1、Iodine 12/02 IODINE CAS # 7553-56-2 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI November 2002 Copyright 2002 NSF International Iodine 12/02 TABLE OF CONTENTS 1.0 INTRODUCTION 1 2.0 PHYSICAL AND CHEMICAL PROPERTIES. 3 2.1 Organoleptic Properties 4 3.0 PRODUCTION AND USE. 4 3.1 Produ
2、ction 4 3.2 Use . 5 3.2.1 Disinfection. 5 3.2.2 Food and Drug Applications. 7 4.0 ANALYTICAL METHODS 7 4.1 Biological Samples . 7 4.2 Environmental Samples 7 5.0 SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 8 5.1 Food. 8 5.2 Water 9 5.3 Iodine-containing Pharmaceuticals and Supplements . 9 6.0 THYROI
3、D PHYSIOLOGY AND IODINE PHARMACOKINETICS IN HUMANS10 6.1 Key Definitions. 10 6.2 Thyroid Gland 11 6.3 Iodine Metabolism . 11 6.3.1 Absorption 12 6.3.2 Distribution 12 6.3.3 Elimination / Excretion . 13 6.4 Thyroid Hormone Synthesis . 13 6.5 Thyroid Hormone Secretion . 14 6.6 Regulation of Thyroid Ho
4、rmone Synthesis and Secretion. 15 6.7 Thyroid Hormone Binding and Transport 15 6.8 Thyroid Hormone Functions 16 6.9 Thyroid Pathology . 16 6.9.1 Hypothyroidism . 16 6.9.2 Hyperthyroidism 17 6.9.3 Nontoxic Goiter17 6.9.4 Thyroid Nodules and Cancer 17 6.9.5 Clinical Assessment of Thyroid Function 18 7
5、.0 EFFECTS ON HUMANS21 7.1 Single-Exposure Studies 21 7.1.1 General Toxicity. 21 7.1.2 Case Reports 22 7.2 Limited-Exposure Effects 23 Iodine 12/02 7.2.1 Irritation and Sensitization. 23 7.2.2 Ocular Exposure 24 7.3 Short-term and Long-term Effects. 24 7.3.1 Euthyroid (No Thyroid Dysfunction). 25 7.
6、3.2 Euthyroid (Preexisting Thyroid Dysfunction). 32 7.3.3 Euthyroid (Preexisting Non-thyroid Illness) . 33 7.3.4 Euthyroid/Hypothyroid. 34 7.3.5 Goiter (Iodine Deficiency). 35 7.3.6 Goiter (Iodine Excess) . 36 7.3.7 Hypothyroidism (Iodine Excess). 38 7.3.8 Thyrotoxicosis (Iodine Excess) 40 7.3.9 Thy
7、rotoxicosis (Drug-induced). 41 7.3.10 Iodine and Autoimmune Thyroid Disease . 41 7.3.11 Iodine and Thyroid Cancer. 43 7.4 Reproductive and Developmental Toxicity . 45 7.4.1 Smyth (1999) 45 7.4.2 Pederson et al. (1993). 46 7.4.3 Momotani et al. (1992). 47 7.4.4 Pharoah and Connolly (1991) . 47 7.4.5
8、Thomas et al. (1979). 48 7.4.6 Ayromlooi (1971) . 48 7.4.7 Carswell et al. (1970) . 49 7.5 Immunological and Neurological Effects. 49 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS .49 8.1 Single Exposure Studies 49 8.1.1 Acute Oral Toxicity Rat (Product Safety Laboratories, 1992a) . 49
9、 8.1.2 Acute Inhalation Toxicity Rat (Product Safety Laboratories, 1993) 50 8.1.3 Acute Dermal Toxicity Rabbit (Product Safety Laboratories, 1992b). 50 8.2 Limited Exposure Studies . 51 8.2.1 Irritation and Sensitization. 51 8.2.2 Ocular Effects. 52 8.3 Short-term Exposure Bioassays (Rat) 52 8.3.1 I
10、odine versus Iodide. 52 8.3.2 Iodine Intake and Lymphocytic Thyroiditis 55 8.3.3 Iodine Intake and Intrathyroidal Metabolism 56 8.4 Short-term Exposure Bioassays (Lamb, Cattle, and Swine) 57 8.5 Long-term Exposure Bioassay (Rat) 57 8.5.1 Tanaami et al. (1985) . 57 8.6 Tumor Promotion Bioassays. 58 8
11、.6.1 Kanno et al. (1992) 58 8.6.2 Yamashita et al. (1990) . 59 8.7 In Vivo Thyroid Cell Bioassay 60 8.7.1 Krupp and Lee (1988) . 60 8.8 In Vitro Thyroid Cell Bioassays 60 8.8.1 Smerdely et al. (1993) 60 8.8.2 Many et al. (1992) 61 8.8.3 Takasu et al. (1985) 61 8.9 Genotoxicity and Related End-Points
12、 62 Iodine 12/02 8.9.1 Mutagenicity Assays 62 8.9.2 Assays of Chromosomal Damage . 63 8.9.3 Other Assays of Genetic Damage . 64 8.10 Reproductive and Developmental Toxicity . 65 8.10.1 Rat Bioassays 65 8.10.2 Multiple Mammalian Species Bioassay 67 8.10.3 Hen Bioassays. 69 8.11 Conclusions Human and
13、Laboratory Animal Responses to Iodine Species 70 9.0 RISK CHARACTERIZATION71 9.1 Hazard Identification 71 9.1.1 Evaluation of Major Non-Cancer Effects and Modes of Action 74 9.1.2 Weight of Evidence Evaluation and Cancer Characterization 75 9.1.3 Selection of Key Study and Critical Effect 75 9.1.4 I
14、dentification of Susceptible Populations. 76 9.2 Dose-Response Assessment . 78 9.2.1 Carcinogenic Responses to Iodine 78 9.2.2 Non-Carcinogenic Responses to Iodine 78 9.3 Exposure Assessment. 82 9.4 TAC Derivation 83 9.5 STEL Derivation 83 10.0 RISK MANAGEMENT.84 10.1 SPAC Derivation 84 11.0 RISK CO
15、MPARISONS AND CONCLUSIONS .84 11.1 Outside Risk Assessments . 84 11.2 Disinfection and Toxicological Risk Comparisons 87 12.0 REFERENCES 89 12.1 Reference Cited 89 12.2 References Not Cited . 102 13.0 APPENDICES105 13.1 Appendix A: Human Iodine Studies 106 14.0 PEER REVIEW HISTORY.110 14.1 Oral Risk
16、 Assessment Peer Review (October, 2000) 110 14.2 Oral Risk Assessment Peer Review (April 2002) 110 Iodine 12/02 i AUTHORS, PEER REVIEWERS, AND ACKNOWLEDGEMENTS Authors: NSF Toxicology Services 1.800.NSF.MARK NSF International 789 Dixboro Road Ann Arbor, MI 48105 Disclaimer: The responsibility for th
17、e content of this document remains solely with NSF International, and the authors noted above should be contacted with comments or for clarification. Mention of trade names, proprietary products, or specific equipment does not constitute an endorsement by NSF International nor does it imply that oth
18、er products may not be equally suitable. Internal NSF Peer Reviewer(s): Gwendolyn Ball, Ph.D. Clif McLellan, M.S. Maryann Sanders, M.S. External Peer Reviewers: NSF gratefully acknowledges the efforts of the following experts on the NSF Health Advisory Board in providing peer review. These peer revi
19、ewers serve on a voluntary basis, and their opinions do not necessarily represent the opinions of the organizations with which they are affiliated. Edward Ohanian, Ph.D. (Chairman, NSF Health Advisory Board) Acting Director, Health and Ecological Criteria Division Office of Science and Technology/Of
20、fice of Water U.S. Environmental Protection Agency Michael Dourson, Ph.D., DABT (Vice Chairman, NSF Health Advisory Board) Director TERA (Toxicology Excellence for Risk Assessment) David Blakey, D.Phil. Acting Director, Environmental Health Science Safe Environments Programme Health Canada Randy Des
21、kin, Ph.D., DABT Director, Toxicology and Product Regulatory Compliance Cytec Industries, Inc. Iodine 12/02 ii Robert Hinderer, Ph.D. Director of Health, Toxicology and Product Safety Noveon, Inc. Jennifer Orme-Zavaleta, M.S. Associate Director for Science U.S. Environmental Protection Agency/NHEERL
22、/WED Adi Pour, Ph.D. Director, Douglas County Health Department Omaha, Nebraska Calvin Willhite, Ph.D. Department of Toxic Substances Control State of California 2002 NSF Iodine 12/02 iii EXECUTIVE SUMMARY Iodine Oral Risk Assessment PARAMETER LEVEL UNITS CALCULATED FOR: NOAEL (no-observed-adverse-e
23、ffect level) 0.03 mg/kg-day 70 kg Adult Oral RfD (oral reference dose) 0.01 mg/kg-day TAC (total allowable concentration) 0.3 mg/L 70 kg Adult SPAC (single product allowable concentration) 0.1 mg/L 70 kg Adult STEL (short term exposure level) 0.3 mg/L 10 kg Child KEY STUDY Freund et al. 1966. Effect
24、 of iodinated water supplies on thyroid function. J Clin Endocrinol Metab 26: 619-624. CRITICAL EFFECT Non-adverse decreases in radioactive iodine uptake (RAI) and increases in serum protein-bound iodine (PBI) by the thyroid. UNCERTAINTY FACTORS Factors applied in calculating the oral RfD: 1x for in
25、terspecies extrapolation 3x for intraspecies extrapolation 1x for short-term to long-term exposure extrapolation 1x for extrapolation from a LOAEL to a NOAEL 1x for database deficiencies The total uncertainty factor is therefore 3x. TOXICITY SUMMARY Longer-term exposure to excess iodine shows little
26、 visible effect on thyroid function in the normal individual due to the highly effective regulatory mechanisms, although excess iodine may induce some degree of thyroid dysfunction in susceptible individuals. Tolerance to iodine is highly variable, with the vast majority of the population able to ha
27、ndle exposure to large quantities of iodine without adverse responses (Dunn, 1998). While individuals with preexisting thyroid conditions, including goiter, Hashimotos thyroiditis, and cancer, as well as children and aged individuals can be significantly more susceptible to elevated iodine levels, t
28、he presence of underlying thyroid disease and/or the age of an individual does not guarantee that the individual will react adversely to elevated iodine concentrations. Likewise, a clinically euthyroid individual may respond atypically to iodine levels at which the general population does not respon
29、d. CONCLUSIONS Because the response to excess iodine is highly individual, it is necessary for risk managers to consider the risk versus benefit of adding iodine to the water supply in any given region of the country or world. Consequently, it is suggested that the calculated risk values be used wit
30、h caution and only after consideration of the environment into which the iodine supplementation is being introduced. 2002 NSF Iodine - 12/02 1 1.0 INTRODUCTION This document has been prepared to allow toxicological evaluation of the unregulated contaminant iodine in drinking water, as an extractant
31、from one or more drinking water system components tested under NSF/ANSI 61 (2002) or as a contaminant in a drinking water treatment chemical under NSF/ANSI 60 (2002). Iodine has also been evaluated as a drinking water treatment chemical for direct addition to water under NSF/ANSI 60 (2002). Both non
32、-cancer and cancer endpoints have been considered, and risk assessment methodology developed by the U.S. Environmental Protection Agency (U.S. EPA) has been used. Non-cancer endpoints are evaluated using the reference dose (RfD) approach (Barnes and Dourson, 1988; Dourson, 1994; U.S. EPA/IRIS, 1993)
33、, which assumes that there is a threshold for these endpoints that will not be exceeded if appropriate uncertainty factors (Dourson et al., 1996) are applied to the highest dose showing no significant effects. This highest dose is derived from human exposure data when available, but more often is de
34、rived from studies in laboratory animals. Either the no-observed-adverse-effect level (NOAEL) taken directly from the dose-response data, or the calculated lower 95% confidence limit on the dose resulting in an estimated 10% increase in response (the LED10or BMDL from benchmark dose programs) can be
35、 used (U.S. EPA, 2001). The lowest-observed-adverse-effect level (LOAEL) can also be used, with an additional uncertainty factor, although the benchmark dose approach is preferred in this case. The RfD is expressed in mg/kg-day. It is defined by the U.S. EPA as “an estimate (with uncertainty spannin
36、g perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime” (Barnes and Dourson, 1988; U.S. EPA/IRIS, 1993; U.S. EPA, 1999a). NSF uses the RfD to derive three p
37、roduct evaluation criteria for non-cancer endpoints. The total allowable concentration (TAC), generally used to evaluate the results of extraction testing normalized to static at-the-tap conditions, is defined as the RfD multiplied by the 70 kg weight of an average adult assumed to drink 2 liters of
38、 water per day. A relative source contribution (RSC), to ensure that the RfD is not exceeded when food and other non-water sources of exposure to the chemical are considered, is also applied in calculating the TAC. The relative source contribution should be data derived, if possible. Alternately, a
39、20% default contribution for water can be used (U.S. EPA, 1991a). The TAC calculation is then as follows: TAC (mg/L) = RfD (mg/kg-day) x 70 kg total contribution of other sources (mg/day) 2L/day or TAC (mg/L) = RfD (mg/kg-day) x 70 kg x 0.2 (RSC) 2L/day The single product allowable level (SPAC), use
40、d for water treatment chemicals and for water contact materials normalized to flowing at-the-tap conditions, is the TAC divided by the estimated total number of sources of the substance in the drinking water treatment and 2002 NSF Iodine - 12/02 2 distribution system. In the absence of source data,
41、a default multiple source factor of 10 is used. This accounts for the possibility that more than one product in the water and/or its distribution system could contribute the contaminant in question to drinking water. Finally, a short-term-exposure level (STEL), at a higher level than the TAC, may be
42、 calculated for contaminants, such as solvents expected to extract at higher levels from new product, but also expected to decay rapidly over time. The STEL is calculated from the NOAEL or the LED10of an animal study of 14- to 90-days duration, with uncertainty factors appropriate to the duration of
43、 the study. The contaminant level must decay to the TAC or below under static conditions, or to the SPAC or below under flowing conditions within 90 days, based on the contaminant decay curve generated from over-time laboratory extraction data. Endpoints related to cancer are evaluated using modelin
44、g to fit a curve to the appropriate dose-response data (U.S. EPA, 1996a; U.S. EPA, 1999b). If there is sufficient evidence to use a nonlinear model, the LED10or BMDL, divided by the anticipated exposure, is calculated to give a margin of exposure. If there is insufficient evidence to document non-li
45、nearity, a linear model drawing a straight line from the LED10or BMDL to zero, is used as a default. If a linear model (generally reflecting a genotoxic carcinogen) is used, a target risk range of 10-6to 10-4is considered by the U.S. EPAto be safe and protective of public health. (U.S. EPA, 1991a).
46、For the purposes of NSF/ANSI 60 (2002) and 61 (2002), the TAC is set at the 10-5risk level, and the SPAC is set at the 10-6risk level. Use of a higher risk level is not ruled out but would generally require documentation of a benefit to balance the additional risk. The RfD, TAC, SPAC, and STEL value
47、s derived in this document are based on available health effects data and are intended for use in determining compliance of products with the requirements of NSF/ANSI 60 (2002) and 61 (2002). Application of these values to other exposure scenarios should be done with care and with a full understandi
48、ng of the derivation of the values and of the comparative magnitude and duration of the exposures. These values do not have the rigor of regulatory values, as data gaps are generally filled by industry or government studies prior to regulation. Data gaps introduce uncertainty into an evaluation and
49、require the use of additional uncertainty factors to protect public health. The general guidelines for this risk assessment include those from the National Research Council (1983) and from The Presidential/Congressional Commission on Risk Assessment and Risk Management (1997a, 1997b). Other guidelines used in the development of this assessment may include the following: Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986), Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996a), draft revised Guidelines for
