 1980). 10 5 Aldrin/ Dieldrin   February 2003 Cotruvo, J. A., V. F. Simmon, and R. J. Spanggord. 1977. Investigation of mutagenic effects of products of ozonation reactions in water. Ann. N. Y. Acad. Sci. 298: 124 140 ( as cited in USEPA, 1992).

Coulston, F., R. Abraham, and R. Mankes. 1980. Reproductive study in female rats given dieldrin, alcohol or aspirin orally. Albany, NY: Albany Medical College of Union University. Institute of Comparative and Human Toxicology ( as cited in IPCS, 1989b; USEPA, 1988).

Crebelli, R., D. Bellincampi, G. Conti, L. Conti, G. Morpurgo, and A. Carere. 1986. A comparative study on selected chemical carcinogens for chromosome malsegregation, mitotic crossing over and forward mutation induction in Aspergillus nidulans. Mutat. Res. 172: 139 149 ( as cited in GAP2000, 2000b).

Cueto, C., Jr. and F. J. Biros. 1967. Chlorinated insecticides and related materials in human urine. Toxicol. Appl. Pharmacol. 10: 261 269 ( as cited in IPCS, 1989b; USEPA, 1980).

Cueto, C. Jr., and W. J. Hayes, Jr. 1962. The detection of deldrin metabolites in human urine. J. Agric. Food Chem. 10: 366 369 ( as cited in IPCS, 1989b; USEPA, 1980).

Curley, A. and R. Kimbrough. 1969. Chlorinated hydrocarbon insecticides in plasm and milk of pregnant and lactating women. Arch. Environ. Health. 18: 156 ( as cited in IARC, 1974b).

Curley, A., M. F. Copeland and R. D. Kimbrough. 1969. Chlorinated hydrocarbon insecticides in organs of stillborn and blood of newborn babies. Arch. Environ. Health. 19: 628 632 ( as cited in IARC, 1974b; IPCS, 1989b)

Dailey, R. E., M. S. Walton, V. Beck, C. L. Leavens, and A. K. Klein. 1970. Excretion, distribution, and tissue storage of a 14C labeled photoconversion product of 14C dieldrin. J. Agric. Food Chem. 18( 3): 443 445 ( as cited in IPCS, 1989b).

Dale, W. E. and G. E. Quinby. 1963. Chlorinated insecticides in the body fat of people in the United States. Science. 142: 593 595 ( as cited in IPCS, 1989b; USEPA, 1980).

Damico, J. N., J. Y. T. Chen, C. E. Costello, and E. O. Haenni. 1968. Structure of Klein's metabolites of aldrin and of dieldrin. J. Assoc. Off. Agric. Chem. 51( 1): 48 55 ( as cited in IPCS, 1989b).

Davies, K. 1988. Concentrations and dietary intake of selected organochlorines, including PCB's in fresh food composites grown in Ontario, Canada. Chemosphere 17: 263 276 ( as cited in ATSDR, 2000).

Davis, K. J. 1965. Pathology report on mice fed aldrin, dieldrin, heptachlor or heptachlor epoxide for two years. Internal FDA memorandum to Dr. A. J. Lehman. July 19. ( as cited in USEPA, 1987, 1992, 1993a, 1993b). 10 6 Aldrin/ Dieldrin   February 2003 Davis, K. J. and O. G. Fitzhugh. 1962. Tumorigenic potential of aldrin and dieldrin for mice. Toxicol. Appl. Pharmacol. 4: 187 189 ( as cited in USEPA, 1987, 1992, 1993a, 1993b)

Davison, K. L. 1973. Dieldrin 14C balance in rats, sheep and chickens. Bull. Environ. Contam. Toxicol. 10: 16 24 ( as cited in ATSDR, 2000; IPCS, 1989b).

de Jong, G., G. M. Swaen, and J. J. Slangen. 1997. Mortality of workers exposed to dieldrin and aldrin: a retrospective cohort study. Occup. Environ. Med. 54: 702 707.

de Jong, G. 1991. Long term health effects of aldrin and dieldrin. A study of exposure, health effects and mortality of workers engaged in the manufacture and formulation of the insecticides aldrin and dieldrin. Toxicol. Lett. Suppl. 1 206 ( as cited in Stevenson et al., 1999).

De Vlieger, M., J. Robinson, M. K. Baldwin, A. N. Crabtree, and M. C. Van Dijk. 1968. The organochlorine insecticide content of human tissue. Arch. Environ. Health. 17: 759 767 ( as cited in ATSDR, 2000; IPCS, 1989b).

Dean, B. J., S. M. A. Doak, and H. Somerville. 1975. The potential mutagenicity of dieldrin ( HOED) in mammals. Food Cosmet. Toxicol. 13: 317 323 ( as cited in ATSDR, 2000; GAP2000, 2000b).

Deichmann, W. B. 1974. Statement of testimony for aldrin/ dieldrin hearings suspension phase, before the U. S. Environmental Protection Agency, August 23, 1974 ( as cited in USEPA, 1987).

Deichmann, W. B., W. E. MacDonald, and D. A. Cubit. 1975. Dieldrin and DDT in the tissues of mice fed aldrin and DDT for seven generations. Arch. Toxicol. 34: 173 182 ( as cited in IPCS, 1989b; TOXLINE, 2000c; USEPA, 1992).

Deichmann, W. B., W. E. MacDonald, A. G. Beasly, and D. A. Cubit. 1971. Subnormal reproduction in beagle dogs induced by DDT and aldrin. Ind. Med. Surg. 40( 2): 10 22 ( as cited in USEPA, 1992, 1987).

Deichmann, W. B., W. E. MacDonald, E. Blum, M. Bevilacqua, J. Radomski, M. Keplinger, and M. Balkus. 1970 ( Sections 7 and 9). Tumorigenicity of aldrin, dieldrin and endrin in the albino rat. Ind. Med. Surg. 39( 10): 426 434 ( as cited in USEPA, 1987, 1992, 1993a, 1993b).

Deichmann, W. B., W. E. McaDonald, E. Blum, M. Bevilacqua, J. Radomski, M. Keplinger, and M. Balkus. 1970 ( Section 8). Tumorigenicity of aldrin, dieldrin and endrin in the albino rat. Ind. Med. 39( 10): 426 434 ( as cited in USEPA, 1992).

Deichmann, W. B., M. Keplinger, I. Dressler, and F. Sala. 1969. Retention of dieldrin and DDT in tissues of dogs fed aldrin and DDT individually and as a mixture. Toxicol. Appl. Pharmacol. 14: 205 213 ( as cited in IPCS, 1989b; USEPA, 1992). 10 7 Aldrin/ Dieldrin   February 2003 Deichmann, W. B., I. Dressler, M. Keplinger, and W. E. MacDonald. 1968. Retention of dieldrin in blood, liver, and fat of rats fed dieldrin for six months. Ind. Med. Surg. 37: 837 839 ( as cited in ATSDR, 2000; IARC, 1974b; IPCS, 1989b; USEPA, 1980).

Deichmann, W. B., M. Keplinger, F. Sala, and E. Glass. 1967. Synergism among oral carcinogens in the simultaneous feeding of four tumorigens to rats. Toxicol. Appl. Pharmacol. 11: 88 103 ( as cited in USEPA, 1987).

Demetrio, R. S., M. Antunes Madeira, and V. M. Madeira. 1998. Effects of aldrin on membrane fluidity and its implications for the mechanisms of toxicity. Med. Sci. Res. 26: 556 561.

Dey, B. P. and C. Manzoor. 1997. Chemical residue limits in meat, poultry, and eggs for residue violation information system development. USDA Food Safety and Inspection Service. ( as cited in Levengood et al., 1999).

Dingle, J. H. P., W. A. Palmer, and R. R. Black. 1989. Residues of DDT and dieldrin in the subcutaneous fat and butterfat of cattle. Australian Journal of Experimental Agriculture 29: 497 501 ( as cited in ATSDR, 2000).

Ditraglia, D., D. P. Brown, T. Namekata, and N. Iverson. 1981. Mortality study of workers employed at organochlorine pesticide manufacturing plants. Scand. J. Work. Environ. Health. 4: 140 146 ( as cited in Stevenson et al., 1999).

Dobbs, A. J. and N. Williams. 1983. Indoor air pollution from pesticides used in wood remedial treatments. Environ. Pollut. ( Series B) 6: 271 296 ( as cited in ATSDR, 2000).

Dulout, F. N., M. C. Pastori, O. A. Olivero, M. Gonzalez Cid, D. Loria, E. Matos, N. Sobe, E. De Bujan, and N. Albiano. 1985. Sister chromatid exchanges and chromosomal aberrations in a population exposed to pesticides. Mutat. Res. 143: 237 244 ( as cited in ATSDR, 2000).

Edwards, J. W. and B. G. Priestly. 1994. Effect of occupational exposure to aldrin on urinary Dglucaric acid, plasma dieldrin, and lymphocyte sister chromatid exchange. Int. Arch. Occup. Environ. Health 66: 229 234.

Eisenreich, S. J., P. D. Capel, J. A. Robbins, and R. Bourbonniere. 1989. Accumulation and digenesis of chlorinated hydrocarbons in lacustrine sediments. Environ. Sci. Technol. 23: 1116 1126 ( as cited in ATSDR, 2000).

Eliason, B. C. and H. S. Posner. 1971. Reduced passage of carbon 14 dieldrin to the fetal rat by phenobarbital but not by eight other drugs or dieldrin. Am. J. Obstet. Gynecol. 110( 7): 943 947 ( as cited in IARC, 1974b; IPCS, 1989b).

Elliot, J. 1975. Monitoring of selected ecological components of the environment in four Alabama counties ( 1972 1974). In: Papers of Environ Chem Hum Anim Health Proc, 4th Annual 10 8 Aldrin/ Dieldrin   February 2003 Conference, Auburn University. Auburn, AL: Alabama Cooperative Extension Service, pp. 233 279.

Epstein, S. S. 1975 ( Section 8 and 9). The carcinogenicity of dieldrin. Part 1. Sci. Total Environ. 4: 1 52 ( as cited in USEPA 1993b).

Epstein, S. S. 1975a ( Section 7). The carcinogenicity of dieldrin. Part 1. Sci. Total Environ. 4: 1 52 ( as cited in USEPA 1993b).

Epstein, S. S. 1975b. The carcinogenicity of dieldrin. Part 2. Sci. Total Environ. 4: 205 217 ( as cited in USEPA 1987, 1993b).

Epstein, S. S., E. Arnold, J. Andrea, W. Bass, and Y. Bishop. 1972. Detection of chemical mutagens by the dominant lethal assay in the mouse. Toxicol. Appl. Pharmacol. 23: 288 325 ( as cited in ATSDR, 2000; GAP2000, 2000a, b).

Fahrig, R. 1974. Comparative mutagenicity with pesticides. IARC Publ. ( U. N.) 10: 161 181 ( as cited in USEPA, 1993b; GAP2000, 2000a).

Fairey, R., K. Taberski, S. Lamerdin, E. Johnson, R. P. Clark, J. W. Downing, J. Newman, and M. Petreas. 1997. Organochlorines and other environmental contaminants in muscle tissues of sportfish collected from San Francisco Bay. Mar. Pollut. Bull. 34 ( 12): 1058 1071.

Farb, R. M., T. Sanderson, B. G. Moor and A. W. Hayes. 1973. Interaction: the effect of selected mycotoxins on the tissue distribution and retention of aldrin and dieldrin in the neonatal rat. In: Deichmann, W. B., ed. Pesticides in the environment. New York, NY: International Medical Book Corporation, pp. 179 187 ( as cited in IPCS, 1989b; USEPA, 1992).

Feil, V. J., R. D. Hedde, R. G. Zaylskie and C. H. Zachrison. 1970. Dieldrin 14C metabolism in sheep. Indentification of trans 6,7 dihydroxydihydroaldrin and 9( syn epoxy) hydroxy 1,2,3,4,10,10 hexachloro 6,7 epoxy 1,4,4a, 5,6,7,8,8a octahydro 1,4 endo 5,8 exo dimethanonaphthalene J. Agric. Food Chem. 18( 1): 120 124 ( as cited in IPCS, 1989b).

Feldmann, R. J. and H. I. Maibach. 1974. Percutaneous penetration of some pesticides and herbicides in man. Toxicol. Appl. Pharmocol. 28: 126 132 ( as cited in ATSDR, 2000; IPCS, 1989b, USEPA, 1992).

Fisher, H. L., B. Most and L. L. Hall. 1985. Dermal absorption of pesticides calculated by deconvolution. J. Appl. Toxicol. 5( 3): 163 177 ( as cited in IPCS, 1989b).

Fitzhugh, O. G., A. A. Nelson and M. L. Quaife. 1964. Chronic oral toxicity of aldrin and dieldrin in rats and dogs. Food Cosmet. Toxicol. 2: 551 562.

Fournier, M., G. Chevalier, D. Nadeau, B. Trottier, and K. Krzystyniak. 1988. Virus pesticide interactions with murine cellular immunity after sublethal exposure to dieldrin and animocarb. J. Toxicol. Environ. Health 25: 103 118 ( as cited in ATSDR, 2000). 10 9 Aldrin/ Dieldrin   February 2003 Gaines, T. B. 1969. Acute toxicity of pesticides. Toxicol. Appl. Pharmacol. 14: 515 534 ( as cited in USEPA, 1992).

Gaines, T. B. 1960. The acute toxicity of pesticides to rats. Toxicol. Appl. Pharmacol. 2: 88 99 ( as cited in ATSDR, 2000).

Galloway, S. M., M. J. Armstrong, C. Reuben, S. Colman, B. Brown, C. Cannon, A. D. Bloom, F. Nakamura, M. Ahmed, S. Duk, J. Rimpo, B. H. Margolin, M. A. Resnick, B. Anderson, and E. Zeiger. 1987. Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: Evaluations of 108 chemicals. Environ. Mol. Mutagen. 10( Suppl. 10): 1 175.

GAP2000. 2000a. Genetic Activity Profiles ( program version 1.3.0, file version <IP_ADDRESS>), data record for aldrin. Database and software are a joint effort of the U. S. Environmental Protection Agency and the International Agency for Research on Cancer. Lohman, P. H. M. and W. J. A. Lohman, authors. Downloaded from http:// www. epa. gov/ gapdb on January 19, 2001.

GAP2000. 2000b. Genetic Activity Profiles ( program version 1.3.0, file version <IP_ADDRESS>), data record for dieldrin. Database and software are a joint effort of the U. S. Environmental Protection Agency and the International Agency for Research on Cancer. Lohman, P. H. M. and W. J. A. Lohman, authors. Downloaded from http:// www. epa. gov/ gapdb on January 19, 2001.

Garrettson, L. K. and A. Curley. 1969. Dieldrin. Studies in a poisoned child. Arch. Environ. Health 19: 814 822 ( as cited in ATSDR, 2000; IARC, 1974b).

Georgian, L. 1975. The comparative cytogenic effects of aldrin and phosphamidon. Mutat. Res. 31: 103 108 ( as cited in USEPA, 1992, 1993a; GAP2000, 2000a).

Gilliom, R. J., D. K. Mueller, and L. H. Nowell. Methods for comparing water quality conditions among National Water Quality Assessment Study Units, 1992 95. U. S. Geological Survey Open File Report 97 589. In press.

Glatt, H., R. Jung, and F. Oesch. 1983. Bacterial mutagenicity investigation of epoxides: drugs, drug metabolites, steroids and pesticides. Mutat. Res. 11: 99 118 ( as cited in GAP2000, 2000b).

Good, E. E. and G. W. Ware. 1969. Effects of insecticides on reproduction in the laboratory mouse. IV. Endrin and dieldrin. Toxicol. Appl. Pharmacol. 14: 201 203 ( as cited in ATSDR, 2000; IPCS, 1989b).

Goolsby, D. A. and W. A. Battaglin. 1993. Occurrence, distribution and transport of agricultural chemicals in surface waters of the Midwestern United States. In: Goolsby, D. A., L. L. Boyer, and G. E. Mallard, compilers. Selected Papers on Agricultural Chemicals in Water Resources of the Midcontinental United States. U. S. Geological Survey Open File Report 94 418. pp. 1 25.

Graham, M. J., F. M. Williams, A. E. Rettie, and M. D. Rawlins. 1987. Aldrin metabolism in the skin: In vitro and in vivo studies. In: Shroot, B. and H. Schaefer, eds. 7th Symposium on 10 10 Aldrin/ Dieldrin   February 2003 advances in skin pharmacology, skin pharmacokinetics, Nice, France, September 26 28, 1986. New York, NY: S. Karger, pp. 252 255 ( as cited ATSDR, 2000).

Griesemer, R. A. and C. Cueto, Jr. 1980. Toward a classification scheme for degrees of experimental evidence for the carcinogenicity of chemicals for animals. In: Montesano, R., H. Bartsch, and L. Tomatis, eds. Molecular and cellular aspects of carcinogen screening tests. IARC Scientific Publications No. 27. Lyon, France: International Agency for Research on Cancer, pp. 259 281.

Griffin III, D. E. and W. E. Hill. 1978. In vitro breakage of plasmid DNA by mutagens and pesticides. Mutat. Res. 52: 161 169 ( as cited in GAP2000, 2000a, b).

Guerzoni, M. E., L. Del Cupolo, and I. Ponti. 1976. Mutagenic activity of pesticides. Riv. Sci. Tecnol. Alimenti Nutr. Um. 6: 161 165 ( as cited in GAP2000, 2000a).

Gunderson, E. L. 1988. FDA Total Diet Study, April 1982 April 1984: dietary intakes of pesticides, selected elements, and other chemicals. J. Assoc. Anal. Chem. 71: 1200 1209 ( as cited in ATSDR, 2000).

Hallberg, G. R., D. G. Riley, J. R. Kantamneni, P. J. Weyer, and R. D. Kelley. 1996. Assessment of Iowa Safe Drinking Water Act Monitoring Data: 1988 1995. Research Report No. 97 1. Iowa City: The University of Iowa Hygienic Laboratory. 132 pp.

Hamilton, H. E., D. P. Morgan, and A. Simmons. 1978. A pesticide ( dieldrin) induced immunohemolytic anemia. Environ. Res. 17: 155 164 ( as cited in USEPA, 1992).

Harner, T., J. L. Wideman, L. M. Jantunen, T. F. Bidleman, and W. J. Parkhurst. 1999. Residues of organochlorine pesticides in Alabama soils. Environ. Pollut. 106 ( 3): 323 332.

Harr J. R., R. R. Claeys, J. F. Bone, and T. W. McCorde. 1970. Dieldrin toxicosis: Rat reproduction. Am. J. Vet. Res. 31: 181 189 ( as cited in ATSDR, 2000; IPCS, 1989b; USEPA, 1987).

Haseman, J. K., J. E. Huff, E. Zeiger and E. E. McConnell. 1987. Comparative results of 327 chemical carcinogenicity studies. Environ. Health Perspect. 74: 229 235.

Hathway, D. E., J. A. Moss, J. A. Rose and D. J. M. Williams. 1967. Transport of dieldrin from mother to blastocyst and from mother to foetus in pregnant rabbits. Eur. J. Pharmacol. 1: 167 175 ( as cited in IPCS, 1989b).

Haworth, S., T. Lawlor, K. Mortelmans, W. Speck and E. Zeigler. 1983. Salmonella mutagenicity test results for 250 chemicals. Environ. Mutag. 5( Suppl. 1): 1 142 ( as cited in USEPA, 1993b; GAP2000, 2000b). 10 11 Aldrin/ Dieldrin   February 2003 Hayes, W. J. 1982. Pesticides studied in man. Baltimore, MD: The Williams and Wilkins Company, pp. 234 247 ( as cited in USEPA, 1992).

Hayes, W. J. 1974. Distribution of dieldrin following a single oral dose. Toxicol. Appl. Pharmacol. 28: 485 492 ( as cited in ATSDR, 2000; IPCS, 1989b; USEPA, 1988, 1980).

Hayes, W. J. and A. Curley. 1968. Storage and excretion of dieldrin and related compounds: Effect of occupational exposure. Arch. Environ. Health 16: 155 162 ( as cited in IARC, 1974b; IPCS, 1989b; USEPA, 1980).

Heath, D. F. and M. Vandekar. 1964. Toxicity and metabolism of dieldrin in rats. Br. J. Ind. Med. 21: 269 279 ( as cited in ATSDR, 2000; USEPA, 1988, 1980).

Hedde, R. D., K. L. Davison, and J. D. Robbins. 1970. Dieldrin 14C metabolism in sheep: distribution and isolation of urinary metabolites. J. Agric. Food Chem. 18: 116 ( as cited in USEPA, 1980).

Hodge, H. C., A. M. Boyce, W. B. Deichmann and H. F. Kraybill. 1967. Toxicology and no effect levels of aldrin and dieldrin. Toxicol. Appl. Pharmacol. 10: 613 675 ( as cited in USEPA, 1992).

HSDB. 2000a. Hazardous Substances Data Bank. Aldrin. Retrieved Sep. 20, 2000. Bethesda, MD: National Library of Medicine, Specialized Information Services Division, Toxicology and Environmental Health Information Program, TOXNET.

HSDB. 2000b. Hazardous Substances Data Bank. Dieldrin. Retrieved Sep. 20, 2000. Bethesda, MD: National Library of Medicine, Specialized Information Services Division, Toxicology and Environmental Health Information Program, TOXNET.

Hunter, C. G., J. Robinson and M. Roberts. 1969. Pharmacodynamics of dieldrin ( HEOD): II. Ingestion by human subjects for 18 to 24 months, and post exposure for 8 months. Arch. Environ. Health. 18: 12 21 ( as cited in ATSDR, 2000; IPCS, 1989b; TOXLINE, 2000b; USEPA, 1980).

Hunter, C. G. and J. Robinson. 1968. Aldrin, dieldrin and man. Food Cosmet. Toxicol. 6: 253 260 ( as cited in ATSDR, 2000).

Hunter, C. G. and J. Robinson. 1967. Pharmacodynamics of dieldrin ( HEOD): I. Ingestion by human subjects for 18 months. Arch. Environ. Health. 15: 614 626 ( as cited in ATSDR, 2000; IARC, 1974b; IPCS, 1989b).

Hutson, D. H. 1976. Comparative metabolism of dieldrin in the rat ( CFE) and in two strains of mouse ( CF1 and LACG). Food Cosmet. Toxicol. 14: 557 591 ( as cited in ATSDR, 2000; IPCS, 1989b). 10 12 Aldrin/ Dieldrin   February 2003 Hyland, J. L., T. R. Snoots, and W. L. Balthis. 1998. Sediment quality of estuaries in the southeastern U. S. Environ. Monit. Assess. 51( 1 2): 331 343.

IARC. 1987. International Agency for Research on Cancer. Evaluation of the carcinogenic risk of chemicals to humans. Overall evaluations of carcinogenicity. Lyon, France: Suppl. 7: 88 89.

IARC. 1982. International Agency for Research on Cancer. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Chemicals, industry process and industries associated with cancer in humans. IARC Monographs. Vols. 1 29, Supplement 4. Geneva, Switzerland: World Health Organization ( as cited in USEPA, 1988).

IARC. 1974 ( Section 9). International Agency for Research on Cancer. Evaluation of the carcinogenic risk of chemicals to humans. Aldrin. Lyon, France: IARC Monograph 5: 25 38.

IARC. 1974a. International Agency for Research on Cancer. Evaluation of the carcinogenic risk of chemicals to humans. Aldrin. Lyon, France: IARC Monograph 5: 25 38.

IARC. 1974b. International Agency for Research on Cancer. Evaluation of the carcinogenic risk of chemicals to humans. Dieldrin. Lyon, France: IARC Monograph 5: 125 156.

Iatropoulos, M. J., A. Milling, W. F. Muller, G. Nohynek, K. Rozman, F. Coulston, and F. Korte. 1975. Absorption, transport and organotropism of dichlorobiphenyl ( DCB), dieldrin and hexachlorobenzene ( HCB) in rats. Environ. Res. 10: 384 389 ( as cited in ATSDR, 2000; IPCS, 1989b).

Ichinose, R. and N. Kurihara. 1985. Uptake of dieldrin, lindane and DDT by isolated hepatocytes. Pestic. Biochem. Physiol. 23: 116 122 ( as cited in IPCS, 1989b).

IPCS. 1989a. International Programme on Chemical Safety. Aldrin and dieldrin health and safety guide. Health and safety guide no. 21. Geneva, Switzerland: World Health Organization, IPCS.

IPCS. 1989b ( Sections 2 and 3). International Programme on Chemical Safety. Aldrin and dieldrin. Environmental health criteria 91. Geneva, Switzerland: World Health Organization, IPCS.

IPCS. 1989 ( Sections 6, 7, 8, 9). International Programme on Chemical Safety. Aldrin and dieldrin. Environmental health criteria 91. Geneva, Switzerland: World Health Organization, IPCS.

Jager, K. W. 1970. Aldrin, dieldrin, endrin and telodrin: an epidemiological and toxicological study of long term occupational exposure. Amsterdam, London, New York: Elsevier Publishing Company, p. 234 ( as cited in IARC, 1974a; IPCS, 1989b; USEPA, 1980). 10 13 Aldrin/ Dieldrin   February 2003 Johns, J. M., J. Liu, N. Bhasin, D. R. Grayson, L. L. Devaud, S. Moy, D. Lubin, and J. M. Lauder. 1998. Prenatal exposure to organochlorine pesticide dieldrin: Effects of postnatal expression of GABA A receptors and behavior in the rat. Society of Neuroscience. 24( Pt 1): 101 ( Abstract).

KAN DO Office and Pesticides Team. 1995. Accumulated Pesticide and Industrial Chemical Findings from a Ten Year Study of Ready to Eat Foods. J. of AOAC Int. 78 ( 3): 614 630.

Kannan, K., S. Tanabe, R. Williams and R. Tatsukawa. 1994. Persistent organochlorine residues in foodstuffs from Australia, Paupa New Guinea and the Solomon Islands: contamination levels and human dietary exposure. Sci. Total Environ. 153: 29 49.

Keane, W. T. and M. R. Zavon. 1969. The total body burden of dieldrin. Bull. Environ. Contam. Toxicol. 4( 1): 1 16 ( as cited in IPCS, 1989b).

Keplinger, M. L., W. B. Deichmann and F. Sala. 1970. Effects of combinations of pesticides on reporduction in mice. In: Pesticides symposia. Miami Beach, FL: Halos and Associates Inc., pp. 125 138 ( as cited in IPCS, 1989b).

Kitselman, C. H. 1953. Long term studies on dogs fed aldrin and dieldrin in sublethal dosages with reference to the histopathological findings and reproduction. J. Am. Vet. Med. Assoc. 123: 28 30 ( as cited in USEPA, 1992).

Kitselman, C. H. and A. R. Borgmann. 1952. A comparative study of the reaction of dogs as a susceptible species to sublethal doses of aldrin and dieldrin. J. Am. Vet. Med. Assoc. 121: 383 385 ( as cited in USEPA 1992).

Klaassen, C. D. 1996. Casarett & Doull's Toxicology. The Basic Science of Poisons. Toxic effects of Pesticides. Fifth Edition. McGraw Hill. C. D. Klaassen, M. O. Amdur, J. Doull ( Editors). p. 652 653.

Klein, A. K., R. E. Dailey, M. S. Walton, V. Beck, and J. D. Link. 1970. Metabolites isolated from urine of rats fed 14C photodieldrin. J. Agric. Food Chem. 18( 4): 705 708 ( as cited in IPCS, 1989b).

Klein, A. K., J. D. Link and N. F. Ives. 1968. Isolation and purification of metabolites found in the urine of male rats fed aldrin and dieldrin. J. Assoc. Anal. Chem. 51: 895 898 ( as cited in ATSDR, 2000; USEPA, 1992); J. Assoc. Off. Agric. Chem. 51: 895 898 ( as cited in IPCS, 1989b); J. Assoc. Off. Chem. 51: 895 ( as cited in USEPA, 1980).

Klevay, L. M. 1970. Diedlrin excretion by the isolated perfused rat liver: a sexual difference. Toxicol. Appl. Pharmacol. 17: 813 815 ( as cited in ATSDR, 2000; IPCS, 1989b). 10 14 Aldrin/ Dieldrin   February 2003 Kohli, K. K., K. K. Magoon, and T. A. Venkitasubramanian. 1977. Induction of mixed function oxidases on oral administration of dieldrin. Chem. Biol. Interact. 17: 249 255 ( as cited in USEPA, 1980).

Kolaja, K. L., Y. Xu, E. F. Walborg, Jr., D. E. Stevenson, and J. E. Klaunig. 1998. Vitamin E modulation of dieldrin induced hepatic focal lesion growth in mice. J. Toxicol. Environ. Health 53: 479 492.

Kolaja, K. L., D. E. Stevenson, J. T. Johnson, E. F. Walborg, Jr., and J. E. Klaunig. 1996a. Subchronic effects of dieldrin and phenobarbital on hepatic DNA synthesis in mice and rats. Fundam. Appl. Toxicol. 29: 219 228.

Kolaja, K. L., D. E. Stevenson, E. F. Walborg, Jr., and J. E. Klaunig. 1996b. Selective dieldrin promotion of hepatic focal lesions in mice. Carcinogenesis 17: 1243 1250.

Kolaja, K. L., D. E. Stevenson, J. T. Johnson, E. F. Walborg, Jr., and J. E. Klaunig. 1995. Hepatic effects of dieldrin and phenobarbital in male B6C3F 1 mice and Fisher 344 rats: species selective induction of DNA synthesis. Prog. Clin. Biol. Res. 391: 397 408.

Kolpin, D. W., J. E. Barbash, and R. J. Gilliom. 1998. Occurrence of pesticides in shallow groundwater of the United States: initial results from the National Water Quality Assessment Program. Environ. Sci. Technol. 32: 558 566.

Korte, F. and H. Arent. 1965. Metabolism of insecticides. IX( 1). Isolation and identification of dieldrin metabolites from urine of rabbits after oral administration of dieldrin 14C. Life Sci. 4: 2017 2026 ( as cited in ATSDR, 2000; IPCS, 1989b; USEPA, 1980).

Korte, F. 1963. Metabolism studies with 14C labeled insecticides. Fifth Int. Pestic. Congress, London, England ( as cited in USEPA, 1980).

Krzystyniak, K., P. Hugo, D. Flipo, and M. Fournier. 1985. Increased susceptibility to mouse hepatitis virus 3 of peritoneal macrophages exposed to dieldrin. Toxicol. Appl. Pharmacol. 80: 397 408 ( as cited in ATSDR, 2000).

Kuehl, D. W., B. Butterworth and P. J. Marquis. 1994. A national study of chemical residues in fish. III: study results. Chemosphere. 29 ( 3): 523 535.

Kurata, M., K. Hirose and M. Umeda. 1982. Inhibition of metabolic cooperation in Chinese hamster cells by organochlorine pesticides. Jpn. J. Cancer Res. 73: 217 221 ( as cited in GAP2000, 2000a, b).

Kurihara, N., N. Hori. and R. Ichinose. 1984. Cytochrome P 450 content and aldrin epoxidation to dieldrin in isolated rat hepatocytes. Pestic. Biochem. Physiol. 21: 63 73 ( as cited in IPCS, 1989b). 10 15 Aldrin/ Dieldrin   February 2003 Kutz, F. W., A. R. Yobs and H. S. C. Yang. 1976. National pesticide monitoring programs. In: Lee R., ed. Air pollution from pesticides and agricultural processes. Cleveland, OH: CRC Press, pp. 95 136 ( as cited in ATSDR, 2000).

Lang, B., K. Frei, and P. Maier. 1986. Prostaglandin synthase dependent aldrin epoxidation in hepatic and extrahepatic tissues of rats. Biochem. Pharmacol. 35: 3643 3645 ( as cited in ATSDR, 1993).

Larson, S. J., R. J. Gilliom, and P. D. Capel. 1999. Pesticides in Streams of the United States Initial Results from the National Water Quality Assessment Program. U. S. Geological Survey Water Resources Investigations Report 98 4222. 92 pp. Available on the Internet at: URL: http:// water. wr. usgs. gov/ pnsp/ rep/ wrir984222/.

Lay, J. P., J. K. Malik, W. Klein, and F. Korte. 1982. Effects of dosing and routes of administration on excretion and metabolism of 14 C dieldrin in rats. Chemosphere 11: 1231 1242 ( as cited in ATSDR, 2000).

Leahy, P. P. and T. H. Thompson. 1994. The National Water Quality Assessment Program. U. S. Geological Survey Open File Report 94 70. 4 pp. Available on the Internet at: http:// water. usgs. gov/ nawqa/ NAWQA. OFR94 70. html Last updated August 23, 2000.

Lehman, A. 1959. Appraisal of the safety of chemicals in foods, drugs and cosmetics. Association of Food and Drug Officials of the United States ( as cited in USEPA, 1992, 1988).

Levengood, J. M., S. C. Ross, M. L. Stahl, and V. R. Beasley. 1999. Organochlorine pesticide and polychlorinated biphenyl residues in Canada geese ( Branta canadensis) from Chicago, Illinois. Vet Hum Toxicol. 41 ( 2): 71 75.

Lewis, Sr., R. J. 1993. Hawley's condensed chemical dictionary, 12th ed. New York, NY: Van Nostrand Reinhold Company, pp. 32, 387.

Lewis, R. G., R. C. Fortmann and D. E. Camann. 1994. Evaluation of methods for monitoring the potential exposure of small children to pesticides in the residential environment. Arch. Environ. Contam. Toxicol. 26 ( 1): 37 46.

Lewis, R. G., A. E. Bond, D. E. Johnson, et al. 1988. Measurement of atmospheric concentrations of common household pesticides: a pilot study. Environ. Monit. Assess. 10: 59 73 ( as cited in ATSDR, 2000).

Liu, J., K. C. Brannen, D. R. Grayson, A. L. Morrow, L. L. Devaud, and J. M. Lauder. 1998. Prenatal exposure to the pesticide dieldrin or the GABA A receptor antagonist bicuculline differentially alters expression of GABA A receptor subunit mRNAs in fetal rat brainstem. Dev. Neurosci. 20: 83 92. 10 16 Aldrin/ Dieldrin   February 2003 Liu, J. A. L. Morrow, L. L. Devaud, D. R. Grayson and J. M. Lauder. 1997. Regulation of GABA A receptor subunit mRNA expression by the pesticide dieldrin in embryonic brainstem cultures: A quantitative competitive reverse transcription Polymerase chain reaction study. J. Neurosci. Res. 49: 645 653.

Loose, L. D. 1982. Macrophage induction of T suppressor cells in pesticide exposed and protozoan infected mice. Environ. Health Perspect. 43: 89 97 ( as cited in ATSDR, 2000; IPCS, 1989b).

Loose L. D., J. B. Silkworth, T. Charbonneau, and F. Blumenstock. 1981. Environmental chemical induced macrophage dysfunction. Environ. Health Perspect. 39: 79 92 ( as cited in ATSDR, 2000; IPCS, 1989b).

Lu, F. C., D. C. Jessup, and A. Lavallee. 1965. Toxicity of pesticide in young versus adult rats. Food Cosmet. Toxicol. 3: 591 596 ( as cited in ATSDR, 2000; IPCS, 1989b).

Ludwig, G., J. Weis and F. Korte. 1964. Excretion and distribution of aldrin 14C and its metabolites after oral administration for a long period of time. Life Sci. 3: 123 130 ( as cited in ATSDR, 2000; IPCS, 1989b; USEPA, 1992, 1988, 1980).

MacDonald, W. E., W. A. D. Anderson, M. Bevilacqua, E. Blum and W. B. Deichmann, unpublished. 1972. The tumorigenicity of dieldrin in the Swiss Webster mouse ( as cited in USEPA, 1987, citing Epstein, 1975a).

MacIntosh, D. L., J. D. Spengler, H. Ozkaynak, L. Tsai, and P. B. Ryan. 1996. Dietary exposures to selected metals and pesticides. Environ Health Perspect. 104 ( 2): 202 209.

MacMonegle Jr., C. W, K. L. Steffey, and W. N. Bruce. 1984. Dieldrin, heptachlor, and chlordane residues in soybeans in Illinois 1974, 1980. J. Environ. Sci. Health, B19: 39 48 ( as cited in Melnyk et al., 1997).

Majumdar, S. K., L. G. Maharam and G. A. Viglianti. 1977. Mutagenicity of dieldrin in the Salmonella microsome test. J. Hered. 68: 184 185 ( as cited in USEPA, 1993b).

Majumdar, S. K., H. A. Kopelman and M. J. Schnitman. 1976. Dieldrin induced chromosome damage in mouse bone marrow and WI 38 human lung cells. J. Hered. 67: 303 307 ( as cited in USEPA, 1988, 1993b).

Markaryan, D. S. 1966. Cytogenic effect of some chlorinated insecticides on mouse bone marrow cell nuclei. Soviet Genetics 2( 1): 80 82 ( as cited in USEPA, 1993b).

Marshall, T. C., H. W. Dorough and H. E. Swim. 1976. Screening of pesticides for mutagenic potential using Salmonella typhimurium mutants. J. Agric. Chem. 24: 560 563 ( as cited in USEPA, 1993b; GAP2000, 2000b). 10 17 Aldrin/ Dieldrin   February 2003 Matthews, H. B., J. D. McKinney, and G. W. Lucier. 1971. Dieldrin metabolism, excretion, and storage in male and female rats. J. Agric. Food Chem. 19( 6): 1244 1248 ( as cited in ATSDR, 2000; IPCS, 1989b; USEPA, 1980).