Appendix B
Glossary


Argus:

Argus Research Laboratories. A division of Charles River Discovery and Development Services, a contract research organization. Argus has 25 years of experience in the conduct of nonclinical reproductive and developmental toxicity safety studies for the pharmaceutical, food, and chemical industries. Argus has a specialization in neurobehavioral studies, a standard component of reproductive and developmental toxicity tests for pharmaceutical products and neurotoxicology safety assessments.

AUC:

area under the curve. A measure of exposure that includes duration and concentration. It is calculated from the curve that results when the concentrations of the test substance in some biologic tissue, typically blood, are plotted against the exposure time.


BMD:

benchmark dose. A dose or concentration that produces a selected change in the response rate or occurrence of an adverse effect or other relevant end point compared with background.1

BRT:

Burleson Research Technologies, Inc. A for-profit contract laboratory specializing in proof-of-concept, preclinical, and toxicology studies.

BW:

body weight.

caliche: a sedimentary deposit rich in sodium nitrate and other soluble salts.2 Sodium perchlorate has been found in caliche from Chile.


CI:

confidence interval. The Frequentist statistical confidence interval describes the relative frequency with which a parameter’s values lie within a calculated interval in a series of repeat samples.3

ClO4:

perchlorate.

colloid:

the stored secretion in follicles of the thyroid gland.4

credible interval:

Bayesian credible interval describes an interval of the



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Health Implications of Perchlorate Ingestion Appendix B Glossary Argus: Argus Research Laboratories. A division of Charles River Discovery and Development Services, a contract research organization. Argus has 25 years of experience in the conduct of nonclinical reproductive and developmental toxicity safety studies for the pharmaceutical, food, and chemical industries. Argus has a specialization in neurobehavioral studies, a standard component of reproductive and developmental toxicity tests for pharmaceutical products and neurotoxicology safety assessments. AUC: area under the curve. A measure of exposure that includes duration and concentration. It is calculated from the curve that results when the concentrations of the test substance in some biologic tissue, typically blood, are plotted against the exposure time. BMD: benchmark dose. A dose or concentration that produces a selected change in the response rate or occurrence of an adverse effect or other relevant end point compared with background.1 BRT: Burleson Research Technologies, Inc. A for-profit contract laboratory specializing in proof-of-concept, preclinical, and toxicology studies. BW: body weight. caliche: a sedimentary deposit rich in sodium nitrate and other soluble salts.2 Sodium perchlorate has been found in caliche from Chile. CI: confidence interval. The Frequentist statistical confidence interval describes the relative frequency with which a parameter’s values lie within a calculated interval in a series of repeat samples.3 ClO4−: perchlorate. colloid: the stored secretion in follicles of the thyroid gland.4 credible interval: Bayesian credible interval describes an interval of the

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Health Implications of Perchlorate Ingestion parameter space such that the probability that the parameter’s value lies in the interval is at least the given percentage. CV: coefficient of variation. A metric useful in comparing the variability of multiple datasets calculated by dividing the standard deviation of a dataset by its mean.5 deiodinases: enzymes that metabolize thyroid hormones, including conversion of the prohormone thyroxine to triiodothyronine by removal of an iodide. diiodotyrosine: an intermediate in the production of thyroid hormones. It contains two iodine atoms.4 dL: deciliter. One-tenth of a liter or 100 milliliters. DL: day of lactation. ecologic study: a type of observational epidemiologic study in which the units of analysis are populations or groups of people rather than individuals. ED10: effective dose 10%. The ED10 is the dose associated with a 10% increase in an adverse effect compared with the control.1 GD: gestation day. geometric mean: the nth root of the product of n observations.5 The geometric mean is similar to the median and always less than the arithmetic mean unless the observations are identical, making the geometric mean equal to the arithmetic mean.6 goiter: a chronic enlargement of the thyroid gland, not due to a neoplasm.4 goitrogen: any substance that induces goiter.4 HEE: human equivalent exposure. HPT: see hypothalamic-pituitary-thyroid axis. hyperplasia: an increase in the number of normal cells in a tissue or organ, excluding tumor formation, whereby the bulk of the part or organ may be increased.4 hyperthyroidism: increased secretion of thyroxine and triiodothyronine from the thyroid gland. hypertrophy: general increase in bulk of a part of organ, not due to tumor formation.4 Hypothalamic-pituitary-thyroid axis: the body’s regulatory system for the thyroid. Thyrotropin-releasing hormone from the hypothalamus stimulates the pituitary gland to secrete thyroid-stimulating hormone, which acts on the thyroid gland to stimulate thyroid hormone synthesis and secretion. High concentrations of thyroid hormone in the blood feed back to the hypothalamus and pituitary and inhibit thyroid-stimulating hormone secretion.4

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Health Implications of Perchlorate Ingestion hypothyroidism: decreased secretion of thyroxine and triiodothyronine from the thyroid gland. I−: iodide. Iodide is the physiologically active anion of iodine. It is a micronutrient essential for thyroid hormone production.7 iodine: an atomic element that occurs nutritionally in the form of iodide. IUI: iodide uptake inhibition. Km: see Michaelis-Menten constant. L/hr per kg: liters per hour per kilogram of body weight. LOAEL: lowest observed-adverse-effect level. The lowest exposure at which there are statistically or biologically significant increases in frequency or severity of adverse effects in an exposed population compared with its appropriate control group.8 mechanism or mode of action: processes causing a biologic effect, for example, toxicity. mg: milligram (one-thousandth of a gram). mg/hr/kg: milligrams per hour per kilogram of body weight. mg/kg: milligrams per kilogram of body weight. mg/L: milligrams per liter (equivalent to parts per million [ppm]). Michaelis-Menten constant: the chemical concentration that can be saturated at half maximal capacity of a physiologic process, such as protein binding or active transport.9 milliunits per liter: a measure of concentration based on the biologic activity of a substance rather than its weight or volume. mL: milliliter (one-thousandth of a liter). mM: millimolar (concentration of 1 millimole per liter). monoiodotyrosine: an intermediate in the production of thyroid hormones that contains a single iodine atom.4 mRNA: messenger ribonucleic acid. mU/L: see milliunits per liter. µg: microgram (one-millionth of a gram). µg/dL: micrograms per deciliter. µg/L: micrograms per liter (equivalent to parts per billion [ppb]). µM: micromolar (a concentration of 1 micromole per liter). ng: nanogram (one-billionth of a gram). ng/hr/kg: nanograms per hour per kilogram of body weight. ng/L: nanograms per liter. NIS: see sodium (Na+)/iodide(I−) symporter. NOAEL: no-observed-adverse-effect level. An exposure level at which there are no statistically or biologically significant increases in the frequency or severity of adverse effects in an exposed population

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Health Implications of Perchlorate Ingestion compared with its appropriate control; some effects may be produced at this level, but they are not considered as adverse nor precursors to specific adverse effects. In an experiment with several NOAELs, the regulatory focus is primarily on the highest one; this leads to the common usage of the term NOAEL as the highest exposure without adverse effect.8 NOEL: no observed-effect level. An exposure level at which there are no statistically or biologically significant increases in the frequency or severity of any effect between the exposed population and its appropriate control.1 OR: odds ratio. A measure of association between exposure and disease development calculated by dividing the odds that an exposed group develops the disease by the odds that a nonexposed group develops the disease.10 PBPK model: see physiologically based pharmacokinetic. PCB: polychlorinated biphenyl. PD: pharmacodynamic. physiologically based pharmacokinetic model: a type of model that estimates the dose delivered to a target tissue or organ by taking into account the rate of absorption into the body, distribution among target organs and tissues, metabolism, and excretion.1 PND: postnatal day. point of departure: the dose-response point that marks the beginning of an extrapolation.1 posterior probability distribution: See prior probability distribution. ppb: parts per billion. ppm: parts per million. prior probability distribution: In a Bayesian statistical approach, expert judgment and available data are modeled in a prior probability distribution. Bayes’ theorem can be applied to update the prior probability distribution with data from new studies to yield a posterior probability distribution. PTU: propylthiouracil. PWG: Pathology Working Group. RAIU: radioactive iodide uptake. reference dose: an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral dose delivered to the human population (including sensitive groups) that is likely to have no appreciable risk of deleterious effects during a lifetime. It can be derived from a NOAEL, LOAEL, or benchmark dose; uncertainty factors can be applied to

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Health Implications of Perchlorate Ingestion reflect limitations of the data used. Generally used in EPA’s noncancer health assessments.1 relative risk: a measure of association between an exposure and development of disease calculated by dividing the disease incidence in an exposed group by the disease incidence in a nonexposed group.10 RfD: see reference dose. RR: see relative risk. RSC: relative source contribution. An estimate of the percentage of a toxicant exposure coming from a particular source, such as drinking water or food. Determining the relative source contribution is an important part of risk assessment and risk management when the toxicant is found in more than one source. Because the RfD is a total daily dose, if the toxicant appears in both water and food, for example, the portion of the exposure dose from each source is determined to set appropriate food and water standards so as not to exceed the RfD. SIR: see standardized incidence ratio. SMR: see standardized mortality ratio. sodium (Na+)/iodide(I−) symporter: a plasma membrane glycoprotein that mediates the active transport of iodide and is expressed in a variety of tissues, including thyroid, salivary glands, lactating breast, and placenta. A sodium gradient maintained by Na (sodium)-K (potassium) adenosine triphosphatase is required for iodide transport by NIS.11 SPR: see standardized prevalence ratio. standardized incidence ratio: a measure of population health calculated by dividing the observed disease incidence in a population of interest by the disease incidence expected on the basis of disease rates of a reference population. standardized mortality ratio: a measure of population health calculated by dividing the number of deaths observed in a population of interest by the number of deaths expected on the basis of the mortality rates of a reference population.12 standardized prevalence ratio: a measure of population health calculated by dividing the observed disease prevalence in a population of interest by the prevalence expected in the population on the basis of disease rates of a reference population. T3: see triiodothyronine. T4: tetraiodothyronine. See thyroxine. TBG: see thyroxine-binding globulin. TCE: trichloroethylene. TERA: Toxicology Excellence for Risk Assessment, a nonprofit corpora-

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Health Implications of Perchlorate Ingestion tion dedicated to the best use of toxicity data for risk assessment. TERA’s mission is to protect public health by developing and communicating risk-assessment values, by offering consulting services to government and industry, improving risk methods through research, and educating the public on risk assessment issues.13 tetraiodothyronine: see thyroxine. thyroglobulin: a thyroid protein that serves as the substrate for production of thyroxine and triiodothyronine and as the storage form of thyroid hormones. thyroid: a butterfly-shaped gland in the front of the neck. It is composed of spherical follicles that are the functional units of the gland. thyroid follicle: the functional unit of the thyroid gland, composed of a single layer of thyroid cells surrounding a lumen that contains thyroglobulin, the storage form of thyroxine and triiodothyronine. thyroid peroxidase: an enzyme that catalyzes iodide organification into thyroglobulin and then promotes thyroid hormone synthesis. thyrotropin: a glycoprotein hormone that stimulates growth and function of the thyroid gland. Also known as thyroid-stimulating hormone.4 thyrotropin-releasing hormone: a hormone that is released from the hypothalamus and stimulates synthesis and secretion of thyroid-stimulating hormone (TSH).14 thyroxine: a biologically inactive prohormone containing four iodine atoms that is activated to triiodothyronine by deiodinase. Also known as tetraiodothyronine. thyroxine-binding globulin: the primary serum protein that binds thyroid hormones in humans. TPO: see thyroid peroxidase. TRC Companies, Inc.: a for-profit consulting organization specializing in energy, environment, infrastructure, and infrastructure security projects.15 TRH: see thyrotropin-releasing hormone. triiodothyronine: thyroid hormone containing three iodine atoms. About 80% of the triiodothyronine produced in the body each day is formed outside the thyroid gland by removal of one iodine atom from thyroxine. Triiodothyronine acts in different organs by binding to nuclear thyroid hormone receptors and stimulates or inhibits gene expression. TSH: thyroid-stimulating hormone. See thyrotropin. tyrosine: an amino acid required for the production of thyroid hormones. UF: uncertainty factor. Factors—typically 1, 3, or 10—used to derive an RfD from experimental data. The factors are intended to account for the variation in sensitivity among the members of the human population

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Health Implications of Perchlorate Ingestion (interindividual variability), the uncertainty in extrapolating animal data to the human population (interspecies uncertainty), the uncertainty in extrapolating from data obtained in a study involving less-than-lifetime exposure (extrapolating from subchronic to chronic exposure), the uncertainty in using LOAEL data rather than NOAEL data, and the uncertainty associated with extrapolation when the database is incomplete.16 A UF of 10 is considered to be a health-protective default value to be used when little is known about a particular source of variability or uncertainty or when information on a relevant health effect is lacking. As additional research becomes available, UFs change as indicated by the new information. VGI: volume of gastrointestinal tract. Vmax: describes, in units of milligrams per hour, the maximal capacity or velocity for binding or transport, such as binding or transport of iodide by the NIS. VmaxC: describes, in units of milligrams per hour per kilogram of body weight, the maximal capacity or velocity for binding or transport scaled by body weight according to the equation: Vmax (mg/hr) = [VmaxC (mg/hr per kg)][body weight (kg)]0.70. VSk: volume of skin. NOTES 1.   EPA (U.S. Environmental Protection Agency). 2003. Glossary of IRIS Terms. Integrated Risk Information System (IRIS). [Online]. Available http://www.epa.gov/iris/gloss8.htm [accessed April 16, 2004]. 2.   CanSIS (Canadian Soil Information System). 1996. Glossary: Caliche. Canadian Soil Information System, Canada Department of Agriculture, Ottawa. [Online]. Available: http://sis.agr.gc.ca/cansis/glossary/index.html [accessed April 16, 2004]. 3.   Colton, T. 1974. Statistics in Medicine, 1st Ed. Boston: Little, Brown and Company. 4.   Stedman, T.L. 2000. Stedman’s Medical Dictionary, 27th Edition. Philadelphia: Lippincott Williams and Wilkins. 5.   Rosner, B. 1995. Pp. 23-24 in Fundamentals of Biostatistics. Belmont, CA: Duxbury Press. 6.   Altman, D.G. 1991. Practical Statistics for Medical Research. London: Chapman and Hall. 7.   IOM (Institute of Medicine). 2000. Iodine. Pp 258-289 in Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press.

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Health Implications of Perchlorate Ingestion 8.   NRC (National Research Council). 2000. Toxicological Effects of Methylmercury. Washington, DC: National Academy Press. 9.   Medinsky, M.A., and C.D. Klaassen. 1996. Toxicokinetics. Pp. 187-198 in Casarett and Doull’s Toxicology: The Basic Science of Poisons, C.D. Klaassen, ed. New York: McGraw-Hill. 10.   Gordis, L. 1996. Epidemiology. Philadelphia: W.B. Saunders. 11.   Dohan, O., A. de la Veija, 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. 12.   Mausner, J.S., S. Kramer, and A.K. Bahn. 1985. Epidemiology: An Introductory Text, 2nd Ed. Philadelphia: W.B. Saunders Company. 13.   Toxicology Excellence for Risk Assessment (TERA). 2004. TERA Homepage. [Online]. Available: http://www.tera.org/ [accessed April 16, 2004]. 14.   Beers, M.H., and R. Berkow, eds. 1999. The Merck Manual of Diagnosis and Therapy, 17th Ed. Whitehouse Station, NJ: Merck Research Laboratories. 15.   TRC Companies, Inc. 2004. TRC Web Site. [Online]. Available: http://www.trcsolutions.com/corporate/home.asp for more information [accessed Dec. 21, 2004]. 16.   EPA (Environmental Protection Agency). 2002. A Review of the Reference Dose and Reference Concentration Processes. EPA/630/P-02/002F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. [Online]. Available: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=55365 [accessed August 31, 2004].