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Question for Barbara Hirsch (maybe OT maybe not)

Question:

Hey, Barbara, do you, or if you have time, can you find out, what kind of thyroid and metabolic problems the chemical perchlorate causes if there’s a lot of it in your drinking water?  Would it be something that could slow down both?  Here’s the link to the article in our local paper that has me concerned:

I didn’t know anything about it. Apparently at high enough levels it can  inhibit the uptake of iodine into the thyroid and stimulate insulin release — I assume leading to hypothyroidism, diabetes and possibly cancer — but I haven’t read any of these studies. Here are a few medlines that should help. You can purchase the full text of some of these on-line. The first one, which is the cheapest, looks like it probably also has the most usable information: Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans. Greer MA, Goodman G, Pleus RC, Greer SE.  Environ Health Perspect. 2002 Aug;110(9):927-37. Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater in the southwestern United States, typically at 0.005-0.020 mg/L (5-20 ppb). Perchlorate is a competitive inhibitor of the process by which iodide is actively transported from the bloodstream into the thyroid. This inhibitory action of perchlorate is the basis of its pharmaceutical use (in the treatment of hyperthyroidism) as well as its potential toxicity. To establish the dose response in humans for perchlorate inhibition of thyroidal iodide uptake and any short-term effects on thyroid hormones, we gave perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day to 37 male and female volunteers for 14 days. In 24 subjects we performed 8- and 24-hr measurements of thyroidal (123)I uptake (RAIU) before exposure, on exposure days 2 (E2) and 14 (E14), and 15 days postexposure (P15). In another 13 subjects we omitted both E2 studies and the 8-hr P15 study. We observed a strong correlation between the 8- and 24-hr RAIU over all dose groups and measurement days. We found no difference between E2 and E14 in the inhibition of RAIU produced by a given perchlorate dose. We also found no sex difference. On both E2 and E14, the dose response was a negative linear function of the logarithm of dose. Based on the dose response for inhibition of the 8- and 24-hr RAIU on E14 in all subjects, we derived estimates of the true no-effect level: 5.2 and 6.4 micro g/kg-day, respectively. Given default body weight and exposure assumptions, these doses would be ingested by an adult if the drinking-water supply contained perchlorate at concentrations of approximately 180 and 220 micro g/L (ppb), respectively. On P15, RAIU was not significantly different from baseline. In 24 subjects we measured serum levels of thyroxine (total and free), triiodothyronine, and thyrotropin in blood sampled 16 times throughout the study. Only the 0.5 mg/kg-day dose group showed any effect on serum hormones: a slight downward trend in thyrotropin levels in morning blood draws during perchlorate exposure, with recovery by P15. Available on line in full text for $4.95 via this link: http://ehpnet1.niehs.nih.gov/members/2002/110p927-937greer/greer-full… The pharmacokinetics of perchlorate and its effect on the hypothalamus-pituitary-thyroid axis in the male rat. Yu KO, Narayanan L, Mattie DR, Godfrey RJ, Todd PN, Sterner TR, Mahle DA,  Lumpkin MH, Fisher JW. Toxicol Appl Pharmacol. 2002 Jul 15;182(2):148-59. Perchlorate, an environmental contaminant, is known to disturb the hypothalamus-pituitary-thyroid (HPT) axis by blocking iodide accumulation in the thyroid. Iodide deficiency can lead to hypothyroidism and goiter in rats. The objective of the study was to characterize the pharmacokinetics of perchlorate in male Sprague-Dawley rats relative to inhibition of thyroidal radiolabeled iodide uptake and onset of up-regulation of the HPT axis. Radiolabeled perchlorate (3.3 mg/kg (36)ClO(-)(4)) was excreted in urine (99.5% over a 48-h period). (36)ClO(-)(4) is rapidly distributed into tissues with preferential sequestration into skin, gastrointestinal tract (GT), and thyroid. Calculated half-lives of (36)ClO(-)(4) from the skin, thyroid, plasma, GT, and GT contents were 32.0, 7.6, 7.3, 10.0, and 8.6 h, respectively. Perchlorate was very effective at inhibiting thyroidal uptake of radiolabeled iodide ((125)I(-)). In animals iv dosed with perchlorate followed by an iv challenge of (125)I(-), thyroidal (125)I(-) uptake was diminished by 11, 29, 55, and 82% at 11 h postdosing in the 0.01, 0.1, 1.0, and 3.0 mg/kg perchlorate dose groups, respectively. In perchlorate drinking water studies, dose-dependent inhibition in thyroidal uptake of (125)I(-) initially occurred with corresponding increases in serum thyroid-stimulating hormone (TSH) levels and decreases in thyroid hormone levels. TSH stimulated recovery from the initial perchlorate blocking effects was evident during 14 days of treatment in the 1.0 and 3.0 mg/kg per day treatment groups. However, recovery of serum thyroid hormones at these doses was much slower despite evidence for iodide sufficiency in the thyroid. These results suggest that the typical homeostatic mechanisms of the thyroid may respond differently at high doses of perchlorate used in this rat study (above 1 mg/kg per day) or perchlorate may be acting on the HPT axis by mechanisms other than thyroidal (125)I(-) uptake inhibition. Available on line in full text for $35 via this link: http://www.idealibrary.com/retrieve/doi/10.1006/taap.2002.9432 Community cancer assessment in response to long-time exposure to perchlorate and trichloroethylene in drinking water. Morgan JW, Cassady RE. J Occup Environ Med 2002 Jul;44(7):616-21. In response to concerns about cancer stemming from drinking water contaminated with  ammonium perchlorate and trichloroethylene, we assessed observed and expected  numbers of new cancer cases for all sites combined and 16 cancer types in a California  community (1988 to 1998). The numbers of observed cancer cases divided by expected numbers defined standardized incidence ratios (SIRs) and 99% confidence intervals (CI).  No significant differences between observed and expected numbers were found for all  cancers (SIR, 0.97; 99% CI, 0.93 to 1.02), thyroid cancer (SIR, 1.00; 99% CI, 0.63 to 1.47), or 11 other cancer types. Significantly fewer cases were observed than expected  for cancer of the lung and bronchus (SIR, 0.71; 99% CI, 0.61 to 0.81) and the colon and  rectum (SIR, 0.86; 0.74 to 0.99), whereas more cases were observed for uterine cancer  (SIR, 1.35; 99% CI, 1.06 to 1.70) and skin melanoma (SIR, 1.42; 99% CI, 1.13 to 1.77).  These findings did not identify a generalized cancer excess or thyroid cancer excess in  this community. Perchlorate stimulates insulin secretion by shifting the gating of L-type Ca2+ currents in mouse pancreatic B-cells towards negative potentials. Larsson-Nyren G, Sehlin J, Rorsman P, Renstrom E. Pflugers Arch. 2001 Feb;441(5):587-95. The effects of the chaotrophic anion perchlorate (ClO4-) on glucose-induced electrical activity, exocytosis and ion channel activity in mouse pancreatic B-cells were investigated by patch-clamp recordings and capacitance measurements. ClO4- stimulated glucose-induced electrical activity and increased the action potential frequency by 70% whilst not affecting the membrane potential when applied in the presence of a subthreshold concentration of the sugar. ClO4- did not influence ATP-dependent K (KATP) channel activity and voltage-gated delayed K+ current. Similarly, ClO4- had no effect on Ca2+-dependent exocytosis. The stimulation of electrical activity and insulin secretion was instead attributable to an enhancement of the whole-cell Ca2+ current. This effect was particularly pronounced at voltages around the threshold for action potential initiation and a doubling of the current amplitude was observed at -30 mV. This was due to a 7-mV shift in the gating of the Ca2+ current towards negative voltages. The action of ClO4- was more pronounced when added in the presence of 0.1 mM BAY K8644, whereas no stimulation was observed when applied at a maximal concentration of the agonist (1 mM). Single-channel recordings revealed that the effect of ClO4- on whole-cell currents was principally due to a 60% increase in the mean duration of the long openings and the number of active channels. We propose that ClO4- stimulates insulin secretion and electrical activity by exerting a BAY K8644-like action on Ca2+ channel gating. Effect of perchlorate on glucose-stimulated insulin release and 45Ca2+ uptake in pancreatic islets from diabetic Chinese hamsters. Frankel BJ, Sehlin J. Pancreas. 1994 Sep;9(5):550-7. Insulin release and 45Ca2+ uptake were studied in isolated islets from Chinese hamsters of genetically diabetic and normal sublines. The calcium channel agonist, perchlorate (ClO4-, 12 mmol/L), augmented both 45Ca2+ uptake and insulin release from normal islets in the presence of 20 but not 1 mmol/L glucose. The agonist also amplified the glucose-stimulated 45Ca2+ uptake and insulin release from diabetic islets but did not normalize the insulin release despite normal insulin concentration in the diabetic Chinese hamster islets. The dry weight of the diabetic islets was subnormal (54%, p < 0.005) but the insulin concentration (insulin per dry weight of islet tissue) was not different from normal (122%). It appears that there are defective mechanisms in addition to the glucose-stimulated influx of Ca2+ in diabetic islet B cells. Perchlorate: low dose exposure and susceptible populations. Brucker-Davis F, Thayer K, Colborn T, Fenichel P. Thyroid 2002 Aug;12(8):739. No abstract available. Full on-line text can be purchased for $33 at: … read more »

Response:

Hey, Barbara, do you, or if you have time, can you find out, what kind of thyroid and metabolic problems the chemical perchlorate causes if there’s a lot of it in your drinking water?  Would it be something that could slow down both?  Here’s the link to the article in our local paper that has me concerned: http://www.lubbockonline.com/stories/100402/reg_1004020093.shtml I have family living in both Howard and Midland Counties. TIA  I really appreciate it. Tonia

Response:

Thanks Barbara.  I’ll try to figure out what all that means! Tonia

– Hide quoted text — Show quoted text – Hey, Barbara, do you, or if you have time, can you find out, what kind of thyroid and metabolic problems the chemical perchlorate causes if there’s a lot of it in your drinking water?  Would it be something that could slow down both?  Here’s the link to the article in our local paper that has me concerned: I didn’t know anything about it. Apparently at high enough levels it can  inhibit the uptake of iodine into the thyroid and stimulate insulin release — I assume leading to hypothyroidism, diabetes and possibly cancer — but I haven’t read any of these studies. Here are a few medlines that should help. You can purchase the full text of some of these on-line. The first one, which is the cheapest, looks like it probably also has the most usable information: Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans. Greer MA, Goodman G, Pleus RC, Greer SE.  Environ Health Perspect. 2002 Aug;110(9):927-37. Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater in the southwestern United States, typically at 0.005-0.020 mg/L (5-20 ppb). Perchlorate is a competitive inhibitor of the process by which iodide is actively transported from the bloodstream into the thyroid. This inhibitory action of perchlorate is the basis of its pharmaceutical use (in the treatment of hyperthyroidism) as well as its potential toxicity. To establish the dose response in humans for perchlorate inhibition of thyroidal iodide uptake and any short-term effects on thyroid hormones, we gave perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day to 37 male and female volunteers for 14 days. In 24 subjects we performed 8- and 24-hr measurements of thyroidal (123)I uptake (RAIU) before exposure, on exposure days 2 (E2) and 14 (E14), and 15 days postexposure (P15). In another 13 subjects we omitted both E2 studies and the 8-hr P15 study. We observed a strong correlation between the 8- and 24-hr RAIU over all dose groups and measurement days. We found no difference between E2 and E14 in the inhibition of RAIU produced by a given perchlorate dose. We also found no sex difference. On both E2 and E14, the dose response was a negative linear function of the logarithm of dose. Based on the dose response for inhibition of the 8- and 24-hr RAIU on E14 in all subjects, we derived estimates of the true no-effect level: 5.2 and 6.4 micro g/kg-day, respectively. Given default body weight and exposure assumptions, these doses would be ingested by an adult if the drinking-water supply contained perchlorate at concentrations of approximately 180 and 220 micro g/L (ppb), respectively. On P15, RAIU was not significantly different from baseline. In 24 subjects we measured serum levels of thyroxine (total and free), triiodothyronine, and thyrotropin in blood sampled 16 times throughout the study. Only the 0.5 mg/kg-day dose group showed any effect on serum hormones: a slight downward trend in thyrotropin levels in morning blood draws during perchlorate exposure, with recovery by P15. Available on line in full text for $4.95 via this link: http://ehpnet1.niehs.nih.gov/members/2002/110p927-937greer/greer-full… The pharmacokinetics of perchlorate and its effect on the hypothalamus-pituitary-thyroid axis in the male rat. Yu KO, Narayanan L, Mattie DR, Godfrey RJ, Todd PN, Sterner TR, Mahle DA,  Lumpkin MH, Fisher JW. Toxicol Appl Pharmacol. 2002 Jul 15;182(2):148-59. Perchlorate, an environmental contaminant, is known to disturb the hypothalamus-pituitary-thyroid (HPT) axis by blocking iodide accumulation in the thyroid. Iodide deficiency can lead to hypothyroidism and goiter in rats. The objective of the study was to characterize the pharmacokinetics of perchlorate in male Sprague-Dawley rats relative to inhibition of thyroidal radiolabeled iodide uptake and onset of up-regulation of the HPT axis. Radiolabeled perchlorate (3.3 mg/kg (36)ClO(-)(4)) was excreted in urine (99.5% over a 48-h period). (36)ClO(-)(4) is rapidly distributed into tissues with preferential sequestration into skin, gastrointestinal tract (GT), and thyroid. Calculated half-lives of (36)ClO(-)(4) from the skin, thyroid, plasma, GT, and GT contents were 32.0, 7.6, 7.3, 10.0, and 8.6 h, respectively. Perchlorate was very effective at inhibiting thyroidal uptake of radiolabeled iodide ((125)I(-)). In animals iv dosed with perchlorate followed by an iv challenge of (125)I(-), thyroidal (125)I(-) uptake was diminished by 11, 29, 55, and 82% at 11 h postdosing in the 0.01, 0.1, 1.0, and 3.0 mg/kg perchlorate dose groups, respectively. In perchlorate drinking water studies, dose-dependent inhibition in thyroidal uptake of (125)I(-) initially occurred with corresponding increases in serum thyroid-stimulating hormone (TSH) levels and decreases in thyroid hormone levels. TSH stimulated recovery from the initial perchlorate blocking effects was evident during 14 days of treatment in the 1.0 and 3.0 mg/kg per day treatment groups. However, recovery of serum thyroid hormones at these doses was much slower despite evidence for iodide sufficiency in the thyroid. These results suggest that the typical homeostatic mechanisms of the thyroid may respond differently at high doses of perchlorate used in this rat study (above 1 mg/kg per day) or perchlorate may be acting on the HPT axis by mechanisms other than thyroidal (125)I(-) uptake inhibition. Available on line in full text for $35 via this link: http://www.idealibrary.com/retrieve/doi/10.1006/taap.2002.9432 Community cancer assessment in response to long-time exposure to perchlorate and trichloroethylene in drinking water. Morgan JW, Cassady RE. J Occup Environ Med 2002 Jul;44(7):616-21. In response to concerns about cancer stemming from drinking water contaminated with  ammonium perchlorate and trichloroethylene, we assessed observed and expected  numbers of new cancer cases for all sites combined and 16 cancer types in a California  community (1988 to 1998). The numbers of observed cancer cases divided by expected numbers defined standardized incidence ratios (SIRs) and 99% confidence intervals (CI).  No significant differences between observed and expected numbers were found for all  cancers (SIR, 0.97; 99% CI, 0.93 to 1.02), thyroid cancer (SIR, 1.00; 99% CI, 0.63 to 1.47), or 11 other cancer types. Significantly fewer cases were observed than expected  for cancer of the lung and bronchus (SIR, 0.71; 99% CI, 0.61 to 0.81) and the colon and  rectum (SIR, 0.86; 0.74 to 0.99), whereas more cases were observed for uterine cancer  (SIR, 1.35; 99% CI, 1.06 to 1.70) and skin melanoma (SIR, 1.42; 99% CI, 1.13 to 1.77).  These findings did not identify a generalized cancer excess or thyroid cancer excess in  this community. Perchlorate stimulates insulin secretion by shifting the gating of L-type Ca2+ currents in mouse pancreatic B-cells towards negative potentials. Larsson-Nyren G, Sehlin J, Rorsman P, Renstrom E. Pflugers Arch. 2001 Feb;441(5):587-95. The effects of the chaotrophic anion perchlorate (ClO4-) on glucose-induced electrical activity, exocytosis and ion channel activity in mouse pancreatic B-cells were investigated by patch-clamp recordings and capacitance measurements. ClO4- stimulated glucose-induced electrical activity and increased the action potential frequency by 70% whilst not affecting the membrane potential when applied in the presence of a subthreshold concentration of the sugar. ClO4- did not influence ATP-dependent K (KATP) channel activity and voltage-gated delayed K+ current. Similarly, ClO4- had no effect on Ca2+-dependent exocytosis. The stimulation of electrical activity and insulin secretion was instead attributable to an enhancement of the whole-cell Ca2+ current. This effect was particularly pronounced at voltages around the threshold for action potential initiation and a doubling of the current amplitude was observed at -30 mV. This was due to a 7-mV shift in the gating of the Ca2+ current towards negative voltages. The action of ClO4- was more pronounced when added in the presence of 0.1 mM BAY K8644, whereas no stimulation was observed when applied at a maximal concentration of the agonist (1 mM). Single-channel recordings revealed that the effect of ClO4- on whole-cell currents was principally due to a 60% increase in the mean duration of the long openings and the number of active channels. We propose that ClO4- stimulates insulin secretion and electrical activity by exerting a BAY K8644-like action on Ca2+ channel gating. Effect of perchlorate on glucose-stimulated insulin release and 45Ca2+ uptake in pancreatic islets from diabetic Chinese hamsters. Frankel BJ, Sehlin J. Pancreas. 1994 Sep;9(5):550-7. Insulin release and 45Ca2+ uptake were studied in isolated islets from Chinese hamsters of genetically diabetic and normal sublines. The calcium channel agonist, perchlorate (ClO4-, 12 mmol/L), augmented both 45Ca2+ uptake and insulin release from normal islets in the presence of 20 but not 1 mmol/L glucose. The agonist also amplified the glucose-stimulated 45Ca2+ uptake and insulin release from diabetic islets but did not normalize the insulin release despite normal insulin concentration in the diabetic Chinese hamster islets. The dry weight of the diabetic islets was subnormal (54%, p

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