Health Implications of Perchlorate Ingestion (2005) / Chapter Skim
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4 Animal Studies
4 Animal Studies
Pages 115-163
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From page 115... ...
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 animalstudiesthatinvestigatedtheeffectsofperchlorateexposureonserum thyroid hormone concentrations, thyroid histopathology, brain morphometry, neurobehavior, and thyroid tumors.
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and triiodothyronine (T3) vary widely among species, and their binding affinities for the thyroid hormones also differ.
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(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.
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The species differences must be carefully considered in interpretingserumthyroidhormone,TSH,andthyroidhistopathology datainstudies 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.
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, 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.
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120 Health Implications of Perchlorate Ingestion 5 Control 4.5 0.01 mg/kg-d *
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concentrations in dams treated with ammonium perchlorate at indicated doses in drinking water. (Middle)
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122 at -re to from triiodo- Serum 0.01; used * easuresm gestation #p F Values 22 Left)
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TABLE 4-2 Thyroid Histopathology in Control and PerchlorateExposed 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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124 d kg/gm d- d- F 010.
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125 from day.l F d g-k g/ d-gk 22 change m g/ d-gk postnata m g/ d-gk/g NDP 01 1 m m 0.
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In the 1998 study, female Sprague-Dawley rats were exposed to ammonium perchlorate at 0, 0.1, 1.0, 3.0 or 10.0 mg/kg per day in the drinking water beginning on gestation day 0 and continuing until postnatal day 10. One male and one female pup from each of six control and six high-dose litters were sacrificed for brainmorphometry on postnatal day 10-12 and postnatal day 82-85.
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Argus (2001) reported a number of statistically significant differences between treatment groups, including increases in the thickness of the corpus callosum of male rats on postnatal days 10 and 22, finding that are consistent with those in the earlier study.
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128 at low ured ured groups ediate not ured ured ured 2003 22 easm easm ed ate but dose dose easm easm easm interm EPA Day Not Not All increas Increas or doses high Not Not Not only not not but but dose or or high low doses doses low at ate dose ate dose 22 lesam change high high change change change a Day Increase in No Decreas intermediate at Increas intermediate at No No No not not not not not not not but but but but but but but Perchlorate or or or or males; or females or females; or males to doses doses doses doses low low low low in low doses in low doses in doses low in 2001 ate dose ate dose ate dose ate dose ate dose ate dose ate dose 10 Exposed high high high high high change change high high Argus Day Increas intermediate at Increas intermediate at Increas intermediate at Increas intermediate at Decreas intermediate at No No Decreas intermediate at Increas intermediate at Pups e e e Rat dos dos dos in high ate lesam high ate lesam high ate lesam ured ured Findings 82-85 in change in in change easm easm Day Increas only No Increas only Increas only No Not Not etric or dose dose or dose low doses high low doses Morphom 1998 ate high high ured ured of ediate at at ate ediate at ryam 10-12 change change not not easm easm rgusA Day No No Decreas interm but ncreaseI only Decreas interm but otN otN Sum 4-3 rus cortex cortex callosum gy portion TABLE Neuroanatomic Region ontalrF rietalaP riatumtS rus Corpus Hippocampus gy Dentate CA1
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; (all per 22 ured ured in easm easm /kggm day change 10 Not Not No points and groups) ; 3, or dose doses (0, dose low evaluation ured ured (all easm easm ate high ediate at 10-12 10 not otN Not Increas interm but different day day at (1998)
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Male and female pups were included in the same analysis with sex nested within a litter, but separate profile analyses were run on the data from postnatal days 10 and 22. In the second approach, univariate ANOVAs and Dunnett's comparisons were used to determine which brain regions and dose groups differed from controls.
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Because all tissues from each Argus study were embedded in paraffin at the same time, differences in how long the tissues were held before sectioning should not be an issue. In addition to questions about fixation of the brains, reviewers have noted what appears to be considerable variability in the plane of section -- both between animals and between hemispheres in the same animal -- in both Argus studies (Harry 2001; Wahlsten 2002)
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in 2003 to resection and remeasure brains from the postnatal day 22 pups from Argus (2001)
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That corpus callosum thickness was increased at multiple doses and at several stages of development (postnatal days 10-12, 22, and 82-85) in two studies is suggestive of a relationship between perchlorate exposure and altered neurodevelopment.
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. Analyses of the effects of perchlorate exposure on the expression of those genes could provide additional information about whether the developing brain responds to perchlorate exposure in a way that is consistent with the response to other manipulations that result in low thyroid hormone concentrations.
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Another important issue related to the biologic plausibility of effects on brain structure is whether perchlorate exposure reduces maternal or pup thyroid hormone concentrations enough to alter neurodevelopment. Most studies of neonatal hypothyroidism in animals have used excessive doses of potent goitrogens that reduce serum T4 concentrations to near the detection limit of the assay.
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Again, no significant effects of perchlorate were noted. As discussed above, neonatal hypothyroidism results in abnormal developmentofvariousbrainregions.Thehippocampusandcerebellumare two of the most severely affected regions, so such learning tests as the radial-arm maze, which is sensitive to hippocampal damage (Becker et al.
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Female Sprague-Dawley rats were treated with ammonium perchlorate at 0, 0.1, 1.0, 3.0, or 10.0 mg/kg per day in the drinking water beginning 2 weeks before gestation and continuing until postnatal day 10. The rats in both studies were tested in an open-field activity monitortransectedby infraredphotobeams.
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Dunson's reanalysis of the Argus data yielded a high posterior probability that the motor activity increased with perchlorate exposure. The probability increased from 58% in the first habituation interval to 94% in the final interval.
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Thyroid hormones are known to play an important role in the development of the cochlea, and neonatal hypothyroidism has been linked to hearing loss in animals (Knipper et al.
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. Future rodent studies should focus on the specific functional end points described above that are likely to be adversely affected by moderate reductions in thyroid hormone.
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It would also be useful to measure the extent to which perchlorate exposure during brain development alters the expression of thyroid hormone-responsive genes and gene products in the brain. That approach has been useful in understanding the actions of other agents that affect the thyroid system (Zoeller et al.
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From page 142... ...
(1991) reported that female Wistar rats administered 1% potassium perchlorate in the drinking water for 1-12 months developed a progressive increase in thyroid gland weight and a diffuse hypertrophy and hyperplasia of follicular cells with increased vascularity and decreased lumenal colloid.
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at ammonium perchlorate doses of 0 (control) , 0.3, 3.0, and 30 mg/kg per day in drinking water provided ad libitum.
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Agents that induce thyroid follicularcelltumorsinrodentsby interferingwith thyroid hormone homeostasis, can with some exceptions, notability the sulfonamides, also
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modeling is one of the methodsofchoicefordetermininghumanequivalentexposures(HEEs) and adjusting default uncertainty factors associated with the derivation of reference doses and reference concentrations for lifetime human exposures from animal studies (EPA 2002a)
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The committee agrees with EPA that PBPK modeling constitutes the best available approach to determining HEEs and adjustments of default uncertainty factors when reference doses are based on animal data. The PBPK models developed by DOD for the adult rat, adult human, pregnant rat and fetus, and lactating rat and neonate represents the current state of the science for integrating available animal and human data on the disposition of perchlorate and iodide and the interactions between these anions at the level of the thyroid NIS.
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FIGURE 4-4 Parallelogram approach for using adult human, adult male rat, and female rat gestation and lactation models to estimate human equivalent exposures for human pregnancy and lactation models. Bold arrows indicate presence of validated PBPK models for estimating relationships between effective internal doses associated with key events and perchlorate exposure; dashed arrows and shadedboxindicatetheoreticalextrapolationsguidedbyphysiologicandbiochemical constraints in models and parallelogram approach.
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In pregnant rats, NIS gene expression in the placenta was higher in response to iodide deficiency and potassium perchlorate administration on gestation day 21 than in control rats (Schroder-van der Elst et al.
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(2000) administered ammonium perchlorate in drinking water to groups of Sprague-Dawley rats (10 rats of each sex per group)
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Changes in thyroid hormones and TSH were observed as low as 0.01 mg/kg per day during exposure periods. However, changes in thyroid gland weight and thyroid histopathology were observed only at the highest dose (10 mg/kg per day)
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. In those studies, mice were exposed to perchlorate in drinking water to achieve doses of 0.1, 1, 3, and 30 mg/kg per day.
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· Exposure to perchlorate can increase the incidence of thyroid tumors in rats when the doses are high enough to decrease thyroid hormone production and increase TSH secretion. · The data favor rejection of a causal relationship between perchlorate exposure and immunotoxicity.
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1998. ANeurobehavioralDevelopmentalStudy of Ammonium Perchlorate Administered Orally in Drinking Water to Rats.
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2000. A Neurodevelopmental Study of Oral Ammonium Perchlorate Exposure on the Motor Activity of Pre-Weanling Rat Pup.
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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.
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2004. Ki-ras mutational analysis in rat follicular-cell proliferative lesions of the thyroid gland induced by radioactive iodine and potassium perchlorate.
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Influence of thyroid hormones on the topography of callosal projections.
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1966. Experimental thyroid tumors caused by long-term potassium perchlorate administration.
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2000. Thyroid hormone deficiency before the onset of hearing causes irreversible damage to peripheral and central auditory systems.
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1991. Outer ring iodothyronine deiodinases and thyroid hormone economy: Responses to iodine deficiency in the rat fetus and neonate.
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2000. A 90-day drinking water toxicity study in rats of the environmental contaminant ammonium perchlorate.
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2000. Report of the Peer Review of the Thyroid Histopathology From Rodents and Rabbits Exposed to Ammonium Perchlorate in the Drinking Water.
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2002. Thyroid hormone, brain development, and the environment.
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