4
Animal Studies

THE quality and relevance of animal studies that have evaluated the effects of perchlorate exposure have been debated. Accordingly, the committee was tasked with evaluation of those published and unpublished studies. In this chapter, the committee reviews the animal studies with particular attention to those critiqued and used to derive the reference dose in the 2002 U.S. Environmental Protection Agency (EPA) draft risk assessment. Because rats have been used as the primary animal model, the committee first compares thyroid function in rats and humans and then discusses animal studies that investigated the effects of perchlorate exposure on serum thyroid hormone concentrations, thyroid histopathology, brain morphometry, neurobehavior, and thyroid tumors. Physiologically based pharmacokinetic models are also reviewed briefly. Because concerns have been raised about the possibility of effects other than those resulting from altered thyroid function, the chapter concludes with a discussion of general toxicologic evaluations with emphasis on immunologic studies. The toxicologic implications of perchlorate’s interaction with the sodium (Na+)/iodide (I) symporter (NIS) of other tissues and organs are also discussed.

COMPARISON OF THYROID FUNCTION IN RATS AND HUMANS

The fundamental mechanisms involved in the function and regulation of the pituitary-hypothalamus-thyroid system in rats are qualitatively similar to those in humans (Bianco et al. 2002). However, the dynamics of the two systems differ substantially. The biochemical and physiologic differences between rats and humans related to thyroid function are described in the following paragraphs.



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Health Implications of Perchlorate Ingestion 4 Animal Studies THE quality and relevance of animal studies that have evaluated the effects of perchlorate exposure have been debated. Accordingly, the committee was tasked with evaluation of those published and unpublished studies. In this chapter, the committee reviews the animal studies with particular attention to those critiqued and used to derive the reference dose in the 2002 U.S. Environmental Protection Agency (EPA) draft risk assessment. Because rats have been used as the primary animal model, the committee first compares thyroid function in rats and humans and then discusses animal studies that investigated the effects of perchlorate exposure on serum thyroid hormone concentrations, thyroid histopathology, brain morphometry, neurobehavior, and thyroid tumors. Physiologically based pharmacokinetic models are also reviewed briefly. Because concerns have been raised about the possibility of effects other than those resulting from altered thyroid function, the chapter concludes with a discussion of general toxicologic evaluations with emphasis on immunologic studies. The toxicologic implications of perchlorate’s interaction with the sodium (Na+)/iodide (I−) symporter (NIS) of other tissues and organs are also discussed. COMPARISON OF THYROID FUNCTION IN RATS AND HUMANS The fundamental mechanisms involved in the function and regulation of the pituitary-hypothalamus-thyroid system in rats are qualitatively similar to those in humans (Bianco et al. 2002). However, the dynamics of the two systems differ substantially. The biochemical and physiologic differences between rats and humans related to thyroid function are described in the following paragraphs.

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Health Implications of Perchlorate Ingestion Thyroid hormones in serum are extensively bound to plasma proteins. The proteins that bind thyroxine (T4) and triiodothyronine (T3) vary widely among species, and their binding affinities for the thyroid hormones also differ. In humans and other primates, thyroxine-binding globulin (TBG) is the principal protein that binds T4 (Dohler et al. 1979). It has a very high affinity for T4: only about 0.03% of the T4 in serum is in the free unbound form (Hill et al. 1989). Binding sharply reduces clearance of T4 from serum. Rats do not have TBG, and most T4 in rat serum is bound to albumin and transthyretin. The binding affinity of T4 for TBG is more than a 100 times greater than that of albumin or transthyretin (Hill et al. 1989), and the difference contributes to the higher rate of T4 clearance in rats. The increased clearance contributes to the need for a higher rate of production of T4 per unit of body weight in rats to maintain normal concentrations of T4 (Dohler et al. 1979). The higher production rate is reflected in the histologic appearance of the rat thyroid, which has small thyroid follicles that contain much less colloid than those of primates (McClain 1995). Those features give the rat thyroid a more “functionally active” histologic appearance than that of primates, including humans. The follicular epithelium in rats is cuboidal; that of monkeys appears flattened in comparison. The change in the height of the follicular cells from flattened to cuboidal to columnar represents follicular-cell hypertrophy and is characteristic of the increased functional activity. There appear to be some differences in the metabolism of T4 by the liver between rats and humans. Some 50% of T4 is eliminated via bile in rats, but only 10-15% in humans (Hill et al. 1989). The difference does not reflect a qualitative difference in metabolism, because the major metabolite in bile (glucuronide conjugate) is the same in both species (Hard 1998). The biochemical and physiologic differences between rats and humans related to the thyroid affect their responses to goitrogens, such as perchlorate. For example, Yu et al. (2002) evaluated inhibition of radioiodide uptake by the thyroid in rats exposed to perchlorate in drinking water at 0, 1.0, 3.0, and 10.0 mg/kg of body weight for 1, 5, and 14 days. After 1 day of perchlorate administration, inhibition of iodide uptake was about 15%, 55%, and 65% at 1.0, 3.0, and 10 mg/kg, respectively. After 5 days, inhibition of iodide uptake was 0, 10%, and 30%. After 14 days, inhibition of iodide uptake was observed only at 10 mg/kg. The data show that the initial inhibition of radioiodide uptake by perchlorate in rats is similar to that in humans. However, rats compensated for the inhibition within 5 days of perchlorate administration, most likely by increasing the expression of NIS in the thyroid. A similar response was not observed in a 14-day human study with perchlorate administration (Greer et al. 2002). The data suggest

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Health Implications of Perchlorate Ingestion that compensation occurs more quickly in rats because rats have a smaller reserve capacity of thyroid hormones than humans. Another example of different responses to perchlorate is related to changes in serum concentrations of thyroid hormones and thyrotropin (thyroid-stimulating hormone, TSH). For example, Siglin et al. (2000) treated male and female rats with ammonium perchlorate at 0.01-10 mg/kg per day. At 14 days, serum T4 concentrations were significantly decreased at 10 mg/kg per day in both male and female rats. Serum T3 concentrations were significantly decreased in males at 0.01 mg/kg per day or higher. No significant decreases were observed in serum T3 concentrations at any dose in female rats. Serum TSH concentrations were significantly increased at 0.20 mg/kg per day or higher in males and at 0.05 mg/kg per day or higher in females. Studies in adult humans have not found increases in serum TSH or decreases in serum T4 or T3 with potassium perchlorate exposure over a similar period. For example, administration of 10 mg of potassium perchlorate per day (0.1 mg/kg of perchlorate per day assuming a 70-kg human) to healthy men for 14 days resulted in no changes in serum thyroid hormone or TSH concentrations during the exposure period (Lawrence et al. 2000). Similarly, Greer et al. (2002) found no decreases in serum thyroid hormones or increases in serum TSH in healthy men and women given perchlorate at up to 0.5 mg/kg per day for 14 days. There are important differences between rats and humans in pituitary-thyroid function during pregnancy. In humans, serum total T4 and T3 concentrations rise progressively—on the average, about 50% during the first trimester of pregnancy—and remain increased during the remainder of pregnancy (Glinoer 1997). That response is due to an increase in serum TBG, which is stimulated by an increase in estrogen production (see Chapter 2). During the first trimester, serum free T4 and T3 concentrations also increase slightly because of stimulation of the thyroid gland by chorionic gonadotropin, a hormone produced by the placenta. The primary action of chorionic gonadotropin is to sustain pregnancy, but it also has weak thyroid-stimulating activity. The increases in serum free T4 and T3 concentrations decrease TSH secretion slightly in pregnant women. Later in pregnancy, the decrease in production of chorionic gonadotropin results in a return of serum free T4, T3, and TSH to concentrations comparable with those in nonpregnant women and in men. Thyroid hormone concentrations change during pregnancy in rats, but detailed studies are limited to gestation days 17-22. During gestation days 17-22, serum T4 concentrations in pregnant rats are significantly lower than those in nonpregnant female rats (Fukuda et al. 1980; Calvo et al. 1990;

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Health Implications of Perchlorate Ingestion Versloot et al. 1994). The differences in serum thyroid hormone concentrations between pregnant rats and women are related largely to the lack of TBG and absence of chorionic gonadotropin production in rats. There are also differences between rats and humans in the timing of development of thyroid function. Thyroid function in rats at birth is relatively immature, equivalent to that of a third-trimester human fetus. The human fetus is protected by maternal thyroid hormone for a longer period of development. In rats, serum total T4 and T3 concentrations increase between postnatal days 5 and 15 in association with an increase in a serum thyroid hormone-binding globulin (Obregon et al. 1991). Thereafter, the production of that binding protein decreases, and therefore, serum T4 and T3 concentrations fall (Vranckx et al. 1994). Thus, thyroid function and regulation are qualitatively similar in rats and humans, but important differences in serum thyroid hormone binding and clearance rates and thyroid stimulation by a placental hormone in pregnant women lead to important quantitative differences between the two species. The species differences must be carefully considered in interpreting serum thyroid hormone, TSH, and thyroid histopathology data in studies that use rats to assess human health risk associated with perchlorate exposure. THYROID HORMONES AND THYROID HISTOPATHOLOGY The committee reviewed published literature and laboratory study reports on the effects of perchlorate exposure on thyroid hormones, TSH, and thyroid histopathology in animals. The discussion here focuses on the Argus (2001) study because it provides a comprehensive evaluation of those entities in the most sensitive populations—pregnant females, fetuses, and neonates. The findings of the Argus study are generally consistent with those of previous studies. Inconsistencies are most likely due to small sample sizes that were used in some of the other studies or to differences in study design, such as use of animals at different stages of development. In Argus (2001), female rats (dams) were exposed to perchlorate through gestation and lactation. Ammonium perchlorate was administered in drinking water at concentrations that provided doses of 0, 0.01, 0.1, 1.0, and 30 mg/kg per day. Administration began 2 weeks before mating and extended through postnatal day 22. The offspring were exposed to perchlorate in utero, through their mother’s milk, and through any consumption of the perchlorate-containing drinking water provided to their mothers. Serum thyroid hormones and TSH were measured on gestation day 21 in the dams

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Health Implications of Perchlorate Ingestion and fetuses, on postnatal days 10 and 22 in the dams, and on postnatal days 5, 10, and 22 in the pups. Histologic thyroid evaluations were conducted on the same schedule as the hormone analyses. Standard toxicologic, reproductive, and developmental end points also were evaluated. Findings regarding neurodevelopmental measures are discussed in the next section. Changes in thyroid hormones and TSH are illustrated in Figures 4-1 and 4-2. Statistically significant differences between control and perchlorate dose groups as determined by Argus (2001) are indicated in the figures. The changes were consistent with those of previous rat studies and with perchlorate’s known mode of action in inhibiting the NIS. There were dose-related increases in serum TSH and dose-related decreases in serum total T4 and T3 in the dams, fetuses, and pups. Overall, the dams appeared to be more sensitive to perchlorate administration than the fetuses or pups, and the most dramatic changes in the dams were observed on gestation day 21. Although a downward trend was observed in serum T3 in the dams, it appeared to be a less sensitive marker than T4. Serum T3 was decreased significantly only during gestation and only at the highest dose (30 mg/kg per day), whereas serum T4 was decreased significantly at all doses during gestation and at the highest dose on postnatal days 10 and 22. An important point is that the serum T4 levels of control rats on gestation day 21 were substantially lower than those of female rats on postnatal days 10 and 22. Those data are consistent with the literature, as discussed previously, and suggest a low thyroid hormone reserve in pregnant rats. Another way to evaluate the data is to calculate the percentage change from the control value. Figure 4-3 illustrates the changes from controls in serum TSH, T4, and T3 in dams, fetuses, and pups at the different evaluation times. Several points should be noted. First, the greatest changes from control values were observed in TSH in the dams, particularly in the highest-dose group. For example, on gestation day 21, when the greatest changes were observed, TSH was increased by 35% at 0.01 mg/kg per day, 50% at 0.1 mg/kg per day, 64% at 1.0 mg/kg per day, and 146% at 30 mg/kg per day. Second, T4 and T3 in the dams differed by only about 10% or less from that in controls at the different evaluation times, with the notable exception of T4 on gestation day 21, which was decreased by 11% at 0.01 mg/kg per day, 45% at 0.1 mg/kg per day, 48% at 1.0 mg/kg per day, and 54% at 30 mg/kg per day. Third, presentation of the data as percentage changes from the control more clearly illustrates the greater sensitivity of T3 in the pups than in the dams and the greater sensitivity of perchlorate-associated decreases in serum T3 than in T4 in the pups. Fourth, the data from postnatal day 22 indicate that males have a greater reduction than females in total T4 and T3 compared with controls.

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Health Implications of Perchlorate Ingestion FIGURE 4-1 (Top) Serum thyroxine (T4) concentrations in dams treated with ammonium perchlorate at indicated doses in drinking water. (Middle) Serum triiodothyronine (T3) concentrations in same animals. (Bottom) Serum thyroid-stimulating hormone (TSH) in same animals. Values presented as mean ± SD of 14-16 animals (data from Argus 2001). Abbreviations: GD, day of gestation; PND, postnatal day; *, significantly different from control, p ≤ 0.05; **, significantly different from control, p ≤ 0.01; *** significantly different from control, p ≤ 0.001.

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Health Implications of Perchlorate Ingestion Histologic evaluations of the thyroid gland were conducted at the same times as those of thyroid hormones and TSH. Absolute and relative thyroid weights were significantly increased in the dams at 30 mg/kg per day at all evaluation times. A similar trend was noted in absolute thyroid weight in male and female pups over the course of the study. Statistically significant increases in absolute thyroid weights also were observed in all groups of male pups on postnatal day 10 and in females at 1.0 mg/kg per day on postnatal day 22. Histologic examination of the thyroid gland revealed colloid depletion, follicular-cell hypertrophy, and follicular-cell hyperplasia in the dams (see Table 4-1). Those effects were mainly restricted to the highest-dose group (30 mg/kg per day), although colloid depletion and follicular-cell hyperplasia were increased at 1.0 mg/kg per day on postnatal days 10 and 22, respectively. The predominant effect in the fetuses and pups was colloid depletion (see Table 4-2). Colloid depletion was present primarily in the highest-dose group (30 mg/kg per day) but was somewhat increased on several evaluation days in the 1.0-mg/kg group. Follicular-cell hyperplasia was noted occasionally in a few pups, but no clear dose-response trends were noted. The committee has concerns about the reliability of the thyroid histopathology data, particularly those on the dams. For example, hyperplasia was observed on postnatal day 22 at the lower doses in the absence of hypertrophy, which typically does not occur in rats. The data at the highest dose appeared to be more reliable inasmuch as the expected TSH-mediated morphologic changes in the thyroid were observed: colloid depletion, follicular-cell hypertrophy, and follicular-cell hyperplasia. The histologic data on the fetuses and pups were more consistent. Colloid depletion of thyroid follicles, although a subjective morphologic end point, was the most consistent histologic finding in rat fetuses and pups on all evaluation days. It was observed consistently in the highest-dose animals and, to a smaller extent, in the 1.0-mg/kg group. The thyroid morphology of the two lower-dose groups of animals (0.01 and 0.1 mg/kg per day) was similar to that of control animals.

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Health Implications of Perchlorate Ingestion FIGURE 4-2 (Upper Left) Serum thyroxine (T4) concentrations in fetus and pups of dams treated with ammonium perchlorate at indicated doses in drinking water. (Upper Right) Serum triiodothyronine (T3) concentrations in same animals. (Lower Left) Serum thyroid-stimulating hormone (TSH) in same animals. Values reported as the mean ± SD of 11-17 animals except for T3 measures at day 21 of gestation, when two to eight animals were used to derive values (data from Argus 2001). F, female; GD, gestation day; M, male; PND, postnatal day; *, significantly different from control, p ≤ 0.05; **, significantly different from control, p ≤ 0.01; ***, significantly different from control, p ≤ 0.001.

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Health Implications of Perchlorate Ingestion TABLE 4-1 Thyroid Histopathology in Control Dams and Dams Given Four Doses of Perchlorate   Dose (mg/kg per day) Evaluation Day and Effect 0 0.01 0.1 1.0 30.0 Gestation day 21 Colloid depletion 0/16 0/16 0/16 0/15 16/16 Follicular-cell hypertrophy 0/16 0/16 0/16 0/15 14/16 Follicular-cell hyperplasia 0/16 0/16 0/16 0/15 2/16 Postnatal day 10 Colloid depletion 0/16 1/16 1/16 5/16 16/16 Follicular-cell hypertrophy 0/16 0/16 1/16 0/16 16/16 Follicular-cell hyperplasia 0/16 0/16 1/16 2/16 9/16 Postnatal day 22 Colloid depletion 0/16 0/16 1/15 1/16 16/16 Follicular-cell hypertrophy 0/16 0/16 0/15 0/16 14/16 Follicular-cell hyperplasia 3/16 4/16 5/15 10/16 10/16 Source: Data from Argus 2001. TABLE 4-2 Thyroid Histopathology in Control and Perchlorate-Exposed Fetuses and Pups Dose (mg/kg per day) Evaluation Day and Effect 0 0.01 0.1 1.0 30.0 Gestation day 21—Fetuses Colloid depletion—males 0/16 2/16 0/16 12/16 16/16 Colloid depletion—females 0/16 1/16 1/16 13/16 16/16 Postnatal day 5—Pups Colloid depletion—males 0/16 2/16 0/16 4/16 16/16 Colloid depletion—females 0/16 0/16 0/16 6/16 16/16 Postnatal day 10—Pups Colloid depletion—males 0/16 1/16 1/16 1/16 16/16 Colloid depletion—females 0/16 0/16 1/16 4/16 15/15 Postnatal day 22—Pups Colloid depletion—males 0/16 0/16 0/15 0/16 11/16 Colloid depletion—females 0/16 0/16 0/15 0/15 12/16 Source: Data from Argus 2001.

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Health Implications of Perchlorate Ingestion

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Health Implications of Perchlorate Ingestion FIGURE 4-3 Changes in serum T4, T3, and TSH in dams (a, c, e) and fetuses and pups (b, d, f) presented as percent change from control (data for calculations were those of Argus 2001). Abbreviations: F, female; GD, gestation day; M, male; PND, postnatal day.

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Health Implications of Perchlorate Ingestion There are no data to suggest that perchlorate has effects that are not mediated through inhibition of iodide transport in the thyroid gland. It is not possible to extrapolate data quantitatively from rodents to humans for purposes of human health risk assessment. Most experimental studies in animals designed to characterize the effects of perchlorate exposure have been done in rats. However, rats are much more sensitive to agents that disturb thyroid function than are humans, so the relevance of rat studies in quantitative terms to humans is limited. REFERENCES Altman, J., and S.A. Bayer. 1997. Epilogue: Behavioral consequences of experimental interference with cerebellar development. Pp. 726-751 in Development of the Cerebellar System: In Relation to Its Evolution, Structure, and Functions. Boca Raton: CRC Press. Alvarez-Dolado, M., M. Ruiz, J.A. Del Rio, S. Alcantara, F. Burgaya, M. Sheldon, K. Nakajima, J. Bernal, B.W. Howell, T. Curran, E. Soriano, and A. Munoz. 1999. Thyroid hormone regulates reelin and dab1 expression during brain development. J. Neurosci. 19(16):6979-6993. Alvarez-Dolado, M., A. Cuadrado, C. Navarro-Yubero, P. Sonderegger, A.J. Furley, J. Bernal, and A. Munoz, A. 2000. Regulation of the L1 cell adhesion molecule by thyroid hormone in developing brain. Mol. Cell. Neurosci. 16(4):499-514. Alvarez-Dolado, M., A. Figueroa, S. Kozlov, P. Sonderegger, A.J. Furley, and A. Munoz. 2001. Thyroid hormone regulates TAG-1 expression in the developing rat brain. Eur. J. Neurosci. 14(8):1209-1218. Andersson, T., J. Angstrom, K.E. Falk, and S. Forsen. 1980. Perchlorate finding to cytochrome c: A magnetic and optical study. Eur. J. Biochem. 110(2):363-369. Arai, Y., L. Oreland, and H. Kinemuchi. 1984. Effect of perchlorate treatment on mitochondrial MAO-A and -B activities. Med. Biol. 62(4):245-249. Argus Research Laboratories, Inc. 1998. A Neurobehavioral Developmental Study of Ammonium Perchlorate Administered Orally in Drinking Water to Rats. ARGUS 1613-002. Argus Research Laboratories, Inc., Horsham, PA. [See also York, R.G., J. Barnett, W.R. Brown, R.H. Garman, D.R. Mattie, and D. Dodd. 2004. A rat neurodevelopmental evaluation of offspring, including evaluation of adult and neonatal thyroid, from mothers treated with ammonium perchlorate in drinking water. Int. J. Toxicol. 23(3):191-214.] Argus Research Laboratories, Inc. 1999. Oral (Drinking Water) Two-Generation (One Litter per Generation) Reproduction Study of Ammonium Perchlorate in Rats. ARGUS 1416-001. Argus Research Laboratories, Inc., Horsham, PA. Argus Research Laboratories, Inc. 2001. Hormone, Thyroid and Neurohistological Effects of Oral (Drinking Water) Exposure to Ammonium Perchlorate in Pregnant and Lactating Rats and in Fetuses and Nursing Pups Exposed to

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Health Implications of Perchlorate Ingestion Ammonium Perchlorate During Gestation or Via Maternal Milk. ARGUS 1416-003. Argus Research Laboratories, Inc., Horsham, PA. Becker, J.T., J.A. Walker, and D.S. Olton. 1980. Neuroanatomical bases of spatial memory. Brain Res. 200(2):307-320. Bekkedal, M.Y.V., T. Carpenter, J. Smith, C. Ademujohn, D. Maken, and D.R. Mattie. 2000. A Neurodevelopmental Study of Oral Ammonium Perchlorate Exposure on the Motor Activity of Pre-Weanling Rat Pup. Report No. TOXDET-00-03. Neurobehavioral Effects Laboratory, Naval Health Research Center Detachment (Toxicology), Wright-Patterson Air Force Base, OH. Berbel, P., A. Guadano-Ferraz, M. Martinez, J.A. Quiles, R. Balboa, and G.M. Innocenti. 1993. Organization of auditory callosal connections in hypothyroid adult rats. Eur. J. Neurosci. 5(11):1465-1478. Berry, S.M. 2000. Meta-analysis versus Large Trials: Resolving the controversy. Pp. 65-81 in Meta-Analysis in Medicine and Health Policy, D. Stangl, and D.A. Berry, eds. New York: Marcel Dekker. Bianco, A.C., D. Salvatore, B. Gereben, M.J. Berry, and P.R. Larsen. 2002. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr. Rev. 23(1):38-89. Bidart, J.M., L. Lacroix, D. Evain-Brion, B. Caillou, V. Lazar, R. Frydman, D. Bellet, S. Filetti, and M. Schlumberger. 2000. Expression of Na+/I- symporter and Pendred syndrome genes in trophoblast cells. J. Clin. Endocrinol. Metab. 85(11):4367-4372. Blalock, J.E. 1994. The syntax of immune-neuroendocrine communication. Immunol. Today 15(11):504-511. Bookstein, F.L., A.P. Streissguth, P.D. Sampson, P.D. Connor, and H.M. Barr. 2002. Corpus callosum shape and neuropsychological deficits in adult males with heavy fetal alcohol exposure. Neuroimage 15(1):233-251. Brosvic, G.M., J.N. Taylor, and R.E. Dihoff. 2002. Influences of early thyroid hormone manipulations: Delays in pup motor and exploratory behavior are evident in adult operant performance. Physiol. Behav. 75(5):697-715. BRT-Burleson Research Technologies, Inc. 2000a. Ammonium Perchlorate: Effect on Immune Function. Quality Assurance Audit: Study No. BRT 19990524—Plaque-Forming Cell (PFC) Assay; Study No. BRT 19990525-Local Lymph Node Assay (LLNA) in Mice. BRT-Burleson Research Technologies, Inc., Raleigh, NC. June 30, 2000. BRT-Burleson Research Technologies, Inc. 2000b. Addendum to Study Report: Ammonium Perchlorate: Effect on Immune Function. BRT 19990524 Study Protocol Plaque-Forming Cell (PFC) Assay; BRT 19990525 Study Protocol Local Lymph Node Assay (LLNA) in Mice. BRT-Burleson Research Technologies, Inc., Raleigh, NC. August 31, 2000. BRT-Burleson Research Technologies, Inc. 2000c. Ammonium Perchlorate: Effect on Immune Function. Study Report. BRT 19990524 Study Protocol Plaque-Forming Cell (PFC) Assay; BRT 19990525 Study Protocol Local Lymph Node Assay (LLNA) in Mice. BRT-Burleson Research Technologies, Inc., Raleigh, NC.

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Health Implications of Perchlorate Ingestion Calvo, R., M.J. Obregon, C. Ruiz de Ona, B. Ferreiro, E. Escobar del Rey, and G. Morreale de Escobar. 1990. Thyroid hormone economy in pregnant rats near term: A “physiological” animal model of nonthyroidal illness? Endocrinology 127(1):10-16. Cho, J.Y., R. Leveille, R. Kao, B. Rousset, A.F. Parlow, W.E. Burak Jr., E.L. Mazzaferri, and S.M. Jhiang. 2000. Hormonal regulation of radioiodide uptake activity and Na+/I− symporter expression in mammary glands. J. Clin. Endocrinol. Metab. 85(8):2936-2943. Clewell, R.A., E.A. Merrill, and P.J. Robinson. 2001. The use of physiologically based models to integrate diverse data sets and reduce uncertainty in the prediction of perchlorate and iodide kinetics across life stages and species. Toxicol. Ind. Health 17(5-10):210-222. Clewell, R.A., E.A. Merrill, K.O. Yu, D.A. Mahle, T.R. Sterner, D.R. Mattie, P.J. Robinson, J.W. Fisher, and J.M. Gearhart. 2003a. Predicting fetal perchlorate dose and inhibition of iodide kinetics during gestation: A physiologically-based pharmacokinetic analysis of perchlorate and iodide kinetics in the rat. Toxicol. Sci. 73(2):235-255. Clewell, R.A., E.A. Merrill, K.O. Yu, D.A. Mahle, T.R. Sterner, J.W. Fisher, and J.M. Gearhart. 2003b. Predicting neonatal perchlorate dose and inhibition of iodide uptake in the rat during lactation using physiologically-based pharmacokinetic modeling. Toxicol. Sci. 74(2):416-436. Crofton, K.M., D. Ding, R. Padich, M. Taylor, and D. Henderson. 2000. Hearing loss following exposure during development to polychlorinated biphenyls: A cochlear site of action. Hear. Res. 144(1-2):196-204. Csernoch, L., L. Kovacs, and G. Szucs. 1987. Perchlorate and the relationship between charge movement and contractile activation in frog skeletal muscle fibers. J. Physiol. 390:213-227. Dohan, O., A. De La Vieja, V. Paroder, C. Riedel, M. Artani, M. Reed, C.S. Ginter, and N. Carrasco. 2003. The sodium/iodide Symporter (NIS): Characterization, regulation, and medical significance. Endocr. Rev. 24(1):48-77. Dohler, K.D., C.C. Wong, and A. von zur Muhlen. 1979. The rat as model for the study of drug effects on thyroid function: Consideration of methodological problems. Pharmacol. Ther. 5(1-3):305-318. Dunson, D.B. 2001. Statistical Analysis of the Effects of Perchlorate on Neurobehavior (Motor Activity) in SD Rats. Memorandum to Annie M. Jarabek, National Center for Environmental Assessment (MD-52), U.S. Environmental Protection Agency, Research Triangle Park, NC, from David B. Dunson, Biostatistics Branch (MD A3-03), National Institute of Environmental Health Sciences, Research Triangle Park, NC. November 11, 2001. [Online]. Available: http://www.epa.gov/ncea/perchlorate/references2/documents/100510.pdf [accessedJuly 19, 2004]. Elberger, A.J. 2003. Omaha Perchlorate Meeting – Module A. Analysis and Interpretation of Neurodevelopmental Rat Brain Morphometry Studies. Presentation at the Second Meeting on Assess the Health Implications of Perchlorate Ingestion, December 13, 2003, Irvine, CA.

OCR for page 115
Health Implications of Perchlorate Ingestion EPA (U.S. Environmental Protection Agency). 1998a. Health Effects Test Guidelines OPPTS 870.6300 Developmental Neurotoxicity Study. EPA 712-C-98-239. Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC. [Online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-6300.pdf [accessed August 23, 2004]. EPA (U.S. Environmental Protection Agency). 1998b. Assessment of Thyroid-Follicular Cell Tumors. EPA/630/R-97/002. Risk Assessment Forum, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. [Online]. Available: http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=13102 [accessed November 22, 2004]. EPA (U.S. Environmental Protection Agency). 2002a. Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization. External Review Draft. NCEA-1-0503. National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. [Online]. Available: http://cfpub1.epa.gov/ncea/cfm/recordisplay.cfm?deid=24002 [accessed August 23, 2004] EPA (U.S. Environmental Protection Agency). 2002b. Report on the Peer Review of the U.S. Environmental Protection Agency’s Draft External Review Document “Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization”. EPA/635/R-02/003. National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. [Online]. Available: http://www.epa.gov/ncea/pdfs/perchlorate/final_rpt.pdf [accessed August 23, 2004]. EPA (U.S. Environmental Protection Agency). 2003. Disposition of Comments and Recommendations for Revisions to "Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization External Review Draft (January 16, 2002). Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. [Online]. Available: http://cfpub2.epa.gov/ncea/cfm/recordisplay.cfm?deid=72117 [accessed August 25, 2004]. Fabris, N., E. Mocchegiani, and M. Provinciali. 1995. Pituitary-thyroid axis and immune system: A reciprocal neuroendocrine-immune interaction. Horm. Res. 43(1-3):29-38. Fernandez Rodriguez, A., H. Galera Davidson, M. Salguero Villadiego, A. Moreno Fernandez, I. Martin Lacave, and J. Fernandez Sanz. 1991. Induction of thyroid proliferative changes in rats treated with antithyroid compound. Anat. Histol. Embryol. 20(4):289-298. Fernandez-Santos, J.M., M. De-Miguel, R. Gonzalez-Campora, M. Salguero-Villadiego, J.J. Cabrera, and H. Galera-Davidson. 2004. Ki-ras mutational analysis in rat follicular-cell proliferative lesions of the thyroid gland induced by radioactive iodine and potassium perchlorate. J. Endocrinol. Invest. 27(1):12-17. Fisher, J.W. 2000. Consultative Letter, AFRL-HE-WP-CL-2000-0035, Physiological Model for Inhibition of Thyroidal Uptake of Iodide by Perchlorate in the Rat. Memorandum to Annie M. Jarabek, National Center for Environmental

OCR for page 115
Health Implications of Perchlorate Ingestion Assessment (MD-52), U.S. Protection Agency, Research Triangle Park, NC, from Jeffrey W. Fisher, Air Force Research Laboratory, Wright-Patterson Air Force Base, OH. June 28, 2000. Frankel, B.J., and J. Sehlin. 1994. Effect of perchlorate on glucose–stimulated insulin release and 45Ca2+ uptake in pancreatic islets from diabetic Chinese hamsters. Pancreas 9(5):550-557. Fukuda, H., K. Ohshima, M. Mori, I. Kobayashi, and M.A. Greer. 1980. Sequential changes in the pituitary-thyroid axis during pregnancy and lactation in the rat. Endocrinology 107(6):1711-1716. Gauger, K.J., Y. Kato, K. Haraguchi, H.J. Lehmler, L.W. Robertson, R. Bansal, and R. Zoeller. 2004. Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors. Environ. Health Perspect. 112(5):516-523. Geller, A.M. 2003. Revised Brain Morphometry Analysis Incorporating Consultant in Veterinary Pathology (2003) Review of Morphometry Data from Argus 1416-003. Memorandum to Annie M. Jarabek, National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC, from A.M. Geller, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC. September 19, 2003. Glinoer, D. 1997. The regulation of thyroid function in pregnancy: Pathways of endocrine adaptation from physiology to pathology. Endocr. Rev. 18(3):404-433. Goldey, E.S., and K.M. Crofton. 1998. Thyroxine replacement attenuates hypothyroxinemia, hearing loss, and motor deficits following developmental exposure to Aroclor 1254 in rats. Toxicol. Sci. 45(1):94-105. Goldey, E.S., L.S. Kehn, C. Lau, G.L. Rehnberg, and K.M. Crofton. 1995a. Developmental exposure to polychlorinated biphenyls (Aroclor 1254) reduces circulating thyroid hormone concentrations and causes hearing deficits in rats. Toxicol. Appl. Pharmacol. 135(1):77-88. Goldey, E.S., L.S. Kehn, G.L. Rehnberg, and K.M. Crofton. 1995b. Effects of developmental hypothyroidism on auditory and motor function in the rat. Toxicol. Appl. Pharmacol. 135(1):67-76. Gomolla, M., G. Gottschalk, and H.C. Luttgau. 1983. Perchlorate-induced alterations in electrical and mechanical parameters of frog muscle fibres. J. Physiol. 343:197-214. Gould, E., A. Westlind-Danielsson, M. Frankfurt, and B.S. McEwen. 1990. Sex differences and thyroid hormone sensitivity of hippocampal pyramidal cells. J. Neurosci. 10(3):996-1003. Gravel, C., and R. Hawkes. 1990. Maturation of the corpus callosum of the rat: I. Influence of thyroid hormones on the topography of callosal projections. J. Comp. Neurol. 291(1):128-146. Greer, M.A., G. Goodman, R.C. Pleus, and S.E. Greer. 2002. Health effects assessment for environmental perchlorate contamination: The dose response

OCR for page 115
Health Implications of Perchlorate Ingestion for inhibition of thyroidal radioiodine uptake in humans. Environ. Health Perspect. 110(9):927-937. Hard, G.C. 1998. Recent developments in the investigation of thyroid regulation and thyroid carcinogenesis. Environ. Health Perspect. 106(8):427-436. Harry, J. 2001. Re: Comments on Original Experimental Design, Study Performance, and Brain Morphometry Results of Argus Research Laboratories, Inc. 14 March 2001 Study (Protocol Number 1416-003) and Supplemental Materials Provided by Dr. Robert Garman, Consultants in Veterinary Pathology, Inc. Letter to Annie M. Jarabek, National Center for Environmental Assessment, U.S. Environmental Protection Agency, from Jean Harry, Acting Chief, Laboratory of Toxicology Neurotoxicology Group Leader, National Institute of Environmental Health Sciences, Research Triangle Park, NC. October 11, 2001. Hiasa, Y., Y. Kitahori, Y. Kato, M. Ohshima, N. Konishi, T. Shimoyama, Y. Sakaguchi, H. Hashimoto, S. Minami, and Y. Murata. 1987. Potassium perchlorate, potassium iodide, and propylthiouracil: Promoting effect on the development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)-nitrosamine. Jpn. J. Cancer Res. 78(12):1335-1340. Hill, R.N., L.S. Erdreich, O.E. Paynter, P.A. Roberts, S.L. Rosenthal, and C.F. Wilkinson. 1989. Thyroid follicular cell carcinogenesis. Fundam. Appl. Toxicol. 12(4):629-697. IARC (International Agency for Research on Cancer). 2001. Pp. 40-41 in Some Thyrotropic Agents, IARC Monographs on the Evaluation of Carcinogenic Risk to Humans, Vol. 79. Lyon, France: International Agency for Research on Cancer. Keil, D., A. Warren, M. Jenny, J. EuDaly, and R. Dillard. 1998. Effects of Ammonium Perchlorate on Immunotoxicological, Hematological, and Thyroid Parameters in B6C3F1 Female Mice. DSWA01-97-0008. Medical University of South Carolina, Charleston, SC. September 30, 1998. [Online]. Available: http://www.epa.gov/ncea/perchlorate/references2/documents/44966.pdf [accessed August 25, 2004.] Keil, D., A. Warren, M. Jenny, J. EuDaly, and R. Dillard. 1999. Effects of Ammonium Perchlorate on Immunotoxicological, Hematological, and Thyroid Parameters in B6C3F1 Female Mice, Final Report. DSWA01-97-0008. Medical University of South Carolina, Charleston, SC. June 19, 1999. [Online]. Available: http://www.epa.gov/ncea/perchlorate/references2/documents/99555.pdf [accessed July 16, 2004]. Kessler, M.E., and H.L. Kruskemper. 1966. Experimental thyroid tumors caused by long-term potassium perchlorate administration. [in German]. Klin Wochenschr. 44(19):1154-1156. Klecha, A.J., A.M. Genaro, A.E. Lysionek, R.A. Caro, A.G. Coluccia, and G.A. Cremaschi. 2000. Experimental evidence pointing to the bidirectional interaction between the immune system and the thyroid axis. Int. J. Immunopharmacol. 22(7):491-500.

OCR for page 115
Health Implications of Perchlorate Ingestion Klintsova, A.Y., C.R. Goodlett, and W.T. Greenough. 2000. Therapeutic motor training ameliorates cerebellar effects of postnatal binge alcohol. Neurotoxicol. Teratol. 22(1):125-132. Knipper, M., C. Zinn, H. Maier, M. Praetorius, K. Rohbock, I. Kopschall, and U. Zimmermann. 2000. Thyroid hormone deficiency before the onset of hearing causes irreversible damage to peripheral and central auditory systems. J. Neurophysiol. 83(5):3101-3112. Koibuchi, N., S. Yamaoka, and W.W. Chin. 2001. Effect of altered thyroid status on neurotrophin gene expression during postnatal development of the mouse cerebellum. Thyroid 11(3):205-210. Kornblatt, M.J., A. Al-Ghanim, and J.A. Kornblatt. 1996. The effects of sodium perchlorate on rabbit muscle enolase--Spectral characterization of the monomer. Eur. J. Biochem. 236(1):78-84. Larsson-Nyren, G. 1996. Perchlorate is hypoglycemic by amplifying glucose-stimulated insulin secretion in mice. Acta Physiol. Scand. 158(1):71-76. Larsson-Nyren, G., J. Sehlin, P. Rorsman, and E. Renstrom. 2001. Perchlorate stimulates insulin secretion by shifting the gating of L-type Ca2+ currents in mouse pancreatic B-cells towards negative potentials. Pflugers Arch. 441(5):587-595. Lasky, R.E., J.J. Widholm, K.M. Crofton, and S.L. Schantz. 2002. Perinatal exposure to Aroclor 1254 impairs distortion product otoacoustic emissions (DPOAEs) in rats. Toxicol. Sci. 68(2):458-464. Lauder, J.M. 1977. The effects of early hypo- and hyperthyroidism on the development of rat cerebellar cortex. III. Kinetics of cell proliferation in the external granular layer. Brain Res. 126(1):31-51. Lawrence, J.E., S.H. Lamm, S. Pino, K. Richman, and L.E. Braverman. 2000. The effect of short-term low-dose perchlorate on various aspects of thyroid function. Thyroid 10(8):659-663. Legrand, J. 1986. Thyroid hormone effects on growth and development. Pp. 503-534 in Thyroid Hormone Metabolism, G. Hennemann, ed. New York: Marcel Dekker. Luster, M.I., A.E. Munson, P.T. Thomas, M.P. Holsapple, J.D. Fenters, K.L. White, Jr., L.D. Lauer, D.R. Germolec, G.J. Rosenthal, and J.H. Dean. 1988. Development of a testing battery to assess chemical-induced immunotoxicity: National Toxicology Program’s guidelines for immunotoxicity evaluation in mice. Fundam. Appl. Toxicol. 10(1):2-19. Magara, F., L. Ricceri, D.P. Wolfer, and H.P. Lipp. 2000. The acallosal mouse strain I/LnJ: A putative model of ADHD? Neurosci. Biobehav. Rev. 24(1):45-50. Mahle, D.A., K.O. Yu, L. Narayanan, D.R. Mattie, and J.W. Fisher. 2003. Changes in cross-fostered Sprague-Dawley rat litters exposed to perchlorate. Int. J. Toxicol. 22(2):87-94. McClain, R.M. 1995. Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment. Mutat. Res. 333(1-2):131-142.

OCR for page 115
Health Implications of Perchlorate Ingestion Merrill, E.A. 2001. Consultative Letter AFRL-HE-WP-CL-2001-0008. PBPK Model for Perchlorate-induced Inhibition of Radioiodide Uptake in Humans. Memorandum with attachments to A. Jarabek, National Center for Environmental Assessment, Washington, DC, from E.A. Merrill, Air Force Research Laboratory, Wright-Patterson AF, OH. June 5, 2001. Merrill, E.A., R.A. Clewell, J.M. Gearhart, P.J. Robinson, T.R. Sterner, K.O. Yu, D.R. Mattie, and J.W. Fisher. 2003. PBPK predictions of perchlorate distribution and its effect on thyroid uptake of radioiodide in the male rat. Toxicol. Sci. 73(2):256-269. Mestas, J., and C.C. Hughes. 2004. Of mice and not men: Differences between mouse and human immunology. J. Immunol. 172(5):2731-2738. Mooij, P., H.J. de Wit, A.M. Bloot, M.M. Wilders-Truschnig, and H.A. Drexhage. 1993. Iodine deficiency induces thyroid autoimmune reactivity in Wistar rats. Endrocrinology 133(3):1197-1204. Ng, L., R.J. Goodyear, C.A. Woods, M.J. Schneider, E. Diamond, G.P. Richardson, M.W. Kelley, D.L. Germain, V.A. Galton, and D. Forrest. 2004. Hearing loss and retarded cochlear development in mice lacking type 2 iodothyronine deiodinase. Proc. Natl. Acad. Sci. U.S.A. 101(10):3474-3479. Obregon, M.J., C. Ruiz de Ona, R. Calvo, F. Escobar del Rey, and G. Morreale de Escobar. 1991. Outer ring iodothyronine deiodinases and thyroid hormone economy: Responses to iodine deficiency in the rat fetus and neonate. Endocrinology 129(5):2663-2673. Olton, D.S., J.T. Becker, and G.E. Handelmann. 1979. Hippocampus, space and memory. Behav. Brain Sci. 2:313-365. Pajer, Z., and M. Kalisnik. 1991. The effect of sodium perchlorate and ionizing irradiation on the thyroid parenchymal and pituitary thyrotropin cells. Oncology 48(4):317-320. Rami, A., A.J. Patel, and A. Rabie. 1986. Thyroid hormone and development of the rat hippocampus: Morphological alterations in granule and pyramidal cells. Neuroscience 19(4):1217-1226. Ribak, C.E. 1986. Contemporary methods in neurocytology and their application to the study of epilepsy. Adv. Neurol. 44:739-764. Robinson Jr., J.B., J.M. Strottmann, and E. Stellwagen. 1983. A globular high spin form of ferricytochrome c. J. Biol. Chem. 258(11):6772-6776. Roegge, C.S., V.C. Wang, B.E. Powers, A.Y. Klintsova, S. Villareal, W.T. Greenough, and S.L. Schantz. 2004. Motor impairment in rats exposed to PCBs and methylmercury during early development. Toxicol. Sci. 77(2):315-324. Rovet, J.F. 2002. Congenital hypothyroidism: An analysis of persisting deficits and associated factors. Neuropsychol. Dev. Cogn. Sect. C. Child Neuropsychol. 8(3):150-162. RTI (Research Triangle Institute). 1999. Pp. 3-28 to 3-31 in Perchlorate Peer Review Workshop Report. EPA Contract No. 68-W98-085. RTI No. 7200-019. Prepared for Office of Solid Waste, U.S. Environmental Protection Agency, Washington, DC, by Center for Environmental Analysis, Research

OCR for page 115
Health Implications of Perchlorate Ingestion Triangle Institute, Research Triangle Park, NC. May 13, 1999. [Online]. Available: http://www.epa.gov/ncea/perchlorate/references2/documents/98020.pdf [accessed August 25, 2004.] Schröder-van der Elst, J.P., D. van der Heide, J. Kastelijn, B. Rousset, and M.J. Obregón. 2001. The expression of the sodium/iodide symporter is up-regulated in the thyroid of fetuses of iodine-deficient rats. Endocrinology 142(9):3736-3741. Schwegler, H., W.E. Crusio, and I. Brust. 1990. Hippocampal mossy fibers and radial-maze learning in the mouse: A correlation with spatial working memory but not with non-spatial reference memory. Neuroscience 34(2):293-298. Seeger, G., U. Gartner, M. Holzer, and T. Arendt. 2003. Constitutive expression of p21H-Ras(Val12) in neurons induces increased axonal size and dendritic microtubule density in vivo. J. Neurosci. Res. 74(6):868-874. Sehlin, J. 1987. Effect of perchlorate on calcium uptake and insulin secretion in mouse pancreatic islets. Biochem. J. 248(1):109-115. Siglin, J.C., D.R. Mattie, D.E. Dodd, P.K. Hildebrandt, and W.H. Baker. 2000. A 90-day drinking water toxicity study in rats of the environmental contaminant ammonium perchlorate. Toxicol. Sci. 57(1):61-74. Spitzweg, C., W. Joba, W. Eisenmenger, and A.E. Heufelder. 1998. Analysis of human sodium iodide symporter gene expression in extrathyroidal tissues and cloning of its complementary deoxyribonucleic acids from salivary gland, mammary gland, and gastric mucosa. J. Clin. Endocrinol. Metab. 83(5):1746-1751. Spitzweg, C., C.M. Dutton, M.R. Castro, E.R. Bergert, J.R. Goellner, A.E. Heufelder, and J.C. Morris. 2001. Expression of the sodium iodide symporter in human kidney. Kidney Int. 59(3):1013-1023. Steinmetz, J.E. 1996. The brain substrates of classical eyeblink conditioning in rats. Pp. 89-114 in The Acquisition of Motor Behavior in Vertebrates, J.R. Bloedel, T.J. Ebner, and S.P. Wise, eds. Cambridge, MA: MIT Press. Tazebay, U.H., I.L. Wapnir, O. Levy, O. Dohan, L.S. Zuckier, Q.H. Zhao, H.F. Deng, P.S. Amenta, S. Fineberg, R.G. Pestell, and N. Carrasco. 2000. The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nat. Med. 6(8):871-878. TERA(Toxicology Excellence for Risk Assessment). 2001. Report on Five Expert Reviews of the Primedica 2001 Study Report (Hormone, Thyroid and Neurohistological Effects of Oral (Drinking Water) Exposure to Ammonium Perchlorate in Pregnant and Lactating Rats and in Fetuses and Nursing Pups Exposed to Ammonium Perchlorate During Gestation or Via Maternal Milk, March 2001). Prepared for Perchlorate Study Group. May 18, 2001. TERA (Toxicology Excellence for Risk Assessment). 2002. Pp. 6-7 in Quantitative Evaluation of Perchlorate Risk Assessment, February 2002. Toxicology Excellence for Risk Assessment, Cincinnati, OH. [Online]. Available: http://www.tera.org/Perchlorate/complete/quantitative%20eval%20perchlorate.pdf [accessed July 16, 2004.].

OCR for page 115
Health Implications of Perchlorate Ingestion Versloot, P.M., J. Gerritsen, L. Boogerd, J.P. Schröder-van der Elst, and D. van der Heide. 1994. Thyroxine and 3,5,3'-triiodothyronine production, metabolism, and distribution in pregnant rat near term. Am. J. Physiol. 267(6 Pt 1):E860-E867. Vranckx, R., M. Rouaze-Romet, L. Savu, P. Mechighel, M. Maya, and E.A. Nunez. 1994. Regulation of rat thyroxine-binding globulin and transthyretin: Studies in thyroidectomized and hypophysectomized rats given tri-iodothyronine or/and growth hormone. J. Endocrinol. 142(1):77-84. Wahlsten, D. 2002. Perchlorate Effects on Rat Brain Morphometry: A Critical Evaluation. Submitted to Eastern Research Group, Inc. for the U.S. EPA /ORD Peer Review Workshop-Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization, March 5-6, Sacramento, CA. February 19. [Online]. Available: http://www.perchloratesymposium.com/docs/Wahlsten2002.pdf [accessed August 23, 2004]. Wasniewska, M., F. De Luca, S. Siclari, G. Salzano, M.F. Messina, F. Lombardo, M. Valenzise, C. Ruggeri, and T. Arrigo. 2002. Hearing loss in congenital hypothalamic hypothyroidism: A wide therapeutic window. Hear Res. 172(1-2):87-91. Widholm, J.J., B.W. Seo, B.J. Strupp, R.F. Seegal, and S.L. Schantz. 2003. Effects of perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on spatial and visual reversal learning in rats. Neurotoxicol. Teratol. 25(4):459-471. Wolf, D.C. 2000. Report of the Peer Review of the Thyroid Histopathology From Rodents and Rabbits Exposed to Ammonium Perchlorate in the Drinking Water. Memorandum to Annie Jarabek and William Farland, National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC, from Douglas C. Wolf, Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC. May 5. 2000. [Online]. Available: http://www.epa.gov/ncea/pdf/perchlorate/ea121000.pdf [accessed August 26, 2004]. Wolf, D.C. 2001. Erratum to the Report of the Peer Review of the Thyroid Histopathology From Rodents and Rabbits Exposed to Ammonium Perchlorate in Drinking Water. Memorandum to Annie Jarabek and William Farland, National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC, from Douglas C. Wolf, Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC. October 26, 2001. York, R.G., W.R. Brown, M.F. Girard, and J.S. Dollarhide. 2001a. Two-generation reproduction study of ammonium perchlorate in drinking water in rats evaluates thyroid toxicity. Int. J. Toxicol. 20(4):183-197. York, R.G., W.R. Brown, M.R. Girard, and J.S. Dollarhide. 2001b. Oral (drinking water) developmental toxicity study of ammonium perchlorate in New Zealand white rabbits. Int. J. Toxicol. 20(4):199-205. Yu, K.O., L. Narayanan, D.R. Mattie, R.J. Godfrey, P.N. Todd, T.R. Sterner, D.A.

OCR for page 115
Health Implications of Perchlorate Ingestion Mahle, M.H. Lumpkin, and J.W. Fisher. 2002. The pharmacokinetics of perchlorate and its effect on the hypothalamus-pituitary-thyroid axis in the male rat. Toxicol. Appl. Pharmacol. 182(2):148-159. Zoeller, T.R., A.L. Dowling, C.T. Herzig, E.A. Iannacone, K.J. Gauger, and R. Bansal. 2002. Thyroid hormone, brain development, and the environment. Environ. Health Perspect. 110(Suppl. 3):355-361.